Interviews

Dr Schweizer Talks Concordance of DNA Damage Repair Gene Mutations in Paired Primary, Metastatic Prostate Cancer Samples

Dr SHi, my name is Michael Schweizer. I am a physician at Seattle Cancer Care Alliance, an associate professor here at the University of Washington and the Fred Hutchinson Cancer Research Center in Seattle, Washington. Today, I would like to discuss abstract number 5020, "Concordance of DNA Damage Repair Gene Mutations in Paired Primary and Metastatic Prostate Cancer Samples."

Recently, a number of different precision medicine strategies have been adopted as standard of care for the treatment of advanced prostate cancers. These include the use of the PARP inhibitors, rucaparib and olaparib, for patients with mutations in homologous recombination repair gene alterations, as well the use of pembrolizumab for patients who have mutations of mismatched repair genes.

Because of this, it is very important that we understand the somatic landscape of metastatic prostate cancer so we can select appropriate therapies. Traditionally, we have relied on metastatic biopsies to assess somatic mutations and to evaluate if patients might be a candidate for precision medicine approaches.

However, in prostate cancer, somatic sequencing of metastatic tissue is challenging due to the bone‑trophic nature of advanced prostate cancer and the fact that the diagnostic yield from sequencing bone metastases can be quite low.

Alternatively, cell‑free circulating tumor DNA can be used as a source of genomic material for next‑generation sequencing. However, this can led to false negative and/or equivocal studies in patients with low disease burden, which has been shown to correlate with low ctDNA concentration in plasma.

Prior studies have suggested that primary prostate tissue accurately reflects the mutational status of actionable DNA damage repair genes, and that these samples could be used to assess eligibility for one of the aforementioned precision treatment strategies. However, the small sample size of these studies limited their ability to make definitive conclusions. Therefore, we sought to evaluate the concordance in DNA repair gene alterations between archival primary prostate tissue and ctDNA or metastatic tissue obtained at a later time across a larger cohort.

We formed a collaboration with FoundationOne and our university to evaluate the mutational concordance between patients' primary prostate tissue as well as downstream samples, either metastatic tissue or cell‑free circulating DNA.

Overall, we identified 72 patients that had paired samples. After excluding cases that were felt to represent germline-only events or clonal hematopoiesis of indeterminate potential (i.e. CHIP) events, we were left with a final cohort of 51 patients. Of note, two of these subjects had three matched samples, which led to a total of 53 pairs for concordance assessmetn. Overall, we did find that there was high concordance between samples, with at least partial concordance observed in 84% of cases.

This led us to conclude that, because of this high concordance, it would be reasonable to use archival primary prostate cancer tissue to assess for actionable DNA damage repair mutations in most men with advanced prostate cancer.

In patients who do not have metastatic tissue that is readily accessible, or are thought to have indeterminate cell‑free DNA sequencing results, this now provides evidence that we can reflex to using archival tissue as a source for somatic tissue sequencing moving forward.

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