Hybrid capture-based genomic profiling of circulating tumor DNA from patients with estrogen receptor-positive metastatic breast cancer.

Chung JH1, Pavlick D1, Hartmaier R1, Schrock AB1, Young L1, Forcier B1, Ye P2, Levin MK3, Burris H4, Gay LM1, Hoffman AD5, Stephens PJ1, Frampton GM1, Lipson DM1, Nguyen DM6, Ganesan S7, Park BH8, Vahdat LT9, Leyland-Jones B2, Mughal TI1,10, Pusztai L11, O'Shaughnessy J3, Miller VA1, Ross JS1,12, Ali SM1.

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Abstract

BACKGROUND:

Genomic changes that occur in breast cancer during the course of disease have been informed by sequencing of primary and metastatic tumor tissue. For patients with relapsed and metastatic disease, evolution of the breast cancer genome highlights the importance of using a recent sample for genomic profiling to guide clinical decision-making. Obtaining a metastatic tissue biopsy can be challenging, and analysis of circulating tumor DNA (ctDNA) from blood may provide a minimally invasive alternative.

PATIENTS AND METHODS:

Hybrid capture-based genomic profiling was performed on ctDNA from 254 female patients with estrogen receptor-positive breast cancer. Peripheral blood samples were submitted by clinicians in the course of routine clinical care between 5/2016-3/2017. Sequencing of 62 genes was performed to a unique median coverage depth of 7503X. Genomic alterations (GAs) in ctDNA were evaluated and compared with matched tissue samples and genomic datasets of tissue from breast cancer.

RESULTS:

At least 1 GA was reported in 78% of samples. Frequently altered genes were TP53 (38%), ESR1 (31%) and PIK3CA (31%). Temporally matched ctDNA and tissue samples were available for 14 patients; 89% of mutations detected in tissue were also detected in ctDNA. Diverse ESR1 GAs including mutation, rearrangement, and amplification, were observed. Multiple concurrent ESR1 GAs were observed in 40% of ESR1- altered cases, suggesting polyclonal origin; ESR1 compound mutations were also observed in 2 cases. ESR1- altered cases harbored co-occurring GAs in PIK3CA (35%), FGFR1 (16%), ERBB2 (8%), BRCA1/2 (5%), and AKT1 (4%).

CONCLUSIONS:

GAs relevant to relapsed/metastatic breast cancer management were identified, including diverse ESR1 GAs. Genomic profiling of ctDNA demonstrated sensitive detection of mutations found in tissue. Detection of amplifications was associated with ctDNA fraction. Genomic profiling of ctDNA may provide a complementary and possibly alternative approach to tissue-based genomic testing for patients with estrogen receptor-positive metastatic breast cancer.