Citations

Abstract Because numerous chemotherapeutic agents exert their cytotoxic effects through generation of reactive oxygen species, the use of antioxidant supplements during treatment is controversial. There are published recommendations to suspend antioxidant supplement use during treatment, despite lack of empirical data from clinical studies; however, it is unclear if patients follow these recommendations. We examined use of multivitamins and vitamin supplements (MV/SP) during treatment for breast cancer, particularly in relation to physician recommendations. High-risk breast cancer patients (n=855) were queried regarding physician recommendations and use of MV/SP via self-administered questionnaires in an ancillary study embedded in a phase III trial of dose-dense compared to metronomic administration of doxorubicin/cyclophosphamide + paclitaxel (SWOG S0221). Of the 658 patients who reported discussing use of supplements during treatment with their physicians, 390 (59%) received no counseling regarding MV/SP use, 85 (13%) received recommendations not to take MV/SP, and 183 (28%) received recommendations to use MV/SP. MV/SP use during treatment was compared to use prior to diagnosis in relation to physician recommendations, with the reference group comprised of those receiving no recommendations. Of those using MV ≥ once/week before diagnosis, recommendations not to take MV/SP were associated with a tenfold reduction in MV use to < once/week during treatment. (OR=10.0, 95% CI=3.7-27.0). MV use was less likely to decrease among patients receiving recommendations to use MV/SP (OR=0.23, 95% CI=0.12-0.44). Similar findings were observed among patients who reported use of vitamin C and vitamin E supplements ≥ once/week before diagnosis, with patients who were advised to take no supplements other than a MV more than 5 times as likely to decrease use of antioxidant supplements. MV use during treatment among previous non-users increased almost sixfold among those whose physicians recommended MV/SP use during treatment (OR=5.92, 95% CI=3.29-10.6). For those reporting vitamin C or vitamin E use < once/week before diagnosis, patients whose physicians recommended MV/SP during treatment were more likely to increase their use of vitamin C (OR=2.05, 95% CI=1.00-4.19) and vitamin E (OR=5.28, 95% CI=2.24-12.4). In this study, physician recommendations were strongly associated with patient use of MV/SP during chemotherapy, regardless of the patient's frequency of use prior to diagnosis. These findings highlight the critical need to better understand the mechanisms by which antioxidants may influence chemotherapeutic outcomes, and to determine if supplement use affects toxicity and/or recurrence. Yearly follow-up in this ongoing study will allow us to assess the impact of MV/SP use treatment outcomes, providing a basis for physician recommendations. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4681. doi:10.1158/1538-7445.AM2011-4681

Abstract Background: Genome-wide association studies (GWAS) identified variants at 19p13.1 and ZNF365 (10q21.2) as risk factors for breast cancer among BRCA1 and BRCA2 mutation carriers, respectively. We explored associations with ovarian cancer and with breast cancer by tumor histopathology for these variants in mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Methods: Genotyping data for 12,599 BRCA1 and 7,132 BRCA2 mutation carriers from 40 studies were combined. Results: We confirmed associations between rs8170 at 19p13.1 and breast cancer risk for BRCA1 mutation carriers [HR, 1.17; 95% confidence interval (CI), 1.07–1.27; P = 7.42 × 10−4] and between rs16917302 at ZNF365 (HR, 0.84; 95% CI, 0.73–0.97; P = 0.017) but not rs311499 at 20q13.3 (HR, 1.11; 95% CI, 0.94–1.31; P = 0.22) and breast cancer risk for BRCA2 mutation carriers. Analyses based on tumor histopathology showed that 19p13 variants were predominantly associated with estrogen receptor (ER)-negative breast cancer for both BRCA1 and BRCA2 mutation carriers, whereas rs16917302 at ZNF365 was mainly associated with ER-positive breast cancer for both BRCA1 and BRCA2 mutation carriers. We also found for the first time that rs67397200 at 19p13.1 was associated with an increased risk of ovarian cancer for BRCA1 (HR, 1.16; 95% CI, 1.05–1.29; P = 3.8 × 10−4) and BRCA2 mutation carriers (HR, 1.30; 95% CI, 1.10–1.52; P = 1.8 × 10−3). Conclusions: 19p13.1 and ZNF365 are susceptibility loci for ovarian cancer and ER subtypes of breast cancer among BRCA1 and BRCA2 mutation carriers. Impact: These findings can lead to an improved understanding of tumor development and may prove useful for breast and ovarian cancer risk prediction for BRCA1 and BRCA2 mutation carriers. Cancer Epidemiol Biomarkers Prev; 21(4); 645–57. ©2012 AACR.

