Molecular Correlates of Response to Eribulin and Pembrolizumab in Hormone Receptor-positive Metastatic Breast Cancer

Overview

Journal Nat Commun

Specialty Biology

Date 2021 Sep 22

PMID 34548479

Citations 20

Authors

Tanya E Keenan

Jennifer L Guerriero

Romualdo Barroso-Sousa

Tianyu Li

Tess OMeara

Anita Giobbie-Hurder

Nabihah Tayob

Jiani Hu

Mariano Severgnini

Judith Agudo

Ines Vaz-Luis

Leilani Anderson

Victoria Attaya

Jihye Park

Jake Conway

Meng Xiao He

Brendan Reardon

Erin Shannon

Gerburg Wulf

Laura M Spring

Rinath Jeselsohn

Ian Krop

Nancy U Lin

Ann Partridge

Eric P Winer

Elizabeth A Mittendorf

David Liu

Eliezer M Van Allen

Sara M Tolaney

Affiliations

Soon will be listed here.

Abstract

Immune checkpoint inhibitors (ICIs) have minimal therapeutic effect in hormone receptor-positive (HR+ ) breast cancer. We present final overall survival (OS) results (n = 88) from a randomized phase 2 trial of eribulin ± pembrolizumab for patients with metastatic HR+ breast cancer, computationally dissect genomic and/or transcriptomic data from pre-treatment tumors (n = 52) for molecular associations with efficacy, and identify cytokine changes differentiating response and ICI-related toxicity (n = 58). Despite no improvement in OS with combination therapy (hazard ratio 0.95, 95% CI 0.59-1.55, p = 0.84), immune infiltration and antigen presentation distinguished responding tumors, while tumor heterogeneity and estrogen signaling independently associated with resistance. Moreover, patients with ICI-related toxicity had lower levels of immunoregulatory cytokines. Broadly, we establish a framework for ICI response in HR+ breast cancer that warrants diagnostic and therapeutic validation. ClinicalTrials.gov Registration: NCT03051659.

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References

Newman A, Steen C, Liu C, Gentles A, Chaudhuri A, Scherer F . Determining cell type abundance and expression from bulk tissues with digital cytometry. Nat Biotechnol. 2019; 37(7):773-782. PMC: 6610714. DOI: 10.1038/s41587-019-0114-2. View

. Comprehensive molecular portraits of human breast tumours. Nature. 2012; 490(7418):61-70. PMC: 3465532. DOI: 10.1038/nature11412. View

Dirix L, Takacs I, Jerusalem G, Nikolinakos P, Arkenau H, Forero-Torres A . Avelumab, an anti-PD-L1 antibody, in patients with locally advanced or metastatic breast cancer: a phase 1b JAVELIN Solid Tumor study. Breast Cancer Res Treat. 2017; 167(3):671-686. PMC: 5807460. DOI: 10.1007/s10549-017-4537-5. View

Sobral-Leite M, Salomon I, Opdam M, Kruger D, Beelen K, van der Noort V . Cancer-immune interactions in ER-positive breast cancers: PI3K pathway alterations and tumor-infiltrating lymphocytes. Breast Cancer Res. 2019; 21(1):90. PMC: 6686400. DOI: 10.1186/s13058-019-1176-2. View

George S, Miao D, Demetri G, Adeegbe D, Rodig S, Shukla S . Loss of PTEN Is Associated with Resistance to Anti-PD-1 Checkpoint Blockade Therapy in Metastatic Uterine Leiomyosarcoma. Immunity. 2017; 46(2):197-204. PMC: 5408320. DOI: 10.1016/j.immuni.2017.02.001. View

Perez-Garcia J, Llombart-Cussac A, G Cortes M, Curigliano G, Lopez-Miranda E, Alonso J . Pembrolizumab plus eribulin in hormone-receptor-positive, HER2-negative, locally recurrent or metastatic breast cancer (KELLY): An open-label, multicentre, single-arm, phase Ⅱ trial. Eur J Cancer. 2021; 148:382-394. DOI: 10.1016/j.ejca.2021.02.028. View

Shen R, Seshan V . FACETS: allele-specific copy number and clonal heterogeneity analysis tool for high-throughput DNA sequencing. Nucleic Acids Res. 2016; 44(16):e131. PMC: 5027494. DOI: 10.1093/nar/gkw520. View

Feng F, Thompson M, Thomas B, Duffy E, Kim J, Kurosawa S . A computational solution to improve biomarker reproducibility during long-term projects. PLoS One. 2019; 14(4):e0209060. PMC: 6469750. DOI: 10.1371/journal.pone.0209060. View

Eisenhauer E, Therasse P, Bogaerts J, Schwartz L, Sargent D, Ford R . New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2008; 45(2):228-47. DOI: 10.1016/j.ejca.2008.10.026. View

10.

