Clinical value of next-generation sequencing in guiding decisions regarding endocrine therapy for advanced HR-positive/HER-2-negative breast cancer

Objective: The mechanism of acquired gene mutation plays a major role in resistance to endocrine therapy in hormone receptor(HR)-positive advanced breast cancer. Circulating tumor DNA(ctDNA) has been allowed for the assessment of the genomic profiles of patients with advanced cancer. We performed this study to search for molecular markers of endocrine therapy efficacy and to explore the clinical value of ctDNA to guide precise endocrine therapy for HR-positive/human epidermal growth factor receptor-2(HER-2)-negative metastatic breast cancer patients.Methods: In this open-label, multicohort, prospective study, patients were assigned to four parallel cohorts and matched according to mutations identified in ctDNA: 1) activation of the phosphatidylinositol-3-kinase(PI3K)/AKT/mammalian target of rapamycin(mTOR) signaling pathway preferred mTOR inhibitor combined with endocrine therapy;2) estrogen receptor 1(ESR1) mutation preferred fulvestrant;3) HER-2 mutations preferred pyrotinib;and 4) no actionable mutations received treatment according to the clinical situation. In all cohorts, patients were divided into compliance group and violation group. The primary outcome measure was progression-free survival(PFS), and the secondary outcome measure was overall survival(OS).Results: In all cohorts, the combined median PFS was 4.9 months, and median PFS for the compliance and violation groups was 6.0 and 3.0 months, respectively [P=0.022, hazard ratio(HR)=0.57]. Multivariate Cox regression model showed the risk of disease progression was lower in compliance group than in violation group(P=0.023, HR=0.55). Among the patients with HER-2 mutations, the median PFS was 11.1 months in the compliance group and 2.2 months in the violation group(P=0.011, HR=0.20). There was no significant difference in the median PFS between patients who did and did not comply with the treatment protocol in patients with activation of the PI3K/AKT/mTOR or ESR1 mutation.Conclusions: The results suggest that ctDNA may help to guide the optimal endocrine therapy strategy for metastatic breast cancer patients and to achieve a better PFS. Next-generation sequencing(NGS) detection could aid in distinguishing patients with HER-2 mutation and developing new treatment strategies.

Nowcasting and forecasting global aging and cancer burden:analysis of data from the GLOBOCAN and Global Burden of Disease Study

Objective:To analyze the impact of global population aging on cancer epidemiology,with a focus on the incidence and mortality rates among individuals aged 60 years and above.Methods:We utilized open-source data,retrieving population age estimates from the United Nations Population Division website.The GLOBOCAN 2020 database provided estimates for cancer cases and deaths in 2020 and 2040,while the Global Burden of Disease 2019 database supplied estimates of new cancer cases worldwide from 2000 to 2019.Inclusion criteria considered individuals aged 60 years and over,focusing on the top five deadliest cancers.The cohort-component method was employed for population prediction,with age-specific incidence and mortality rates estimated for 2020 used to forecast the cancer burden.Results:In 2021,the global population aged over 60 years accounted for 13.7%,with Europe/North America and Australia/New Zealand having the highest proportions.The older population is predicted to reach 19.2%by 2040.In 2020,of the 19.3 million new cancer cases worldwide,64%occurred in individuals aged 60 and above,contributing to 71.3%of cancer-related deaths.The five most common cancer sites were the lung,colorectum,prostate,breast,and stomach.Cancer incidence and deaths are projected to rise significantly among older indi-viduals,reaching 20.7 million new cases and 12.7 million deaths by 2040.Older age,tobacco use,dietary factors,alcohol consumption,and high body mass index(BMI)were identified as major risk factors for various cancers in this demographic.Conclusions:This study reveals a significant rise in cancer incidence and mortality among the elderly due to global population aging.The urgency for targeted interventions in cancer prevention,screening,and treatment for older individuals is emphasized.Despite acknowledged limitations,these findings contribute valuable insights to inform strategies for managing cancer in the elderly amidst evolving demographic trends.

