Analyzing the clinical actionability of germline pharmacogenomic findings in oncology

Wellmann, Rebecca M.; Borden, Brittany A.; Danahey, Keith; Nanda, Rachita; Polite, Blasé N.; Stadler, Walter M.; Ratain, Mark J.; O’Donnell, Peter H.

doi:10.1002/cncr.31382

Cited by 15 publications

(13 citation statements)

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“…The use of NGS information (as well as identification of some inherited germline predisposition syndromes) 31 has revolutionized oncology, guiding treatment strategies in up to 20% to 40% of cancer patients 28,29,32‐34 . Less emphasized and much less considered is the evidence supporting therapeutic dosing decisions based on germline pharmacogenomic associations 3,11,13,35 . Our results suggest that the proportion of patients (up to one‐third) who could benefit from their providers considering germline PGx information within just 5 key pharmacogenes is similar to the estimated impact of somatic NGS 28‐30 …”

Section: Discussionmentioning

confidence: 67%

“…Many oncology therapies have narrow therapeutic windows and significant interindividual variation in drug response, and these factors may predispose patients to treatment failure and/or harmful adverse drug events (ADEs) 2 . Pharmacogenomics (PGx), the study of how germline genetic variants affect individual response to medications, is a potentially valuable tool that may help optimize the safety of anticancer drug dosing in oncology patients 3 …”

Section: Introductionmentioning

confidence: 99%

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Clinically actionable genotypes for anticancer prescribing among >1500 patients with pharmacogenomic testing

Reizine

Danahey

Truong

et al. 2022

Cancer

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BACKGROUND In recent years, there has been increasing evidence supporting the role of germline pharmacogenomic factors predicting toxicity for anticancer therapies. Although somatic genomic data are used frequently in oncology care planning, germline pharmacogenomic testing is not. This study hypothesizes that comprehensive germline pharmacogenomic profiling could have high relevance for cancer care. METHODS Between January 2011 and August 2020, patients at the University of Chicago Medical Center were genotyped across custom germline pharmacogenomic panels for reasons unrelated to cancer care. Actionable anticancer pharmacogenomic gene/drug interactions identified by the FDA were defined including: CYP2C9 (erdafitinib), CYP2D6 (gefitinib), DPYD (5‐fluorouracil and capecitabine), TPMT (thioguanine and mercaptopurine), and UGT1A1 (belinostat, irinotecan, nilotinib, pazopanib, and sacituzumab‐govitecan hziy). The primary objective was to determine the frequency of individuals with actionable or high‐risk genotypes across these 5 key pharmacogenes, thus potentially impacting prescribing for at least 1 of these 11 commonly prescribed anticancer therapies. RESULTS Data from a total of 1586 genotyped individuals were analyzed. The oncology pharmacogene with the highest prevalence of high‐risk, actionable genotypes was UGT1A1, impacting 17% of genotyped individuals. Actionable TPMT and DPYD genotypes were found in 9% and 4% of patients, respectively. Overall, nearly one‐third of patients genotyped across all 5 genes (161/525, 31%) had at least one actionable genotype. CONCLUSIONS These data suggest that germline pharmacogenomic testing for 5 key pharmacogenes could identify a substantial proportion of patients at risk with standard dosing, an estimated impact similar to that of somatic genomic profiling. LAY SUMMARY Differences in our genes may explain why some drugs work safely in certain individuals but can cause side effects in others. Pharmacogenomics is the study of how genetic variations affect an individual's response to medications. In this study, an evaluation was done for important genetic variations that can affect the tolerability of anticancer therapy. By analyzing the genetic results of >1500 patients, it was found that nearly one‐third have genetic variations that could alter recommendations of what drug, or how much of, an anticancer therapy they should be given. Performing pharmacogenomic testing before prescribing could help to guide personalized oncology care.

