Molecular correlates of response to eribulin and pembrolizumab in hormone receptor-positive metastatic breast cancer

Tanya E Keenan; Jennifer L Guerriero; Romualdo Barroso-Sousa; Tianyu Li; Tess O'Meara; 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

doi:10.1038/s41467-021-25769-z

Molecular correlates of response to eribulin and pembrolizumab in hormone receptor-positive metastatic breast cancer

Nat Commun. 2021 Sep 21;12(1):5563. doi: 10.1038/s41467-021-25769-z.

Authors

Tanya E Keenan^#^{1

2

3}, Jennifer L Guerriero^#^{4

5

6}, Romualdo Barroso-Sousa^#^{1

3

7}, Tianyu Li⁸, Tess O'Meara^{1

3}, Anita Giobbie-Hurder⁸, Nabihah Tayob⁸, Jiani Hu⁸, Mariano Severgnini⁹, Judith Agudo¹⁰, Ines Vaz-Luis¹¹, Leilani Anderson^{1

3}, Victoria Attaya^{1

3}, Jihye Park^{1

2}, Jake Conway^{1

2}, Meng Xiao He^{1

2

12}, Brendan Reardon^{1

2}, Erin Shannon², Gerburg Wulf¹³, Laura M Spring¹⁴, Rinath Jeselsohn^{1

3}, Ian Krop^{1

3}, Nancy U Lin^{1

3}, Ann Partridge^{1

3}, Eric P Winer^{1

3}, Elizabeth A Mittendorf^{3

4

5

6}, David Liu^{1

2}, Eliezer M Van Allen^{15

16}, Sara M Tolaney^{17

18}

Affiliations

¹ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
² Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA.
³ Breast Oncology Program, Dana-Farber/Brigham and Women's Cancer Center, Boston, MA, USA.
⁴ Breast Tumor Immunology Laboratory, Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
⁵ Division of Breast Surgery, Department of Surgery, Brigham and Women's Hospital, Boston, MA, USA.
⁶ Ludwig Center for Cancer Research at Harvard, Harvard Medical School, Boston, MA, USA.
⁷ Oncology Center, Hospital Sírio-Libanês, Brasília, Brazil.
⁸ Division of Biostatistics, Department of Data Sciences, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
⁹ Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
¹⁰ Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA.
¹¹ Medical Oncology Department, INSERM Unit 981, Molecular Predictors and New Targets in Oncology, Institut Gustave Roussy, Villejuif, France.
¹² Harvard Graduate Program in Biophysics, Boston, MA, USA.
¹³ Hematology/Oncology, Beth Israel Deaconess Medical Center, Boston, MA, USA.
¹⁴ Breast Cancer, Cancer Center, Massachusetts General Hospital, Boston, MA, USA.
¹⁵ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. eliezerm_vanallen@dfci.harvard.edu.
¹⁶ Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA. eliezerm_vanallen@dfci.harvard.edu.
¹⁷ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. sara_tolaney@dfci.harvard.edu.
¹⁸ Breast Oncology Program, Dana-Farber/Brigham and Women's Cancer Center, Boston, MA, USA. sara_tolaney@dfci.harvard.edu.

^# Contributed equally.

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.

Publication types

Clinical Trial, Phase II
Randomized Controlled Trial
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Adult
Aged
Antibodies, Monoclonal, Humanized / therapeutic use*
Antigen Presentation / genetics
Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
B7-H1 Antigen / metabolism
Breast Neoplasms / drug therapy*
Breast Neoplasms / genetics*
Breast Neoplasms / immunology
Breast Neoplasms / mortality
Cytokines / blood
Cytokines / immunology
Drug Resistance, Neoplasm / genetics
Estrogens / metabolism
Female
Furans / therapeutic use*
Gene Expression Profiling
Genetic Heterogeneity
Genome, Human / genetics
Genomics
Humans
Immune Checkpoint Inhibitors / therapeutic use
Ketones / therapeutic use*
Lymphocytes, Tumor-Infiltrating / immunology
Male
Middle Aged
Mutation
Neoplasm Metastasis
Receptors, Estrogen / metabolism
Receptors, Progesterone / metabolism
Signal Transduction / genetics
Survival Rate
Treatment Outcome

Substances

Antibodies, Monoclonal, Humanized
B7-H1 Antigen
CD274 protein, human
Cytokines
Estrogens
Furans
Immune Checkpoint Inhibitors
Ketones
Receptors, Estrogen
Receptors, Progesterone
pembrolizumab
eribulin

Associated data

ClinicalTrials.gov/NCT03051659

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding