Neil M. Iyengar and Chau T. Dang
Biology & Epidemiology
• Human epidermal growth factor receptor 2 (HER2) on chromosome 17q encodes transmembrane TK receptor member of EGFR family involved in signal transduction pathways that promote cellular proliferation
• HER2/neu gene amp observed in 20–30% of invasive breast CA
• A/w worse prognosis: ↑ risk of disease progression, ↓ OS
• IHC: 3+ = HER2+; 0–1+ = HER2−; 2+ = equivocal → refer for FISH, + if ≥2
Anti-HER2+ Agents
• H (Trastuzumab, Herceptin): Recombinant, humanized monoclonal Ab binds to extracellular HER2 domain
• P (Pertuzumab): Monoclonal Ab, inhibits HER2 dimerization
• L (Lapatinib): Reversible, small molecule, dual HER1/HER2 TKI
• T-DM1 (Trastuzumab emtansine): Ab -drug conjugate of H+ antimicrotubule agent
First-line Treatment of HER2+ Metastatic Disease
• Dual anti-HER2 tx preferred: ↑ PFS & ↑ OS with DHP vs. DH (CLEOPATRA NEJM 2012;366:109); alternatively can use weekly T + HP (THP, JCO 2012;suppl 27)
Treatment of Metastatic HER2+ Disease: Beyond First Line
• T-DM1 > L+Cap: ↑ PFS & ↑ OS (EMILIA NEJM 2012;367:1783)
• HP ± cytotoxic Rx for one line of Rx beyond first-line Rx in pts previously treated with chemotherapy + H in the absence of P (NCCN compendia listing, category 2A)
• May continue H + 2nd-line chemo options (ie, taxane ± platin, vinorelbine, Cap, GEM (NCCN 2012))
• L regimens: L + Cap (NEJM 2006;355:2733); L + H (JCO 2010;28:1124)
• Asx ER+/PR+/HER2+, consider hormone + anti-HER2 Rx:
• H + anastrozole > anastrozole ↑ PFS (4.8 vs. 2.4 mos, p < 0.05) but no ↑ OS (TAnDEM JCO 2009;27:5529)
• L + letrozole > let ↑ PFS (8.2 vs. 3 mos, p = 0.02) but no ↑ OS benefit (JCO 2009;27:5538)
• Note: Avoid concurrent anthra + H outside of trial
Early Breast Cancer-HER2+ Disease: Adjuvant (adj) Trastuzumab (H)
• When to give chemo – see Localized breast CA
• Standard chemo + H options: AC → TH (B-31/N9831, SABCS 2012; Abstract S5–5); ddAC Æ TH (no ↑ in cardiotoxicity, JCO 2008;26:1216); DCbH (BCIRG 006 NEJM 2011;365:1273)
• Concurrent AC → TH > sequential AC → T → H (N9831 JCO 2011;29:3366)
• Adj H × 1 y is standard; 12 mos likely > 6 mos (PHARE, other studies ongoing) & 24 = 12 mos (HERA SABCS 2012;Abstract S5–2)
• Give H concurrently with hormone Rx and/or adjuvant RT
• Addition of H to adj chemo ↓ recurrence risk by 40–50%
Cardiotoxicity
• Metastatic studies: NYHA class III–IV 2–4% but highest w/concurrent anthra + H (16%, JCO 2002;20:1215); AVOID concurrent anthra + H
• Adjuvant studies: NYHA III–IV or G 3–4 cardiac events ≤ 4%
• Consider nonanthra regimens (ie, DCbH) for pts w/pre-existing cardiac conditions or who have contraindications to receive anthracyclines
• RF for cardiac events: Older age, marginal baseline/postanthracycline LVEF, use of antihypertensive meds, BMI > 25, ↑ anthracycline cumulative dose
• Monitoring: ECHO/MUGA at baseline, postanthracycline, & serially→ If sx ↓ EF or asx ↓ EF ≥10–< 50%, hold H & reassess in 3–4 wks