三阴性乳腺癌患者因新辅助或辅助化疗引起的早发性心脏事件与其基因组DNA中某些新的自噬相关单核苷酸多态性的相关性研究：一项真实世界研究

背景与目的越来越多的癌症患者死于心血管疾病。三阴性乳腺癌(triple-negative breast cancer,TNBC)可选的治疗方法有限,因此化疗引起的心脏毒性对该类患者非常重要。心脏自噬是心脏毒性的重要机制之一。本研究旨在研究化疗对TNBC患者的心脏毒性,筛选易感人群,探讨心脏毒性与自噬相关基因多态性的相关性。方法在2450例I–III期TNBC患者中,有147例纳入了本研究。大多数患者在化疗周期前进行心电图(electrocardiography,ECG)检查,并根据临床需要进行超声心动图(echocardiography,UCG)检查。所有ECG和UCG资料均由阜外医院国家心血管病中心的心血管专家重新评判。根据美国国家生物技术信息中心数据库和癌症体细胞突变目录数据库,我们筛选了25个与自噬相关的单核苷酸多态性(single nucleotide polymorphisms,SNPs),并对147例TNBC患者进行了基因分型。采用配对样本T检验、卡方检验和logistic回归模型进行分析。结果每个化疗周期后,只有46(31.3%)例患者的ECG完全正常。在接受UCG的16例患者中,有2(12.5%)例患者左心室射血分数可逆性下降。使用蒽环类药物和过量饮酒是ECG异常的危险因素。随着化疗的持续,心率逐渐增加。蒽环类药物与QRS期持续异常有关(P=0.043)。我们对25个与自噬有关的SNP进行基因分型后发现,自噬相关基因13(ATG13)rs10838611的G等位基因与ECG异常显著相关(优势比=2.258,95%置信区间:1.318–3.869;P=0.003)。结论化疗引起的ECG异常在真实世界中很常见。自噬相关单核苷酸多态性与化疗引起的心脏毒性相关,本研究为自噬是化疗所致心脏损害的原因提供了新的证据。

Multi-omics fusion analysis models with machine learning predict survival of HER2-negative metastatic breast cancer: a multicenter prospective observational study

To the Editor:Oncology precision medicine aims to identify patientsmostlikely torespondeffectivelytotherapies.Efforts to establish a survival prediction model using a single platform have not yet met the precision medicine goals.

Clinical spectrum and prognostic value of TP53 mutations in circulating tumor DNA from breast cancer patients in China

Background:TP53 mutations are common in breast cancer.There is currently no large-scale cohort study to investigate the TP53 landscape in breast cancer patients from China.The predictive value of TP53 mutations for the efficacy of human epidermal growth factor receptor 2(HER2)-targeted therapy in breast cancer remains controversial.In the present study,we aimed to analyze the clinical spectrum and prognostic value of TP53 mutations in circulating tumor DNA(ctDNA)from breast cancer patients in China.Methods:We retrospectively analyzed the clinical data and TP53 mutation features in ctDNA samples from 804 patients withmetastatic breast cancer.TP53 mutations were detected by target region capture-based next-generation sequencing.The relationship between TP53 mutation status and disease-free survival(DFS)was analyzed in 444 patientswithmetastatic breast cancer.Moreover,the relationship between TP53 mutation status and progression-free survival(PFS)was analyzed in 55 HER2-positive patients treated with first-line trastuzumab-based therapy.Kaplan-Meier analysis was performed to estimate the survival curves of the different subgroups,and the log-rank test was used to compare the curves.A Cox regression model was used to estimate multivariable-adjusted hazard ratios and their 95%confidence intervals(CIs)associated with the DFS and PFS.Results:Among the 804 investigated patients,431(53.6%)patients harbored TP53 mutations.TP53 mutations were differentially distributed among different molecular subtypes of breast cancer(P<0.05).Patients with TP53 mutations had a shorter DFS than those with wild-type TP53(hazard ratio=1.32,95%CI=1.09-1.61,P=0.005).TP53 mutations in exons 5-8 were associated with worse outcome(hazard ratio=1.50,95%CI=1.11-2.03,P=0.009).However,TP53 mutation status was not significantly associated with PFS in HER2-positive patients who received firstline trastuzumab-based therapy(P=0.966).Interestingly,in the taxane combination group,patients with TP53 mutations exhibited longer PFS than those without TP53 mutations(hazard ratio=0.08,95%CI=0.02-0.30,P<0.001).However,in the nontaxane combination group,patients with TP53 mutations displayed shorter PFS than those with wild-type TP53(hazard ratio=4.84,95%CI=1.60-14.66,P=0.005).Conclusions:TP53 mutations in exons 5-8 may be an independent prognostic marker for short DFS in patients with metastatic breast cancer.TP53 mutations had opposite effects on trastuzumab-treated patients treated with and without taxanes.

