Breast cancer screening, diagnosis, and treatment

Volume 45 Number 9 September 1999

H, and Treatment

Kelly Ford, MD

Attending Physician Beth Israel Deaconess Medical Center

Boston, Massachusetts

Elizabeth Marcus, MD

Chair, Division of Breast Oncology Department of Surgery Cook County Hospital

Chicago, Illinois

Bennett Lum, MD

Senior Attending Physician and Acting Division Head of Mammography Department of Radiology

Cook County Hospital Chicago, Illinois

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Breast Cancer Screening, Diagnosis, and Treatment

Abstraa n

337

In Brief 338

Epidemiology of Breast Cancer Rates of Incidence and Mortality in the United States Worldwide Trends Trends Over Time

340 340 341 341

Breast Cancer Risk Individual Breast Cancer Risk Assessment of Women With an Increased Risk

of the Development of Breast Cancer

342 342 346

Breast Cancer Screening 347 Physical Examination 347 Imaging 348 Screening of Patients at High Risk 351

Prevention of Breast Cancer 352 Medical Prevention 352 Surgical Prevention 354 Lifestyle Modification 355

Diagnostic Evaluation of Breast Abnormalities Physical Examination Radiologic Evaluation Biopsy Methods Image-Guided Localization and Biopsy of Nonpalpable Breast Abnormalities

357 357 358 369 372

Pathologic Diagnosis

Treatment of Breast Cancer Prognosis and Staging Management of Early-Stage Breast Cancer Locally Advanced Breast Cancer Metastatic Breast Cancer

375

377 377 378 386 388

DM, September 1999 335

Psychologic Aspects of Breast Cancer Care Long-Term Surveillance

Conclusion

References

336

389 390

393

394

DM, September 19%

Breast Cancer Screening, Dlagplosls, and Treatment

Abstract.-The incidence of breast cancer in US women remainsdisturbinglyhigh,andun.fortu~telyprimarycare physicians still frequently encounter patients in whom the disease is suspected or, even worse, con6rmed. Fotiately, however, the body of knowledge suITounding the disease has grown dramatically during the past decade, and major advances have been made in the understanding of breast cancer risk, prevention, diagnosis, and treatment. Controversies peti particularly those concerning the screening of younger women, but consensus now exists regarding many clinical issues relevant to primary care practice. Altbough multidisciplinary subspecialty expertise must be made available to all women with known or suspeded breast cancer, the primary care physician has an important role to play when dealing with patients witb this condition. The following article focuses on what primary care practitioners need to know to expertly contribute to the diagnosis, counseling, and initial treatment of women withthisdisease.


Breast cancer is the most common cancer in women worldwide and a major cause of mortality and morbidity. A woman’s risk for breast cancer increases with age, prior breast malignancy, prolonged estrogen stimulation, and genetic mutations. The impact of this disease has led to increased and improved screening for it, which has resulted in a 30% reduction in breast cancer mortality. The majority of the benefit from screening is derived from earlier detection through mammography. The role of antiestrogens in breast cancer prevention is currently being investigated.

Increased screening has led to a greater need for the diagnostic evaluation of abnormalities. Radiographically guided biopsies have become the standard of care, resulting in less expensive and less invasive procedures that have nearly equivalent accuracy with surgical methods. New imaging modalities, such as magnetic resonance imaging and scintimamm ography, hold promise for both the screening for and treatment of breast cancer.

More frequent detection of tumors at earlier stages, less toxic chemotherapy, and changes in surgical techniques have greatly altered the treatment of patients with breast cancer. Breast conservation surgery is now widely used in conjunction with radiation therapy in patients with early-stage disease. Sentinel node biopsies are negating the need for full axillary node dissections. With greater concern for distant micrometas- tasis and less toxic chemotherapy, adjuvant chemotherapy is being used in patients with earlier-stage disease. Hormonal agents with fewer side effects are currently the subjects of extensive research. Prognoses for patients with advanced breast cancer have been markedly improved through the use of multimodality treatments. As more women survive breast cancer, more attention will need to be focused on appropriate long-term surveillance of these patients.

338 DM, September 1999

WY /

Doctor Kelly Ford is an associate attending physician at the Beth Israel Deaconess Medical Center in Boston and an instructor of clinical medicine

at Harvard Medical School. Doctor Ford received her undergraduate degree from Mount Holyoke College and her Doctor of Medicine from the University of Chicago, and she completed her residency training at the Beth Israel Hospital in Boston. Between her previous and current tenures in Boston, Dr Ford was the director of the Breast and Cervical Cancer Screening Program at Cook County Hospital in Chicago, where she coor- dinated these activities for the Cook County Bureau of Health Services and served as a primary care internist in the division of general internal medicine at Cook County Hospital and Rush Medical College. Doctor Ford’s academic interests include geriatrics, women’s health, preventive care, and primary care internal medicine.

Doctor Elizabeth Marcus is the chair of the division of breast oncology at Cook County Hospital and an assis- tant professor of surgery at

Rush Medical College in Chicago. Doctor Marcus received her undergraduate training at the University of Michigan and her Doctor of Medicine from the University of Pittsburgh; she then completed a surgical residency at Boston University and a surgical oncology fellowship at the Roswell Park Cancer Institute in Buffalo. Her current research interests involve many aspects of breast cancer care and include new approaches to the treatment of locally advanced breast cancer.

Doctor Bennett Lum is a senior attending physician and the acting division head of mammography in

the department of radiology at Cook County Hospital in Chicago. Doctor Lum received his undergraduate and graduate training at the University of Hawaii, after which he served as resident and chief resident in radiology at Cook County Hospital. He completed his fellowship in body imaging at Rush-Presbyterian-St. Luke’s Medical Center in Chicago. In addition to breast imaging, Dr Lum’s academic interests include interventional radiology and computed tomography and magnetic resonance imaging of the extremities.


Breast Cancer Screening, Diagnosis,

Epidemiology of Breast Cancer

Rates of Incidence and Morthy in the United States

In the United States, breast cancer is the most common cancer found in women and the second greatest cause of women’s death from cancer.l The American Cancer Society estimates, in 1999, there will be 175,000 new cases of female breast cancer and that 43,300 women will die of the disease. The incidence rate of breast cancer in the United States far exceeds that of any other cancer site, with 29% of all new cancers in women occurring in the breast. However, the mortality rate of 16% that is associated with this disease is less than that associated with lung cancer, which causes 25% of cancer deaths in women.”

These figures are dramatic, but they can lead patients to misinterpret the risk of breast cancer. It is often quoted that a woman in the United States has a 1 in 8 chance of developing breast cancer; however, this figure is a lifetime estimate and includes the assumption that the woman will live to be 85 years old. A woman’s risk for the development of breast cancer between the ages of 40 and 59 years is 1 in 25, and the lifetime risk of a woman’s death from breast cancer is only 3.6%. It is estimated that in 1999 about 41% of deaths in women will be from heart disease or stroke and that 3.8% will be from breast cancer.2 Women need to understand the high prevalence of breast cancer, but they also need to understand it in a way that will not produce excessive fear or unduly high estimation of risk, which may inhibit appropriate screening behaviors and not allow them to appropriately care for other medical problems they may have.

The incidence and mortality rates of breast cancer vary among the different ethnic groups in the United States. The 1990 to 1995 incidence of female breast cancer per 100,000 was 113 for white women, 99 for African-American women, and 69 for Hispanic women. Although the incidence of breast cancer was lower in African-American women, the mortality from this condition was highest in that group at 3 1 per 100,000 women as compared with 26 per 100,000 for white women and 15 per 100,000 for Hispanic women. From 1974 to 1994, the 5-year survival rate for female patients with breast cancer increased from 75% to 87%


for white women but only from 63% to 71% for African-American women. This disparity in survival in part stems from the stage at which the disease is diagnosed; between 1989 and 1994, 62% of white women had localized disease, whereas only 50% of African-American women had early-stage disease. This may be partially explained by complex socioeconomic differences, but tumor differences may exist.2p3

Worldwide Trends

Worldwide, breast cancer is the most common cancer in women, and it accounts for 21% of all new cancers in women. Although the compila- tion of precise figures is problematic, it is estimated that, worldwide, 796,000 new cases of this disease occur annually and that there are 314,000 deaths from this disease. When all nations are considered, it is found that female breast cancer has the highest mortality rate of all cancers, 14%, and that the next highest mortality rates are from lung and stomach cancers.B5

In the world’s population, differences in incidence and mortality rates of breast cancer with respect to ethnicity are even more divergent. The incidence of this condition is highest in developed areas, with rates that range from 35 to 86 per 100,000. Lower rates are seen in less well-developed areas, such as Sub-Saharan Africa, where rates may be as low as 12 to 14 per 100,000. North America has the highest incidence (86/100,000) followed by Australia (72/100,000), temperate South America (69/100,000), and Northern/Western Europe (68/100,000).4 It is likely that many elements, including genetic and reproductive factors, contribute to these variations, but environmental and dietary influences are also suspected.

Trends Over Time

The incidence of breast cancer has changed significantly over time. In the United States from 1979 to 1982, breast cancer incidence increased by 1% per year; from 1982 to 1987, incidence increased by 4% per year; and from 1987 to 1995 the incidence was stable. This increase in incidence has been seen worldwide, with an average annual increase of 0.5% since 1985. Areas with the lowest rates of breast cancer have had the most marked increases; for example, in Asia, the annual increase may be as high as 5%. The stabilization seen in the United States has not yet been seen worldwide. In the United States, the incidence of this disease among young women has declined during the 1990s. The overall increase in incidence may in part be because of increased screening and improved detection of early-stage disease, but some change in the actual


frequency is also suspected. The cause of the increase in breast cancer frequency is unknown.2~4~5

Breast Cancer Risk

Individual Breast Cancer Risk When planning breast care, it is essential to assess a woman’s indi-

vidual risk for breast cancer and to confirm her understanding of this risk. For all women, age is the greatest risk for breast cancer. The incidence increases most during the reproductive years, but it continues to rise throughout the life span. The risk of developing breast cancer between the ages of 20 to 40 years is 0.49%, whereas the risk increases to 4.67% between the ages of 50 and 70 years.3*6

The risk that is associated with sex hormone exposure is also highly significant and has an impact on all women. The longer the breast is exposed to estrogen, the greater the risk of breast cancer. Thus, longer phases of uninterrupted ovulation confer greater risk, and anovulatory phases such as those induced by pregnancy, lactation, and exercise decrease risk. An earlier menarche (usually before age 12 years) or a later menopause (usually after age 55 years) confers a slightly increased risk. The relative risk of disease is estimated to be 1.1 to 1.3 for a woman with an early menarche and 2.03 for a woman with a later menopause. A low parity and the delivery of the first child after the age of 30 also increases a woman’s relative risk for breast cancer to 1.3 to 1.9. The increased risk is secondary to a longer uninterrupted period of estrogen stimulation and the failure of breast cells to undergo the tertiary and quatemary differentiation that occurs with the process of lactation. It is theorized that this higher level of differentiation reduces the risk of a later malignant clonal expansion. Paradoxically, pregnancy also induces a short-term increase in a woman’s risk for breast cancer, a risk that may persist for as long as 10 years. This phenomenon, which is more pronounced after a woman’s first pregnancy for reasons that are not fully understood, may be related to altered hormone levels and an increased mitotic rate in the breast.7 Although most of the discussion about breast cancer risk centers on the influence of estrogen, the role of progesterone is not clearly understood and should not be discounted.

The endogenous estrogen risk factors have clearly increased the concern surrounding a woman’s risk of breast cancer from exogenous estrogen stimulation. The variability of dosing schedules and the addition of progestin agents has hampered the exact determination of risk elevation that is related to hormonal replacement therapy. Thus far, the


most comprehensive review of the world’s data on this topic was published in the Lancet in 1997.* According to this study, it is estimated that the relative risk for breast cancer in any woman who has used estrogen replacement is 1.14. The risk increases by 1.023 for each year of use, which is equivalent to the increase in risk for each year of menstruation beyond age 50. The elevated risk does not become significant until after a woman has taken estrogen continuously for 5 or more years, at which time the relative risk reaches 1.35. Five years after the discontinuation of hormonal replacement therapy, the risk returns to baseline. The use of hormonal replacement therapy-particularly that which includes continuous estrogen and progesterone-may increase mammographic breast density, which in itself has been associated with increased risk, and it also decreases the sensitivity and specificity of mammographic screening.9

Concern regarding exogenous hormones has extended to use of hormonal contraceptives. Although the risk for breast cancer in very young women who use contraceptives is low, questions regarding risk of oral contraceptive pills have been raised. An extensive review of available data has shown that the relative risk for breast cancer in current users of oral contraceptive pills is 1.24. Risk returns to average 10 years after use of oral contraceptives has been discontinued. Breast cancers detected in women taking oral contraceptive pills are often less advanced; this may be a result of biologic behavior or early detection.‘O

Age and hormone exposure have an impact on all women, but other factors influence the risk of only a limited proportion of women. A previous occurrence of breast cancer greatly increases a woman’s risk for both recurrent breast cancer and a new primary breast cancer. When a woman has a history of breast cancer, her relative risk is elevated to 2 to 3, and the absolute risk is just under 1% per year. The presence of carcinoma in situ also increases the risk for the subsequent development of breast cancer. Previous ductal carcinoma in situ (DCIS) increases a patient’s relative risk to 1 to 2; lobular carcinoma in situ (LCIS) increases the patient’s relative risk of breast cancer to 4.5, with an absolute 20-year risk of 15%.’ 1

An important but more difficult risk factor to assess is the mitotic or proliferative milieu of the breast. Proliferative states in general increase a woman’s risk for breast cancer, and those states with atypical features increase that risk even more. Fibrocystic breast disease does not significantly increase a woman’s risk of breast cancer unless atypical hyperplasia is present. Atypical hyperplasia is present in about 4% of benign breast biopsies, and it is reflective of a proliferative process present in both breasts, so excision of a focal area does not modify risk. The pres-


ence of atypical hyperplasia elevates a woman’s relative risk of developing breast cancer to about 4, with the absolute 20-year risk of breast cancer reaching 11% to 14% in either breast. The elevated risk seems to decrease over the 10 to 20 years after the condition is diagnosed.12 Unfortunately many women with nodular breasts are diagnosed with fibrocystic breast disease without pathologic confirmation, and these women then perceive themselves to be at a greater risk for the development of breast cancer.

Secondary markers of increased proliferation can also be helpful for the assessment of risk. Denser breast parenchyma found on a mammogram may reflect more fibrocystic breast tissue, but it is unclear if denser breast parenchyma reflects an increased risk for breast cancer. This increased density may decrease the effectiveness of screening, independent of baseline risk.i3*i4 The number of benign breast biopsies has been used in the Gail model as an independent risk factor for breast cancer.15 The number of breast biopsies a woman undergoes is clearly confounded by many other issues, but it may serve as a marker for a more nodular and proliferative breast milieu.16

A genetic predisposition to breast cancer may be uncovered in a woman’s oncologic family history. It is estimated that only 5% of all breast cancers are genetic in basis, but this risk is frequently overestimated by patients. With 1 in 8 women experiencing breast cancer during their life- times, a moderate sized family is likely to have at least 1 case of breast cancer; this does not indicate a familial pattern. In general, patients with 2 or more cases of breast cancer in their family and those who have any first- degree relatives with breast cancer should receive further attention. Risk is also increased if any members of the family had bilateral disease or if their disease developed before menopause. The estimated relative risk for breast cancer in a woman with a first-degree relative with postmenopausal breast cancer is about 1.5, but it is 3 if that relative had premenopausal disease.17 This relative risk rises to 8 if both a woman’s mother and sister have breast cancer, with the absolute 20-year risk for breast cancer in these patients reaching 32%. l2 A relatively brief family history can generally determine the women for whom genetic counseling, increased surveillance, and risk modification may be of benefit.

Several variables have received significant publicity for increasing breast cancer risk, but few have any scientifically proven influence on breast cancer risk. Dietary influences have received much attention, and fat consumption has been the most studied. Multiple studies have now shown that a high-fat diet has a negligible impact on a woman’s risk of developing breast cancer. 18J9 It is possible that a high-fat diet has a very


TABLE 1. Conditions ond associated breast cancer risk

Condition Estimated relative risk

Oral contraceptive use Early menarche (< 12 years old) More than 5 years of estrogen replacement therapy Daily alcohol consumption (2 to 4 drinks) One firstdegree relative with p&menopause breast cancer First live birth after age 30 years Late menopause (> 55 years old) Previous ductal carcinoma in situ in self One firstdegree relatii with premenopause breast cancer Previous breast cancer in setf Atypical hyperplasia in breast biopsy Previous LCIS in self

1.2 1.3 1.4 1.4 1.5 1.6 2.0 2.0 3.0

> 3.0 4.0 4.0

Two first~ee relatives with breast cancer Carrier of BRCAI or Bf?CAZ mutation (absolute risk)

8.0 85% by age 70

small influence, but larger studies will be required to detect a significant difference. The effect of alcohol consumption on the development of breast cancer has also been considered. In vitro experiments have shown an increase of mammary tumors with increased levels of alcohol; it is theorized that alcohol increases the estrogenic stimulation of breast tissue. Some studies have shown a modest increase in breast cancer rates as alcohol consumption rates increase. For example, a recent review showed an increase in relative risk from 1 for nondrinkers to 1.41 for women who had 2 to 4 drinks per day. 2o Other studies have found no risk association with alcohol use in postmenopausal women or in those not taking estrogen replacement therapy. 21,22 Further large prospective trials are needed to better assess this risk factor. With respect to the worldwide increases in breast cancer, environmental triggers have been postulated. A variety of chemicals have been investigated, especially organochlo- rides such as polychlorinated biphenyls (PCBs), but no clear association has been uncovered.23 Environmental risks may exist, but they are currently unknown.

All of the risk factors discussed may increase or decrease an individual woman’s risk for the development of breast cancer; Table 1 summarizes the most common risk factors. Some estimated relative and absolute risks have been given, but the discussion of individual risk with patients can be difficult, and incorrect assumptions may be made by patients. It is currently unknown which risk factors work independently and which may work synergistically. Thus, in the case of an individual woman, it is sometimes difficult to determine her total risk on the basis of all risk factors involved.


