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68 BREAST CANCER

68 BREAST CANCER
Harrison’s Manual of Medicine

68

BREAST CANCER

Incidence and Epidemiology
Genetics
Diagnosis
Staging
Bibliography

Incidence and Epidemiology
The most common tumor in women, 182,800 women in the U.S. are diagnosed and 40,000 die each year with breast cancer. Men also get breast cancer at a rate of 150:1. Breast cancer is hormone-dependent. Women with late menarche, early menopause, and first full-term pregnancy by age 18 have a significantly reduced risk. The average American woman has about a 1 in 9 lifetime risk of developing breast cancer. Dietary fat is controversial risk factor. Oral contraceptives have little, if any, effect on risk. Estrogen replacement therapy may slightly increase the risk, but the beneficial effects of estrogen on quality of life, bone mineral density, and decreased risk of cardiovascular mortality appear to far outweigh the risk. Women who received therapeutic radiation before age 30 are at increased risk. Breast cancer risk is increased when a sister and mother also had the disease.
Genetics
Perhaps 8–10% of breast cancer is familial. BRCA-1 mutations account for about 5%. BRCA-1 maps to chromosome 17q21 and appears to be involved in transcription-coupled DNA repair. Ashkenazi Jewish women have a 1% chance of having a common mutation (deletion of adenine and guanine at position 185). The BRCA-1 syndrome includes an increased risk of ovarian cancer in women and prostate cancer in men. BRCA-2 on chromosome 11 may account for 2– 3% of breast cancer. Mutations are associated with an increased risk of breast cancer in men and women. Germline mutations in p53 (Li-Fraumeni syndrome) are very rare, but breast cancer, sarcomas, and other malignancies occur in such families. Sporadic breast cancers show many genetic alterations including overexpression of HER-2/neu in 25% of cases, p53 mutations in 40%, and loss of heterozygosity at other loci.
Diagnosis
Breast cancer is usually diagnosed by biopsy of a nodule detected by mammogram or by palpation. Women should be strongly encouraged to examine their breasts monthly. In premenopausal women, questionable or nonsuspicious (small) masses should be reexamined in 2–4 weeks (Fig. 68-1). A mass in a premenopausal woman that persists throughout her cycle and any mass in a postmenopausal woman should be aspirated. If the mass is a cyst filled with non-bloody fluid that goes away with aspiration, the pt is returned to routine screening. If the cyst aspiration leaves a residual mass or reveals bloody fluid, the pt should have a mammogram and excisional biopsy. If the mass is solid, the pt should undergo a mammogram and excisional biopsy. Screening mammograms performed every other year beginning at age 50 have been shown to save lives. The controversy regarding screening mammograms beginning at age 40 relates to the following facts: (1) the disease is much less common in the 40- to 49-year age group; screening is generally less successful for less common problems; (2) workup of mammographic abnormalities in the 40- to 49-year age group less commonly diagnoses cancer; and (3) about 35% of women who are screened annually during their forties have an abnormality at some point that requires a diagnostic procedure (usually a biopsy); yet very few evaluations reveal cancer. However, many believe in the value of screening mammography beginning at age 40. After 13–15 years of follow-up, women who start screening at age 40 have a small survival benefit.

FIGURE 68-1. Approach to a palpable breast mass.

Staging
Therapy and prognosis are dictated by stage of disease (Table 68-1). Unless the breast mass is large or fixed to the chest wall, staging of the ipsilateral axilla is performed at the time of lumpectomy (see below). Within pts of a given stage, individual characteristics of the tumor may influence prognosis: expression of estrogen receptor improves prognosis, while overexpression of HER-1/neu, mutations in p53, high growth fraction, and aneuploidy worsen the prognosis. Breast cancer can spread almost anywhere but commonly goes to bone, lungs, liver, soft tissue, and brain.

Table 68-1 Staging of Breast Cancer

TREATMENT
Five-year survival rate by stage is shown in Table 68-2. Treatment varies with stage of disease.

Table 68-2 5-Year Survival Rate for Breast Cancer by Stage

Ductal carcinoma in situ is noninvasive tumor present in the breast ducts. Treatment of choice is wide excision with breast radiation therapy. In one study, adjuvant tamoxifen further reduced the risk of recurrence.
Invasive breast cancer can be classified as operable, locally advanced, and metastatic. In operable breast cancer, outcome of primary therapy is the same with modified radical mastectomy or lumpectomy followed by breast radiation therapy. Axillary dissection may be replaced with sentinel node biopsy to evaluate node involvement. The sentinel node is identified by injecting a dye in the tumor site at surgery; the first node in which dye appears is the sentinel node. Women with tumors <1 cm and negative axillary nodes require no additional therapy beyond their primary lumpectomy and breast radiation. Adjuvant combination chemotherapy for 6 months appears to benefit premenopausal women with positive lymph nodes, pre- and postmenopausal women with negative lymph nodes but with large tumors or poor prognostic features, and postmenopausal women with positive lymph nodes whose tumors do not express estrogen receptors. Estrogen receptor–positive tumors >1 cm with or without involvement of lymph nodes are treated with tamoxifen; one study suggests chemotherapy plus tamoxifen may be superior. Various regimens have been used. In women with up to three positive nodes, CMF (cyclophosphamide, 100 mg/m2; PO days 1–14 or 600 mg/m2; IV days 1 and 8; methotrexate, 40 mg/m2; IV days 1 and 8; 5-fluorouracil, 600 mg/m2; IV days 1 and 8) or CAF (cyclophosphamide, 500 mg/m2; IV days 1 and 8; doxorubicin, 50 mg/m2; IV days 1 and 8; 5-fluorouracil, 500 mg/m2; IV days 1 and 8) are commonly given for six cycles. Women with 4–10 positive nodes may benefit from doxorubicin, 75 mg/m2; IV q21d × 4 followed by CMF (same doses as above given on day 1 only, not days 1 and 8; cycles repeated q21d × 6). Tamoxifen adjuvant therapy (20 mg/d for 5 years) is used for pre- or postmenopausal women with tumors expressing estrogen receptors whose nodes are positive or whose nodes are negative but with large tumors or poor prognostic features. Breast cancer will recur in about half of pts with localized disease.
Pts with locally advanced breast cancer benefit from neoadjuvant chemotherapy that includes an anthracycline (CAF) followed by surgery plus breast radiation therapy.
Treatment for metastatic disease depends upon estrogen receptor status and treatment philosophy. No therapy is known to cure pts with metastatic disease, but many pts receive high-dose therapy with autologous stem cell transplantation, some of whom have excellent survival. Randomized trials do not show that the use of high-dose therapy improves survival. Median survival is about 16 months with conventional treatment; tamoxifen for estrogen receptor–positive tumors, and combination chemotherapy for receptor-negative tumors. Pts progressing on adjuvant tamoxifen may benefit from a selective aromatase inhibitor such as letrozole or anastrazole. Bisphosphonates reduce skeletal complications and may promote antitumor effects of other therapy. Radiation therapy is useful for palliation of symptoms.

Bibliography

For a more detailed discussion, see Lippman ME: Breast Cancer, Chap. 89, p. 571, in HPIM-15.

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