Abstract 141P
Background
Gene-expression landscape may reveal biological pathways associated with pathological complete response (pCR) and Ki67 down-regulation to chemo-free regimens in the NA-PHER2 study.
Methods
Patients with ER+/HER2+ BC were treated in two non-randomized cohorts with neoadjuvant trastuzumab, pertuzumab, palbociclib with (Fulv, n=30) or without (NoFulv, n=28) fulvestrant (+/-LHRH analogues). We performed RNA-seq on core biopsies obtained pre-treatment [n=53/58 (91.4%)], at week 2 [n=49/58 (84.5%)], and on residual disease at surgery [SX, n=42/45 (93.3%)]. We investigated curated gene sets from Hallmark (n=50), KEGG (n=186) and Reactome (n=1520). We evaluated in the overall population and in each cohort the association with pCR and Ki67 dynamic (pre-treatment, week 2, SX). Significance defined by Benjamini-Hochberg adjusted p<0.05.
Results
In the biomarker population, pCR rate was 28.6% and 16.0% in Fulv and NoFulv cohorts, respectively. High pre-treatment expression of interferons, allograft rejection, IL6/JAK/STAT3 and IL2/STAT5 signaling were associated with pCR, whereas NOTCH signaling and glycerophospholipid biosynthesis with residual disease. In Fulv cohort, high expression of metabolic pathways (i.e., reactive oxygen species, fatty acid metabolism) and PI3K/AKT/mTOR signaling were associated with pCR. At week 2, most of these pathways were also predictive of pCR, with the addition of trafficking and processing of endosomal toll-like receptors (TLR, p=4.0E-06, adj p=0.006), with a similar effect in Fulv and NoFulv cohorts (p=0.001 and p=0.0006, respectively). Pre-treatment signatures were poorly predictive of Ki67 dynamic. Among tumor with low Ki67 (Ki67<10%) at week 2, 71% had a rebound at SX (Ki67>=10%). High pre-treatment NOTCH signaling was predictive of rebound.
Conclusions
In ER+/HER2+ BC, pre- and on-treatment expression of interferon, JAK/STAT and TLR-related signatures were associated with pCR. Metabolic pathways emerged as associated with both sensitivity and resistance in Fulvestrant cohort. NOTCH signaling was associated with lower pCR rate and Ki67 rebound at SX, indicating a significant role of this pathway in resistance.
Clinical trial identification
NCT02530424.
Editorial acknowledgement
Legal entity responsible for the study
Fondazione Michelangelo, Milan, Italy.
Funding
Foundations: Breast Cancer Research Foundation; Associazione Italiana per la Ricerca sul Cancro (AIRC) (IG 21787). The study was supported by an unrestricted grant from Roche S.p.A. Italy and Pfizer Italia S.R.L.
Disclosure
M.A. Colleoni: Financial Interests, Institutional, Research Grant: Roche; Non-Financial Interests, Personal, Member: Breast International Group; Non-Financial Interests, Personal, Leadership Role: International Breast Cancer Study Group. M. Mansutti: Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: Eli Lilly; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Advisory Board: MSD Italia; Financial Interests, Personal, Advisory Board: Eisai; Financial Interests, Personal, Advisory Board: Pierre Fabre; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Advisory Board: Celgene; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Invited Speaker: Eli Lilly; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Invited Speaker: EISAI. C. Zamagni: Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Other, travel accomodation: Roche; Financial Interests, Personal, Advisory Board: Eisai; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Other, travel accomodation: Novartis; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Other, travel accomodation: Pfizer; Financial Interests, Personal, Advisory Board: PharmaMar; Financial Interests, Personal, Other, travel accomodation: PharmaMar; Financial Interests, Personal, Advisory Board: Amgen; Financial Interests, Personal, Advisory Board: Tesaro; Financial Interests, Personal, Other, travel accomodation: Tesaro; Financial Interests, Personal, Advisory Board: QuintilesIMS; Financial Interests, Personal, Other, travel accomodation: PierreFabre; Financial Interests, Personal, Other, travel accomodation: Istituto Gentili; Financial Interests, Personal, Advisory Board: Lilly; Financial Interests, Personal, Advisory Board: Celgene; Financial Interests, Personal, Other, travel accomodation: Celgene; Financial Interests, Institutional, Funding, research funding to Institution: Roche; Financial Interests, Institutional, Funding, research funding to Institution: Novartis; Financial Interests, Institutional, Funding, research funding to Institution: AstraZeneca; Financial Interests, Institutional, Funding, research funding to Institution: Pfizer; Financial Interests, Institutional, Funding, research funding to Institution: Seattle Genetics; Financial Interests, Institutional, Funding, research funding to Institution: Tesaro; Financial Interests, Institutional, Funding, research funding to Institution: Pierre Fabre; Financial Interests, Institutional, Funding, research funding to Institution: Istituto Gentili; Financial Interests, Institutional, Funding, research funding to Institution: Takeda; Financial Interests, Institutional, Funding, research funding to Institution: TEVA; Financial Interests, Institutional, Funding, research funding to Institution: Medivation; Financial Interests, Institutional, Funding, research funding to Institution: AbbVie; Financial Interests, Institutional, Funding, research funding to Institution: Array BioPharma; Financial Interests, Institutional, Funding, research funding to Institution: Morphotek; Financial