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Authors Wu, Cieślik, Lonigro et al.
Review Date June 2018
Citation Cell. 173(7):1770-1782
Immunotherapy to target solid tumours has been gaining traction over the past decade. Various types of immunotherapy now exist, with the goal of stimulating the immune system to attack and kill cancer cells by recognising tumour-associated antigens (neoantigens) presented by the cancer. Immunotherapy is remarkably effective in killing certain cancers, particularly those with a high mutational burden, such as melanoma and certain types of lung cancer.
In prostate cancer, vaccine-based and immune-checkpoint inhibitor immunotherapies against tumour neoantigens are under clinical trial, with varying levels of efficacy. Given that prostate cancer generally has a low mutation rate and low levels of neoantigens it is often not very detectable by the immune system. However, in some cases patient response to immunotherapy is exceptional. Selecting which patients have a prostate cancer type that is detectable by the immune system and therefore would respond to immunotherapy is the holy grail.
Using gene sequencing, the authors determined the genetic make-up of advanced metastatic prostate cancers, to identify subgroups of patients that could benefit from therapies targeted specifically to their cancer’s genetic identity.
Integrative genomic analyses were performed on metastatic castration-resistant prostate cancer (mCRPC) cases (n=360). Pathological tissues were collected using image-guided prostate biopsy; tumour genomic DNA and total RNA and matched normal genomic DNA were subjected to exome sequencing. TCGA sequence data from cases of primary prostate cancer were also analysed (n=498). The tumour immune microenvironment of mCRPC samples was studied using immunohistochemical staining of T-lymphocytes in fixed tumour sections, and profiling of the immune repertoire using immunosequencing of tumour DNA (n=60).
Genetic defects (mutations) causing biallelic loss (both copies) of the CDK12 gene occurred almost six times more frequently in mCRPC tumours than primary prostate cancers (6.9% vs 1.2%; p<0.0001). Prostate cancers harbouring CDK12 mutations belonged to their own unique ‘molecular’ subclass, being genetically dissimilar to other prostate cancers associated with common primary genetic drivers. Novel neoantigens were present in CDK12 mutant tumours, identifying possible new candidates for immunotherapy. Tumour microenvironment analyses found that CDK12 defective tumours were enriched for pro-tumour cytokines and exhibited increased tumour-infiltrating T cells compared to other prostate tumours. Retrospective clinical data identified a small sample of patients with CDK12 defective mCRPC who were exposed to immune checkpoint inhibitor anti-PD-1 monotherapy (n=4). In two of the four cases, PSA very significantly declined and in one patient treatment led to reduced pelvic lymph node disease.
This study identified a unique sub-class of mCRPC characterised by loss of CDK12 gene function; these tumours were genetically and immunophenotypically distinct from other prostate cancers. Therefore, patients with a CDK12 mutant mCRPC might benefit significantly from immunotherapeutic management that other cases of metastatic prostate cancer would not. These preliminary findings should serve the basis of a prospective randomised clinical trial to determine the true efficacy of immunotherapy for advanced prostate cancer treatment on a personalised basis.
Points to Note
1. CDK12 is required for several key biological processes in the cell and performs an important role in genomic stability through the control of DNA repair genes.
2. Inactivation of both copies of CDK12 was strongly linked to genomic instability in the form of focal copy-number gains (tandem duplications) found across the genome, leading to the generation of novel neoantigens.
3. CDK12 mutant metastatic prostate tumours are molecularly distinct from tumours associated with deficient DNA repair, including homologous recombination-deficient (HRD) and mismatch repair-deficient (MMRD) metastatic prostate cancer.