Mechanisms of acquired resistance of BRCA1/2-driven tumors to platinum compounds and PARP inhibitors

Molecular pathogenesis of tumors arising in BRCA1/2 germ-line mutation carriers usually includes somatic inactivation of the remaining allele of the involved gene.Consequently,BRCA1/2-driven cancers are sensitive to platinum-based therapy and poly(ADP-ribose)polymerase inhibitors(PARPi).Long-term exposure to these drugs may result in the emergence of secondary BRCA1/2 mutations,which restore the open-reading frame of the affected allele.This platinum/PARPi crossresistance mechanism applies both for BRCA1 and BRCA2 genes and has been repeatedly validated in various laboratory models and multiple clinical studies.There are some other routes associated with the partial rescue of BRCA1/2 function or the development of BRCA1/2-independent pathways for genomic maintenance;however,their actual clinical relevance remains to be established.In addition,studies on the short-term neoadjuvant therapy for ovarian cancer revealed that even chemonaive BRCA1-driven tumors contain a small proportion of BRCA1-proficient cells.These pre-existing cells with retained BRCA1 heterozygosity rapidly repopulate the tumor mass during platinum exposure,but become outcompeted by BRCA1-deficient cells during therapy holidays.Understanding of the platinum/PARPi resistance pathways has led to the development of novel therapeutic approaches,which aim to improve the management of BRCA1/2-related cancers and are currently undergoing preclinical and clinical evaluation.

Molecular testing for colorectal cancer:Clinical applications

Molecular genetic analysis is an integral part of colorectal cancer(CRC)management.The choice of systemic therapy for CRC is largely based on the results of tumor molecular testing.Evaluation of the KRAS and NRAS gene status is mandatory for consideration of anti-epidermal growth factor receptor(EGFR)therapy.Tumors with the BRAF V600E substitution are characterized by aggressive behaviour,may require intensified cytotoxic regimens and benefit from combined BRAF and EGFR inhibition.The inactivation of DNA mismatch repair(MMR),or MUTYH gene,or DNA polymerase epsilon results in excessive tumor mutational burden;these CRCs are highly antigenic and therefore sensitive to immune checkpoint inhibitors.Some CRCs are characterized by overexpression of the HER2 oncogene and respond to the appropriate targeted therapy.There are CRCs with clinical signs of hereditary predisposition to this disease,which require germline genetic testing.Liquid biopsy is an emerging technology that has the potential to assist CRC screening,control the efficacy of surgical intervention and guide disease monitoring.The landscape of CRC molecular diagnosis is currently undergoing profound changes due to the increasing use of next generation sequencing.

Tumor irradiation may facilitate the detection of tumor-specific mutations in plasma

BACKGROUND The mutation-based analysis of circulating tumor DNA(ctDNA)is a promising diagnostic tool for clinical oncology.However,it has low success rate because many cancer patients do not have detectable ctDNA in the bloodstream.AIM To evaluate whether preoperative tumor irradiation results in a transient increase of plasma ctDNA concentration due to the induction of apoptosis in radiationexposed cells.METHODS This study focused on patients with locally advanced rectal cancer,because preoperative tumor irradiation is a part of their standard treatment plan.Nine subjects,whose tumors contained KRAS,NRAS or BRAF mutations,donated serial blood samples 1 h prior to the first fraction of irradiation(at baseline),immediately after the first fraction(time 0),and 1,3,6,12,24,36,48,72 and 96 h after the first fraction.The amount of mutated gene copies was measured by droplet digital PCR.RESULTS Five out of nine patients were mutation-negative by ctDNA test at baseline;two of these subjects demonstrated an emergence of the mutated DNA copies in the bloodstream within the follow-up period.There were 4 patients,who had detectable ctDNA in the plasma at the start of the experiment;three of them showed an evident treatment-induced increase of the content of mutated RAS/RAF alleles.CONCLUSION Local tumor irradiation may facilitate the detection of tumor-specific DNA in the bloodstream.These data justify further assessment of the clinical feasibility of irradiation-assisted liquid biopsy.