Shoulder-arm morbidity following axillary dissection is a frustrating polysymptomatic disease that seems to be relatively unaffected by therapeutic measures. The surgical trauma necessary for adequate tumor staging (removal of 10 lymph nodes) seems decisive for the postsurgery syndrome following axillary dissection. For node-positive patients complete axillary clearing may improve tumor control without worsening long-termmorbidity. New techniques, such as the sentinel-node-biopsy, that selects patients with negative axillary status while preserving the integrity of axillary structures, may improve the overall morbidity.

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 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.

Background: In HR+/HER2- N0 early breast cancer (EBC), patients (pts) with Recurrence Score™ (RS)&lt;26 (postmenopausal) and &lt;16 (premenopausal) have excellent prognosis and do not benefit fromadditional chemotherapy. However, prognostic impact of RS in N+ disease and importance of Ki67response after short preoperative endocrine therapy (ET) in the context of genomic signatures remainunclear. For the first time, we present survival results from the large prospective phase III WSG-ADAPTHR+/HER- trial combining both static (RS in baseline core biopsy) and dynamic (Ki67 response)biomarkers to optimize adjuvant therapy in luminal EBC. Methods: 5625 pts were registered and 4691 finally treated by ET (n=2356) or CT (n=2335) within ADAPTHR+/HER2-. ET-trial ITT population comprised 2290 pts: n=868 RS0-11, n=1422 RS12-25/ET-response(30% premenopausal, 26% N1). 5y-iDFS was 93.9% (95%-CI: [91.8% to 95.4%]) in RS0-11 and 92.6%(95%-CI: [90.8% to 94.0%]) in RS12-25/ET-responders. Since the one-sided upper 95% confidence limitof the 5y-iDFS difference was 3.3%, the pre-specified criterion to accept the primary NI-hypothesis wasmet (p=.05).5y-dDFS was 96.3% [94.6% to 97.5%] vs. 95.6% [94.2% to 96.7%]) in RS0-11 vs. RS12-25/ET-responders,respectively (95%-CI for 5y-dDFS difference: [-1.2% to 2.6%]). 5y-OS was also excellent and similar(98.0% [96.7% to 98.9%] vs. 97.3% [96.1 to 98.1%]) in RS0-11 vs. RS12-25/ET-responders, respectively(95% CI for the 5y-OS difference: [-0.7% to 2.2%]). Results: 5625 pts were registered and 4691 finally treated by ET (n=2356) or CT (n=2335) within ADAPTHR+/HER2-. ET-trial ITT population comprised 2290 pts: n=868 RS0-11, n=1422 RS12-25/ET-response(30% premenopausal, 26% N1). 5y-iDFS was 93.9% (95%-CI: [91.8% to 95.4%]) in RS0-11 and 92.6%(95%-CI: [90.8% to 94.0%]) in RS12-25/ET-responders. Since the one-sided upper 95% confidence limit of the 5y-iDFS difference was 3.3%, the pre-specified criterion to accept the primary NI-hypothesis was met (p=.05) 5y-dDFS was 96.3% [94.6% to 97.5%] vs. 95.6% [94.2% to 96.7%]) in RS0-11 vs. RS12-25/ET-responders, respectively (95%-CI for 5y-dDFS difference: [-1.2% to 2.6%]). 5y-OS was also excellent and similar (98.0% [96.7% to 98.9%] vs. 97.3% [96.1 to 98.1%]) in RS0-11 vs. RS12-25/ET-responders, respectively (95% CI for the 5y-OS difference: [-0.7% to 2.2%]). Conclusions: In pN0-1 luminal EBC pts receiving ET alone, pts with RS12-25/ET-response had 5y-iDFSwell above 90% and very close to RS0-11 pts. Both groups had excellent similar dDFS and OS. DynamicET response thus complements RS as a key selection criterion for omission of chemotherapy in pN0-1HR+/HER2- EBC. Citation Format: Nadia Harbeck, Oleg Gluz, Sherko Kuemmel, Matthias Christgen, Michael Braun, Bahriye Aktas, Kerstin Luedtke-Heckenkamp, Helmut Forstbauer, Eva-Maria Grischke, Claudia Schumacher, Maren Darsow, Katja Krauss, Benno Nuding, Marc Thill, Jochem Potenberg, Christoph Uleer, Mathias Warm, Hans H. Fischer, Wolfram Malter, Michael Hauptmann, Ronald Kates, Monika Graeser, Rachel Wuerstlein, Steve Shak, Rick Baehner, Hans Kreipe, Ulrike Nitz, West German Study Group. Endocrine therapy alone in patients with intermediate or high-risk luminal early breast cancer (0-3 lymph nodes), Recurrence Score &lt;26 and Ki67 response after preoperative endocrine therapy: Primary outcome results from the WSG-ADAPT HR+/HER2- trial [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr GS4-04.

