Citations

Abstract Background: CA125 is elevated in 80% of ovarian cancer cases and has proven utility in assessing response to therapy and prognosis. Unfortunately, CA125 is elevated in a variety of benign conditions and only in 50% of early stage ovarian cancers, resulting in a sensitivity and specificity unacceptable for population-based screening. Therefore, understanding factors that influence CA125 at presentation could provide important insights for interpreting CA125 values. Methods: Using pre-treatment CA125 and detailed epidemiologic data from 12 studies participating in the Ovarian Cancer Association Consortium (OCAC), we evaluated factors previously reported to influence CA125 levels, including age, race, oral contraceptive use, parity, tubal ligation, endometriosis, body mass index (BMI), personal history of breast cancer, or a family history of breast or ovarian cancer. We used linear regression to estimate the association between each variable and CA125 probit scores, which we used to standardize values between studies. Secondary analyses included adjustment for histologic subtype. We also estimated the associations within each study using log-transformed CA125 as the outcome and estimated summary measures using random effects meta-analyses. Results: Of the 4417 cases included in the analysis, 2918 (66%) were serous, 227 (5%) were mucinous, 484 (11%) were endometrioid, and 258 (6%) were clear cell carcinomas. Median CA125 values varied between studies with a high of 831 U/mL and a low of 271 U/mL. We observed no association between race, oral contraceptive use, tubal ligation, endometriosis, prior breast cancer, and family history of breast cancer and pre-treatment CA125. However, we observed increased pre-treatment CA125 levels with older age (>70 vs. < 50, p=0.03), parity (p=0.01), number of children (p=0.02), obesity (BMI>30 vs. 21-25, p=0.03), and family history of ovarian cancer (p=0.05). Results were similar but attenuated when we calculated summary estimates of the association using meta-analysis of study specific estimates of the association with log-transformed CA125 rather than probit scores. Age and BMI remained predictive of pre-treatment CA125 values after adjustment for histologic subtype. Our data are limited by between site variability in CA125 assays; therefore, validation of these findings is needed with adjustment for type of assay used or in a study population in which all cases had pre-treatment CA125 values measured with the same assay. Conclusions: Despite these limitations, results from this analysis of over 4000 ovarian cancer cases suggest that age and body size may influence pre-treatment CA125 values. Citation Format: KL Terry, A Babic, BY Karlan, MT Goodman, D Lambrechts, F Heitz, K Matsuo, I McNeish, T Pejovic, S Kruger Kjaer, PM Webb, E Hogdall, EL Goode, DW Cramer, for the Ovarian Cancer Association Consortium. Epidemiologic predictors of pre-treatment CA125 in women with ovarian cancer [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr AS13.

Purpose Given that the clinical course of oxaliplatin-induced neuropathy is not well defined, the current study was performed to better understand clinical parameters associated with its presentation. Methods Acute and chronic neuropathy was evaluated in patients receiving adjuvant FOLFOX (fluorouracil, leucovorin, and oxaliplatin) on study N08CB (North Central Cancer Treatment Group, Alliance). Acute neuropathy was assessed by having patients complete daily questionnaires for 6 days with each cycle of FOLFOX. Before each dose of FOLFOX and as long as 18 months after chemotherapy cessation, chronic neurotoxicity was assessed with use of the 20-item, European Organisation for Research and Treatment of Cancer quality-of-life questionnaire for patients with chemotherapy-induced peripheral neuropathy. Results Three hundred eight (89%) of the 346 patients had at least one symptom of acute neuropathy with the first cycle of FOLFOX; these symptoms included sensitivity to touching cold items (71%), sensitivity to swallowing cold items (71%), throat discomfort (63%), or muscle cramps (42%). Acute symptoms peaked at day 3 and improved, although they did not always resolve completely between treatments. These symptoms were about twice as severe in cycles 2 through 12 as they were in cycle 1. For chronic neurotoxicity, tingling was the most severe symptom, followed by numbness and then pain. During chemotherapy, symptoms in the hands were more prominent than they were in the feet; by 18 months, symptoms were more severe in the feet than they were in the hands. Patients with more severe acute neuropathy during the first cycle of therapy experienced more chronic sensory neurotoxicity (P < .0001). Conclusion Acute oxaliplatin-induced neuropathy symptoms do not always completely resolve between treatment cycles and are only half as severe on the first cycle as compared with subsequent cycles. There is a correlation between the severities of acute and chronic neuropathies.

