Effect of Primary Systemic Therapy on PD-1, PD-L1, and PD-L2 mRNA Expression in Advanced Breast Cancer

Objective: The association between PD-1, PD-L1, and PD-L2 expression and prognosis has been extensively studied in various cancers but remained controversial in breast cancer. Besides, little is known about the prognostic value of PD-1, PD-L1, and PD-L2 upregulation or downregulation following systemic therapy (chemotherapy and hormonal therapy) in breast cancer. Therefore, we aim to investigate the change of PD-1, PD-L1, and PD-L2 expression in mRNA level after primary systemic therapy in breast cancer patients and its clinical implications. Methods: Expression of PD-1, PD-L1, and PD-L2 mRNA were measured before-after chemotherapy and hormonal therapy with real-time PCR in 80 advanced breast cancer patients. The correlation between alteration of PD-1, PD-L1, and PD-L2 expression and clinicopathological characteristics as well as overall survival was also statistically analyzed. Results: Chemotherapy and hormonal therapy altered PD-1, PD-L1, and PD-L2 expression in breast cancer with most patients have an increase expression. As much as 57.1%, 62.9% and 60% patients have an increase PD-1, PD-L1, and PD-L2 expression after chemotherapy, while 60%, 60%, and 64% patients have an increase PD-1, PD-L1, and PD-L2 expression after hormonal therapy. Alteration of PD-1, PD-L1, and PD-L2 expression was not correlated with all clinicopathological characteristics. Increase in PD-1, PD-L1, and PD-L2 expression was significantly associated with better OS (p=0.031, p=0.019, and p=0.019 for PD-1, PD-L1, and PD-L2, respectively), which remained significant in multivariate analysis including age, stage, primary systemic therapy, histology grade, subtype and primary tumor histology (HR PD-1 0.5 (95% CI 0.28-0.88) p=0.031; HR PD-L1 0.43 (95% CI 0.24-0.8) p=0.019; HR PD-L2 (95% CI 0.24-0.87) p=0.019).  Conclusion: Expression of PD-1, PD-L1, and PD-L2 in breast cancer patients is mostly enhanced after chemotherapy and hormonal therapy, and the enhancement is associated with good OS. This result revealed the potential of measuring PD-1, PD-L1, and PD-L2 mRNA expression in predicting clinical outcome.     

免疫治疗相关蛋白PD-1/PD-L1在三阴性乳腺癌中的表达及临床意义

目的探讨程序性死亡受体1(PDCD1,也称PD-1)及程序性死亡受体配体1(PDCD1LG1,也称PD-L1)在三阴性乳腺癌中的表达情况及其临床意义。方法收集39例三阴性乳腺癌患者和39例非三阴性乳腺癌患者的乳腺癌组织,采用免疫组织化学法检测不同乳腺癌组织中PD-1、PD-L1的表达情况,并对PD-1、PD-L1表达情况与三阴性乳腺癌患者临床特征的关系进行分析。结果三阴性乳腺癌组织中PD-1和PD-L1的阳性表达率均高于非三阴性乳腺癌组织(P﹤0.05)。不同年龄、绝经情况、组织学分级、肿瘤直径、淋巴结转移情况、肿瘤侵犯神经情况及脉管内癌栓情况三阴性乳腺癌患者的PD-1和PD-L1阳性表达率比较,差异均无统计学意义(P﹥0.05)。结论在三阴性乳腺癌中,PD-1、PD-L1具有较高的阳性表达率,检测PD-1和PD-L1的表达对早期诊断三阴性乳腺癌可能具有积极意义,同时,阻断PD-1和PD-L1信号通路可能成为三阴性乳腺癌潜在的治疗靶点。     

PD-1/PD-L1在三阴乳腺癌中的研究进展

三阴乳腺癌特指雌激素受体、孕激素受体及人表皮生长因子受体2均阴性的乳腺癌患者,由于其对内分泌治疗无效,使其临床预后极差,因此,探索新的治疗方法尤为重要.近年来,肿瘤的免疫治疗已成为继放疗、化疗和手术治疗之后的第4种有效的治疗方法.研究表明,大约20%的三阴乳腺癌表达PD-L1,在介导肿瘤细胞免疫逃逸中起重要作用.本文就PD-1及其配体PD-L1在三阴乳腺癌中的表达、表达机制及其运用作一综述.     

PD-1/PD-L1抑制剂联合抗血管生成药物治疗晚期三阴性乳腺癌的研究进展

晚期三阴性乳腺癌较其他亚型乳腺癌的治疗手段少、生存期短、预后差.近年飞速发展的免疫治疗有望延长晚期三阴性乳腺癌的生存时间,但是多项临床研究提示PD-1/PD-L1抑制剂单药治疗晚期三阴性乳腺癌有效率低.新近研究显示抗血管生成药物的治疗不仅可以使血管正常化,抑制肿瘤生长,还可以增强免疫治疗的疗效,与PD-1/PD-L1抑...     

The Role of Biomarkers for the Prediction of Response to Checkpoint Immunotherapy and the Rationale for the Use of Checkpoint Immunotherapy in Cervical Cancer

Checkpoint immunotherapy has revolutionised the way that melanoma is treated and has also shown significant effectiveness in lung, bladder, renal, and head and neck cancers. At the present time, trials of checkpoint immunotherapy in cervical cancer are at early phases, but there is very good rationale for pursuing this as a treatment option, especially as cervical cancer is a virally driven cancer and therefore should be recognised by the immune system as being foreign. This review explores the biomarkers for the selection of patients for immunotherapy in other cancers, such as programmed death ligand 1 (PD-L1) expression, tumour infiltrating lymphocytes and total mutational burden, and relates these biomarkers to cervical cancer. A PubMed search was carried out for publications published in English with the terms ‘immunotherapy’ OR ‘cervical cancer’ OR ‘checkpoint blockade’ OR ‘tumour infiltrating lymphocytes’ OR ‘total mutational burden’. Articles that met these criteria and were available on PubMed before 8 October 2018 were included. The results showed that PD-L1 is positive in up to 90% of cervical cancers and that the total mutational burden is moderately high, with 5–6 mutations per megabase. In addition, the tumour microenvironment in cervical cancer has an impact on prognosis, with higher ratios of CD8+ tumour infiltrating lymphocytes to CD4+ T regulatory cells being associated with improved survival. Clinical studies to date have shown the response rate of cervical cancer to checkpoint immunotherapy to be in the region to 10–25%. Cervical cancer exhibits many of the features that have been shown to be correlated with response to checkpoint immunotherapy in other tumour sites. However, response rates to date are in the region of 10–25%. Therefore, combinations of immunotherapeutic agents or checkpoint inhibitors with radiotherapy may be required to maximise the therapeutic benefit of harnessing the host immune system to fight cancer.     

Clinical and Radiologic Assessments to Predict Breast Cancer Pathologic Complete Response to Neoadjuvant Chemotherapy

SummaryPurpose. To prospectively compare the ability of clinical examination, mammography, vascularity-sensitive ultrasound, and magnetic resonance imaging (MRI) to determine pathologic complete response (CR) in breast cancer patients undergoing neoadjuvant chemotherapy.Patients and methods. Participants were women with primary measurable, operable invasive breast cancer (Stages I–III) who presented to the University of Michigan Breast Care Center. Eligibility criteria were based on clinical need for chemotherapy as part of the overall treatment plan. The chemotherapy consisted of doxorubicin and docetaxel administered every 3 weeks for four cycles. Tumor size measurements by physical examination and by the three imaging modalities were performed before chemotherapy was initiated and after its completion, prior to definitive surgery. Response criteria were pre-specified in this prospective design, and study radiologists analyzed the mammographic, sonographic and MRI image sets blinded to information from the other modalities and blinded to final histological diagnosis. The pathologic CR rate obtained by the clinical and imaging modalities was compared to pathologic CR as determined pathologically.Results. 41 of 43 enrolled patients had a determination of pathologic response, and 4 patients had a pathologic CR to this chemotherapy (9.8%). The accuracy of physical examination, mammography, ultrasound, and MRI in determining pathologic CR was 75, 89, 82, and 89% respectively (NS).Conclusion. Biopsy after neoadjuvant chemotherapy remains absolutely necessary to determine pathologic CR to neoadjuvant chemotherapy, as the accuracy of current imaging modalities is insufficient to make this determination. The accuracy of mammography, vascularity-sensitive ultrasound, and MRI were not observed to be significantly different.     

