ESMO 2021: Clinical Perspectives for the Individual Patient and the Community

(UroToday.com) As a portion of the European Society for Medical Oncology (ESMO) Annual Congress, an Educational Session focused on precision management of patients with prostate cancer was held. In this context, Dr. Cora Sternberg presented clinical perspectives for both individual patients and for the community. She began by highlighting that personalized cancer medicine has been popularized in the lay media and wider community through discussion from celebrities of their own personal and family experiences.

However, the underlying importance of this is driven by the relatively high prevalence. Cited data from Dr. Pritchard and colleagues, she emphasized that 12% of unselected men with metastatic prostate cancer have evidence of pathogenic DNA repair germline mutations. These findings have both direct personal therapeutic considerations as well as for their families. Moving from germline mutations to examine the tumor tissue, up to 90% of tumor harbour clinically actionable molecular alterations and 20% harbour DNA repair pathway aberrations. She emphasized that there are many genes involved in homologous recombination repair. Thus, alterations in genes other than BRCA1 and BRCA2 may generate a similar phenotype.

She then cited data from the TOPARP-A trial which demonstrated differential responses to the PARP inhibitor olaparib among those with alterations in DNA repair genes for men with heavily pre-treated metastatic castration resistant prostate cancer (mCRPC), with a response rate of 80% in those with the genomic signature. This was followed by the TOPARP-B trial which demonstrated that patients with BRCA 1 and 2 mutations had the best response to olaparib, though there were responses among patients with other mutations. These data informed the PROfound trial which has been previously presented, published, and discussed extensively. In particular, the data from TOPARP-B informed the selection of the genes used for distinguishing cohort A (BRCA 1, BRCA 2, and ATM) from cohort B. This randomized trial compared olaparib to a switch of androgen axis targeting agent switch. In cohort A, both radiographic progression-free survival and overall survival were improved among patients receiving olaparib. No survival benefit was seen in cohort B, including patients with other DNA repair alterations.

Dr. Sternberg then moved to the 2021 NCCN guidelines which emphasize the importance of genetic and molecular testing in all patients with regional (ie. nodal involvement) or metastatic prostate cancer. In particular, testing for homologous recombination gene mutations, microsatellite instability, and mismatch repair deficiency is recommended. Testing is further recommended among those with a strong family history, those with Ashkenazi Jewish ancestry, with a family history of BRCA 1 or 2, as well as those with high-risk or very high-risk disease.

Considering next the ESMO guidelines, she emphasized that these are similar. Germline testing for DNA damage repair gene mutations is recommended in patients with family history and should be considered in all with metastatic disease. Further, testing for homologous recombination gene mutations, microsatellite instability, and mismatch repair deficiency is recommended in patients with metastatic disease. Additionally, those with pathogenic mutations in tumor testing should undergo germline testing and genetic counseling.

She highlighted that there is huge variability in the availability of genetic testing between countries. Some of this is driven by clinicians’ decision-making and understanding whereas practical considerations also come into play. In particular, she emphasized that testing is often tied to access to licensed or almost licensed drugs. Further, testing is not reimbursed in many countries, or outside of academic institutions. Additionally, lack of access to genetic counselors is cited as a barrier to further genetic testing.

In her own institution, she cited a variety of currently clinically utilized genomic tests including AmpliSeq, Oncomine, Myeloid, and EXaCT-1. Each of these is approved in New York State. Across the United States, she again highlighted that there is significant variation between institutions. At some institutions, it has been noted that there is increasing use of testing through private companies which occurs prior to referral.

Moving forward, she highlighted that liquid biopsies may make testing more accessible, as well as enable longitudinal and sequential testing.

She thus concluded that both NCCN and ESMO guidelines recommend genomic and genetic testing. However, there is huge variability in utilization and access.