The gene encoding the receptor-tyrosine kinase RET was first discovered more than three decades ago, and activating RET rearrangements and mutations have since been identified as actionable drivers ...of oncogenesis. Several multikinase inhibitors with activity against RET have been explored in the clinic, and confirmed responses to targeted therapy with these agents have been observed in patients with RET-rearranged lung cancers or RET-mutant thyroid cancers. Nevertheless, response rates to RET-directed therapy are modest compared with those achieved using targeted therapies matched to other oncogenic drivers of solid tumours, such as sensitizing EGFR or BRAF
mutations, or ALK or ROS1 rearrangements. To date, no RET-directed targeted therapeutic has received regulatory approval for the treatment of molecularly defined populations of patients with RET-mutant or RET-rearranged solid tumours. In this Review, we discuss how emerging data have informed the debate over whether the limited success of multikinase inhibitors with activity against RET can be attributed to the tractability of RET as a drug target or to the lack, until 2017, of highly specific inhibitors of this oncoprotein in the clinic. We emphasize that novel approaches to targeting RET-dependent tumours are necessary to improve the clinical efficacy of single-agent multikinase inhibition and, thus, hasten approvals of RET-directed targeted therapies.
Immune checkpoint inhibition has been shown to generate profound and durable responses in mismatch repair deficient (MMR-D) solid tumors and has elicited interest in detection tools and strategies to ...guide therapeutic decision-making. Herein we address questions on the appropriate screening, detection methods, patient selection, and initiation of therapy for MMR-D pancreatic ductal adenocarcinoma (PDAC) and assess the utility of next-generation sequencing (NGS) in providing additional prognostic and predictive information for MMR-D PDAC.
Archival and prospectively acquired samples and matched normal DNA from
= 833 PDAC cases were analyzed using a hybridization capture-based, NGS assay designed to perform targeted deep sequencing of all exons and selected introns of 341 to 468 cancer-associated genes. A computational program using NGS data derived the MSI status from the tumor-normal paired genome sequencing data. Available germline testing, IHC, and microsatellite instability (MSI) PCR results were reviewed to assess and confirm MMR-D and MSI status.
MMR-D in PDAC is a rare event among PDAC patients (7/833), occurring at a frequency of 0.8%. Loss of MMR protein expression by IHC, high mutational load, and elevated MSIsensor scores were correlated with MMR-D PDAC. All 7 MMR-D PDAC patients in the study were found to have Lynch syndrome. Four (57%) of the MMR-D patients treated with immune checkpoint blockade had treatment benefit (1 complete response, 2 partial responses, 1 stable disease).
An integrated approach of germline testing and somatic analyses of tumor tissues in advanced PDAC using NGS may help guide future development of immune and molecularly directed therapies in PDAC patients.
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As the use of breast reconstruction and postmastectomy radiotherapy (PMRT) has increased over the past decade, the typical approach to integrating radiotherapy with breast reconstruction has provoked ...intense controversy in the management of breast cancer. PMRT can lead to an increased frequency of complications in the reconstructed breast. Conversely, the reconstructed breast can increase the complexity of radiotherapy delivery. How to minimise the frequency of complications without compromising oncological or cosmetic outcomes of the reconstructed breast is an important shared multidisciplinary goal for oncologists and their patients. Several questions remain, however, regarding the type of reconstruction that should be used with PMRT, when reconstruction should be done relative to PMRT and whether radiotherapy treatment should be directed towards the tissue expander or the implant for women who opt for a two-stage expander–implant reconstruction. Following advances in the planning of radiotherapy treatment, new questions about the application of these technologies in the setting of breast reconstruction have arisen. In this Review, we address these questions by reviewing contemporary evidence on the optimal integration of radiotherapy and breast reconstruction in the management of breast cancer.
Malignant mesothelioma is an aggressive cancer with a poor prognosis and limited treatment options. For many years, the only US Food and Drug Administration‐approved first‐line treatment for ...unresectable mesothelioma was pemetrexed plus cisplatin. However, the recent approval of nivolumab plus ipilimumab as frontline treatment for patients with pleural mesothelioma marks a significant milestone for the treatment of this disease. In this review, the authors describe recent advances in therapeutic strategies for the treatment of patients with advanced, unresectable mesothelioma, highlighting the emerging use of immunotherapy and mesothelin‐targeted therapies for the management of malignant mesothelioma.
The emerging use of immunotherapy and mesothelin‐targeted therapies for the management of malignant mesothelioma is reviewed. The future outlook for patients with mesothelioma is promising, and progress in the treatment of advanced mesothelioma offers patients more options beyond standard chemotherapy and opportunities to achieve better outcomes.
