bims-tumhet 2021-09-19 papers

Issue of 2021–09–19
four papers selected by
Sergio Marchini, Humanitas Research

Mol Cancer Ther. 2021 Sep 13. pii: molcanther.0500.2021. [Epub ahead of print]

Ovarian cancers include several distinct malignancies which differ with respect to clinicopathological features and prognosis. High-grade serous cancer is the most common histological subtype and accounts for most ovarian cancer deaths. HGSOC is treated with surgery and platinum-based chemotherapy, but most patients relapse and succumb to chemoresistant disease. The genetic concept of synthetic lethality, in which the synergy of mutations in multiple genes results in cell death, provides a framework to design novel therapeutic approaches to overcome chemoresistance in ovarian cancer. Recent progress in understanding the genomic architecture and hereditary drivers of ovarian cancer has shown potential for synthetic lethality strategies designed around homologous DNA repair. Clinical trials have validated high response rates for poly (ADP-ribose) polymerase (PARP) inhibitors in patients with BRCA1 or BRCA2 mutations. Here we discuss the biological rationale behind targeting BRCA-PARP synthetic lethality based on genetic context in ovarian cancer and how this approach is being assessed in the clinic. Applying the concept of synthetic lethality to target non-BRCA-mutant cancers is an ongoing challenge, and we discuss novel approaches to target ovarian cancer using synthetic lethality in combination with and beyond PARP inhibitors. This review will also describe obstacles for synthetic lethality in ovarian cancer and new opportunities to develop potent targeted drugs for ovarian cancer patients.

DOI: https://doi.org/10.1158/1535-7163.MCT-21-0500

Biochem J. 2021 Sep 17. 478(17): 3373-3393

The roles of epigenetics in cancer progression and metastasis.

Jocelyn F Chen, Qin Yan.

Cancer metastasis remains a major clinical challenge for cancer treatment. It is therefore crucial to understand how cancer cells establish and maintain their metastatic traits. However, metastasis-specific genetic mutations have not been identified in most exome or genome sequencing studies. Emerging evidence suggests that key steps of metastasis are controlled by reversible epigenetic mechanisms, which can be targeted to prevent and treat the metastatic disease. A variety of epigenetic mechanisms were identified to regulate metastasis, including the well-studied DNA methylation and histone modifications. In the past few years, large scale chromatin structure alterations including reprogramming of the enhancers and chromatin accessibility to the transcription factors were shown to be potential driving force of cancer metastasis. To dissect the molecular mechanisms and functional output of these epigenetic changes, it is critical to use advanced techniques and alternative animal models for interdisciplinary and translational research on this topic. Here we summarize our current understanding of epigenetic aberrations in cancer progression and metastasis, and their implications in developing new effective metastasis-specific therapies.

Keywords: cancer metastasis; chromatin opening; enhancer reprogramming; epigenetics; histone modification; tumor progression

DOI: https://doi.org/10.1042/BCJ20210084

Ann Oncol. 2021 Sep 11. pii: S0923-7534(21)04478-1. [Epub ahead of print]

Association of RAD51 with Homologous Recombination Deficiency (HRD) and clinical outcomes in untreated triple-negative breast cancer (TNBC): analysis of the GeparSixto randomized clinical trial.

