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BACKGROUND: Pancreatic cancer presents as advanced disease in >80% of patients; yet, appropriate ages to consider prevention and early detection strategies are poorly defined. We investigated age-specific associations and attributable risks of pancreatic cancer for established modifiable and non-modifiable risk factors. PATIENTS AND METHODS: We included 167 483 participants from two prospective US cohort studies with 1190 incident cases of pancreatic cancer during >30 years of follow-up; 5107 pancreatic cancer cases and 8845 control participants of European ancestry from a completed multicenter genome-wide association study (GWAS); and 248 893 pancreatic cancer cases documented in the US Surveillance, Epidemiology, and End Results (SEER) Program. Across different age categories, we investigated cigarette smoking, obesity, diabetes, height, and non-O blood group in the prospective cohorts; weighted polygenic risk score of 22 previously identified single nucleotide polymorphisms in the GWAS; and male sex and black race in the SEER Program. RESULTS: In the prospective cohorts, all five risk factors were more strongly associated with pancreatic cancer risk among younger participants, with associations attenuated among those aged >70 years. The hazard ratios comparing participants with three to five risk factors with those with no risk factors were 9.24 [95% confidence interval (CI) 4.11–20.77] among those aged ≤60 years, 3.00 (95% CI 1.85–4.86) among those aged 61–70 years, and 1.46 (95% CI 1.10–1.94) among those aged >70 years (P(heterogeneity) = 3×10(−5)). These factors together were related to 65.6%, 49.7%, and 17.2% of incident pancreatic cancers in these age groups, respectively. In the GWAS and the SEER Program, the associations with the polygenic risk score, male sex, and black race were all stronger among younger individuals (P(heterogeneity) ≤0.01). CONCLUSIONS: Established risk factors are more strongly associated with earlier-onset pancreatic cancer, emphasizing the importance of age at initiation for cancer prevention and control programs targeting this highly lethal malignancy.

Background: Clinical/epidemiologic observational studies frequently rely on participants' recall for information about breast procedures. However, there is limited data on the accuracy of self-reported breast procedures. To address this knowledge gap and inform future study design and collection and interpretation of similar data, we investigated the impact of type, diagnosis, age, time, and other patient characteristics on the accuracy of self-report in a prospective cohort. Methods: All benign breast biopsies, lumpectomies, and mastectomies for breast cancer treatment among women enrolled in the BOSS Cohort, a prospective study of women and men with a familial risk of breast/ovarian cancer, were identified. Study staff obtained pathology reports for 93% of women from self-reported breast procedure locations. For this analysis, we focused on 577 women who had at least one ascertained pathology report, and who self-reported at least one breast procedure at baseline. We estimated the percentage of self-reports (95% confidence interval (CI)) with matching pathology report within 6 months (+/- 6 months), and agreement between self-reported procedures and pathology-confirmed diagnoses (normal/benign vs. atypical hyperplasia vs. LCIS, and DCIS vs. invasive cancer) with the Kappa statistic. We also examined predictors of an accurate biopsy self-report, including age at baseline, personal and family history of breast cancer, educational attainment, and time between biopsy and baseline, using logistic regression models. Results: At baseline, 158 women reported having at least one benign biopsy, 193 women reported having a lumpectomy for cancer treatment, and 174 women reported having a mastectomy for cancer treatment. The median time between biopsy, lumpectomy, mastectomy, and baseline was 9 years, 2 years, and 2 years, respectively. Fifty-seven percent (95% CI: 49-64.5%) of benign biopsy self-reports, 90.7% (95% CI: 85.6-94.1%) of lumpectomy self-reports, and 85.1% (95% CI: 78.9-89.7%) of mastectomy self-reports had a matching pathology report within 6 months. Further diagnostic agreement was moderate for biopsies, lumpectomies, and mastectomies with Kappa statistics of 0.65, 0.66, 0.65, respectively. Age at baseline (p-interaction =0.01) and time (p-interaction = 0.03) were independent and joint predictors of accurate biopsy self-reports. Women less than 49 years old had the largest reduction in odds of having an accurate self-report (26%) for every additional year between biopsy and baseline [adjusted odds ratio = 0.74 (95% CI: 0.63-0.88)]. Similarly, women with a biopsy within 4 years prior to baseline had a 10% reduction in the odds of having an accurate self-report with increasing age [adjusted odds ratio = 0.9 (95% CI: 0.84-0.97)]. Conclusions: In this highly-educated cohort, the overall accuracy of self-report of benign biopsies was only modest, and the accuracy of self-report of lumpectomies and mastectomies was lower than expected. This study suggests that age at baseline and time between procedure and baseline are important predictors of accuracy of self-report and should be considered when utilizing self-reported information. Furthermore, where possible, prospective collection of breast procedure data should be prioritized. Citation Format: Schaeffer ML, May B, Cimino-Mathews A, Orellana M, McCullough M, Hogan B, Armstrong D, Visvanathan K. Factors impacting the accuracy of self-reported breast procedures among women with and without breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-10-06.

