BREAST CANCERTREATMENT

BY DR. M. MAHER KHAWATMI

DIAGNOSIS OF BREAST CANCER

Diagnosis is usually made by excisional biopsy performed under local anesthesia. FNA cytology is highly accurate for cancer but requires formal histologic confirmation, because FNA usually cannot distinguish invasive from noninvasive (in situ) cancers. Invasive cancers have traversed the basement membrane of the originating duct or lobule and have metastatic potential.Noninvasive cancers have no metastatic potential to lymph nodes or distant sites and, therefore, do not warrant lymph node dissection.Tru-cut core biopsy may be considered a definitive diagnosis of cancer and is more accurate than FNA in

distinguishing invasive from noninvasive cancers .

If a cyst is aspirated and does not chronically recur, it is safe to assume that it is benign.If a cyst is aspirated and the palpable mass does not fully disappear, it needs to be evaluated further.Dark brown or black fluid may be old blood and should be sent for cytology. Cytologic examination of clear or straw-colored fluid does not need to be requested. Microcalcifications, the earliest mammographic findings of cancer, appear like clustered pinpoints. The shape, number, and tendency to group determine the likelihood of malignancy. Microcalcifications often but not always warrant biopsy.

Patients with mammographic lesions that have low probability for malignancy by radiographic criteria and appear unchanged from prior mammograms can be carefully observed by serial mammography.

A negative mammogram does not negate the need for biopsy of a palpable mass. Among the palpable masses, 15% are missed by mammography. In particular, invasive lobular carcinoma (in contrast to invasive ductal carcinoma) tends to grow in sheets rather than a rounded masses, inducing subtle mammographic changes until the cancer is fairly extensive.Mammography is important before and after breast conservation therapy (BCT). Women with highly dense or cystic breasts often have mammograms that defy accurate interpretation. Local cancer recurrence in such women is difficult to detect promptly. Mammography after BCT is most valuable for identifying additional cancers in the same or opposite breast.

STAGING OF BREAST CANCER

Histology consists of five different subtypes: infiltrating ductal (75% to 80%), infiltrating lobular (5% to 10%), medullary (5% to 7%), mucinous (3%), and tubular (1% to 2%). Stages correlate with likelihood of relapse and fatality. In general, stage I breast cancers are small cancers without axillary nodal metastases; stage II cancers are medium-sized cancers with or without axillary nodal metastases; stage III cancers are locally advanced cancers, usually with axillary nodal metastases; and stage IV cancers have already metastasized to distant sites.The 10-year survival rate after definitive treatment is 70-90% for stage I, 50-70% for stage II, and 20-50% for

stage III breast cancer patients .

1 .TNM CLASSIFICATION

Primary Tumor (T)

T0 No evidence of primary tumorTis Carcinoma in situT1 Tumor 2 cm or less in greatest dimensionT2 Tumor > 2 cm but not > 5 cm in greatest dimensionT3 Tumor > 5 cm in greatest dimensionT4 Tumor of any size with direct extension into chest wall (not including pectoral muscles) or skin edema (peau d ’orange) or skin ulceration or satellite skin nodules or

inflammatory carcinoma

Regional Lymph Node Involvement (N)

N0 No regional lymph node involvementN1 Metastasis to movable ipsilateral axillary lymph node(s)N2 Metastasis to ipsilateral axillary lymph node(s) fixed to one another or to other structuresN3 Metastasis to ipsilateral internal mammary lymph nodes

Distant Metastasis (M)

M0 No distant metastasisM1 Distant metastasis (including ipsilateral supraclavicular lymph nodes)

Stage 0TisN0M0

Stage IT1N0M0

Stage IIAT0-1T2

N1No

M0M0

Stage IIBT2T3

N1N0

M0M0

Stage IIIAT0-2T3

N2N1-2

M0M0

Stage IIIBT4Any T

N1-2N3

M0M0

Stage VIAny TAny NM1

2 .STAGE GROUPING

DIAGNOSTIC TESTS FOR IDENTIFYING DISTANT METASTASES

Stage IV cancers represent 5% of all initially diagnosed breast cancers. Metastatic studies, therefore, should be used selectively at first diagnosis. Breast cancers most commonly metastasize to bone, lung, liver, and brain.Screening for bone metastases begins with whole-body bone scanning. Lesions seen on bone scan are further studied by standard radiographic techniques to distinguish metastases from benign inflammatory conditions. Lung metastases are identified by chest radiograph or CT scan.Liver function tests (LFTs) are are neither specific nor sensitive to screen for liver metastases. Liver imaging studies (ultrasound or abdominal CT) are more reliable.Brain metastases are identified by CT or MRI scanning.