Assessment of Women With an Increased Risk of the Development of Breast Cancer

Most women do not require precise determination of breast cancer risk or referral for genetic counseling; however, women with multiple risk factors, great concern, or evidence of a familial pattern may benefit from referral to a genetic counselor. Genetic consultation should provide a more precise assessment of risk on which clinical decisions can be based.

Genetic counselors use two main models for the assessment of breast cancer risk. The Claus model only considers risk on the basis of family history.24 With this model, a woman’s risk is calculated on the basis of information taken from a database of more than 5000 cases of breast cancer in the United States. This may identify only one subgroup of women at risk for breast cancer on the basis of familial patterns. The Gail model is the second major risk assessment tool currently in use,15 and it was used in the recent Breast Cancer Prevention Tria1.25 This model takes age, reproductive history, maternal family history, and benign breast disease into consideration. Risk calculations made with this model may be biased toward a subgroup of breast cancers that are induced by hormonal factors rather than genetic factors. Familial risk from the paternal line may be greatly underestimated, and risk from multiple but entirely benign breast biopsies may be overestimated. Each of these two models has its advantages, but they may each be biased toward different subgroups at risk for breast cancer.

If, on the basis of a detailed pedigree and quantitative risk assessment, a genetic counselor determines that a woman’s risk for breast cancer is substantially elevated, genetic testing may be recommended. The clinical and emotional ramifications of genetic testing must be discussed with an individual patient and her family before any testing is completed. In general, only a patient with confirmed cancer is offered genetic testing, because if no genetic susceptibility is identified there is no value in testing other unaffected family members. If a genetic trait is identified, other family members can be screened for the same genetic mutation. Most studies have shown that carefully completed genetic testing relieves anxiety and leads to constructive screening and risk reduction. Also, patients found to have genetic mutations have not had increased psychiatric symptoms or shown any avoidance of medical care.26

Currently the main genetic traits known to increase breast cancer risk are the BRCAI and BRCA2 mutations. A woman with a BRCAI or BRCAZ mutation has an 85% risk of developing breast cancer by age 70 years, and her disease will usually develop at an earlier age. The risk for the development of ovarian cancer is more variable, but it is estimated to be 26%


to 85% by age 70 years in women with the BRCAl mutation and less than 10% in those with the BRCA2 mutation.27v28 The prevalence of the BRCAl and BRCA2 traits is somewhat unclear because the initial studies were performed on high-risk populations, but the gene frequency is estimated to be 0.0006%.29 Studies on lower-risk populations have found fewer mutations than expected and less correlation between pedigree and discovered mutations.30,31 This finding is of concern because limiting genetic testing to those cases with concerning family histories may have low sensitivity and result in missed cases of genetic risk for cancer. There is currently no evidence that women with BRCAI or BRCA2 mutations have a worse outcome than those without the mutations.32

Testing for genetic mutations is a clinically and scientifically chal- lenging endeavor. The BRCAl and BRCA2 mutations are the only mutations commonly tested for; other mutations have been identified and will likely continue to be discovered, but clinically useful screening tests have not yet been developed. Direct sequencing is the most sensitive screening test for mutations, but it is time-consuming and very expensive. Linkage studies are substantially less expensive, but they are also less sensitive.33 These genetic tests are not available in all clinical settings and may cost thousands of dollars, depending on the laboratory. Many insurers do not cover genetic testing, and many patients are reluctant to reveal that they had such testing to their insurers because of concerns about possible discrimination. The identification of genetic mutations may help modify risk, but many issues must be addressed before genetic testing can be considered the standard of care.

Breast Cancer Screening When screening for any condition, it must first be established that the

prevalence and mortality of the condition warrant screening; this is certainly the case with breast cancer. Second, it must be determined that early detection improves outcome; this is also without debate with regard to breast cancer. After the need has been established, tests with adequate sensitivity and specificity, reasonable cost, and acceptability to patients must be developed. Data that supports current breast cancer screening tests and recommendations will now be discussed.

Physical Examination

Bred Self-Examination. The breast self-examination has been recommended since the 1930s as the first step in breast cancer screening, but no study has definitively determined that the breast self-examination results in earlier-stage diagnosis or mortality reduction. The best


evidence comes from a Finnish study that made use of the Mama Program approach, which resulted in a modest reduction in mortality but no trend toward earlier-stage diagnosis.34 Many other studies have had serious flaws or conflicting results. A World Health Organization study that involved 120,310 Russian women will conclude in 1999, but interim results have shown no benefit with breast self-examinations.35 Despite the limited data, most professional associations recommend monthly breast self-examinations for women from about age 20 on. This recommendation is made on the basis that the intervention is without risk, has very low cost, and may offer some benefit. However, the estimated sensitivity is only 20% to 30%. 36 For any benefit to be realized, teaching of the technique needs to be thorough, patient proficiency needs to be checked, and performance needs to be regularly reinforced.37

Clinical Breast Examination. The value of the clinical breast examination has been repeatedly documented, but its exact contribution is difficult to determine because of variation in examiner skill and because the examination is always paired with mammography. The groundbreaking breast cancer screening study, the Health Insurance Plan Clinical Trial, was started in the early 1960s and was the first to document the benefit of a screening clinical breast examination and mammogram. The clinical breast examination is responsible for, at most, 40% to 60% of the combined benefit of screening, annual clinical breast examinations, and mammograms.38 In a later Canadian study that made use of highly trained nurses, the sensitivity of the clinical examination was about 74% and the specificity was about 94%. 39 Most other studies have shown a greater variation and a lower sensitivity. The benefit of the clinical examination is greater in younger women, in whom mammograms are less sensitive. Improved training for physicians and other health care providers would standardize the practice and increase the benefit of this examination.

Imaging

Mammugraphy. There is clearly a decrease in the mortality rate of women that have received screening mammography for breast cancer. The risk of radiation associated with the mammogram is a concern in some women, but studies have shown that, for women who are screened annually from ages 50 to 75 years, there is 100 times more benefit of early detection than risk of radiation-induced malignancy. The mean radiation dose to the breast with each mammographic film is 1.38 mGy. The breast is more sensitive to radiation when a woman is in her 2Os, so mammograms should rarely be performed before a woman has reached the age of 30.40


TABLE 2. Summary of mammography trials of women between the ages of 50 and 69 years

StUdy Relative risk Conlldence interval

Health Insurance Plan Clinical Trial= 0.66% 0.49 - 0.96 Canadian/NBSSp 0.97% 0.62 - 1.52 Swedish combined44s45 0.71% 0.56 - 0.91 Stockholm46 0.57% 0.30 - 1.10 Edinburgh47 0.60% 0.54 - 1.17

The benefit of screening mammography has been documented during the past 30 years in 8 major randomized controlled trials that included more than 500,000 women. All of the studies show a significant reduction in mortality rate associated with screening women more than 50 years old with serial manunograms. The relative risks for screening women more than 50 years old ranges from 0.68 to 0.97, and the only 2 studies whose confidence intervals include 1 had also included women more than 70 years old. The screening interval used in these studies varies from 12 to 33 months. Thus debate still exists regarding the optimal screening interval. Overall, serial mammography provides a 20% to 30% reduction in the breast cancer mortality rate for women 50 years old and older (Table 2).38,39*41-48

Most American professional societies recommend annual mammograms for women more than 50 years old, with no set point for stopping this screening if the woman remains healthy. Because the incidence of breast cancer continues to rise with age, the screening of women more than 70 years old is beneficial and cost-effective, albeit underperformed. In these women, the screening interval might be increased with a minimal loss of sensitivity.49

Mammography in Women 40 to 49 Years OLd. Debate continues to rage about the benefit of mammography for women 40 to 49 years old. About 35% of all years of life lost to breast cancer occur in women whose symptoms appear when they are between 40 and 49 years old; this reflects that the tumors developed in these women at a younger age, but it is also evidence that the tumors are more aggressive.5o The potential benefit of screening women 40 to 49 is significant, but the prevalence of breast cancer in this age group is much lower, so the overall benefit of screening is likely to be lower than it is in older women. The evidence that women 40 to 49 years old can be effectively screened is debatable. The major studies of screening mammography in younger women show a relative risk of 0.5 1 to 1.36; there is high variance in the data because the confi-


TABLE 3. Summary of mammography trials of women between the ages of 40 and 49

Study Relative risk Confidence interval

Heaith Insurance Plan Clincial Trial= 0.77% 0.5 - 1.16 Canadian NBSS13g 1.36% 0.84 - 2.21 Swedish 2 cou@ 0.75%/1.280/o 0.41- 2.33 Malmo45 0.51% 0.22 - 1.17 Stockholm46 1.04% 0.5 - 2.05 Edinburgh47 0.86% 0.41- 1.80 Gothenburp 0.55% 0.31- 0.96

dence intervals are wide and all include 1 .38y39~44-48 The mortality benefit for this age group has been estimated to be anywhere between 4.7% and 23% for women 40 to 49 years old!l A more recent trial from Gothenburg, Sweden, that focused on screening women who were 39 to 49 years old was more promising, with a relative risk of 0.55, a confidence interval that did not include 1, and a 45% reduction in the mortality rate of women who were screened (Table 3).48 There may be some benefit to screening younger women, but the benefit has yet to be conclusively documented, and it is very likely less than that found for older women.

The debate about the benefits of providing screening mammography for younger women highlights the strengths and weaknesses of mammograms. In older women, the breast becomes more fat-replaced; this makes abnormalities more apparent on the mammogram. In women more than 50 years old, the sensitivity of the mammogram is at least 75%.42 With newer techniques, sensitivity will likely reach 85% to 90%, with a specificity of 83% to 98%.13,14,42 In younger, more dense breasts, the sensitivity of mammograms is 71% to 87%, with a specificity 82% to 93%.13714 Sensitivity may be as low as 68% in young women with a family history of breast cancer.14 Some of the decreased benefit associated with the screening of younger women is related to the lower sensitivity of the mammogram and the lower prevalence of breast cancer in these women. It is estimated that, to save one woman from death from breast cancer, as many as 2500 women 40 to 49 years old must be screened annually; however, only 270 women 50 to 69 years old must be screened annually to save one life.51

The reduced specificity of mammograms in younger women results in more false-positives; this can generate substantial emotional stress, needless medical evaluation with its associated risk, and additional cost. If a woman receives annual mammograms from age 40 to 49 years, her lo-year cumulative risk of a false-positive mammogram is 49%. After 10 mammograms from age 40 to 49 years, a woman without cancer has a 18.6% risk that she will be advised to undergo a biopsy because of the appearance of her


mammogram. In this age group, for every $100 spent screening, another $33 is spent evaluating false-positives. 52 Even if a definitive benefit of early screening is documented, it must be recognized that this benefit is derived at a higher cost-in many respects-than it is in older women.

In 1997, in the midst of this swirling debate and under great political pressure, the National Cancer Institute reversed its decision and recommended mammograms every 1 to 2 years for women 40 to 49 years old.53 At the same time, the American Cancer Society strengthened its position and recommended annual mammograms for women 40 to 49 years old. Other professional societies, such as the American College of Physicians, the US Preventive Services Task Force, and the American Academy of Family Physicians, do not endorse annual screening in this age group, and they encourage the discussion of the risks and benefits of this procedure. A benefit of screening women 40 to 49 years old may exist, but current data confirm- ing this does not meet the usual standards required for broad acceptance of national screening. Some authorities believe that, because of the aggressive nature of tumors in younger women, if any benefit is to be found annual mammograms will be required to prevent interval malignancies.50 A risk- based strategy that makes use of algorithms tailored to the individual woman’s risks has also been proposed. 54 More investigation is clearly needed to determine the best means of screening younger women for breast cancer.

In addition to age, other factors influence the value of mammography. For all women, the value of mammography is dependent on the quality of the images produced and the experience and skill of the mammogra- pher. In the United States, the amount of radiation used to perform a mammogram has decreased and the quality of the images has increased. Regardless of quality, infrequent mammograms offer far less benefit. Serial mammograms are essential so that earlier-stage breast cancers may be detected. Particularly in older women and in those that are members of ethnic minorities, lower compliance with annual mammograms has led to diminished screening benefit.55T56

Other imaging modalities exist, but none are currently used for screening. The ultrasound is not a screening tool, and it is only helpful in diagnostic evaluations. In the future, magnetic resonance imaging and some form of thermography may be used, but so far these methods have not been proved effective by large-scale studies.

Screening of Patients at High Risk There are currently no studies that indicate that the screening of

patients at high risk offers a reduction in mortality rate. It is also yet to be determined which patients at what level of increased risk might


benefit from heightened surveillance, and the age at which to commence screening and the interval at which this screening should be performed are also still uncertain. A 1997 consensus statement has recommended that BRCAI and BRCA2 carriers begin annual or semi-annual clinical breast examinations and annual mammograms somewhere between the ages of 25 and 35 27* these recommendations were developed on the basis , of expert opinion only. Other authorities have recommended that screening begin 5 to 10 years before the age at which the first familial cancer was detected.57 Although intuitively it is logical to start screening earlier in higher risk women, it is possible that cancers will develop more quickly and that the rate of interval cancers will be unacceptable. Another theoretical concern exists regarding the possibility that women at genetic risk for cancer may be more susceptible to radiation-induced tumors, so greater risk than benefit could occur with an earlier start of mammography in these patients. 58 This theory has not been demonstrated, but studies are needed to exclude it. No recommendations have been made for women at moderately increased risk (eg, those with atypical hyperplasia). Hopefully future studies will include more precise evaluations of risk so that these questions can be answered.

For all high-risk women-especially those with less formal educa- tion-support and information about the benefits of screening need to be provided to encourage regular screening. Studies have shown that higher- risk women may experience psychologic stress that can impede their ability to follow through with screening recommendations.59*60

Prevention of Breast Cancer The early detection of breast cancer is the first step toward the reduc-

tion of mortality and morbidity from the disease, but preventing the development of cancer in the first place is the ultimate goal. Much recent research and press has been devoted to the issue of prevention, but in almost all cases, the data is incomplete.

Medical Prevention The largest studies performed thus far have focused on the prevention

of breast cancer through the use of pharmacologic agents that act as antiestrogens in the breast. 25$1-63 This presumes that the mechanism for the development of breast cancer is estrogen-mediated, but this may not be the case for all tumors.@ The first agents studied for the prevention of breast cancer were selected on the basis of their performance in the treatment of the disease. Patients with breast cancer who were treated with tamoxifen for 5 years were shown to have a 47% reduction in breast


cancer incidence in the unaffected breast. (j5@j This impressive reduction in breast cancer incidence led to curiosity about whether tamoxifen could prevent breast cancer in women without cancer.67

The Breast Cancer Prevention Trial (BCPT) is the largest study to date that examined pharmacologic breast cancer prevention.25 More than 13,000 women 60 years old or older or with the breast cancer risk of a 60-year-old woman (on the basis of the Gail model) were enrolled in the BCFT. The participants had a 5-year absolute risk for breast cancer of 3.2% to 3.9%. Twenty percent of women in the United States have a similar risk for breast cancer. Women were randomized to receive either placebo or 20 mg of tamoxifen a day, and they were followed for a mean of 48 months. The trial was stopped early because women of all ages on tamoxifen were found to have a 49% reduction in invasive breast cancer; this reduction was entirely due to estrogen-receptor-positive tumors. Sixty-seven high-risk women need to take tamoxifen for 5 years to prevent 1 case of invasive breast cancer. A modest increase in endometrial cancer and thromboembolic events was seen in women more than 50 years old. One in 130 women on tamoxifen will suffer an adverse event such as a deep venous thrombosis or endometrial cancer.”

Although the results of the BCPT provide hope that breast cancer will eventually be preventable, many questions remain. Because the study was terminated early, it is unknown if tamoxifen offers a reduction in the mortality rate or for how long tamoxifen is beneficial. This is particularly of concern because, in women with established breast cancer, tamoxifen is usually ineffective after 5 years because most tumors develop resistance. It is unclear if tamoxifen prevents the development of cancer, if it treats occult estrogen-sensitive tumors, or if it delays their development.68369

These concerns are further established by 2 smaller tials also published in 1998 that did not show a benefit with tamoxifen use.61>62 In an Italian study, 5400 women at low to average risk for breast cancer were randomized to receive either tamoxifen or placebo and were then followed for 4 years; no reduction in breast cancer frequency was observed.61 Compliance problems affect the conclusions of this study, but they raise the question of whether women at average risk for breast cancer will derive a preventive benefit from an antiestrogenic agent. A British study followed 2500 women who had an elevated risk of breast cancer on the basis of family history alone for a median of 6 years.62 Compliance was excellent and the study had adequate power to detect a difference of the magnitude found in the BCPT, but no benefit was seen with tamoxifen use. This study raised issues about whether tamoxifen can offer a benefit to women whose breast cancers are mediated by a genetic risk.


Overall these studies are encouraging and suggest that breast cancer may be preventable, but it seems hasty to apply these results broadly to clinical practice. It is still not clear which women will likely benefit from antiestrogens, for how long such agents should be given, and what the risk-benefit ratio is over time. 7o In addition to its effects with regard to breast cancer, the impact of tamoxifen on bones, lipids, endometrium, and vasomotor symptoms will have to be further defined.71 Despite ambiguities, the Food and Drug Administration has approved the use of tamoxifen for the prevention of breast cancer.

An even more promising class of drugs, .selective estrogen receptor modulators (SERMs), is being rapidly developed. These medications act selectively to maximize benefits and minimize risks. For example, raloxifene has an antiestrogenic effect on the breast and uterus, but it has an estrogenic effect on bones and lipids. Preliminary results of the Multiple Outcomes of Raloxifene Evaluation show a reduction of both breast and endometrial cancer with raloxifene use.63 The second phase of the BCPT will randomize women to receive either tamoxifen or raloxifene; enroll- ment for this part of the study will begin in 1999. A special effort will be needed to increase the participation of women who are members of ethnic minorities; the representation of these groups was low in the BCPT I. This way the results of the study can be generalized and more applicable to a greater proportion of American women. Optimally, women interested in taking an antiestrogen should be given the medica- tion on protocol to maximize the benefit to the individual and to society.

