Abstract P5-06-06: Clinically significant changes of receptors status (ER, PR and HER2) after receiving neoadjuvant chemotherapy (NACT) in breast cancer (BC) predicts the prognosis and guides the choice of the optimal adjuvant therapy (AT): Retesting of the receptor status should be mandatory
Authors: Abdel-Fatah Tarek M. a. , Webb Rebekah , Walker Jennifer , Lim Jun , Pockley A. Graham , Ball Graham , Griffiths Matthew , Ellis Ian , Rakhah Emad , Hodi Zsolt , Lee Andrew , Chan Arlene , Chan Stephen 
Published: March 2020

Background: NACT is a standard option for BC (T2-4, N0-3, M0) and certain BC phenotypes. The choice of AT based on the pre-NACT biomarkers status may not be optimum for individual patient because dynamic phenotypic changes induced by NACT may alter the response to treatment. Aim: The aim of this study is to determine the incidence of changes in the receptor status (ER, PR and HER2) and other proliferation biomarkers (Ki67 and SPAG5) before and after NACT and to assess the clinical significance of such changes. Methods Immunohistochemistry staining of ER, PR, HER2, Ki67 and SPAG5 in pre and post NACT tumors tissues from a consecutive series of 850 of BC (T2-4, N0-3, M0) treated at the Nottingham University Hospital (NUH) from 2000 to 2018, have been centrally evaluated according to ASCO guidelines. All cases with conversion in HER2 status had also been retested by HER2-FISH. The results were validated in an external cohort of 250 cases. Treatment options and patients characteristics are the same between the centres: (68%) received anthracycline plus Taxane (AC+T) NACT and 32% of patients have received NACT Anthracycline only (AC). Neoadjuvant HER2 targeting agents (Trastuzumab) or (Trastuzumab + Petruzumab) had been prescribed to 16% of patients in addition to AC+T followed by adjuvant Trastuzumab (total=18 cycles). All pre-NACT ER+ patients were given at least 5 year of adjuvant endocrine therapy (ET). In 2013 NUH started a prospective audit of retesting of receptor status in all post NACT surgical tumour samples. The results of the tests were presented to the weekly tumour board meeting and any change in the receptor status (ER and HER2) from negative (in the pre NACT core biopsies) to positive (in the post NACT surgical specimen) being considered for additional AT (ET for ER+ and Trastuzumab for HER2+ cases).The primary end points for this study are the % changes of biomarker changes and the disease free survival (DFS). The median follow up was 72 months. Results In pre NACT core biopsies 32% and 68% were HER2+ and HER2-; respectively. Twelve percent (12%) of the pre NACT HER2- tumours had a conversion to HER2+ in the post NACT surgical specimens. In this group of patients who subsequently received adjuvant Trastuzumab, 95% 3-year DFS was reported; which was similar to those patients who achieved pCR (3-year DFS; 90%) and was superior to cases which remained HER- in post NACT specimens (3-year DFS; 41%); (p&lt;0.0001). Furthermore, similar group of patients with pre NACT HER- tumour before the 2013 audit, who did not receive Trastuzumab for the change to post NACT HER2+ receptors, has inferior 3-year DFS to those received adjuvant Trastuzumab based on the conversion (HR (95% CI)= 7.40 (1.04-52.86); p=0.046). In pre NACT HER2+ BC, 20% of cases had been converted into HER2- in the post NACT surgical specimens. These patients had better 3y-DFS (94%) compared to those who remained HER2+ in post NACT specimens (3y-DFS=70%; HR (95% CI)= 0.86 (0.77-0.97); p=0.01). Furthermore those patients who received neoadjuvant HER2 targeting therapy had statistically higher incidence of post HER2- conversion (p=0.005) and lower level of post NACT proliferation markers (Ki67 and SPAG5); p=0.01. In pre NACT ER+/PR+ patients, those who has converted into ER+/PR- in post NACT specimens had shorter 5-year DFS (40%) in spite of receiving ET, compared to those who remained ER+/PR+ in post NACT specimen [5-DFS= 72%]; HR (95% CI)= 1.98 (1.18-3.31); p=0.009). Conclusion: To our knowledge, this is the first report, which showed the significant clinical benefit of adjuvant therapy, based on the re-testing of the standard receptors status.

Citation Format: Tarek M. a. Abdel-Fatah, Rebekah Webb, Jennifer Walker, Jun Lim, A. Graham Pockley, Graham Ball, Matthew Griffiths, Ian Ellis, Emad Rakhah, Zsolt Hodi, Andrew Lee, Arlene Chan, Stephen Chan. Clinically significant changes of receptors status (ER, PR and HER2) after receiving neoadjuvant chemotherapy (NACT) in breast cancer (BC) predicts the prognosis and guides the choice of the optimal adjuvant therapy (AT): Retesting of the receptor status should be mandatory [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-06-06.