Mismatch repair deficiency predicts response to HER2 blockade in HER2-negative breast cancer

Abstract

Resistance to endocrine treatment occurs in ~30% of ER+ breast cancer patients resulting in ~40,000 deaths/year in the USA. Preclinical studies strongly implicate activation of growth factor receptor, HER2 in endocrine treatment resistance. However, clinical trials of pan-HER inhibitors in ER+/HER2− patients have disappointed, likely due to a lack of predictive biomarkers. Here we demonstrate that loss of mismatch repair activates HER2 after endocrine treatment in ER+/HER2− breast cancer cells by protecting HER2 from protein trafficking. Additionally, HER2 activation is indispensable for endocrine treatment resistance in MutL- cells. Consequently, inhibiting HER2 restores sensitivity to endocrine treatment. Patient data from multiple clinical datasets supports an association between MutL loss, HER2 upregulation, and sensitivity to HER inhibitors in ER+/HER2− patients. These results provide strong rationale for MutL loss as a first-in-class predictive marker of sensitivity to combinatorial treatment with endocrine intervention and HER inhibitors in endocrine treatment-resistant ER+/HER2− breast cancer patients.

Modulation of the Estrogen/erbB2 Receptors Cross-talk by CDK4/6 Inhibition Triggers Sustained Senescence in Estrogen Receptor– and ErbB2-positive Breast Cancer

“…In our experiments we confirm in ER-positive/HER2 low MCF7 and T47D the efficacy of concomitant Fulvestrant/Palbociclib, but we also show that the maximal synergy is reached when the anti-HER2 monoclonal antibodies were added. This is in agreement with the observation of HER2 functional activation that may represent an escape pathway for survival [42][43][44][45] in HER2+ and HER2 low BC.…”

HER2 Low, Ultra-low, and Novel Complementary Biomarkers: Expanding the Spectrum of HER2 Positivity in Breast Cancer

“…This finding was reflected by an increased sensitivity to HER inhibition. The data published in this study suggest that MutL loss inclines ER+/HER2− tumors to respond to a combination of anti-HER agents and endocrine treatment (Punturi et al, 2021). On the other hand, the currently available HER2 tests (IHC, ISH) provide information on the protein expression or gene amplification, which do not include the functional status of the HER2 biomarker.…”

“…A recent study has proposed the application of anti-HER agents for ER+/HER2- breast cancers in the context of mismatch repair (MMR) status ( Punturi et al, 2021 ). MMR is known as one of the fundamental DNA repair pathways ( Piciotti et al, 2021 ) Defects in the MMR system are commonly due to molecular alterations involving the MutS and MutL dimeric homologs ( Corti et al, 2019 ; Lopez et al, 2020 ).…”

“…This HER2 “ultra-low” phenotype might explain some promising evidence on treatment response in HER2-negative breast cancer ( Denkert et al, 2021 ). Recent preclinical studies on HER2 targeting in MutL-deficient estrogen receptor (ER)+/HER2-negative breast cancers have shown positive results ( Punturi et al, 2021 ). These data might provide a further rationale for expanding our pathological armamentarium towards mismatch repair (MMR)-related biomarkers ( Venetis et al, 2020b ; Sajjadi et al, 2021b ).…”

Commentary: Mismatch Repair Deficiency and Microsatellite Instability in Triple-Negative Breast Cancer: A Retrospective Study of 440 Patients

“…The topic is of great importance considering the growing interest on the implementation of consistent MMR testing for prognostication, immune checkpoints inhibitors (ICI) prediction, and identification of therapy resistance/susceptibility in both adjuvant and neoadjuvant settings (6)(7)(8). To date, in the neoadjuvant setting, several clinical trials have examined the efficacy of programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) blockade in early high-risk TNBC (9)(10)(11).…”