Surgical Prevention Some women, especially those at very high risk, have sought a more

definitive risk reduction through surgery, primarily prophylactic mastectomy. The performance of prophylactic mastectomy has generated much debate in the medical community and the general public, but it is increasingly being considered for the treatment of women with extremely high risks such as those with BRCAl or BRCA2 genetic mutations. All women considering surgical options for risk reduction should have a clear assessment of their relative and absolute risks for developing breast cancer. Both medical and surgical options should be explained to these patients, and they should also be fully informed about existing risk- reduction strategies. The impact of prophylactic mastectomy on a woman’s self-esteem and body image should be directly addressed; no rushed or panicked decisions should be made.72,73

The current data that documents the risk-reducing value of prophylactic mastectomy is difficult to interpret. In the past, some women have under-


gone subcutaneous mastectomies, which produce a better cosmetic result by preserving more skin and the nipple complex; however, these opera- tions do not as effectively reduce the risk for breast cancer. The simple ma*ctomy removes all breast tissue, including the nipple complex, and provides greater risk reduction. Thus, in studies, the 2 procedures cannot be grouped together when risk reduction assessments are to be made.

The amount of risk reduction provided by surgery depends on the breast cancer risk of the individual woman. Many studies have included women at very variable risks for breast cancer, including those at average risk; many studies have not adequately evaluated risk before surgery, so accurate risk reductions cannot be calculated.

The most recent study of this type came from the Mayo clinic.74 Although the discussed limitations did apply to this series, it is estimated that prophylactic mastectomy decreased the risk for breast cancer by about 90%. In cases of women at high risk, bilateral prophylactic mastectomy reduced the risk of death from breast cancer by 80.9%.74 If a woman chooses surgical risk reduction, many surgeons believe that if she has a very high risk of developing breast cancer (eg, she has the BRCAl or BRCA2 mutation) she should be offered a simple mastectomy rather than a subcutaneous mastectomy.75

lifestyle Modification

There has been much public debate about the lifestyle choices that may reduce a woman’s risk of breast cancer or that may possibly prevent the development of breast cancer in the first place. The research about many of these topics has been limited, in part because the impact of factors is suspected to be low. Very large studies may be needed to detect the differences that these changes can make.76 On a population basis the impact of these factors may be significant, but on an individual basis they may be minimal.

The most researched of these lifestyle topics is the relationship between dietary fat and breast cancer. The idea that there may be a connection between these 2 factors developed in part because of the differences in breast cancer prevalence in nations with very different dietary patterns. Many studies have been completed, some with conflicting results, but all of the larger studies (the Nurses’ Health Study19 included more than 88,000 women) show no relationship between dietary fat intake and the development of breast cancer.18a19

Other dietary influences, including the consumption of soy products, have been investigated because of lower rates of breast cancer in Asia. It has been theorized that the isoflavones present in soy products may act


as antioxidants to reduce overall cancer risk, and they may specifically act as antiestrogens in the breast. Experimental work on tissue culture and in mice has been promising, but there is no significant proof of a benefit to humans.77 One small study found a lower urinary excretion of phytoestrogens in women with breast cancer than was found in matched controls78; thus it is possible that increased soy consumption may have a protective effect with regard to breast cancer, but no broad recommendations can be made as of yet.

A few studies have shown a significant correlation between a reduced risk of breast cancer and an increase of exercise. The protective effects of exercise appear more significant in younger women, in those with a lower body mass index (BMI), and in those who exercise frequently. Two studies have shown a 50% reduction of breast cancer frequency in women who exercise 4 or more hours per week.79y80 These results are somewhat confounded by the influence of body weight, which has a complex relationship with breast cancer risk. In premenopausal women, a higher BMI has been linked to a lower rate of breast cancer. In postmenopausal women, a higher BMI or a higher amount of weight gain has been linked to higher rate of breast cancer, which may be a result of higher levels of estrogen.81 Overall, increased exercise and an avoidance of weight gain may slightly decrease a woman’s risk of developing breast cancer.

Because of their roles in the development of other cancers, tobacco and alcohol have been investigated with regard to breast cancer. No consistent link has been made with tobacco use, but one study has suggested that postmenopausal women who are slow acetylators and who also smoke may have an increased risk for cancer.82 A more consistent relationship between alcohol and breast cancer has been discovered. There appears to be a modest increase in breast cancer frequency among women who drink 2 to 5 drinks per day, with the relative risk increasing to 1.4. However, a clear dose-response relationship is not seen, and the effect is more pronounced in postmenopausal women20

The increase in breast cancer incidence worldwide has led to specula- tion there may be an environmental toxin at work. Some organochlo- rides, such as polychlorinated biphenyls, have a weak estrogenic effect, so they have received more attention. Animal models have suggested a possible link, but the studies in humans currently have shown no clear and consistent association.23,83 Clearly more research into the impact of synthetic endocrine regulators on breast cancer risk is needed.

Lifestyle modifications remain popular, probably because they offer partial control to the individual woman. However, their overall benefit is likely to be small. To the population as a whole such changes may be


TABLE 4. Breast cancer risk interventions

Proved interventions

Use of antiestrogens (ie, tamoxifen) Prophylactic mastectomy (generally only in

cases of very high risk) Avoidance of prolonged estrogen exposure (ie,

earlier pregnancy, no hormonal therapy with estrogens or progestins)

High levels of exercise (> 4 hours per week from an early age)

Unproved interventions

Lowfat diet (good studies refute) High soy or isoflavone consumption (no

large studies confirm) Low alcohol consumption (not known if

avoidance decreases risk, but high consumption may increase risk)

Environmental toxins (currently only a theory)

significant, but they should not be confused with significant risk reduction or prevention strategies for the individual woman, especially one with a high risk for developing breast cancer. Risk-reducing interventions are summarized in Table 4.

Diagnostic Evaluation of Breast Abnormalities

Physical Examination The diagnostic examination does not differ from the screening, but it is

helpful to determine a baseline by examining the normal breast first. Any dimpling, skin changes, recent nipple inversion, spontaneous nipple discharge, or focal masses require immediate evaluation.84,85 More subtle asymmetric differences in breast texture make differentiation between benign nodular&y and possible masses that require biopsy more difficult; the character and symmetry of the tissue can be helpful indications for making these distinctions. Hormonal status can significantly alter breast texture, so often the repetition of an examination during a different phase of the menstrual cycle or when hormone replacement therapy is not occurring can be helpful. Only findings of very low suspi- cion in low-risk women should be followed-up with repeat clinical examinations alone.

Certain normal breast findings can sometimes create concern in a patient or physician. A greater proportion of breast tissue can be found in the upper outer quadrant of the breast, and this area can be markedly more nodular than the rest of the breast. The distribution of breast tissue should be roughly symmetric in both breasts, and only an asymmetry in breast density or texture should prompt further evaluation. The breast tissue in the periareolar area is usually finely nodular and does not require biopsy unless asymmetry exists. It is critical to ascertain the overall symmetry of the breast tissue when examining possible breast abnormalities.


Radiologic Evaluation Mammography. The annual mammogram is currently the most useful

method for screening for breast cancer. On the basis of several randomized controlled trials, mammographic screening has been shown to reduce the breast cancer mortality rate by 30% to 40% in women 50 years old and older. 86-92 However, there are no abrupt changes that occur in the incidence of breast cancer or in the appearance of the breast when a woman reaches the age of 50 years. Although there has been controversy surrounding the mammographic screening of women 40 to 49 years old, recent evidence suggests that there is a statistically significant benefit to screening women in this age group.87,92-96 The value of the mammogram is in its ability to detect earlier-stage cancers that are clinically occult.

It is the recommendation of the American Cancer Society and the American College of Radiology that annual screening mammograms for women should begin at age 40. 97*98 Those women with increased risk for breast cancer may begin their annual screening at an earlier age. Women with a history of breast cancer should be screened every year after the diagnosis of the initial cancer. For women who are at high risk, it has been suggested that screening may begin when they are 10 years younger than the age that their first-degree relatives were diagnosed, but screening should not begin before the woman reaches the age of 25 years.27~99~100

Although mammography is the most useful screening test for breast cancer, it must be remembered that it is only a screening test. Mammography cannot rule out breast cancer, and it can be expected to miss up to 15% of breast tumors.101

Routine Mammograms. The quality of mammography has improved significantly since the passage of the mammography quality standards act of 1992, and the final regulations. became effective April 28, 1999.‘02,‘03 The goals of the mammographic screening program are to produce high-quality mammograms; to provide quality interpretations of these mammograms; to convey the results of these mammograms to patients and referring physicians in a timely manner; and to maintain outcomes data of all mammograms performed.

To comply with these goals, each routine mammogram is obtained in a way that will maximize the amount of breast tissue imaged. This usually includes 2 standard views of each breast: the mediolateral oblique view and the craniocaudal view. Additional views may be necessary for the evaluation of fibroglandular areas that are not included in the standard views and for the inspection of suspected abnormalities that are detected by the standard views or by clinical examination.lo4


Exaggerated craniocaudal-lateral and axillary tail views are used to visualize the fibroglandular tissue deep in the upper outer quadrant of the breast. A cleavage view is used to evaluate medial breast tissues.

The breast is a 3dimensional gland for which additional images may be necessary for full visualization. Spot compression views, mediolateral views, and rolled views may be used to separate overlapping structures. These additional views help distinguish between summation shadows and true abnormalities.104 The spot compression view is also useful to distinguish a mass from overlapping fibroglandular tissue and to better define the margins of a mass. Magnification views are useful for the evaluation of microcalcifications and for the determination of the margins of a mass.

Znterpretation of the Mammogram. When standard mammographic views are analyzed, they are positioned as mirror images. The mediolat- era1 oblique views of each breast are positioned so that the chest wall sides of each image abut each another and the labels of the mammography film are at the top. The craniocaudal views are placed similarly, with the label or axillary sides up (Figure 1). The breasts are usually fairly symmetric, and positioning the films this way facilitates the detection of subtle differences between the two breasts.

Abnormalities in the mammogram come in the form of masses, calcifications, and focal asymmetries. A finding must be verified, and this may require additional views. If the finding of the abnormality is judged to be real, the abnormality must be localized. The location of an abnormality is usually described by which quadrant of the breast it is located in or by clock position; its depth should also be noted.

A final assessment of the finding must be made on the basis of mammographic features. Is it benign, suspicious, or indeterminate? The radiologist generates a report about the findings and makes a final assessment with the use of the American College of Radiology Breast Imaging Reporting and Data System. lo5 This system has provided a means of standardizing the language of mammographic reports and facilitating their entry into breast cancer databases. The final assessment categories are as follows: category 0, needs additional imaging; category 1, negative mammogram; category 2, benign finding; category 3, probably benign finding, short interval follow-up recommended; category 4, suspicious finding, biopsy should be considered; and category 5, highly suggestive of malignancy, appropriate action should be taken.

A reasonable time interval for short-term follow-up of a probably benign finding is halfway between screening studies (6 months). A finding must have a high likelihood of being benign (95% to 98%) to be considered to be in category 3.


Figure 1. Standard mammogram. A, Mediolateral oblique views. B, Craniocaudal views. Spiculated category 5 mass seen deep in lower inner quadrant of left breast.

Findings of the Mammogram. The breasts are predominantly composed of fibroglandular tissue and fat. The larger the volume of fibroglandular tissue, the denser the breast and the lower the sensitivity of the mammogram; this is because a small mass can easily be hidden by the dense breast tissue (Figure 2).


Figure 2. Right medioloterol oblique and craniocoudol mammographic views from 2 different women.

A, Markedly dense breast that could easily hide a small mctss. B, Breast composed of predominontly fatty tissue, benign vascular calcifications present.

Specific morphologic features of masses and microcalcifications can help in the final assessment of a mammogram. A true mass will be seen in 2 different projections. A finding is called a “density” if it is not confirmed to be 3-dimensional. A mass can be characterized by its shape and by the appearance of its margins. Circumscribed round, oval, or gently lobulated masses favor benignity. Suspicious masses


Figure 3. A, Left medioloteral oblique mammographic view showing 3 separate masses. largest and most

posterior mass has illdefined, irregular margin, characteristic of suspicious mass. Anterior mass gently lobulated with distinct margins and contains large coarse calcifications, typical of fibroadenoma. Central mass

is ovoid and also has distinct margins, characteristic of benignity. (Continued on next page.)

are irregular with spiculated, microlobulated, or indistinct margins (Figure 3). lo6-lo8

Asymmetric breast tissue usually represents a normal variation, unless it is associated with a clinically palpable abnormality. If the asymmetry is centralized, additional imaging is required to exclude a mass. Fat containing masses, such as lipomas and oil cysts, are benign.

Calcifications can be placed into 3 groups: benign, suspicious, and indeterminate.106-108 They are characterized in terms of shape, form, size, distribution, density, and number. Many calcifications can be identified as typically benign. These include skin calcifications with lucent centers; vascular calcifications; large rod-like secretory calcifications; rim calcifications; milk of calcium; large dystrophic calcifications (eg, fibroadenoma, healing abscess); and lobular calcifications


Figure 3, continued. B, Right mediolateral oblique mammographic view demonstrating a highly suspi-

cious rounded mass with illdefined margins. (Continued on next page.)

(Figure 4). Scattered punctate calcifications also favor a benign process.

Suspicious calcifications are pleomorphic, heterogeneous, and granular. They are irregular with varying sizes and shapes, and they usually measure less than 0.5 mm wide. They can be fine and linear with branching, they can be clustered, or they can be ductally oriented (Figure 5).

Those calcifications not obviously benign or malignant are deemed indeterminate. Malignant and indeterminate calcifications require biopsy. This will usually be performed with guidance from the mammogram or ultrasound, unless there is an associated palpable mass.

DM. September 1999 363

C Figure 3, continued. C, Left craniocaudol mommogrophic view showing large spiculated mass in outer

portion of breast.

Other abnormal findings that should be noted include focal skin thick- ening, nipple retraction, architectural distortion, and abnormal lymph nodes (eg, indistinct margins, loss of fatty hilum).

Ultrasound of the Breast. The most important role of ultrasound of the breast is in the determination of whether a mammographically or clinically found mass is cystic or solid. 109J10 Finding a simple cyst by ultrasound obviates the need for further work-up (Figure 6). Complex cysts with thick internal septations or mural nodules will generally require aspiration or biopsy to exclude a malignant process.


B Figure 4. Benign calcifications. A, Bilateral craniocaudal mammographic views demonstrating thick rod-

like secretory calcifications and vasc&lar calcifications. B, Typical skin calcifications in 2 different women. Individual calcifications have lucent centers. (Continued on next page.)

Solid masses will have internal echoes whereas cysts are devoid of echoes and demonstrate posterior enhancement. Certain sonographic characteristics favor a benign mass; these include an ovoid or macrolobulated shape and smooth margins. It has been proposed that, with the use of strict sonographic criteria, certain masses that previ- ously would have required a biopsy can be followed-up instead.“‘?’ l2 Benign characteristics suggested include uniform hyperechogenicity, 2 to 3 lobulations, ellipsoid shape, and a thin surrounding capsule. In one study, of the 426 masses that met the above criteria, only 0.5% were found by biopsy to be malignant. Of the masses deemed indeterminate or suspicious by ultrasound, the sensitivity for cancer was 98.4%. 1 1 1,1 l2 Sonographic characteristics that favor malignancy include spiculated margins; greater height than width; angular


C Figure 4, continued. Benign calcifications. C, Calcified oil cyst in retrooreolar region. Two small nodules with distinct margins also seen at outer portion of this left craniocaudal mammographic view; they were

proved stable by older studies (not shown).

margins; marked hypoechogenicity; shadowing; calcifications; ductal extension; a branching pattern; and microlobulations (Figure 7). These sonographic findings are useful for the clarification of mammographic and clinical abnormalities and may prove to be useful in the reduction of the number of unnecessary biopsies.

Aside from its use for the differentiation of cysts from solid masses, ultrasound of the breast has a definite role in the evaluation of palpable masses in patients with mammographically dense breasts; in the evalua-


Figure 5. Typical malignant microcalcifications seen in cluster near axilla in this right mediolateral

oblique mammogrophic view; they are ossocioted with irregular category 5 mass. (Also see Figure 9.)

tion of palpable masses in younger patients; in cases that involve abscesses; and in the guidance of interventional procedures. log

Ultrasound of the breast, however, has not proved to be a good screening method because it has high false-negative (near 21%) and false-positive rates. logJ lo In addition, microcalcifications cannot be consistently demonstrated by ultrasound.

Magnetic Resonance Imaging of the Breast. Recent reports indicate that high contrast, high spatial resolution magnetic resonance imaging (MRI) of the breast may be a method for better defining the extent of a


Figure 6. Breast ultrasound. Typical simple cyst; mass with sharply defined margins and imperceptible wall, void of internal echoes, and demonstrating posterior enhancement.

breast tumor. 1 13y1 l4 For example, a treatment plan can be optimized if it is known whether the cancer is multicentric or multifocal. It was reported in one series that MRI of the breast demonstrated twice the sensitivity and three times the specificity of mammography.t13 Indications for MRI of the breast include evaluation of the compromised mammogram (eg, cases of dense breasts or silicone-augmented breasts); staging of the breast cancer; and evaluation of difficult histology (eg, lobular carcinoma, carcinoma in situ). 1 t3 MRI of the breast may also be useful in the evaluation of high-risk patients with negative clinical or mammographic examinations.

Major limitations of MRI of the breast include its lack of availability and its considerable cost. Although there is evidence that the specificity of MRI is higher than that of mammography, there is still some overlap of the MRI characteristics of benign and malignant lesions.115 By comparison, minimally invasive stereotactic and ultrasound-guided biopsies can provide tissue diagnosis at a lower cost than either MRI or surgical biopsy. For MRI to play a significant role in breast cancer screening, it will need to be available at a lower cost. Another problem arises when an abnormality is seen only by MRI, thus requiring a biopsy to be performed with the use of MRI guidance. Such a device is not commercially available at this time.r l3

Scintimammography. Scintimammography is a nuclear medicine examination in which uptake of an intravenously injected radiotracer, such as technetium Tc 99m sestamibi, is imaged in the breasts (Figure 8).


