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.

INTRODUCTION

Umbrella, basket, and enrichment trials (with eligibility determined by tumor genomic testing results) are increasingly common.¹ In clinical practice, at least four strategies have been used to identify rare subsets: (1) testing as part of screening for a specific clinical trial (eg, NCI-MATCH)²; (2) testing in a selected patient population, with the explicit goal of trial matching (eg, SAFIR-01)³; (3) commercial testing outside of a trial; and (4) enterprise-level testing in all patients in a defined cohort across an institution but not part of a therapeutic trial.

In breast cancer, there have been relatively few studies published on the real-world effectiveness of enterprise-level genomic testing to guide accrual of patients with metastatic breast cancer (MBC) to molecularly defined trials.⁴ One of the challenges in reporting this outcome is that the ability to enroll a patient in a molecularly matched trial depends not only on the presence of the biomarker, but also on the availability of a corresponding clinical trial.⁵ The conversion rate from identification of the molecular target to trial accrual may be artificially reduced by trial or slot unavailability at the time of clinical need.

We describe the effectiveness of institute-wide genomic testing in identifying subsets of patients with human epidermal growth factor receptor 2 (HER2), also known as ERBB2, mutations who subsequently enrolled in a clinical trial of the oral ERBB2 inhibitor neratinib. As a secondary aim, we evaluated the enrollment on the same clinical trial of a second cohort of patients who consented to a fresh research biopsy in the metastatic setting.

Context

• Key Objective

• Although tumor genomic sequencing has become more accessible, bridging the gap between patients with targetable mutations and recruitment to specific trials remains a challenge. For rare mutations, many patients must be screened to recruit a small number of patients. Strategies to ensure that patients with rare alterations are aware of and can access clinical trials are needed.

• Knowledge Generated
In this study, despite a large number of individuals tested, the use of an institute-wide genomic tumor profiling test performed at initial visit and coordinated approach strategies were able to achieve a high conversion rate of 36.8% of the eligible patients in a cohort of patients with human epidermal growth factor receptor 2–negative metastatic breast cancer.

• Relevance

• Our data strongly suggest that broad-based testing, not linked to time of disease progression, and the development of approaching systems with the ability to easily query genomic testing results for potentially eligible patients will be critical to the success of studies enrolling rare subsets.

PATIENTS AND METHODS

Institute-Wide Genomic Testing

Since 2011, patients with MBC seen at least once at Dana-Farber Cancer Institute (DFCI) have been offered genomic testing of archival tumor in a Clinical Laboratory Improvement Amendments (CLIA)–certified environment as part of an institution-wide clinical research protocol (PROFILE; Dana-Farber/Harvard Cancer Center [DF/HCC] Protocol No. 11-104/17-000).⁶ To determine the efficiency of trial enrollment on the basis of molecular results, we focused on the presence of activating ERBB2 mutations, given that a multicenter phase II trial evaluating neratinib (plus fulvestrant in patients with estrogen receptor [ER]–positive disease; MutHER, ClinicalTrials.gov identifier: NCT01670877) was available at DFCI and required ERBB2 activating mutations for eligibility. This phase II study has been active at DFCI since 2013, with consistent slot availability during this time.

Patients

We included 1,817 patients in the PROFILE cohort with MBC who had available genomic profiling results between August 1, 2011, and June 1, 2017. Patients with clinically HER2-positive disease (defined by immunohistochemistry [IHC] and/or fluorescence in situ hybridization [FISH]) were excluded (n = 772; Fig 1).

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.

Separately, patients could elect to consent to a research biopsy as part of an initiative through the Center for Cancer Precision Medicine (CCPM; DF/HCC Institutional Review Board No. 05-246). From the CCPM cohort, we included patients with metastatic HER2-negative (per IHC and/or FISH) breast cancer in whom targeted genomic panel results were available between June 22, 2015, and June 30, 2017, because testing has been performed in samples only since 2015.

Database

We collected data on those patients who consented to be in the PROFILE cohort and who had available OncoMap or OncoPanel. Clinical data abstraction was performed via medical record review and included age and stage at initial diagnosis, date of recurrence, histologic features, and date of death or last follow-up. ER, progesterone receptor, and HER2 status were abstracted from clinical pathology reports. Clinical HER2 status was defined by the 2013 ASCO/College of American Pathologists guidelines.⁷ Survival data were collected through a combination of medical record review and linkage to the National Death Index. All data are stored in a custom RedCap database.

