HER2-Mutated Breast Cancer Responds to Treatment With Single-Agent Neratinib, a Second-Generation HER2/EGFR Tyrosine Kinase Inhibitor

Activating mutations in the HER2 tyrosine kinase have been identified in human breast cancers that lack HER2 gene amplification. These patients are not candidates for HER2-targeted drugs under current standards of care, but preclinical data strongly suggest that these patients will benefit from anti-HER2 drugs. This case report describes a young woman with metastatic breast cancer whose tumor was found to carry a HER2 L755S mutation, which is in the kinase domain of HER2. Treatment with the second-generation HER2/EGFR tyrosine kinase inhibitor neratinib resulted in partial response and dramatic improvement in the patient's functional status. This partial response lasted 11 months, and when the patient's cancer progressed, she was treated with neratinib plus capecitabine and her cancer again responded. This second response parallels the benefit seen with continuing trastuzumab in HER2-amplified breast cancer after disease progression. This case represents the first report, to our knowledge, of successful single-agent treatment of HER2-mutated breast cancer. Two clinical trials of neratinib for HER2-mutated metastatic breast cancer are currently enrolling patients. Further, data from The Cancer Genome Atlas project have identified HER2 mutations in a wide range of solid tumors, including bladder, colorectal, and non–small cell lung cancers, suggesting that clinical trials of neratinib or neratinib-based combinations for HER2-mutated solid tumors is warranted.

Abstract

Activating mutations in the HER2 tyrosine kinase have been identified in human breast cancers that lack HER2 gene amplification. These patients are not candidates for HER2-targeted drugs under current standards of care, but preclinical data strongly suggest that these patients will benefit from anti-HER2 drugs. This case report describes a young woman with metastatic breast cancer whose tumor was found to carry a HER2 L755S mutation, which is in the kinase domain of HER2. Treatment with the second-generation HER2/EGFR tyrosine kinase inhibitor neratinib resulted in partial response and dramatic improvement in the patient's functional status. This partial response lasted 11 months, and when the patient's cancer progressed, she was treated with neratinib plus capecitabine and her cancer again responded. This second response parallels the benefit seen with continuing trastuzumab in HER2-amplified breast cancer after disease progression. This case represents the first report, to our knowledge, of successful single-agent treatment of HER2-mutated breast cancer. Two clinical trials of neratinib for HER2-mutated metastatic breast cancer are currently enrolling patients. Further, data from The Cancer Genome Atlas project have identified HER2 mutations in a wide range of solid tumors, including bladder, colorectal, and non–small cell lung cancers, suggesting that clinical trials of neratinib or neratinib-based combinations for HER2-mutated solid tumors is warranted.

Breast cancer genome sequencing has identified HER2-activating mutations in cancers that are HER2-negative by immunohistochemistry or fluorescence in situ hybridization.1,2 These HER2-activating mutations cause an oncogenic transformation of breast epithelial cells in tissue culture and increase tumor growth in xenograft models.2,3 The sensitivity of these HER2-activating mutations to HER2-targeted drugs has been measured,2,4 and 2 clinical trials are screening patients with metastatic breast cancer for HER2 mutations, and treating patients with HER2-positive breast cancer with the second-generation HER2/EGFR tyrosine kinase inhibitor neratinib (HKI-272) (ClinicalTrials.gov identifiers: NCT01670877 and NCT01953926). This report describes the first case of a HER2-mutated breast cancer that clinically benefited from neratinib monotherapy. When this patient's cancer progressed, she was placed on neratinib plus capecitabine combination therapy and she again experienced response.

