E D I T O R I A L

See referenced original article on pages 429–38,this issue.

Address for reprints: Monica Morrow, M.D., De-partment of Surgery, Lynn Sage Breast Center,Northwestern University Medical School, 333 E.Superior Street, Suite 250 Chicago, IL 60611.

Received April 26, 1999; accepted April 30, 1999.

Understanding Ductal CarcinomaIn SituA Step in the Right Direction

Monica Morrow, M.D.

Department of Surgery, Lynn Sage Breast Center, Northwestern University Medical School,Chicago, Illinois.

Ideally, the intensity of cancer treatment is tailored to an individualpatient’s risk for recurrence. In women with intraductal carcinoma

(ductal carcinoma in situ, DCIS), the major risk is the development ofan invasive carcinoma in the breast. The debate over the use of breastirradiation (RT) in the treatment of patients with DCIS is a reflectionof our inability to answer the question, “Which DCIS will becomeinvasive carcinoma during a woman’s lifetime?”

Attempts to answer this question have been confounded by thefact that, until the 1980s, DCIS was a relatively rare lesion and themajority of patients were treated by mastectomy, providing littleopportunity to understand the natural history of the disease. Morerecently, we have come to recognize that DCIS is actually a hetero-geneous group of lesions rather than a single entity. Much attentionhas been devoted to developing morphologic classifications of DCISthat will distinguish “high risk” from “low risk” DCIS and potentiallyprovide guidance in the selection of treatment. A prospective dem-onstration that any of the growing number of DCIS classificationschema are useful in predicting the behavior of DCIS is currentlylacking. In this vacuum, the results of the updated pathologic analysisof the National Surgical Adjuvant Breast and Bowel Project (NSABP)B-17 trial published in this issue of Cancer1 are particularly welcome.

The B-17 trial was designed to determine whether the addition ofRT after excision with negative margins was beneficial in maintaininglocal control and extending survival in patients with DCIS.2,3 Althoughit is generally accepted that the gold standard of clinical research isthe large-scale clinical trial,4 the results of the B-17 trial have beensubjected to a variety of criticisms.5 These primarily relate to the factthat the detailed mammographic and pathologic evaluations whichtoday are regarded as part of the optimal management of DCIS werenot in use in 1985, when accrual of patients for this study began. Inspite of these limitations, the NSABP B-17 data base represents thelargest group of prospectively evaluated, randomized patients under-going uniform treatment, and for this reason it is important to un-derstand what it can and cannot tell us about the risk of invasivecarcinoma after the treatment of patients with DCIS with a breast-conserving approach.

One of the major findings of this study is that none of thecharacteristics of the original DCIS lesion predict which patients will

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develop an invasive breast recurrence and which willhave a recurrence of DCIS. Smaller, retrospectivestudies have suggested that low grade DCIS lesions arelikely to recur as more DCIS or Grade 1 invasive car-cinoma, whereas high grade lesions recur as Grade 2or 3 invasive carcinoma.6,7 Based on the findings ofthe NSABP study, local recurrence after the therapy ofany grade of DCIS must be considered to have thepotential to be an invasive recurrence with a small butreal risk of breast carcinoma mortality.

Of the nine pathologic features analyzed in theNSABP report, only the presence of moderate-to-marked comedo necrosis was found to be a significantpredictor of disease recurrence in the breast for bothirradiated and nonirradiated patients. For patientswith moderate or marked comedo necrosis, RT re-duced the 8-year risk of recurrence in the breast from40% to 14% (relative risk, 0.30), whereas for patientswith absent or slight comedo necrosis, recurrencerates fell from 23% to 13% (relative risk, 0.52). This isclinically useful information because there is goodagreement among pathologists regarding the presenceor absence of comedo necrosis,8 suggesting that theseresults can be duplicated in a variety of clinical set-tings. Somewhat surprisingly, margin status was notfound to correlate with the risk of breast recurrence, adirect contradiction of the earlier findings of thisstudy9 and many nonrandomized studies.10 –13 Al-though the authors suggest that this may be due to thepredominance of early recurrences in their study, Ithink it is more likely due to the lack of accuratesegregation of patients with clear and involved mar-gins. The NSABP definition of a clear margin was onein which tumor-filled ducts did not touch an inkedsurface. Some specimens were not inked, making anassessment of margin status extremely difficult. Be-cause complete pathologic processing of the entirespecimen was not required and margin sampling var-ied, it is likely that some patients classified as havingnegative margins had DCIS on other unsampled mar-gin surfaces. In addition, the demonstration thatDCIS, particularly low or intermediate grade, growsdiscontinuously14 indicates that a significant amountof residual tumor may be present at a biopsy site evenwhen DCIS approaches but does not touch an inkedmargin. The use of postexcision mammography todocument removal of all suspicious calcifications isuseful in this circumstance, but it was not a require-ment of the NSABP study. For these reasons, I do notbelieve that we can confidently say that this studyindicates that clear margins are not necessary tomaintain low rates of local failure in DCIS. Furtherinformation on the relation between margin statusand local recurrence should be available from the

