In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 4_Supplement ( 2021-02-15), p. PD8-05-PD8-05
Abstract:
Estrogen receptor positive (ER+) breast cancer is a leading cause of cancer-related death globally. Resistance to standard of care endocrine treatment occurs in at least 30% of ER+ breast cancer patients resulting in ~40,000 deaths every year in the US alone. Preclinical studies strongly implicate activation of growth factor receptor, HER2 in endocrine treatment resistance of ER+ breast cancer that is HER2- at diagnosis. 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 MLH1, a principal mismatch repair gene, causally activates HER2 in ER+/HER2- breast cancer upon endocrine treatment. Additionally, we show that HER2 activation is indispensable for endocrine treatment resistant growth of MLH1-defective cells in vitro and in vivo. Consequently, inhibiting HER2 restores sensitivity to endocrine treatment in multiple experimental models including patient-derived xenograft tumors. Patient data from multiple clinical datasets (TCGA, METABRIC, Alliance (Z1031) and E-GEOD-28826) supports an association between MLH1 loss, HER2 upregulation, and sensitivity to trastuzumab in endocrine treatment-resistant ER+/HER2- patients. These results provide strong evidence that MLH1 could serve as a first-in-class predictive marker of sensitivity to combinatorial treatment with endocrine drugs and HER2 inhibitors in endocrine treatment-resistant ER+/HER2- breast cancer patients. Implications of this study extend beyond breast cancer to Lynch Syndrome cancers. Citation Format: Svasti Haricharan, Nindo Punturi, Sinem Seker, Vaishnavi Devarakonda, Rashi Kalra, Ching-Hui Chen, Aloran Mazumder, Shungqiang Li, Tina Primeau, Matthew Ellis, Shyam Kavuri. Mismatch repair deficiency predicts response to HER2 blockade in HER2-negative breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD8-05.
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.SABCS20-PD8-05
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2021
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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