Schmid P, Adams S, Rugo H, Schneeweiss A, Barrios C, Iwata H . Atezolizumab and Nab-Paclitaxel in Advanced Triple-Negative Breast Cancer. N Engl J Med. 2018; 379(22):2108-2121. DOI: 10.1056/NEJMoa1809615. View

11.

Gettinger S, Choi J, Hastings K, Truini A, Datar I, Sowell R . Impaired HLA Class I Antigen Processing and Presentation as a Mechanism of Acquired Resistance to Immune Checkpoint Inhibitors in Lung Cancer. Cancer Discov. 2017; 7(12):1420-1435. PMC: 5718941. DOI: 10.1158/2159-8290.CD-17-0593. View

12.

Miao D, Margolis C, Gao W, Voss M, Li W, Martini D . Genomic correlates of response to immune checkpoint therapies in clear cell renal cell carcinoma. Science. 2018; 359(6377):801-806. PMC: 6035749. DOI: 10.1126/science.aan5951. View

13.

Tarhini A, Zahoor H, Lin Y, Malhotra U, Sander C, Butterfield L . Baseline circulating IL-17 predicts toxicity while TGF-β1 and IL-10 are prognostic of relapse in ipilimumab neoadjuvant therapy of melanoma. J Immunother Cancer. 2015; 3:39. PMC: 4570556. DOI: 10.1186/s40425-015-0081-1. View

14.

Danaher P, Warren S, Lu R, Samayoa J, Sullivan A, Pekker I . Pan-cancer adaptive immune resistance as defined by the Tumor Inflammation Signature (TIS): results from The Cancer Genome Atlas (TCGA). J Immunother Cancer. 2018; 6(1):63. PMC: 6013904. DOI: 10.1186/s40425-018-0367-1. View

15.

Ayers M, Lunceford J, Nebozhyn M, Murphy E, Loboda A, Kaufman D . IFN-γ-related mRNA profile predicts clinical response to PD-1 blockade. J Clin Invest. 2017; 127(8):2930-2940. PMC: 5531419. DOI: 10.1172/JCI91190. View

16.

Skoulidis F, Goldberg M, Greenawalt D, Hellmann M, Awad M, Gainor J . Mutations and PD-1 Inhibitor Resistance in -Mutant Lung Adenocarcinoma. Cancer Discov. 2018; 8(7):822-835. PMC: 6030433. DOI: 10.1158/2159-8290.CD-18-0099. View

17.

Gainor J, Shaw A, Sequist L, Fu X, Azzoli C, Piotrowska Z . EGFR Mutations and ALK Rearrangements Are Associated with Low Response Rates to PD-1 Pathway Blockade in Non-Small Cell Lung Cancer: A Retrospective Analysis. Clin Cancer Res. 2016; 22(18):4585-93. PMC: 5026567. DOI: 10.1158/1078-0432.CCR-15-3101. View

18.

Terranova-Barberio M, Pawlowska N, Dhawan M, Moasser M, Chien A, Melisko M . Exhausted T cell signature predicts immunotherapy response in ER-positive breast cancer. Nat Commun. 2020; 11(1):3584. PMC: 7367885. DOI: 10.1038/s41467-020-17414-y. View

19.

Nanda R, Liu M, Yau C, Shatsky R, Pusztai L, Wallace A . Effect of Pembrolizumab Plus Neoadjuvant Chemotherapy on Pathologic Complete Response in Women With Early-Stage Breast Cancer: An Analysis of the Ongoing Phase 2 Adaptively Randomized I-SPY2 Trial. JAMA Oncol. 2020; 6(5):676-684. PMC: 7058271. DOI: 10.1001/jamaoncol.2019.6650. View

20.

Sade-Feldman M, Jiao Y, Chen J, Rooney M, Barzily-Rokni M, Eliane J . Resistance to checkpoint blockade therapy through inactivation of antigen presentation. Nat Commun. 2017; 8(1):1136. PMC: 5656607. DOI: 10.1038/s41467-017-01062-w. View