HEMATOLOGY-ONCOLOGY
BREAST CANCER
Epidemiology and genetics (risk assessment tool: www.cancer.gov/bcrisktool/)
• In U.S., most common cancer in women; 2nd leading cause of cancer death in women
• Age: incidence rates ↑ with age, with possible ↓ in slope after menopause
• Genetics (Nature 2012;490:61): Mutations in TP53, PIK3CA and GATA3; HER2 amplified. 15–20% have 
FHx → 2× ↑ risk; ~45% of familial cases a/w known germline mutation
BRCA1/2: 35–85% lifetime risk of breast cancer & ↑ risk of ovarian cancer; ? ↑ colon & prostate cancer; prog not worse than in noncarriers w/ breast ca (NEJM 2007;357:115); BRCA2: a/w ↑ malebreast cancer & pancreatic cancer. Rare mutations in CHEK2, HRAS, TP53 a/w ↑ risk in familial breast cancer (Breast Cancer Treat Res 2011;127:309)
• Estrogen: ↑ risk with early menarche, late menopause, late parity or nulliparity (NEJM 2006;354:270); ↑ risk with prolonged HRT (RR = 1.24 after 5.6 y, JAMA 2003;289:3243);
no ↑ risk shown with OCP use (NEJM 2002;346:2025)
• Benign breast conditions: ↑ risk w/ atypia (atypical ductal or lobular hyperplasia) & proliferative (ductal hyperplasia, papilloma, radial scar or sclerosing adenosis) features; no ↑ risk w/ cysts, fibroadenoma or columnar changes (NEJM 2005;352:229)
• ↑ risk with h/o ionizing radiation to chest for treatment of Hodgkin lymphoma
Clinical manifestations
• Breast mass (hard, irregular, fixed, nontender), nipple discharge (higher risk if unilateral, limited to one duct, bloody, associated with mass)
• Special types: Paget’s disease → unilateral nipple eczema + nipple discharge; inflammatory breast cancer → skin erythema and edema (peau d’orange)
• Metastases: lymph nodes, bone, liver, lung, brain
Screening (NEJM 2011;365:1025)
• Self breast exam (SBE): no proven mortality benefit (JNCI 2002;94:1445); not recommended
• Clinical breast exam (CBE): benefit independent of mammography not established
• Mammography: ~20–30% ↓ in breast cancer mortality (smaller abs. benefit in women <50 y) (Lancet 2006;368:2053; Annals 2009;151:727); 75% of all abnl findings benign; suspicious: clusteredmicrocalcifications, spiculated, enlarging adding U/S ↑ Se, but ↓ PPV (JAMA 2008;299:3151)
• ACS/NCI recommend annual mammo + CBE beginning at age 40; USPSTF recommends beginning at 50 and biennially (Annals 2009;151:716), controversial (NEJM 2009;361:2499)
• ↑ risk: screen earlier w/ CBE and mammo (age 25 in BRCA1/2 carrier, 5–10 y before earliest FHx case, 8–10 y after thoracic RT, upon dx of ↑ risk benign disease)
• MRI: superior to mammo in high-risk Pts; consider annually if >20% lifetime risk (eg, FHx, BRCA1/2, prior chest RT) (Lancet 2011;378:1804)
• Genetic testing should be considered in women with strong FHx
Diagnostic evaluation
• Palpable breast mass: age <30 y → observe for resolution over 1–2 menstrual cycles;
age <30 y, unchanging mass → U/S → aspiration if mass not simple cyst;
age >30 y or solid mass on U/S or bloody aspirate or recurrence after aspiration → mammo (detect other lesions) and either fine-needle asp. or core-needle bx clearly cancerous on exam or indeterminate read or atypia on bx → excisional bx
• Suspicious mammogram with normal exam: stereotactically guided bx
• MRI: detects contralateral cancer in 3% of women w/ recently dx breast cancer & negative contralateral mammogram (but PPV only 21%) (NEJM 2007;356:1295); whether to use routinely remains unclear
Staging
• Anatomic: tumor size, chest wall invasion, axillary LN mets (strongest prognostic factor)
• Histopathologic: type (little prognostic relevance) & grade; lymphatic/vascular invasion
In situ carcinoma: no invasion of surrounding stroma
Ductal (DCIS): ↑ risk of invasive cancer in ipsilateral breast (~30%/10 y)
Lobular (LCIS): marker of ↑ risk of invasive cancer in either breast (~1%/y)