The Role of Immunotherapy in Pancreatic Cancer

Pancreatic adenocarcinoma remains one of the most lethal cancers globally, with a significant need for improved therapeutic options. While the recent breakthroughs of immunotherapy through checkpoint inhibitors have dramatically changed treatment paradigms in other malignancies based on considerable survival benefits, this is not so for pancreatic cancer. Chemotherapies with modest benefits are still the cornerstone of advanced pancreatic cancer treatment. Pancreatic cancers are inherently immune-cold tumors and have been largely refractory to immunotherapies in clinical trials. Understanding and overcoming the current failures of immunotherapy through elucidating resistance mechanisms and developing novel therapeutic approaches are essential to harnessing the potential durable benefits of immune-modulating therapy in pancreatic cancer patients.     

PD-1/PD-L1抑制剂治疗乳腺癌：现状、问题与对策

PD-1/PD-L1抑制剂在乳腺癌免疫治疗中的应用已逐渐成为一种重要的治疗手段,然而对乳腺癌,尤其是三阴性乳腺癌（TNBC）的免疫治疗仍存在某些亟待解决的科学问题,包括PD-1/PD-L1抑制剂单药治疗的有效率欠佳,目前尚无明确的生物标志物来有效筛查治疗敏感人群,免疫相关不良反应（irAE）的发生率高。为了提高疗效和减少irAE的发生,采取以下措施是非常重要的：探讨PD-1/PD-L1抑制剂与其他药物的联合应用方案;采用纳米技术开发选择性靶向肿瘤细胞的纳米载体,降低抗肿瘤药物毒性并提高疗效;探寻开发可预测免疫治疗反应潜力的生物标志物;早期识别和诊疗irAE并建设多学科诊疗协作组（MDT）模式。随着这些措施的积极推进和问题的不断解决,PD-1/PD-L1抑制剂在乳腺癌的治疗中必将呈现出更为广阔的应用前景。     

Pembrolizumab and Trastuzumab in High Tumor Mutational Burden and POLE-Mutated HER2-Positive Refractory Breast Cancer

Metastatic breast cancer (mBC) is an incurable disease, and it is not sensitive to immunotherapy due to its low immunogenicity. Recently, inactivated DNA polymerase epsilon (POLE) mutations have been found to be associated with high tumor mutational burden (TMB), which is an effective immuno-oncology biomarker. Patients with POLE mutations with different types of cancer have properly responded to immunotherapy. We aimed to report the first case of programmed death-ligand 1 (PD-L1)-negative mBC presenting with high TMB and POLE mutations, in which a complete response to 5 cycles of chemotherapy and 1 year of pembrolizumab and trastuzumab was noted after failing several lines of HER2-targeted therapies. Our findings also suggest that biomarker-driven patient selection is highly significant for further clinical development of combination therapies via anti-HER2 plus immune-checkpoint inhibitors for HER2+ BC patients.     