Interests, Institutional, Funding, research funding to Institution: Synthon; Non-Financial Interests, Personal, Leadership Role: Europa Donna italy, Susan J Komen Emilia-Romagna, LOTO Onlus, Mamazone Sudtirol; Non-Financial Interests, Personal, Member: Europa Donna italy, Susan J Komen Emilia-Romagna, LOTO Onlus, Mamazone Sudtirol. L. Del Mastro: Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Invited Speaker: Eli Lilly; Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Invited Speaker: Ipsen; Financial Interests, Institutional, Other, edicational events: Novartis; Financial Interests, Personal, Other, travel grant: Roche; Financial Interests, Personal, Other, travel grant: Pfizer; Financial Interests, Personal, Other, travel grant: Celgene; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Advisory Board: Eli Lilly; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Personal, Advisory Board: Genomic Health; Financial Interests, Personal, Advisory Board: Pierre Fabre; Financial Interests, Personal, Advisory Board: Daiichi Sankyo; Financial Interests, Personal, Advisory Board: Seagen; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Eisai. A. Frassoldati: Financial Interests, Personal, Advisory Role: Roche; Financial Interests, Personal, Advisory Role: Novartis; Financial Interests, Personal, Advisory Role: Daiichi Sankyo; Financial Interests, Personal, Advisory Role: Seagen; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Invited Speaker: Amgen. G. Viale: Financial Interests, Personal, Advisory Board: Roche Genentech; Financial Interests, Personal, Advisory Board: MSD Oncology; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Advisory Board: Daiichi Sankyo; Financial Interests, Personal, Advisory Board: Ventana; Financial Interests, Personal, Advisory Board: Dako Agilent; Financial Interests, Personal, Advisory Role: Menarini; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Role: AstraZeneca; Financial Interests, Institutional, Other, Research contract: Roche; Financial Interests, Institutional, Other, Research contract: Cepheid; Financial Interests, Institutional, Other, Research contract: Dako Agilent; Financial Interests, Institutional, Other, Research contract: Ventana. M. Callari: Financial Interests, Personal, Advisory Role: Novartis. L. Gianni: Financial Interests, Personal, Advisory Board: ADC Therapeutics; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Celgene; Financial Interests, Personal, Advisory Board: Eli Lilly; Financial Interests, Personal, Advisory Board: G1 Therapeutics; Financial Interests, Personal, Advisory Board: GENENTECH; Financial Interests, Personal, Advisory Board: Genomic Health; Financial Interests, Personal, Advisory Board: Merck Sharp & Dohme; Financial Interests, Personal, Advisory Board: Oncolytics Biotech; Financial Interests, Personal, Advisory Board: Odonate Therapeutics; Financial Interests, Personal, Advisory Role: Odonate Therapeutics; Financial Interests, Personal, Advisory Board: Onkaido Therapeutics; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Other, Support for attending meeting: Pfizer; Financial Interests, Personal, Advisory Board: Taiho Pharmaceutical; Financial Interests, Personal, Advisory Board: Hexal Sandoz; Financial Interests, Personal, Advisory Board: Seattle Genetics; Financial Interests, Personal, Advisory Board: Synthon; Financial Interests, Personal, Advisory Board: Zymeworks; Financial Interests, Personal, Advisory Role: Zymeworks; Financial Interests, Personal, Advisory Board: Sanofi Aventis; Financial Interests, Personal, Advisory Role: Forty Seven (CD47); Financial Interests, Personal, Advisory Role: Genenta; Financial Interests, Personal, Advisory Role: METIS Precision Medicine; Financial Interests, Personal, Advisory Role: Novartis; Financial Interests, Personal, Advisory Role: Revolution Medicines; Financial Interests, Personal, Advisory Role: Synaffix; Financial Interests, Personal, Advisory Role: MENARINI RICERCHE; Financial Interests, Personal, Advisory Role: AMGEN; Financial Interests, Personal, Advisory Role: Biomedical Insights Inc; Financial Interests, Institutional, Funding, Support For Research Projects: Zymeworks; Financial Interests, Institutional, Funding, Support For Research Projects: Revolution Medicines; Other, Personal, Other, Co-Inventor of \"European Patent Application N. 12195182.6 and 12196177.5\" titled \"PDL-1 expression in anti-HER2 therapy\"- Roche - Issued No compensation provided: Roche. G. Bianchini: Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Invited Speaker: Lilly; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Invited Speaker: Neopharm Israel; Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Personal, Invited Speaker: Chugai; Financial Interests, Personal, Invited Speaker: Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: Eisai; Financial Interests, Personal, Training: MSD; Financial Interests, Personal, Training: Pfizer; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Advisory Board: Daiichi Sankyo; Financial Interests, Personal, Advisory Board: Lilly; Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Genomic Health; Financial Interests, Personal, Advisory Board: Eisai; Financial Interests, Personal, Advisory Board: Amgen; Financial Interests, Personal, Advisory Board: Sanofi; Financial Interests, Personal, Other, travel grants: Roche; Financial Interests, Personal, Other, travel grants: Pfizer; Financial Interests, Personal, Other, travel grants: AstraZeneca; Financial Interests, Personal, Other, travel grants: Eisai. All other authors have declared no conflicts of interest.