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Many tumors have well-defined vulnerabilities, thus potentially allowing highly specific and effective treatment. There is a spectrum of actionable genetic alterations which are shared across various tumor types and, therefore, can be targeted by a given drug irrespective of tumor histology. Several agnostic drug-target matches have already been approved for clinical use, e.g., immune therapy for tumors with microsatellite instability (MSI) and/or high tumor mutation burden (TMB), NTRK1-3 and RET inhibitors for cancers carrying rearrangements in these kinases, and dabrafenib plus trametinib for BRAF V600E mutated malignancies. Multiple lines of evidence suggest that this histology-independent approach is also reasonable for tumors carrying ALK and ROS1 translocations, biallelic BRCA1/2 inactivation and/or homologous recombination deficiency (HRD), strong HER2 amplification/overexpression coupled with the absence of other MAPK pathway-activating mutations, etc. On the other hand, some well-known targets are not agnostic: for example, PD-L1 expression is predictive for the efficacy of PD-L1/PD1 inhibitors only in some but not all cancer types. Unfortunately, the individual probability of finding a druggable target in a given tumor is relatively low, even with the use of comprehensive next-generation sequencing (NGS) assays. Nevertheless, the rapidly growing utilization of NGS will significantly increase the number of patients with highly unusual or exceptionally rare tumor-target combinations. Clinical trials may provide only a framework for treatment attitudes, while the decisions for individual patients usually require case-by-case consideration of the probability of deriving benefit from agnostic versus standard therapy, drug availability, associated costs, and other circumstances. The existing format of data dissemination may not be optimal for agnostic cancer medicine, as conventional scientific journals are understandably biased towards the publication of positive findings and usually discourage the submission of case reports. Despite all the limitations and concerns, histology-independent drug-target matching is certainly feasible and, therefore, will be increasingly utilized in the future. [ABSTRACT FROM AUTHOR]

Our study aimed to analyze the evolution of molecular portraits of BRCA1‐driven ovarian cancer (OC) during treatment. BRCA1 loss‐of‐heterozygosity status (LOH) and exome profiles were investigated in serial OC samples from 13 patients, which included primary tumors (n = 11) obtained before neoadjuvant therapy (NACT) or at primary debulking surgery, residual post‐NACT cancer tissues (n = 13) and tumor relapses (16 samples from 13 patients). Loss of the wild‐type BRCA1 allele was detected in 11/11 (100%) primary tumors, 6/13 (46%) residual post‐NACT OC samples and 15/16 (94%) OC relapses. Full tumor triplets were available for four patients undergoing NACT; whereas primary carcinomas from these patients demonstrated BRCA1 LOH, the retention of the wild‐type allele was detected in all four post‐NACT residual tumors. These four women provided to the study 5 recurrent OC samples; 4 out of 5 tumor relapses had BRCA1 LOH thus resembling BRCA1 status observed in primary but not residual OC tissues. TP53 mutation was detected in 12 out of 13 patients and was retained across all serial samples. OC relapses tended to acquire additional intragenic mutations in genes involved in cell migration, adhesion and cell junction assembly. BRCA1‐driven OCs demonstrate the plasticity of BRCA1 status during the treatment course. NACT results in rapid selection of pre‐existing BRCA1‐proficient cells. However, BRCA1 proficiency appears to be disadvantageous in the absence of platinum exposure, as tumor relapses usually re‐acquire BRCA1 LOH during therapy holidays. What's new? Ovarian cancers carrying BRCA1 mutations are characterized by intratumoural heterogeneity, in which most malignant cells show a loss of the remaining BRCA1 allele, while some cells retain BRCA1 function. Here, investigation of BRCA1 mutation among ovarian cancer patients over the course of treatment reveals plasticity in somatic BRCA1 status, with impacts on primary cancer development, therapeutic response, and disease relapse. In particular, relapses following treatment holidays were characterized by the re‐appearance of somatic BRCA1 inactivation. Plasticity in BRCA1 status likely explains the failure of systemic therapy to eradicate tumor clones and accounts for platinum sensitivity in recurrent BRCA1‐driven ovarian cancers. [ABSTRACT FROM AUTHOR]