Case report: Near-complete response to neratinib-based treatment in HR-positive HER2-amplified metastatic breast cancer refractory to trastuzumab deruxtecan

Abstract

Breast cancer (BC) is the leading cause of cancer-related mortality among women. The backbone of first-line treatment in HR+/HER2+ BC is dual anti-HER2 blockade combined with taxane chemotherapy. Although this regimen exhibits high rates of response and disease control in both HR+ and HR- cohorts, some patients could have intrinsic or develop acquired resistance to trastuzumab and/or pertuzumab. Here, we achieved a near-complete response in HR+ HER2-amplified and overexpressing metastatic BC twice through molecular tumor board (MTB) discussions: initially, with trastuzumab deruxtecan (T-DXd) when HER2 IHC was positive, and, then, with neratinib plus fulvestrant plus paclitaxel when IHC was negative. Our case presents GATA3 and NOTCH2 mutations, MCL1 and CKS1B amplifications, as well as ERBB3/KRAS overexpression and ER signaling as potential new mechanisms of resistance to T-DXd. Furthermore, we demonstrated that triplet combination could induce a remarkable response in the T-DXd-refractory setting, which could be explored in future clinical trials in HR+ and HER2-activated (by RNA or protein overexpression, amplification, and mutation) patients. Our case also highlights the importance of the MTBs to dynamically and reactively manage the course of disease and treatment on a per-patient basis.

Keywords: HER2 antibody-drug conjugates (HER2 ADC); breast cancer; cancer genomics; molecular tumor board (MTB); neratinib; precision oncology; trastuzumab deruxtecan.

Figure 1

Near-complete responses in an HR+/HER2-amplified metastatic breast cancer patient, initially with trastuzumab deruxtecan (HER2 IHC–positive) and then with a neratinib-based combination (IHC-negative). (A) The December 2022 PET result showed multiple lesions with FDG uptake in the liver parenchyma consistent with metastasis. (B) The PET scan in February 2023 after T-DXd treatment did not reveal any lesions with significant FDG uptake. (C) In the September 2023 PET result, liver parenchyma shows several lesions with FDG uptake in the right and left lobes, consistent with metastasis (arrows). (D) In the January 2024 PET examination, no lesions showing FDG uptake could be detected in these lobes. (E) Disease and treatment timeline.