Abstract LBO1-05: Impact of age and ovarian function suppression (OFS) on endocrine response to short preoperative endocrine therapy (ET): Results from the multicenter ADAPTcycle trial (n=4,334)
Authors: Oleg Gluz, Matthias Christgen, Ulrike Nitz, Sherko Küemmel, Michael Braun, Marc Thill, Rachel Wuerstlein, Pauline Wimberger, Andreas Hartkopf, Christian Schem, Matthias Zaiss, Vesna Bjelic-Radisic, Marianne Just, Kristina Veselinovic, Myriam Vincent, Monika Graeser, Katja Krauss, Oliver Hoffmann, Kerstin Lüdtke-Heckenkamp, Ronald Kates, Christine zu Eulenburg, Katarzyna Jozwiak, Sandy Burmeister, Rick Baehner, Peter Schmid, Hans-Heinrich Kreipe, Nadia Harbeck
Journal: Cancer Research (2024)

Abstract Background: In HR+/HER2- early breast cancer (EBC), short preoperative endocrine therapy (ET) is a promising tool for ET-efficacy assessment based on Ki67-decrease after 2-4 weeks of ET. Low post-endocrine Ki67 (Ki67post) is associated with good prognosis in large prospective trials. WSG-ADAPT demonstrated that ET-response is a valid criterion for decisions in uncertain adjuvant chemotherapy indications, e.g., in premenopausal patients (pts) with N0 and Recurrence Score (RS, Oncotype DX®) RS 16-25 or with N1 and RS ≤25. Preliminary results from the phase III ADAPTcycle trial indicated higher efficacy of preoperative ET in premenopausal pts. if ovarian function suppression (OFS) was used together with tamoxifen (TAM) or aromatase inhibitors (AI). In the final screening population, we are now able to confirm these results and investigate the influence of age subgroups, RS, individual biological markers, and OFS on ET-response. Methods: In ADAPTcycle (n=5,290 screened, 1,670 randomized by 06/23; 84 sites in Germany), N0-1 pts with RS &amp;gt;25 or N2-3 pts with RS ≤25 and ET-response were randomized to (neo)adjuvant chemotherapy (CT) followed by ET vs. ribociclib + AI (premenopausal: +GnRH). In premenopausal pts, participation with N1-disease and RS ≤25 or N0 and RS 16-25 was allowed irrespective of ET-response, but randomization recommended only for ET-responders; in the preoperative phase, OFS+TAM or AI for ET-response assessment was protocol-recommended. Results: This analysis includes all pts with complete baseline characteristics (including RS) and ET-response data (n=4,334); ET-response was defined as Ki67post ≤10% (central pathology) after 2-4 weeks (if OFS: 4 weeks) of therapy. ER, PR, and HER2-levels were analyzed by IHC and mRNA. Median age was 56 years (22-87y). 55% had cT2-4 tumors; 28% had cN+ disease; 42% were G3 (central lab). Median RS was 20, median baseline Ki67 25%. n=1,368 were ≤50y and premenopausal (“≤50y”): n=314 (23.0%) and 255 (18.6%) were treated by AI+OFS and TAM+OFS, respectively. 2,966 were &amp;gt;50y or postmenopausal (“ &amp;gt;50y”), of whom 2,565 received AI (86.5%). ET-response occurred in 48.2% of “≤50y” vs. 72.7% in “ &amp;gt;50y” pts (p&amp;lt; 0.001). We observed significant differences in ET-response rates between “≤50y” vs. “ &amp;gt;50y” with TAM alone (34.7% vs. 46.4%); In “≤50y” pts, 55.7% ET-response occurred with TAM+OFS vs. 76.4% with AI+OFS, comparable to 76.8% in “ &amp;gt;50y” patients with AI. Moreover, OFS led to higher ET-response rates (by uni- and multivariable analysis) even in the small (n=78) group of premenopausal pts &amp;gt;50y. Remarkably, even in pts with RS &amp;gt;25, substantial ET-response rates were observed with AI: 66.7% (“≤50y”, AI+OFS), 55.6% (“ &amp;gt;50y”, AI) vs. lower rates with TAM alone (&amp;gt;50y: 18.2%; &amp;lt; 50y: 15.8%). ET-response rate in “≤50y” pts was associated with ET type, RS, and baseline Ki67 in both uni- and multivariable analysis, but not age subgroup (≤40 vs. 41-50y). ER, PR, and HER2 expression by IHC or RT-PCR were associated with ET-response by univariable (but not multivariable) analysis. In “ &amp;gt;50y” pts, by uni- and multivariable analysis, again ET-type, RS, and baseline Ki67, as well as ER-expression (by IHC) and ESR1, PR, and HER2-expression (by RT-PCR) were associated with higher ET-response rates. Conclusions: With about 10,000 pre- and postmenopausal pts, ADAPT and ADAPTcycle provide the largest international database regarding ET-response. ADAPTcycle confirms ADAPT ET-response rates in pts receiving TAM or AI; adding OFS to either improves ET-response, irrespective of RS. ET-response measurement adds value in therapy decisions, particularly in ≤50y N0-1 pts. ET-response might provide key information even in pts with high RS; outcome data of ADAPTcycle will reveal potential clinical consequences. Optimal preoperative ET, especially in premenopausal pts, might even enable sparing chemotherapy in additional pts. Citation Format: Oleg Gluz, Matthias Christgen, Ulrike Nitz, Sherko Küemmel, Michael Braun, Marc Thill, Rachel Wuerstlein, Pauline Wimberger, Andreas Hartkopf, Christian Schem, Matthias Zaiss, Vesna Bjelic-Radisic, Marianne Just, Kristina Veselinovic, Myriam Vincent, Monika Graeser, Katja Krauss, Oliver Hoffmann, Kerstin Lüdtke-Heckenkamp, Ronald Kates, Christine zu Eulenburg, Katarzyna Jozwiak, Sandy Burmeister, Rick Baehner, Peter Schmid, Hans-Heinrich Kreipe, Nadia Harbeck. Impact of age and ovarian function suppression (OFS) on endocrine response to short preoperative endocrine therapy (ET): Results from the multicenter ADAPTcycle trial (n=4,334) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr LBO1-05.