TREATMENT OF INVASIVE BREAST CANCER

1. Modjfied radical mastectomy

Removal of breast and dissection of axillary lymph nodes have survival benefit equivalent to radical mastectomy. The pectoralis minor muscle may be removed to facilitate dissection of level III axillary lymph nodes (Patey-procedure).Scanlon modified the procedure by dividing and not removing the pectoralis minor muscle. Auchincloss-procedure differs from Patey-procedure by not removing or dividing the pectoralis minor muscle.This modification limits the removal of level III axillary lymph nodes but is justified by Auchincloss, who calculated that only 2% of patients benefit by removal

of level III nodes.

2 .Breast conservation therapy (BCT) BCT includes lumpectomy with a margin of normal breast tissue, axillary dissection, and postoperative radiation. Contraindications to BCT include: (1) cancers that cannot be excised with negative margins without mastectomy, (2) cancers that are too large relative to the breast to obtain acceptable cosmetic results, (3) multicentric cancers, (4) breasts in which cancer recurrence would be difficult to identify by mammographic follow-up, and (5) patients who do not desire or who have contraindication to radiation

therapy (e.g., pregnancy) .

The National Surgical Adjuvant Breast Project B-06(NSABP B-06) is a multicentric study that randomized nearly 2000 women with stages I and II tumors (< 4 cm) to three treatment modalities: lumpectomy alone, lumpectomy with radiation, and mastectomy. All patients underwent axillary dissection, and patients with positive nodes received adjuvant chemotherapy. At least two significant conclusions were reached.1. Patients who underwent lumpectomy alone had lower rates of disease-free survival than patients who underwent lumpectomy with radiation. There was no difference in overall survival rates between the two groups, but radiation was of benefit in control of local tumor. 2. In patients who underwent lumpectomy (with or without radiation), there was no difference in disease-free survival or overall survival rates, indicating that BCT is effective.

Patients with noninvasive (in situ) or early invasive (stage I and selected stage II) breast cancers may be offered immediate reconstruction with either a myocutaneous flap or a breast implant. It is disadvantageous to perform immediate reconstruction in stage III cancers because:(1) the patient may require chest wall irradiation and (2) a subsequent chest wall recurrence becomes difficult to detect with an overlying flap.

3 .Management of the axilla

a. Sentinel lymph node biopsy (SLNB)

The sentinel lymph node is the first node in the ipsilateral axilla to drain the breast tumor. If the sentinel node is histologically negative, the patient is spared a complete axillary dissection.The sentinel node is located by injection of isosulfan blue (Lymphazurin) or technetium radiolabeled sulfur colloid. If blue dye is used, the node is located by meticulous dissection into the axilla until either a blue stained node or lymphatic afferent is located. If radiolabeled colloid is used, the node is located using a handheld gamma-detector.Although there is no consensus as to where the Although there is no consensus as to where the injectioninjection should be given, data suggest that should be given, data suggest that intratumoral should be avoided and that the best intratumoral should be avoided and that the best uptake is achieved with intradermal or subdermal uptake is achieved with intradermal or subdermal injectioninjection..

b. Axillab. Axillary lymph node dissection (ALND)lymph node dissection (ALND) Patients with clinically positive lymph nodes, or with Patients with clinically positive lymph nodes, or with positive SLNB (micrometastasis 0.2 mm or larger, not positive SLNB (micrometastasis 0.2 mm or larger, not isolated tumor cells) should undergo ALNDisolated tumor cells) should undergo ALND . .

ALND involves dissection of level I and level II nodes ALND involves dissection of level I and level II nodes and, if grossly involved , possibly level III nodesand, if grossly involved , possibly level III nodes . .

ALND should remove 10 or more nodes. Patients with 4 ALND should remove 10 or more nodes. Patients with 4 or more positive lymph nodes should undergo adjuvant or more positive lymph nodes should undergo adjuvant radiation to the axillaradiation to the axilla . .

Lymphedema occurs in 10% to 40% of women Lymphedema occurs in 10% to 40% of women undergoing ALND; radiation to the axilla increases the undergoing ALND; radiation to the axilla increases the risk. Blood draws, blood pressure cuffs, and intravenous risk. Blood draws, blood pressure cuffs, and intravenous lines should be avoided in the affected arm. Infections of lines should be avoided in the affected arm. Infections of the hand or arm should be treated promptly with the hand or arm should be treated promptly with antibiotics and arm elevation because infection can antibiotics and arm elevation because infection can damage lymphatics further and cause irreversible damage lymphatics further and cause irreversible lymphedemalymphedema..