《新型冠状病毒肺炎疫情期间乳腺癌合理化诊疗指南》解读

新型冠状病毒肺炎在全球的暴发占用大量医疗资源,极大影响乳腺癌的正常诊疗。乳腺癌患者机体免疫力差,是新型冠状病毒肺炎的易感人群,感染后引发重症的风险极高。如何平衡新型冠状病毒肺炎疫情的有效防控和合理化安排肿瘤诊疗行为,是疫情期间亟待解决的主要临床问题。为此国家肿瘤质控中心乳腺癌专家委员会组织相关领域专家,紧急编撰《新型冠状病毒肺炎疫情期间乳腺癌合理化诊疗指南》,希望为疫情期间乳腺癌诊疗提供科学、可行的解决方案。本文将从乳腺癌诊疗各环节,对指南核心内容进行解读。

乳腺腺样囊性癌与三阴性浸润性导管癌的临床病理特征及预后比较

目的:比较乳腺腺样囊性癌(adenoid cystic carcinoma of the breast,ACCB)与三阴性浸润性导管癌(invasive ductal carcinoma,IDC)临床病理特征及预后。方法:分析2004年1月至2020年12月就诊于中国医学科学院肿瘤医院的26例ACCB与216例三阴性IDC患者的临床病理资料。采用Kaplan-Meier法绘制无疾病生存(disease free survival,DFS)和总生存(overall survival,OS)曲线,Log-rank法进行组间比较。结果:中位随访时间72.4个月,4例ACCB患者出现复发转移,肺和肝是常见的转移部位。与IDC相比,ACCB的发病年龄>60岁、Ki-67低表达、神经侵犯、分期早(Ⅰ期和Ⅱ期)、无淋巴结转移的比例更高(P<0.05)。与IDC相比,ACCB患者的5年DFS率和OS率有获益趋势,但差异无统计学意义。Ki-67低表达ACCB患者的中位DFS显著高于Ki-67高表达者(χ^(2)=4.633,P=0.031)。无神经侵犯的患者较有神经侵犯者的DFS显著改善(χ^(2)=3.861,P=0.049)。结论:Ki-67高表达和神经侵犯是ACCB复发转移的危险因素。与三阴性IDC相比,ACCB具有Ki-67低表达、神经侵犯、腋窝淋巴结阴性、分期早的临床病理特点和以保乳术为主、不行辅助化疗的治疗方式。

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。

Efficacy and safety of first‐line regimens for advanced HER2‐positive breast cancer:A Bayesian network meta‐analysis

Background:The current standard of care for advanced human epidermal growth factor receptor 2(HER2)‐positive breast cancer is pertuzumab plus trastuzumab and docetaxel as first‐line therapy.However,with the development of newer treatment regimens,there is a lack of evidence regarding which is the optimal treatment strategy.The aim of this network meta‐analysis was to evaluate the efficacy and safety of first‐line regimens for advanced HER2‐positive breast cancer by indirect comparisons.Methods:A systematic review and Bayesian network meta‐analysis were conducted.The PubMed,EMBASE,and Cochrane Library databases were searched for relevant articles published through to December 2023.The hazard ratio(HR)and 95%credible interval(CrI)were used to compare progressionfree survival(PFS)between treatments,and the odds ratio and 95%CrI were used to compare the objective response rate(ORR)and safety.Results:Twenty randomized clinical trials that included 15 regimens and 7094 patients were analyzed.Compared with the traditional trastuzumab and docetaxel regimen,PFS was longer on the pyrotinib and trastuzumab plus docetaxel regimen(HR:0.41,95%CrI:0.22–0.75)and the pertuzumab and trastuzumab plus docetaxel regimen(HR:0.65,95%CrI:0.43–0.98).Consistent with the results for PFS,the ORR was better on the pyrotinib and trastuzumab plus docetaxel regimen and the pertuzumab and trastuzumab plus docetaxel regimen than on the traditional trastuzumab and docetaxel regimen.The surface under the cumulative ranking curve indicated that the pyrotinib and trastuzumab plus docetaxel regimen was most likely to rank first in achieving the best PFS and ORR.Comparable results were found for grade≥3 AE rates of≥10%.Conclusions:Our results suggest that the pyrotinib and trastuzumab plus docetaxel regimen is most likely to be the optimal first‐line therapy for patients with HER2‐positive breast cancer.

