De-escalation strategies in HER2-positive early breast cancer (EBC): final analysis of the WSG-ADAPT HER2+/HR- phase II trial: efficacy, safety, and predictive markers for 12 weeks of neoadjuvant dual blockade with trastuzumab and pertuzumab ± weekly paclitaxel.

BACKGROUND: Response rates in HER2-overexpressing EBC treated with neoadjuvant chemotherapy and trastuzumab (T) have been improved by addition of pertuzumab (P). The prospective, phase II, neoadjuvant WSG-ADAPT HER2+/HR- trial assessed whether patients with strong early response to dual blockade alone might achieve pathological complete response (pCR) comparable to that of patients receiving dual blockade and chemotherapy. PATIENTS AND METHODS: Female patients with HER2+/HR- EBC (M0) were randomized (5:2) to 12 weeks of T + P ± weekly paclitaxel (pac) at 80 mg/m2. Early response was defined as proliferation decrease ≥30% of Ki-67 (versus baseline) or low cellularity (<500 invasive tumor cells) in the 3-week biopsy. The trial was designed to test non-inferiority for pCR in early responding patients of the T + P arm versus all chemotherapy-treated patients. RESULTS: From February 2014 to December 2015, 160 patients were screened, 92 were randomized to T + P and 42 to T + P+pac. Baseline characteristics were well balanced (median age 54 versus 51.5 years, cT2 51.1 versus 52.4%, cN0 54.3 versus 61.9%); 91.3% of patients completed T + P per protocol and 92.9% T + P+pac. The pCR rate in the T + P+pac arm was 90.5%, compared with 36.3% in the T + P arm as a whole. In the T + P arm, 24/92 were classified as non-responders, and their pCR rate was only 8.3% compared with 44.7% in responders (38/92) and 42.9% in patients with unclassified early response (30/92). No new safety signals were observed in the study population. CONCLUSION: Addition of taxane monotherapy to dual HER2 blockade in a 12-week neoadjuvant setting substantially increases pCR rates in HER2+/HR- EBC compared with dual blockade alone, even within early responders to dual blockade. Early non-response under dual blockade strongly predicts failure to achieve pCR.

Triple-negative high-risk breast cancer derives particular benefit from dose intensification of adjuvant chemotherapy: results of WSG AM-01 trial.

BACKGROUND: This paper evaluates the prognostic and predictive impact of protein expression of various molecular markers in high-risk breast cancer (HRBC) patients with >9 involved lymph nodes, who received different chemotherapy dose-intensification strategies within a prospective randomized WSG AM-01 trial. MATERIALS AND METHODS: Paraffin-embedded tumors from 236 patients, who were randomly assigned to dose-dense conventional chemotherapy with four cycles of E(90)C(600) followed by three cycles of C(600)M(40)F(600) every 2 weeks (DD) or a rapidly cycled tandem high-dose regimen with two cycles of E(90)C(600) every 2 weeks followed by two cycles of E(90)C(3000)Thiotepa(400) every 3 weeks (HD), were available for retrospective central pathological review (116 HD/120 DD). Expression of estrogen receptor (ER), progesterone receptor (PR), MIB-1, epidermal growth factor receptor, and Her-2/neu was evaluated immunohistochemically using tissue microarrays. Results were correlated with follow-up data and treatment effects by proportional hazard Cox regression models (including interaction analysis). RESULTS: After a median follow-up of 61.7 months, 5-year event-free survival (EFS) as well as overall survival (OS) rates for the 236 patients were significantly better in the HD arm: EFS: 62% versus 41% [hazard ratio (HR) = 0.60, 95% CI 0.43-0.85, P = 0.004]; OS: 76% versus 61% (HR = 0.58, 95% CI 0.39-0.87, P = 0.007). In multivariate analysis, HD, tumor size <3 cm, positive PR, negative MIB-1 staining, and grade 1/2 were associated with favorable outcome. Interaction analysis showed that regarding predictive effects, triple negative (ER/PR/Her-2/neu) and G3 tumors derived most benefit from HD. CONCLUSION: Tandem HD improves both EFS and OS in HRBC. This therapy effect may be partly attributable to superior efficacy in the subgroup of triple-negative tumors and/or G3 with their poor prognostic marker profile.