Case Presentation

The patient was diagnosed with stage IV invasive ductal carcinoma in 2003. She was 43 years old and presented with a 2-cm mass in the left breast and bone metastases. Biopsy demonstrated that this tumor was estrogen receptor (ER)–positive, progesterone receptor (PR)–negative, and HER2-negative by immunohistochemistry. Her family history was negative for breast and ovarian cancer and her test results were negative for germline mutations of BRCA1 and BRCA2. She was treated with oophorectomy, letrozole, and zoledronic acid, and experienced an excellent clinical and radiologic response. In 2005, a new breast mass was found in the same breast and biopsy results revealed invasive ductal carcinoma that was hormone receptor–negative and HER2-negative on immunohistochemistry. A modified radical mastectomy was performed, and chemotherapy with doxorubicin and cyclophosphamide was administered. Therapy with letrozole and zoledronic acid was also continued. In 2010, liver metastases were diagnosed and changing from letrozole to tamoxifen produced disease stabilization. In May 2011, massive hepatic progression was noted, with obstructive jaundice, ascites, and pleural effusion. Treatment with capecitabine and intensive supportive measures resulted in slow resolution of the jaundice, normalization of liver function tests (LFTs), and decline of tumor markers. The ascites did not resolve and analysis revealed chylous content with no malignant cells, possibly caused by secondary cirrhosis. Treatment with capecitabine was discontinued and fulvestrant, 500 mg every 4 weeks was initiated.

In October 2012, progressive disease was observed with peritoneal and omental metastases, a left adrenal mass, and enlargement of liver metastases. Hormonal treatment was stopped and oral vinorelbine was started, with no response. Liver biopsy results showed metastatic breast cancer that was ER-negative, PR-negative, and HER2-negative on immunohistochemistry, and next-generation sequencing by a Clinical Laboratories Improvement Amendments (CLIA)–certified commercial laboratory (Foundation Medicine, Cambridge, MA) identified a HER2 L755S mutation, amplifications of the MDM2 and MYC genes, and APC I1307K mutation. The HER2 L755S mutation is an activating mutation located in the tyrosine kinase inhibitor binding site of the HER2 kinase domain. It produces resistance to lapatinib, but in preclinical studies is highly sensitive to neratinib, a second-generation HER2/EGFR tyrosine kinase inhibitor.2,4 This mutation is different from the EGFR gatekeeper mutation T790M, which would be T798M in HER2.5 HER2 L755S has been observed in patients who have not received prior lapatinib, and this patient had never been treated with lapatinib.

Her ECOG performance status deteriorated to 3, and she was essentially homebound with massive ascites and profound weakness. Neratinib (240 mg orally daily) was obtained through a compassionate access protocol (with approval of the local and central Institutional Review Board), and was started in April 2013. Within 2 months, her performance status dramatically improved to 1, she was able to resume daily activities, including gardening, and she was able to travel abroad on long trips. Her liver enzymes and tumor markers improved (Figure 1) and a CT scan performed in June 2013 showed a 30% reduction of the left adrenal mass corresponding to a partial response by RECIST criteria 1.0. This response persisted for 11 months. In February 2014, clinical worsening was noted with elevated LFTs and tumor markers, and worsening ascites. Capecitabine (3000 mg daily, days 1–14 of a 21-day cycle) was added. The patient's tumor again responded with significant improvement in LFTs and tumor markers. Treatment with both neratinib monotherapy and neratinib plus capecitabine combination therapy was very well tolerated by the patient. She received diarrhea prophylaxis for the first 3 days (loperamide, 4 mg loading dose followed by 2 mg every 4 hours for 3 days) and was then tapered off loperamide. With this prophylactic regimen, the patient experienced no diarrhea.

Discussion

This patient had a HER2 L755S mutation and she had a partial response from neratinib monotherapy. This response markedly improved her performance status and quality of life. After 11 months, her cancer progressed and treatment with neratinib plus capecitabine produced another disease response, which is analogous to the benefit seen with continuing trastuzumab after progression in HER2-positive (HER2 gene–amplified) breast cancer.6 Although a prior case report of HER2-mutated, inflammatory breast cancer describes treatment with chemotherapy and HER2-targeted drugs (lapatinib and trastuzumab),7 this case is the first published report of a patient with HER2-mutated

Figure 1
Figure 1

Laboratory and imaging results with neratinib treatment. (A) CA 15-3 (blue) and CEA (green) tumor markers. (B) Alkaline phosphatase values (red). The trend line in both A and B represents a 3-point moving average for the period before neratinib (February–March 2013), on neratinib monotherapy (June 2013–February 2014), and on the neratinib + capecitabine combination (June–September 2014). The time period of neratinib monotherapy and neratinib + capecitabine combination therapy is marked by pink and blue shading, respectively. CA27.29 testing is not routinely available in Israel and no CA27.29 values were available for the patient. (C) CT imaging before neratinib therapy. (D) CT imaging after 2 months of neratinib monotherapy.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 13, 9; 10.6004/jnccn.2015.0131

breast cancer responding to treatment with a single-agent, HER2-targeted drug. Furthermore, lapatinib would not have been an appropriate drug for our patient, because the HER2 L755S mutation alters the kinase inhibitor binding site and causes lapatinib resistance.2,4

Two clinical trials of neratinib monotherapy for HER2-mutated, metastatic breast cancer are currently enrolling patients,5,6 and trials of neratinib-based combination regimens for HER2-mutated breast cancer should be considered in the future. Phase I trials of neratinib with paclitaxel, capecitabine, or vinorelbine have demonstrated that these combinations are safe810; neratinib has also been combined with other targeted therapy drugs, such as trastuzumab and temsirolimus.11,12 A phase I trial of a 3-drug, neratinib-containing regimen (neratinib, trastuzumab, and paclitaxel) for HER2-positive breast cancer showed good patient tolerability.13 The main toxicity was diarrhea. With diarrhea prophylaxis, no cases of grade 3/4 diarrhea were observed and grade 2 and 1 diarrhea rates were 17% and 50%, respectively.13

The Cancer Genome Atlas project has identified HER2 mutations in a wide range of solid tumors, including breast, colorectal, bladder, and non–small cell lung cancers.1,3,14,15 Further, the specific mutations seen in HER2 are highly recurrent, with the most common mutations occurring either in the kinase domain or at residues 309–310 of the extracellular domain.2,3 These mutations can be potently inhibited with neratinib,2 and therefore, investigation of neratinib or neratinib-based combinations for the treatment of multiple solid tumors with HER2 mutations is warranted. Continuation of neratinib in a different drug combination after progression should be considered, because this patient had a second response with the addition of capecitabine to neratinib.

Dr. Bose has disclosed that he is a consultant for Genentech, Inc., and has received honoraria from the speaker's bureaus of Novartis Pharmaceuticals Corporation and RGA International. Dr. Kavuri has disclosed that he has no financial interests, arrangements, affiliations, or commercial interests with the manufacturers of any products discussed in this article or their competitors. Dr. Ma is the principal investigator of a phase II clinical trial funded in part by Puma Biotechnology, Inc.; Drs. Bose and Ellis are subinvestigators on this trial. Dr. Ellis has ownership interest (including patents) in Bioclassifier LLC and has performed ad hoc consulting for Puma Biotechnology, Inc., Genentech, Inc., Novartis Pharmaceuticals Corporation, AstraZeneca Pharmaceuticals LP, and Pfizer Inc.

Acknowledgments

This work was supported by the NIH (grant R01CA161001 to R. Bose and R01CA095614 to M.J. Ellis) and the Siteman Cancer Center-Foundation for Barnes-Jewish Hospital Cancer Frontier Fund.

References

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    The Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumors. Nature2012;490:6170.

  • 2.

    BoseRKavuriSMSearlemanAC. Activating HER2 mutations in HER2 gene amplification negative breast cancer. Cancer Discov2013;3:224237.

  • 3.

    GreulichHKaplanBMertinsP. Functional analysis of receptor tyrosine kinase mutations in lung cancer identifies oncogenic extracellular domain mutations of ERBB2. Proc Natl Acad Sci U S A2012;109:1447614481.

    • Search Google Scholar
    • Export Citation
  • 4.

    KanchaRKvon BubnoffNBartoschN. Differential sensitivity of ERBB2 kinase domain mutations towards lapatinib. PLoS ONE2011;6:e26760.

  • 5.

