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CANCER

Neratinib is effective in breast tumors bearing both amplification and mutation of ERBB2 (HER2)

Emiliano Cocco, F. Javier Carmona, Pedram Razavi, Helen H. Won, Yanyan Cai https://orcid.org/0000-0002-2779-6163, Valentina Rossi https://orcid.org/0000-0003-2471-7500, Carmen Chan https://orcid.org/0000-0001-9086-6622, James Cownie, Joanne Soong https://orcid.org/0000-0002-8220-1601, Eneda Toska https://orcid.org/0000-0002-8974-9792, Sophie G. Shifman https://orcid.org/0000-0002-5794-1691, Ivana Sarotto https://orcid.org/0000-0002-6958-5698, Peter Savas https://orcid.org/0000-0001-5999-428X, Michael J. Wick https://orcid.org/0000-0001-5683-8687, Kyriakos P. Papadopoulos https://orcid.org/0000-0002-0667-2620, Alyssa Moriarty, Richard E. Cutler Jr., Francesca Avogadri-Connors https://orcid.org/0000-0003-0671-0620, Alshad S. Lalani, Richard P. Bryce, Sarat Chandarlapaty https://orcid.org/0000-0003-4532-8053, David M. Hyman https://orcid.org/0000-0001-8150-9762, David B. Solit https://orcid.org/0000-0002-6614-802X, Valentina Boni https://orcid.org/0000-0002-8675-0018, Sherene Loi https://orcid.org/0000-0001-6137-9171, José Baselga https://orcid.org/0000-0003-1361-4063, Michael F. Berger https://orcid.org/0000-0003-3882-5000, Filippo Montemurro https://orcid.org/0000-0003-4231-2291 [email protected], and Maurizio Scaltriti https://orcid.org/0000-0002-5522-1447 [email protected]
Science Signaling • 9 Oct 2018 • Vol 11, Issue 551 • DOI: 10.1126/scisignal.aat9773
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Neratinib for resistant metastatic breast cancer

Breast cancers with amplification or mutation in the epidermal growth factor receptor (EGFR) family member HER2 are usually treated with targeted inhibitors, but resistance is common. Amplification and mutation of HER2 are generally considered mutually exclusive occurrences in treatment-naïve patients. However, Cocco et al. discovered a small proportion of treatment-naïve and, more often, previously treated patients with metastatic breast cancer in which HER2 amplification and mutation were coincident. It is not yet clear why, but these co-amplified/mutant cells were resistant to currently approved HER2-specific and HER2/EGFR-specific inhibitors but were sensitive to the new pan-EGFR inhibitor neratinib. Neratinib, which inhibits EGFR and HER2, as well as HER3 and HER4, was more effective at blocking the activity of the EGFR pathway and other receptor tyrosine kinases, common modes of resistance in HER2-driven tumors. Patients and mice bearing their tumor cells showed improved survival and even tumor regression on neratinib, suggesting that this may be a treatment option for certain breast cancer patients.

Abstract

Mutations in ERBB2, the gene encoding epidermal growth factor receptor (EGFR) family member HER2, are common in and drive the growth of “HER2-negative” (not ERBB2 amplified) tumors but are rare in “HER2-positive” (ERBB2 amplified) breast cancer. We analyzed DNA-sequencing data from HER2-positive patients and used cell lines and a patient-derived xenograft model to test the consequence of HER2 mutations on the efficacy of anti-HER2 agents such as trastuzumab, lapatinib, and neratinib, an irreversible pan-EGFR inhibitor. HER2 mutations were present in ~7% of HER2-positive tumors, all of which were metastatic but not all were previously treated. Compared to HER2 amplification alone, in both patients and cultured cell lines, the co-occurrence of HER2 mutation and amplification was associated with poor response to trastuzumab and lapatinib, the standard-of-care anti-HER2 agents. In mice, xenografts established from a patient whose HER2-positive tumor acquired a D769Y mutation in HER2 after progression on trastuzumab-based therapy were resistant to trastuzumab or lapatinib but were sensitive to neratinib. Clinical data revealed that six heavily pretreated patients with tumors bearing coincident HER2 amplification and mutation subsequently exhibited a statistically significant response to neratinib monotherapy. Thus, these findings indicate that coincident HER2 mutation reduces the efficacy of therapies commonly used to treat HER2-positive breast cancer, particularly in metastatic and previously HER2 inhibitor–treated patients, as well as potentially in patients scheduled for first-line treatment. Therefore, we propose that clinical studies testing the efficacy of neratinib are warranted selectively in breast cancer patients whose tumors carry both amplification and mutation of ERBB2/HER2.
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Supplementary Material