BACKGROUND: Current genetic and genomic tests measuring homologous recombination deficiency (HRD) show limited predictive value. This study compares the performance of an immunohistology-based RAD51 test with genetic/genomic tests to identify patients with HRD primary triple-negative breast cancer (TNBC) and evaluates its accuracy to select patients sensitive to platinum-based neoadjuvant chemotherapy (NACT).
PATIENTS AND METHODS: This is a retrospective, blinded, biomarker analysis from the GeparSixto randomized clinical trial. TNBC patients received neoadjuvant paclitaxel plus Myocet-nonpegylated liposomal doxorubicin (PM) or PM plus carboplatin (PMCb), both arms including bevacizumab. Formalin-fixed paraffin-embedded (FFPE) tumor samples were laid on tissue microarrays. RAD51, BRCA1 and γH2AX were quantified using an immunofluorescence assay. The predictive value of RAD51 was assessed by regression models. Concordance analyses were performed between RAD51 score and tumor BRCA (tBRCA) status or genomic HRD score (myChoiceHRD). Associations with pathological complete response (pCR) and survival were studied. Functional HRD was pre-defined as a RAD51 score ≤10% (RAD51-low).
RESULTS: Functional HRD by RAD51-low was evidenced in 81/133 tumors (61%). RAD51 identified 93% tBRCA-mutated tumors and 45% non-tBRCA mutant cases as functional HRD. The concordance between RAD51 and genomic HRD was 87% (95%CI 79-93%). In patients with RAD51-high tumors, pCR was similar between treatment arms (PMCb 31% vs PM 39%, odds ratio (OR) 0.71, 0.23-2.24, p=0.56). Patients with RAD51-low tumors benefited from PMCb (pCR 66% vs 33%, OR 3.96, 1.56-10.05, p=0.004; interaction test p=0.02). This benefit maintained statistical significance in the multivariate analysis. Carboplatin addition showed similar disease-free survival in RAD51-high (hazard ratio (HR) 0.40, log-rank p=0.11) and RAD51-low (0.45, p=0.11) groups.
CONCLUSIONS: The RAD51 test identifies tumors with functional HRD and is highly concordant with tBRCA mutation and genomic HRD. RAD51 independently predicts clinical benefit from adding Cb to NACT in TNBC. Our results support further development to incorporate RAD51 testing in clinical decision-making.

Keywords: BRCA; HRD biomarkers; RAD51; personalized medicine; platinum-based neoadjuvant chemotherapy; triple-negative breast cancer

DOI: https://doi.org/10.1016/j.annonc.2021.09.003

Cancer Epidemiol. 2021 Sep 08. pii: S1877-7821(21)00125-9. [Epub ahead of print] 102008

Clinicopathologic predictors of early relapse in advanced epithelial ovarian cancer: development of prediction models using nationwide data.

Sherin A Said, Reini W Bretveld, Hendrik Koffijberg, Gabe S Sonke, Roy F P M Kruitwagen, Joanne A de Hullu, Anne M van Altena, Sabine Siesling, Maaike A van der Aa.

OBJECTIVE: To identify clinicopathologic factors predictive of early relapse (platinum-free interval (PFI) of ≤6 months) in advanced epithelial ovarian cancer (EOC) in first-line treatment, and to develop and internally validate risk prediction models for early relapse.
METHODS: All consecutive patients diagnosed with advanced stage EOC between 01-01-2008 and 31-12-2015 were identified from the Netherlands Cancer Registry. Patients who underwent cytoreductive surgery and platinum-based chemotherapy as initial EOC treatment were selected. Two prediction models, i.e. pretreatment and postoperative, were developed. Candidate predictors of early relapse were fitted into multivariable logistic regression models. Model performance was assessed on calibration and discrimination. Internal validation was performed through bootstrapping to correct for model optimism.
RESULTS: A total of 4,557 advanced EOC patients were identified, including 1,302 early relapsers and 3,171 late or non-relapsers. Early relapsers were more likely to have FIGO stage IV, mucinous or clear cell type EOC, ascites, >1 cm residual disease, and to have undergone NACT-ICS. The final pretreatment model demonstrated subpar model performance (AUC = 0.64 [95 %-CI 0.62-0.66]). The final postoperative model based on age, FIGO stage, pretreatment CA-125 level, histologic subtype, presence of ascites, treatment approach, and residual disease after debulking, demonstrated adequate model performance (AUC = 0.72 [95 %-CI 0.71-0.74]). Bootstrap validation revealed minimal optimism of the final postoperative model.
CONCLUSION: A (postoperative) discriminative model has been developed and presented online that predicts the risk of early relapse in advanced EOC patients. Although external validation is still required, this prediction model can support patient counselling in daily clinical practice.

Keywords: Early relapse; Epithelial ovarian cancer; Platinum-based chemotherapy; Population-based study; Prediction model

DOI: https://doi.org/10.1016/j.canep.2021.102008