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Metastatic HER2-Positive Breast Cancer Resource Center


ERBB2 Mutation in HER2-Nonamplified Breast Cancer

Last Updated: Monday, September 11, 2023

Initial Diagnosis

At age 53, Jen is diagnosed with de novo metastatic ER+/PR+/HER2– breast cancer involving the right breast and axillary nodes. At diagnosis, a right breast biopsy shows lobular breast cancer and extensive skeletal metastases in the sternum and throughout the spine (left 10th and 12th rib). No bone biopsy is performed. She is started on tamoxifen and denosumab.  

Progression and Treatment

One year later, a restaging PET/CT shows worsening disease with a new FDG-avid lesion measuring 2.0 x 1.8 cm in segment 5 of the liver. There is also increased FDG uptake in the left ilium. A liver biopsy reveals ER+/PR+/HER2– breast cancer. Jen is premenopausal, so she is started on goserelin, letrozole, and denosumab.  

Two years later, a PET/CT reveals progression in the liver and a right femur lesion. Her treatment is changed to fulvestrant and palbociclib. Of note, she is now post-menopausal (age 56). 

Three years later, her disease progresses in the bone, and her treatment is changed to letrozole and alpelisib on the BYLieve trial.1

After only 4 months on this regimen, Jen’s disease progresses in the bilateral ureters, requiring stent placement. Her treatment is changed to capecitabine.  

After another 16 months, her disease again progresses in the bone. Her oncologist orders a Guardant 360 CDx liquid biopsy to check for targetable mutations, and she is found to have an ERBB2 mutation and tumor mutational burden of 47.61. Her treatment is changed to trastuzumab, neratinib, and fulvestrant based on the MutHER trial.2

Jen’s neratinib is started at 120 mg daily for 7 days and then increased to 160 mg for 7 days. On day 3 of the 160-mg dosing, she experiences decreased appetite and grade 2 diarrhea with six episodes in 24 hours despite taking loperamide 4 mg at the first episode. She contacts the clinic. Neratinib is held, and she continues loperamide but is advised to take it more often with a max of 16 mg in a 24-hour period.  

After 2 days her diarrhea improves to less than four episodes in a day, and neratinib is restarted at the 160-mg dose. She is advised to increase loperamide to 4 mg twice daily as prophylaxis and continue 2–4 mg as needed. Her diarrhea remains improved. Seven days later, she increases to the final dose of 240 mg daily. Her diarrhea continues to be controlled well.  


HER2 positivity is defined as HER2 (ERBB2) gene amplification (wild type) and high levels of the HER2 receptors in cancer cells. Another definition of HER2 positivity, although the incidence is much lower, is cancer cells with mutations in the ERBB2 gene (not wild type).3 The incidence of ERBB2 wild-type amplification in breast cancer is 20% to 25%, while the incidence of ERBB2 mutations in breast cancer is about 4%.3

In the phase II, single-arm MutHER trial, patients with ER+ HER2 nonamplified metastatic breast cancer with ERBB2 mutations were given fulvestrant and neratinib and then followed.2 They were stratified by previous exposure to fulvestrant. The clinical benefit rate was 38% (95% CI: 18%-62%) and 30% (95% CI: 7%-65%) in the fulvestrant-treated and fulvestrant-naïve cohorts, respectively. The addition of trastuzumab at progression in five patients resulted in three partial responses and one stable disease ≥ 24 weeks.  

In the ExteNET trial, neratinib was found to result in grade 3 diarrhea in 40% of patients, with discontinuation in 17% of patients.4 The follow-up CONTROL trial aimed to determine the best way to mitigate the risk of diarrhea and therefore discontinuation of neratinib.5 There were several arms using preemptive prophylaxis—loperamide, budesonide + loperamide, colestipol + loperamide, and colestipol + as-needed loperamide—as well as one arm in which the neratinib dose was escalated slowly over several weeks. The dose escalation arm had the lowest grade 3 diarrhea rate at 15%, compared to the prophylaxis cohorts, which ranged from 21% to 32%.  

Based on the ExteNET trial6, neratinib should be started at a 240-mg dose; however, based on the CONTROL trial, a 2-week dose escalation—starting with 120-mg daily for the first week, 160 mg daily for the second week, and 240 mg daily onwards—may be considered to mitigate diarrhea and avoid premature discontinuation of neratinib. 



  1. Study Assessing the Efficacy and Safety of Alpelisib Plus Fulvestrant or Letrozole, Based on Prior Endocrine Therapy, in Patients With PIK3CA Mutant, HR+, HER2- Advanced Breast Cancer Who Have Progressed on or After Prior Treatments (BYLieve). NCT03056755. Updated May 22, 2023. Accessed August 13, 2023.
  2. Ma CX, Luo J, Freedman RA, et al. The phase II MutHER study of neratinib alone and in combination with fulvestrant in HER2-mutated, non-amplified metastatic breast cancer. Clin Cancer Res. 2022;28:1258-1267.
  3. Gaibar M, Beltrán L, Romero-Lorca A, et al. Somatic mutations in HER2 and implications for current treatment paradigms in HER2-positive breast cancer. J Oncol. 2020;2020:6375956. 
  4. Martin M, Holmes FA, Ejlertsen B, et al. Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2017;18:1688-1700.
  5. Barcenas CH, Hurvitz SA, Di Palma JA, et al. Improved tolerability of neratinib in patients with HER2-positive early-stage breast cancer: The CONTROL trial. Ann Oncol. 2020;31:1223-1230.
  6. Nerlynx (neratinib). Prescribing information. Puma Biotechnology; 2017.


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Last Updated: Monday, September 11, 2023
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