Identifying ERBB2 Activating Mutations in HER2-Negative Breast Cancer: Clinical Impact of Institute-Wide Genomic Testing and Enrollment in Matched Therapy Trials

Abstract

Purpose: The yield of comprehensive genomic profiling in recruiting patients to molecular-based trials designed for small subgroups has not been fully evaluated. We evaluated the likelihood of enrollment in a clinical trial that required the identification of a specific genomic change based on our institute-wide genomic tumor profiling.

Patients and methods: Using genomic profiling from archived tissue samples derived from patients with metastatic breast cancer treated between 2011 and 2017, we assessed the impact of systematic genomic characterization on enrollment in an ongoing phase II trial (ClinicalTrials.gov identifier: NCT01670877). Our primary aim was to describe the proportion of patients with a qualifying ERBB2 mutation identified by our institutional genomic panel (OncoMap or OncoPanel) who enrolled in the trial. Secondary objectives included median time from testing result to trial registration, description of the spectrum of ERBB2 mutations, and survival. Associations were calculated using Fisher's exact test.

Results: We identified a total of 1,045 patients with metastatic breast cancer without ERBB2 amplification who had available genomic testing results. Of these, 42 patients were found to have ERBB2 mutation and 19 patients (1.8%) were eligible for the trial on the basis of the presence of an activating mutation, 18 of which were identified by OncoPanel testing. Fifty-eight percent of potentially eligible patients were approached, and 33.3% of eligible patients enrolled in the trial guided exclusively by OncoPanel testing.

Conclusion: More than one half of eligible patients were approached for trial participation and, significantly, one third of those were enrolled in NCT01670877. Our data illustrate the ability to enroll patients in trials of rare subsets in routine clinical practice and highlight the need for these broadly based approaches to effectively support the success of these studies.

Conflict of interest statement

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center. Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments). Rachel A. FreedmanResearch Funding: Puma Biotechnology (Inst), Eisai (Inst)Lorenzo TrippaConsulting or Advisory Role: Galera TherapeuticsRomualdo Barroso-SousaConsulting or Advisory Role: Lilly Speakers' Bureau: Roche, Bristol-Myers Squibb Travel, Accommodations, Expenses: RocheSimona Di LascioHonoraria: Roche/GenentechEthan CeramiStock and Other Ownership Interests: Blueprint Medicines Honoraria: Merck Travel, Accommodations, Expenses: MerckMargaret S. MerrillStock and Other Ownership Interests: Abbott Laboratories, AbbVie, Alcon, NovartisSara M. TolaneyConsulting or Advisory Role: Novartis, Pfizer, Merck, Lilly, Nektar, NanoString Technologies, AstraZeneca, Puma Biotechnology, Genentech, Eisai, Immunomedics, Sanofi, Celldex, Bristol-Myers Squibb, Paxman, Seattle Genetics Research Funding: Genentech/Roche (Inst), Merck (Inst), Exelixis (Inst), Pfizer (Inst), Lilly (Inst), Novartis (Inst), Bristol-Myers Squibb (Inst), Eisai (Inst), AstraZeneca (Inst), NanoString Technologies (Inst), Cyclacel (Inst), Nektar (Inst), Immunomedics (Inst) Travel, Accommodations, Expenses: AstraZeneca, Lilly, Merck, Nektar, Novartis, Pfizer, Genentech/Roche, Immunomedics, Eisai, NanoString Technologies, Puma Biotechnology, CelldexIan E. KropEmployment: AMAG Pharmaceuticals (I) Leadership: AMAG Pharmaceuticals (I) Stock and Other Ownership Interests: AMAG Pharmaceuticals (I) Honoraria: Genentech/Roche Consulting or Advisory Role: Genentech/Roche, Daiichi Sankyo, Context Therapeutics, Macrogenics, Taiho Pharmaceutical Research Funding: Genentech/Roche (Inst), Seattle Genetics (Inst), Pfizer (Inst), Daiichi Sankyo (Inst)Ron BoseHonoraria: Genentech, Foundation Medicine Consulting or Advisory Role: Genentech Research Funding: Puma Biotechnology (Inst)Bruce E. JohnsonResearch Funding: Novartis (Inst), Toshiba (Inst), Novartis (Inst), Novartis (Inst) Patents, Royalties, Other Intellectual Property: Dana-Farber Cancer InstituteCynthia X. MaConsulting or Advisory Role: Pfizer, Novartis, Syndax, Lilly, Biovica, Tempus, Seattle Genetics, Agendia, Myriad Genetics, Lilly Research Funding: Pfizer (Inst), Eisai (Inst), Puma (Inst) Travel, Accommodations, Expenses: Syndax, Lilly, Agendia, PfizerDeborah A. DillonConsulting or Advisory Role: Oncology Analytics, Novartis Travel, Accommodations, Expenses: NovartisEric P. WinerStock and Other Ownership Interests: Verastem Honoraria: Genentech/Roche, Tesaro, Genomic Health Consulting or Advisory Role: Leap Therapeutics, Seattle Genetics, Jounce Therapeutics, GlaxoSmithKline, Carrick Therapeutics, Lilly Research Funding: Genentech (Inst), Novartis (Inst), Merck (Inst)Nikhil WagleStock and Other Ownership Interests: Foundation Medicine Honoraria: Lilly Consulting or Advisory Role: Novartis, Lilly Research Funding: Novartis, Puma BiotechnologyNancy U. LinConsulting or Advisory Role: Genentech/Roche, Seattle Genetics, Puma Biotechnology, Novartis, Daiichi Sankyo Research Funding: Genentech, Pfizer, Novartis, Seattle Genetics Patents, Royalties, Other Intellectual Property: Royalties for chapter in Up-to-Date regarding management of breast cancer brain metastases No other potential conflicts of interest were reported.

© 2019 by American Society of Clinical Oncology.

Figures

FIG 1.

REMARK diagram flow of study patients for PROFILE and Center for Cancer Precision Medicine (CCPM) cohorts until trial registration. DFCI, Dana-Farber Cancer Institute; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; MBC, metastatic breast cancer.

FIG 2.

Timelines for patients enrolled before and after OncoPanel and Center for Cancer Precision Medicine (CCPM) results. Patients who enrolled in the trial had received a median of four (range, one to six) lines of systemic treatment in the metastatic (Mets) setting before OncoPanel results were available. In addition, 75% (six of eight) of the registered patients were enrolled after the first progression after the OncoPanel result was available and 25% (two of eight) after the second progression. CMF, cyclophosphamide plus methotrexate plus fluorouracil; DL, doxorubicin pegylated liposomal; OS, ovarian suppression; TAM, tamoxifen. (*) Clinical trial regimen.

FIG 3.

Overall survival of patients without ERBB2 mutations, patients with nonactivating ERBB2 mutations, and patients with activating ERBB2 mutations in the PROFILE cohort.