Treatment with checkpoint inhibitors has shown durable responses in a number of solid tumors, including melanoma, lung, and renal cell carcinoma. However, most breast cancers are resistant to ...monotherapy with checkpoint inhibitors. Radiation therapy (RT) has been shown to have a number of immunostimulatory effects, including priming the immune system, recruiting immune cells to the tumor environment, and altering the immunosuppressive effects of the tumor microenvironment. RT therefore represents a promising adjuvant therapy to checkpoint blockade in breast cancer.
We review the data from the checkpoint blockade studies on breast cancer reported to date, the mechanisms by which RT potentiates immune responses, the preclinical and clinical data of checkpoint blockade and RT combinations, and the landscape of current clinical trials of RT and immune checkpoint inhibitor combinations in breast cancer.
Clinical trials with checkpoint blockade therapy have demonstrated response rates of up to 19% in breast cancer, and many of the responses are durable. Preclinical data indicate that RT combined with checkpoint inhibition synergizes not only to enhance antitumor efficacy but also to induce responses outside of the radiation field. Thus multiple clinical trials are currently investigating the combination of checkpoint inhibition with RT.
The use of combination strategies that incorporate chemotherapy and/or local strategies such as RT may be needed to augment responses to immune therapy in breast cancer. Preclinical and clinical results show that RT in combination with checkpoint blockade may be a promising therapeutic option in breast cancer.
Background
The current study was conducted to evaluate the efficacy and safety of pembrolizumab‐mediated programmed cell death protein 1 inhibition plus radiotherapy (RT) in patients with metastatic ...triple‐negative breast cancer who were unselected for programmed death‐ligand 1 expression.
Methods
The current study was a single‐arm, Simon 2‐stage, phase 2 clinical trial that enrolled a total of 17 patients with a median age of 52 years (range, 37‐73 years). An RT dose of 3000 centigrays (cGy) was delivered in 5 daily fractions. Pembrolizumab was administered intravenously at a dose of 200 mg within 3 days of the first RT fraction, and then every 3 weeks ± 3 days until disease progression. The median follow‐up was 34.5 weeks (range, 2.1‐108.3 weeks). The primary endpoint of the current study was the overall response rate (ORR) at week 13 in patients with unirradiated lesions measured using Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1). Secondary endpoints included safety and progression‐free survival. Exploratory objectives were to identify biomarkers predictive of ORR and progression‐free survival.
Results
The ORR for the entire cohort was 17.6% (3 of 17 patients; 95% CI, 4.7%‐44.2%), with 3 complete responses (CRs), 1 case of stable disease, and 13 cases of progressive disease. Eight patients died prior to week 13 due to disease progression. Among the 9 women assessed using RECIST version 1.1 at week 13, 3 (33%) achieved a CR, with a 100% reduction in tumor volume outside of the irradiated portal. The CRs were durable for 18 weeks, 20 weeks, and 108 weeks, respectively. The most common grade 1 to 2 toxicity (assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0) was dermatitis (29%). Four grade 3 adverse events were attributed to pembrolizumab: fatigue, lymphopenia, and infection. No were no grade 4 adverse events or treatment‐related deaths reported.
Conclusions
The combination of pembrolizumab and RT was found to be safe and demonstrated encouraging activity in patients with poor‐prognosis, metastatic, triple‐negative breast cancer who were unselected for programmed death‐ligand 1 expression. Larger clinical trials of checkpoint blockade plus RT with predictive biomarkers of response are needed.
The current phase 2, multi‐institutional study evaluates whether the combination of the programmed cell death protein 1 immune checkpoint inhibitor pembrolizumab and radiotherapy (RT) is safe and effective in patients with metastatic triple‐negative breast cancer (mTNBC). Among 17 women in the current study with pretreated mTNBC who received pembrolizumab and RT, the combination appears safe and demonstrates an encouraging signal within a poor‐prognosis population, indicating that further study of the combination is warranted.
A firmer understanding of the genomic landscape of lung cancer has recently led to targeted, therapeutic advances in non‐small cell lung cancer. Historically, the reference standard for the diagnosis ...and genetic interrogation for advanced‐stage patients has been tissue acquisition via computed tomography‐guided core or fine needle aspiration biopsy. However, this process can frequently put the patient at risk and remains complicated by sample availability and tumor heterogeneity. In addition, the time required to complete the diagnostic assays can negatively affect clinical care. Technological advances in recent years have led to the development of blood‐based diagnostics or “liquid biopsies” with great potential to quickly diagnose and genotype lung cancer using a minimally invasive technique. Recent studies have suggested that molecular alterations identified in cell‐free DNA (cfDNA) or circulating tumor DNA can serve as an accurate molecular proxy of tumor biology and reliably predict the response to tyrosine kinase therapy. In addition, several trials have demonstrated the high accuracy of microRNA (miRNA) platforms in discerning cancerous versus benign nodules in high‐risk, screened patients. Despite the promise of these platforms, issues remain, including varying sensitivities and specificities between competing platforms and a lack of standardization of techniques and downstream processing. In the present report, the clinical applications of liquid biopsy technologies, including circulating tumor cells, proteomics, miRNA, and cfDNA for NSCLC, are reviewed and insight is provided into the diagnostic and therapeutic implications and challenges of these platforms.