PD-1/PD-L1抑制剂联合曲妥珠单抗在HER2阳性乳腺癌中的研究进展

乳腺癌中有20%~30%的患者表达HER2基因,HER2阳性乳腺癌预后较差,易发生复发和转移。但HER2的表达为乳腺癌治疗提供了新方向。曲妥珠单抗是抗HER2治疗的经典基础药物,然而其原发继发耐药问题引起了大家的注意,研究发现其不敏感及耐药机制的发生可能与肿瘤细胞表面PD-L1上调相关。因此大量关于PD-1/PD-L1抑制剂联合曲妥珠单抗的研究展开意在提高其敏感度,改善其耐药问题。本文就PD-1/PD-L1抑制剂在HER2阳性乳腺癌的临床前及临床研究作一综述。     

肿瘤浸润性淋巴细胞在乳腺癌预后评估及免疫治疗中的应用进展

2020年女性乳腺癌已超越肺癌成为全球最常见的癌症,大量研究证实肿瘤浸润性淋巴细胞（TILs）对肿瘤具有杀伤力,并在识别肿瘤抗原中发挥重要作用,因此TILs在临床免疫治疗及乳腺癌预后评估中的应用受到广泛关注。本文综述了近期TILs在不同分子分型乳腺癌中的基础研究进展和临床应用现状,评估了TILs对乳腺癌预后评估及临床免疫治疗的价值。     

肿瘤免疫治疗PD-1/PD-L1靶向核素分子探针的研究进展

PD-1/PD-L1免疫治疗已成为继放化疗以外治疗多种难治性、复发性肿瘤的一种重要方法,但只有部分患者从中获益。PD-1/PD-L1靶向核素分子探针核医学显像可以无创、实时、重复地进行全身(包括肿瘤及其他组织中)的PD-1/PD-L1表达水平的活体检测,便于:(1)帮助临床筛选获益患者;(2)免疫治疗的疗效评价;(3)动态监测PD-1/PD-L1在治疗过程中的变化,为治疗方案调整提供有力依据。本文将对PD-1/PD-L1靶向核素分子探针的临床前及临床转化研究进行综述,以期为肿瘤免疫治疗的临床应用及进一步研究提供参考。     

PD-1及PD-L1抑制剂在前列腺癌治疗中的研究现状

前列腺癌是男性常见的恶性肿瘤,目前主要的治疗手段是根治性前列腺切除术(RP)以及雄激素剥夺疗法(ADT),但两者均有其各自的局限性。近年来免疫治疗发展迅速,其中细胞程序性死亡受体-1(PD-1)及细胞程序性死亡配体-1(PD-L1)作为免疫治疗的理想靶点,其抑制剂在治疗肺癌、结肠癌等多种癌症中发挥了越来越重要的作用。而随着PD-1/PD-L1在前列腺癌方面的研究进展及深入,其在前列腺癌中的作用机制也逐渐明了,PD-1/PD-L1抑制剂在前列腺癌治疗上也将具有广阔的前景。本文将就PD-1及PD-L1在前列腺癌中的表达、作用机制及其抑制剂治疗前列腺癌的相关研究进展作一综述。     

以PD-1/PD-L1为靶点的肺癌免疫治疗临床研究进展

免疫检查点的研究在近几年实现突破性进展,PD-1/PD-L1信号通路与免疫逃逸机制密切相关,针对阻断PD-1/PD-L1 通路免疫检查点的治疗在肺癌中取得明显效果。从Checkmate-017、Checkmate-057研究到KEYNOTE-010研究和OAK研究,逐 步奠定了PD1/PD-L1抑制剂作为化疗失败晚期NSCLC的标准治疗的地位;PD-1/PD-L1抑制剂可联合其他治疗方式,包括放疗、 化疗、靶向治疗以及其他免疫治疗等方式,在肺癌综合治疗中起到协同作用,从而提高了疗效。免疫检查点抑制剂带来了肺癌治 疗模式的改变,也对肿瘤疗效评价模式、治疗相关不良反应的处理带来挑战。另外,免疫检查点抑制剂的研发也有力地推动了精 准医疗的进展。     

PD-1/PD-L1抑制剂治疗晚期或复发性子宫内膜癌的临床研究进展

一个改善子宫内膜癌预后的策略是放弃基于传统的两分型诊疗模式,而转向分子肿瘤分析.2020年3月,美国国立综合癌症网络(national comprehensive cancer network,NCCN)首次推荐子宫内膜癌TCGA分子分型并将其列入子宫内膜癌临床实践指南,标志着子宫内膜癌的临床治疗从基于病理类型、组织学...     

