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Purpose: Associations between taxane-related sensory neuropathy (TRSN) and single-nucleotide polymorphisms (SNP) have previously been reported, but few have been replicated in large, independent validation studies. This study evaluates the association between previously investigated SNPs and TRSN, using genotype data from a study of chemotherapy-related toxicity in patients with breast cancer.Experimental Design: We investigated 73 SNPs in 50 genes for their contribution to TRSN risk, using genotype data from 1,303 European patients. TRSN was assessed using National Cancer Institute common toxicity criteria for adverse events classification. Unconditional logistic regression evaluated the association between each SNP and TRSN risk (primary analysis). Cox regression analysis assessed the association between each SNP and cumulative taxane dose causing the first reported moderate/severe TRSN (secondary analysis). The admixture likelihood (AML) test, which considers all SNPs with a prior probability of association with TRSN together, tested the hypothesis that certain SNPs are truly associated.Results: The AML test provided strong evidence for the association of some SNPs with TRSN (P = 0.023). The two most significantly associated SNPs were rs3213619(ABCB1) [OR = 0.47; 95% confidence interval (CI), 0.28–0.79; P = 0.004] and rs9501929(TUBB2A) (OR = 1.80; 95% CI, 1.20–2.72; P = 0.005). A further 9 SNPs were significant at P-value ≤ 0.05.Conclusion: This is currently the largest study investigating SNPs associated with TRSN. We found strong evidence that SNPs within genes in taxane pharmacokinetic and pharmacodynamic pathways contribute to TRSN risk. However, a large proportion of the inter-individual variability in TRSN remains unexplained. Further validated results from GWAS will help to identify new pathways, genes, and SNPs involved in TRSN susceptibility. Clin Cancer Res; 20(9); 2466–75. ©2014 AACR.

PDF file - 237KB, Supplementary Table 1: Published Studies of Putative Functional SNPs Supplementary Table 2a: Drug Regimens and Doses of Taxanes by Study Supplementary Table 2b: Comparison of Toxicity grades/rates by recruiting trial in PGSNPS included in Taxane Related Sensory Neuropathy Study Supplementary Table 3: PGSNPS Taxane Treated Patient Characteristics Supplementary Table 4: All Putative Functional SNPs Replicated in the PGSNPS dataset (phenotype: cumulative dose to TRSN) Supplementary Table 5: All Putative Functional SNPs Replicated in the PGSNPS dataset (phenotype: maximum TRSN) Supplementary Figure 1: Percentage of Patients with TRSN ≥ grade 2 by genotype, for three statistically significant SNPs that were genotyped in PGSNPS (maximum TRSN) Supplementary Figures 2a-c: Kaplan-Meier curves Kaplan-Meier curves: Shows for each SNP, by genotype, the probability of TRSN grade 0-1 (i.e., the probability of not experiencing moderate/severe TRSN) as the cumulative dose increases.

Background The relationship between chemotherapy-related toxicities and prognosis is unclear. Previous studies have examined the association of myelosuppression parameters or neuropathy with survival and reported conflicting results. This study aims to investigate 13 common chemotherapy toxicities and their association with relapse-free survival and breast cancer-specific survival. Methods Chemotherapy-related toxicities were collected prospectively for 6,248 women with early-stage breast cancer from four randomised controlled trials (NEAT; BR9601; tAnGo; Neo-tAnGo). Cox proportional-hazards modelling was used to analyse the association between chemotherapy-related toxicities and both breast cancer-specific survival and relapse-free survival. Models included important prognostic factors and stratified by variables violating the proportional hazards assumption. Results Multivariable analysis identified severe neutropenia (grades ≥3) as an independent predictor of relapse-free survival (hazard ratio (HR) = 0.86; 95 % confidence interval (CI), 0.76–0.97; P = 0.02). A similar trend was seen for breast cancer-specific survival (HR = 0.87; 95 % CI, 0.75–1.01; P = 0.06). Normal/low BMI patients experienced more severe neutropenia (P = 0.008) than patients with higher BMI. Patients with fatigue (grades ≥3) showed a trend towards reduced survival (breast cancer-specific survival: HR = 1.17; 95 % CI, 0.99–1.37; P = 0.06). In the NEAT/BR9601 sub-group analysis by treatment component, this effect was statistically significant (HR = 1.61; 95 % CI, 1.13–2.30; P = 0.009). Conclusions This large study shows a significant association between chemotherapy-induced neutropenia and increased survival. It also identifies a strong relationship between low/normal BMI and increased incidence of severe neutropenia. It provides evidence to support the development of neutropenia-adapted clinical trials to investigate optimal dose calculation and its impact on clinical outcome. This is important in populations where obesity may lead to sub-optimal chemotherapy doses. Electronic supplementary material The online version of this article (doi:10.1186/s12916-015-0547-5) contains supplementary material, which is available to authorized users.

