Jai N. Patel

Clinical Implementation of Germ Line Cancer Pharmacogenetic Variants During the Next‐Generation Sequencing Era

More than 100 medications approved by the US Food and Drug Administration include pharmacogenetic biomarkers in the drug label, many with cancer indications referencing germ line DNA variations. With the advent of next‐generation sequencing (NGS) and its rapidly increasing uptake into cancer research and clinical practice, an enormous amount of data to inform documented gene–drug associations will be collected that must be exploited to optimize patient benefit. This review focuses on the implementation of germ line cancer pharmacogenetics in clinical practice. Specifically, it discusses the importance of germ line variation in cancer and the role of NGS in pharmacogenetic discovery and implementation. In the context of a scenario in which massive amounts of NGS‐based genetic information will be increasingly available to health stakeholders, this review explores the ongoing debate regarding the threshold of evidence necessary for implementation, provides an overview of recommendations in cancer by professional organizations and regulatory bodies, and discusses limitations of current guidelines and strategies to improve third‐party coverage.

Implications of genome-wide association studies in cancer therapeutics

Genome wide association studies (GWAS) provide an agnostic approach to identifying potential genetic variants associated with disease susceptibility, prognosis of survival and/or predictive of drug response. Although these techniques are costly and interpretation of study results is challenging, they do allow for a more unbiased interrogation of the entire genome, resulting in the discovery of novel genes and understanding of novel biological associations. This review will focus on the implications of GWAS in cancer therapy, in particular germ-line mutations, including findings from major GWAS which have identified predictive genetic loci for clinical outcome and/or toxicity. Lessons and challenges in cancer GWAS are also discussed, including the need for functional analysis and replication, as well as future perspectives for biological and clinical utility. Given the large heterogeneity in response to cancer therapeutics, novel methods of identifying mechanisms and biology of variable drug response and ultimately treatment individualization will be indispensable.

A Community-Based Multicenter Trial of Pharmacokinetically Guided 5-Fluorouracil Dosing for Personalized Colorectal Cancer Therapy

BACKGROUND Pharmacokinetically guided (PK-guided) versus body surface area-based 5-fluorouracil (5-FU) dosing results in higher response rates and better tolerability. A paucity of data exists on PK-guided 5-FU dosing in the community setting. PATIENTS AND METHODS Seventy colorectal cancer patients, from one academic and five community cancer centers, received the mFOLFOX6 regimen (5-FU 2,400 mg/m(2) over 46 hours every 2 weeks) with or without bevacizumab at cycle 1. The 5-FU continuous-infusion dose was adjusted for cycles 2-4 using a PK-guided algorithm to achieve a literature-based target area under the concentration-time curve (AUC). The primary objective was to demonstrate that PK-guided 5-FU dosing improves the ability to achieve a target AUC within four cycles of therapy. The secondary objective was to demonstrate reduced incidence of 5-FU-related toxicities. RESULTS At cycles 1 and 4, 27.7% and 46.8% of patients achieved the target AUC (20-25 mg × hour/L), respectively (odds ratio [OR]: 2.20; p = .046). Significantly more patients were within range at cycle 4 compared with a literature rate of 20% (p < .0001). Patients had significantly higher odds of not being underdosed at cycle 4 versus cycle 1 (OR: 2.29; p = .037). The odds of a patient being within range increased by 30% at each subsequent cycle (OR: 1.30; p = .03). Less grade 3/4 mucositis and diarrhea were observed compared with historical data (1.9% vs 16% and 5.6% vs 12%, respectively); however, rates of grade 3/4 neutropenia were similar (33% vs 25%-50%). CONCLUSION PK-guided 5-FU dosing resulted in significantly fewer underdosed patients and less gastrointestinal toxicity and allows for the application of personalized colorectal cancer therapy in the community setting.

Pharmacogenetic Discovery in CALGB (Alliance) 90401 and Mechanistic Validation of a VAC14 Polymorphism that Increases Risk of Docetaxel-Induced Neuropathy.