The association between early-onset cardiac events caused by neoadjuvant or adjuvant chemotherapy in triple-negative breast cancer patients and some novel autophagy-related polymorphisms in their genomic DNA: a real-world study

Background:An increasing number of cancer patients die of cardiovascular diseases.The cardiotoxicity of chemo-therapy is particularly important in triple-negative breast cancer(TNBC)with limited therapeutic options.Cardiac autophagy is an important mechanism of cardiotoxicity.This research was aimed to investigate the cardiotoxicity of chemotherapy in TNBC,screen the susceptible population,and determine the relationship between cardiotoxicity and autophagy-related polymorphisms.Methods:From a total of 2450 stage I-III TNBC patients,147 met the inclusion criteria and finally recruited.Electro-cardiography(ECG)was performed before most chemotherapy cycles,and echocardiography(UCG)was performed according to clinical needs.All ECG and UCG records were re-interpreted by cardiologists at the National Center for Cardiovascular Disease,Fuwai Hospital.According to the National Center for Biotechnology Information and the Catalog of Somatic Mutations in Cancer database,we selected 25 single nucleotide polymorphisms(SNPs)related to autophagy and genotyped the 147 TNBC patients.Paired-sample T tests,Chi squared tests,and logistic regression models were employed for the analysis.Results:Only 46(31.3%)patients had normal ECG records after every chemotherapy cycle.Among the 16 patients who underwent UCG,2(12.5%)had a reversible decrease of left ventricular ejection fraction.The use of anthracyclines and excessive alcohol consumption were risk factors of ECG abnormalities.With the continuation of chemotherapy,heart rate gradually increased.Anthracyclines were associated with QRS duration abnormalities(P=0.043).After genotyping for 25 autophagy-related SNPs,we found that the G allele of autophagy-related 13(ATG13)rs10838611 was significantly associated with ECG abnormalities(odds ratio=2.258,95%confidence interval=1.318-3.869;P=0.003).Conclusion:ECG abnormalities caused by chemotherapy are common in the real world.Autophagy-related SNPs are associated with chemotherapy-induced cardiotoxicity,thereby providing new evidence for autophagy as a cause of chemotherapy-induced cardiac damage.

Antibody-drug conjugates in HER2-positive breast cancer

Antibody-drug conjugates(ADCs)combine the high specificity of monoclonal antibodies with the high anti-tumor activity of small molecular cytotoxic payloads.The anti-tumor activity of ADCs is mainly achieved by the direct blocking of the receptor by monoclonal antibodies,direct action and bystander effect of cytotoxic drugs,and antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity.ADCs have been used in adjuvant therapy and rescue treatment of human epidermal receptor 2(HER2)-positive breast cancer,greatly improving the prognosis of breast cancer patients.Several ongoing clinical trials of ADC for breast cancer and other solid tumors proved the potential of ADCs will provide more promising treatment options for patients with malignant tumors.This review introduces the mechanism and latest clinical progress of ADC drugs approved for HER2-positive breast cancer to guide clinical practice and conduct research.

Mutational characteristics determined using circulating tumor DNA analysis in triple-negative breast cancer patients with distant metastasis

Dear editor,Breast cancer has been considered as the most common malignancy and the leading cause of death in women worldwide[1].Triple-negative breast cancer(TNBC)accounts for 10%-20%of breast cancers,which are characterized by the absence of estrogen receptor(ER),progesterone receptor(PR),and amplification of human epidermal growth factor receptor 2(HER2)[2].TNBC is well known for its rapid progressiveness,high rate of distant organ recurrence,and poor prognosis.Metastasis remains the major cause of death for patients with TNBCs.Up to date,the only direct treatment for metastatic TNBCs is chemotherapy,which has been challenged by tumor heterogeneity and drug resistance.Lack of effective targeted therapy for metastatic TNBCs impels researchers to focus on discovering potentially actionable targets through mutational profiling.

