Abstract
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Objectives: Pharmacogenomics, the science of exploring germline and somatic mutations as predictors of therapy response in cancer patients, is envisaged to become the cornerstone in precision oncology. In this study a) we explored the frequency of germline mutations in metastasized prostate cancer (mPCa) patients referred for prostate specific membrane antigen (PSMA) guided radioligand therapy (PRLT) and b) assess the efficacy of PRLT in patients with germline mutations in comparison to historical data.
Methods: Local ethical committee approved this study and all patients signed written informed consent. De-identified records and results of tests were reviewed. The following genes (n=19) in the PCa specific panel analyses were included: ATM, BRCA1, BRCA2, CHEK2, EPCAM, HOXB13, MLH1, MSH2, NSH6, NBN, PMS2, TP53, PAL82, RAD51D. PSA response (according to the PCWG 3) of patients after PRLT was retrieved from institutional databank. Results of gene tests are expressed in frequency (absolute number and percentage). PRLT was performed according to the institutional standard of care.
Results: 29/81 (35.8%) of patients were identified positive for at least one variant classified as pathogenic or risk allele or of uncertain clinical significance. Amongst these 29 patients, the frequency (n;%) was highest for FANCA and CHEK2 (each n= 5; 17.2), followed by BRCA2 (3; 10.3), HOXB13 (3; 10.3), BRIP1 (3; 10.3), ATR (3; 10.3), BRCA1 (2; 6.9) ; each of MSH2, PMS2, RAD51D, TP53, ATM, ATM+NBN showed a frequency of 1;3.4. Out of 29 patients, PSA response (n;%) according to PCWG 3.0 was seen (18; 62.1) with complete PSA regression in 5 patients (17.2 %). Amongst 10 patients with germline mutations known to be radiosensitizers (FANCA, BRCA1, ATR), the PSA reduced by more than 50% in only 3 patients (30 %), progressed in 6 (60 %) and was stable in 1 patient. In 6 patients with germline mutations known to be associated with poor prognoses (HOXB13 or BRCA2), on the contrary, 4 (66.7 %) had PSA response and 1 each (16.7 %) showed progressive disease / stable disease. The best response was noted in patients with CHEK2 germline mutations with all 5 patients (100 %) revealing a PSA response, 2 of whom had a complete remission. The one patient with TP53 mutation also had a renal cell carcinoma.
Conclusions: In this explorative study we report for the first time, a high frequency (35.8 %) of germline mutations in a larger patient cohort referred for PRLT. The CHEK2 germline mutations seem to be associated with the best PSA response. In this pilot study, the treatment outcome appeared to not correlate with the presence of radiosensitizer (FANCA, BRCA1, ATR) or historically prognosis-determining (HOXB13 or BRCA2) germline gene variants. The influence of all germline mutations on overall survival - in comparison to historical data of patients treated with PRLT at our institution (n=312) - will be analyzed next.
