108P - Copy loss enrichment at metastatic disease progression in hormone receptor-positive (HR+)/HER2-negative metastatic breast cancer patients treated with endocrine therapy and CDK4/6 inhibition

Background

Blood copy number burden (bCNB), derived from a low-pass whole genome sequencing assay (PredicineCNB^TM) is a comprehensive measure of copy number variation (CNV), including amplifications and deletions across the entire genome. We previously reported that increasing bCNB levels in blood samples collected from HR+/HER2-negative metastatic breast cancer patients at baseline and during treatment with endocrine therapy and CDK4/6 inhibition (ET + CDK4/6i) preceded radiographic detection of disease progression. Here, we present the results of an analysis of these samples using a boosted whole exome sequencing assay (PredicineWES+^TM) to compare the relative levels of single nucleotide variations (SNVs) vs. CNVs at baseline and progression timepoints.

Methods

Circulating tumor DNA (ctDNA) was isolated from plasma samples collected from 51 patients with metastatic HR+ /HER2- metastatic breast cancer at baseline and during treatment with ET + CDK4/6i. The PredicineWES+^TM assay was performed at baseline and clinical progression to profile SNVs and CNVs in 28 patients who had progressed at the time of data censoring.

Results

Relative levels of SNVs and CNVs at baseline vs. progression timepoints varied significantly (P=1.2E-08, Chi-Squared Test). While SNVs decreased, an increase in CNVs, reflected primarily by a higher number of deletions was observed at progression relative to baseline.

Table: 108P

Conclusions

Our results suggest that deletions are preferentially selected during the development of treatment resistance to ET + CDK4/6i. As our previous study demonstrated that increasing bCNB levels precede radiographic detection of progression in approximately two-thirds of patients, LP-WGS may constitute a low-cost approach to detect these events through serial blood monitoring during treatment.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Predicine, Inc.

Funding

Pfizer.

Disclosure

T. Zheng: Financial Interests, Institutional, Full or part-time Employment, Stock ownership: Predicine. C. Dai: Financial Interests, Institutional, Full or part-time Employment, Stock ownership: Predicine. F.O. Ademuyiwa: Financial Interests, Institutional, Advisory Role: Eisai, Immunomedics, AstraZeneca, Athenex, Cardinal Health, Pfizer, AbbVie, Best Doctors, Advance Medical; Financial Interests, Institutional, Other, Contracted Research: Immunomedics, Pfizer, Seattle Genetics, NeoImmuneTech, RNA Diagnostics, Astellas. X. Wang: Financial Interests, Institutional, Full or part-time Employment, Stock ownership: Predicine. P. Du: Financial Interests, Institutional, Full or part-time Employment, Stock ownership: Predicine. S. Jia: Financial Interests, Institutional, Full or part-time Employment, Stock ownership: Predicine. B.L. King: Financial Interests, Institutional, Full or part-time Employment: Predicine. J. Krishnamurthy: Financial Interests, Institutional, Advisory Board: Tempus, AstraZeneca, Merck. C.X. Ma: Financial Interests, Institutional, Advisory Board: Sanofi, Olaris, Gilead, Jacobio Pharmaceuticals; Financial Interests, Institutional, Advisory Role: Inviata, Pfizer, Novartis; Financial Interests, Institutional, Other, Contracted Research: Pfizer; Financial Interests, Institutional, Other, Honoraria: Eisai. All other authors have declared no conflicts of interest.