Implications for Practice:
Although tumor biopsies remain the reference standard for the diagnosis and genotyping of non‐small cell lung cancer, they remain fraught with logistical complexities that can delay treatment decisions and affect clinical care. Liquid diagnostic platforms, including cell‐free DNA, proteomic signatures, RNA (mRNA and microRNA), and circulating tumor cells, have the potential to overcome many of these barriers, including rapid and accurate identification of de novo and resistant genetic alterations, real‐time monitoring of treatment responses, prognosis of outcomes, and identification of minimal residual disease. The present report provides insights into new liquid diagnostic platforms in non‐small cell lung cancer and discusses the promise and challenges of their current and future clinical use.
摘要
对肺癌基因组图谱的深入理解使非小细胞肺癌 (NSCLC) 的靶向治疗在近年得到了长足进展。从历史上来说, 肺癌晚期患者的诊断及基因鉴定参考标准物通常为在计算机体层摄影 (CT) 引导下粗针/细针穿刺活检获取的组织。然而, 这一步骤常使患者处于危险之中, 且结果也可能因样本可用性及肿瘤异质性的差异而较为混杂。此外, 完成这一诊断检验需要一定的时间, 这可能对临床治疗造成不利的影响。近年来临床技术的进展引领了基于血液的诊断学 (或称“液体活检”) 的飞速发展, 从而使应用微创技术对肺癌进行快速诊断和基因分型成为可能。最近有研究提示从无细胞DNA (cfDNA) 或循环肿瘤细胞中发现的分子学突变可以作为肿瘤活检的一项精准分子指标, 进而能可靠地预测患者对酪氨酸激酶抑制剂 (TKI) 治疗的反应。另外, 多项研究均证实microRNA (miRNA) 平台在高危筛查患者中鉴别恶性与良性结节时具有高准确性。尽管这些平台的前景令人瞩目, 但目前尚有许多问题, 包括各竞争平台之间敏感性和特异性的差异, 以及技术和下游操作程序缺乏规范化标准等。本文回顾总结了液体活检技术在NSCLC中的临床应用, 包括循环肿瘤细胞、蛋白质组学、miRNA及cfDNA等, 并对这些平台在诊断和治疗上的临床意义及面临的挑战提出了展望。The Oncologist 2016;21:1121–1130
对临床实践的提示: 尽管肿瘤活检是非小细胞肺癌诊断和基因分型的参考标准, 但其流程复杂, 可能延误治疗决策并影响临床治疗。液体诊断平台 包括无细胞 DNA、蛋白质组学信号、RNA (mRNA 和 miRNA) 及循环肿瘤细胞 有潜力克服这些障碍, 如快速并准确鉴定新发及耐药基因突变、实时监测治疗应答、预测患者转归并发现微小残留病灶等。本文对非小细胞肺癌的新型液体诊断平台提出了展望, 并讨论了当前和将来临床应用的前景和挑战。
Technological advances in recent years have led to the development of blood‐based diagnostics or “liquid biopsies” with great potential to quickly diagnose and genotype lung cancer using a minimally invasive technique. The clinical applications of liquid biopsy technologies, including circulating tumor cells, proteomics, microRNA, and cell free DNA for lung cancer, are reviewed and insight is provided into the diagnostic and therapeutic implications and challenges of these platforms.
The abscopal effect refers to the ability of localized radiation to trigger systemic antitumor effects. Over the past 50 years, reports on the abscopal effect arising from conventional radiation have ...been relatively rare. However, with the continued development and use of immunotherapy strategies incorporating radiotherapy with targeted immunomodulators and immune checkpoint blockade, the abscopal effect is becoming increasingly relevant in less immunogenic tumors such as breast cancer. Here, we review the mechanism of the abscopal effect, the current preclinical and clinical data, and the application of the abscopal effect in designing clinical trials of immunotherapy combined with radiotherapy in breast cancer.
BAP1 is a tumor suppressor gene implicated in DNA repair and cell growth. Individuals with germline BAP1 mutations are at a significantly increased risk for developing many different cancers ...including malignant mesothelioma, uveal melanomas, cutaneous melanomas and renal clear cell carcinomas. Meningiomas with absent BAP1 expression have been reported to be more aggressive and present often with rhabdoid features. Here, we report the co-occurrence of pleural mesotheliomas and meningiomas in patients with germline BAP1 mutations. We describe the cancer history, family pedigrees, clinical management, and outcomes of four BAP1 germline mutation carrier families with a history of malignant mesothelioma and meningioma.
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