Purpose: Discovery of SNPs that predict a patients risk of docetaxel-induced neuropathy would enable treatment individualization to maximize efficacy and avoid unnecessary toxicity. The objectives of this analysis were to discover SNPs associated with docetaxel-induced neuropathy and mechanistically validate these associations in preclinical models of drug-induced neuropathy. Experimental Design: A genome-wide association study was conducted in metastatic castrate-resistant prostate cancer patients treated with docetaxel, prednisone and randomized to bevacizumab or placebo on CALGB 90401. SNPs were genotyped on the Illumina HumanHap610-Quad platform followed by rigorous quality control. The inference was conducted on the cumulative dose at occurrence of grade 3+ sensory neuropathy using a cause-specific hazard model that accounted for early treatment discontinuation. Genes with SNPs significantly associated with neuropathy were knocked down in cellular and mouse models of drug-induced neuropathy. Results: A total of 498,081 SNPs were analyzed in 623 Caucasian patients, 50 (8%) of whom experienced grade 3+ neuropathy. The 1,000 SNPs most associated with neuropathy clustered in relevant pathways including neuropathic pain and axonal guidance. An SNP in VAC14 (rs875858) surpassed genome-wide significance (P = 2.12 × 10−8, adjusted P = 5.88 × 10−7). siRNA knockdown of VAC14 in stem cell–derived peripheral neuronal cells increased docetaxel sensitivity as measured by decreased neurite processes (P = 0.0015) and branches (P < 0.0001). Prior to docetaxel treatment, VAC14 heterozygous mice had greater nociceptive sensitivity than wild-type litter mate controls (P = 0.001). Conclusions: VAC14 should be prioritized for further validation of its potential role as a predictor of docetaxel-induced neuropathy and biomarker for treatment individualization. Clin Cancer Res; 22(19); 4890–900. ©2016 AACR.

Application of genotype-guided cancer therapy in solid tumors

Given the interpatient biological heterogeneity and narrow therapeutic index of anticancer drugs, a practical method for personalizing cancer therapy is essential. Genotype-guided cancer therapy will provide an optimal approach to normalize systemic drug exposures, predict drug toxicities and/or enrich clinical efficacy. To date, over a dozen anticancer drugs approved by the US FDA require labeling regarding pharmacogenetic biomarkers (both germline and somatic). Many, but not all, have prospective, genotype-guided evidence-based data. Optimizing output from retrospective, prospective, cost-effectiveness and adaptive biomarker driven clinical trials will help drive the success of personalized cancer therapy. This review will discuss prospective genotype-guided clinical trials in patients with solid tumors and address barriers in clinical translation.

Clinically relevant cancer biomarkers and pharmacogenetic assays

Background The number of pharmacogenetic assays available is continuously expanding as more molecularly targeted anticancer drugs are under clinical development. While the literature regarding drug–gene associations and therapeutic implications is often robust, reviews regarding clinical assay availability and profiling methodologies of commonly used cancer biomarkers are often lacking. Objective To concisely identify and describe cancer biomarkers and their respective pharmacogenetic assays currently available in clinical practice. Discussion Analysis of germ-line DNA mutations can often help to predict pharmacokinetic and pharmacodynamic responses, whereas somatic DNA mutations are particularly useful in predicting tumor response. Molecular profiling and pre-emptive identification of cancer biomarkers can help to predict disease prognosis as well as response to anticancer therapy. Dozens of pharmacogenetic assays, utilizing several common methodologies, are currently available in clinical practice. It is essential for clinicians to understand the molecular pathways for anticancer drugs, the therapeutic implications of mutations within these pathways, the clinical assay(s) available to test for pharmacogenetic differences, and the common profiling methodology employed. Conclusion As research continues to unveil more drug–gene and disease–gene associations, it is critical that clinicians understand which pharmacogenetic assays are available to identify inter-individual differences that predict safety and efficacy of anticancer drugs as we move toward the concept of personalized medicine.

Gastric cancer pharmacogenetics: progress or old tripe?

