While tumor genome sequencing has become widely available in clinical and research settings, the interpretation of tumor somatic variants remains an important bottleneck. Here we present the Cancer ...Genome Interpreter, a versatile platform that automates the interpretation of newly sequenced cancer genomes, annotating the potential of alterations detected in tumors to act as drivers and their possible effect on treatment response. The results are organized in different levels of evidence according to current knowledge, which we envision can support a broad range of oncology use cases. The resource is publicly available at http://www.cancergenomeinterpreter.org .
Comprehensive genomic profiling is expected to revolutionize cancer therapy. In this Prospective, we present the prevalence of mutations and copy-number alterations with predictive associations ...across solid tumors at different levels of stringency for gene-drug targetability. More than 90% of The Cancer Genome Atlas samples have potentially targetable alterations, the majority with multiple events, illustrating the challenges for treatment prioritization given the complexity of the genomic landscape. Nearly 80% of the variants in rarely mutated oncogenes are of uncertain functional significance, reflecting the gap in our understanding of the relevance of many alterations potentially linked to therapeutic actions. Access to targeted agents in early clinical trials could affect treatment decision in 75% of patients with cancer. Prospective implementation of large-scale molecular profiling and standardized reports of predictive biomarkers are fundamental steps for making precision cancer medicine a reality.
Cancer treatment has made significant strides towards the promise of personalized medicine. Recent scientific advances have shown that there are numerous genetic deregulations that are common in ...multiple cancer types, raising the possibility of developing drugs targeting those deregulations irrespective of the tumour type. Precision Cancer Medicine (PCM) was born out of accumulated evidence matching targeted agents with these tumour molecular deregulations. At the same time, the therapeutic armamentarium is rapidly increasing and the number of new drugs (including immune‐oncology agents) entering drug development continues to rise. These factors, added to strong collaboration with regulatory agencies, which have approved novel agents based on data obtained from phase 1/2 trials, have led to unprecedented evolution in the design of early‐stage clinical trials. Currently, we have seen rapid phase 1 dose‐escalation trials followed by remarkably large expansion cohorts, and are witnessing the emergence of new trials, such as adaptive studies with basket and umbrella designs aimed at optimizing the biomarker–drug co‐development process. Alongside the growing complexity of these clinical trials, new frameworks for stronger and faster collaboration between all stakeholders in drug development, including academic institutions and frameworks, clinicians, pharma companies and regulatory agencies, have been established. In this review article, we describe the main challenges and opportunities that these new trial designs may provide for a more efficient drug development process, which may ultimately help ensure that PCM becomes a reality for patients.
New clinical trial designs are helping optimize early drug development. An umbrella trial is a master protocol for which the patient's eligibility is defined by the presence of a tumour type that is substratified according to specific molecular alterations matched to different anticancer therapies. Basket trials include patients with different tumour types with a common molecular alteration who are treated with the same matched therapy.
In addition to being present in tumor cells, many targets of signal transduction inhibitors are also found in normal tissue. Side effects attributable to the mechanism of action of molecular targeted ...agents thus represent “on‐target” modulation in normal tissues. These mechanism‐based toxicities can be pharmacodynamic effects of pathway inhibition and, in tumors depending on the inhibited pathway for proliferation, might be biomarkers of efficacy. The development of rash with tyrosine kinase inhibitors or monoclonal antibodies targeting the epidermal growth factor receptor is associated with superior outcomes in lung, head and neck, colorectal, and pancreatic cancer studies. Correlated with superior efficacy in retrospective analyses of large studies in advanced colorectal, breast, and renal cell carcinoma, arterial hypertension as an adverse event of antiangiogenic agents may also be a marker of effective target inhibition. An association between hypothyroidism and the activity of multitargeted tyrosine kinase inhibitors has been identified in renal cell carcinoma patients. Tumor growth addiction to the specific pathway that is effectively targeted may be the link between a mechanism‐based toxicity and efficacy. The biological basis for this correlation can be pharmacological, with higher drug exposure being associated with greater toxicity and antitumor activity, and can also be genetic, because single nucleotide polymorphisms play an important role in drug pharmacokinetic and pharmacodynamic processes. Investigators have proposed that interpatient differences and associated toxicities can be exploited for dose selection and titration, and clinical trials are currently exploring intrapatient “dosing‐to‐toxicity” strategies. Ultimately, the predictive value of a side effect of molecular targeted therapies requires validation in prospective trials.
