Abstract 10P
Background
Various predictive biomarkers regarding PI3K inhibitors in patients with estrogen receptor-positive breast cancer (BC) have been identified, including oncogenic alterations in PIK3CA, but the main response and resistance pathways are still unknown. Here we explored the transcriptomic landscape and response to the PIK3CA inhibitor taselisib and endocrine therapy in relation to PIK3CA mutations and treatment in the LORELEI trial (NCT02273973).
Methods
LORELEI enrolled postmenopausal patients with HR-positive/HER2-negative early BC. Neoadjuvant therapy was given for 16 weeks. RNA sequencing (RNAseq) was performed on baseline tumor biopsies. Gene set and cell type enrichment analyses were performed using fgsea and xCell. Intrinsic subtypes by AIMS were calculated. PIK3CA status was assessed using a ISO15189-validated assay. Overall response rate by centrally assessed breast MRI classified tumors as responders (complete or partial response) and non-responders.
Results
RNAseq data were generated for 187 patients (56% of the entire population enrolled in the trial). In total, 78% had T2, 67% N0 and 63% grade 2 tumors, and 64% had invasive ductal carcinoma. There were 81 patients with PIK3CA mutant (MT) and 106 patients with PIK3CA wild-type (WT) tumors, with MT tumors enriched in Luminal A subtypes compared to WT tumors (Fisher’s test, p<0.01). We observed an enrichment of the epithelial mesenchymal transition gene set and the hematopoietic stem cell type in MT tumors, while WT tumors were enriched in proliferation and immune related gene sets. Among the 187 tumors, 77 (41%) were classified as responders and 110 (59%) as non-responders. No difference in PIK3CA mutation-associated gene signature was observed between the two groups. Comparing responders and non-responders with MT tumor indicated no statistically significant difference between intrinsic subtypes. Non-responder PIK3CA MT tumors in the taselisib arm showed enrichment of interferon alpha response and natural killer T cells.
Conclusions
These preliminary results show relevant differences between PIK3CA MT and WT tumors. Non-responders with PIK3CA MT tumors showed enrichment of immune related signaling in the taselisib arm. Further analyses will be presented.
Clinical trial identification
EudraCT 2013-000568-28 (2014-10-16).
Legal entity responsible for the study
The study was run in collaboration with BIG, ABCSG and SOLTI.
Funding
Genentech.
Disclosure
P.G. Nuciforo: Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Advisory Board: MSD Oncology, Bayer; Financial Interests, Personal, Other, Consultant: Targos Molecular Pathology GmbH. E. de Azambuja: Financial Interests, Personal, Advisory Board: Roche/GNE, Novartis, Seagen, MSD; Financial Interests, Personal, Invited Speaker: Zodiac, Libbs, Pierre Fabre, Lilly, AstraZeneca, Gilead Sciences; Financial Interests, Personal, Other, Chair of the Gilead Sciences Research Scholars Program in Solid Tumours: Gilead Sciences; Financial Interests, Institutional, Research Grant: Roche/GNE, AstraZeneca, GSK/Novartis, Servier; Financial Interests, Institutional, Other, Travel Grant: Roche/GNE; Financial Interests, Institutional, Invited Speaker: MSD, ABCSG, Nektar, Gilead, Immunomedics, Synthon, Odonate Therapeutics; Financial Interests, Invited Speaker, ASCENT 04: Gilead; Financial Interests, Invited Speaker, Aphinity, Lorelei, Impassion03: Roche; Financial Interests, Invited Speaker, AURORA: Breast International Group; Financial Interests, Invited Speaker, Olympia: AstraZeneca; Financial Interests, Personal, Other, Travel grant: AstraZeneca; Non-Financial Interests, Advisory Role, Member of the cardio-oncology council: European Society for Cardiology (ESC); Non-Financial Interests, Advisory Role, Belgium governmental institution for cancer: KCE; Non-Financial Interests, Other, Editorial board member: ESMO Open; Non-Financial Interests, Advisory Role: Anticancer Fund; Non-Financial Interests, Leadership Role, President 2023-2026: Belgian Society of Medical Oncology (BSMO). T. Wilson: Financial Interests, Personal, Full or part-time Employment: Genentech; Financial Interests, Personal, Stocks/Shares: Roche. A. Prat: Financial Interests, Personal, Invited Speaker: Roche, 1TRIALSP, S.L.; Financial Interests, Personal, Invited Speaker, Lecture fees: Novartis, Daiichi Sankyo; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Novartis, Pfizer, Oncolytics Biotech, Guardant Health, Peptomyc; Financial Interests, Institutional, Invited Speaker, Clinical trials: Daiichi Sankyo; Financial Interests, Institutional, Other, Contracted research: Boehringer, Medica Scientia inno. Research; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Member of Board of Directors, Leadership role: Reveal Genomics, SL.; Financial Interests, Personal, Stocks/Shares: Reveal Genomics, Oncolytics Biotech; Financial