Practical considerations for optimising homologous recombination repair mutation testing in patients with metastatic prostate cancer

Abstract

Analysis of the genomic landscape of prostate cancer has identified different molecular subgroups with relevance for novel or existing targeted therapies. The recent approvals of the poly(ADP-ribose) polymerase (PARP) inhibitors olaparib and rucaparib in the metastatic castration-resistant prostate cancer (mCRPC) setting signal the need to embed molecular diagnostics in the clinical pathway of patients with mCRPC to identify those who can benefit from targeted therapies. Best practice guidelines in overall biospecimen collection and processing for molecular analysis are widely available for several tumour types. However, there is no standard protocol for molecular diagnostic testing in prostate cancer. Here, we provide a series of recommendations on specimen handling, sample pre-analytics, laboratory workflow, and testing pathways to maximise the success rates for clinical genomic analysis in prostate cancer. Early involvement of a multidisciplinary team of pathologists, urologists, oncologists, radiologists, nurses, molecular scientists, and laboratory staff is key to enable optimal workflow for specimen selection and preservation at the time of diagnosis so that samples are available for molecular analysis when required. Given the improved outcome of patients with mCRPC and homologous recombination repair gene alterations who have been treated with PARP inhibitors, there is an urgent need to incorporate high-quality genomic testing in the routine clinical pathway of these patients.

Keywords: homologous recombination repair; mCRPC; metastatic prostate cancer; molecular diagnostics; poly(ADP-ribose) polymerase inhibitors.

Figure 1

Schematic mechanism of PARP inhibition. PARP inhibitors trap PARP at sites of single‐strand breaks, leading to generation of double‐strand breaks and cell death in cancer cells with deficiency in HRR. PARPi, PARP inhibitor. Adapted from O'Connor [3].

Figure 2

Schematic representation of tissue sample pathway for molecular diagnostic testing. cfDNA, circulating cell‐free DNA. *Storage conditions 18–25 °C and low humidity. ^†For liquid biopsies, use cell‐stabilisation tubes and process within 3 days.

Figure 3

Illustrative examples of differences in neoplastic cell content in two prostate biopsy samples. (A) Core needle biopsy sample of approximately 1 mm × 10 mm showing that the sample predominantly has neoplastic cell content with minimal non‐neoplastic prostate cell content or adjacent soft tissues and (B) similar‐sized core needle biopsy showing much less neoplastic cell content and more non‐neoplastic content. The black dashed line areas (marked T) indicate the area of neoplastic cells. Red dashed lines represent the area of magnification of the tumour cell content. H&E staining.