Figure i’. Breast ultrasound. A, Small mass showing sanagraphically benign features; avoid with distinct

margins and homogeneous echo pattern. B, Sanagraphic appearance of breast cancer. Margins irregular and angular, suggestion of acoustic shadowing. Several tiny echagenic foci seen within the mass;

consistent with associated micracalcifications.

Depending on the pattern and the degree of uptake by the breasts or by a lesion, a cancer can be found. Scintimammography should be considered as a complementary procedure to mammography when the mammogram is nondiagnostic or difficult to interpret; it cannot be used as a screening tool because sensitivity is low for lesions that are less than 1 cm in size. The overall sensitivity of scintimammography for the detection of cancer is 85% with a specificity of 89% and positive and negative predictive values of 89% and 84%, respectively. 1 l6 Nuclear imaging may be useful in the evaluation of patients with dense breasts, iatrogenic architectural distortion, implants, or multifocal disease; it is also useful in cases of high-risk patients, to determine a patient’s response to chemotherapy, and to establish the presence of metastatic axillary nodes.l16

Scintimammography’s high negative predictive value for palpable lesions can potentially decrease the number of unnecessary biopsies. It also has the potential for identifying multidrug resistance in breast tumors.l17 Technetium Tc 99m sestamibi is a transport substrate of the transmembrane p-glycoprotein, which is present in cells that overexpress the multidrug resistance gene (MDR I). There is a significant decrease in the radiotracer uptake by tumors that overexpress this gene. For all of these reasons scintimammography may play an increasingly important role in the diagnosis and treatment of breast cancer.

Biopsy Methods

Biopsy of Palpable Breast Abnormalities. Unless a definitive benign diagnosis is made on the basis of the physical examination and imaging


Figure 8. Scintimammagram. Faint, nonhomogeneous bilateral uptake of the radiopharmaceutical. Findings more consistent with fibrocystic changes than cancer; a malignant mass would appear as

center of high radiotracer uptake.

studies, a tissue biopsy of almost every palpable abnormality is required. Fibrocystic conditions that prompt patients to consult their physicians occur in the third and fourth decades of life; this overlaps with the age when breast cancer increases as a major health concern. Regardless of previous biopsies or pathologic confirmation of fibrocystic changes, a new finding during an examination should always be pursued. Concerns about cost containment, coupled with the need for prompt diagnosis, have shifted the emphasis away from surgical excisional biopsy and onto less invasive methods of diagnosis. Fine needle aspirate and core biopsies are increasingly being adopted as the standard of care. Both are excellent techniques that can be used to evaluate breast disease in an office setting, and both demonstrate a high degree of diagnostic accuracy. Furthermore, they allow for a rapid diagnosis, they do not require special surgical facilities, and they leave no visible scar or deformity.


Fine Needle Aspiration. The least invasive and easiest biopsy to perform is the fine needle aspiration (FNA). 1 l&1 l9 The highest sensitivity and specificity rates are achieved by combining the results of the physical examination, the mammogram, and the FNA in what is called the “triple test.” In this system, the results of these 3 procedures are scored in the following way: 1, benign; 2, suspicious; and 3, malignant. The results are then totaled. Masses with scores of 4 or less are generally found to be benign, and those with scores of 6 or higher are generally found to be malignant. This method has positive and negative predictive values of near 100%. Only lesions with a score of 5 require further evaluation, usually with core biopsy or possibly even with open biopsy. The triple test technique limits the need for more invasive biopsies without any loss of sensitivity.120

When an FNA or a core biopsy is to be performed, the area to be studied should be cleaned with an antiseptic (eg, alcohol, iodine). Local anesthesia is usually not necessary when performing an FNA, but it should be used when performing a core biopsy. The most common agent for this procedure is 1% lidocaine.

To perform an FNA, a l-inch 21- or 22-gauge needle should be attached to a 5 cc or 10 cc syringe that preferably should be coupled with a device that will facilitate the one-handed withdrawal of material. A longer needle may be needed for deeper lesions. The syringe should be withdrawn 3 cc to 5 cc before it punctures the skin. The needle should enter the skin tangentially from the palpated nodule so that 3 to 10 passes can be made at different angles to gather representative samples from the mass. The vacuum in the syringe should be released before the needle is removed from the breast. Only a small amount of tissue will appear in the hub of the needle. Multiple, separate aspirations, usually 2 to 4, increase the cellular yield but also increase the discomfort the patient experiences, because passage through the skin causes the greatest amount of pain.121“23 The yield of cells is maximized by removing the needle from the syringe, filling the syringe with air, and then carefully expressing the cells from the replaced needle. The cells should be smeared with 2 clear slides and sprayed with cytofixative or fixed in 95% ethyl alcohol.121 Ideally a cytopathologist should be available to stain the specimen and assess its adequacy, but in actuality this is rarely possible.123

Cure Biopsy. Core biopsies are usually performed with 1 I- or 14-gauge core biopsy needles. Manual-type mechanisms and biopsy guns are also available. Again, the lesion must be entered tangentially after the anesthetic has taken effect. A #l 1 blade is used to make a puncture wound in the skin; this will allow for easier entry of the large-gauge needle. Three or 4 separate core samples should be collected to obtain representative


tissue from the entire nodule, and each core should be placed in formalin solution. The physician must be careful not to contaminate needles in between each core sampling.

Although FNAs allow for the diagnosis of a malignancy, they are unable to yield information about invasiveness, and in many institutions the hormone receptor status and HER-2/neu expression cannot be ascer- tained with their use. In addition, FNA requires a pathologist with expertise in breast cytology. On the other hand, core samples can yield all the aforementioned information. The disadvantages of core biopsy are the need for local anesthetic, the increased discomfort of the patient, and the increased risk of hematoma.

The yield for both of these types of biopsies is mostly dependent on sampling, but it also depends on the reading of the pathologist. For FNAs, the sensitivity quoted in the literature ranges from 65% to 98%, with most reports being more than 95%; specificity ranges from 34% to lOO%, with most operators reporting more than 80%.121,123~124 The ability to collect an adequate amount of cells depends on the skill of the operator and the size and cellular composition of the lesion.125 Lesions smaller than 1 cm wide have a very low cellular yield. The pathology of the lactating breast is difficult and can lead to false-positives in FNAs, so core biopsy should always be used in these cases.123 Fat necrosis and sclerosing adenosis can lead to false-positive readings.124

FNAs and core biopsies have significantly lower morbidity rates than open biopsy; they also cause significantly less patient discomfort and have increased cost-effectiveness. There are no postbiopsy changes on the mammogram that can later mimic a malignancy or interfere with the diagnosis of future cancer. Possible complications include bleeding, hematoma, and, very rarely, infections and pneumothorax. Another important benefit associated with FNAs and core biopsies is that because they render a diagnosis quickly in the office, the patient has the psychologic advantage of being able to actively participate in the treatment plans and mentally prepare for definitive treatment.

ImageGuided localizution and Biopsy of Nonpalpable Breast Abnormalities

Needle Localization. Needle localization is used to localize a nonpalpable breast lesion to ensure that the entire lesion is removed during surgery. 109J26 The procedure often occurs after an image-guided biopsy that has already confirmed a malignant lesion. The localization can be done with the use of mammographic or sonographic guidance, and the


goal of the procedure is to have the anchoring hook wire through or very close to (within 5 mm) the abnormality and the hook itself approximately 1 cm beyond the abnormality (Figure 9). Orthogonal views are obtained for the surgeon to review, and the woman is then brought to the operating room for excision of the localized lesion. The excised specimen is radi- ographed to ensure that the lesion and the localizing device have been removed. A properly performed needle localization followed by surgical excision should have an error rate between 1% and 4%.

Potential complications of needle localization include bleeding, infection, vasovagal reaction, pneumothorax with ultrasound, wire migration, and wire transection during surgery. 126 It is also a more invasive and costly procedure as compared with image-guided large-core biopsies.

Fine Needle Aspiration Biopsy. Image-guided FNA biopsy is one of the more simple methods of acquiring cellular material from a nonpalpable mass. It is usually done with the use of ultrasound guidance. Under aseptic precautions and local anesthesia, a fine needle (eg, 21-gauge) is used to make multiple rotating passes through the mass while negative pressure is applied with a syringe. The success of an FNA biopsy depends on the availability of a highly trained breast cytopathologist. This procedure does not provide histologic data to determine cancer invasion or the histologic grade of the cancer.

Image-Guided Needle Core Biopsy. Ultrasound-guided needle core biopsy is a good method to use to obtain a histologic specimen from a breast mass.109~110~127 It allows for the real-time visualization of the biopsy needle as it enters the mass. Ultrasound guidance is quicker than stereotactic biopsy, does not include radiation exposure, and is more cost-effective than surgical or stereotactic biopsy.12* Ultrasound guidance for the biopsy of a nonpalpable mass should be the first choice when the mass is visible with the use of ultrasound imaging.

Stereotactically guided biopsy is the other major method for acquiring tissue for diagnosis from a suspicious nonpalpable abnormality. This procedure is usually performed with the woman in a prone position with her breast stabilized in an opening in the procedure table. The breast is compressed and the abnormality is localized with the use of digital stereotactic images. A computer is then used to guide the needle to the site of the abnormality. This procedure is performed with the use of aseptic precautions and local anesthesia.

The needle commonly used for this procedure is the Mammotome Probe (Biopsys Medical Instruments, Inc, San Juan Capistrano, Calif). The Mammotome Probe is an 1 l-gauge needle with a rotating sampling chamber that is positioned at the site of the abnormality in the breast. A


Figure 9. Needle localization. A, Right craniocaudal view obtained with lateral exaggeration. Cluster

of malignant microcalcifications localized deep in outer portion of breast; anchored localizing wire in

good position. (Continued on next page.)

vacuum is used to draw tissue into the sampling chamber while a hollow coaxial cutter takes the specimen. The specimen is retrieved by drawing back the cutter, which also has suction applied to it. The sampling chamber in the breast is then rotated to the next clock position, and the process is repeated.

Stereotactic needle core biopsy has shown excellent accuracy in the histologic diagnosis of breast cancer; it is in the same range as surgical


Figure 9, continued. B, Specimen radiograph from lumpectomy in another patient. These radiographs

usually taken with magnification. Note malignant microcalcifications within surgical specimen.

biopsy (96% to 98%),129-131 and this is especially true in 1 l-gauge needle vacuum-assisted breast biopsies.132 Stereotactic needle core biopsy is particularly useful for the sampling of suspicious or indeterminate microcalcifications. 133 A small percent of false-negative biopsies do occur (2% to 4%), so a 6-month follow-up mammogram image is advis- able for those lesions that have a benign histologic report.

Complications (eg, bleeding, infection) for both ultrasound-guided biopsy and stereotactic biopsy are rare. Pneumothorax is a very rare possibility in ultrasound-guided biopsy. Overall, image-guided biopsies are minimally invasive, have a low rate of complications, and have a similar yield to surgical biopsy, which is more invasive and more expensive.

Pathologic Diagnosis After a patient has undergone a biopsy, interpreting the results of the

pathologic findings becomes an important clinical task. If the diagnosis is invasive carcinoma or noninvasive carcinoma, interpretation is fairly straightforward; however, the interpretation of benign pathology is more complicated. Some benign pathology is associated with an increased risk of subsequent breast cancer development, whereas some is not. Many


attempts have been made to determine the relative risk of subsequent breast cancer development in the face of benign lesions. In a retrospec- tive cohort study that reviewed the benign biopsy specimens of more than 3000 women, a useful categorization system was developed.‘34-136 The specimens were sorted into the following 3 categories: nonproliferative lesions, proliferative lesions without atypia, and atypical hyperplasias (Table 5).134-136

Women who have undergone biopsies for nonproliferative lesions do not have an increased risk of the subsequent development of breast cancer as compared with women who have never had a breast biopsy.134~‘37~‘38 Nonproliferative lesions include papillary apocrine changes, epithelial related calcifications, cysts, and mild hyperplasia. Proliferative lesions without atypia include sclerosing adenosis, moderate or florid hyperplasia without atypia, and intraductal papillomas. These types of lesions confer a moderately increased risk of subsequent breast cancer development, with a relative risk of 1.3 to 1.9, depending on the series.134,137,138 Atypical hyperplasias confer a relative risk of 3.7 to 13, depending on the series.134T137,138 These lesions, characterized as ductal or lobular in origin, are proliferative in nature and demonstrate some of the architectural and cytologic features of in situ lesions. However, they do not meet all of the necessary criteria to be considered in situ lesions.

Another benign lesion that merits mention is fibroadenoma. Clinically these lesions develop as well-circumscribed, mobile, firm masses, and they can be diagnosed by cytology or core biopsy. They are frequently found in young women, and they usually appear shortly after puberty; however, they can occur at any time during a woman’s life. Although most are small (1 cm to 3 cm in diameter), they may grow to a very large size. Some will regress spontaneously whereas others may remain static. If these lesions begin to grow, surgical excision is warranted. The diagnosis of fibroadenoma does not confer an increased risk of the subsequent development of breast cancer.

Numerous other lesions may be found in the breast, including benign lesions such as those associated with granular cell tumors, sarcoidosis, tuberculosis, lipomas, adenolipomas, hemangiomas, leiomyomas, neurofibromas, and radial scars. Aside from cancers of ductal or lobular origin, sarcomas, phyllodes tumors, lymphomas, and lesions metastatic to the breast from other sites are all possible findings within the breast.

Considering that there is such a variety of possible pathologic entities, a careful review of biopsy specimens with the pathologist is warranted.


TABLE 5. Relative risk of subsequent development of breast cancer associated with various benign

lesions

TWX of lesion Relative risk

Nonproliferative lesio-pocrine changes (eg, apocrine metaplasia); cysts; epithelial calcifications

Proliferative lesion without atypia-sclerosing adenosis; intraductal papillomatosis; hypetplasia without atypia

Atypical hyperplasia-atypical ductal hyperplasia; atypical lobular hwerplasia

1.0

1.3 - 1.9

3.7 - 13.0

Treatment of Breast Cancer

Prognosis and Staging

The outcome for patients with breast cancer is directly related to the stage at which their disease is diagnosed. The American Joint Commission on Cancer (AJCC) publishes a staging manual to standardize staging across institutions, thus allowing data to be accumulated and compared all across the United States.139 The staging of cancer also plays a role in the making of decisions about therapy, the prediction of outcome, and the advancement of cancer study. The AJCC classification system is identical to that of the Union Internationale Contre le Cancer, thus allowing data to be compared among countries. The AJCC system is the one most commonly used by institutions, and it is the system used for the National Cancer Data Bank and the National Cancer Institute’s Surveillance, Epidemiology, and End Results database. The staging system currently used is the TNM system, which combines information about the tumor (T), nodal status (N), and metastasis (M) to classify the cancer and to predict outcome (Table 6).139 The basic premise of this system is the belief that cancers at the same anatomic site and with similar histologic characteristics share similar patterns of growth and spread. The system also takes into account the known prognostic factors that influence the natural history of each particular type of tumor.

The clinical staging of breast cancer occurs at the time of initial diagnosis and takes into account the size of the tumor, the status of the associated lymph nodes, and the evidence of metastatic disease that is identified during the clinical examination. Pathologic staging requires the evaluation of a surgically resected specimen, and it may differ from the initial clinical staging. The results of clinical staging may influence the choice of initial therapy, and the results of pathologic staging may influence the choice of adjuvant therapies, particularly in the case of the pathologic staging of axil-


TABLE 6. American Joint Committee on Cancer Staging’s breast cancer categorization

Primary tumor TX Tumor cannot be assessed TO No evidence of primary tumor TIS Carcinoma in situ Tl Tumor % 2 cm wide T2 Tumor > 2 cm wide but < 5 cm wide T3 Tumor > 5 cm wide T4 Tumor of any size with direct extension to chest wall or skin T4a Extension to chest wall T4b Edema (including peau d’orange) or ulceration of the breast or

satellite skin nodules comined to the same breast T4c Both T4a and T4b T4d Inflammatory carcinoma

Regional lymph nodes NX NO Nl N2

N3

Regional nodes cannot be assessed No regional lymph node metastasis Metastasis to movable ipsilateral axillary lymph node(s) Metastasis to ipsilateral axillary lymph node(s) fixed to one

another or to other structures Metastasis to ipsilateral internal mammary lymph node(s)

Metastasis MO Ml

No distant metastasis Distant metastasis, including metastasis to ipsilateral

supraclavicular lymph node(s)

lary lymph nodes. Restaging after treatment can facilitate the evaluation of therapy. Staging is also used to estimate prognosis on the basis of the survival statistics for a given stage of a specific type of disease (Table 7).

Management of Early-Stage Breast Cancer

Breast Conservation Surgery. Twenty years ago a discussion about the possible treatments for breast cancer was relatively simple. The concept of the behavior of the disease, put forward by William Halstead at the turn of the century, was one of a local-regional disease with later distant spread. The belief was that the cancer started in the breast, gradually grew until it spread to the lymph nodes, and then later spread in an orderly and predictable fashion to distant sites. This orderly concept of the behavior of the disease made radical mastectomy a perfectly logical treatment choice; if the disease could be controlled through aggressive local treatment, such as surgery, then a cure could be effected. If breast cancer behaved according to this paradigm, then no woman with a 1 cm breast cancer treated by radical mastectomy should ever die of distant spread. However, this is not the case, and the last 20 years have seen a


TABLE 7. Stage-based breast cancer prognosis

Stage 0 Stage I Stage IIA Sage IIB Stage IIIA Stage IIIB Stage IV

Stage Syear relative survival

TIS, NO, MO >99% Tl, NO, MO > 95% TO, Nl, MO: Tl. Nl, MO: T2. NO, MO BB% T2, Nl, MO; T3, NO, MO 76% TO, N2, MO; Tl, N2, MO; T2, N2, MO; T3, Nl or N2, MO 56% T4, any N, MO; any T, N3, MO 49% Any T, any N, Ml 16%

shift in the paradigm of this disease from one of a local-regional disease to one where the belief is that the disease is potentially systemic at the time of diagnosis. Numerous studies performed during the past 20 years have reinforced this latter paradigm, and the shift away from extensive local procedures has not had an impact on survival.