Abstract Background: BRCA1 and BRCA2 mutation carriers have a lifetime breast cancer risk of 40% to 80%, suggesting the presence of risk modifiers. We previously identified significant associations in genetic variants in the insulin-like growth factor (IGF) signaling pathway. Here, we investigate additional IGF signaling genes as risk modifiers for breast cancer development in BRCA carriers. Methods: A cohort of 1,019 BRCA1 and 500 BRCA2 mutation carriers were genotyped for 99 single-nucleotide polymorphisms (SNP) in 13 genes. Proportional hazards regression was used to model time from birth to diagnosis of breast cancer for BRCA1 and BRCA2 carriers separately. For linkage disequilibrium (LD) blocks with multiple SNPs, an additive genetic model was used. For an SNP analysis, no additivity assumptions were made. Results: Significant associations were found between risk of breast cancer and LD blocks in IGF2 for BRCA1 and BRCA2 mutation carriers (global P values of 0.009 for BRCA1 and 0.007 for BRCA2), HTRA1 for BRCA1 carriers (global P value of 0.005), and MMP3 for BRCA2 carriers (global P = 0.0000007 for BRCA2). Conclusions: We identified significant associations of genetic variants involved in IGF signaling. With the known interaction of BRCA1 and IGF signaling and the loss of PTEN in a majority of BRCA1 tumors, this suggests that signaling through AKT may modify breast cancer risk in BRCA1 carriers. Impact: These results suggest potential avenues for future research targeting the IGF signaling pathway in modifying risk in BRCA1and BRCA2 mutation carriers. Cancer Epidemiol Biomarkers Prev; 20(8); 1690–702. ©2011 AACR.

Abstract Rationale: Given recent success in delivering interferon-beta (IFNβ) using replication incompetent adenovirus in patients with malignant pleural effusions, we hypothesized that vectors that could replicate (inducing oncolysis) and express IFNβ at high level would be more effective. Both vaccinia virus (VV) and vesicular stomatitis (VSV) expressing mouse IFNβ have been constructed in a manner to improve their safety and efficacy as oncolytic vectors. In this study, we evaluated these two oncolytic vectors in different murine thoracic cancer models for clinical translation. Experimental procedures: We compared the efficacy of VVIFNβ and VSVIFNβ to kill 3 mouse lung cancer and 4 mouse mesothelioma lines in vitro over a 5 day-period assessing cell viability by MTT assay. The amount of IFNβ produced by these two vectors were measured with ELISA. The viral replication in infected mice was assessed by measuring viral titers in both immunocompetent and immunodeficient mice bearing an IFN-non-responsive AB12 tumor, following intratumoral injection of either vector at 108 pfu/mouse. To assess their anti-tumor activity, the two vectors were also given at 108 pfu/mouse intratumorally in mice bearing two lung cancer tumors on their flanks. Results: The replication of VSVIFNβ and its killing ability was limited in some of the tumor lines. This appeared to be due to an intact IFN response pathway. In contrast, VVIFNβ was able to kill all of the tumor lines. In culture, VSV replicates faster than VV, which resulted in faster cell killing (in susceptible cell lines), but with less IFNβ production. The amount of IFNβ production by VVIFNβ was comparable with AdIFNβ over a 5 day period. VVIFNβ-infected immunodeficient mice showed minimal or no toxicity when given virus intravenously, while all 5 mice infected with VSVIFNβ developed neurotoxicity within a week. In the TC-1 lung cancer model, VVIFNβ caused tumor regression, while VSVIFNβ and AdIFNβ were completely ineffective. In a second model using LKRM2, all 3 viral vectors were equivalent. The anti-tumor effect of VVIFNβ was shown to be mainly CD8 dependant, as depletion of CD8 with antibody dampened the tumor growth inhibition from 48% to 20%. Conclusions: Overall, VVIFNβ appears to be a better oncolytic vector than VSVIFNβ for a number of reasons: 1) it is safer, 2) it is able to replicate in vitro and in vivo in almost every cell line tested, 3) it induces longer and larger IFNβ production, and 4) it can potentially be given intravenously. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1513.