Genomic Analysis

Genomic testing was performed in a CLIA-certified environment within the Center for Advanced Molecular Diagnostics at Brigham and Women’s Hospital. Either the archival primary breast tumor or a metastatic site of disease was tested with OncoPanel. The metastatic sample was prioritized for testing when feasible. All samples underwent histopathologic review and tumor microdissection before DNA extraction, as described previously.⁶

Between August 2011 and July 2013, archived tumor specimens were tested using OncoMap, which included the following exact point mutations in ERBB2: L755P, L755S, D769H, Y772_A755dup, A755_G776insYVMA, G776S, G776VC, and V777L.⁸ Starting in August 2013, archived tumor specimens included in the PROFILE cohort were tested using targeted exome sequencing to detect somatic mutations, copy number variations, and structural variants, with the current version (OncoPanel Version 3) activated in October 2016; it includes 447 cancer genes and 191 regions across 60 genes for rearrangement detection (Data Supplement).^9,10

MutHER Trial

This multi-institutional phase II clinical trial (ClinicalTrials.gov identifier: NCT 01670877) evaluates the efficacy of neratinib in patients with HER2-negative (per IHC and/or FISH), ERBB2-mutant MBC. Eligible ERBB2 mutations were defined per protocol as those with preclinical evidence to induce cellular transformation (Data Supplement). Initially, patients received neratinib monotherapy, but a later cohort included fulvestrant in patients with ER-positive disease. The overall study activation date was December 11, 2012. The study opened to accrual at DFCI on September 20, 2013, and it remains open as of December 18, 2018.

Trial Matching

In 2016, we instituted several programs, such as the Ending Metastatic Breast Cancer for Everyone (EMBRACE) program for patients with MBC,¹¹ the MatchMiner platform,¹² and an interactive Web-based trial-matching tool¹³ (Data Supplement) to assist physicians in trial selection. Through these programs, key data from OncoPanel (derived either from the PROFILE or CCPM protocols), as well as results from other research testing conducted in a CLIA-environment, were collated into a central database. The Data Supplement presents details of the EMBRACE program. A custom report (Data Supplement) was shared with the medical oncologist by a designated research coordinator at the time of a patient’s visit to facilitate real-time trial matching. In addition, a custom query for ERBB2 alterations was created within the MatchMiner platform and allowed for the identification of all patients with breast cancer with an ERBB2 alteration at DFCI. This list was used to reach out directly to treating physicians as an extra outreach method to capture patients who might not have a return visit to DFCI scheduled.

Statistical Analysis

The primary objective of our study was to describe the proportion of patients in the prespecified PROFILE cohort with eligible ERBB2 mutations detected by genomic analysis who enrolled in the selected trial. Secondary objectives included describing the proportion of patients approached for trial screening, the median time from genomic testing results to trial enrollment, the median time from genomic testing to death, and overall survival (OS). OS was defined as the time from diagnosis of metastatic disease (by imaging or biopsy) to death from any cause and was estimated using the Kaplan-Meier method. Specific drug activity of neratinib or neratinib plus fulvestrant in patients with ERBB2 mutations enrolled in the trial was not evaluated in this report.

Variables were described using percentages and medians. Categorical variables were analyzed using Fisher’s exact test, and continuous variables using the Wilcoxon sum rank test. We also repeated the analyses within the cohort of patients who consented to a fresh metastatic biopsy (CCPM cohort), as a secondary aim. All tests were two sided, and P values < .05 were considered statistically significant. SAS 9.4 was used for the analyses.

All data analyses were conducted after approval from the PROFILE Users Committee and the DF/HCC Breast Cancer Users Committee and project-specific approval from the DF/HCC Institutional Review Board.

RESULTS

Patient and Tumor Characteristics

PROFILE cohort.

Between August 2011 and June 2017, 1,045 patients with HER2-negative MBC consented to the PROFILE protocol and had successful genomic testing. OncoPanel was performed in most of the patients of this cohort (98.8%, n = 1,032 of 1,045). Patient and disease characteristics are listed in Table 1. Forty-two patients (4.0%) were found to have ERBB2 mutations in their tumors, and of these, 19 (1.8%) had mutations eligible for the trial (18 detected by OncoPanel, none by OncoMap, and one by commercial panel). The most frequently detected mutations were L755S, V777L, and D769Y (Table 2).

TABLE 1.