Gastric cancer remains the second most frequent cause of cancer-related mortality. While surgery is traditionally the initial treatment for early-stage disease, the addition of chemotherapy has been shown to significantly increase overall survival and progression-free survival in advanced and metastatic stages of disease. However, despite the incorporation of newer chemotherapies and regimens into gastric cancer clinical trials, the response rate and median overall survival for treated patients has not significantly improved throughout the years; therefore, newer therapeutic approaches to improve upon the medication selection process are warranted. Treatment and dose selection based on patient factors, such as genetic variation, may provide a more rational and potentially more powerful means of personalizing chemotherapy. This review provides an update on the current status of pharmacogenetic studies regarding germline DNA mutations that may alter response to chemotherapeutic agents used to treat gastric cancer, including perspectives on clinical translation and future work.

Bevacizumab and the risk of arterial and venous thromboembolism in patients with metastatic, castration‐resistant prostate cancer treated on Cancer and Leukemia Group B (CALGB) 90401 (Alliance)

Bevacizumab is associated with an increased risk of arterial thromboembolism (ATE); however, its effect on venous thromboembolism (VTE) remains controversial. Scant data exist on the factors that increase the risk of ATE/VTE in patients with prostate cancer. The authors investigated the association of bevacizumab treatment and clinical factors with ATE/VTE risk in patients who were treated on Cancer and Leukemia Group B (CALGB) trial 90401.

Valproic acid reduces the tolerability of temsirolimus in children and adolescents with solid tumors

A pediatric study has established a maximum tolerated dose (MTD) for temsirolimus (Tem) of more than 150 mg/m2 intravenously/week. A phase I trial was conducted to establish the MTD for Tem in combination with valproic acid (VPA) in children and adolescents with refractory solid tumors. The secondary aims included expression of mammalian target of rapamycin (mTOR) markers on archival tumor tissue; Tem pharmacokinetics; assessment of histone acetylation (HA); and tumor response. Patients were treated with VPA (5 mg/kg orally three times daily) with a target serum level of 75–100 mcg/ml. Tem was started at an initial dose of 60 mg/m2/week. Pharmacokinetics and HA measurements were performed during weeks 1 and 5. Two of the first three patients experienced dose-limiting toxicity (grade 3 mucositis). Tem at 35 mg/m2/week was found to be tolerable. Peak Tem concentrations were higher in all patients compared with those in previously published reports of single agent Tem. Increases in HA are correlated with VPA levels. All tumor samples expressed mTORC1 and mTORC2. An objective response was observed in one patient (melanoma), whereas transient stable disease was observed in four other patients (spinal cord ependymoma, alveolar soft part sarcoma, medullary thyroid carcinoma, and hepatocellular carcinoma). The MTD of Tem when administered with VPA is considerably lower than when used as a single agent, with mucositis the major dose-limiting toxicity. The combination merits further study and may have activity in melanoma. Attention to drug–drug interactions will be important in future multiagent trials including Tem.

Personalizing chemotherapy dosing using pharmacological methods

PurposeGiven the toxic nature and narrow therapeutic index of traditional chemotherapeutics, better methods of dose and therapy selection are critical. Pharmacological methods, including pharmacogenomics and pharmacokinetics, offer a practical method to enrich drug exposure, reduce toxicity, and improve quality of life for patients.MethodsPubMed and key abstracts from the American Society of Clinical Oncology (ASCO) and American Association for Cancer Research (AACR) were searched until July 2015 for clinical data relating to pharmacogenomic- and/or pharmacokinetic-guided dosing of anticancer drugs.ResultsBased on the results returned from a thorough search of the literature and the plausibility of utilizing pharmacogenomic and/or pharmacokinetic methods to personalize chemotherapy dosing, we identified several chemotherapeutic agents with the potential for therapy individualization. We highlight the available data, clinical validity, and utility of using pharmacogenomics to personalize therapy for tamoxifen, 5-fluorouracil, mercaptopurine, and irinotecan, in addition to using pharmacokinetics to personalize dosing for 5-fluorouracil, busulfan, methotrexate, taxanes, and topotecan.ConclusionA concerted effort should be made by researchers to further elucidate the role of pharmacological methods in personalizing chemotherapy dosing to optimize the risk–benefit profile. Clinicians should be aware of the clinical validity, utility, and availability of pharmacogenomic- and pharmacokinetic-guided therapies in clinical practice, to ultimately allow optimal dosing for each and every cancer patient.