NSABP B-24 trial, in which DCIS patients with bothpositive and negative margins received RT and wererandomized to receive either tamoxifen or placebo.Until a detailed analysis of this study is published andrecurrence rates can be quantitated, excision of DCISto negative margins remains the prudent course.

Does the NSABP study definitively establish thatall women with DCIS treated with a breast-conservingapproach require RT? The answer to this question isno; but the study does provide valuable data to assistthe individual woman with DCIS in selecting a treat-ment that meets her personal definition of an accept-able level of risk. The B-17 study shows that for pa-tients with absent or slight comedo necrosis and freemargins, the addition of RT to lumpectomy results ina 7% absolute reduction in the rate of recurrence inthe breast at 8 years. Is this clinically meaningful?Intellectually, or from a cost-analysis standpoint, theanswer may be no. However, recurrence in thebreast, when invasive, carries with it an increased riskof death, the potential need for chemotherapy, andthe necessity of additional surgery. Even when a re-currence is more DCIS, it can be psychologically dev-astating. Studies have indicated that women withinvasive breast carcinoma would opt to receive che-motherapy for a 0.5% to 1% survival benefit.15 For thewoman who is averse to risk, radiation for “low risk”DCIS is a viable option.

The NSABP B-17 study provides useful informa-tion for counseling patients about treatment, butmany important questions about the management ofDCIS remain unanswered. The demonstration that ta-moxifen reduces the risk of invasive cancer develop-ment in women with DCIS has important therapeuticimplications.16 Is this effect observed only in estrogenreceptor positive DCIS? The majority of low gradeDCIS lesions express the estrogen receptor, but estro-gen receptor expression is seen in only approximately35% of high grade DCIS lesions. Can tamoxifen replaceRT for a subset of DCIS patients? If so, which strategyis less morbid, and which has the greatest long termbenefit? It is likely that the answers to these questionswill vary depending on the specific population of DCISpatients studied. Ultimately, our approach to DCISshould become much more individualized as we iden-tify molecular markers that differentiate lesions withthe propensity to grow in situ from those which willinvade and metastasize.

In the meantime, it is important to keep in mindthe final point emphasized in the B-17 trial: The risk ofbreast cancer death after a diagnosis of DCIS was only1.6% at 8 years. Having faced numerous terrifiedwomen over the years who were convinced that the“bad” characteristics of their DCIS (high grade,

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comedo necrosis, and large tumor size) doomed themto death from breast carcinoma, this point cannot beoveremphasized. The recent work in sentinel lymphnode biopsy has been expanded to patients with DCIS,with the somewhat alarming finding that 7% of DCISpatients have cytokeratin positive sentinel lymphnodes.16 Are these prognostically significant? Facedwith a large number of studies that indicate that thecause specific mortality for women with DCIS treatedwith local therapy alone is less than 5%,1,2,10 –13 theanswer is unclear. Enthusiasm for new technologyshould not be allowed to supersede 15 years of datawhich indicate that DCIS is almost always a localizedlesion. The patient with DCIS provides the clinicianwith an opportunity to understand the progression ofneoplastic changes in the breast. The NSABP B-17study is an important first step in this journey. It isnow time to move on, and reach a consensus regard-ing what future studies will allow us to define theappropriate intensity of therapy for the individualwoman with DCIS.

REFERENCES1. Fisher ER, Dignam J, Tan-Chiu E, Costantino J, Fisher B,

Paik S, et al. Pathologic findings from the National SurgicalAdjuvant Breast Project (NSABP) eight-year update of pro-tocol B-17: intraductal carcinoma. Cancer 1999;86:429 –38.