Patient and Disease Characteristics

TABLE 2.

Activating Eligible ERBB2 Mutations Diagnosed by OncoPanel or OncoMap in Both Cohorts

The overall frequency of eligible mutations in patients with lobular carcinoma and ductal carcinoma was 5.5% (n = 8 of 144) and 1.3% (n = 9 of 719), respectively (P = .0032). In addition, ERBB2 mutations were present in 2.3% of patients (n = 18 of 771) with ER-positive/HER2-negative disease and in only 0.4% of patients (n = 1 of 232) with ER-negative/HER2-negative disease (P = .03). There were no statistically significant differences in histologic grade between ERBB2-mutated patients and nonmutated patients (P = .67).

CCPM cohort.

Between June 2015 and June 2017, 166 patients with HER2-negative MBC underwent successful OncoPanel testing of a fresh tumor biopsy as part of the CCPM initiative (Fig 1). For this cohort, we report patient and tumor characteristics only in those patients with ERBB2 mutations (Data Supplement).

Ten patients (6.0%) were identified with ERBB2 tumor mutations and, of these, six of 166 (3.6%) had eligible mutations for the trial. Detected eligible mutations included V777L, S653C, and L755S (Table 2).

Trial Enrollment

PROFILE cohort.

The REMARK flowchart is displayed in Fig 1. Among patients without mutations, the median time from metastatic diagnosis to OncoPanel result was 14.4 months (range, 0.7 to 173.5 months). Patients with ERBB2 mutations had a median time from metastatic diagnosis to OncoPanel result of 7.0 months (range, 1.8 to 79.4 months). Median time from OncoPanel results to death was 10.0 months (range, 0.03 to 50.6 months) for the nonmutated cohort population and 12.7 months (range, 1.6 to 34.1 months) for patients with ERBB2 mutations. Median time from OncoPanel results to trial enrollment was 6.8 months (range, 1.1 to 18.5 months), and median time from the first progression after OncoPanel result to trial enrollment was 1.6 months (range, 0.3 to 15.3 months).

Among 19 patients with eligible ERBB2 mutations, 18 were identified by OncoPanel result, of whom 11 patients were approached for consideration of the targeted neratinib trial, corresponding to 58% of the eligible ERBB2-mutated cohort. One additional patient was enrolled in a different neratinib-based trial. In terms of our prespecified primary end point, the proportion of patients with eligible ERBB2 mutations who enrolled in the selected neratinib trial on the basis of only OncoPanel results was 33.3% (six of 18), representing 0.5% of the total tested population (six of 1,045). The reasons why patients elected not to participate in the trial are detailed in the Data Supplement. One additional patient with a previously known ERBB2 mutation detected through commercial testing enrolled in the neratinib trial; another patient enrolled in the trial on the basis of testing of a fresh metastatic specimen collected in the CCPM protocol (Fig 1).

All patients who enrolled in the trial had other multiple mutations detected by OncoPanel (Data Supplement), but none received additional treatment guided by another specific mutation. Figure 2 illustrates the timeline of therapies administered to the eight enrolled patients before and after the OncoPanel result.

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.

After a median follow-up of 21.8 months (95% CI, 0.1 to 191.2 months), the median OS for nonmutated patients was 44.3 months (95% CI, 41.3 to 47.5 months) and 56.9 months (95% CI, 26.26 to 75.27 months) for patients with any ERBB2 mutation. In patients with eligible ERBB2 mutations, the median follow-up was 29.7 months (95% CI, 0.7 to 110.63 months), and the median OS was 66.1 months (95% CI, 26.3 to 110.6 months).

No statistically significant differences in OS among the tee groups were observed (hazard ratio, 0.9; 95% CI, 0.58 to 1.45; P = .70 for patients with any ERBB2 mutation v nonmutated patients; and hazard ratio, 0.84; 95% CI, 0.43 to 1.62; P = .59 for patients with activating ERBB2 mutations v nonmutated patients). The Kaplan-Meier curve for OS is presented in Fig 3.

FIG 3.

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

CCPM cohort.

Among the 10 patients with ERBB2 mutations identified via the CCPM protocol (Fig 1), the median time from metastatic diagnosis to OncoPanel result was 8.7 months (range, 1.7 to 79.8 months). Median time from OncoPanel result to death was 15.2 months (range, 0.7 to 18.0 months).

