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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.

PURPOSE To our knowledge, WSG-ADAPT-HR+/HER2– ( NCT01779206 ; n = 5,625 registered) is the first trial combining the 21-gene expression assay (recurrence score [RS]) and response to 3-week preoperative endocrine therapy (ET) to guide systemic therapy in early breast cancer. MATERIALS AND METHODS Baseline and postendocrine Ki67 (Ki67post) were evaluated centrally. In the endocrine trial, all patients received exclusively ET: patients with pathologic regional lymph node status (pN) 0-1 (ie, 0-3 involved lymph nodes) entered control arm if RS ≤ 11 and experimental arm if RS12-25 with ET response (Ki67post ≤ 10%). All other patients (including N0-1 RS12-25 without ET response) received dose-dense chemotherapy (CT) followed by ET in the CT trial. Primary end point of the endocrine trial was noninferiority of 5-year invasive disease-free survival (5y-iDFS) in experimental ( v control) arm; secondary end points included distant DFS, overall survival, and translational research. RESULTS Intention-to-treat population comprised 2,290 patients (n = 1,422 experimental v n = 868 control): 26.3% versus 34.6% premenopausal and 27.4% versus 24.0% pN1. One-sided 95% lower confidence limit of the 5y-iDFS difference was –3.3%, establishing prespecified noninferiority ( P = .05). 5y-iDFS was 92.6% (95% CI, 90.8 to 94.0) in experimental versus 93.9% (95% CI, 91.8 to 95.4) in control arm; 5-year distant DFS was 95.6% versus 96.3%, and 5-year overall survival 97.3% versus 98.0%, respectively. Differences were similar in age and nodal subgroups. In N0-1 RS12-25, outcome of ET responders (ET alone) was comparable with that of ET nonresponders (CT) for age > 50 years and superior for age ≤ 50 years. ET response was more likely with aromatase inhibitors (mostly postmenopausal) than with tamoxifen (mostly premenopausal): 78.1% versus 41.1% ( P < .001). ET response was 78.8% in RS0-11, 62.2% in RS12-25, and 32.7% in RS > 25 (n = 4,203, P < .001). CONCLUSION WSG-ADAPT-HR+/HER2– demonstrates that guiding systemic treatment by both RS and ET response is feasible in clinical routine and spares CT in pre- and postmenopausal patients with ≤ 3 involved lymph nodes.

Background: Endocrine therapy with a standard duration of 5 years is well known as an effective treatment for endocrinesensitive breast cancer. Summary: In the adjuvant setting this treatment reduces the 15-year mortality rates by about 30 and 40% with tamoxifen and aromatase inhibitor, respectively. The well-known long-term recurrence risk of luminal cancers led to multiple trials examining the benefit of extended endocrine treatment for up to 15 years. Additional benefit with extended therapy was seen for patients with high recurrence risk. Also, additional ovarian suppression for premenopausal women exhibited a significant benefit for patients at higher risk. Key Messages: The data of the last years will be summarized and discussed, also considering the side effects of the different treatment options.

