Efficacy of platinum in advanced triple-negative breast cancer with germline BRCA mutation determined by next generation sequencing

Objective:To compare the efficacy of platinum-and non-platinum-based regimens as first-line treatment for advanced triple-negative breast cancer(TNBC)and analyze the relationship between their efficacy and BRCA gene status.Methods:Retrospectively analyze clinical data of 220 patients diagnosed pathologically with advanced TNBC and treated at the Department of Breast Oncology,Peking University Cancer Hospital from 2013 to 2018 and evaluate the efficacy of chemotherapy.A total of 114 patients had BRCA1/2 gene tested by next generation sequencing(NGS)using peripheral blood,and we analyzed the correlation between their efficacy and BRCA1/2 gene status.Results:Non-platinum-based chemotherapy(NPCT)was administered to 129 and platinum-based chemotherapy(PBCT)to 91 study patients.The clinical benefit rate(CBR)and median progression-free survival(PFS)were not statistically different between NPCT and PBCT groups.The median overall survival(OS)was 30.0 and 22.5 months for PBCT and NPCT group,respectively[P=0.090,hazard ratios(HR)=0.703].BRCA status was assessed in 114 patients,14 of whom had deleterious germline BRCA1/2(g BRCA)mutations(seven in each group).In PBCT group,the CBR was 85.7%and 35.1%for patients with and without deleterious g BRCA mutations,respectively(P=0.039).The median PFS were 14.9 and 5.3 months and median OS were 26.5 and 15.5 months for patients with and without deleterious g BRCA mutations,respectively(P=0.001,P=0.161,respectively).Patients in PBCT group had significantly greater rates of grade 3-4 anemia(5.5%vs.0%)and thrombocytopenia(8.8%vs.0%),whereas palmar-plantar erythrodysesthesia(12.4%vs.0%)and peripheral neuropathy(8.6%vs.1.1%)occurred more frequently in NPCT group.Conclusions:Platinum-based regimens are more effective in patients with deleterious g BRCA mutations,but no difference in patients without BRCA gene mutations,so non-platinum is an option in patients without BRCA gene mutations considering the toxicity and side effect.And we recommend that patients with advanced TNBC should have BRCA gene test.

Effect of BRCA2 Mutation on Familial Breast Cancer Survival:A Systematic Review and Meta-analysis

Reports of BRCA2 genetic mutations on the prognosis of familial breast cancer（BC） patients have been contradictory. True difference in survival,if it exists,would have important implications for genetic counseling and in treatment of hereditary BC. The purpose of this study was to compare overall survival rate（OSR） among BRCA2 mutation carriers,non-carriers and sporadic BC patients. We searched the PUBMED and EMBASE databases and retrieved 4529 articles using keywords that included breast cancer,BRCA,prognosis and survival. Nine articles were selected for systematic review and among them 6 were included in our meta-analysis. We used the fixed and random effect models to calculate the summary odds ratio（OR） and corresponding 95% confidence interval（CI）. BRCA2 mutation carriers had significantly higher long-term OSR than non-carriers（OR=0.69 [95% CI=0.5–0.95]）,while both short-term and long-term OSR of BRCA2 mutation carriers did not differ from those of patients with sporadic disease（OR=1.11 [95% CI=0.74–1.65]; 0.85 [95% CI=0.38–1.94],respectively）. For BC-specific survival rate（BCSSR）,BRCA2 mutation carriers had a similar BCSSR to the non-carriers（OR=0.61 [95% CI=0.28–1.34]）. There was no significant difference in disease-free survival（DFS） between BRCA2 mutation carriers and patients with sporadic disease. Our results suggest that BRCA2 mutation increases long-term OSR in hereditary BC,which reminds us a new prospect of management of the disease.

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.

Uncertainty following an inconclusive result from the BRCA1/2 genetic test:A review about psychological outcomes

BACKGROUND An inconclusive result from BRCA1/2 genetic testing indicates that a genetic variant of uncertain significance is detected.This case constitutes the majority of genetic test results,but studies specifically addressing the psychological adjustment of people with inconclusive results are scarce.AIM To examine psychological outcomes of receiving an uninformative BRCA1/2 test result.METHODS PubMed,PsychInfo,and Cochrane Central Register of Controlled Trials were screened for studies focusing on distress,anxiety,and depression levels in individuals with inconclusive genetic test results.This review is based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses method.RESULTS Studies on psychological outcomes of inconclusive BRCA1/2 focused on general and specific distress,anxiety,and depression.Overall,they produced mixed results.These inconsistent findings are probably due to the uncertainty caused by this type of result,that may also influence the decisions of individuals about surveillance and prophylactic options,reducing their compliance.In addition,this review highlights specific risk and protective factors that affect psychological adjustment in individuals with an inconclusive genetic testing result.CONCLUSION Individuals with inconclusive genetic test results need specific educational programs and support to better understand the meaning of their results in order to be able to make decisions about surveillance and prophylactic options.

Targeting DNA repair for cancer treatment: Lessons from PARP inhibitor trials

Ionizing radiation is frequently used to treat solid tumors,as it causes DNA damage and kill cancer cells.However,damaged DNA is repaired involving poly-(ADP-ribose)polymerase-1(PARP-1)causing resistance to radiation therapy.Thus,PARP-1 represents an important target in multiple cancer types,including prostate cancer.PARP is a nuclear enzyme essential for single-strand DNA breaks repair.Inhibiting PARP-1 is lethal in a wide range of cancer cells that lack the homologous recombination repair(HR)pathway.This article provides a concise and simplified overview of the development of PARP inhibitors in the laboratory and their clinical applications.We focused on the use of PARP inhibitors in various cancers,including prostate cancer.We also discussed some of the underlying principles and challenges that may affect the clinical efficacy of PARP inhibitors.

The Achilles’ Heel of Pancreatic Cancer: Targeting pancreatic cancer’s unique immunologic characteristics and metabolic dependencies in clinical trials

Pancreatic ductal adenocarcinoma(PDAC)has a high mortality rate and is notoriously refractory to multiple cancer treatments.In recent years,cancer therapy has expanded beyond traditional cytotoxic chemotherapy to targeted agents and immunotherapy which have been successfully implemented in many cancers.Despite robust pre-clinical research,these novel therapies have only had a small impact on PDAC.However,there have been successes with emerging clinical data supporting a potential role for checkpoint inhibitor therapy and targeted therapy with poly(ADP-ribose)polymerase inhibitors for select subsets of PDAC patients.In this clinical review,we discuss recent pre-clinical evidence for targeting metabolic pathways as well as prevalent intratumoral immune subsets,and focus on clinical trials designed to test novel agents in PDAC.The challenge of translating pre-clinical findings to patients remains substantial and many clinical trials yield negative results,but collaborative efforts and renewed focus on novel clinical trials have led to optimism that we will identify additional options for PDAC patients and change outcomes for this deadly disease.