Background: Pathological complete response (pCR) is associated with improved outcome in patients with high-risk HR+/HER2- breast cancer (BC) but the use of (neo)adjuvant chemotherapy in early HR+/HER2- BC remains controversial. Oncotype DX / Recurrence Score (RS) and dynamic Ki67 response after short preoperative endocrine therapy are potentially predictive for pCR. Still, no prospective data are available so far to predict chemotherapy efficacy in this key patient group. Use of dose-dense chemotherapy is associated with improved outcome in meta-analysis, but its use in the neoadjuvant setting is less studied. Furthermore, use of nab-paclitaxel instead of solvent-based paclitaxel has shown promising results in some studies. Here, we present for the first time data from a randomized prospective trial comparing these risk-selection strategies according to RS and Ki67 decrease in high-risk HR+/HER2- BC. Methods: High-risk BC patients [cN0-1 with RS&gt;25 or (RS 12-25 AND (centrally measured) post-endocrine Ki67 &gt;10%] OR [cN2-3 status] OR [G3 AND Ki67&gt;40%] were randomized to (neo)adjuvant 4x paclitaxel175 q2w or 8xnab-paclitaxel 125 mg/m2q1w followed by 4x E90C600 q2w. pCR was defined as no invasive tumor in breast and lymph nodes. Results: 858 patients with available surgery data randomized to neoadjuvant Pac-EC (N=423) or nab-Pac-EC (N=435) were analyzed. Median age was 51 years; median RS was 30 (N=572); 34% had node-positive; 46% (locally) G3 tumors. Baseline characteristics were well balanced between study arms. Patients receiving nab-Pac-EC had higher pCR than those with Pac-EC (20.3% vs. 12.3%, p=.002); patients with RS&lt;25 (about 27%) had a lower pCR rate than those with RS&gt;25 (6.5% vs. 15.8%, p=.003). The association of RS with pCR appeared more pronounced in premenopausal women, but a test of interaction was not significant; RS was about 3 points higher (mean 32.9 vs. 29.8, p&lt;.001) in postmenopausal cases (p=.001). Clinical tumor stage cT2-4 was reported in 65%, with a lower pCR rate than in cT1 tumors (14% vs. 20%, p=.02). RS was moderately correlated (R=.45) with baseline Ki67. In multivariable analysis with tumor stage, RS, Ki67, menopausal status, and ER and PR positivity, higher RS and cT1 stage were favorable for pCR. Excluding RS, higher Ki67 and lower ER (as well as cT1) were favorable. In patients with RS&lt;25, there was no pCR with Pac-EC (0/72 pCR); pCR was almost 20% with RS&gt;25 and nab-Pac-EC. Further details and data including impacts of Ki67 dynamics and additional markers on pCR will be presented at the meeting. Conclusions: Use of neoadjuvant nab-paclitaxel instead of solvent-based paclitaxel appears promising within a short (16-weeks) dose-dense chemotherapy schedule in high-risk HR+/HER2- BC. For the first time, data from a large neoadjuvant randomized trial confirm RS could help to select patients for neoadjuvant chemotherapy in high-risk HR+/HER2- breast cancer (BC). Citation Format: Sherko Kuemmel, Oleg Gluz, Ulrike Nitz, Michael Braun, Matthias Christgen, Kerstin Luedtke-Heckenkamp, Raquel von Schumann, Maren Darsow, Helmut Forstbauer, Jochem Potenberg, Eva-Maria Grischke, Bahriye Aktas, Claudia Schumacher, Ronald Kates, Monika Graeser, Rachel Wuerstlein, Christoph Uleer, Michael Hauptmann, Steve Shak, Rick Baehner, Hans Kreipe, Nadia Harbeck, West German Study Group. Neoadjuvant nab-paclitaxel weekly versus dose-dense paclitaxel followed by dose-dense EC in high risk HR+/HER2- early BC by: Results from the neoadjuvant part of ADAPT HR+/HER2- trial [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr GS4-03.