Abstract Background: Taxane-induced peripheral neuropathy is a dose-limiting side effect that leads to suboptimal cancer treatment and diminished quality of life. The mode of taxane neurotoxicity is unclear, but may be through stabilization of microtubules and induction of spindle checkpoint, leading to cell cycle arrest at G2/M. Fanconi Anemia (FA) genes, including FANCD2, and FANCA, appear to be involved in G2/M phase checkpoint maintenance as well as spindle checkpoint in response to internal and external signals, such as taxane treatment. Thus, we hypothesized that variants in FA genes could impact severity of taxane-induced neuropathies.Methods: Using DNA extracted from blood collected from 893 breast cancer patients participating in a trial evaluating metronomic dosing of cyclophosphamide, doxorubicin and paclitaxel (S0221), we genotyped for single nucleotide polymorphisms (SNPs) that represent all of the variability across FANCA (44 SNPs) and FANCD2 (24 SNPs) in all race/ethnicity groups, as well as a panel of ancestry informative markers to control for potential population stratification, using Illumina GoldenGate platform. SNPs with minor allele frequency (MAF) less than 0.10 and those out of Hardy Weinberg Equilibrium (HWE) proportions (p<0.001) were removed from analyses. Ordinal regression was used to test for allelic and haplotypic association with grade 3 or 4 toxicities relative to 0, 1, and 2 toxicities, adjusting for age, genetic admixture index and treatment arm. To adjust for multiple testing, permutation analyses were performed on both single SNP and haplotype models.Results: Eighteen SNPs in FANCD2 and 38 SNPs in FANCA passed MAF and HWE proportion requirements. For FANCD2, 4 SNPs spanning 67.5 Kb (rs7648104, rs2272125 [coding SNP], rs6786638 and rs644215), were significantly associated with taxane-induced neuropathy (p<0.001) after controlling for multiple testing, with each SNP resulting in approximately a twofold increase in odds of severe taxane-induced neuropathy. Haplotype estimation showed that all 18 SNPs comprise a single haplotype. Two major (>1% frequency) haplotypes were found. The frequencies of the risk haplotype in cases (patients with grade 3 or 4 neuropathy) and controls (patients with ≤ grade 2 neuropathy) were 0.25 and 0.15, respectively. Ordinal regression analyses were highly significant (p<0.0005); patients with at least one copy of the risk haplotype had more than a twofold increased risk of grade 3 or 4 taxane-induced neuropathy (OR=2.2, 95% CI 1.44, 3.44). For FANCA, no SNPs or haplotypes were significantly associated with grade 3 or 4 neurotoxicity, either prior to or after correction for multiple testing.Conclusions: These results indicate that the Fanconi-Anemia pathway may be important for neurological sensitivity to taxanes, and that genotypic markers might be able to be used to identify patients at increased risk for severe taxane-induced neuropathy. Further studies will elucidate potential associations with survival outcomes. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2001.

Abstract Inherited BRCA1/2 mutations confer elevated ovarian cancer risk. Knowledge of factors that can improve ovarian cancer risk assessment in BRCA1/2 mutation carriers is important because no effective early detection for ovarian cancers exists. A cohort of 1,575 BRCA1 and 856 BRCA2 mutation carriers was used to evaluate haplotypes at ATM, BARD1, BRIP1, CTIP, MRE11, NBS1, RAD50, RAD51, and TOPBP1 in ovarian cancer risk. In BRCA1 carriers, no associations were observed with ATM, BARD1, CTIP, RAD50, RAD51, or TOPBP1. At BRIP1, an association was observed for one haplotype with a multiple testing corrected P (Pcorr) = 0.012, although no individual haplotype was significant. At MRE11, statistically significant associations were observed for one haplotype (Pcorr = 0.007). At NBS1, we observed a Pcorr = 0.024 for haplotypes. In BRCA2 carriers, no associations were observed with CTIP, NBS1, RAD50, or TOPBP1. Rare haplotypes at ATM (Pcorr = 0.044) and BARD1 (Pcorr = 0.012) were associated with ovarian cancer risk. At BRIP1, two common haplotypes were significantly associated with ovarian cancer risk (Pcorr = 0.011). At MRE11, we observed a significant haplotype association (Pcorr = 0.012), and at RAD51, one common haplotype was significantly associated with ovarian cancer risk (Pcorr = 0.026). Variants in genes that interact biologically withBRCA1 and/or BRCA2 may be associated with modified ovarian cancer risk in women who carry BRCA1/2 mutations. [Cancer Res 2009;69(14):5801–10]