This abstract was withdrawn by the authors. Citation Format: Schoemaker MJ, Nichols HB, Wright LB, Brook MN, Jones ME, O'Brien KM, Adami H-O, Baglietto L, Bernstein L, Bertrand KA, Boutron-Ruault M-C, Chen Y, Connor AE, Dorronsoro M, Dossus L, Eliassen AH, Giles GG, Gram IT, Hankinson SE, Kaaks R, Key TJ, Kirsh VA, Kitahara CM, Koh W-P, Larsson SC, Linet MS, Ma H, Masala G, Merritt MA, Milne RL, Overvad K, Ozasa K, Palmer JR, Riboli E, Rohan TE, Sadakane A, Sund M, Tamimi RM, Trichopoulou A, Ursin G, Van Gils CH, Visvanathan K, Weiderpass E, Willett WC, Wolk A, Yuan J-M, Zeleniuch-Jacquotte A, Sandler DP, Swerdlow AJ. Withdrawn [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-08-01.

The work was partially supported by Fondo de Investigaciones Sanitarias (FIS), Instituto de Salud Carlos III, Spain (PI061614, PI11/01542, PI0902102, PI12/01635, PI12/00815, PI15/01573, PI18/01347); Red Temática de Investigación Cooperativa en Cáncer, Spain (RD12/0036/0034, RD12/0036/ 0050, RD12/0036/0073); Spanish Ministerio de Ciencia, Innovación y Universidades (BFU2017-85926-P), López de Maturana, E., Rodríguez, J.A., Alonso, L., Lao, O., Molina-Montes, E., Martín-Antoniano, I.A., Gómez-Rubio, P., Lawlor, R., Carrato, A., Hidalgo, M., Iglesias, M., Molero, X., Löhr, M., Michalski, C., Perea, J., O’Rorke, M., Barberà, V.M., Tardón, A., Farré, A., Muñoz-Bellvís, L., Crnogorac-Jurcevic, T., Domínguez-Muñoz, E., Gress, T., Greenhalf, W., Sharp, L., Arnes, L., Cecchini, L., Balsells, J., Costello, E., Ilzarbe, L., Kleeff, J., Kong, B., Márquez, M., Mora, J., O’Driscoll, D., Scarpa, A., Ye, W., Yu, J., García-Closas, M., Kogevinas, M., Rothman, N., Silverman, D.T., Albanes, D., Arslan, A.A., Beane-Freeman, L., Bracci, P.M., Brennan, P., Bueno-de-Mesquita, B., Buring, J., Canzian, F., Du, M., Gallinger, S., Gaziano, J.M., Goodman, P.J., Gunter, M., LeMarchand, L., Li, D., Neale, R.E., Peters, U., Petersen, G.M., Risch, H.A., Sánchez, M.J., Shu, X.-O., Thornquist, M.D., Visvanathan, K., Zheng, W., Chanock, S.J., Easton, D., Wolpin, B.M., Stolzenberg-Solomon, R.Z., Klein, A.P., Amundadottir, L.T., Marti-Renom, M.A., Real, F.X., Malats, N., PanGenEU Investigators, SBC/EPICURO Investigators

Repeated exposure to the acute proinflammatory environment that follows ovulation at the ovarian surface and distal fallopian tube over a woman's reproductive years may increase ovarian cancer risk. To address this, analyses included individual-level data from 558,709 naturally menopausal women across 20 prospective cohorts, among whom 3,246 developed invasive epithelial ovarian cancer (2,045 serous, 319 endometrioid, 184 mucinous, 121 clear cell, 577 other/unknown). Cox models were used to estimate multivariable-adjusted HRs between lifetime ovulatory cycles (LOC) and its components and ovarian cancer risk overall and by histotype. Women in the 90th percentile of LOC (>514 cycles) were almost twice as likely to be diagnosed with ovarian cancer than women in the 10th percentile ( Significance: Although ovarian cancer is rare, risk of most ovarian cancers doubles as the number of lifetime ovulatory cycles increases from approximately 300 to 500. Thus, identifying an important area for cancer prevention research.