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503 Background: Optimal use of de-escalated, particularly chemotherapy(CT)-free, neoadjuvant regimens in HER2+ early breast cancer (EBC) is currently unclear as there are limited survival data so far. In ADAPT-HR-/HER2+, we previously showed an excellent pCR rate of 90% after 12-week neoadjuvant paclitaxel (Pac) +pertuzumab (P) +trastuzumab (T) and a substantial and clinically meaningful pCR rate of 34% after P+T alone in HR-/HER2+ EBC. Here, we present first survival data. Methods: The prospective multicenter WSG-ADAPT-HR-/HER2+ phase II-trial is part of the ADAPT-umbrella protocol. Patients with cT1-cT4c, cN0-3 HR-/HER2+ EBC (n = 134) were randomized to 4 cycles of P+T +/- pac d1,8,15 q3w. All tumors were HR-negative (ER and PR < 1%) and HER2-positive (central lab, i.e., 2+ FISH positive or 3+ by immunohistochemistry. Primary endpoint was pCR (ypT0/is/ypN0); omission of further CT was allowed in pts with pCR. Trial objective was to compare pCR in P+T+pac arm vs. early responders in P+T arm (defined as low cellularity and/or Ki67 decrease >30% after 3 weeks). The trial was stopped early due to the observed pCR superiority in the P+T+pac arm. Secondary endpoints included safety, 5-y (distant)-DFS, OS and translational research. Cox-regression analysis was applied. PAM50 subtype was assessed using the BC360 panel. Results: 134 patients were randomized to P+T (n = 92) or P+T+pac (n = 42). 60% of tumors were cT2-4, 42% clinically node-positive. After a median follow-up of 5 years, no significant differences between study arms were observed regarding DFS, dDFS, and OS; only 13 iDFS events (7 dDFS) were observed in the whole ITT population. pCR (vs. non-pCR) after the 12-week study treatment (irrespective of study arm) was strongly associated with improved iDFS (5y DFS 98.5% vs. 82%, HR = 0.14, 95% CI 0.03-0.64). Of the 69 patients with pCR, 39 (56.5%) received no further CT (P+T arm: n = 9, 29% vs. (P+T+pac arm n = 30, 79%); only 1 distant relapse (1.4%) was observed in these patients. In the CT-free P+T arm, no pCR was observed in patients with low HER2 expression (IHC 1+/2+ and FISH positive) and/or basal-like subtype by PAM50 (n = 17, 19%). In the total study population, low HER2 expression and/or no early response was strongly associated with worse dDFS (p =.029) and iDFS (p =.068). No new safety signals were observed. Conclusions: For the first time, we have shown both excellent pCR and survival in patients treated by de-escalated neoadjuvant CT+P+T irrespective of further CT use in a prospective multicenter study. Investigation of CT-free regimens may need to be focussed on selected patients only (e.g. with high HER2 expression/non-basal-like tumors). In ADAPT HR-/HER2+, early pCR after only 12 weeks of neoadjuvant P+T+pac was strongly associated with improved outcome and may thus serve as a predictive clinical marker for further treatment (de)-escalation. Clinical trial information: NCT01779206.

Background: Endocrine sensitivity, as determined by response of the proliferation marker Ki-67 to short-term preoperative endocrine therapy (ET), is currently not included in adjuvant treatment decisions in hormone receptor (HR)+/human epidermal growth factor receptor 2 (HER2)− breast cancer (BC). Methods: The prospective WSG-ADAPT HR+/HER2− trial included patients with N0/N1 early BC who were candidates for adjuvant chemotherapy based on clinical–pathological criteria alone. The trial utilized a genomic assessment [the Recurrence Score (RS)] plus endocrine sensitivity testing to guide treatment. All patients received 3 (±1) weeks of preoperative induction ET. According to protocol, patients with RS 0–11 or RS 12–25 plus endocrine proliferation response (EPR, post-induction Ki-67 ⩽ 10%) were to be spared adjuvant chemotherapy. Results: The ADAPT HR+/HER2− trial run-in phase included 407 patients with baseline RS, of whom 386 (median age: 54 years) had complete data for Ki-67 at both baseline and post-induction. RS distribution: 23.1% RS 0–11, 58.3% RS 12–25, and 18.7% RS 26–100. EPR occurred in 84.3%, 76.0%, and 36.1% of these RS groups, respectively. Differences in EPR proportions (RS 26–100 versus others, RS 0–11 versus others) were significant (both p < 0.001); Ki-67 quotients were higher for RS 26–100 ( p = 0.02, Mann–Whitney). In premenopausal women ( n = 146, mostly tamoxifen-treated), median quotient of Ki-67 level (post/pre) was significantly higher than in postmenopausal women ( n = 222, mostly aromatase-inhibitor treated; 0.67 versus 0.25, p < 0.001). EPR was significantly associated with baseline estrogen-receptor status as determined by immunohistochemistry ( p = 0.002) or real-time polymerase chain reaction ( p < 0.001). Also, a strong correlation was observed between RS measured pre- and post-ET (RS = 0.7, n = 181). Conclusions: This phase of the WSG-ADAPT HR+/HER2− trial confirms trial design estimates of RS and EPR. It indicates that the ADAPT concept of combining static and dynamic biomarker assessment for individualized therapy decisions in early BC is feasible using the EPR criterion post-induction Ki-67 ⩽ 10%. Clinicaltrials.gov identifier: NCT01779206.

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