Faculty Collaboration Database

Efficacy of systemic therapies in men with metastatic castration resistant prostate cancer harboring germline ATM versus BRCA2 mutations. Prostate 2021 Dec;81(16):1382-1389

Date

09/14/2021

Pubmed ID

34516663

Pubmed Central ID

PMC8563438

DOI

10.1002/pros.24236

Scopus ID

2-s2.0-85114718067 (requires institutional sign-in at Scopus site)   10 Citations

Abstract

BACKGROUND: Among men with metastatic prostate cancer, about 10% have germline alterations in DNA damage response genes. Most studies have examined BRCA2 alone or an aggregate of BRCA1/2 and ATM. Emerging data suggest that ATM mutations may have distinct biology and warrant individual evaluation. The objective of this study is to determine whether response to prostate cancer systemic therapies differs between men with germline mutations in ATM (gATM) and BRCA2 (gBRCA2).

METHODS: This is an international multicenter retrospective matched cohort study of men with prostate cancer harboring gATM or gBRCA2. PSA₅₀ response (≥50% decline in prostate-specific antigen) was compared using Fisher's exact test.

RESULTS AND LIMITATIONS: The study included 45 gATM and 45 gBRCA2 patients, matched on stage and year of germline testing. Patients with gATM and gBRCA2 had similar age, Gleason grade, and PSA at diagnosis. We did not observe differences in PSA₅₀ responses to abiraterone, enzalutamide, or docetaxel in metastatic castration resistant prostate cancer between the two groups; however, 0/7 with gATM and 12/14 with gBRCA2 achieved PSA₅₀ response to PARPi (p < .001). Median (95% confidence interval) overall survival from diagnosis to death was 10.9 years (9.5-not reached) versus 9.9 years (7.1-not reached, p = .07) for the gATM and gBRCA2 cohorts, respectively. Limitations include the retrospective design and lack of mutation zygosity data.

CONCLUSIONS: Conventional therapies can be effective in gATM carriers and should be considered before PARPi, which shows limited efficacy in this group. Men with gATM mutations warrant prioritization for novel treatment strategies.

Author List

Sokolova AO, Marshall CH, Lozano R, Gulati R, Ledet EM, De Sarkar N, Grivas P, Higano CS, Montgomery B, Nelson PS, Olmos D, Sokolov V, Schweizer MT, Yezefski TA, Yu EY, Paller CJ, Sartor O, Castro E, Antonarakis ES, Cheng HH

Author

Navonil De Sarkar PhD Assistant Professor in the Pathology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Androstenes
Antineoplastic Agents
Ataxia Telangiectasia Mutated Proteins
BRCA2 Protein
Benzamides
Germ-Line Mutation
Humans
Male
Medication Therapy Management
Middle Aged
Neoplasm Grading
Neoplasm Staging
Nitriles
Patient Selection
Phenylthiohydantoin
Poly(ADP-ribose) Polymerase Inhibitors
Prostate-Specific Antigen
Prostatic Neoplasms, Castration-Resistant
Retrospective Studies
Survival Analysis