Atl

Gorodnova, Tatyana; Kotiv, Khristina; Ivantsov, Alexandr O.; Mikheyeva, Olga N; Михайлюк, Г И; Lisyanskaya, Alla; Mikaya, Nikolay; Guseynov, Konstantin D; Bondarev, Nikolay; Matveyeva, Nataliya S; Nekrasova, Ekatherina A; Sidoruk, A; Roman, L.; Manikhas, G.; Belyaеv, Alexey M.; Sokolenko, Anna P.; Berlev, Igor; Imyanitov, Evgeny N.

doi:10.1097/igc.0000000000001352

Cited by 17 publications

(3 citation statements)

References 35 publications

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“…Our findings are consistent with other reports that BRCA mutation status alone does not unequivocally determine platinum chemotherapy response. Similar to Gorodnova and colleagues ( 44 ), we found that patients with BRCA mutations had longer survival and about 40% of these patients achieved a pCR ( 44–46 ). Within the discovery cohort, 44% ( n = 4) of tumors with BRCA mutations were scored as RAD51-High, and these patients all had poor responses to platinum chemotherapy and decreased survival.…”

Section: Discussionsupporting

confidence: 88%

RAD51 Foci as a Biomarker Predictive of Platinum Chemotherapy Response in Ovarian Cancer

Compadre

Biljon

Valentine

et al. 2023

Clinical Cancer Research

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Purpose: To determine the ability of RAD51 foci to predict platinum chemotherapy response in high-grade serous ovarian cancer (HGSOC) patient-derived samples. Experimental Design: RAD51 and γH2AX nuclear foci were evaluated by immunofluorescence in HGSOC patient-derived cell lines (n=5), organoids (n=11), and formalin-fixed, paraffin-embedded tumor samples (discovery n=31, validation n=148). Samples were defined as RAD51-High if >10% of geminin-positive cells had ≥5 RAD51 foci. Associations between RAD51 scores, platinum chemotherapy response, and survival were evaluated. Results: RAD51 scores correlated with in vitro response to platinum chemotherapy in established and primary ovarian cancer cell lines (Pearson r=0.96, P=0.01). Organoids from platinum-nonresponsive tumors had significantly higher RAD51 scores than those from platinum-responsive tumors (P<0.001). In a discovery cohort, RAD51-Low tumors were more likely to have a pathologic complete response (RR 5.28, P<0.001) and to be platinum-sensitive (RR ∞, P = 0.05). The RAD51 score was predictive of chemotherapy response score (AUC 0.90, 95% CI 0.78-1.0; P<0.001). A novel automatic quantification system accurately reflected the manual assay (92%). In a validation cohort, RAD51-Low tumors were more likely to be platinum-sensitive (RR ∞, P < 0.001) than RAD51-High tumors. Moreover, RAD51-Low status predicted platinum sensitivity with 100% positive predictive value and was associated with better progression-free (HR 0.53, 95% CI 0.33-0.85, P<0.001) and overall survival (HR 0.43, 95% CI 0.25-0.75, P=0.003) than RAD51-High status. Conclusions: RAD51 foci are a robust marker of platinum chemotherapy response and survival in ovarian cancer. The utility of RAD51 foci as a predictive biomarker for HGSOC should be tested in clinical trials.

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Section: Discussionsupporting

confidence: 88%

RAD51 Foci as a Biomarker Predictive of Platinum Chemotherapy Response in Ovarian Cancer

Compadre

Biljon

Valentine

et al. 2023

Clinical Cancer Research

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“…Neoadjuvant combination of cisplatin and mitomycin C resulted in complete pathological responses, i.e. in the elimination of all detectable cancer cells, in some BRCA1/2-driven OCs[ 44 ].…”

Section: Discussionmentioning

confidence: 99%

“…BRCA1-driven cancers are particularly sensitive to systemic platinum-based treatment; hence, this category of OC is usually amenable to complete surgical debulking. Despite that presumably efficient platinum-based therapy is administered again after the surgery, it apparently cannot eliminate the residual cancer cells, given that almost all OC treated by this scheme eventually relapse[ 44 ].…”

Section: Selection Of Pre-existing Brca1-proficient Cells During Platinum-based Therapymentioning

confidence: 99%

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

Imyanitov¹,

Sokolenko²

2021

WJCO

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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 cross-resistance 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.

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Molecular profiles of BRCA1‐associated ovarian cancer treated by platinum‐based therapy: Analysis of primary, residual and relapsed tumors

Sokolenko

Bizin

Preobrazhenskaya

et al. 2019

Intl Journal of Cancer

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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.Additional Supporting Information may be found in the online version of this article.

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Atl

Cited by 17 publications

References 35 publications

RAD51 Foci as a Biomarker Predictive of Platinum Chemotherapy Response in Ovarian Cancer

RAD51 Foci as a Biomarker Predictive of Platinum Chemotherapy Response in Ovarian Cancer

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

Molecular profiles of BRCA1‐associated ovarian cancer treated by platinum‐based therapy: Analysis of primary, residual and relapsed tumors

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