Germline DNA Damage Repair Alterations in Patients with Localized Prostate Cancer Treated with Neoadjuvant Androgen Deprivation Therapy - Expert Commentary

Germline DNA damage repair (gDDR) alterations are common in men with prostate cancer (PCa). Men with PCa and gDDR alterations showed poor clinical outcomes. It is unclear if men with high-risk PCa and gDDR alterations would respond differently to neoadjuvant androgen deprivation therapy (ADT) than men without gDDR alterations.


A recent study by Berchuck et al. published in European Urology investigated the prevalence of pathogenic gDDR alterations in patients with localized prostate cancer and their association with pathologic response following neoadjuvant ADT. The investigators performed germline panel sequencing in 201 men with intermediate- and high-risk localized PCa from five randomized clinical trials. Exceptional pathologic response was defined as complete response or minimal residual disease to intense neoadjuvant ADT. A total of 19 (9.5%) patients harbored pathogenic gDDR alterations. Six patients had BRCA2 alterations, and four patients had ATM alterations. The baseline patient characteristics between men with and without gDDR alterations were not significantly different.

Patients with gDDR alterations showed similar rates of exceptional pathologic response compared to patients without gDDR (26% vs. 22%, p >0.05). Other clinical factors were not statistically different, including pT3 disease, lymph node involvement, extraprostatic extension (35% vs. 54%), and positive margins. Similarly, the 3-yr biochemical recurrence-free survival was similar between the two subgroups (45% for men with gDDR alterations and 55% for men without gDDR alterations).

This study provides important data on the efficacy of ADT in men with gDRR alterations. Large prospective trials are needed to confirm these results.

Written by: Bishoy M. Faltas, MD, Director of Bladder Cancer Research, Englander Institute for Precision Medicine, Weill Cornell Medicine, New York City, New York

References:

  1. Castro E, Goh C, Olmos D, Saunders E, Leongamornlert D, Tymrakiewicz M, et al. Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer. J Clin Oncol. 2013;31(14):1748–57. PMID: 23569316
  2. Berchuck JE, Zhang Z, Silver R, Kwak L, Xie W, Lee G-SM, et al. Impact of Pathogenic Germline DNA Damage Repair alterations on Response to Intense Neoadjuvant Androgen Deprivation Therapy in High-risk Localized Prostate Cancer. Eur Urol. 2021 Apr;doi.10.1016/j.eururo.2021.03.031. PMID: 33888356
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