Germline pathogenic variants, primarily in DNA damage repair genes, are present in about 12% of patients with malignant pleural mesothelioma, report US researchers.

In patients with metastatic urothelial carcinoma treated with agents targeting programmed cell death protein 1 or its ligand, the presence of alterations in tumoral DNA damage response and repair genes is associated with better outcomes, findings indicate.

There were no significant associations between NLR and selected variants of interest, namely EGFR , KRAS , TP53 , KEAP1 , STK11 , SMARCA4 , ARID1A , and targeted DNA damage response and repair genes.

Phase 2 study data show that the PARP inhibitor talazoparib has antitumor activity in men with heavily pretreated metastatic castration-resistant prostate cancer bearing DNA damage response alterations in genes associated with homologous recombination repair.

Masayuki Hagiwara (Dana-Farber Cancer Institute, Boston, Massachusetts, USA) and co-investigators investigated PARP1 as a potential biomarker because “[s]everal recent studies have shown that the absence of PARP alters the tumor immune microenvironment by inhibiting repair of DNA damage, thereby promoting response to ICI [therapy].”

These individuals had at least one of either DNA mismatch repair deficiency (MMRD), DNA damage repair deficiency excluding MMRD, or a high level (>20%) of tumor infiltrating lymphocytes (TILs).

Clinically significant pathogenic/likely pathogenic germline variants, particularly in DNA damage repair genes, are common in patients with advanced urothelial cancer according to sequencing data.

As reported at the virtual 2020 ASCO Annual Meeting, all participants of the phase 2 trial had stage IV breast cancer, had received no more than two chemotherapy regimens for metastatic disease, and either carried germline mutations in DNA damage response pathway genes other than BRCA1 / 2 (cohort 1) or somatic mutations in BRCA1 / 2 or other genes (cohort 2).

The degree of response to olaparib among patients with heavily pretreated metastatic castration-resistant prostate cancer varies according to the type of DNA damage repair alteration the tumor carries, research shows.

The investigators also took a closer look at mutations in four DNA damage response genes ( BRCA1 , BRCA2 , RAD51C , and PALB2 ) thought to be associated with PARP inhibitor activity and found these to be relatively rare, affecting just 9.4% of patients.

The study was powered to investigate rucaparib in all-comers (regardless of the presence or not of DNA damage response mutations), but also in the subset of patients with high genome-wide loss of heterozygozity.

Germline mutations in the BRCA2 gene, but not other DNA damage repair genes, are associated with poorer outcomes among patients with metastatic castration-resistant prostate cancer, study findings indicate.

Together with previous results, the team concludes that “these data support the further development of strategies that combine induction of DNA damage with PARP inhibition.”

Inherited pathogenic variants in the DNA repair gene CHEK2 are associated with an increased risk for developing testicular germ cell tumors, findings indicate.

This book chapter explores newly-discovered molecular subtypes of triple-negative breast cancer and how genetic profiling can be used to target therapy. Summary points Triple-negative breast cancers (TNBC) are those that lack expression of the breast cancer prognostic markers estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 (HER2), and account for about 15% of all breast cancers. Recent increased understanding of the molecular mechanisms responsible for the initiation and propagation of this breast cancer subtype has been gained through gene expression profiling, the study of cancer genetics and the study of host antitumor immunity. The majority of TNBCs cluster within a basal-like subgroup, characterized by a low expression of hormone receptor and HER2-related genes and high expression of proliferation genes characteristic of the basal epithelial cell layer. The therapeutic significance of basal-like versus non-basal-like TNBC is yet to be determined. Despite this association, substantial molecular heterogeneity in TNBC defined by immunophenotyping exists. Six subtypes of TNBC have been identified, including two basal-like (BL-1 and BL-2), an immunomodulatory (IM), a mesenchymal (M), a mesenchymal stem-like (MSL), and a luminal androgen receptor (LAR) subtype. Breast cancer in women with a germline BRCA1 mutation are overwhelmingly triple negative. Given the known role of BRCA1 and BRCA2 in homologous recombination DNA repair, treatment with platinum chemotherapy and poly(ADP-ribose) polymerase (PARP) inhibitors has been associated with high levels of anticancer activity. In addition to germline BRCA1 and BRCA2 mutation status, biomarkers of genomic instability have been developed that detect genomic ‘scarring’ caused by accumulated DNA damage. Therapeutic strategies are currently being investigated to assess whether these germline and genetic biomarkers can identify groups of patients with TNBC with underlying DNA repair deficiency more likely to benefit from DNA repair defect targeted therapies. Telli ML. In: Molecular Pathology of Breast Cancer . Edited by Badve S and Gökmen-Polar Y. Springer, Cham, 2016. doi:10.1007/978-3-319-41761-5_6

They postulated that carboplatin, which is a DNA-crosslinking agent, would have greater activity than the microtubule-disrupting drug docetaxel in patients who were deficient in DNA damage response.