One of the earliest studies to challenge the Halsteadian concept of breast cancer was performed by the National Surgical Adjuvant Breast Project (NSABP) in the early 1970s. The NSABP B-04 protocol asked the question, “Does more extensive resection in the Halsteadian tradition improve survival?’ Approximately 1700 women with clinically node- negative breast cancer were randomized to receive treatment with either radical mastectomy, total mastectomy with regional radiation, or total mastectomy with delayed axillary node dissection at the time of the development of clinically positive nodes. No survival differences were found among the groups; this fact was made more interesting by the finding that although nearly 40% of the patients treated with radical mastectomy were found to have occult positive nodes, only approximately 15% of the women treated with total mastectomy alone subse- quently developed clinically apparent axillary metastasis, and their overall survival was not influenced. This finding-that leaving behind occult positive nodes did not seem to alter rates of systemic spread-led investigators to conclude that lymph nodes were not the instigator of distant spread, as Halstead had presumed, but rather that they were a marker for disseminated disease. 140

The NSABP B-04 trial, which refuted the basic Halsteadian theory of breast cancer behavior, made it possible for subsequent trials to further evaluate the role of local therapy in the treatment of the disease. The B- 04 trial set the stage for the B-06 trial, which questioned of what extent local procedure was in fact necessary. In the B-06 trial, which included patients enrolled from 1976 to 1984, nearly 2000 women were randomized to receive either modified radical mastectomy (the standard-of-care


arm of the study), lumpectomy followed by radiation to the breast, or lumpectomy alone. The first report of this study was published in 1985 and included data about approximately 1800 women.141 No significant differences were found among the disease-free survival rates or the overall survival rates of the women in the different treatment arms. There was a significant difference in the local control rate between the patients who received lumpectomy alone and the patients who received lumpectomy plus breast irradiation, with a greater rate of local control found in the patients who received radiation. Despite subsequent controversy surrounding this trial, a reanalysis 12 years after the completion of the trial showed no difference in survival rates among the treatment arms and a persistent improvement in local control rates when breast irradiation was part of the treatment.142

At the same time that the NSABP was evaluating lumpectomy and mastectomy, several other institutions were looking at the same question. Studies performed at the Institut Gustave-Roussy,143 the National Cancer Institute in Milan,14 the National Cancer Institute in the United States,145 the European Organization for Research and Treatment of Cancer,146 and the Danish Breast Cancer Group’47 all failed to find a survival difference between patients treated with conservative surgery and radiation therapy and those treated with mastectomy. At a 1990 National Institutes of Health Consensus Conference, the available data was reviewed and the panel concluded that breast conservation was an appropriate method of primary therapy for the majority of women with stage I or II breast cancer; this treatment was also deemed preferable because it provided survival rates equivalent to those of modified radical mastectomy, and it preserved the breast.148

In the 199Os, the choices of therapy for early-stage breast cancer (stages I and II) have been developed on the basis of the essential prin- cipal that mastectomy and breast conservation are equivalent options in terms of survival rates. The therapy decision is made on the basis of whether a woman is a conservation candidate; this means that an adequate lumpectomy can be performed (ie, negative margins can be obtained), the surgery would result in a cosmetically acceptable breast, and the woman wishes to have her breast conserved.

Role of Axilhy Node Dissection and Sentinel Node Biopsy. The role of axillary node dissection (ALND) in the treatment of breast cancer has evolved: in the clinically negative axilla it has a staging role, and in the clinically positive axilla it has a therapeutic role. Although ALND does provide good local control in patients with a clinically negative axilla (1% recurrence rate), a similar control rate (3%) is seen in patients who


receive radiation alone.149 The primary use of ALND in the clinically negative axilla has been to provide staging information for prognosis and for the selection of adjuvant therapy. The number of positive lymph nodes-along with tumor size-remains one of the strongest prognostic factors in cases of breast cancer. Although ALND has a low incidence of major complications, it carries with it a small but significant morbidity rate that can include lymphedema (range, 5% to 41%, depending on the extent of dissection and the use of adjuvant radiation), breast edema, risk of injury to long thoracic and thoracodorsal nerves, pain, limitations on range of motion, and loss of sensation from the division of intercostal brachial nerves. When only patients with node-positive disease were treated with chemotherapy, the results of the axillary dissection were of primary importance in making decisions about adjuvant therapy. In recent years, with the widespread use of chemotherapy for premenopausal women with node-negative disease and the increase in the number of small mammographically detected tumors with less likelihood of nodal metastasis, there has been a reexamination of the widespread use of ALND. Attempts have been made to determine which patients are likely to harbor occult metastasis and to then limit the use of ALND to this group. During the past 5 years, new technology has been developed and evaluated that may make routine ALND unnecessary; this technology would provide the necessary staging information and limit full dissection to only patients with positive axillary nodes.

Sentinel node biopsy was originally developed for patients with melanoma.150 This procedure evolved on the basis of the principle that nodal metastasis proceeds in an orderly fashion and does not include skip metastasis. The tumor is presumed to drain to a first node in the chain- the “sentinel node”-before it proceeds to higher levels of nodes within the chain. If this hypothesis is true, then the finding of a sentinel node that is negative for metastasis negates the need for further axillary dissection. Sentinel node biopsy is performed by injecting the tumor site with either a radioactive isotope or a dye such as isosulfan blue. A small inci- sion is made over the axilla and, with the use of either a gamma counter looking for a “hot spot” or visual identification of a blue node, a node is identified as the sentinel node. This node is removed and examined for its pathologic characteristics. It has been demonstrated that this technique allowed for the accurate staging of disease 95% of the time,15’ and during the last 5 years several multicenter and single institution trials have confirmed this.152-156 This finding has led to many surgeons aban- doning full ALND in patients that are found to be negative for metastasis when a sentinel node biopsy is performed. Consideration and caution


should be exercised with this technique because it has been shown that there is a definite learning curve associated with it151; surgeons should be certain that these good results will be reproducible in his or her own hands. There are still questions that surround this new technology. Because only a single node is examined, more careful examination with serial sections and immunohistochemical staining can be performed. The significance of a finding of micrometastatic disease in such sections is not known, and it should be the subject of future studies.

Adjuvant Therapy: Cytotoxk Chemotherapy. With the recognition during the last 30 years that breast cancer could be systemic at the time of its detection, there has been a need to improve adjuvant therapy for the disease; this has happened because physicians have come to realize that the best surgical results are futile if occult micrometastatic disease is left untreated. During the last few decades more than 100 randomized clinical trials of breast cancer adjuvant chemotherapy have been completed, and many have included 15 to 20 years of follow-up data. Early trials focused on women with a high risk of recurrence (eg, those with larger tumors and positive nodes); in these cases the risk of recurrence was felt to justify the toxicity of the treatment. As less toxic therapies have been developed, they have been evaluated for use in women at lower risk (eg, those with node-negative disease). These trials have allowed for the critical examination of the use of adjuvant chemotherapy and the development of rational treatment protocols.

The Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) performed a me&analysis of all available prospective randomized trials of adjuvant systemic therapy for operable breast cancer. This meta-analysis was first performed in 1985, and it was updated in 1992 and 1995.157-159 The 1995 overview of the trials that compared the use of chemotherapy with no chemotherapy showed a benefit in those patients that had been treated with adjuvant chemotherapy: it reduced the risk of recurrence by 35% in women less than 50 years old and by 20% in women between the ages of 50 and 69 years, and it reduced the risk of mortality by 27% in women less than 50 years old and by 11% in women between the ages of 50 and 69 years, which is a statistically significant difference. These risk reductions translate into an absolute improvement of approximately 7% to 11% in the lo-year survival of women whose disease develops when they are less than 50 years old and a 2% to 3% improvement for women whose disease develops when they are between the ages of 50 and 69 years. These benefits were apparent regardless of a woman’s estrogen receptor status, whether adjuvant tamoxifen had been part of her treatment, and what her menopausal status was when her disease was diagnosed. Clearly, the


higher the risk of recurrence, the greater the absolute benefit the individual stands to gain from the administration of chemotherapy. It therefore becomes necessary to estimate a patient’s risk of recurrence with the use of known prognostic factors and to evaluate the potential role of chemotherapy in that patient’s treatment. It is also necessary to take into account the patient’s overall medical condition and her risk of death from comorbid conditions when assessing the possible role of chemotherapy. The aforementioned meta-analysis also found that the use of cytotoxic chemotherapy reduced the risk of the development of contralateral breast cancer by about a fifth, and it did not have any adverse effects on deaths from causes not related to breast cancer.

The standard chemotherapy agents currently used carry with them both short-term and long-term side effects that need to be considered when evaluating the potential role of chemotherapy. Short-term side effects include nausea, vomiting, alopecia, anorexia, weight gain, mucositis, neutropenia, anemia, and neurotoxicity, all of which may occur to varying degrees, depending on the chemotherapeutic agents used. Amenorrhea may also be a consequence of chemotherapy. The average incidence rate of amenorrhea related to chemotherapy can be as high as 76%, with increasing rates seen as cumulative doses of cyclophosphamide increase,159 and it is worth noting that this condition may be irreversible. Long-term effects can also include the features of cardiac toxicity, particularly in patients in whom doxorubicin-based therapy has been used.

The last decade has seen the increased use of doxorubicin-based regimens, particularly for patients with node-positive disease, and the emer- gence of newer agents such as the taxanes. Controversies-such as the role of dose-intense therapy, the sequencing of multiple agent regimens, the role of high-dose chemotherapy, the role of immune modulation, and the optimal duration of therapy-remain the subjects of ongoing trials.

Adjuvant Therapy: Hormonal Thecapy. Early attempts at the hormonal manipulation of patients with breast cancer saw the use of ovarian ablation as a form of adjuvant therapy. In 1966, with the synthesis of tamoxifen, a nonsteroidal antiestrogenic compound, a new era of hormonal therapy for patients with breast cancer was ushered in. Since its initial approval by the Food and Drug Administration in 1977 for use in postmenopausal women with metastatic breast cancer, the role of tamoxifen has been expanded to the adjuvant setting for hormone- receptor-positive women. The role of tamoxifen as a chemopreventative agent is currently being examined.

The meta-analysis performed by the EBCTCG found that, in looking at all of the trials of tamoxifen versus no therapy, the use of tamoxifen


reduced the risk of breast cancer recurrence by 26% f 4% for women with node-negative disease and by 28% + 2% for women with node- positive disease. 157 There was also a reduction in the annual odds of death from any cause by 17% f 5% in node-negative women and by 18% f 2% in node-positive women. The 1995 update of the EBCTCG meta-analysis, which included data about approximately 30,000 women, demonstrated a continued benefit of the use of tamoxifen.65

The most efftcacious duration of therapy has been another area of debate. The part of the EBCTCG meta-analysis that compared the use of tamoxifen for less than 2 years with the use of tamoxifen for more than 2 years suggested that a longer duration of therapy benefits premenopausal women but that it does not benefit postmenopausal women. 157 One study that addresses this issue is the NSABP B-14 study in which women were randomized to receive tamoxifen for 5 years or to receive no therapy. t60 At the end of the 5 years, women who had received tamoxifen were randomized to receive either another 5 years of tamoxifen therapy or to receive no treatment. The results of this study were made public in November 1995, and they showed that there was no additional therapeutic benefit associated with the continuation of tamoxifen treatment beyond the initial 5 years of therapy. The Scottish Tamoxifen Trial also studied the question of the’duration of treatment by random- izing patients to receive tamoxifen either for 5 years or to receive it indefinitely. 161 The results of this study were similar to those of the NSABP B-14 trial, with no advantage seen for more than 5 years of treatment. Further research will be required to determine whether 5 years of tamoxifen therapy is superior to 2 years of tamoxifen therapy. Outside of a clinical trial, the current recommendation (supported by the NSABP B- 14 data) is for 5 years of therapy in the patients that receive tamoxifen.

The last few years have seen the development of alternate treatments for second- and third-line hormonal therapy. The aromatase inhibitors have emerged as a class of drugs with anti-breast-cancer effects. These compounds work because they block the synthesis of estradiol and estrone, thereby inhibiting the stimulatory effect of these compounds with regard to tumor growth. However, this strategy does not work in premenopausal women, where estrogen synthesis is under the control of pituitary gonadotropins and the use of aromatase inhibitors does not result in a significant decrease in estrogen levels. 162 Aromatase inhibitors are currently used as second-line therapy for postmenopausal women with estrogen- receptor-positive tumors and for whom tamoxifen therapy has failed.

Another emerging area of investigation is in the developing role of selective estrogen receptor modulators such as raloxifene. Although


tamoxifen has antiestrogenic effects on breast tissue, it exerts an estrogen-agonist effect on other tissues, particularly the endometrium. The proliferative effects of this drug on the endometrium carry with them an increased incidence of the development of endometrial cancer in the women treated who take the drug. Selective estrogen receptor modulators do not possess this agonist effect on the endometrium, and therefore, in theory, they do not carry the same risk of encouraging the development of endometrial cancer. These agents are currently being compared with tamoxifen in clinical trials to assess whether or not they possess equivalent anti-breast-cancer effects. Although this is an exciting area of investigation, there is not currently enough data to support their replacement of tamoxifen in the adjuvant treatment of breast cancer.

Adjuvant Therapy: Radiation Therapy. Trials of breast conservation support the use of adjuvant radiation therapy for the decrease of local recurrence after breast conservation surgery occurs. 163 Currently most patients receive between 5000 cGy and 6000 cGy to the breast after breast-conserving surgery. With modern tangential radiation fields and techniques, this treatment is well tolerated. It requires the delivery of daily fractions of radiation until the whole dose has been delivered. Acute side effects include skin changes (eg, pigmentation changes, local edema, desquamation); fatigue; and changes in blood counts that are more pronounced in patients who have received previous chemotherapy. Long-term complications include changes to skin, muscle and bone (< 1%) although many patients have permanent changes in pigmentation; pulmonary complications (c 1%) and cardiac complications (< I%), most usually pericarditis, have also been found. With the use of modem tangential techniques, cardiomyopathy is rare.

During the last few years, the question of the role of radiation therapy after mastectomy has been reexamined. The primary question is about whether improvements in local control can translate into improved survival and, if so, in which group of patients is this seen? Two recent studies, one from the Danish Breast Cancer Group’@’ and one from British Colum- bia,165 confirm the benefit of postmastectomy radiation in patients with larger tumors (> 5 cm), multiple positive lymph nodes (> 4 positive nodes), and the presence of nodes with extracapsular extension. These characteristics are found in patients with an increased risk (+ 30% to 40%) of subsequent local recurrence. The difference in distant recurrence rates between the patients who received postmastectomy radiation and those who did not was approximately lo%, which corresponded (in these studies) to the increased survival rate among patients who had received radiation therapy. Both of these studies raise the question of whether there is a role for post-


TABLE 8. Treatment of early-stage breast cancer

Local control: Tumor < 5 cm wide:

Lumpectomy + radiation Mastectomy It reconstruction

+ radiation if > 4 positive nodes + radiation if nodes have extra capsular extension + radiation if tumor has positive deep margins

For clinically negative axilla: sentinel node biopsy or level l/II ALND for staging For clinically positive axilla: ALND for local control and staging

Distant Control: Premenopausal patient:

Nodenegative disease < 1 cm wide: ER+: no adjuvant treatment or rt tamoxifen x 5 years ER-: no acjuvant treatment or consider chemotherapy if tumor has unfavorable characteristics

Nodenegative disease > 1 cm wide: ER+: chemotherapy + tamoxifen x 5 years, consider tamoxifen alpne if tumor has

favorable characterktics Nodepositive disease:

ER+: chemotherapy + tamoxifen x 5 years ER- : chemotherapy

Postmenopausal patient: NC&negative disease < 1 cm wide:

Same treatment as premenopausal women Nodenegative disease > 1 cm wide:

ER+: tamoxifen x 5 years, consider chemotherapy for unfavorable features ER- : chemotherapy

Nodepositive disease: ER+ : tamoxifen x 5 years, consider chemotherapy ER- : chemotherapy

Et?+, Estrogen-receptor-positive disease; Ef?-, estrogen-receptor-negative disease.

mastectomy radiation in patients with 1 to 3 positive nodes. In neither of these studies did this improvement in survival achieve statistical significance in the group of patients with 1 to 3 positive nodes, although that may have been because of the small number of patients studied. Although these patients do benefit in terms of local control, it is not clear whether this benefit translates into improved survival for this group of patients, who are already at a lower risk for local and distant recurrence; further research is necessary to establish an answer to this question. Table 8 summarizes the current available data about the treatment of early-stage breast cancer. Of course, the generalized information presented must be tailored to each individual woman’s needs and medical issues.

f.ocally Advanced Breast Cancer Despite advances in recent years in the public awareness of breast

cancer and despite improvements in compliance with screening


programs for early detection, approximately 10% to 15% of breast cancer patients are diagnosed with locally advanced disease.166 In certain environments, the incidence of locally advanced breast cancer (LABC) may be higher, At Cook County Hospital, which serves the medically indigent of Chicago and the Illinois county of Cook, approximately 25% to 30% of patients are not diagnosed with cancer until their disease is already locally advanced.

Historically, patients with LABC did extremely poor in terms of both local control and overall survival. For many years, surgery alone was the standard of care for LABC, and 5-year survival rates with single modality therapy were less than satisfactory. Surgery typically consisted of a Halstead radical mastectomy. Despite the extensive nature of the surgical extirpation, patients had high rates of local and distant recurrence. Five-year survival rates with surgery alone vary, depending on the series, from 5% to 55%.167-169 Many of these series are made up of a mix of patients, and better results are seen in the series that have more patients who are diagnosed when their disease is at a less advanced stage.

Like surgery, radiation therapy alone was not particularly effective in the control of LABC. When radiation therapy alone was used, 5-year disease-free survival rates were even lower than with surgery alone, ranging from 18% to 28%. 170-172 It was not until the 1970s when the first reports on neoadjuvant chemotherapy and multimodality therapy for LABC started appearing in the literature,173 that an improvement in results was noted. With the use of combined modality approaches to LABC, relapse-free survival rates improved. In a study from M.D. Anderson, there was an improvement of 55% to 75% found in the 5-year survival rates of patients with stage IIIA disease who were treated with triple-modality therapy (chemotherapy, radiation, and surgery) as compared with patients treated with surgery and radiation alone.174 Similar improvements (20% to 35%) were seen in patients with stage IIIB disease who were treated with multimodality therapy.

