Near-complete Response to Neratinib-based Treatment in HR-positive HER2-amplified Metastatic Breast Cancer Refractory to Trastuzumab Deruxtecan

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+, HER2amplified and overexpressing MBC twice through molecular tumor board (MTB) discussions: initially with trastuzumab deruxtecan (T-DXd) while 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, mutation) patients. Our case also highlights the importance of the MTBs to dynamically and reactively manage the course of disease and treatment on a perpatient basis.