Abstract 4P
Background
HR+/HER2+ BC is heterogeneous and there is a need to identify predictive biomarkers. We previously reported the ability of the PAM50-based CES to predict chemoendocrine sensitivity in HR+/HER2-negative BC beyond intrinsic subtype and risk of relapse (ROR) (Prat.CCR.2017). Here we evaluate the association of CES with pCR and DFS following different anti-HER2 combinations in HR+/HER2+ BC.
Methods
Intrinsic subtype and clinicopathologic data were obtained from 8 independent studies for a total of 485 HR+/HER2+ early BC. Patients (pts) were treated with anti-HER2 therapy either with endocrine therapy (PAMELA and PER-ELISA) or with chemotherapy (CHERLOB, OptiHER, LPT109096, ICO, HCB, PER-ELISA and CALGB 40601 [Alliance]). CES was evaluated as a continuous variable and categorically (CES-E [endocrine-sensitive], CES-U [uncertain] and CES-C [chemosensitive]) using previously reported cutoffs. We first performed statistical analyses in each dataset individually, and then all 8 combined. Multivariable analyses were used to test the association of the CES score with pCR and DFS.
Results
In the combined cohort, CES-E, CES-U and CES-C were identified in 16%, 22% and 62% of the pts, respectively. CES (continuous variable) was associated with higher pCR rates independent of clinical characteristics, treatment type, intrinsic subtype and study (adjusted Odd Ratio [OR]=0.42; p = 0.02). In the PER-ELISA trial, CES was also found associated with response (decrease in ki67) following 2 weeks of letrozole alone (OR=29.1, p 0.01). 295 pts (CHERLOB, ICO, HCB and CALGB40601) were analyzed for DFS with a median follow-up of 66 months (IQR 37-82). The adjusted DFS hazard ratio of the CES (continuous variable) was 0.13 (p < 0.01) independent of pCR, clinical characteristics, ROR and intrinsic subtype. In pts without pCR, disease recurrence occurred in 4% of CES-E, 19% of CES-U and 34% of CES-C pts (p < 0.01).
Conclusions
In HR+/HER+ BC, CES shows clinical validity for predicting chemoendocrine sensitivity in combination with anti-HER2 targeted therapies and is a good prognostic factor beyond intrinsic subtype and clinicopathologic characteristics.
Clinical trial identification
CALGB-40601: NCT00770809; Per-ELISA: NCT02411344; SOLTI-PAMELA: NCT01973660; SOLTI-Opti-HER:NCT01669239; LPT109096: NCT00524303; CHERLOB: NCT00429299.
Editorial acknowledgement
Legal entity responsible for the study
Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS).
Funding
Becas FSEOM para Formación en Investigación en Centros de Referencia en el Extranjero 2018 (TP). Fundación SEOM, Becas FSEOM para Formación en Investigación en Centros de Referencia en el Extranjero 2016 (AF-M). Conquer Cancer Foundation -YIA in Breast Cancer 2019 (GG). BCRF, Susan G Komen, NCI SPORE (P50-CA58823), R01-CA229409 and Alliance U10CA180821(LAC, CMP). Instituto de Salud Carlos III - PI16/00904 (AP), Pas a Pas (AP), Save the Mama (AP), Breast Cancer Now - 2018NOVPCC1294 (AP).
Disclosure
M.V. Dieci: Honoraria (self): Genomic Health; Honoraria (self): Eli Lilly; Honoraria (self): Celgene. S. Pernas Simon: Travel/Accommodation/Expenses: Roche; Travel/Accommodation/Expenses: Novartis; Advisory/Consultancy: Polyphor; Advisory/Consultancy: TFS. J. Gavila Gregori: Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Roche; Honoraria (self), Advisory/Consultancy: Novartis; Honoraria (self), Advisory/Consultancy: Pfizer; Honoraria (self), Advisory/Consultancy: MSD Oncology. V. Guarneri: Honoraria (self): Eli Lilly; Honoraria (self): Roche/Genentech; Honoraria (self): Novartis. P. Villagrasa: Speaker Bureau/Expert testimony: NanoString Technologies. M.J. Vidal: Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Roche; Honoraria (self): Daiichi Sankyo; Honoraria (self), Advisory/Consultancy: Novartis; Honoraria (self), Travel/Accommodation/Expenses: Pfizer. M. Oliveira: Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): Philips Healthcare; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Genentech/Roche; Honoraria (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Novartis; Research grant/Funding (institution): Immunomedics; Honoraria (self), Research grant/Funding (institution): Seattle Genetics; Advisory/Consultancy, Research grant/Funding (institution): GSK; Research grant/Funding (institution): Boehringer-Ingelheim; Advisory/Consultancy, Research grant/Funding (institution): PUMA Biotechnology; Research grant/Funding (institution): Zenith Epigenetics; Travel/Accommodation/Expenses: Pierre-Fabre; Travel/Accommodation/Expenses: GP Pharma; Travel/Accommodation/Expenses: Grünenthal; Travel/Accommodation/Expenses: Eisai. C.M. Perou: Advisory/Consultancy, Shareholder/Stockholder/Stock options: BioClassifier LLC; Licensing/Royalties: Breast PAM50 assay. A. Prat: Honoraria (self), Travel/Accommodation/Expenses: Daiichi Sankyo; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): Novartis; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): Roche; Honoraria (self), Advisory/Consultancy: Pfizer; Honoraria (self): MSD Oncology; Honoraria (self): Lilly; Advisory/Consultancy: NanoString Technologies; Advisory/Consultancy: Amgen; Advisory/Consultancy: Bristol-Myers Squibb. All other authors have declared no conflicts of interest.