5081Background: The effect of novel drugs can be studied in primary prostate cancer (PC), if given prior to radical prostatectomy (RP). Altered PI3K/AKT/mTOR signalling is associated with aggressiv...

97 Background: Additional systemic therapy given to unselected patients (pts) around RP has yet to improved pt survival. Further trials should use appropriate pt selection, i.e. men at highest risk of relapse, ideally biomarker stratified. Using novel drugs prior to RP allows direct study of effects in primary prostate cancer (PC) that may guide design of future trials. Altered PI3K/AKT/mTOR pathway signalling is associated with aggressive PC hence we have undertaken a study vistusertib, an oral, dual mTORC1/mTORC2 inhibitor prior to RP. Methods: Primary endpoint was to measure mTOR1/2 inhibition by immunohistochemistry (IHC). Secondary endpoints were feasibility, safety, tolerability and determining plasma concentrations of vistusertib. Exploratory objectives included measurement of anti-cancer effects. Men, due for RP, with high volume or aggressive PC consented and received vistusertib, 50mg bd, for 15 days prior to RP. Diagnostic biopsy and RP tissue were collected for IHC. Adverse events (AE) were graded according to CTCAE v4. Plasma was collected to determine vistusertib concentrations. Results: 21 men, median age 62 (range 50 – 69) included 11 intermediate and 10 high risk PC. 18/21 were evaluable for primary endpoint. On day of RP mean plasma vistusertib concentration at RP was 648 ng/mL (range 386-852) and 6-8 hr post dose 484 ng/mL (range 211-660). Majority of related AEs were Grade (Gr) 1, the most common being rash, thrombocytopenia, oral mucositis, diarrhoea, lymphopenia and fatigue. Six pts experienced Gr3 AEs (3 pt lymphopenia, 1 pt each rash, mucositis and ALT rise). Two pts discontinued due to AEs (mucositis, thrombocytopenia) and one withdrew consent. Surgery was delayed in one pt (Gr 1 thrombocytopenia). IHC confirmed at RP: 4EBP1 was reduced in 100% pt (75% no staining post vistusertib) and pS6 was reduced in 67%, not changed in 25% and increased in 8%. A fall in PSA occurred in 4/18 pts. Conclusions: 2 weeks of AZD2014 can be given prior to RP. Active plasma concentrations were achieved. mTOR pathway inhibition was confirmed on IHC and a PSA fall occurred in 22% of pt. Analysis is ongoing, to be informed by concomitant studies in a PTEN null PC model. Clinical trial information: NCT02064608.

Purpose: Associations between taxane-related sensory neuropathy (TRSN) and single-nucleotide polymorphisms (SNP) have previously been reported, but few have been replicated in large, independent validation studies. This study evaluates the association between previously investigated SNPs and TRSN, using genotype data from a study of chemotherapy-related toxicity in patients with breast cancer. Experimental Design: We investigated 73 SNPs in 50 genes for their contribution to TRSN risk, using genotype data from 1,303 European patients. TRSN was assessed using National Cancer Institute common toxicity criteria for adverse events classification. Unconditional logistic regression evaluated the association between each SNP and TRSN risk (primary analysis). Cox regression analysis assessed the association between each SNP and cumulative taxane dose causing the first reported moderate/severe TRSN (secondary analysis). The admixture likelihood (AML) test, which considers all SNPs with a prior probability of association with TRSN together, tested the hypothesis that certain SNPs are truly associated. Results: The AML test provided strong evidence for the association of some SNPs with TRSN (P = 0.023). The two most significantly associated SNPs were rs3213619(ABCB1) [OR = 0.47; 95% confidence interval (CI), 0.28–0.79; P = 0.004] and rs9501929(TUBB2A) (OR = 1.80; 95% CI, 1.20–2.72; P = 0.005). A further 9 SNPs were significant at P-value ≤ 0.05. Conclusion: This is currently the largest study investigating SNPs associated with TRSN. We found strong evidence that SNPs within genes in taxane pharmacokinetic and pharmacodynamic pathways contribute to TRSN risk. However, a large proportion of the inter-individual variability in TRSN remains unexplained. Further validated results from GWAS will help to identify new pathways, genes, and SNPs involved in TRSN susceptibility. Clin Cancer Res; 20(9); 2466–75. ©2014 AACR.