Abstract Background: Genome-wide association studies (GWAS) have so far reported 12 loci associated with serous epithelial ovarian cancer (EOC) risk. We hypothesized that some of these loci function through nearby transcription factor (TF) genes and that putative target genes of these TFs as identified by coexpression may also be enriched for additional EOC risk associations. Methods: We selected TF genes within 1 Mb of the top signal at the 12 genome-wide significant risk loci. Mutual information, a form of correlation, was used to build networks of genes strongly coexpressed with each selected TF gene in the unified microarray dataset of 489 serous EOC tumors from The Cancer Genome Atlas. Genes represented in this dataset were subsequently ranked using a gene-level test based on results for germline SNPs from a serous EOC GWAS meta-analysis (2,196 cases/4,396 controls). Results: Gene set enrichment analysis identified six networks centered on TF genes (HOXB2, HOXB5, HOXB6, HOXB7 at 17q21.32 and HOXD1, HOXD3 at 2q31) that were significantly enriched for genes from the risk-associated end of the ranked list (P &lt; 0.05 and FDR &lt; 0.05). These results were replicated (P &lt; 0.05) using an independent association study (7,035 cases/21,693 controls). Genes underlying enrichment in the six networks were pooled into a combined network. Conclusion: We identified a HOX-centric network associated with serous EOC risk containing several genes with known or emerging roles in serous EOC development. Impact: Network analysis integrating large, context-specific datasets has the potential to offer mechanistic insights into cancer susceptibility and prioritize genes for experimental characterization. Cancer Epidemiol Biomarkers Prev; 24(10); 1574–84. ©2015 AACR.

Abstract Purpose: Chemotherapy resistance remains a major challenge in the treatment of ovarian cancer. We hypothesize that germline polymorphisms might be associated with clinical outcome. Experimental Design: We analyzed approximately 2.8 million genotyped and imputed SNPs from the iCOGS experiment for progression-free survival (PFS) and overall survival (OS) in 2,901 European epithelial ovarian cancer (EOC) patients who underwent first-line treatment of cytoreductive surgery and chemotherapy regardless of regimen, and in a subset of 1,098 patients treated with ≥4 cycles of paclitaxel and carboplatin at standard doses. We evaluated the top SNPs in 4,434 EOC patients, including patients from The Cancer Genome Atlas. In addition, we conducted pathway analysis of all intragenic SNPs and tested their association with PFS and OS using gene set enrichment analysis. Results: Five SNPs were significantly associated (P ≤ 1.0 × 10−5) with poorer outcomes in at least one of the four analyses, three of which, rs4910232 (11p15.3), rs2549714 (16q23), and rs6674079 (1q22), were located in long noncoding RNAs (lncRNAs) RP11-179A10.1, RP11-314O13.1, and RP11-284F21.8, respectively (P ≤ 7.1 × 10−6). ENCODE ChIP-seq data at 1q22 for normal ovary show evidence of histone modification around RP11-284F21.8, and rs6674079 is perfectly correlated with another SNP within the super-enhancer MEF2D, expression levels of which were reportedly associated with prognosis in another solid tumor. YAP1- and WWTR1 (TAZ)-stimulated gene expression and high-density lipoprotein (HDL)-mediated lipid transport pathways were associated with PFS and OS, respectively, in the cohort who had standard chemotherapy (pGSEA ≤6 × 10−3). Conclusions: We have identified SNPs in three lncRNAs that might be important targets for novel EOC therapies. Clin Cancer Res; 21(23); 5264–76. ©2015 AACR.

AbstractIntroductionAfrican‐American (AA) individuals have a higher risk for late‐onset Alzheimer's disease (LOAD) than Americans of primarily European ancestry (EA). Recently, the largest genome‐wide association study in AAs to date confirmed that six of the Alzheimer's disease (AD)‐related genetic variants originally discovered in EA cohorts are also risk variants in AA; however, the risk attributable to many of the loci (e.g., APOE, ABCA7) differed substantially from previous studies in EA. There likely are risk variants of higher frequency in AAs that have not been discovered.MethodsWe performed a comprehensive analysis of genetically determined local and global ancestry in AAs with regard to LOAD status.ResultsCompared to controls, LOAD cases showed higher levels of African ancestry, both globally and at several LOAD relevant loci, which explained risk for AD beyond global differences.DiscussionExploratory post hoc analyses highlight regions with greatest differences in ancestry as potential candidate regions for future genetic analyses.