    RexerBNGhoshRNarasannaA. Human breast cancer cells harboring a gatekeeper T798M mutation in HER2 overexpress EGFR ligands and are sensitive to dual inhibition of EGFR and HER2. Clin Cancer Res2013;19:53905401.

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    • Export Citation
  • 6.

    von MinckwitzGdu BoisASchmidtM. Trastuzumab beyond progression in human epidermal growth factor receptor 2-positive advanced breast cancer: German Breast Group 26/Breast International Group 03-05 study. J Clin Oncol2009;27:19992006.

    • Search Google Scholar
    • Export Citation
  • 7.

    AliSMAlpaughRKDowningSR. Response of an ERBB2-mutated inflammatory breast carcinoma to human epidermal growth factor receptor 2-targeted therapy. J Clin Oncol2014;32:e8891.

    • Search Google Scholar
    • Export Citation
  • 8.

    ChowLWXuBGuptaS. Combination neratinib (HKI-272) and paclitaxel therapy in patients with HER2-positive metastatic breast cancer. Br J Cancer2013;108:19851993.

    • Search Google Scholar
    • Export Citation
  • 9.

    AwadaADirixLManso SanchezL. Safety and efficacy of neratinib (HKI-272) plus vinorelbine in the treatment of patients with ErbB2-positive metastatic breast cancer pretreated with anti-HER2 therapy. Ann Oncol2013;24:109116.

    • Search Google Scholar
    • Export Citation
  • 10.

    SauraCGarcia-SaenzJAXuB. Safety and efficacy of neratinib in combination with capecitabine in patients with ErbB2-positive breast cancer [abstract]. Cancer Res2011;71(24 Suppl):Abstract P1-12-09.

    • Search Google Scholar
    • Export Citation
  • 11.

    GandhiLBahledaRTolaneySM. Phase I study of neratinib in combination with temsirolimus in patients with human epidermal growth factor receptor 2-dependent and other solid tumors. J Clin Oncol2014;32:6875.

    • Search Google Scholar
    • Export Citation
  • 12.

    GajriaDKingTPannuH. Combined inhibition of mTORC1 with temsirolimus and HER2 with neratinib: a phase I/II study in patients with metastatic HER2-amplified or triple-negative breast cancer [abstract]. Cancer Res2011;71(24 Suppl):Abstract PD 09-08.

    • Search Google Scholar
    • Export Citation
  • 13.

    JankowitzRCAbrahamJTanAR. Safety and efficacy of neratinib in combination with weekly paclitaxel and trastuzumab in women with metastatic HER2positive breast cancer: an NSABP Foundation Research Program phase I study. Cancer Chemother Pharmacol2013;72:12051212.

    • Search Google Scholar
    • Export Citation
  • 14.

    The Cancer Genome Atlas Consortium. Comprehensive molecular characterization of human colon and rectal cancer. Nature2012;487:330337.

    • Search Google Scholar
    • Export Citation
  • 15.

    The Cancer Genome Atlas Network. Comprehensive molecular characterization of urothelial bladder carcinoma. Nature2014;507:315322.

If the inline PDF is not rendering correctly, you can download the PDF file here.

Dr. Efrat Ben-Baruch is an investigator on 4 clinical trials sponsored by Puma Biotechnology, Inc.

Correspondence: Noa Efrat Ben-Baruch, MD, Department of Oncology, Kaplan Medical Center, POB 1, Rehovot 76100, Israel. E-mail: Noa_B@clalit.org.il; Ron Bose, MD, PhD, Division of Oncology, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8069, St. Louis, MO 63110. E-mail: rbose@dom.wustl.edu

Article Sections

Figures

  • View in gallery

    Laboratory and imaging results with neratinib treatment. (A) CA 15-3 (blue) and CEA (green) tumor markers. (B) Alkaline phosphatase values (red). The trend line in both A and B represents a 3-point moving average for the period before neratinib (February–March 2013), on neratinib monotherapy (June 2013–February 2014), and on the neratinib + capecitabine combination (June–September 2014). The time period of neratinib monotherapy and neratinib + capecitabine combination therapy is marked by pink and blue shading, respectively. CA27.29 testing is not routinely available in Israel and no CA27.29 values were available for the patient. (C) CT imaging before neratinib therapy. (D) CT imaging after 2 months of neratinib monotherapy.

