Polygenic inheritance of paclitaxel-induced sensory peripheral neuropathy driven by axon outgrowth gene sets in CALGB 40101 (Alliance)

Chhibber, Aparna; Mefford, Joel; Stahl, Eli A.; Pendergrass, Sarah A.; Baldwin, Margaret; Owzar, Kouros; Li, M.; Winer, Eric P.; Hudis, Clifford A.; Zembutsu, Hitoshi; Kubo, Michiaki; Nakamura, Yusuke; McLeod, Howard L.; Ratain, Mark J.; Shulman, Lawrence N.; Ritchie, Marylyn D.; Plenge, Robert M.; Witte, John S.; Kroetz, Deanna L.

doi:10.1038/tpj.2014.2

Cited by 35 publications

(43 citation statements)

References 60 publications

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“…MLM and polygenic modeling methods are now being applied to PGx data. MLM/GCTA analyses have been used to investigate asthma PGx traits [87], and paclitaxel-induced sensory peripheral neuropathy [88]. …”

Section: What Have We Learned?mentioning

confidence: 99%

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Genomic Architecture of Pharmacological Efficacy and Adverse Events

et al. 2014

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The pharmacokinetic and pharmacodynamic disciplines address pharmacological traits, including efficacy and adverse events. Pharmacogenomics studies have identified pervasive genetic effects on treatment outcomes, resulting in the development of genetic biomarkers for optimization of drug therapy. Pharmacogenomics-based tests are already being applied in clinical decision making. However, despite substantial progress in identifying the genetic etiology of pharmacological response, current biomarker panels still largely rely on single gene tests with a large portion of the genetic effects remaining to be discovered. Future research must account for the combined effects of multiple genetic variants, incorporate pathway-based approaches, explore gene-gene interactions and nonprotein coding functional genetic variants, extend studies across ancestral populations, and prioritize laboratory characterization of molecular mechanisms. Because genetic factors can play a key role in drug response, accurate biomarker tests capturing the main genetic factors determining treatment outcomes have substantial potential for improving individual clinical care.

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Section: What Have We Learned?mentioning

confidence: 99%

“…Chhibber et al (2014) [88] investigated a polygenic etiology of paclitaxel-induced neuropathy. They estimated the variance explained by common SNPs (MAF >1%) for two outcomes: the maximum grade of sensory peripheral neuropathy, and the dose at first instance of peripheral neuropathy.…”

Section: What Have We Learned?mentioning

confidence: 99%

Genomic Architecture of Pharmacological Efficacy and Adverse Events

et al. 2014

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“…In a Cancer and Leukemia Group B clinical trial, the loci identifi ed that were associated with paclitaxel-induced neuropathy were in genes involved in axon outgrowth (Baldwin et al 2012 ;Chhibber et al 2014 ). Although, in retrospect, these fi ndings make sense, they provide a new perspective or paradigm for pharmacogenetics.…”

Section: Does Genetic Make-up Infl Uence Recurrence and Survival?mentioning

confidence: 88%

Host Factors and Risk of Breast Cancer Recurrence: Genetic, Epigenetic and Biologic Factors and Breast Cancer Outcomes

Ambrosone

Hong

Goodwin

2015

Improving Outcomes for Breast Cancer Survivors

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Among women with breast cancer, there is wide variability in outcomes, both in treatment-related toxicities and disease-free survival (DFS). Primary predictors of DFS are those related to the extent of the disease and tumor characteristics, associated not only with tumor aggressiveness, but also responsiveness to targeted therapies. Inherited germline variation may also play a role in cancer treatment outcomes, and there have been studies targeting drug metabolism and other candidate pathways as well as genome-wide association studies (GWAS), which take a more agnostic approach and interrogate hundreds of thousands single nucleotide polymorphisms (SNPs) to determine those that modify response to breast cancer treatment. While this field of pharmacogenetics and pharmacogenomics has held exciting promise for personalized medicine, the results have not been as consistent, or the effects as profound, as first hoped. An emerging field in studies of cancer prognosis is epigenetics, which regulates DNA expression and can be influenced by numerous biologic processes as well as environmental exposures. Although young, this field of research likely holds promise for understanding of epigenetic mechanisms driving cancer and cancer outcomes, with a potential to modify these factors through drugs or other approaches. Finally, circulating markers in blood that reflect some lifestyle factors have also been studies in relation to cancer outcomes, particularly Vitamin D. In this chapter, we highlight advances in the areas noted above, and comment on factors that can impact interpretation of results from observational studies. We also discuss future directions, and avenues necessary to move the field forward.

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“…FDG4 is associated with the hereditary neuropathy condition of CharcotMarie-Tooth disease. Subsequent pathway and modeling work with this data set have suggested that a hereditable predisposition to this toxicity may lie in genes involved in axon outgrowth (Chhibber et al 2014 ). Another trial specifi cally focused on more rare variants using massively parallel sequencing of 20,794 genes associated with heredity neuropathy from patients who had received paclitaxel-based chemotherapy (Beutler et al 2013 ).…”

Section: Identifying Host Factors Related To Risk For Cipnmentioning

confidence: 98%

Symptoms: Chemotherapy-Induced Peripheral Neuropathy

Schneider

Hershman

Loprinzi

2015

Advances in Experimental Medicine and Biology

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Chemotherapy-induced peripheral neuropathy (CIPN) is a problematic, treatment-induced toxicity that has the potential to impact quality of life and limit the doses of curative intent therapy. This therapy-induced side effect is one of the most troublesome in oncology clinical practices, considering the morbidity, the frequency, and the potential irreversibility of this problem. Patients with breast cancer are particularly impacted by this side effect as multiple agents commonly used for this disease can cause neuropathy. In this chapter, we provide an overview of CIPN, including: clinical predictors, frequency, and its impact on quality of life. Further, we highlight the pathophysiology and review the literature to date for agents designed to prevent or treat CIPN. We also highlight the most important ongoing clinical and translational research questions that hope to help better predict and prevent this toxicity. This includes optimizing the methods of assessment, using host specific factors (Race and genetics) to predict those more likely to experience CIPN, and determining how CIPN might impact clinical decisions toward therapy.

show abstract

Polygenic inheritance of paclitaxel-induced sensory peripheral neuropathy driven by axon outgrowth gene sets in CALGB 40101 (Alliance)

Cited by 35 publications

References 60 publications

Genomic Architecture of Pharmacological Efficacy and Adverse Events

Genomic Architecture of Pharmacological Efficacy and Adverse Events

Host Factors and Risk of Breast Cancer Recurrence: Genetic, Epigenetic and Biologic Factors and Breast Cancer Outcomes

Symptoms: Chemotherapy-Induced Peripheral Neuropathy

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