Invasive carcinoma: infiltrating ductal (70–80%); invasive lobular (5–10%); tubular, medullary and mucinous (10%, better prognosis); papillary (1–2%); other (1–2%)
Inflammatory breast cancer (see above): not a histologic type but a clinical reflection of tumor invasion of dermal lymphatics; very poor prognosis
Paget disease: ductal cancer invading nipple epidermis ± associated mass
• Biomarkers: determine estrogen, progesterone receptor (ER/PR) and HER2/neu status for all invasive breast cancers
• Oncotype DX 21-gene risk recurrence score has predictive and prognostic value in ER , node 
or Pts (JCO 2007;25:5287 & 2010;28:1829; Lancet 2011;378:1812)
• Circulating tumor DNA may serve as biomarker of met tumor burden (NEJM 2013;368:1199)
Treatment
• Local control: surgery and radiation therapy (RT)
Breast-conserving = lumpectomy + breast RT + axillary node dissection (ALND) is equivalent to mastectomy + ALND (NEJM 2002;347:1227); contraindications: multicentric disease, diffuse microcalcifications, prior RT, pregnancy, ? tumor >5 cm
Sentinel lymph node dissection (SLND) prior to ALND preferred if w/o palp axillary LNs; T1-2 w/ SLND & Rx w/ lumpect./RT/chemo may not need ALND (JAMA 2011;305:569)
Radiation therapy (RT) after mastectomy for ≥4 LN, tumor >5 cm or surgical margins → ↓ locoregional recurrence and ↑ survival (Lancet 2011;378:1707)
• Systemic therapy: for stage I-III except tumors <1 cm (complex risk assessment needed). http://www.adjuvantonline.com/index.jsp can guide use of chemo and/or hormonal Rx.
Chemotherapy (Lancet 2008;371:29): in neoadjuvant setting usually anthracycline-based (eg, adriamycin + cyclophosphamide). Sequential Rx w/ taxane (eg, paclitaxel) → small ↑ survival (NEJM2007;357:1496; 2010;362:2053 & 2010;363:2200).
Anti-HER2 therapy (growing list of agents) in HER2 tumors (NEJM 2012;366:176)
trastuzumab (Herceptin; anti-HER2 mAb) ↑ survival (NEJM 2001;344:783); give after anthracycline or w/ taxane to avoid cardiotox (JCO 2002;20:125 & NEJM 2011;365:1273) lapatinib (tyrosine kinase inhib. of HER2 & EGFR) + trastuzumab ↑ survival after failing trastuzumab (JCO 2012;30:2585); dual inhib. initial Rx ↑ response (Lancet 2012;379:633) pertuzumab (anti-HER2 mAb, prevents dimerization) ↑ progression-free survival when added to trastuzumab as first-line Rx for metastatic dis. (NEJM 2012;366:109) trastuzumab emtansine (T-DM1, HER2 mAb conjugated to microtubule inhibitor) ↑ survival compared to second-line lapatinib + capecitabine (NEJM 2012;367:1783)
Bevacizumab (anti-VEGF): ? in neoadjuvant Rx if HER2 (NEJM 2012;366:299 & 310)
Hormonal (in ER/PR or unknown status)
tamoxifen: 39% ↓ recurrence and 30% ↓ breast cancer mortality in pre- and post-menopausal patients; 10 y of Rx superior to 5 y (Lancet 2011;378:771 & 2013;381:805)
aromatase inhibitors (AI) (anastrozole, letrozole, exemestane): ~18% ↓ recurrence vs. tamoxifen in postmenopausal Pts (Lancet 2005;365:60; NEJM 2005;353:2747)
everolimus ↑ progression-free survival if postmenopausal & failed AI (NEJM 2012;366:520)
2nd-line: ovarian ablation with LHRH agonists (goserelin) or oophorectomy if premenopausal; pure antiestrogens (fulvestrant) if postmenopausal
Prevention (with selective estrogen receptor modulator [SERM] or AI)
• Tamoxifen: ↓ risk contralat. breast CA as adjuvant Rx. Approved for 1° prevent. if ↑ risk: ↓ invasive breast ca, but ↑ DVT & uterine CA; ? ↑ in mortality (Lancet 2002;360:817 ).
• Raloxifene: ↓ risk of invasive breast cancer & vertebral fx, ↑ risk of stroke & DVT/PE (NEJM 2006;355:125); 
tamoxifen in prevention of breast cancer w/ ↓ risk of DVT/PE & cataracts, trend toward ↓ uterine cancer ( JAMA 2006;295:2727 )
• Exemestane in high-risk postmenopausal ↓ invasive breast ca by 65% (NEJM 2011;364:2381)
• BRCA1/2 : intensified surveillance as described above. Prophylactic bilat. mastectomy → ~90% ↓ risk; bilat. salpingo-oophorectomy ↓ risk of ovarian and breast cancer.