During the last 20 years, neoadjuvant (induction) chemotherapy has been used with the intent of improving survival rates. There are few randomized clinical trials that compare neoadjuvant chemotherapy to postoperative adjuvant therapy. 175-178 No clear survival advantage to one strategy or the other has yet been demonstrated. Potential advantages of induction chemotherapy include downstaging tumors and thus allowing for the consideration of breast conservation179-181 and for the assessment of tumor responsiveness in vivo. Although some staging information (ie, nodal status at diagnosis) is lost with the use of the neoadjuvant approach, the preoperative response of a tumor to induction therapy is


TABLE 9. Principles of locally advanced breast cancer. Disease at this stage includes the following:

tumors > 5 cm wide, bulky nodal disease, skin or chest wall disease. Five-year survival rate with multimodality therapy is 50% to 75%.

Resectable disease Unresectable disease

Local control Surgical options

Radiation therapy

Always indicated

Always indicated

Only if resectable after neoadjuvant chemotherapy

Always indicated

Distant control Chemotherapy Hormonal agents

Adjuvant or neoadjuvant Neoadjuvant Consider tamoxifen if Consider tamoxifen if

estrogeMeceptor-pc&itive estrogenreceptor-p&ti~

prognostic of outcome. 178J82 With the lack of data that suggest a clear survival advantage or disadvantage, neoadjuvant chemotherapy is one reasonable approach to use in women with LABC even if the cancers are potentially surgically resectable when they are diagnosed.

Even with combined modality therapy, the survival rates of patients with LABC remain far from satisfactory. Combined modality treatment has improved disease-free and overall survival, but the majority of patients with LABC still die of metastatic disease. Even in the setting of a good objective response to therapy (> 80%), overall 5-year survival rates for multimodality therapy regimens are approximately 50% to 60% (Table 9).lg3-lg5

Metastutic Breast Cancer, Although only 10% of patients have metastatic disease when the condi-

tion is diagnosed, many patients who are diagnosed at earlier stages will eventually experience recurrences with disease at distant sites, despite initial treatment. The natural history of the breast cancer is a varied one, with some patients experiencing recurrences within short periods of time and others experiencing recurrences after many years of disease-free survival. Once metastasis has occurred, the chance of long-term cure becomes unlikely. However, the disease can also follow a more indolent course that includes long-term remissions. Metastasis in breast cancer occurs most frequently to the bone, liver, lung, or brain, and the site at which the distant disease occurs affects survival. Patients who have metastasis to the bone as the sole site tend to do better than those with visceral disease.186T187

Many therapeutic strategies have been used to treat stage IV breast cancer. Hormonal therapies including antiestrogens; aromatase inhibitors; progestational agents (eg, megestrol acetate); medical oophorectomy with


TABLE 10. Treatment intent

Stage Curative Increase survival time Palliate

0 X X

I X X

II X X

III X X

IV X X

luteinizing hormone releasing hormone agonists (eg, goserelin); and surgical oophorectomy have all been used. Many chemotherapeutic agents are active against breast cancer, and several agents and dosing regimens have been used to treat metastatic disease. New agents and drug combinations are currently being tested in clinical trials. Modifications of dose density and dose intensity, the development of non-cross-resistant regimens, and the alteration of the duration of therapy are all the subjects of research in the hopes that drug resistance will be overcome and the body’s response to these drugs will be more durable.

Herceptin (Genentech, San Francisco, Calif), which received Food and Drug Administration approval in 1998, represents another strategy for the treatment of breast cancer. Herceptin targets the HER-2/neu receptor that is expressed by approximately 30% of breast cancers. Although tested initially in a population of women with me&static disease, Herceptin demonstrated efficacy when used both alone and in combination with chemotherapy.188l189 Although the study of this drug is ongoing, a recent report showed that, at a median follow-up of 25 months, an advantage in terms of overall survival was seen in the group that received Herceptin plus chemotherapy as compared with the group that received chemotherapy alone.lgO

Emphasis in the treatment of metastatic disease is on the palliation and the prolongation of apparent disease-free intervals. The goal of therapy becomes the relief of symptoms while keeping the toxicity of the treatment low, and the ultimate intent of therapy is to balance these to provide optimal palliation and a good quality of life. Table 10 summarizes the treatment goals at each stage of breast cancer.

Psychologic Aspects of Breast Cancer Care

Recent years have seen breast cancer go from a disease that is whispered about to one that is openly discussed. With this change has come an increasing awareness on the part of women and their health care providers of the importance of dealing openly with the multitude of psychologic challenges faced by a woman going through breast cancer diagnosis, treat-


ment, and beyond. Breast cancer represents a major stress to women faced with the diagnosis. From the time of the initial diagnosis a multitude of psychologic challenges are encountered. Loss of control, fear, anger, anxiety, depression, confusion, altered body image, issues of identity and sexuality, changes in relationships, and survivorship issues can all be encountered at several points in a patient’s experience with the disease.

How these challenges are met can be influenced by the social context of the patient’s life, the patient’s social support system, the patient’s preexisting coping mechanisms, other concurrent life stresses in the patient’s life, and the patient’s belief system about health and illness. In addition, the patient’s health care team can have a significant effect on the patient’s experience of her breast cancer. Primary care physicians and oncology specialists who are sensitive to the patient’s concerns, who take the time to explain things and help a patient through the decision-making process, and who are clearly concerned with the patient’s emotional and physical well-being can make a significant difference in helping the patient adjust to her situation.

Physicians and patients have numerous resources available to help address the social and psychologic concerns of the women and the families of the women faced with breast cancer. A variety of books have made their way into the nonmedical literature, and the Internet provides easy access to a wealth of information. Support organizations have hotlines where questions can be addressed and fears confronted. An increasing number of support groups have been started as both part of treatment facilities and as free-standing programs. In addition to helping with the patient’s adjustment process, there is some work that suggests that addressing psychosocial concerns may also improve patient outcome. In a study of women with metastatic breast cancer, those who took part in a year of weekly supportive group therapy survived an average of 18 months longer as compared with a group that received no therapy.lgl By addressing the psychosocial concerns of patients with breast cancer and those who have survived it, physicians can make a real impact on a patient’s health and well-being.

Long-Term Surveillance Because of the long natural history of breast cancer, the possibility of

late recurrence, and the chance of the development of second primary cancers, long-term surveillance of patients with breast cancer is an issue faced by most physicians. Surveillance strategies have to balance the early detection of recurrence and the likelihood of outcome improvement by early detection with quality-of-life issues and cost containment.


Surveillance patterns currently vary widely in the United States.1923193 Physicians are faced with the desires and expectations of the patients and the demands of third-party payers.

Surveillance strategies should be developed on the basis of whether there is a way to detect recurrence early and if, when the recurrence is discovered, effective treatment will be available. The hope is that, if recurrence could be detected earlier and treatment made available, women could live longer and better lives. However, the reality is that other than some cases of local recurrence (ie, in-breast recurrence after breast conservation), recurrent disease is usually incurable, except in rare instances. Although there are many indirect means of searching for recurrence, there is no perfect test that reassures both the physician and the patient that the patient is 100% free of disease.

Many tumor markers have been investigated for their use as surveillance tools. CEA, Cu 15-3, and Cu 27-29 have all been used for the early detection of recurrence; however, these markers have been found to have a low positive predictive value, they generally only identify a percentage of clinically occult disease, and they require an average lead-time of 6 months.194 In addition, there is little evidence in currently existing breast cancer research to support the notion that the early detection of distant disease (ie, before it becomes symptomatic) has an impact on survival. If better systemic therapies are developed in future years, this idea may need to be reevaluated.

Many clinicians have patients with breast cancer tested multiple times, and patients often request tests that they have read or heard about. Numerous studies have examined the efficacy of routine testing as a part of surveillance. Two randomized studies published in 1994 looked at the role of intensive surveillance that included routine testing. One study randomized 1243 patients treated for invasive breast cancer to receive either clinical or intensive follow-up.195 Although both groups were examined every 3 months for the first 2 years and every 6 months for the next 3 years, the intensive surveillance group received chest x-rays and bone scans every 6 months, whereas the clinical surveillance group had tests only when clinically indicated. It was found that, although the intensive surveillance group had a lower 5-year relapse-free survival, there was no difference in the 5-year overall mortality between the 2 groups. A second study randomized patients to receive either a clinically directed regimen or an intensive surveillance regimen that had a similar regimen of clinical visits as the previous study but included liver function tests at each visit, a chest x-ray every 6 months, a bone scan every 12 months, and a liver ultrasound every 12 months. 196 Like the first study, although


TABLE IA. Issues to be oddressed during long-term follow-up

Surveillance for the detection of disease recurrence Early detection of contralateral breast cancer Surveillance and treatment for long-term effects of therapy Rehabilitation after treatment Psychologic support for survivor issues (eg, fear of recurrence, altered body im%e, sexuality) Risk counseling for patient and family

clinically occult metastases were detected more frequently in the inten- sively followed group, no difference in overall survival was found.

What, then, constitutes “appropriate surveillance”? Several tasks need to be accomplished during the surveillance of the patient with breast cancer. The first is the early detection of recurrences for which treatment is available (eg, local recurrence). The second is the early detection of second primary tumors in the contralateral breast, a risk in any woman who has had previous breast cancer. The third is the identification and treatment of the long-term effects of initial therapy. The fourth is the provision of long-term support for the psychosocial issues that affect the survivors of breast cancer and their families. The last-and most often forgotten-goal is to provide for the woman’s overall health and well- being. Routine health maintenance is often forgotten as the patient and physician become preoccupied with the cancer. Although there are many appropriate clinical regimens, excessive testing that includes frequent imaging tests and tumor marker analysis probably does not have a role in the surveillance of a patient with breast cancer and does little aside from increasing patient anxiety and health care costs.

The routine at Cook County Hospital is to see patients who have completed active treatment once every 3 months for the first 2 years; every 4 to 6 months during year 3, depending on the risk of recurrence; every 6 months during years 4 and 5; and yearly for life after year 5. Patients who have had breast cancer have a risk of recurrence into the second decade of follow-up and a life-long risk of developing a second primary tumor; thus, life-long surveillance is appropriate. A yearly mammogram should always be obtained. A yearly chest x-ray and yearly liver function tests have been the routine, but a strong argument can be made that these tests have no effect in the prediction of a patient’s outcome. Women on tamoxifen therapy should undergo yearly Papanicolaou tests and pelvic examinations with pelvic ultrasound; endometrial biopsy should only be performed if findings support its use. Other tests, such as bone scans and computed tomography scans, are only ordered if clinically indicated. Table 11 reviews issues associated with long-term surveillance.


Conclusion Breast cancer is clearly one of the leading causes of cancer mortality and

morbidity for women both nationally and worldwide, and incidence rates have increased recently. Breast cancer risk is elevated with age; previous breast malignancy; prolonged estrogen stimulation, either endogenously or exogenously; proliferative breast processes, such as atypical hyperplasia; and, in less than 5% of cases, genetic predisposition. Breast cancer screening has effectively reduced the breast cancer mortality rate by about 30%, primarily because mammography detects tumors earlier in their development. It is theorized that earlier screening for higher-risk women (eg, those carrying BRCAI or BRCA2 mutations) will improve survival, but this has not yet been proved. Breast cancer prevention is the ultimate goal, and current studies are exploring the use of antiestrogens such as tamoxifen and raloxifene. Prophylactic mastectomy may markedly reduce risk in women with a very high risk of breast cancer. Lifestyle modifications have shown little impact on individual risk.

Diagnostic evaluation of breast abnormalities has become much less invasive and much more accurate. The interpretation of mammograms has become more standardized with higher quality images that require less radiation to obtain. Other imaging modalities (eg, magnetic resonance, scintimammography) hold the promise of improving the sensitivity and specificity of diagnosis and of advancing the management of the disease itself. Surgical excision is now rarely necessary to make the diagnosis of cancer. Biopsies of palpable masses can be performed with a fine needle aspirate or a core biopsy, and nonpalpable masses can be localized for biopsy with the use of ultrasound or mammography.

Breast cancer treatment has been revolutionized during the last 30 years. Breast conservation, in conjunction with adjuvant radiation therapy, is now widely accepted as treatment for patients with early-stage breast cancer. Fewer full axillary node dissections are being performed, and more sentinel node biopsies are being performed. As chemotherapy has become less toxic and its side effects more manageable, its use has broadened, especially in patients with early-stage breast cancer. Hormonal therapy is undergoing expansion and has included the development of aromatase inhibitors and selective estrogen receptor modulators. The frequency of good prognoses for patients with locally advanced breast cancer remains significantly below that of patients with early- stage cancers, but multimodality therapy has dramatically improved the survival rates of these patients. Survival with metastatic breast cancer is variable, and a cure is unlikely to be found. The monoclonal antibody Herceptin offers some hope for targeted chemotherapy, especially for


patients with advanced aggressive tumors. Complete care of the patient with breast cancer includes appreciation of and assistance with psychologic issues. No set protocol has been identified for long-term surveillance, but more aggressive testing has not been shown to improve survival rates.

REFERENCES 1. American Cancer Society. Cancer facts & figures. Atlanta (GA): The Society;

1998. 2. Landis SH, Murray T, Bolden S, Wingo PA. Cancer statistics, 1999. CA Cancer J

Clin 1999;49:8-31. 3. Brinton LA, Devesa SS. Incidence, demographics, and environmental factors. In:

Harris JR, Lippman ME, Morrow M, Hellman S, editors. Diseases of the breast. Philadelphia: Lippincott-Raven; 1996. p. 159-61.

4. Parkin DM, Pisani P, Ferlay J. Global cancer statistics. CA Cancer J Clin 1999;49:33-64.

5. Forbes JF. The incidence of breast cancer: the global burden, public health consid- erations. Semin Oncol 1997;24(1 Suppl l)Sl-2O-S1-35.

6. Seidman H, Mushinski MI-I, Gelb SK, Silverberg E. Probabilities of eventually developing or dying of cancer-United States, 1985. CA Cancer J Clin 1985;35:36-56.

7. Henderson BE, Bernstein L. Endogenous and exogenous hormonal factors. In: Harris JR, Lippman ME, Morrow M, Hellman S, editors. Diseases of the breast. Philadelphia: Lippincott-Raven; 1996. p. 185-200.

8. Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 5 1 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer. Lancet 1997;350: 1047-59.

9. Persson I, ThurfJell E, Holmberg L. Effect of estrogen and estrogen-progestin replacement regimens on mammographic breast parenchymal density. J Clin Oncol 1997;15:3201-7.

10. Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormonal contraceptives: collaborative reanalysis of individual data on 53,297 women with breast cancer and 100,239 women without breast cancer from 54 epidemiological studies. Lancet 1996;347: 1713-27.

11. Donegan WL, Spratt JS. Cancer of the breast. 4th ed. Philadelphia (PA): WB Saunders; 1995.

12. Schnitt ST, Connolly JL. Pathology of benign breast disorders. In: Harris JR, Lippman ME, Morrow M, Hellman S, editors. Diseases of the breast. Philadelphia: Lippincott-Raven; 1996. p. 27-41.

13. Rosenberg RD, Hunt WC, Williamson MR, Gilliland FD, Wiest PW, Kelsey CA, et al. Effects of age, breast density, ethnicity, and estrogen replacement therapy on screening mammographic sensitivity and cancer stage at diagnosis: review of 183,134 screening mammograms in Albuquerque, New Mexico. Radiology 1998;209:511-8.

14. Kerlikowske K, Grady D, Barclay J, Sickles EA, Emster V. Effect of age, breast density, and family history on the sensitivity of first screening mammography. JAMA 1996:276:33-g.


15.

16.

17.

18.

19.

20.

21.

22.

23.

24.

25.

26.

27.

28.

29.

30.

31.

Gail MH, Brinton LA, Byar DP, Corle DK, Green SB, Schairer C, et al. Projecting individualized probabilities of developing breast cancer for white females who are being examined annually. J Nat1 Cancer Inst 1989;8 1: 1879-86. Garber JE, Smith BL. Management of the high-risk and the concerned patient. In: Harris JR, Lippman ME, Morrow M, Hellman S, editors. Diseases of the breast. Philadelphia: Lippincott-Raven; 1996. p. 323-34. Weber BL, Garber JE. Familial breast cancer. In: Harris JR, Lippman ME, Morrow M, Hellman S, editors. Diseases of the breast. Philadelphia: Lippincott-Raven; 1996. p. 168-85. Hunter DJ, Spiegelman D, Adami HO, Beeson L, van den Brandt PA, Folsom AR, et al. Cohort studies of fat intake and the risk for breast cancer-a pooled analysis. N Engl J Med 1996;334:356-61. Holmes MD, Hunter DJ, Colditz GA, Stampfer MJ, Hankinson SE, Speizer FE, et al. Association of dietary intake of fat and fatty acids with risk of breast cancer. JAMA 1999;281:914-20. Smith-Warner SA, Spiegehnan D, Yaun SS, van den Brandt PA, Folsom AR, Goldbohm RA, et al. Alcohol and breast cancer in women: a pooled analysis of cohort studies. JAMA 1998;279:535-40. Gapstur SM, Potter JD, Sellers TA, Folsom AR. Increased risk of breast cancer with alcohol consumption in postmenopausal women. Am J Epidemioll992; 136: 1221-3 1. Friedenreich CM, Howe GR, Miller AB, Jain MG. A cohort study of alcohol consumption and risk of breast cancer. Am J Epidemiol 1993;137:512-20. Krieger N, Wolff MS, Hiatt RA, Rivera M, Vogelman J, Orentreich N. Breast cancer and serum organochlorines: a prospective study among white, black, and Asian Women. J Natl Cancer Inst 1994;86:589-99. Claus EB, Risch N, Thompson WD. Autosomal dominant inheritance of early- onset breast cancer. Implications for risk predicition. Cancer 1994;73:643-5 1. Fisher B, Constantino JP, Wickerham DL, Redmond CK, Kavanah M, Cronin WM, et al. Tamoxifen for prevention of breast cancer: Report of the National Surgical Adjuvant Breast and Bowel Project P-l Study. J Nat1 Cancer Inst 1998;90:1371-88. Lerman C, Narod S, Schulman K, Hughes C, Gomez-Caminero A, Bonney G, et al. BRCAl testing in families with hereditary breast-ovarian cancer. A prospective study of patient decision making and outcomes. JAMA 1996;275:1885-92. Burke W, Daly M, Garber J, Botkin J, Kahn MJ, Lynch P, et al. Recommendations for follow-up care of individuals with an inherited predisposition to cancer. II. BRCAl and BRCA2. Cancer Genetics Studies Consortium. JAMA 1997;277:997-1003. Ford D, Easton DF, Bishop DT, Narod SA, Goldgar DE. Risks of cancer in BRCAl- mutation carriers. Breast Cancer Linkage Consortium. Lancet 1994;343:692-5. Ford D, Easton DF, Peto J. Estimates of the gene frequency of BRCAI and its contribution to breast and ovarian cancer incidence. Am J Hum Genet 1995;57: 1457-62. Couch FJ, DeShano ML, Blackwood MA, Calzone K, Stopfer K, Campeau L, et al. BRCAl mutations in women attending clinics that evaluate the risk of breast cancer. N Engl J Med 1997;336:1409-15. Malone KE, Daling JR, Thompson JD, O’Brien CA, Francisco LV, Ostrander EA. BRCAl mutations and breast cancer in the general population: analyses in women before age 35 years and in women before age 45 years with first-degree family history. JAMA 1998;279:922-9.