Axillary lymph node dissection plus radiotherapy may be an optimal strategy for patients with occult breast cancer

Background:Because of the rarity of occult breast cancer(OBC)and limited experience in OBC treatment,the optimal treatment strategy is unknown.This study aimed to compare the efficacy of axillary lymph node dissection(ALND)plus radiotherapy with that of mastectomy plus ALND in patients with OBC.Methods:Relevant clinical data between January 2004 and December 2015 were retrospectively collected from the Surveillance,Epidemiology,and End Results database.The clinical characteristics and prognoses of patients who underwent ALND plus radiotherapy or mastectomy plus ALND were compared before and after propensity score matching.Results:Overall,569 eligible patients with OBC were included in this study.Of these,247 patients underwent ALND plus radiotherapy and 322 underwent mastectomy plus ALND.The 5-year overall survival(OS)rates in the ALND plus radiotherapy group and the mastectomy plus ALND group were 89.2%and 80.6%,respectively;and the corresponding 5-year breast cancer-specific survival(BCSS)rates were 95.2%and 93.0%,respectively.After propensity score matching,the OS in the ALND plus radiotherapy group was significantly better than that in the mastectomy plus ALND group.In addition,further subgroup analyses revealed that ALND plus radiotherapy prolonged OS in the pN3 subgroup.Among patients receiving adjuvant chemotherapy,those who underwent ALND plus radiotherapy had better BCSS and OS than those who underwent mastectomy plus ALND.Conclusions:ALND plus radiotherapy could improve the OS of patients with OBC,especially those with pN3 disease and those receiving chemotherapy.ALND combined with radiotherapy is the optimal treatment strategy for patients with imaging-negative OBC.

Applications of digital Medicine in oncology: Prospects and challenges

The current state of oncology medical services is not encouraging and is unable to fully meet the needs of patients with cancer.In recent years,rapidly developing artificial intelligence technology and gradual advancements in mobile phones,sensors,and wearable devices,which have made these more compact,affordable,and popular,have greatly expanded the development of digital medicine.Digital medicine refers to clinical evidence-based technology and products with a direct impact on disease management and research.Integrating digital medicine into clinical practice has the advantages of broader applicability,greater cost-effectiveness,better accessibility,and improved diagnostic and therapeutic performance.Digital medicine has emerged in different clinical application scenarios,including cancer prevention,screening,diagnosis,and treatment,as well as clinical trials.Additionally,big data generated from digital medicine can be used to improve levels of clinical diagnosis and treatment.However,digital medicine also faces many challenges,including security regulation and privacy protection,product usability,data management,and optimization of algorithms.In summary,the application and development of digital medicine in the field of cancer face numerous opportunities and challenges.

Integrative analyses identified gap junction beta‐2 as a prognostic biomarker and therapeutic target for breast cancer

Background:Increasing evidence has shown that connexins are involved in the regulation of tumor development,immune escape,and drug resistance.This study investigated the gene expression patterns,prognostic values,and potential mechanisms of connexins in breast cancer.Methods:We conducted a comprehensive analysis of connexins using public gene and protein expression databases and clinical samples from our institution.Connexin mRNA expressions in breast cancer and matched normal tissues were compared,and multiomics studies were performed.Results:Gap junction beta‐2 mRNA was overexpressed in breast cancers of different pathological types and molecular subtypes,and its high expression was associated with poor prognosis.The tumor membrane of the gap junction beta‐2 mutated group was positive,and the corresponding protein was expressed.Somatic mutation and copy number variation of gap junction beta‐2 are rare in breast cancer.The gap junction beta‐2 transcription level in the p110αsubunit of the phosphoinositide 3‐kinase mutant subgroup was higher than that in the wild‐type subgroup.Gap junction beta‐2 was associated with the phosphoinositide 3‐kinase‐Akt signaling pathway,extracellular matrix–receptor interaction,focal adhesion,and proteoglycans in cancer.Furthermore,gap junction beta‐2 overexpression may be associated with phosphoinositide 3‐kinase and histone deacetylase inhibitor resistance,and its expression level correlated with infiltrating CD8+T cells,macrophages,neutrophils,and dendritic cells.Conclusions:Gap junction beta‐2 may be a promising therapeutic target for targeted therapy and immunotherapy and may be used to predict breast cancer prognosis.

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.

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.