References

  • 1.

    The Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumors. Nature2012;490:6170.

  • 2.

    BoseRKavuriSMSearlemanAC. Activating HER2 mutations in HER2 gene amplification negative breast cancer. Cancer Discov2013;3:224237.

  • 3.

    GreulichHKaplanBMertinsP. Functional analysis of receptor tyrosine kinase mutations in lung cancer identifies oncogenic extracellular domain mutations of ERBB2. Proc Natl Acad Sci U S A2012;109:1447614481.

    • Search Google Scholar
    • Export Citation
  • 4.

    KanchaRKvon BubnoffNBartoschN. Differential sensitivity of ERBB2 kinase domain mutations towards lapatinib. PLoS ONE2011;6:e26760.

  • 5.

    RexerBNGhoshRNarasannaA. Human breast cancer cells harboring a gatekeeper T798M mutation in HER2 overexpress EGFR ligands and are sensitive to dual inhibition of EGFR and HER2. Clin Cancer Res2013;19:53905401.

    • Search Google Scholar
    • Export Citation
  • 6.

    von MinckwitzGdu BoisASchmidtM. Trastuzumab beyond progression in human epidermal growth factor receptor 2-positive advanced breast cancer: German Breast Group 26/Breast International Group 03-05 study. J Clin Oncol2009;27:19992006.

    • Search Google Scholar
    • Export Citation
  • 7.

    AliSMAlpaughRKDowningSR. Response of an ERBB2-mutated inflammatory breast carcinoma to human epidermal growth factor receptor 2-targeted therapy. J Clin Oncol2014;32:e8891.

    • Search Google Scholar
    • Export Citation
  • 8.

    ChowLWXuBGuptaS. Combination neratinib (HKI-272) and paclitaxel therapy in patients with HER2-positive metastatic breast cancer. Br J Cancer2013;108:19851993.

    • Search Google Scholar
    • Export Citation
  • 9.

    AwadaADirixLManso SanchezL. Safety and efficacy of neratinib (HKI-272) plus vinorelbine in the treatment of patients with ErbB2-positive metastatic breast cancer pretreated with anti-HER2 therapy. Ann Oncol2013;24:109116.

    • Search Google Scholar
    • Export Citation
  • 10.

    SauraCGarcia-SaenzJAXuB. Safety and efficacy of neratinib in combination with capecitabine in patients with ErbB2-positive breast cancer [abstract]. Cancer Res2011;71(24 Suppl):Abstract P1-12-09.

    • Search Google Scholar
    • Export Citation
  • 11.

    GandhiLBahledaRTolaneySM. Phase I study of neratinib in combination with temsirolimus in patients with human epidermal growth factor receptor 2-dependent and other solid tumors. J Clin Oncol2014;32:6875.

    • Search Google Scholar
    • Export Citation
  • 12.

    GajriaDKingTPannuH. Combined inhibition of mTORC1 with temsirolimus and HER2 with neratinib: a phase I/II study in patients with metastatic HER2-amplified or triple-negative breast cancer [abstract]. Cancer Res2011;71(24 Suppl):Abstract PD 09-08.

    • Search Google Scholar
    • Export Citation
  • 13.

    JankowitzRCAbrahamJTanAR. Safety and efficacy of neratinib in combination with weekly paclitaxel and trastuzumab in women with metastatic HER2positive breast cancer: an NSABP Foundation Research Program phase I study. Cancer Chemother Pharmacol2013;72:12051212.

    • Search Google Scholar
    • Export Citation
  • 14.

    The Cancer Genome Atlas Consortium. Comprehensive molecular characterization of human colon and rectal cancer. Nature2012;487:330337.

    • Search Google Scholar
    • Export Citation
  • 15.

    The Cancer Genome Atlas Network. Comprehensive molecular characterization of urothelial bladder carcinoma. Nature2014;507:315322.

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