Abstract A genome-wide association study (GWAS) of prostate cancer in Kaiser Permanente health plan members (7,783 cases, 38,595 controls; 80.3% non-Hispanic white, 4.9% African-American, 7.0% East Asian, and 7.8% Latino) revealed a new independent risk indel rs4646284 at the previously identified locus 6q25.3 that replicated in PEGASUS (N = 7,539) and the Multiethnic Cohort (N = 4,679) with an overall P = 1.0 × 10−19 (OR, 1.18). Across the 6q25.3 locus, rs4646284 exhibited the strongest association with expression of SLC22A1 (P = 1.3 × 10−23) and SLC22A3 (P = 3.2 × 10−52). At the known 19q13.33 locus, rs2659124 (P = 1.3 × 10−13; OR, 1.18) nominally replicated in PEGASUS. A risk score of 105 known risk SNPs was strongly associated with prostate cancer (P &lt; 1.0 × 10−8). Comparing the highest to lowest risk score deciles, the OR was 6.22 for non-Hispanic whites, 5.82 for Latinos, 3.77 for African-Americans, and 3.38 for East Asians. In non-Hispanic whites, the 105 risk SNPs explained approximately 7.6% of disease heritability. The entire GWAS array explained approximately 33.4% of heritability, with a 4.3-fold enrichment within DNaseI hypersensitivity sites (P = 0.004). Significance: Taken together, our findings of independent risk variants, ethnic variation in existing SNP replication, and remaining unexplained heritability have important implications for further clarifying the genetic risk of prostate cancer. Our findings also suggest that there may be much promise in evaluating understudied variation, such as indels and ethnically diverse populations. Cancer Discov; 5(8); 878–91. ©2015 AACR. This article is highlighted in the In This Issue feature, p. 783

Abstract Background. The increase in breast cancer risk during pregnancy and postpartum is well known; however, the molecular phenotype of breast cancers occurring shortly after pregnancy has not been well studied. Given this, we investigated whether nulliparity and the time interval since pregnancy among parous women affects the breast cancer phenotype in young women. Materials and Methods. We examined molecular phenotype in relation to time since pregnancy in a prospective cohort of 707 young women (aged ≤40 years) with breast cancer. Parity was ascertained from study questionnaires. Using tumor histologic grade on central review and biomarker expression, cancers were categorized as luminal A- or B-like, HER2 enriched, and triple negative. Results. Overall, 32% were luminal A-like, 41% were luminal B-like, 9% were HER2 enriched, and 18% were triple negative. Although, numerically, patients diagnosed &gt;5 years after pregnancy had more luminal A-like subtypes than women with shorter intervals since pregnancy, there was no evidence of a relationship between these intervals and molecular subtypes once family history of breast cancer and age at diagnosis were considered. Conclusion. Distribution of breast cancer molecular phenotype did not differ significantly among young women by parity or time interval since parturition when important predictors of tumor phenotype such as age and family history were considered. Implications for Practice: Distribution of breast cancer molecular phenotype did not differ among parous young women by time interval since pregnancy. The implication of these findings for clinical practice suggests that pregnancy-associated breast cancers may be seen up to 5 years beyond parturition.