Of these 10 patients, six harbored eligible mutations and only one (10%) was enrolled in the trial. The time from the OncoPanel result to trial enrollment was 3.0 months. The reasons for lack of approach of eligible patients in this cohort are listed in the Data Supplement.

The median follow-up time in this cohort was 25.5 months (95% CI, 1.9 to 82.9 months). The OS of patients with any ERBB2 mutation was 73.5 months (95% CI, 1.87 to not estimated). For patients with eligible ERBB2 mutations, the median OS was not reached (Data Supplement).

DISCUSSION

Among 1,045 patients with HER2-negative MBC with available genomic results between 2011 and 2017 and included in our PROFILE cohort, we identified a total of 19 patients with ERBB2 mutations that rendered them eligible for the neratinib trial. Although only seven patients (0.6%) of the total cohort of HER2-negative patients who were tested were enrolled in the trial, more than one half (11 of 19; 58%) of the eligible population were approached by the study team for trial participation, and ultimately 36.8% (seven of 19) of these patients were enrolled in the trial (six exclusively on the basis of OncoPanel result and one on the basis of commercial testing result). One additional patient enrolled on the basis of the results of a fresh metastatic biopsy via the CCPM protocol. Although the total number of enrolled patients (n = 8) at DFCI was low, our site was the second-highest accruing site nationally, reflecting the low overall prevalence of ERBB2 mutations in breast cancer.

We observed that the conversion rate from genomic result to trial enrollment was numerically higher in the PROFILE cohort compared with the CCPM cohort, although the patients in the CCPM cohort were not approached because they had stable disease on current therapy. In PROFILE, patients were approached for testing at their initial visit. Patients enrolled in the CCPM cohort typically consented to research biopsies at the time of disease progression. Our results suggest that broad-based testing, not linked to time of progression, may be the more successful strategy in terms of trial accrual.

Our study results confirm prior reports that activating ERBB2 mutations are rare in patients with HER2-negative MBC, with an overall 1.8% frequency. We also confirmed a higher frequency in ER-positive (v triple-negative) and lobular (v ductal) tumors.^14-16 In contrast to previous data, we did not observe statistically significant differences in survival outcomes according to ERBB2 mutation status, and although our median time of follow-up was short, our findings suggest that ERBB2 mutations may not necessarily drive worse outcomes. A direct assessment of the drug activity of neratinib (with or without fulvestrant) will be performed in the MutHER trial, and progression-free survival will be evaluated as a secondary end point.¹⁷

A strength of our study is the selection of a specific clinical trial with wide slot availability over an extended period to evaluate the conversion rate from biomarker result to trial enrollment. Enrollment in a molecularly matched clinical trial was not limited by lack of an available trial or slots. Our rate of trial enrollment guided by genomic testing was higher than that reported in previous studies. A slightly lower conversion rate was observed by Wheler et al,⁵ who prospectively evaluated 500 patients (only 16% with breast cancer); 22% of them received directly guided treatment after tumor molecular profiling. Meric-Bernstam et al¹⁸ evaluated 2,000 patients with different cancer types; 7% of patients with potentially actionable alterations were enrolled in a specific mutation-driven trial, and 4% were treated in a trial with a molecular rationale. The SAFIR-01 study enrolled 423 patients with advanced breast cancer, and 13% of them were considered eligible for a mutation-guided clinical trial.³

Our study has several limitations. Although all new patients to DFCI were approached for participation in the overarching protocol allowing for tumor testing, we did not prospectively collect the decline rate, nor did we collect reasons for decline. Not all consented patients with MBC underwent tumor testing, for a variety of reasons, including lack of an adequate archival sample, insufficient archival material, or technical test failure (the last being uncommon). Because patients were not randomly assigned to undergo testing, we cannot definitively comment on the impact of enterprise-wide testing versus an approach of more selective testing at the time of clinical need. Given the study’s retrospective nature, we depended on documentation in the medical record as to whether patients were approached for the trial. The potential for referral bias, given the long median interval between initial metastatic diagnosis and OncoPanel testing, and the possibility that only more fit patients were able to travel to our site later in their disease course, could have diluted differences in survival by ERBB2 mutation status. In addition, 20% of patients with eligible mutations were lost to follow-up.

The rarity of the patient population meant that only 0.5% of the total tested population ultimately enrolled in the neratinib study. It is notable that the median time from metastatic diagnosis to OncoPanel result in mutated patients was 7.0 months, and in large part, this reflected patients being referred to our institution after having lived with a diagnosis of MBC for some time before their initial visit.