Level I includes lymph nodes located lateral to the pectoralis minor muscle (PM); level II includes lymph nodes located deep to the PM; and level III includes lymph nodes located medial to the PM .

Level I includes (a) the axillary vein group (lateral), which consists of four to six nodes; (b) the external mammary group (anterior), which consists of five or six nodes; and (c) the scapular group (posterior or subscapular), which consists of five to seven nodes.Level II (the central group) consists of three or four nodes .

Level III (the subclavicular or apical group) consists of six to twelve nodes .

The interpectoral group (Rotter's nodes) consists of one to four nodes located between the pectoralis major and minor muscles .

Axillary lymph node groups. Level I includes lymph nodes located lateral to the pectoralis minor

muscle (PM); level II includes lymph nodes located deep to the PM; and level III includes lymph nodes located medial to the PM. Arrows

indicate the direction of lymph flow.

TREATMENT OF DUCTAL CARCINOMA IN SITU (DCIS)

Data from NSABP B-17 suggest that DCIS (also known as intraductal carcinoma) can be safely treated by BCT, provided that it can be excised with negative margins and that the remainder of the breast can be adequately evaluated and followed for development of subsequent malignancy.On the basis of Lagios’ report, a number of cancer centers no longer recommend the use of radiation after lumpectomy for cases of DCIC that are (1) nonpalpable (mammographically detected); (2) < 2.5 cm; (3) detected with negative margins; and (4) without comedo-type on histologic examination.Recent reports suggest that late local recurrence rates without radiation may exceed 25%.

TREATMENT OF LOBULAR CARCINOMA IN SITU (LCIS)

LCIS behaves differently from its ductal counterpart.LCIS may not invariably degenerate into invasive cancer, but women with LCIS have a 20-25% chance of developing ipsilateral or contralateral breast breast cancer during their lifetime; the cancer may be ductal or lobular.Most authorities suggest careful surveillance with serial mammography and physical examination. Bilateral mastectomy is extreme and tamoxifen is under

evaluation .

INOPERABLE BREAST CANCER

Inoperable breast cancer has advanced beyond the boundaries of surgical resection. The spread may be regional (involvement of internal mammary lymph nodes, stage lll B) or distant (distant metastases, stage IV). Supraclavicular lymph node metastases are staged as distant metastases.Primary therapy of such cancers is systemic treatment (chemotherapy or hormonal therapy) rather than surgery.Surgery combined with radiation becomes an adjuvant therapy for local control of disease after a good response

to systemic treatment.

NEOADJUVANT THERAPY FOR BREAST CANCER

Locally advanced but operable cancers (stage IIIA and some stage II) have a high likelihood of recurrence after surgery.Neoadjuvant therapy is induction of chemotherapy before surgery to decrease local tumor burden and to begin treatment of micrometastatic disease at the earliest possible time.If a cancer is so locally advanced that negative margins are unlikely to be obtainable even by mastectomy, neoadjuvant chemotherapy should be considered. In addition, neoadjuvant therapy may convert some cancers that would otherwise require mastectomy into potential candidates for BCT, although the safety of this

approach warrants careful scrutiny.

ANTIESTROGEN THERAPY

Within the cytosol of breast cancer cells are estrogen receptors that bind and transfer estrogen and progesterone into the cell nucleus to exert hormonal effects. Tamoxifen blocks estrogen receptors. Clinical responses are evident in > 60% of women with hormone receptor-positive, but in < 10% of women with hormone receptor-negative cancers. Bone pain, hot flushes, nausea, vomiting, and fluid retention may occur. Thrombotic events occur in < 3% of women.A rare long-term risk of tamoxifen use is endometrial cancer. Tamoxifen is discontinued after 5 years.Node-negative women with hormone receptor-positive cancers 1-3 cm in size are candidates for tamoxifen therapy, with or without chemotherapy. For node-positive women and women with cancers > 3 cm in size, tamoxifen, in addition to chemotherapy, is

appropriate.

ANTI-HER2/NEU ANTIBODY THERAPY The determination of HER2/neu expression for all breast cancer patients is recommended, because response rates appear to be better with Adriamycin-based chemotherapy in patients that overexpress HER2/neu.Patients that overexpress HER2/neu may benefit if anti-HER2/neu therapy (trastuzumab, Herceptin) is added to paclitaxel. Considerable cardiotoxicity may develop if trastuzumab is added to Adriamycin-based

chemotherapy .