Circulating tumor DNA genomic profiling reveals the complicated olaparib-resistance mechanism in prostate cancer salvage therapy: A case report

Abstract

BACKGROUND The poly (ADP-ribose) polymerase (PARP) inhibitor olaparib has displayed superior clinical effect in metastatic castration-resistant prostate cancer (mCRPC) patients with the homologous recombination repair ( HRR ) genes mutations. However, when a patient’s tumor tissue volume is insufficient for genomic profiling of HRR gene mutations, circulating tumor DNA (ctDNA) may be useful in helping to determine and monitor the efficacy of olaparib, as well as in abiraterone-combination treatment, and for understanding any resistance mechanism related to such mutations. CASE SUMMARY A 61-year-old man who was diagnosed with metastatic prostate adenocarcinoma was initially hormone sensitivity, showing high Gleason score (5 + 5 = 10) and absolute positive rate (14/14 biopsied specimens). Following failure of several standard therapies, the patient progressed to mCRPC. Surprisingly, the patient showed good response to olaparib-abiraterone-prednisone combination treatment (an androgen-deprivation therapy, provided as the ‘final choice’ in China). Serum total prostate-specific antigen (TPSA) level reduced and symptoms remitted for 4 months. However, thereafter, serum TPSA levels began slowly increasing, indicating development of olaparib resistance. Subsequent comprehensive genomic profiling of ctDNA, screening 508 cancer-related genes by next-generation sequencing, identified 10 somatic variants as well as 3 copy number alterations. Two identified reverse missense mutations in partner and localizer of BRCA2 ( PALB2 ) may have recovered the reading frame, restoring function of the primary germline PALB2 mutation and causing resistance to the PARP inhibitor olaparib. CONCLUSION Reverse mutations in PALB2 , discovered via genomic profiling of ctDNA, may represent a potential resistance mechanism against olaparib in mCRPC.

Cell-free DNA in the management of prostate cancer: Current status and future prospective

“…In a real-world mCRPC case that firstly showed a response to olaparib and then progressed, Yuan et al. [ 143 ] also identified two reverse missense mutations in BRCA2 from ctDNA. These two mutations shared the same loci with the germline deleterious variant c.751C>T and restored the open reading frame of BRCA2 and could explain the progressing mechanism during olaparib treatment.…”