32. Breast Cancer Linkage Consortium. Pathology of familial breast cancer: differences between breast cancers in carriers of BRCAI or BRCA2 mutations and sporadic cases. Lancet 1997;349:1505-10.

33. Cummings S, Olopade 0. Predisposition testing for inherited breast cancer. Oncology 1998;12:1227-42.

34. Gastrin G, Miller AB, To T, Aronson KJ, Wall C, Hakama M, et al. Incidence and mortality from breast cancer in the Mama Program for Breast Screening in Finland, 1973-1986. Cancer 1994;73:2168-74.

35. Semiglazov VF, Moiseyenko VM, Protesenko SA, Kharikova RS, Manihas AG. Breast self-examination for the early detection of breast cancer: Russia/WHO controlled trial in St. Petersburg. Poster presented at: San Antonio Breast Cancer Symposium; December 15, 1998; San Antonio, TX.

36. O’Malley MS, Fletcher SW. US Preventive Services Task Force. Screening for breast cancer with breast self-examination. A critical review. JAMA 1987;257:2196-203.

37. Champion V. The role of breast self-examination in breast cancer screening. Cancer 1992;69(7 Suppl): 1985-91.

38. Shapiro S, Venet W, Strax P, Venet L, Roeser R. Ten- to fourteen-year effect of screening on breast cancer mortality. J Nat1 Cancer Inst 1982;69:349-55.

39. Baines CJ, Miller AB, Bassett AA. Physical examination. Its role as a single screening modality in the Canadian National Breast Screening Study. Cancer 1989;63:1816-22.

40. Mettler FA, Upton AC, Kelsey CA, Ashby RN, Rosenberg RD, Linver MN. Benefits versus risks from mammography: a critical reassessment. Cancer 1996;77:903-9.

41. Rimer BK. Breast cancer screening. In: Harris JR, Lippman ME, Morrow M, Helhnan S, editors. Diseases of the breast. Philadelphia: Lippincott-Raven; 1996. p. 307-22.

42. Fletcher SW, Black W, Harris R, Rimer BK, Shapiro S. Report of the International Workshop on Screening for Breast Cancer. J Natl Cancer Inst 1993;85:1644-56.

43. Miller AB, Baines CJ, To T, Wall C. Canadian National Breast Screening Study: 2. Breast cancer detection and death rates among women aged 50 to 59 years. CMAJ 1992;147:1477-88.

44. Tabar L, Fagerberg G, Duffy SW, Day NE. The Swedish two county trial of mammographic screening for breast cancer: recent results and calculation of benefit. J Epidemiol Community Health 1989;43:107-14.

45. Andersson I, Aspegren K, Janzon L, Landberg T, Lindholm K, Line11 F, et al. Mammographic screening and mortality from breast cancer: the Malmo mammographic screening trial. BMJ 1988;297:943-8.

46. Frisell J, Ecklund G, Hellstrom L, Lidbrink E, Rutqvist LE, Sonnell A. Randomized study of mammography screening-preliminary report on mortality in the Stockholm trial. Breast Cancer Res Treat 1991;18:49-56.

47. Roberts MM, Alexander FE, Anderson TJ, Chetty U, Donnan PT, Forrest P, et al. Edinburgh trial of screening for breast cancer: mortality at seven years. Lancet 1990;335:241-6.

48. Bjurstam N, Bjomeld L, Duffy SW, Smith TC, Cahlin E, Eriksson 0, et al. The Gothenburg breast screening trial: first results on mortality, incidence, and mode of detection for women ages 39-49 years at randomization. Cancer 1997;80:2091-9.

49. Morrow M. Breast disease in elderly women. Surg Clin North Am 1994;74:145-61. 50. Tabar L, Duffy SW, Burhenne LW. New Swedish breast cancer detection results

for women aged 40-49. Cancer 1993:72:1437-48.


51.

52.

53.

54.

55.

56.

57.

58.

59.

60.

61.

62.

63.

64. 65.

66.

67.

Salzman P, Kerlikowske K, Phillips K. Cost-effectiveness of extending screening mammography guidelines to include women 40 to 49 years of age. Ann Intern Med 1997;127:955-65. Elmore JG, Barton MB, Moceri VM, Polk S, Arena PJ, Fletcher SW. Ten-year risk of false positive screening mammograms and clinical breast examinations. N Engl J Med 1998;338:1089-96. Woolf SH, Lawrence RS. Preserving scientific debate and patient choice: lessons from the Consensus Panel on Mammography Screening. National Institutes of Health. JAMA 1997;278:2105-7. Gail M, Rimer B. Risk-based recommendations for marnmographic screening for women in their forties. J Clin Oncol 1998;16:3105-14. May DS, Lee NC, Nadel MR, Henson RM, Miller DS. The National Breast and Cervical Cancer Early Detection Program: a report on the Iirst 4 years of mammography provided to medically underserved women. AJR Am J Roentgen01 1998;170:97-104. McCarthy EP, Burns RB, Coughlin SS, Freund KM, Rice J, Marwill SL, et al. Mammography use helps to explain differences in breast cancer stage at diagnosis between older black and white women. Ann Intern Med 1998;128:729-36. Vasen HF. Screening in breast cancer families: is it useful? Ann Med 1994;26:185-90. Den Otter WD, Merchant TE, Beijerinck D, Koten JW. Breast cancer induction due to mammographic screening in hereditarily affected women. Anticancer Res 1996;16:3173-5. Lerman C, Daly M, Sands C, Balshem A, Lustbader E, Heggan T, et al. Mammography adherence and psychological distress among women at risk for breast cancer. J Nat1 Cancer Inst 1993;85: 1074-80. Kash KM, Holland JC, Halper MS, Miller DG. Psychological distress and surveillance behaviors of women with a family history of breast cancer. J Nat1 Cancer Inst 1992;84:24-30. Veronesi U, Maissoneuve P, Costa A, Sacchini V, Maltoni C, Robertson C, et al. Prevention of breast cancer with tamoxifen: preliminary findings from the Italian randomised trial among hysterectomised women. Italian Tamoxifen Prevention Study. Lancet 1998;352:93-7. Powles T, Eeles R, Ashley S, Easton D, Chang J, Dowsett M, et al. Interim analysis of the incidence of breast cancer in the Royal Marsden Hospital tamoxifen randomised chemoprevention trial. Lancet 1998;352:98-101. Cummings SR, Norton L, Eckert S, Grady D, Cauley J, Knickerbocker R, et al. Raloxifene reduces the risk of breast cancer and may decrease the risk of endometrial cancer in post menopausal women. Two-year findings from the Multiple Outcomes of Raloxifene Evaluation (MORE) trial. In: Proceedings of the American Society of Clinical Oncology, Vol. 17;1998. Abstract 3. O’Shaughnessy JA. Chemoprevention of breast cancer. JAMA 1996;275:1349-53. Early Breast Cancer T&lists Collaborative Group. Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet 1998;351:1451-67. Osborne CK. Tamoxifen in the treatment of breast cancer. N Engl J Med 1998;339:1609-18. Fisher B, Redmond C. New perspective on cancer of the contralateral breast: a marker for assessing tarnoxifen as a preventive agent. J Natl Cancer Inst 1991;83:1278-80.


68. Margolese RG. How do we interpret the results of the Breast Cancer Prevention trial? CMAJ 1998;158:1613-4.

69. Goel V. Tamoxifen and breast cancer prevention: what should you tell your patients? CMAJ 1998;158:1615-7.

70. Pitchard KI. Is tamoxifen effective in prevention of breast cancer? Lancet 1998;352:80-1.

71. Powles TJ, Hickish T, Kanis JA, Tidy A, Ashley S. Effect of tamoxifen on bone mineral density measured by dual-energy x-ray absorptiometry in healthy premenopausal and postmenopausal Women. J Clin Oncol 1996;14:78-84.

72. Grann VR, Panageas KS, Whang W, Antman KH, Neugut AI. Decision analysis of prophylactic mastectomy and oophorectomy in BRCAl-positive or BRCAZ positive patients. J Clin Oncol 1998;16:979-85.

73. Klijn JG, Janin N, Cortes-Furies H, Colomer R. Should prophylactic surgery be used in women with a high risk of breast cancer? Eur J Cancer 1997;33:2149-59.

74. Hartmann LC, Schaid DJ, Woods JE, Crotty TP, Myers JL, Arnold PG, et al. Efficacy of bilateral prophylactic mastectomy in women with a family history of breast cancer. N Engl J Med 1999;340:77-84.

75. Eisen A, Weber BL. Prophylactic mastectomy-the price of fear. N Engl J Med 1999;340:137-8.

76. Davis DL, Axelrod D, Osborne M, Telang N, Bradlow I-IL, Sinner E. Avoidable causes of breast cancer: the known, unknown, and the suspected. Ann N Y Acad Sci 1997;833:112-28.

77. Wu AH, Ziegler RG, Nomura AM, West DW, Kolonel LN, Horn-Ross PL, et al. Soy intake and risk of breast cancer in Asians and Asian Americans. Am J Clin Nutr 1998;68(6 suppl):1437S43S.

78. Ingram D, Sanders K, Kolybaba M, Lopez D. Case-control study of phyto- oestrogens and breast cancer. Lancet 1997;350:990-4.

79. Bernstein L, Henderson BE, Hanisch R, Sullivan Halley J, Ross RK. Physical exercise and reduced risk of breast cancer in young women. J Nat1 Cancer Inst 1994;86: 1403-8.

80. Thune I, Brenn T, Lund E, Gaard M. Physical activity and the risk of breast cancer. N Engl J Med 1997;336:1269-75.

8 1. Huang Z, Hankinson SE, Colditz GA, Stampfer MJ, Hunter DJ, Manson JE, et al. Dual effects of weight and weight gain on breast cancer risk. JAMA 1997;278:1407-11.

82. Ambrosone CB, Freudenheim JL, Graham S, Marshall JR, Vena JE, Brasure JR, et al. Cigarette smoking, N-acetyltransferase 2 genetic polymorphisms, and breast cancer risk. JAMA 1996;276: 1494-501.

83. Hoyer AP, Grandjean P, Jorgensen T, Brock JW, Hartvig HB. Organochlorine exposure and risk of breast cancer. Lancet 1998;352:1816-20.

84. Morrow M. Physical examination of the breast. In: Harris JR, Lippman ME, Morrow M, Hellman S, editors. Diseases of the breast. Philadelphia: Lippincott- Raven; 1996. p. 67-70.

85. Cady B, Steele GD Jr, Morrow M, Gardner B, Smith BL, Lee NC, et al. Evaluation of common breast problems: guidance for primary care providers. CA Cancer J Clin 1998;48:49-63.

86. Feig SA. Role and evaluation of mammography and other imaging methods for breast cancer detection, diagnosis, and staging. Semin Nucl Med 1999;29:3-15.

87. Hendrick RE, Smith RA, Rutledge JH 3rd, Smart CR. Benefit of screening


88.

89.

90.

91.

92.

93.

94.

95.

96.

97.

98.

99. 100.

101.

102.

103.

104.

105.

mammography in women aged 40-49: a new meta-analysis of randomized controlled trials. J Nat1 Cancer Inst Monogr 1997;22:87-92. Screening for breast cancer. In: Kopans DB, editor. Breast imaging. Philadelphia: Lippincott-Raven; 1998. p. 55-99. Anderson I, Janzon L. Reduced breast cancer mortality in women under age 50: updated results from the Malmo Mammographic Screening Program. J Nat1 Cancer Inst Monogr 1997;22:63-7. Game JP, Aspegren K, Balldin G, Ranstam J. Increasing incidence of and declining mortality from breast carcinoma. Trends in Malmo, Sweden, 1961- 1992. Cancer 1997;79:69-74. Sickles EA. Screening for breast cancer with mammography. Clin Imaging 1991;15:253-60. Sickles EA. Breast cancer screening outcome in ages 40-49: clinical experience with service screening using modem mammography. J Nat1 Cancer Inst Monogr 1997;22:99-104. Tabar L, Duffy SW, Chen HH. Re: quantitative interpretation of age-specific mortality reductions from Swedish Breast Cancer-Screening Trials. J Nat1 Cancer Inst 1996;88:52-5. Larsson LG, Andersson I, Bjurstam N, Fagerberg G, Frisell J, Tabar L, et al. Updated overview of the Swedith Randomized Trials on Breast Cancer Screening with Mammography: age group 40-49 at randomization. J Nat1 Cancer Inst Monogr 1997;22:57-61. Smart CR. Highlights of the evidence of benefit for women aged 40-49 years from the 1Cyear follow-up of the Breast Cancer Detection Demonstration Project. Cancer 1994;74 (1 Suppl):296-300. McPherson CP, Swenson KK, Jolitz G, Murray CL. Survival of women ages 40- 49 years with breast carcinoma according to method of detection. Cancer 1997;79: 1923-32. Leitch M, Dodd CD, Costanza M, Linver M, Pressman P, McGinnis L, et al. American Cancer Society guidelines for the early detection of breast cancer: update 1997. CA Cancer J Clin 1997;47:150-3. Feig SA, D’Orsi C, Hendrick RE, Jackson VP, Kopan DB, Monsees B, et al. American College of Radiology guidelines for breast cancer screening. AJR Am J Roentgen01 1998;171:29-33. Dershaw DD. Questions and answers. AJR Am J Roentgen01 1999; 172: 1136-7. Hoskins KF, Stopfer JE, Calzone KA, Merajver SD, Rebbeck TR, Garber JE, et al. Assessment and counseling for women with a family history of breast cancer. A guide for clinicians. JAMA 1995;273:577-85. Baker LH. Breast Cancer Detection Demonstration Project: five-year summary report. CA Cancer J Clin 1982;32:194-225. Suleiman OH, Spelic DC, McCrohan JL, Symonds GR, Houn F. Mammography in the 1990s: the United States and Canada. Radiology 1999;210:345-5 1. Houn F, Elliott ML, McCrohan JL. The Mammography Quality Standards Act of 1992. History and philosophy. Radio1 Clin North Am 1995;33: 1059-65. Kopans DB, editor. Mammographic positioning. In: Breast imaging. Philadelphia: Lippincott-Raven; 1998. p. 17 l-209. Smith R, Osuch JR, Linver MN. A national breast cancer database. Radio1 Clin North Am 1995;33:1247-57.


106. Kopans DB, editor. Analyzing the mammogram. In: Breast imaging. Philadelphia: Lippincott-Raven; 1998. p. 247-350.

107. Dorsi CJ. Use of the American College of Radiology Breast Imaging and Data Sys- tem. In: Kopans DB, Menelson EB, editors. Syllabus: a categorical course in breast imaging. Oak Brook (IL): Radiological Society of North Amercia 1995. p. 77-80.

108. Evans WP. Breast masses. Appropriate evaluation. Radio1 Clin North Am 1995;33:1085-108.

109. Jackson VP, Reynolds HE, Hawes DR. Sonography of the breast. Semin Ultrasound CT MR 1996;17:460-7.5.

110. Venta LA, Dudiak CM, Salomon CG, Flisak ME. Sonographic evaluation of the breast. Radiographics 1994;14:29-50.

111. Stavros AT, Thickman D, Rapp CL, Dennis MA, Parker SH, Sisney GA. Solid breast nodules: use of sonography to distinguish between benign and malignant lesions. Radiology 1995;196:123-34.

112. Stavros AT. Sonography of solid breast nodules: benign or malignant. In: Park S, course director. Course syllabus: breast imaging and intervention into the 21st century. Denver (CO): Radiology Imaging Association and Sally Jobe Breast Centre; 1998. p. 4-14-16.

113. Harms SE. Breast magnetic resonance imaging. Semin Ultrasound CT MR 1998;19:104-20.

114. Soderstrom CE, Harms SE, Copit DS, Evans WP, Savino DA, Krakos PA, et al. Three-dimensional RODEO breast MR imaging of lesions containing ductal carcinoma in situ. Radiology 1996;201:427-32.

115. Ore1 SG. High-resolution MR imaging for detection, diagnosis, and staging of breast cancer. Radiographics 1998;18:903-12.

116. Taillefer R. The role of 99mTc-sestamibi and other conventional radiophatmaceu- ticals in breast cancer diagnosis. Semin Nucl Med 1999;29: 16-40.

117. Williams MB, Pisano ED, Schnall MD, Fajardo LL. Future directions in imaging of breast diseases. Radiology 1998;206:297-300.

118. Osuch JR. Abnormalities on physical exam. In: Harris JR, Lippman ME, Morrow M, Hellman S, editors. Diseases of the breast. Philadelphia: Lippincott-Raven; 1996. p. 110-4.