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Section: Discussionmentioning

confidence: 67%

Section: Introductionmentioning

confidence: 99%

Clinically actionable genotypes for anticancer prescribing among >1500 patients with pharmacogenomic testing

Reizine

Danahey

Truong

et al. 2022

Cancer

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“…A lot of work needs to be done in the context of implementation of pharmacogenetics. In a study that analyzed pharmacogenomics literature of 125 drugs used in oncology, more than half of the drugs (55%) did not have pharmacogenomics data while only 12 of those which did, had actionable associations [61] . Understanding the pharmacogenetics of ASNase can help refining treatment strategies for other cancers in which asparagine and/or glutamine depletion can be indicated, such as in subtypes of acute myeloid leukemia, sarcomas, pancreatic and ovarian malignancies [62][63][64][65] .…”

Section: Resultsmentioning

confidence: 99%

Pharmacogenetics of asparaginase in acute lymphoblastic leukemia

Abaji¹,

Krajinović²

2019

CDR

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Asparaginase is a key component in leukemias and lymphomas treatment protocols and is suggested as a treatment for other malignancies in which an amino acid depletion strategy is indicated. Asparaginase intolerance is subject to inter-individual variability and can manifest as hypersensitivity reactions, pancreatitis, thrombosis, as well as metabolic abnormalities, and may affect treatment outcome. Pharmacogenetics aims at enhancing treatment efficacy and safety by better understanding the genetic basis of variability and its effect on the pharmacological responses. Many groups tried to tackle the pharmacogenetics of asparaginase but the potential implementation of such findings remains debatable. In this review, we highlight the most important findings reported in studies of the pharmacogenetics of asparaginase related complications and treatment outcome in acute lymphoblastic leukemia.

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“…ACYP2 (Acylphosphatase 2) gene located on chromosome 2p16.2, encodes a small cytosolic acylphosphatase enzyme that catalyzes the hydrolysis of carboxyl‐phosphate bonds (Wellmann et al, ). Genome wide association study has demonstrated that genetic polymorphisms in ACYP2 are associated with telomere length (He et al, ), which has led to studies of the association between ACYP2 and various diseases, including various cancers (Thiesen et al, ).…”

Section: Introductionmentioning

confidence: 99%

The influence of ACYP2 polymorphisms on gastrointestinal cancer susceptibility in the Chinese Han population

Duan

Hong

Wang

et al. 2019

Molec Gen & Gen Med

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Background Gastrointestinal cancer (GI cancer) is a type of cancer that has a high death rate. It has been reported that ACYP2 gene was associated with the development of gastric cancer and colorectal cancer, but it is not clear that the relationship between ACYP2 gene and GI cancer in Chinese Han population. This study aimed to investigate the association between polymorphisms of ACYP2 and GI cancer in the Chinese Han population. Methods We used Agena MassARRAY to determine the genotypes of 1,160 GI cancer patients and 495 healthy controls. The correlation between ACYP2 variants and GI cancer risk was examined by logistic regression analysis. Results We identified that rs6713088 (OR = 1.17, 95% CI: 1.00–1.36, p = 0.047), rs843711 (OR = 1.17, 95 CI: 1.01–1.36, p = 0.035), and rs11896604 (OR = 1.20, 95% CI: 1.00–1.45, p = 0.048) were correlated with an increased risk of GI cancer under allele model. Rs11125529 under the recessive model (OR = 2.05, 95% CI: 1.00–4.23, p = 0.038), rs843711 in recessive model (OR = 1.37, 95% CI: 1.04–1.82, p = 0.026), and rs11896604 under log‐additive model (OR = 1.23, 95% CI: 1.01–1.51, p = 0.042) were associated with an increased risk of GI cancer. Conclusion Our study suggested that polymorphisms of ACYP2 gene might be associated with susceptibility to GI cancer.

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Analyzing the clinical actionability of germline pharmacogenomic findings in oncology

Abstract: Several oncology drugs have actionable germline pharmacogenomic information, justifying their delivery through institutional pharmacogenomic implementations to determine clinical utility. Cancer 2018;124:3052-65. © 2018 American Cancer Society.

Cited by 15 publications

References 50 publications

Clinically actionable genotypes for anticancer prescribing among >1500 patients with pharmacogenomic testing

Clinically actionable genotypes for anticancer prescribing among >1500 patients with pharmacogenomic testing

Pharmacogenetics of asparaginase in acute lymphoblastic leukemia

The influence of ACYP2 polymorphisms on gastrointestinal cancer susceptibility in the Chinese Han population

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