Untapped Potential of Poly(ADP-Ribose) Polymerase Inhibitors: Lessons Learned From the Real-World Clinical Homologous Recombination Repair Mutation Testing.

Background: Testing for homologous recombination deficiency (HRD) mutations is pivotal to assess individual risk, to proact preventive measures in healthy carriers and to tailor treatments for cancer patients. Increasing prominence of poly(ADP-ribose) polymerase (PARP) inhibitors with remarkable impact on molecular-selected patient survival across diverse nosologies, ingrains testing for BRCA genes and beyond in clinical practice. Nevertheless, testing strategies remain a question of debate. While several pathogenic BRCA1/2 gene variants have been described as founder pathogenic mutations frequently found in patients from Russia, other homologous recombination repair (HRR) genes have not been sufficiently explored. In this study, we present real-world data of routine HRR gene testing in Russia. Methods: We evaluated clinical and sequencing data from cancer patients who had germline/somatic next-generation sequencing (NGS) HRR gene testing in Russia (BRCA1/2/ATM/CHEK2, or 15 HRR genes). The primary objectives of this study were to evaluate the frequency of BRCA1/2 and non-BRCA gene mutations in real-world unselected patients from Russia, and to determine whether testing beyond BRCA1/2 is feasible. Results: Data of 2,032 patients were collected from February 2021 to February 2023. Most had breast (n = 715, 35.2%), ovarian (n = 259, 12.7%), pancreatic (n = 85, 4.2%), or prostate cancer (n = 58, 2.9%). We observed 586 variants of uncertain significance (VUS) and 372 deleterious variants (DVs) across 487 patients, with 17.6% HRR-mutation positivity. HRR testing identified 120 (11.8%) BRCA1/2-positive, and 172 (16.9%) HRR-positive patients. With 51 DVs identified in 242 formalin-fixed paraffin-embedded (FFPE), testing for variant origin clarification was required in one case (0.4%). Most BRCA1/2 germline variants were DV (121 DVs, 26 VUS); in non-BRCA1/2 genes, VUS were ubiquitous (53 DVs, 132 VUS). In silico prediction identified additional 4.9% HRR and 1.2% BRCA1/2/ATM/CHEK2 mutation patients. Conclusions: Our study represents one of the first reports about the incidence of DV and VUS in HRR genes, including genes beyond BRCA1/2, identified in cancer patients from Russia, assessed by NGS. In silico predictions of the observed HRR gene variants suggest that non-BRCA gene testing is likely to result in higher frequency of patients who are candidates for PARP inhibitor therapy. Continuing sequencing efforts should clarify interpretation of frequently observed non-BRCA VUS.

Advantages of Long-Wavelength Photosensitizer meso-Tetra(3-pyridyl) Bacteriochlorin in the Therapy of Bulky Tumors.

This research presents a novel synthetic photosensitizer for the photodynamic therapy (PDT) of malignant tumors: meso-tetra(3-pyridyl) bacteriochlorin, which absorbs at 747 nm (in the long-wavelength region of the spectrum) and is stable when stored in the dark. H2Py4BC demonstrates pronounced photoinduced activity in vitro against tumor cells of various geneses (IC50 varies from 21 to 68 nM for HEp2, EJ, S37, CT26, and LLC cultured cells) and in vivo provides pronounced antitumor efficacy in the treatment of mice bearing small or large S37, Colo26, or LLC metastatic tumors, as well as in the treatment of rats bearing RS-1 liver cholangioma. As a result, total regression of primary tumor nodules and cure of 40 to 100% of the animals was proven by the experiment criteria, MRI, and histological analysis. Meso-tetra(3-pyridyl) bacteriochlorin quickly penetrates and accumulates in the tumor tissue and internal organs of mice, and after 24 h, 80% of the dye is excreted from the skin in addition to 87-92% from the liver, kidneys, and spleen.