119. Morris A, Pommier RF, Schmidt WA, Shih RL, Alexander PW, Vetto JT. Accurate evaluation of palpable breast masses by the triple test score. Arch Surg 1998;133:930-4.

120. Foster RS. Techniques for diagnosis of palpable breast masses. In: Harris JR, Lippman ME, Morrow M, Helhnan S, editors. Diseases of the breast. Philadelphia: Lippincott-Raven; 1996. p. 133-5.

121. Costa MJ, Tadros T, Hilton G, Birdsong G. Breast fine needle aspiration cytology. Utility as a screening tool for clinically palpable lesions. Acta Cytol 1993;37:461-71.

122. Willis SL, Ramzy I. Analysis of false results in a series of 835 fine needle aspi- rates of breast lesions. Acta Cytol 1995;39:858-64.

123. O’Neil S, Castelli M, Gattuso P, Kluskens L, Madsen K, Aranha G. Fine needle aspiration of 697 palpable breast lesions with histopathologic correlation. Surgery 1997;122:824-8.

124. Rubin M, Horiuchi K, Joy N, Haun W, Read R, Ratzer E, et al. Use of fine needle aspiration for solid breast lesions is accurate and cost-effective. Am J Surg 1997;174:694-8.

125. NIH Consensus Development Conference. The uniform approach to breast fine- needle aspiration biopsy. Am J Surg 1997; 174:37 I-86.


126.

127.

128.

129.

130.

131. 132.

133.

134.

135.

136.

137.

138.

139.

140.

141.

142.

143.

144.

Jackson VP. Needle localization to guide excisional biopsy. In: Kopans DB, Mendelson EB, editors. Syllabus: a categorical course in breast imaging. Oak Brook (IL): Radiological Society of North America; 1995. p. 161-6. Parker SH, Jobe WE, Dennis MA, Stavros AT, Johnson KK, Yakes WF. US-guided automated large-core breast biopsy. Radiology 1993;187:507-11. Liberman L, Feng TL, Dershaw DD, Morris EA, Abramson AF. US-guided core breast biopsy: use and cost-effectiveness. Radiology 1998;208:717-23. Parker SH, Burbank F, Jackman RJ, Aucreman CJ, Cardenosa G, Cink TM, et al. Percutaneous large-core breast biopsy: a multi-institutional study. Radiology 1994;193:359-64. Jackman RJ, Nowels KW, Rodriguez-Sot0 J, Marzoni FA Jr, Finkelstein SI, Shepard MJ. Stereotactic, automated, large-core needle biopsy of nonpalpable breast lesions: false-negative and histologic underestimation rates after long-term follow-up. Radiology 1999;210:799-805. Bernstein JR. Role of stereotactic breast biopsy. Semin Surg Oncol 1996;12:290-9. Burbank E Stereotactic breast biopsy: comparison of 14- and 1 l-gauge Mammotome probe performance and complication rates. Am Surg 1997;63:988-95. Liberman L, Smolkin JH, Dershaw DD, Morris EA, Abramson AF, Rosen Pl? Calcification retrieval at stereotactic, 1 l-gauge, directional, vacuum-assisted breast biopsy. Radiology 1998;208:25 l-60. DuPont WD, Page DL. Risk factors for breast cancer in women with proliferative breast disease. N Engl J Med 1985;312:146-51. Page DL, DuPont WD, Rogers LW, Rados MS. Atypical hyperplastic lesions of the female breast. A long-term follow-up study. Cancer 1985;55:2698-708. Page DL, Rogers LW. Combined histologic and cytologic criteria for the diagnosis of mammary atypical ductal hyperplasia. Hum Path01 1992;23:1095-7. London SJ, Connolly JL, Schnitt SJ, Colditz GA. A prospective study of benign breast disease and the risk of breast cancer. JAMA 1992;267:941-4. Palli D, Rosselli de1 Turco MR, Simoncini R, Bianchi S. Benign breast disease and breast cancer: a case-control study in a cohort in Italy. Int J Cancer 1991;47:703-6. American Joint Committee on Cancer. AJCC cancer staging manual. 5th ed. Philadelphia (PA): Lippincott-Raven; 1998. Fisher B, Montague E, Redmond C, Barton B, Borland D, Fisher ER, et al. Comparison of radical mastectomy with alternative treatments for primary breast cancer. A first report of results from a prospective randomized clinical trial. Cancer 1977;39:2827-39. Fisher B, Bauer M, Margolese R, Poisson R, Pilch Y, Redmond C, et al. Five-year results of a randomized clinical trial comparing total mastectomy and segmental mastectomy with or without radiation in the treatment of breast cancer. N Engl J Med 1985;312:665-73. Fisher B, Anerson S, Redmond C, Wolmark N, Wickerham DL, Cronin WM. Reanalysis and results after 12 years of follow-up in a randomized clinical trial comparing total mastectomy with lumpectomy with or without irradiation in the treatment of breast cancer. N Engl J Med 1995;333:1456-61. Sarrazin D, Le MG, Arriagada R, Contesso G, Fontaine F, Spielmann M, et al. Ten-year results of a randomized trial comparing a conservative treatment to mastectomy in early breast cancer. Radiother Oncol 1989;14: 177-84. Veronesi U, Banfi A, Salvadori B, Luini A, Saccozzi R, Zucali R, et al. Breast


145.

146.

147.

148.

149.

150.

151.

152.

153.

154.

155.

156.

157.

158.

159.

160.

conservation is the treatment of choice in small breast cancer: long-term results of a randomized trial. Eur J Cancer 1990;26:668-70. Lichter AS, Lippman ME, Danforth DN Jr, d’ Angelo T, Steinberg SM, de Moss E, et al. Mastectomy versus breast conserving therapy in the treatment of stage I and II carcinoma of the breast: a randomized trial at the National Cancer Institute. J Clin Oncol 1992;10:976-83. van Dongen JA, Bartelink H, Fentiman IS, Lerut T, Mignolet F, Olthuis G, et al. Randomized clinical trial to assess the value of breast-conserving therapy in stage I and II breast cancer, EORTC 10801 trial. J Natl Cancer Inst Monogr 1992;11:15-8. Blichert-Toft M, Rose C, Andersen JA, Overgaard M, Axelsson CK, Andersen KW, et al. Danish randomized trial comparing breast conservation therapy with mastectomy: six years of life-table analysis. Danish Breast Cancer Cooperative Group. J Nat1 Cancer Inst Monogr 1992;ll: 19-25. NIH Consensus Conference. Treatment of early stage breast cancer. JAMA 1991;265:391-5. Recht A, Pierce SM, Abner A, Vicini F, Osteen RT, Love SM, et al. Regional nodal failure after conservative surgery and radiotherapy for early-stage breast carcinoma. J Clin Oncol 1991;9:988-96. Morton DL, Wen DR, Wong JH, Economou JS, Cagle LA, Storm FK, et al. Technical details of intraoperative lymphatic mapping for early stage melanoma. Arch Surg 1992;127:392-9. Giuliano AE, Kirgan DM, Guenther JM, Morton DL. Lymphatic mapping and sentinel lymphadenectomy for breast cancer. Ann Surg 1994;220:391-401. Veronesi U, Paganelli G, Galimberti V, Viale G, Zurrida S, Bedoni M, et al. Sentinel-node biopsy to avoid axillary dissection in breast cancer with clinically negative lymph-nodes. Lancet 1997;349: 1864-7. Veronesi U, Paganelli G, Viale G, Galimberti V, Luini A, Zunida S, et al. Sentinel node biopsy and axillary node dissection: results in a large series. J Natl Cancer Inst 1999;91:368-73. Winchester DJ, Sener SF, Winchester DP, Perlman RM, Goldschmit RA, Motykie G, et al. Sentinel lymphadenectomy for breast cancer: experience with 180 consec- utive patients: efficacy of filtered technetium 99m sulphur colloid with overnight migration time. J Am Co11 Surg 1999;188:597-603. Krag D, Weaver D, Ashikaga T, Moffat F, Klimberg VS, Shriver C, et al. The sentinel node in breast cancer-a multicenter validaton study. N Engl J Med 1998;339:941-6. O’Hea BJ, Hill AD, El-Shirbiny AM, Yeh SD, Rosen PP, Coit DG, et al. Sentinel lymph node biopsy in breast cancer: initial experience at Memorial Sloan-Kettering Cancer Center. J Am Co11 Surg 1998;186:423-7. Early Breast Cancer Trialists’ Collaborative Group. Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy. 133 randomised trials involving 31,000 recurrences and 24,000 deaths among 75,000 women. Lancet 1992;339:1-15. Early Breast Cancer Trialists’ Collaborative Group. Effects of adjuvant tamoxifen and of cytotoxic therapy on mortality in early breast cancer. An overview of 61 randomized trials among 28,896 women. N Engl J Med 1988;3 19: 168 l-92. Bines J, Oleske DM, Cobleigh MA. Gvarian function in pmmenopausal women treated with adjuvant chemotherapy for breast cancer. J Clin Gncol1996;14: 1718-29. Fisher B, Dignam J, Bryant J, DeCillis A, Wickerham DL, Wolmark N, et al. Five

402 DM. September 1999

161. Stewart HJ, Forrest AP, Ever&ton D, McDonald CC, Dewar JA, Hawkins RA, et al. Random&d comparison of 5 years of adjuvant tamoxifen with continuous therapy for operable breast cancer. The Scottish Cancer Trials Breast Group. Br J Cancer 1996;74:297-9.

162. Tellez C, Jordan VC. Hormonal treatment of advanced breast cancer. Surg Oncol Clin N Am 1995;4:751-77.

163. Early Breast Cancer Trial&s’ Collaborative Group. Effects of radiotherapy and surgery in early breast cancer. An overview of the randomized trials. N Engl J Med 1995;333:1444-55.

164.

165.

166.

167.

168.

Overgaard M, Hansen PS, Overgaard J, Rose C, Andersson M, Bach F, et al. Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy. Danish Breast Cancer Cooperative Group. N Engl J Med 1997;337:949-55. Ragaz J, Jackson SM, Le N, Plenderleith IH, Spinelli JJ, Basco VE, et al. Adjuvant radiotherapy and chemotherapy in node-positive premenopausal women with breast cancer. N Engl J Med 1997;337:956-62. Wingo PA, Tong T, Bolden S. Cancer statistics, 1995. CA Cancer J Clin 1995;45:8-30.

169.

170.

171.

Haagensen C, Stout A. Carcinoma of the breast. II: Criteria of operability. Ann Surg 1943;118:859-70. Schottenfeld D, Nash AG, Robbins GF, Beattie EJ Jr. Ten-year results of the treatment of primary operable breast carcinoma: a summary of 304 patients evaluated by the TNM system. Cancer 1976;38:1001-7. Arnold DJ, Lesnick GJ. Survival following mastectomy for stage III breast cancer. Am J Surg 1979;137:362-6. Rubens RD, Armitage P, Winter PJ, Tong D, Hayward JL. Prognosis in inoperable stage III carcinoma of the breast. Eur J Cancer 1977;13:805-11. Harris JR, Sawicka J, Gelman R, Hellman S. Management of locally advanced carcinoma of the breast by primary radiation therapy. Int J Radiat 0~01 Biol Phys 1983;9:345-9.

172.

173.

Rao DV, Bedwinek J, Perez C, Lee J, Fineberg B. Prognostic indicators in stage III and localized stage IV breast cancer. Cancer 1982;50:2037-43. DeLena M, Zucali R, Viganotti G, Valagussa P, Bonadonna G. Combined chemotherapy-radiotherapy approach in locally advanced (T3b-T4) breast cancer. Cancer Chemother Pharmacol 1978;1:53-9.

174.

175.

176.

Hortobagyi GN, Singletary SE, McNeese MD. Treatment of locally advanced and inflammatory breast cancer. In: Harris JR, Lippman ME, Morrow M, Hellman S, editors. Diseases of the breast. Philadelphia: Lippincott-Raven; 1996. p. 585-99. Mauriac L, Durand M, Avril A, Dilhuydy JM. Effects of primary chemotherapy in conservative treatment of breast cancer patients with operable tumors larger than 3 cm. Results of a randomized trial in a single centre. Ann Oncol 1991;2:347-54. Scholl SM, Forquet A, Asselain B, Pierga JY, Vilcoq JR, Durand JC, et al. Neoadjuvant versus adjuvant chemotherapy in premenopausal patients with tumors considered too large for breast conserving surgery: preliminary results of a randomized trial: S6. Eur J Cancer 1994;3OA:645-52.

177. Powles TJ, Hickish TF, M&is A, Ashley SE, O’Brien ME, Tidy VA, et al.

versus more than five years of tamoxifen therapy for breast cancer patients with negative lymph nodes and estrogen receptor-positive tumors. J Natl Cancer Inst 1996;88: 1529-42.


178.

179.

180.

181.

182.

183.

184.

185.

186.

187.

188.

189.

190.

Randomized trial of chemoendocrine therapy started before or after surgery for treatment of primary breast cancer. J Clin Oncol; 1995;13:547-52. Fisher B, Bryant J, Wolmark N, Mamounas E, Brown A, Fisher ER, et al. Effect of preoperative chemotherapy on the outcome of women with operable breast cancer. J Clin Oncol 1998;16:2672-85. Single&try SE, McNeese MD, Hortobagyi GN. Feasibility of breast-conservation surgery after induction chemotherapy for locally advanced breast carcinoma. Cancer 1992;69:2849-52. Veronesi U, Bonadonna G, Zurrida S, Galimberti V, Greco M, Brambilla C, et al. Conservation surgery after primary chemotherapy in large carcinomas of the breast. Ann Surg 1995;222:612-8. Merajver SD, Weber BL, Cody R, Zhang D, Strawderman M, Calzone KA, et al. Breast conservation and prolonged chemotherapy for locally advanced breast cancer: the University of Michigan experience. J Clin Oncol 1997;15:2873-81. Kuerer HM, Newman LA, Smith TL, Ames FC, Hunt KK, Dhingra K, et al. Clinical course of breast cancer patients with complete pathologic primary tumor and axillary lymph node response to doxorubicin-based neoadjuvant chemotherapy. J Clin Oncol 1999;17:460-9. Colozza M, Gori S, Mosconi AM, Anastasi P, de Angelis V, Giansanti M, et al. Induction chemotherapy with cisplatin, doxorubicin, and cyclophosphamide (CAP) in a combined modality approach for locally advanced and inflammatory breast cancer. Long-term results. Am J Clin Oncol 1996;19: 10-7. Valagussa P, Zambetti M, Bignami P, de Lena M, Varini M, Zucali R, et al. T3b- T4 breast cancer: factors affecting results in combined modality treatments. Clin Exp Metastasis 1983;1:191-202. Buzdar AU, Singletary SE, Booser DJ, Frye DK, Wasaff B, Hortobagyi GN. Combined modality treatment of stage III and inflammatory breast cancer. M.D. Anderson Cancer Center experience. Surg Oncol Clin N Am 1995;4:715-34. Perez JE, Machiavelli M, Leone BA, Romero A, Rabinovich MG, Vallejo CT, et al. Bone-only versus visceral-only metastatic pattern in breast cancer: analysis of 150 patients. A GOCS Study. Grupo Oncologico Cooperativo de1 Sur. Am J Clin Oncol 1990;13:294-8. Leone BA, Romero A, Rabinovich MG, Vallejo CT, Bianco A, Perez JE, et al. Stage IV breast cancer: clinical course and survival of patients with osseous versus extraosseous metastases at initial diagnosis. The GOCS (Grupo Oncologico Cooperative de1 Sur) experience. Am J Clin Oncol 1988;11:618-22. Cobleigh MA, Vogel CL, Tripathy D, Robert NJ, Scholl S, Fehrenbacher L, et al. Efficacy and safety of herceptin (humanized anti-HER2 antibody) as a single agent in 222 women with HER2 overexpression who relapsed following chemotherapy for metastatic breast cancer. In: Proceedings of the American Society of Clinical Oncology, Vol. 17; 1998. Abstract 376. Slamon D, Leyland-Jones B, Shak S, Paton V, Bajamonda A, Fleming T, et al. Addition of hetceptin (humanized anti-HER2 antibody) to first line chemotherapy for HER2 over expressing metastatic breast cancer (HER2+/MBC) markedly increases anticancer activity: a randomized multinational controlled phase III trial. In: Proceedings of the American Society of Clinical Oncology, Vol. 17; 1998. Abstract 377. Norton L, Slamon D, Leyland-Jones B, Wolter J, Fleming T, Eiiann W, et al. Overall survival (OS) advantage to simultaneous chemotherapy plus the human-


ized anti-HER2 monoclonal antibody herceptin (H) in HER2-over expressing (HER2+) metastatic breast cancer (MBC). In: Proceedings of the American Society of Clinical Oncology, Vol. 18; 1999. Abstract 483.

19 1. Spiegel D, Bloom JR, Kraemer HC, Gottheil E. Effect of psychosocial treatment on survival of patients with metastatic breast cancer. Lancet 1989;2:888-91.

192. Simon MS, Hoff M, Hussein M, Martin0 S, Walt A. An evaluation of clinical follow- up in women with early stage breast cancer among physician members of the American Society of Clinical Oncology. Breast Cancer Res Treat 1993;27:211-9.

193. Richert-Boe KE. Heterogeneity of cancer surveillance practices among medical oncologists in Washington and Oregon. Cancer 1995;75:2605-12.

194. Hayes DF, Kaplan W. Evaluation of patients after primary therapy. In: Harris JR, Lippman ME, Morrow, Hellman S, editors. Diseases of the breast. Philadelphia: Lippincott-Raven; 1996. p. 629-48.

195. Rosselli Del Turco M, Palli D, Cariddi A, Ciatto S, Pacini P, Distante V. Intensive diagnostic follow-up after treatment of primary breast cancer. A randomized trial. National Research Council Project on Breast Cancer follow-up. JAMA 1994;271:1593-7.

196. The GIVIO Investigators. Impact of follow-up testing on survival and health- related quality of life in breast cancer patients. A multicenter randomized controlled trial. JAMA 1994;271:1587-92.


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Breast cancer screening, diagnosis, and treatment