Interests, Personal, Royalties: Reveal Genomics, International Oncology Bureau, S.L.,; Financial Interests, Institutional, Invited Speaker: Roche, AstraZeneca, Novartis; Financial Interests, Personal and Institutional, Invited Speaker: Daiichi Sankyo; Non-Financial Interests, Institutional, Other, Leadership roles: Patronage committee: SOLTI Foundation, Actitud Frente al Cáncer Foundation; Non-Financial Interests, Personal, Other, Asociación Española de Investigación sobre el Cáncer: ASEICA. M. Filipits: Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker: Boehringer Ingelheim, Eli Lilly, Biorad, Merck, Novartis. G. Pfeiler: Financial Interests, Personal, Other, Grants and Honoraria: Pfizer, Seagen, Daiichi, Roche Accord, Lilly, Novartis, AstraZeneca, Menarini, Merck, MSD, Gilead. J. Aimi, C. Metcalfe: Financial Interests, Personal, Full or part-time Employment: Genentech; Financial Interests, Personal, Stocks/Shares: Roche. T.J. Stout: Financial Interests, Personal, Full or part-time Employment: Genentech. S. El-Abed: Financial Interests, Personal, Full or part-time Employment: Breast International Group; Financial Interests, Institutional, Research Grant: Genentech, Pfizer, AstraZeneca, BCRF. M.I. Gnant: Financial Interests, Personal, Invited Speaker: AstraZeneca, Novartis, PierreFabre, Amgen, EPG Health; Financial Interests, Personal, Advisory Board: DaiichiSankyo, Eli Lilly, MSD, Menarini-Stemline; Financial Interests, Personal, Expert Testimony: Veracyte; Financial Interests, Personal, Member of Board of Directors: ABCSG GmbH, ABCSG Research Services GmbH; Financial Interests, Invited Speaker: Pfizer, AstraZeneca, Eli Lilly; Other, Spouse is employed by Sandoz: Sandoz. M. Oliveira: Financial Interests, Personal, Advisory Board: AstraZeneca, Daiichi Sankyo / AstraZeneca, Gilead, Lilly, MSD, Relay Therapeutics, Roche, Seagen, Cureo Science, iOne, Pfizer; Financial Interests, Personal, Invited Speaker: Eisai, Gilead, Pfizer, Roche, Seagen, AstraZeneca, Lilly, Medscape, AstraZeneca, AstraZeneca; Financial Interests, Personal, Other, Educational activity: Libbs; Financial Interests, Institutional, Invited Speaker: AstraZeneca, Boehringer-Ingelheim, GSK, Roche, Seattle Genetics, Zenith Epigenetics, Gilead, Ayala Pharmaceuticals, Pfizer; Financial Interests, Invited Speaker: Roche; Non-Financial Interests, Member of Board of Directors, Head: SOLTI Breast Cancer Research; Other, Travel Grant: Pierre Fabre, Eisai, Gilead, AstraZeneca. C. Saura Manich: Financial Interests, Personal, Advisory Board: AstraZeneca, Daiichi Sankyo, Eisai, Exact Sciences, Exeter Pharma, F. Hoffmann - La Roche Ltd., Gilead, Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Philips, Pierre Fabre, PintPharma, Puma, Roche Farma, Sanofi Avenits, Seagen, Zymeworks, Pharmalex Spain SLU; Financial Interests, Personal, Expert Testimony: Boehringer Ingelheim, Bristol Meyers Squibb, Genentech, Innoup, Millenium; Financial Interests, Personal, Other, SC: Byondis B.V., GSK, Macrogenics, Menarini, Merus, Synthon Biopharpaceuticals; Financial Interests, Institutional, Research Grant: AstraZeneca, Bayer Pharma, Boehringer Ingelheim, Bristol Myers Squibb (BMS), Cytomx Therapeutics, Daiichi Sankyo, Eli Lilly and Company, F. Hoffmann-La Roche Ltd., Genentech, GSK, Immunomedics, Innoup Farma, Macrogenics, Menarini Ricerche, Merus, Novartis, Pfizer, Puma, Roche, Sanofi-Aventis, Seattle Genetics; Financial Interests, Institutional, Invited Speaker: Byondis B.V.; Non-Financial Interests, Member: Spanish Society of Medical Oncology (SEOM), American Society for Clinical Oncology (ASCO), Geicam (Spanish Breast Cancer Research Group), European Society for Medical Oncology (ESMO), Sinology Society of the Official College of Physicians of Barcelona (COMB); Non-Financial Interests, Member, Junta Directiva y Comité Científico: SOLTI group (Academic research group in breast cancer). F. André: Financial Interests, Personal, Advisory Board: Lilly France; Financial Interests, Institutional, Advisory Board: AstraZeneca, Daiichi Sankyo, Roche, Lilly, Pfizer, Owkin, Novartis, Guardant Health, N-Power Medicine, Servier, Gilead, Boston Pharmaceutics; Financial Interests, Institutional, Research Grant: AstraZeneca, Lilly, Novartis, Pfizer, Roche, Daiichi, Guardant Health, Owkin. C. Sotiriou: Financial Interests, Institutional, Advisory Board: Astellas, Vertex, Seattle Genetics, Amgen, Inc., Merck & Co; Financial Interests, Personal, Advisory Board: Cepheid, Puma; Financial Interests, Personal, Invited Speaker: Eisai, Prime oncology, Teva; Financial Interests, Institutional, Other, Travel: Roche; Financial Interests, Institutional, Other, Internal speaker: Genentech; Financial Interests, Personal, Other, Regional speaker: Pfizer; Financial Interests, Institutional, Invited Speaker: Exact Sciences. All other authors have declared no conflicts of interest.