Our data illustrate the hurdles involved in identifying and enrolling patients with rare molecular alterations in clinical trials. We believe that our data suggest that broad-based testing, the development of systems with the ability to query genomic testing results across a clinic population, and robust strategies to approach patients will be critical to the success of studies enrolling rare subsets. We tested > 1,000 women to enroll eight patients in the selected trial; however, this testing simultaneously identified patients for multiple other trials, in a tissue- and time-efficient manner.

One half of the patients enrolled in the neratinib trial were also potentially eligible for other simultaneous trials on the basis of targetable mutations such as in PALB2 or PIK3CA (Data Supplement). Furthermore, nearly 40% of patients tested had an alteration that was included in at least one arm of the NCI-Match trial (ClinicalTrials.gov identifier: NCT02465060) inclusive of patients with breast cancer as of August 31, 2016 (manuscript in preparation).

In summary, we believe our study underscores the pitfalls and promise of precision medicine and highlights the need for innovative approaches to leverage the increasing amounts of genomic data generated by genomic platforms to enhance the success of biomarker-directed studies.

AUTHOR CONTRIBUTIONS

Conception and design: Pedro Exman, Ana C. Garrido-Castro, Rachel A. Freedman, Ethan Cerami, Bruce E. Johnson, Deborah A. Dillon, Eric P. Winer, Nancy U. Lin

Administrative support: Neal I. Lindeman, Bruce E. Johnson

Provision of study material or patients: Melissa E. Hughes, Bruce E. Johnson, Cynthia X. Ma

Collection and assembly of data: Pedro Exman, Ana C. Garrido-Castro, Melissa E. Hughes, Rachel A. Freedman, Brittany L. Bychkovsky, Romualdo Barroso-Sousa, Simona Di Lascio, Colin Mackichan, Max R. Lloyd, Max Krevalin, Margaret S. Merrill, Rebecca Santiago, Lindsey Crowley, Nicole Kuhnly, Janet Files, Neal I. Lindeman, Laura E. MacConaill, Sara M. Tolaney, Cynthia X. Ma, Nikhil Wagle, Nancy U. Lin

Data analysis and interpretation: Pedro Exman, Ana C. Garrido-Castro, Rachel A. Freedman, Tianyu Li, Lorenzo Trippa, Brittany L. Bychkovsky, Lindsey Crowley, Neal I. Lindeman, Laura E. MacConaill, Priti Kumari, Sara M. Tolaney, Ian E. Krop, Ron Bose, Bruce E. Johnson, Cynthia X. Ma, Deborah A. Dillon, Nancy U. Lin

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST AND DATA AVAILABILITY 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.

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Rachel A. Freedman

Research Funding: Puma Biotechnology (Inst), Eisai (Inst)

Lorenzo Trippa

Consulting or Advisory Role: Galera Therapeutics

Romualdo Barroso-Sousa

Consulting or Advisory Role: Lilly

Speakers' Bureau: Roche, Bristol-Myers Squibb

Travel, Accommodations, Expenses: Roche

Simona Di Lascio

Honoraria: Roche/Genentech

Ethan Cerami

Stock and Other Ownership Interests: Blueprint Medicines

Honoraria: Merck

Travel, Accommodations, Expenses: Merck

Margaret S. Merrill

Stock and Other Ownership Interests: Abbott Laboratories, AbbVie, Alcon, Novartis

Sara M. Tolaney

Consulting 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, Celldex

Ian E. Krop

Employment: 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 Bose

Honoraria: Genentech, Foundation Medicine

Consulting or Advisory Role: Genentech

Research Funding: Puma Biotechnology (Inst)

Bruce E. Johnson

Research Funding: Novartis (Inst), Toshiba (Inst), Novartis (Inst), Novartis (Inst)

Patents, Royalties, Other Intellectual Property: Dana-Farber Cancer Institute

Cynthia X. Ma

Consulting 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, Pfizer

Deborah A. Dillon

Consulting or Advisory Role: Oncology Analytics, Novartis

Travel, Accommodations, Expenses: Novartis

Eric P. Winer

Stock 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 Wagle

Stock and Other Ownership Interests: Foundation Medicine

Honoraria: Lilly

Consulting or Advisory Role: Novartis, Lilly

Research Funding: Novartis, Puma Biotechnology

Nancy U. Lin

Consulting 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.