#AACR19: Morphologic and genomic characterization of circulating tumor cells in patients with ERBB2 mutant HER2 non-amplified metastatic breast cancer treated with neratinib

USC scientists Dr. Stephanie Shishido will present results from a small cohort study from a clinical trial in which metastatic breast cancer patients with a rare form of the disease (ERBB2 mutated, HER2 non-amplified) were treated with the combination of Neratinib and Fulvestrant. This work focuses on the use of a blood sample for a comprehensive analysis of the disease state for each individual over the course of treatment.

Presenters:

Stephanie Nicole Shishido, Rahul Masson, Lisa Welter, Liya Xu, Anishka D’Souza, Darcy Spicer, James Hicks, Janice Lu, Peter Kuhn.

University of Southern California, Los Angeles, CA

Abstract:

Metastatic breast cancer patients have a high risk of progression and face poor prognosis overall, with about one third (34%) surviving 5 years or more. In rare instances (2-4% of cases) patients with metastatic breast cancer have ERBB2 (HER2) activating mutations, but are HER2 negative (non-amplified. Neratinib is a potent, irreversible inhibitor that binds HER2 and inhibits downstream signaling. We used the previously validated high-definition single cell analysis (HD-SCA) workflow to investigate the clinical significance of circulating tumor cells (HD-CTCs) in HER2-mutant, HER2 non-amplified, post-menopausal metastatic breast cancer patients starting neratinib and fulvestrant combinational therapy. Genomic analysis of the cell-free DNA (cfDNA) and single cell HD-CTCs was conducted to monitor tumor evolution and identify potential mutational variants unique to the patientโ€™s clinical response. A subset of 5 patients presented here were from the MutHER (NCT01670877) and/or SUMMIT (NCT01953926) trials. Patients had an average of 5.4 lines of therapy before enrollment, variable hormone receptor status, and ERBB2 mutations at diagnosis and during treatment. HD-CTC enumeration alone was not sufficient to predict clinical response. Interestingly, treatment pressure was shown to lead to an observable change in HD-CTC morphology and genomic instability, suggesting these parameters may inform prognosis. Single cell copy number variation (CNV) analysis indicated that the persistence or development of a clonal population of HD-CTCs during treatment was associated with a worse response. Hierarchical clustering analysis of the single cells across all patients and timepoints identified distinct aberrant regions shared among patients, comprised of 26 genes that are similarly affected and may be related to drug resistance. Additionally at the cfDNA level, we identified new mutations in ERBB2PIK3CA, and TP53 that arose due to treatment pressure in a patient with poor response, further informing us on the dynamics of the cancer genome over the course of therapy. The data presented in this small cohort study demonstrates the feasibility of real-time molecular profiling of the cellular and acellular fractions of the liquid biopsy using the HD-SCA platform. Additional insight is warranted to determine the potential use of morphometric and genomic analysis as a prognostic tool to advance personalized oncology.

For a deeper understanding with a blood test can help monitor treatment efficacy in metastasis breast cancer, come see Dr. Shishido talk on April 2, 2019, 3:20 PM – 3:35 PM at Room B405 – Georgia World CC

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Stephanie Shishido, PhD

Postdoctoral research fellow

Breast cancer is the most frequent cancer diagnosis among women in industrialized countries, and rates in North America are among the highest in the world. The American Cancer Society estimated that about 295,000 new cases of cancer would be diagnosed among US women in 2014 and that approximately 40,000 deaths would occur. Metastatic breast cancer is the most lethal, in which cancer has spread beyond the breast and nearby lymph nodes to other parts of the body. When breast cancer spreads, it most commonly goes to the bones, liver, and lungs. It may also spread to the brain or other organs. Most women with metastatic breast cancer are treated with systemic therapy. The types of drugs used for stage IV breast cancer depend on the hormone receptor status and the HER2 status of cancer. Determining the efficacy of treatment is challenging, but utilizing the blood provides a unique opportunity to monitor treatment response to improve patient outcomes