Abstract PD13-09: Primary analysis from NEOS trial: A randomized phase III study that assessed the long-term prognosis of estrogen receptor positive (ER+) primary breast cancer (PBC) pts who received neoadjuvant endocrine therapy (NET) with/without adjuvant chemotherapy (CT)
Authors: Iwata Hiroji , Toyama Tatsuya , Taira Naruto , Masuda Norikazu , Yamamoto Yutaka , Fujisawa Tomomi , Ohtani Shoichiro , Kashiwaba Masahiro , Sakai Takehiko , Hasegawa Yoshie , Nakamura Rikiya , Akabane Hiromitsu , Shibahara Yukiko , Sasano Hironobu , Yamaguchi Takuhiro 
Published: March 2022

Abstract
Background: NET is one of option in postmenopausal PBC with ER+ and molecular signature is useful tool to determine with/without CT after surgery. We presented a relationship between molecular signature and response of NET in this study cohort (BCRT; 2018). Here we report the primary analysis of NEOS trial, a Phase III study that evaluated long-term prognosis with/without CT in ER+ PBC who received NET. Methods: Postmenopausal BC pts with ER +/HER2 negative, T1c-2, clinically node negative, under 76 years old were enrolled at primary registration. Pts were treated by letrozole (LET) in weeks 24-28 after primary enrollment. Pts experienced progression disease (PD) during neoadjuvant phase or with more than 4 positive lymph nodes in pathological findings after surgery were excluded at randomization and received any systemic therapy driven by investigators before or after surgery. Pts who met eligibility criteria were randomized 1:1 to LET for 4.5-5 years after CT or LET alone for 4.5-5 years without CT after surgery. Primary endpoint is disease-free survival (DFS) with/without adjuvant CT. Secondary endpoints include distant DFS (DDFS), overall survival (OS), DFS/DDFS/OS according clinical response of NET and QoL. Statistical analysis plan is as follow. The Hazard ratio (HR) will be compared with the threshold HRs obtained in a pre-study questionnaire survey to reach a conclusion about the choice between LET plus chemotherapy or LET alone. Based on these survey results, the HR thresholds used to choose between the two treatments were set at 0.9 and 0.6. After amendment, the selection probability was finally set as 80-85%. About 170 events were required for both arms. Results: Between May 2008 and June 2013, 904 patients were enrolled at primary registration from 100 institutions in Japan and 21 pts were withdrawn before neoadjuvant phase. 42pts were excluded by PD during NET. 172pts were not randomized because of non-eligible for second enrolled criteria after surgery and patient’s preference. 669pts were randomized (1:1) to adjuvant CT + ET (333pts) or ET alone (336pts). Patients’ characteristics (age, tumor size, progesterone receptor(PgR) status, nuclear grade (NG), clinical and pathological response of NET and a number of Ax LN metastasis) were well balance among two arms. Median follow up is 7.8 years. Primary endpoint (DFS) was not able to evaluated for necessity of chemotherapy because DFS events (CT+ET:46, ET alone:61) was lower compared with planned numbers (HR:0.74 (95%CI; 0.51, 1.09), P=0.13). DDFS was also not able to evaluated similar with DFS (HR:0.79 (95%CI; 0.46, 1.35) P=0.39). DFS/DDFS rate at 8Y were 85.6%/93.1% and 82.7%/91.7% in CT+ ET and ET alone, respectively. OS was not difference between two arms (HR 0.46 (95%CI; 0.20, 1.07) P=0.072). Both DDFS and locoregional events were lower in CT+ET than ET alone arm. A number of any secondary cancers was higher than DDFS events among both arms. DFS was statistically significant better in CT+ET arm than ET alone arm among any subgroups who &lt; 60 years (HR:0.30, p=0.003, clinical T2 (HR:0.56, p=0.012) and ki67 &gt;20% cases (HR:0.49, P=0.026) at baseline characteristics. No statistically significant difference of DFS between two arms according to response of NET (HR:0.76, P=0.35 in CR and PR group, HR:0.70, p=0.19 in SD group). PgR status, NG, a number of Ax LN metastasis were also not predictive factors about the difference of DFS between CT+ET and ET alone. Conclusion: The decision to use adjuvant chemotherapy could not be based solely on clinical response of NET. Adjuvant chemotherapy should be selected by any clinical factors and genomic tool regardless of response by NET for ER+ PBC. UMIN000001090
Citation Format: Hiroji Iwata, Tatsuya Toyama, Naruto Taira, Norikazu Masuda, Yutaka Yamamoto, Tomomi Fujisawa, Shoichiro Ohtani, Masahiro Kashiwaba, Takehiko Sakai, Yoshie Hasegawa, Rikiya Nakamura, Hiromitsu Akabane, Yukiko Shibahara, Hironobu Sasano, Takuhiro Yamaguchi. Primary analysis from NEOS trial: A randomized phase III study that assessed the long-term prognosis of estrogen receptor positive (ER+) primary breast cancer (PBC) pts who received neoadjuvant endocrine therapy (NET) with/without adjuvant chemotherapy (CT) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD13-09.