Summary

Text S1. Clinical case details.
Fig. S1. Prevalence of coincident HER2 amplification and mutation in the MSKCC breast cancer cohort.

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Science Signaling
Volume 11 | Issue 551
October 2018

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Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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Received: 24 April 2018
Accepted: 7 September 2018

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Acknowledgments

This work was funded by the NIH grants R03CA187094-01 and P30CA008748, the Breast Cancer Research Foundation, the Geoffrey Beene Cancer Research Center, the Australian New Zealand Breast Cancer Trials Group (ANZBCTG), the 5 X 1000 FPRC (Onlus) Fondi Ministero della Salute 2013, and from a Puma Biotechnology grant. F.J.C. held a fellowship from the Terri Brodeur Breast Cancer Foundation. E.C. is a recipient of a MSK Society Scholar Prize. Author contributions: E.C., F.J.C., P.R., F.M., and M.S. planned the experiments and interpreted the data. H.H.W., P.S., and M.F.B. assisted with the sequencing analyses. M.J.W., K.P.P., and A.M. performed the in vivo work. V.R., I.S., S.C., D.M.H., D.B.S., V.B., and S.L. provided tissue samples and clinical histories of the patients. Y.C., C.C., J.C., E.T., S.G.S., and J.S. provided technical support for the experimental work. D.M.H., D.B.S., J.B., F.A.-C., A.S.L., R.E.C., and R.P.B. provided logistic support for patient enrollment and interpreted the clinical data. E.C., F.J.C., P.R., H.H.W., M.F.B., F.M., and M.S. wrote the manuscript. Competing interests: R.E.C., R.P.B., F.A.-C., and A.S.L. are employees of Puma Biotechnology. J.B. has received honoraria from Roche, Lilly, and Novartis; serves as the board of director for Varian Medical Systems, Bristol-Myers Squibb, and Foghorn; is a past board member of Grail, Aura Biosciences, and Infinity Pharmaceuticals; is on the scientific advisory boards of Grail, PMV Pharma, ApoGen, Juno, Roche, Lilly, Novartis, Northern Biologicals, and Tango Therapeutics; is a founder of Venthera; and has stock or other ownership interests in PMV Pharma, Grail, Varian, Foghorn, Aura, Infinity, and ApoGen, as well Tango and Venthera. M.S. received research funds from Puma Biotechnoloy, Daiichi-Sankio, and Menarini Ricerche and is a cofounder of Medendi Medical Travel. D.M.H. has consulting or advisory roles at Atara Biotherapeutics, Chugai Pharma, CytomX Therapeutics, Boehringer Ingelheim, AstraZeneca, Pfizer, Bayer, Debiopharm Group, ArQule, and Genentech and has received research funding from AstraZeneca, Puma Biotechnology, and Loxo. D.B.S. is on the advisory boards for Pfizer and Loxo and has received honoraria from Pfizer, Illumina, and Interzyme. All other authors declare that they have no competing interests. Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper or the Supplementary Materials, and further will be made directly available upon request to M.S.

