Nejm 1998;339:974

Cause:Neoplasia; genetic component in some (esp Ashkenazi Jews) when have BRCA-1 or -2 gene, mutations of Myocarditis/Dilated Cardiomyopathies area of chromosome 17; BRCA-1 present in 10% of women w cancer onset before age 35 yr (Nejm 1996;334:137, 143); women w gene have 85% lifetime risk for breast and 20-40% risk for ovarian Ca, while BRCA-2 women have same breast cancer risk and a 10-20% ovarian Ca risk, but environmental factors may ameliorate (Nejm 1997;336:1448); at present 3-5% of breast CA and up to 15% ovarian CAs in BRCA1/2 carriers; other cancer risk, including male breast, prostate and pancreatic CA increased with BRCA 1/2

Incidence = 100/100 000 women, 37/1000 women die of it; 45 000 die/yr in US; 12% of women will get in their lifetime; 0.5% of all male cancers (Ann IM 2002;137:688), esp in undescended testicles or Kleinfelter's syndrome, which is found in 20% of men w the dx.

Increased incidence with: obesity; infertility; smoking in postmenopausal women who are slow acetylators (Jama 1996;276:1494); late motherhood (age >30 yr); uterine cancer; h/o breast cancer in 1st-degree relatives (× 3-10); postirradiation, eg, Hiroshima, fluoroscopy, even thymus radiation in childhood (Nejm 1989;321:1281), and mammography over age 40 yr causes 40/million women after a 20-yr lag (Nejm 1989;321:1285); moderate alcohol use (Ann IM 2002;137:799), linear incr w incr use (Jama 1998;279:535); hereditary ataxia telangiectasia heterozygotes who may represent 9% of all US breast cancer (Nejm 1986;316:1289), and in whom radiation from mammograms, etc, may increase incidence a lot (Nejm 1991;325:1831); generally in women exposed to more estrogen (mechanisms—Nejm 2006;354:270), eg, perimenopausal users of estrogen and/or progesterone where relative risk increased × 1.7 (Arch IM 2006;166:760; Jama 1999;281:2091 vs 2141; Nejm 1995;332:1589; 1989;321:293), ductal less incr by ERT than lobular (Jama 2003;289:1421); low dietary vit A intake (Nejm 1993;329:234); fibroadenomas of breast before age 24 yr (Nejm 1994;331:10); in women w h/o benign proliferative breast bx's esp w atypia (Nejm 2005;355:229, 275, 297); in males with gynecomastia

No increase with: abortions (Nejm 1997;336:81); bcp use (Nejm 2002;346:2025); high dietary fat consumption (Nejm 1996;334:356 vs Jama 2006:295:629); low fiber intake (Jama 1992;268:2037); silicone breast implants (Nejm 1995;332:1535); exposure to PCBs or DDT (Nejm 1997;337:1253); "fibrocystic disease" except in the 1/3 w proliferative or atypical pathology who are at increased risk (Nejm 1985;312:146)

Lowered incidence in: women with 1st pregnancy before age 30-35 yr, 1/3 fewer if 1st pregnancy before age 23 yr, although pregnancy transiently increases risk for ~15 yr or until 2nd pregnancy, esp if over 35 yr w 1st pregnancy, but protects long term (Nejm 1994;331:5); nursing (more is better) protects against premenopausal type only (Nejm 1994;330:81 vs Lancet 1996;347:431); women who regularly exercise; weight loss after menopause (Jama 2006;296:193)

Sx: Breast mass, usually nontender; nipple discharge or bleeding sometimes

Si:Breast mass, nontender, single, firm, in upper outer quadrant in 60%. Sometimes bloody breast discharge. PAGET'S DISEASE OF BREAST, an areolar dermatitis, if present is strongly correlated with cancer.

Survival worse with increasing age (Nejm 1986;315:559)

Metastases, to skeleton have prognosis better than those to viscera. Cancer in opposite breast in 7-12%

r/o "FIBROCYSTIC DISEASE" (Nejm 1985;312:146) present clinically in 50% of women, histologically in 90%. DUCTAL CARCINOMA IN SITU (Nejm 2004;350:1430), 5-10% prevalence in autopsy series, over half progress to invasive cancer over 5-8 yr, represent 20% of mammographically detected cancers because often cause microcalcifications; rx'd w mastectomy or lumpectomy and radiation, + tamoxifen if estrogen receptor+; relatively benign w local resection and irradiation (Jama 1996;275:913, 948) as are lobular Ca's

Lab:

Chem:Screen pts in high-risk families for breast and ovarian Ca w BRCA-1 and -2 testing (Jama 1996;275:1885); cost = $2000; beware of overenthusiastic application (Nejm 1997;336:1448)

Path:Aspiration cytology for invasive cancer with experienced pathologists, 95% sens, 98% specif. Breast bx; estrogen receptors (ER) crucial to f/u rx; must freeze tissue within 30 min to –70°F; progesterone receptors (PR) also used. Cyclin E levels predict metastases (Nejm 2002;347:1566)

Xray:Mammograms (Secondary Prevention); maybe MRI w contrast esp in BRCA/other high-risk women (Nejm 2004;351:427) or pts w Ca in contralateral breast (Nejm 2007;356:1295); not helpful as f/u of mammography findings (Jama 2004;292:2735)

Rx:

(Nejm 1998;339:974; Jama 1995;273:142) Classified by TNM (lesion size, nodes, mets) system

• Prevent perhaps w ASA or other COX inhibitors daily (Jama 2004;291:2433); or by various screening strategies including self-exam, clinical exam, mammography, (Secondary Prevention)
• for BRCA-1 and -2 mutations: see table (Jama 2011;305:2211, 1997;277:999); prophylactic mastectomy (Nejm 1999;340:77, 141; 1997;336:1472) reduces risk by 90%, NNT = 33.
• for high-risk women:
• Estrogen receptor blockers, which suppress ER+ tumors effectively (Jama 1999;281:2189), like
• Tamoxifen 20 mg po qd × 5 yr (Med Let 1999;41:1; Nejm 1998;339:1609) decr incid ×60% in BCRA-2 but not BCRA-1 women since they lack ER (Jama 2001;286:2251); also helps lipids and osteoporosis, although incr risk of thromboembolic disease and endometrial Ca; $120/mo
• Raloxifene (Evista) 60 mg po qd; almost as effective as tamoxifen w fewer side effects (Jama 2006:2727, 2742, 2784)
• Aromatase inhibitors, see below
• Avastin no longer FDA approved for breast CA indication due to ineffectiveness
• Surgical prophylactic mastectomy, eg w BRCA-1 or -2 mutations (Nejm 2001;345:159; Jama 2000;284:319); and/or oophorectomy post-childbearing (decr risk by 75%) for BRCA-1 and -2 (Nejm 2002;346:1609, 1616, 1660)
• Surgery, if <4-5 cm, lumpectomy, sentinel node (Nejm 2003;349:546) dissection w axillary node dissection only if positve, and radiation (Nejm 1995;332:907); total mastectomy no better long term (Nejm 2002;347:1227, 1233, 1270)
• Postop prophylaxis:
• Endocrinologic:
• Anti-estrogen rx w
• Tamoxifen, if age >50 yr, ER positive, and positive nodes, 10 mg po bid × 5 yr, or × 2-3 yr w switch to aromatase inhibitor × 5+ yr; as above
• Fulvestrant (Faslodex) (Med Let 2002;44:65) 250 mg im q 1 mo; estrogen receptor antagonist; $1000/mo
• Trastuzumab (Nejm 2005;353:1659, 1673, 1734) perhaps; but 4+% risk of cardiotoxicity esp in older women
• Aromatase inhibitors; prevent peripheral adrenal androgen conversion to estrogens but w/o endometrial or thromboembolic cmplcs
• Anastrozole (Arimidex) (Nejm 2005;353:2747); in ER-pos postmenopausal women after 5 yr of tamoxifen (Nejm 2003;349:1793); $250/mo
• Exemestane (Aromasin) (Med Let 2000;42:35) 25 mg po qd, used × 3 yr after 2 yr postop tamoxifen improves recurrence and survival better than cont'd tamoxifen (Nejm 2004;350:1081); adv effects: diarrhea; $250/mo
• Letrozole (Femara) (Nejm 2009;361:766; 2005;353:2747), as good as or better than tomoxifen; $250/mo
• Chemotherapy, adjuvant, for endocrine receptor negative tumors and young high-risk women
• TAC (docetaxel, doxorubicin, cyclophosphamide) × 6 cycles (Nejm 2010;363:2200); or FAC (cyclophosphamide, doxorubicin, 5-FU), CMF (cyclophosphamide, methotrexate, 5-FU), epirubicin (Nejm 2006;355:1851, 1920), or alternating combinations. All improve 5-yr survival to 80-90%; but all also have significant adverse effects (Nejm 2001;344:1997), like wgt gain, ovarian failure, fatigue, cognitive dysfunction, and cardiac toxicity in doxorubicin regimens.
• Radiation along w adjuvant chemoRx improves survival (Nejm 1997;337:949, 956); node negative ER+ women age 50-70 yr have 6% absolute risk reduction of local recurrence but by age 70 yr is only 3%, ? when to stop offering radiation (Nejm 2004;351:963, 971, 1021)
• Postop f/u for metastatic disease: routine PEs and annual mammograms enough, no survival benefit in annual bone scans, labs, chest xrays, or liver imaging done on asx pts (Jama 1995;273:142; 1994;271:1587, 1593)
• of metastatic disease:
• Radiation good for local recurrences and bone pain
• Stereotactic surgery and whole brain radiation for brain mets results in 50% disease free at 1 yr (Jama 2006;295:2483)
• Chemotherapy first if ER neg w CMF or adriamycin + vincristine, paclitaxel (Taxol) (Nejm 1995;332:1004); trastuzumab (monoclonal antibody) or capecitabine (Med Let 1998;40:106)
• Anti-estrogen rx as above, first if ER positive or over age 50 yr
• Surgical oophorectomy in premenopausal women or medically w leuprolide, an FSH inhibitor; adrenalectomy, surgically or medically with aminoglutethimide + dexamethasone (as good as surgical—Nejm 1981;305:545); androgens; pituitary ablation
• Autologous hematopoietic stem cell transplantation + high dose ChemoRx? (Nejm 2003;349:7, 17, 80)
• Biphosphonates, if bone mets, to prevent sx: pamidronate (Nejm 1996;335:1785) iv q mo, or clodronate (Nejm 1998;339:357) po qd