Significance of ABO-Rh Blood Groups in Response and Prognosis in Breast Cancer Patients Treated with Radiotherapy and Chemotherapy

Background: To evaluate whether ABO-Rh blood groups have significance in the treatment response andprognosis in patients with non-metastatic breast cancer. Materials and Methods: We retrospectively evaluatedfiles of 335 patients with breast cancer who were treated between 2005 and 2010. Demographic data, clinicpathologicalfindings, treatments employed, treatment response, and overall and disease-free survivals werereviewed. Relationships between clinic-pathological findings and blood groups were evaluated. Results: 329women and 6 men were included to the study. Mean age at diagnosis was 55.2 years (range: 26-86). Of the cases,95% received chemotherapy while 70% were given radiotherapy and 60.9% adjuvant hormone therapy aftersurgery. Some 63.0% were A blood group, 17.6% O, 14.3% B and 5.1% AB. In addition, 82.0% of the cases wereRh-positive. Mean follow-up was 24.5 months. Median overall and progression-free survival times were 83.9 and79.5 months, respectively. Overall and disease-free survival times were found to be higher in patients with A andO blood groups (p<0.05). However rates did not differ with the Rh-positive group (p=0.226). In univariate andmultivariate analyses, ABO blood groups were identified as factors that had significant effects on overall anddisease-survival times (p=0.011 and p=0.002). Conclusions: It was seen that overall and disease-free survivaltimes were higher in breast cancer patients with A and O blood groups when compared to those with other bloodgroups. It was seen that A and O blood groups had good prognostic value in patients with breast cancer.     

PD-1/PD-L1在dMMR/MSI-H结直肠癌患者临床试验中的研究进展

结直肠癌是目前常见的肿瘤之一,关于DNA错配修复缺陷（dMMR）/微卫星高频不稳定（MSI-H）结直肠癌PD-1/PD-L1免疫疗法是目前关注的热点,多项临床试验已取得良好的疗效,2017年NCCN指南更新推荐纳武单抗(nivolumab)和派姆单抗(pembrolizumab)作为dMMR/MSI-H转移性结直肠癌二线或三线的药物选择。本文对当前dMMR/MSI-H结直肠癌特点、PD-1/PD-L1生物学功能、PD-1/PD-L1在结直肠癌中的治疗以及研究过程中出现的严重不良反应方面的研究进展作一综述。     

PD-1/PD-L1 在胃癌组织中的表达及其临床意义

目的：探讨PD-1 和PD-L1 蛋白在胃癌（gastric cancer, GC）组织中的表达及其临床意义。方法：收集河北医科大学第四医院2007 年1 月至2007 年12 月82 例GC患者术后癌石蜡组织标本及其对应的临床病例资料,随访其生存状况。采用免疫组织化学法检测肿瘤组织中PD-1 和PD-L1 蛋白的表达情况,采用Kaplan-Meier 法及Log-Rank检验分析其生存数据,并绘制生存曲线。结果：GC组织中PD-1 蛋白表达阳性率为13.41%,PD-L1 蛋白表达阳性率为42.68%;术前无远处转移患者GC组织中PD-1、PD-L1 及癌间质中PD-L1 表达阳性率明显低于术前有远处转移（PD-1：3.28% vs 42.86%;PD-L1：13.11% vs 90.48%;癌间质中PD-L1：13.11% vs 47.62%,均P<0.01）。胃的切除范围、PD-L1 蛋白过表达及术前有无远处转移是影响GC患者预后的不良因素（P<0.05）。结论：GC组织中PD-1 和PD-L1 蛋白的表达与患者术前有无远处转移和肿瘤的浸润深度密切相关,PD-L1 阳性表达者较阴性表达者术后生存时间短。