Abstract P6-10-07: Activating HER2 missense mutations in HER2-negative metastatic breast cancer
Authors: Shah Mirat , Ensminger Jennifer , Wang Chenguang , Ali Siraj , Chung Jon , Lauring Josh , Park Ben Ho , Stearns Vered 
Published: March 2020

Background: Activating HER2 missense mutations can develop in HER2-negative metastatic breast cancer, particularly in ER-positive disease. These mutations may be targeted with anti-HER2-directed therapy, providing a novel therapeutic option for women with HER2-negative metastatic breast cancer. The clinical behavior and significance of these mutations in the era of cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) for ER-positive breast cancer are unknown.

Methods: We examined patients enrolled onto an ongoing single institution prospective study entitled Individualized Molecular Analyses Guide Efforts (IMAGE) II. The purpose of IMAGE II was to identify potentially targetable tumor genetic alterations, and the purpose of this analysis was to identify HER2 missense mutations. Patients eligible for IMAGE II had metastatic breast cancer of any subtype that had progressed on at least one standard-of-care therapy. Genetic profiling of blood was performed using the FoundationOne Liquid platform; metastatic tumor tissue profiling was performed using one of several commercially available next-generation sequencing platforms. All assays were capable of detecting common point mutations in the ERBB2 gene.

Results: As of June 1, 2019, 54 patients were enrolled onto IMAGE II and had available genetic profiling results. Approximately half had ER+HER2- disease (n=29, 54%), one-third had triple negative breast cancer-TNBC (n=18, 33%), and the rest had HER2-positive disease (n=7, 13%). Six patients had activating HER2 missense mutations, with the same mutation(s) found in both tissue and blood in all patients. Five of these patients had ER+HER2- disease and the prevalence of HER2 mutations among patients with ER+HER2- disease was 17% (5/29) in our cohort.

All five patients had received CDK4/6i with endocrine therapy in the metastatic setting prior to enrollment on IMAGE II. Four patients had markedly rapid tumor progression with this therapy. The median time to progression on CDK4/6i and endocrine therapy was 3.7 months (range 2.4-14.7) among patients with ER+HER2- disease and a HER2 missense mutation, compared to 9.4 months (range 2.3-40.9) among patients with ER+HER2- disease without a missense mutation. A summary of the patients with a HER2 missense mutation is shown in Table 1.

Three patients with a HER2 missense mutation received HER2-directed therapy with trastuzumab and pertuzumab. One patient has an ongoing clinical response at 9.4 months, one patient has a clinical response after 1.8 months of therapy, and one patient recently began treatment with no follow-up data available yet.

Conclusions: The frequency of HER2 missense mutations in patients with ER+HER2- metastatic breast cancer in our small cohort was higher than previously reported, and patients with this mutation had early tumor progression on CDK4/6i therapy regardless of endocrine therapy pairing. We hypothesize that activating HER2 missense mutations may be important drivers of resistance to CDK4/6i therapy. Testing patients who progress rapidly on CDK4/6i therapy for activating HER2 missense mutations may provide a novel therapeutic option.

PatientSubtypeHER2 Mutation(s)Found whereReceived CDK4/6iLineWith which endocrine therapyTime to progression (in months)1ER+HER2-L755STissue/bloodYes2ndfulvestrant14.82ER+HER2-V777LTissue/bloodYes1sttamoxifen3.73ER+HER2-L755PTissue/bloodYes1stfulvestrant3.34ER+HER2-L755S, V697LTissue/bloodYes2ndfulvestrant4.15ER+HER2-L869RTissue/bloodYes1stletrozole2.46TNBCD769YTissue/bloodNoNANANA

Citation Format: Mirat Shah, Jennifer Ensminger, Chenguang Wang, Siraj Ali, Jon Chung, Josh Lauring, Ben Ho Park, Vered Stearns. Activating HER2 missense mutations in HER2-negative metastatic breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-10-07.