Objective: To review the literature evaluating gabapentin for alcohol withdrawal and dependence. Data Sources: A literature search of MEDLINE (1966 to end of March 2015) and PubMed was performed using the terms alcohol, gabapentin, withdrawal, and dependence. Additional references were identified from a review of literature citations. Study Selection and Data Extraction: English-language prospective studies evaluating gabapentin for alcohol withdrawal and dependence were evaluated. Data Synthesis: A total of 10 publications utilizing gabapentin in alcohol withdrawal (n = 5) and alcohol dependence (n = 5) were included in this review. Limited data suggest that gabapentin can provide benefit in managing mild alcohol withdrawal syndrome. There were 5 reported or suspected seizures in the withdrawal studies, suggesting that additional safety data are necessary before gabapentin monotherapy can be routinely considered. Sleep and mood/anxiety-related outcomes were positively influenced by gabapentin, which may result in long-term benefits if continued beyond the withdrawal period for the treatment of alcohol dependence. Studies evaluating gabapentin for alcohol dependence demonstrated dose-dependent benefits for complete abstinence, rates of no heavy drinking, and cravings. Gabapentin used to treat alcohol dependence was well tolerated with no severe adverse reactions reported in the extant literature. Conclusion: Gabapentin may have a role in the treatment of mild alcohol withdrawal, but future studies should focus on adequate dosing strategies. Gabapentin should be considered for the treatment of alcohol dependence when barriers prevent the use of traditional agents. Additional studies should be conducted to further validate findings from the research conducted to date, but the current literature is promising for gabapentin in the treatment of alcohol dependence.

Abstract Intro: Male BC is a rare disease (&lt;1% male tumors); knowledge is limited and management extrapolated from female BC. An international consortium, coordinated by EORTC and TBCRC, was created to better characterize and manage this disease, with 3 parts: 1) retrospective joint analysis 2) prospective registry 3) clinical trial(s). We report 1st results of part 1. Methods: Joint analysis of male BC pts with available FU & FFPE samples, treated in 1990-2010, in 23 centers from 9 countries. Clinical data, long term outcomes, local pathology were centrally analyzed at EORTC. FFPE samples were analyzed at 3 central labs (UK, NL, US) for histology, grade, ER, PR, AR, HER-2, Ki67. Cut-off for positivity: Allred score ≥ 3 for ER/ AR/PR; 20% for Ki67; ASCO-CAP for HER2. Outcome data (OS & RFS) analyzed per Kaplan Meier, p-values correspond to logrank test, CI’s by Brookmeyer & Crowley. Reported % use number of non-missing values as denominator. Results: 1822 pts enrolled; 349 (19%) ineligible (no valid central lab assessment); of 1473 eligible pts (1384 from EU, 89 from US) 63% diagnosed in 2001-2010. Median age at diagnosis (Dx) was 68.5 ys. Of pts with known M status at Dx, 56 (5.1%) were M1; of 1046 M0 cases, 60% were N0 and 51% had T1 tumors at Dx; 4% of pts had BCS and 18% had SLNB; half received adjuvant RT. (Neo)adjuvant CT was used in 30% of M0 pts, most (44%) anthracycline-only; 77% of M0 pts received adjuvant ET, most tamoxifen (88.4%). Central pathology: 697 cases with central histology & grade (full series ongoing): 87% ductal, 53% grade 2. In 1473 pts, at least 1 biomarker centrally assessed; 92% ER highly+ (Allred 7-8), PR had wider variation (35% highly+); 87% AR highly+; 25% Ki67 high; 5% HER2pos. Using IHC surrogates: 58% Luminal A-like, 35% LuminalB-like/HER2neg, 6% LuminalB-like/HER2pos; 0.1% HER2pos/non-Luminal; 1% TNBC (16% not classified). Outcome: For 1046 M0 pts, median FU was 5.7 yrs (0-19.2); 63% alive at analysis; in 88% cause of death was reported, mainly 33% non-cancer and 28% progression(PD)/toxicity. Significant OS improvement over time is seen. 75% (42/56) M1 pts died, mainly due PD. In M0 pts, median OS (yrs) was significantly correlated with ER+ p=0.001 [Allred 0-2: 3.9 (0.1, 6.0); 3-6: 7.1 (4.7, 11.7); 7-8: 8.8 (8.3, 10.0)] & with PR+ p=0.022 [Allred 0-2: 7.3 (6.1, 10.3), 3-6: 8.0 (7.0, 9.3), 7-8: 9.5 (8.4, 12.8)]; less correlation for AR; no major differences for HER2 or Ki67. Median OS & grade (394 cases; full series ongoing): Grade1: 12.8 yrs (6.1-15.6); Grade2: 7.9 (6.5-10.7); Grade3: 9.3 (4.9-21.1). Median OS for IHC surrogates: 8.7 (7.8-9.7) for Luminal A; 8.3 (6.9-9.4) for Luminal B/HER-2neg; 9.3 years (5.9-21.1) for Luminal B/HER-2+. Similar results were seen for RFS. ER/PR/AR using histoscores will be presented. Conclusions: a) 56% pts had T1 tumors at Dx but only 4% had BCS; b) ER was highly + in &gt;90% but adjuvant ET given in only 77% pts; c) Male BC is usually ER+, PR+ & AR+ and of Luminal A-like subtype (5% HER2pos & 1% TNBC); d) Significant improvement in OS over time; e) ER and PR (Allred) are prognostic (high expression/better prognosis), less for AR, not for Ki67 nor IHC surrogates; f) In-depth characterization of samples is ongoing. Funding: BCRF, EBCC Council, Pink Ribbon NL, BRO. Citation Format: Fatima Cardoso, John Bartlett, Leen Slaets, Carolien van Deurzen, Elise van Leewen-Stok, Peggy Porter, Barbro Linderholm, Ingrid Hedenfalk, Carolien Schroder, John Martens, Jane Bayani, Christi van Asperen, Melissa Murray, Clifford Hudis, Lavinia Middleton, Joanna Vermeij, Stephanie Peeters, Judith Fraser, Monica Nowaczyk, Isabel Rubio, Stefan Aebi, Catherine Kelly, Kathryn Ruddy, Eric Winer, Cecilia Nilsson, Lissandra Dal Lago, Larissa Korde, Kim Benstead, Danielle Van Den Weyngaert, Oliver Bogler, Theodora Goulioti, Nicolas Dif, Carlo Messina, Konstantinos Tryfonidis, Jan Bogaerts, Sharon Giordano. Characterization of male breast cancer: First results of the EORTC10085/TBCRC/BIG/NABCG International Male BC Program [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr S6-05.

