Genomic amplifications identified by circulating tumor DNA analysis guide prognosis in metastatic castration-resistant prostate cancer

Toros A Dincman; Joseph A Q Karam; Antonio Giordano; Hong Li; Leylah M Drusbosky; Theodore S Gourdin; Philip H Howe; Michael B Lilly

doi:10.3389/fonc.2023.1202277

Genomic amplifications identified by circulating tumor DNA analysis guide prognosis in metastatic castration-resistant prostate cancer

Front Oncol. 2024 Feb 21:13:1202277. doi: 10.3389/fonc.2023.1202277. eCollection 2023.

Authors

Toros A Dincman^{1

2

3}, Joseph A Q Karam³, Antonio Giordano^{1

2

4

5}, Hong Li^{2

6}, Leylah M Drusbosky⁷, Theodore S Gourdin^{1

2}, Philip H Howe³, Michael B Lilly^{1

2}

Affiliations

¹ Department of Medicine, Division of Hematology and Oncology, Medical University of South Carolina, Charleston, SC, United States.
² Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, United States.
³ Department of Biochemistry and Molecular Biology, College of Medicine, Medical University of South Carolina, Charleston, SC, United States.
⁴ Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States.
⁵ Medical Oncology, Harvard Medical School, Boston, MA, United States.
⁶ Department of Public Health Sciences, University of California- Davis, Davis, CA, United States.
⁷ Guardant Health, Redwood City, CA, United States.

Abstract

Purpose: Analysis of circulating tumor DNA (ctDNA) in patients with metastatic prostate cancer (mPC) provides an opportunity to identify and monitor genomic alterations during a patient's treatment course. We evaluated whether the presence of specific gene amplifications (GAs) and plasma copy number (PCN) alterations are associated with disease features.

Methods: This is a single-institution retrospective study of patients with mPC who underwent ctDNA profiling using Guardant360^® (Guardant Health Inc.). This test identifies single nucleotide variants (SNVs) and GAs of select genes by next-generation sequencing. A total of 155 men with mPC were studied. Patients were stratified by GA status. The Kaplan-Meier method and multivariate cox regression models were used to estimate overall survival (OS) or failure-free survival (FFS) from either the date of GA detection or the initiation of systemic therapy. The chi-square test was used to evaluate associations between clinical factors and GAs.

Results: The presence of liver and/or lung metastases was associated with GAs of BRAF, CDK6, PI3KCA, and FGFR1. Survival analyses were completed on a subset of 83 patients with metastatic castration-resistant prostate cancer (mCRPC). Median OS was improved in patients with 1 GA compared to patients with ≥2 GAs, whether determined from the date of initial GA(s) detection (14.9 mo vs. 8.9 mo) or date of therapy initiation nearest to GA detection (16.7 mo vs. 9.0 mo). Patients without GAs had not reached median OS. Patients with androgen receptor (AR) GA only were also found to have better median OS compared to patients with AR GA plus at least one other additional GA (19.3 mo vs. 8.9 mo). Patients with PIK3CA GA had significantly lower median OS compared to patients with GAs that did not have a PIK3CA GA (5.9 mo vs. 16.0 mo). In patients with AR and/or MYC GA(s), median OS improved in those with reduced AR or MYC PCN during therapy compared to those without such a reduction (25.1 mo vs. 15.9 mo).

Conclusions: The association of select GAs with survival provides an additional tool for assessing mCRPC prognosis and informing management. Serial monitoring of ctDNA GAs is also useful to guide prognosis and therapeutic response.

Keywords: PIK3CA; androgen receptor; aneuploidy; castration-resistant prostate cancer; circulating tumor DNA; genomic amplification; metastasis; prostate cancer.

Abstract

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