Background The increasing trend for incorporation of biological sample collection within clinical trials requires sample collection procedures which are convenient and acceptable for both patients and clinicians. This study investigated the feasibility of using saliva-extracted DNA in comparison to blood-derived DNA, across two genotyping platforms: Applied Biosystems TaqmanTM and Illumina BeadchipTM genome-wide arrays. Method Patients were recruited from the Pharmacogenetics of Breast Cancer Chemotherapy (PGSNPS) study. Paired blood and saliva samples were collected from 79 study participants. The Oragene DNA Self-Collection kit (DNAgenotek®) was used to collect and extract DNA from saliva. DNA from EDTA blood samples (median volume 8 ml) was extracted by Gen-Probe, Livingstone, UK. DNA yields, standard measures of DNA quality, genotype call rates and genotype concordance between paired, duplicated samples were assessed. Results Total DNA yields were lower from saliva (mean 24 μg, range 0.2–52 μg) than from blood (mean 210 μg, range 58–577 μg) and a 2-fold difference remained after adjusting for the volume of biological material collected. Protein contamination and DNA fragmentation measures were greater in saliva DNA. 78/79 saliva samples yielded sufficient DNA for use on Illumina Beadchip arrays and using Taqman assays. Four samples were randomly selected for genotyping in duplicate on the Illumina Beadchip arrays. All samples were genotyped using Taqman assays. DNA quality, as assessed by genotype call rates and genotype concordance between matched pairs of DNA was high (>97%) for each measure in both blood and saliva-derived DNA. Conclusion We conclude that DNA from saliva and blood samples is comparable when genotyping using either Taqman assays or genome-wide chip arrays. Saliva sampling has the potential to increase participant recruitment within clinical trials, as well as reducing the resources and organisation required for multicentre sample collection.

INTRODUCTION: Tamoxifen is one of the most effective adjuvant breast cancer therapies available. Its metabolism involves the phase I enzyme, cytochrome P4502D6 (CYP2D6), encoded by the highly polymorphic CYP2D6 gene. CYP2D6 variants resulting in poor metabolism of tamoxifen are hypothesised to reduce its efficacy. An FDA-approved pre-treatment CYP2D6 gene testing assay is available. However, evidence from published studies evaluating CYP2D6 variants as predictive factors of tamoxifen efficacy and clinical outcome are conflicting, querying the clinical utility of CYP2D6 testing. We investigated the association of CYP2D6 variants with breast cancer specific survival (BCSS) in breast cancer patients receiving tamoxifen. METHODS: This was a population based case-cohort study. We genotyped known functional variants (n = 7; minor allele frequency (MAF) > 0.01) and single nucleotide polymorphisms (SNPs) (n = 5; MAF > 0.05) tagging all known common variants (tagSNPs), in CYP2D6 in 6640 DNA samples from patients with invasive breast cancer from SEARCH (Studies of Epidemiology and Risk factors in Cancer Heredity); 3155 cases had received tamoxifen therapy. There were 312 deaths from breast cancer, in the tamoxifen treated patients, with over 18000 years of cumulative follow-up. The association between genotype and BCSS was evaluated using Cox proportional hazards regression analysis. RESULTS: In tamoxifen treated patients, there was weak evidence that the poor-metaboliser variant, CYP2D6*6 (MAF = 0.01), was associated with decreased BCSS (P = 0.02; HR = 1.95; 95% CI = 1.12-3.40). No other variants, including CYP2D6*4 (MAF = 0.20), previously reported to be associated with poorer clinical outcomes, were associated with differences in BCSS, in either the tamoxifen or non-tamoxifen groups. CONCLUSIONS: CYP2D6*6 may affect BCSS in tamoxifen-treated patients. However, the absence of an association with survival in more frequent variants, including CYP2D6*4, questions the validity of the reported association between CYP2D6 genotype and treatment response in breast cancer. Until larger, prospective studies confirming any associations are available, routine CYP2D6 genetic testing should not be used in the clinical setting.