Pocket Oncology (Pocket Notebook Series), 1st Ed.

LOCALIZED BREAST CANCER

Neil M. Iyengar and Chau T. Dang

Epidemiology

• Most common female malignancy & 2nd most common cause of CA death in the United States

• Approx. 225000 new cases in 2012 & approx. 40000 D due to breast CA

• Approx. 1 million new cases diagnosed annually worldwide

• ↑ incidence but ↓ mortality in past few decades

Risk Factors

• Strongest: Female gender, ↑ age

• ↑ estrogen: Early menarche, late menopause, late parity, or nulliparity (NEJM 2006;354:270); prolonged HRT (RR 1.24 after 5.6 y, JAMA 2003;289:3243); no ↑ risk w/OCP use (NEJM 2002;346:2025)

• Benign breast conditions: ≠ risk: Proliferative features (ductal hyperplasia, papilloma, radial scar, sclerosing adenosis); atypia (atypical ductal or lobular hyperplasia); dense breast tissue (↓ mammographic Sn); no ↑ risk: Cysts, fibroadenoma, columnar changes (NEJM 2005;352:229)

• Other: ↑ BMI, FHx (see below), smoking, alcohol consumption, prior thoracic irradiation

• Modified Gail model: Multivariate logistic regression model (www.cancer.gov/bcrisktool/)

Genetics (See Cancer Genetics Syndromes)

• BRCA 1/2 Mt: 56–84% lifetime risk of breast CA

• Other familial/hereditary breast CA: TP53, PTEN, ATM gene Mt

Screening

• Mammography: 20–30% ↓ in breast CA mortality (<50 y smaller absolute benefit) (Lancet 2001;358:1340 & 2002;359:909; Annals 2002;137:347; Lancet 2006;368:2053)

• Annual breast MRI: For high-risk pts – BRCA Mt or unknown BRCA status & 1st-degree relative of BRCA carrier, lifetime risk ≥20%, chest irradiation between age 10 & 30 y, genetic syndrome (JAMA2006;295:2375 & CA 2007;57:75)

Prevention

• Tamoxifen: Risk-benefit: 43% 7-y risk reduction of invasive breast CA but  DVT/PE,  endometrial CA (NSABP P-1 (BCPT) JNCI 1998;90:1371 & Lancet 2002;360:817)

• Raloxifene: 76% as effective as tamoxifen for risk reduction also ↓ vertebral fractures,  risk of stroke, DVT/PE, cataracts but < tamoxifen (RUTH NEJM 2006;355:125), trend toward ↓ uterine CA (NSABP P-2 (STARJAMA 2006;295:2727)

• Prophylactic bilateral mastectomy: 90% risk reduction for women at high risk (ie, BRCA 1/2, TP53, PTEN Mt)

• Prophylactic bilateral salpingooophorectomy: ↓ risk of ovarian & breast CA (NEJM 2002;346:1609 & JAMA 2006;296:185)

Staging

• Stage 0: Carcinoma in situ; Stage IA: T1 (tumor ≤ 2 cm), N0; Stage IB: T1N1mi (micrometastasis to LN > 0.2 mm but ≤ 2 mm); Stage IIA: T2 (tumor 2–5 cm), N0 or T1N1 (1–3 axillary nodes); Stage IIB: T2N1 or T3 (tumor >5 cm), N0; Stage IIIA: N2 (4–9 axillary nodes) or T3N1; Stage IIIB: T4 (direct extension to CW and/or skin or inflammatory); Stage IIIC: N3 (≥10 axillary nodes or any infraclavicular or ipsilateral supraclavicular nodes); Stage IV: Distant mets

Pathology

• Invasive: Ductal (IDC) – most common of invasive carcinomas; lobular (ILC)

• Molecular & Receptor classification (JCO 2010;28:1684)

Local Management

• Mastectomy = lumpectomy + breast RT in OS, ie, BCS (NEJM 2002;347:1227–1233)

• BCS is 1° tx for Stage I & Stage II.