The molecular tumor burden index as a response evaluation criterion in breast cancer

Circulating tumor DNA(ctDNA)is a potential biomarker of prognosis and therapeutic response.We conducted this study to explore the role of the molecular tumor burden index(mTBI)in ctDNA as a therapeutic response and prognostic biomarker in a larger cohort prospective phase III randomized multicenter study.We collected 291 plasma samples from 125 metastatic breast cancer patients from the CAMELLIA study(NCT01917279).Target-capture deep sequencing of 1021 genes was performed to detect somatic variants in ctDNA from the plasma samples.The pretreatment mTBI value was correlated with tumor burden(P=0.025).Patients with high-level pretreatment mTBI had shorter overall survival than patients with low-level pretreatment mTBI,and the median overall survival was 40.9 months and 68.4 months,respectively(P=0.011).Patients with mTBI decrease to less than 0.02%at the first tumor evaluation had longer progression-free survival and overall survival(P<0.001 and P=0.007,respectively).The mTBI has good sensitivity to identify complete response/partial response and progressive disease based on computed tomography scans(88.5%and 87.5%,respectively).The patients classified as molecular responders had longer progression-free survival and overall survival than the nonmolecular responders in the overall cohort(P<0.001 and P=0.036,respectively),as well as in the cohort in which computed tomography scans were defined as representing stable disease(P=0.027 and P=0.015,respectively).The mTBI in ctDNA detected in liquid biopsies is a potential biomarker of therapeutic response and prognosis in patients with metastatic breast cancer.

Characteristics of homologous recombination repair pathway genes mutation in ovarian cancers

Background:Few studies have investigated the characteristics of non‐BRCA homologous recombination repair(HRR)pathway somatic mutations,and the impact of these mutations on efficacy of treatment in ovarian cancer patients is not clear.Therefore,we conducted this study to analyze the frequency and spectrum of somatic mutations in HRR pathway genes in patients with ovarian cancer and to examine the relationships between somatic mutations in HRR pathway genes and their effects on the efficacy of platinum‐based chemotherapy.Methods:We performed targeted sequencing of 688 genes related to the occurrence,development,treatment,and prognosis of solid tumors.Somatic mutations were identified by paired analysis of tumor tissue and germline DNA in blood cells.Results:A total of 38 patients with ovarian cancer were included in the study,and 35(92.1%)patients were diagnosed with high‐grade serous carcinoma.All patients exhibited somatic mutations in the tumor tissue samples.The commonly mutated genes were TP53(73.7%),BRCA2(55.3%),NF1(52.6%),BRCA1(47.4%),and CDH1(47.4%).Overall,71.1%of the patients exhibited mutation in at least one HRR pathway gene.The most frequently altered HRR genes were BRCA2(55.3%),followed by BRCA1(47.4%),ATM(44.7%),BARD1(42.1%),and CHEK1(36.8%).The median progression‐free survival(PFS)in patients with HRR pathway mutation was 36.0 months compared with 13.6 months in patients with no HRR pathway mutation(hazard ratio[HR],0.25;95%confidence interval[CI],0.08–0.77;p=0.016).Patients harboring BRCA1/2 and/or CDK12 mutations displayed a longer PFS(median,36.0 months)compared with patients with no BRCA1/2 or CDK12 mutation(median,13.6 months;HR,0.21;95%CI,0.07–0.61;p=0.004).In multivariate analysis Cox proportional hazards models,after adjustment for tumor stage at diagnosis and histology of initial diagnosis,patients with HRR pathway mutation had a longer PFS than patients with HRR wild‐type genes(p=0.006).Conclusions:HRR pathway somatic mutations are common in Chinese patients with ovarian cancer.HRR pathway somatic mutations were associated with improved sensitivity to platinum-based chemotherapy.Large-scale prospective studies are needed to verify our findings.