Authors

Affiliations

Emiliano Cocco*
Human Oncology & Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
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F. Javier Carmona*
Human Oncology & Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
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Pedram Razavi
Human Oncology & Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
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Helen H. Won
Human Oncology & Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
Department of Pathology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
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Yanyan Cai https://orcid.org/0000-0002-2779-6163
Human Oncology & Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
Department of Pathology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
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Valentina Rossi https://orcid.org/0000-0003-2471-7500
Unit of Investigative Clinical Oncology (INCO), Candiolo Cancer Institute, FPO-IRCCS, Str. Provinciale 142, 10060 Candiolo, Italy.
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Carmen Chan https://orcid.org/0000-0001-9086-6622
Human Oncology & Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
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James Cownie
Human Oncology & Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
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Joanne Soong https://orcid.org/0000-0002-8220-1601
Human Oncology & Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
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Eneda Toska https://orcid.org/0000-0002-8974-9792
Human Oncology & Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
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Sophie G. Shifman https://orcid.org/0000-0002-5794-1691
Human Oncology & Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
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Ivana Sarotto https://orcid.org/0000-0002-6958-5698
Unit of Surgical Pathology, Fondazione del Piemonte per l’Oncologia, Candiolo Cancer Institute, FPO-IRCCS, Str. Provinciale 142, 10060 Candiolo, Italy.
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Peter Savas https://orcid.org/0000-0001-5999-428X
Division of Research and Cancer Medicine, Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, VIC 3000, Australia.
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Michael J. Wick https://orcid.org/0000-0001-5683-8687
START, 4383 Medical Dr, San Antonio, TX 78229, USA.
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Kyriakos P. Papadopoulos https://orcid.org/0000-0002-0667-2620
START, 4383 Medical Dr, San Antonio, TX 78229, USA.
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Alyssa Moriarty
START, 4383 Medical Dr, San Antonio, TX 78229, USA.
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Richard E. Cutler Jr.
Puma Biotechnology Inc., 10880 Wilshire Blvd, Los Angeles, CA 90024, USA.
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Francesca Avogadri-Connors https://orcid.org/0000-0003-0671-0620
Puma Biotechnology Inc., 10880 Wilshire Blvd, Los Angeles, CA 90024, USA.
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Alshad S. Lalani
Puma Biotechnology Inc., 10880 Wilshire Blvd, Los Angeles, CA 90024, USA.
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Richard P. Bryce
Puma Biotechnology Inc., 10880 Wilshire Blvd, Los Angeles, CA 90024, USA.
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Sarat Chandarlapaty https://orcid.org/0000-0003-4532-8053
Human Oncology & Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
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David M. Hyman https://orcid.org/0000-0001-8150-9762
Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
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David B. Solit https://orcid.org/0000-0002-6614-802X
Human Oncology & Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
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Valentina Boni https://orcid.org/0000-0002-8675-0018
START Madrid, Centro Integral Oncológico Clara Campal, Hospital Universitario Madrid Sanchinarro, Calle de Oña 10, 28050 Madrid, Spain.
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Sherene Loi https://orcid.org/0000-0001-6137-9171
Division of Research and Cancer Medicine, Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, VIC 3000, Australia.
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José Baselga https://orcid.org/0000-0003-1361-4063
Human Oncology & Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
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Michael F. Berger https://orcid.org/0000-0003-3882-5000
Human Oncology & Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
Department of Pathology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
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Filippo Montemurro† https://orcid.org/0000-0003-4231-2291 [email protected]
Unit of Investigative Clinical Oncology (INCO), Candiolo Cancer Institute, FPO-IRCCS, Str. Provinciale 142, 10060 Candiolo, Italy.
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Maurizio Scaltriti† https://orcid.org/0000-0002-5522-1447 [email protected]
Human Oncology & Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
Department of Pathology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
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Funding Information

Terri Brodeur Foundation

Notes

*
These authors contributed equally to this work.
†Corresponding author. Email: [email protected] (F.M.); [email protected] (M.S.)

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