• Sentinel LN bx for (1) clinically negative axillary exam or (2) negative axillary FNA or core bx

• Axillary LND for (1) >2 positive sentinel nodes, (2) clinically palpable nodes, or (3) positive axillary FNA or core bx

• RT: Postmastectomy CW RT for ≥4 + LNs (1–3 + LNs send to radiation oncologist to decide), tumor >5 cm, Stage III, or + surgical margins: ↓ locoregional recurrence &  survival (Lancet 2005;366:2087)

• Consider regional RT after BCS for 1–3 + LNs (MA.20 JCO 2011;29(18_suppl):LBA1003)

Adjuvant Management: When to Use Systemic Chemotherapy

• Give chemotherapy to high risk – biologically (HER2 +, triple negative) or histologically (node-positive) for “most” pts to eradicate occult micrometastatic disease

• Computer-based risk model: Adjuvant. Online (www.adjuvantonline.com) determines risk of recurrence based on age, comorbidities, tumor size/grade, hormone receptor status, nodal status; does not account for HER2 status (JCO2001;19:980)

• OncotypeDX: 21-gene signature RT-PCR assay to calculate RS – predicts 10-y distant recurrence rate; low (RS < 18) 6.8%; intermediate (RS 18–30) 14.3%; high (RS ≥ 31) 30.5%. Trials assessing chemo benefit in intermediate group based on Oncotype DX: TAILORx trial (completed) for node (−) & RxPONDER trial (ongoing) for postmenopausal pts w/1–3 (+) nodes

• Pts w/ER+, LN−, & low RS derive min. benefit while pts w/high RS have improved DFS w/adjuvant chemotherapy (NSABP B20 JCO 2006;24:3726)

• MammaPrint: 70-gene signature to catergorize into 2 groups – good or poor prognosis irrespective of ER status; study ongoing (MINDACT Lancet 2005;365:671)

Adjuvant Management: Chemotherapeutic Regimens

• CMF (Cyclophosphamide, MTX, & fluorouracil)  OS at 30-y follow-up (RR of D = 0.79, p = 0.04) compared to no chemotherapy after surgery (BMJ 2005;330:217); not recommended for high-risk disease

•  DFS & OS w/anthra (anthracycline) containing regimens > CMF (EBCTCG Lancet 2005;365:1687)

•  DFS & OS when taxane added to anthra-based regimens (EBCTCG Lancet 2012;379:432; CALGB 9344 JCO 2003; NSABP B-28: JCO 2005;23:3686)

• Standard Chemo Options for High-risk Pts:

• ddAC Æ T (dose dense doxorubicin + C (AC) × 4 cycles → paclitaxel (T) × 4 cycles given q2wks w/g-CSF) > q3w AC → T (CALGB 9741 JCO 2003;21:1431)

• AC Æ wT (weekly T) or AC Æ D (q3w docetaxel) > q3w AC → T or D (ECOG 1199, NEJM 2008;358:1663)

• TAC (docetaxel, doxorubicin, cyclophosphamide) > FAC (Fluorouracil, doxorubicin, cyclophosphamide) (BCIRG 001, NEJM 2005;352:2302)

• FEC Æ D (fluorouracil, epirubicin, cyclophosphamide → docetaxel) (PACS 01, SABCS 2009)

• FEC Æ wT (GEICAM 9906, JNCI 2008;100:805)

• E Æ CMF (EpirubicinCMF) (NEAT/BR9601, NEJM 2006;355:1851)

• CEF (cyclophosphamide, epirubicin, fluorouracil) (MA 21, JCO 2010;28:77)

• Nonanthra regimens

• Consider DC: DC > AC ( DFS & OS; US Oncology 9735 JCO 2009;27:1177) but inferior to anthra-based regimen followed by taxane (NSABP B-30 SABC 2008); DC not recommended for high-risk disease

Adjuvant Management: Hormone Therapy for ER/PR Positive Disease

• Premenopausal: ↓ breast CA mortality w/tam (Tamoxifen) – 31% ↓ × 5 y (NEJM 1998;339:1609) & 48% ↓ × 10 y & only slight  DVT/PE & endometrial CA (ATLAS Lancet 2012)

• Postmenopausal: AI either upfront or sequentially w/tamoxifen. AIs: (1) Nonsteroidal: Anas (anastrozole), let (letrozole); (2) steroidal: Exe (exemestane)

Neoadjuvant Management: Chemotherapy

• Give to down-size (for inoperable Stage III or large tumors; tumors requiring mastectomy but lumpectomy desired)

• Same DFS & OS as adjuvant, but  BCS w/neoadj (NSABP B-18 & B-27 JCO 2008;26:778)