摘要
信号转导抑制剂的许多靶点除见于肿瘤细胞, 也见于正常组织. 因此, 基于分子靶向药物作用机制产生的一些副作用往往代表正常组织中的 ”中靶” 调控效应. 这些机制相关毒性反应可以是通路抑制的某些药效学效应, 在这些通过抑制增殖通路的肿瘤中, 可能成为疗效的生物标记. 酪氨酸激酶抑制剂或靶向作用于表皮细胞生长因子受体的单克隆抗体在肺癌, 头颈部肿瘤, 结直肠癌和胰腺癌患者治疗过程中发生的皮疹的程度, 与这些患者的临床疗效成正相关. 对晚期结直肠癌, 乳腺癌, 肾细胞癌大样本研究的回顾性分析显示, 抗血管生成药物治疗过程中的血压升高不良事件与更好的疗效相关, 可提示靶标被有效抑制. 肾细胞癌中, 甲状腺功能减退与多靶点酪氨酸激酶抑制剂的活性相关. 药物有效地靶向作用于肿瘤生长所依赖的特异性通路, 可解释机制相关毒性反应与疗效之间的关联. 二者相关性的生物学基础既可以是药理学方面的, 药物暴露量高与毒性大, 抗肿瘤活性强相关; 也可以是遗传学方面的, 因为单核苷酸多态性对药物的药代学和药效学有重要影响. 研究人员建议, 可按患者间差异及关联毒性反应来选择不同的剂量和剂量滴定, 多项临床试验目前正在探索同一患者的“加量直至出现毒性反应”策略. 分子靶向药物这类副作用的预测价值最终还须经前瞻性试验的验证.
The various mechanism‐based toxicities of targeted agents, including rash associated with epidermal growth factor receptor inhibitors and hypertension/hypothyroidism associated with antiangiogenic drugs, are reviewed with the aim of assessing their utility as potential proof of pharmacodynamic effects or as predictive biomarkers.
The addition of molecular targeted agents (MTAs) to R-CHOP has been one of the main focuses of research in patients with DLBCL. Despite encouraging preliminary results, recent randomized controlled ...trials (RCT) have not shown a definitive benefit over standard R-CHOP. Here we conducted a systematic review and meta-analysis to investigate the impact of this strategy. A systematic literature review was conducted to identify RCT that evaluated the addition of MTA to R-CHOP-based regimen versus R-CHOP alone in previously untreated DLBCL patients. Fixed and random effects models were used to estimate pooled hazard ratios (HRs) and odds ratios (ORs) with 95% confidence intervals (CI). Progression-free survival (PFS), overall survival, and adverse events (AE) were analyzed. A total of seven RCT including 3,255 patients with DLBCL met the eligibility criteria. Three different types of MTAs (bortezomib, ibrutinib, and lenalidomide) were investigated in combination with R-CHOP. Overall, R-CHOP plus MTA showed a slightly better PFS (HR=0.86; 95% CI: 0.76–0.98). No differences were observed according to the cell of origin subtype of DLBCL. Interestingly, patients younger than 60 years had a significantly better PFS with R-CHOP plus MTAs (HR=0.72; 95% CI: 0.56–0.93), while no benefit was observed in patients older than 60 years (HR=0.96). The combination strategy showed higher odds to develop serious AEs (OR= 1.46, 95% CI 1.11–1.91). R-CHOP plus MTA seems only to slightly improve PFS in patients with DLBCL, particularly in younger patients. An increase in toxicity was observed in comparison to R-CHOP.
