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1000 SNPs with greatest statistical association with cumulative docetaxel dose at grade 3+ neuropathy in CALGB 90401 discovery GWAS.

Peripheral neuronal cells (Peri.4U) treated with docetaxel were found to have a significant decrease in sensitivity for A) mean process lengths but not for B) mean outgrowth intensity or C) relative straightness as measured after 24 hours post-drug treatment. For paclitaxel treatment at the same time point, the cells were also found to have significantly decreased sensitivity for D) relative mean process length and E) mean outgrowth intensity but not for F) relative straightness. Neurite parameters measured with MetaXPress® software were averaged from 3 independent experiments. Error bars represent the standard error of the mean from three independent transfection experiments. NTC = non-targeting control, UT= untransfected control.

Number of patients who experienced neuropathy, completed treatment without neuropathy and discontinued treatment early without having neuropathy while on study and within each range of cumulative treatment.

Sensitivity to mechanical stimuli with Von Frey filaments for C57BL/6J mice and litter-mates heterozygous for VAC14 prior to docetaxel treatment. The figure displays the estimate of the proportion of mice without a hind-paw withdrawal response to stimulation by each Von Frey fiber weight, e.g., no mice respond to fibers {less than or equal to}0.2 g and all mice respond to fibers{greater than or equal to}1.4 g. The VAC14 heterozygous mice (hatched line) are more likely than wild-type mice (solid line) to respond, meaning they are more sensitive to nociceptive stimuli (p=0.0012). Gray lines denote 95% confidence intervals.

CONSORT diagram illustrating patient flow from enrollment on parent study to population included in pharmacogenetic discovery analysis and quality control filtering of SNPs from the Illumina HumanHap610-Quad into the pharmacogenetic analysis.

Most Highly Enriched Canonical Pathways

Purpose: Discovery of SNPs that predict a patient's 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.

Background Cabozantinib is approved for treatment of renal cell cancer (RCC) in a starting dose of 60 mg. However, in the registration studies dose reductions were needed in 46-62% of patients due to toxicity. Improved clinical efficacy of cabozantinib was observed in RCC patients with an average exposure of > 750 ug/L. Data about cabozantinib pharmacokinetics in patients routinely treated with this drug is scarce, while treatment is challenging due to toxicity. Therefore, we explored the cabozantinib exposure in patients with two different tumour types in our clinic. Methods Clinical data and cabozantinib trough concentrations (Cmin) were collected from all patients treated with cabozantinib with at least one measured Cmin at steady state in our clinic between Jan 2018 - Aug 2020. We included salivary gland cancer (SGC) patients treated in a phase II study and RCC patients from our outpatient clinic. Geometric mean (GM) Cmin at the start dose, at 40 mg and at best tolerated dose (BTD) were compared between the two tumour types. Results In total 47 patients were included. All patients with SGC (n=22) started with 60 mg, while 13 of 25 patients with RCC started with 40 mg. GM Cmin level at the start dose was 1350 µg/L (95% CI 1182-1781) vs. 689 µg/L (95% CI 576-823) (P750 ug/L. Conclusion Unexpectedly, cabozantinib levels were significantly higher in patients with SGC compared to those with RCC at the dose of 40 mg. However, cabozantinib levels at BTD were comparable between patients with SGC and RCC. At BTD, the majority of patients did not reach the target of >750 µg/L. For most patients with RCC, the cabozantinib level at BTD corresponded to a dose of 40 mg. Therefore, 40 mg instead of 60 mg as a starting dose followed by dose-adjustment based on exposure and tolerability may be preferred in patients with RCC. Although cabozantinib is not registered for SGC, an even lower starting dose of 20 mg/day may be required in these patients based on cabozantinib levels at BTD. Future studies should focus on identifying an optimal and tolerable exposure-response target value for cabozantinib and elucidate factors that contribute to the differences in exposure, in order to individualise and improve treatment. Citation Format: Stefanie D. Krens, Wim van Boxtel, Maike J. Uijen, Frank G. Jansman, Ingrid M. Desar, Sasja F. Mulder, Carla M. van Herpen, Nielka P. van Erp. Exposure-toxicity analysis of cabozantinib in patients with salivary gland cancer and renal cell cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1363.