Abstract Background: There is an increasing recognition that many young women with breast cancer will have favorable outcomes without chemotherapy. We sought to characterize decision-making surrounding adjuvant chemotherapy treatment (CT) in this population for whom chemotherapy has historically been a standard of care. Methods: As part of an ongoing, multi-center, prospective cohort of young women diagnosed with breast cancer at age 40 and younger, we identified 657 women with Stage I-III breast cancer. Participants were asked to complete surveys by mail that included questions about socio-demographics, decision-making, and treatment history within the first year following diagnosis. Tumor characteristics were ascertained via pathology and medical record review. We used Chi-square tests to compare: decisional involvement (patient-driven vs. shared vs. physician-driven), degree of confidence, and feeling informed about the CT decision (the latter two measured on a 0-10 scale, categorized as follows: 0-5=low; moderate=6-8; 9-10=high) between women who did and did not receive CT. To explore clinical appropriateness of the CT decision, we used logistic regression to assess the relationship between tumor characteristics and non-receipt of CT among women with Stage I/II disease. Results: Among women with Stage I (n=250), II (n=312), and III (n=95), disease, 66%, 95%, and 100%, received CT, respectively. A greater proportion of women who had CT were highly confident with their decision compared with women who did not have CT (80% vs. 60%, p&lt;0.0001); women who did not have CT were more likely to report a low level of feeling informed about the CT decision compared to women who received CT (20% vs. 5%, p&lt;0.0001). Women who did not have CT were also more likely to report the final CT decision as made by their doctor (49% vs. 28%) and less likely to report a shared decision (33% vs. 59%, p&lt;0.0001). Non-receipt of CT in women with Stage I/II disease (n=546) was associated within having node negative disease, T1 (vs. T2 or larger), Her2- negative, and hormone receptor positive tumors. Conclusion: Although non-receipt of CT would be expected to be viewed favorably by patients and doctors, we found that women who received CT felt more confident and better informed than those who received no CT. Given that women who did not have CT were also less likely to perceive the CT decision as shared, improved communication together with better decisional support may be beneficial, especially for women who do not receive adjuvant chemotherapy. Citation Format: Shoshana M Rosenberg, Karen Sepucha, Kathryn J Ruddy, Lidia Schapira, Steven Come, Virginia Borges, Evan Morgan, Nancy U Lin, Shari Gelber, Rulla M Tamimi, Ann H Partridge. Decision-making surrounding adjuvant chemotherapy in young women with early stage breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P2-10-03.