Precision oncology based on next-generation sequencing (NGS) test is growing in daily clinical practice. However, the real impact of this strategy in patients’ outcome on a large scale remains ...uncertain. In this review, we summarise existing literature on this topic, limitations for broad NGS implementation, bottlenecks in genomic variant interpretation and the role of molecular tumour boards.
CheckMate 743 trial demonstrated survival benefit of immunotherapy in first line in MPM with some differences in the efficacy of chemotherapy according to histology. The objective of this study is to ...characterize the impact of chemotherapy according to histology in patients diagnosed with MPM at our institution. Clinical records of all MPM patients diagnosed at Vall d'Hebron University Hospital between November 2002 and April 2020 were reviewed. Associations between clinical variables and outcomes were assessed with Cox regression models. Survival data were calculated by the Kaplan-Meier method. 189 patients were included with 76% of tumors classified as epithelioid subtype. First line chemotherapy was offered to 85% of patients. Median survival in overall population was 21.3 months (95% CI 17.2-24.3). We found that patients with epithelioid tumors had better overall survival (OS) and progression free survival (PFS). Median OS of epithelioid patients treated with first line chemotherapy was 26.7 months versus 15.0 months in non-epithelioid patients (HR 2.25 CI 95% 1.4-3.4; p < 0.001). Median PFS for patients with epithelioid tumors treated with chemotherapy was 4.8 months versus 3.6 months in non-epithelioid (HR 1.5 CI 95% 1.0-2.3; p = 0.03). The improvement of outcomes in patients with epithelioid histology was detected in patients treated with cisplatin or carboplatin. Histology was not a predictive factor for the platinum agent sensitivity (p of interaction PFS = 0.09, p of interaction OS = 0.65). In our series, patients with non-epithelioid tumors presented worse prognosis. Although epithelioid tumors exposed to cisplatin had higher PFS, histology was not a clear predictor of chemotherapy efficacy.
CDK4/6 inhibitors combined with endocrine therapy have demonstrated higher antitumor activity than endocrine therapy alone for the treatment of advanced estrogen receptor-positive breast cancer. Some ...of these tumors are de novo resistant to CDK4/6 inhibitors and others develop acquired resistance. Here, we show that p16 overexpression is associated with reduced antitumor activity of CDK4/6 inhibitors in patient-derived xenografts (n = 37) and estrogen receptor-positive breast cancer cell lines, as well as reduced response of early and advanced breast cancer patients to CDK4/6 inhibitors (n = 89). We also identified heterozygous RB1 loss as biomarker of acquired resistance and poor clinical outcome. Combination of the CDK4/6 inhibitor ribociclib with the PI3K inhibitor alpelisib showed antitumor activity in estrogen receptor-positive non-basal-like breast cancer patient-derived xenografts, independently of PIK3CA, ESR1 or RB1 mutation, also in drug de-escalation experiments or omitting endocrine therapy. Our results offer insights into predicting primary/acquired resistance to CDK4/6 inhibitors and post-progression therapeutic strategies.
Colorectal cancer (CRC) is a heterogeneous disease representing a therapeutic challenge, which is further complicated by the common occurrence of several molecular alterations that confer resistance ...to standard chemotherapy and targeted agents. Mechanisms of resistance have been identified at multiple levels in the epidermal growth factor receptor (EGFR) pathway, including mutations in KRAS, NRAS, and BRAFV600E, and in the HER2 and MET receptors. These alterations represent oncogenic drivers that may co-exist in the same tumor with other primary and acquired alterations via a clonal selection process. Other molecular alterations include DNA damage repair mechanisms and rare kinase fusions, potentially offering a rationale for new therapeutic strategies. In recent years, genomic analysis has been expanded by a more complex study of epigenomic, transcriptomic, and microenvironment features. The Consensus Molecular Subtype (CMS) classification describes four CRC subtypes with distinct biological characteristics that show prognostic and potential predictive value in the clinical setting. Here, we review the panorama of actionable targets in CRC, and the developments in more recent molecular tests, such as liquid biopsy analysis, which are increasingly offering clinicians a means of ensuring optimal tailored treatments for patients with metastatic CRC according to their evolving molecular profile and treatment history.
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