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NPJ Breast Cancer. 2018 Aug 2;4:22. doi: 10.1038/s41523-018-0075-5. eCollection 2018.

Unraveling the clinicopathological features driving the emergence of ESR1 mutations in metastatic breast cancer.

Author information

1
1Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA 02215 USA.
2
2Department of Medical Oncology, Dana Farber-Cancer Institute, Boston, MA 02215 USA.
3
3Beth Israel Deaconess Medical Center, Boston, MA 02215 USA.
4
4Department of Biostatistics & Comp Biology, Dana-Farber Cancer Institute, Boston, MA 02215 USA.
5
5Center for Functional Cancer Epigenetics, Dana Farber-Cancer Institute, Boston, MA 02215 USA.
6
6Breast Oncology Center, Dana-Farber Cancer Institute, Boston, MA 02215 USA.
7
7Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA 02215 USA.

Abstract

ESR1 mutations were recently found to be an important mechanism of endocrine resistance in ER-positive (ER + ) metastatic breast cancer. To determine the clinicopathological features driving the emergence of the ESR1 mutations we studied plasma cfDNA and detailed clinical data collected from patients with metastatic breast cancer. Droplet Digital PCR was performed for the detection of the most common ESR1 mutations and PIK3CA mutations. Among the patients with ER + /HER2- disease, ESR1 mutations were detected in 30% of the patients. There were no associations between the pathological features of the primary disease or time to distant recurrence and the emergence of ESR1 mutations in metastatic disease. The prevalence of the ESR1 mutations was significantly associated with prior treatment with an aromatase inhibitor in the adjuvant or metastatic setting. The prevalence of the ESR1 mutations was also positively associated with prior fulvestrant treatment. Conversely, the prevalence of ESR1 mutations was lower after treatment with a CDK4/6 inhibitor. There were no significant associations between specific systemic treatments and the prevalence of PIK3CA mutations. These results support the evolution of the ESR1 mutations under the selective pressure of treatment with aromatase inhibitors in the adjuvant and metastatic settings and have important implications in the optimization of adjuvant and metastatic treatment in ER + breast cancer.

Conflict of interest statement

Dr. Pasi A. Jänne has received consulting fees from AstraZeneca, Boehringer Ingelheim, Pfizer, Merrimack Pharmaceuticals, Roche/Genentech, Chugai Pharmaceuticals, ACEA Biosciences, Ignyta, LOXO Oncology, Ariad Pharmaceuticals, Eli Lilly and Company and Araxes Pharmaceuticals; sponsored research funding from Astellas Pharmaceuticals, AstraZeneca, Daiichi Sankyo, PUMA and Eli Lilly and Company and receives post-marketing royalties on DFCI owned intellectual property on EGFR mutations licensed to Lab Corp. Dr. Cloud P. Paweletz has received honoraria from AstraZeneca, Clovis Oncology, and Bio-RAD and is a SAB member of DropWorks. Drs. Cloud P. Paweletz, Yanan Kuang, and Pasi A. Jänne are inventors on a pending patent related to non-invasive genotyping of cfDNA. The other authors declare no competing interests.

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