2. Fisher B, Costantino J, Redmond C, Fisher E, Margolese R,Dimitrov N, et al. Lumpectomy compared with lumpectomyand radiation therapy for the treatment of intraductal breastcancer. N Engl J Med 1993;328:1581– 6.

3. Fisher B, Dignam J, Wolmark N, Mamounas E, Costantino J,Poller W, et al. Lumpectomy and radiation therapy for thetreatment of intraductal breast cancer: findings from theNational Surgical Adjuvant Breast and Bowel Project B-17.J Clin Oncol 1998;16:441–52.

4. Gelman R. Techniques in the interpretation of clinical trials.In: Harris JR, Lippman ME, Morrow M, Hellman S. Diseasesof the breast. Philadelphia: Lippincott-Raven, 1996:986 –1005.

5. Page DL, Lagios MD. Pathologic analysis of the NationalSurgical Adjuvant Breast Project (NSABP) B-17 trial. Unan-swered questions remain unanswered considering currentconcepts of ductal carcinoma in situ. Cancer 1995;75:1219 –21.

6. Schwartz GF. Treatment of subclinical ductal carcinoma insitu by local excision and surveillance: a personal experi-ence. In: Silverstein MJ. Ductal carcinoma in situ of thebreast. Baltimore: Williams and Wilkins, 1997:353– 60.

7. Lampejo OT, Barnes DM, Smith P, Millis RR. Evaluation ofinfiltrating ductal carcinomas with a DCIS component: cor-relation of the histologic type of the in situ component withgrade of the infiltrating component. Semin Diagn Pathol1994;11:215–22.

8. Sloane JP, Ellman R, Anderson TJ, Brown CL, Coyne J, Dal-limore NS, et al. Consistency of histopathological reportingof breast lesions detected by screening: findings of the U.K.National External Quality Assessment (EQA) Scheme. Eur JCancer 1994;30A:1414 –9.

9. Fisher ER, Costantino J, Fisher B, Palekar AS, Redmond C,Mamounas E. Pathologic findings from the National Surgi-cal Adjuvant Breast Project (NSABP) Protocol B-17: intra-ductal carcinoma (ductal carcinoma in situ). Cancer 1995;75:1310 –9.

10. Silverstein MJ. Van Nuys experience by treatment. In: Sil-verstein MJ. Ductal carcinoma in situ of the breast. Balti-more: Williams and Wilkins, 1997:443–7.

11. Solin LJ, Kurtz J, Fourquet A, Amalric R, Recht A, BornsteinBA, et al. Fifteen year results of breast-conserving surgeryand definitive breast irradiation for the treatment of ductalcarcinoma in situ of the breast. J Clin Oncol 1996;14:754 – 63.

12. Ray GR, Adelson J, Hayhurst E, Marzoni A, Gregg D, BronkM, et al. Ductal carcinoma in situ of the breast: results oftreatment by conservative surgery and definitive irradiation.Int J Radiat Oncol Biol Phys 1993;28:105–11.

13. Sniege N, McNeese MD, Atkinson EN, Ames FC, Kemp B,Sahin A, et al. Ductal carcinoma in situ treated with lumpec-tomy and irradiation: histopathological analysis of 49 spec-imens with emphasis on risk factors and long term results.Hum Pathol 1995;26:642–9.

14. Faverly DRG, Burgers L, Bult P, Holland R. Three-dimen-sional imaging of mammary ductal carcinoma in situ: clin-ical implications. Semin Diagn Pathol 1994;11:193– 8.

15. Ravdin PM, Siminoff IA, Harvey JA. Survey of breast cancerpatients concerning their knowledge and expectations ofadjuvant therapy. J Clin Oncol 1998;16:515–21.

16. Wolmark N, Dignam J, Fisher B. The addition of tamoxifento lumpectomy and radiotherapy in the treatment of ductalcarcinoma in situ (DCIS): preliminary results of NSABP B24.Breast Cancer Res Treat 1998;50:227.

17. Cox CE, Haddad F, Bass S, Cox JM, Ku NN, Berman C, et al.Lymphatic mapping in the treatment of breast cancer. On-cology 1998;12:1283–98.

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