Abstract OT1-08-01: Concurrent versus sequential chemo-endocrine therapy in er positive and her2 negative non-metastatic breast cancer- an open-label, phase III, randomized controlled trial
Authors: Joshi Shalaka , Murali-Nanavati Sridevi , Vanmali Vaibhav , Hawaldar Rohini , Shaikh Mujahid Gafur , Ansari Mohammad Sadique , Rath Sushmita , Ghosh Jaya , Gulia Seema , Bajpayi Jyoti , Nair Nita , Parmar Vani , Thakkar Purvi , Chitkara Garvit , Shet Tanuja , Desai Sangeeta , Sahay Ayushi , Gupta Sudeep , Badwe Rajendra 
Published: March 2022

Abstract
Background-Traditionally, endocrine therapy follows chemotherapy for hormone receptor (HR) positive breast cancer (BC) in the adjuvant setting. Concurrent chemo-hormonal therapy fell into disrepute due to previous studies showing a probable, small detriment in survival. (Albain et al, Lancet, 2009; Bedognetti et al, JNCI, 2009; Pico et al, Ann Oncol, 2004) However, the early studies are fraught with biases. The biological rationale was that endocrine therapy is cytostatic, pushing cancer cells into G0 phase which was feared to reduce the efficacy of chemotherapy which is known to act best on rapidly dividing cells. Thus, the two mechanisms of actions were thought to be antagonistic. However, this fear may be irrational and evidence at molecular level is contradictory. The current sequential strategy delays the start of an equally effective treatment modality in HR+ BC patients. Recent studies have shown that concurrent chemo-endocrine therapy is safe in metastatic HR+ setting. (Sledge et al, J Clin Oncol, 2000) One also needs to rethink neoadjuvant strategies in these patients to improve the current dismal pathological complete response (pCR) rates in this subset. (Cortazar et al, Lancet, 2014) Concurrent treatment seems to have improved pCR rate. (Sagiu K et al, Acta Med Okayama, 2015) Here, we describe a phase III, randomized study aimed to evaluate the efficacy of concurrent chemo-endocrine therapy in the adjuvant and neoadjuvant setting. (CTRI/2018/09/015643) Aims and Objectives- The primary objective is to assess the improvement in disease-free survival by administering concurrent versus sequential, (neo) adjuvant chemo-endocrine therapy in HR+, HER2 negative, non-metastatic BC. The secondary objectives are to assess improvement in overall survival, pCR rates, breast conservation rates. Biomarkers of response to treatment and tumour dormancy in HR+ BC will be studied in a subset of patients.Patients and methods-This is a prospective, open label study where non-metastatic, biopsy proven, HR+, HER2- BC patients who warrant chemotherapy in the adjuvant or neoadjuvant setting are considered. The study started accrual in December 2018 and 285 patients are randomized till date. Pregnant or lactating women and those with inflammatory breast carcinoma are excluded. After obtaining informed consent, patients are randomized to receive concurrent versus sequential chemo-endocrine treatment. Patients will receive all chemo and endocrine therapy as per the institutional standard protocols otherwise. Stratification criteria are neoadjuvant vs adjuvant therapy, pre vs postmenopausal status, node positive vs node negative status, 1st gen (anthracyclines alone) versus 2nd gen (including taxanes) chemotherapy. A two-sided log-rank test with an overall sample size of 2316 (2432 with a 5% dropout rate) (1158 in control and 1158 in treatment group) achieves 80% power at a 0.05 significance level to detect a hazard ratio of 0.80 when the proportion surviving in the control group is 0.70. An interim with respect to safety is planned in the protocol. Expected results and conclusion-Ours is a large, prospective trial evaluating the efficacy of concurrent chemo-endocrine therapy in HR+ BC patients. This has the potential to improve pCR rates in the neoadjuvant setting and change the standard of care in the management of HR+ BC patients. The biomarker analysis will help us further understand the biology of HR+ BC and shed light upon tumour dormancy signatures.
Citation Format: Shalaka Joshi, Sridevi Murali-Nanavati, Vaibhav Vanmali, Rohini Hawaldar, Mujahid Gafur Shaikh, Mohammad Sadique Ansari, Sushmita Rath, Jaya Ghosh, Seema Gulia, Jyoti Bajpayi, Nita Nair, Vani Parmar, Purvi Thakkar, Garvit Chitkara, Tanuja Shet, Sangeeta Desai, Ayushi Sahay, Sudeep Gupta, Rajendra Badwe. Concurrent versus sequential chemo-endocrine therapy in er positive and her2 negative non-metastatic breast cancer- an open-label, phase III, randomized controlled trial [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 OT1-08-01.