Background: Our group previously reported that young breast cancer (BC) survivors have a higher risk of osteopenia/osteoporosis compared to their cancer-free peers. In order to develop successful interventions we need to understand the major contributing factors. Therefore, we investigated bone loss in young BC survivors by age at diagnosis, tumor characteristics and BC treatment compared to their cancer-free peers. Methods: We studied 775 women (211 BC survivors, 564 cancer-free) with familial risk of breast and/or ovarian cancer in the Breast and Ovarian Surveillance Service (BOSS) cohort at Johns Hopkins. Survivors were diagnosed with stage 0-III BC Results: Mean time from BC diagnosis to enrollment was 1.4 years for survivors and mean age at BC diagnosis was 47 years. At baseline, BC survivors were more likely to be slightly older, postmenopausal, and current vitamin D users and less likely to have had an early bilateral oophorectomy compared to cancer-free women. During a mean follow-up time of 5.7 years, 66% of BC survivors and 54% of cancer-free women reported having ≥1 bone density exam and 112 incident cases of osteopenia/osteoporosis were identified (75% osteopenia only). BC survivors diagnosed at age ≤50 years had a 2-fold increased risk of osteopenia/osteoporosis compared to cancer-free women (HR=2.05, 95% CI=1.24-3.40). Risk of bone loss was similar among survivors with ER-positive tumors compared to cancer-free women (HR=2.04, 95% CI=1.30-3.22). No association was observed for BC survivors treated with tamoxifen only or chemotherapy only. BC survivors treated with aromatase inhibitors (AIs) only had almost 3-fold increased risk of osteopenia/osteoporosis compared to cancer-free women (HR=2.92, 95% CI=1.38-6.17). BC survivors treated with chemotherapy + tamoxifen and chemotherapy + AIs had over 2- and 4-fold increased risk of osteopenia/osteoporosis compared to cancer-free women (HR=2.28, 95% CI=1.04-5.00; HR=4.09, 95% CI=1.99-8.42, respectively). Results suggest that risk of bone loss was highest within 5 years after BC diagnosis. Conclusion: Our results demonstrate that osteopenia/osteoporosis incidence is higher in BC survivors compared to cancer-free women and risk varies by age at diagnosis, ER-status and BC treatment. Our findings provide support for a baseline evaluation of bone density close to diagnosis in BC survivors with familial risk. Future studies are needed to address the frequency of monitoring among specific age and treatment groups. Citation Format: Ramin CA, May BJ, Roden RBS, McCullough M, Armstrong DK, Visvanathan K. Understanding the etiology of osteopenia and osteoporosis in young breast cancer survivors compared to cancer-free women [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P6-08-12.

There are many accepted surgical approaches for the evacuation of chronic subdural hematoma. Although the burrhole drainage is the most commonly used approach, few articles using mini-craniotomy as a treatment modality have shown similar outcomes. We describe the outcomes in our series of patients who underwent mini craniotomy and evacuation of chronic subdural hematoma as the primary surgical procedure in a tertiary care centre in Tamil Nadu, India. We found a lower recurrence rate of 4.3%, no mortality and similar duration of hospital stay. Our data suggest that minicraniotomy can be done quickly with good clinical outcomes, lesser rates of recurrence and complications. However, well designed multi-centre randomized clinical trials comparing the various techniques for chronic subdural hematoma is required in order to provide evidence for recommending clinical best practice guidelines.

Auto-antibodies to tumor suppressor p53 are found in a subset of colorectal cancer (CRC) patients. A prospective cohort study in the US (Cancer Prevention Study II) has recently reported a statistically significant 1.8-fold increased odds for the development of CRC based on pre-diagnostic sero-positivity for p53; the magnitude of this association decreased with longer time-span between blood sampling and diagnosis. In the present study, we sought to examine this association in a large US CRC cohort consortium to evaluate the potential utility of p53 auto-antibodies as an early CRC detection biomarker. Methods: Antibody responses to p53 were measured in pre-diagnostic blood samples of 3,702 incident CRC cases (median [range] follow-up: 7.3 years [0–40 years]) and an equal number of controls, matched by age, race, and sex, from 9 US prospective cohorts. The association of sero-positivity to p53 with CRC risk, overall and by time between blood draw and diagnosis, was determined by conditional logistic regression. Results: Overall, 5% of controls and 7% of cases were sero-positive to p53, resulting in a statistically significant 33% increased CRC risk (OR: 1.33; 95% CI: 1.09, 1.61). The association was strongest for CRC diagnoses within 2 years after blood draw (OR: 2.73; 95% CI: 1.67, 4.45), with 15% sero-positive cases compared to 6% sero-positive controls. The number of sero-positive cases decreased with longer follow-up time (2–

Introduction: Lifestyle factors and metabolic derangements have wide-ranging effects including on immune activity. The association of circulating immune cells and outcomes in patients with early stage breast cancer remain incompletely understood. Objective: To evaluate the effects of smoking, body mass index (BMI), and alcohol intake on the association between circulating immune cell levels and patient outcomes. Methods: We retrospectively screened the electronic medical record of 950 patients with early stage breast cancer at the Johns Hopkins Hospital between 2003-2008 with at least 5 years of follow-up data for information on complete blood cell (CBC) counts. Absolute lymphocyte, monocyte, and neutrophil counts were obtained from the CBC differential performed closest to time of diagnosis within a period of ±1 year, and prior to any systemic treatment. Statistical analyses used were t-test for comparison of recurrence vs non-recurrence and Cox proportional hazard models for survival analysis, and linear regression for association between counts and BMI. Covariates adjusted for include grade, stage, smoking status, and alcohol use. Results: A total of 433 patients with stage 0-III breast cancer had complete data and were included in the analytical population. The populations of analyzed and non-analyzed patients were not significantly different in age or ethnic composition. The median age was 53 years old (range 26-86); 24% (n=103) were African American, and 76% (n=330) were Caucasian. Median BMI at baseline was 27 (range 18-53). Breast cancer subtypes were 68% (n=293) hormone receptor-positive, 19% (n=82) HER2 positive, and 13% (n=53) triple negative. 7.6% (n=33) experienced a recurrence and 6.9% (n=30) died of all causes. Patients with the highest quartile of lymphocytes at diagnosis, compared to the lowest quartile, had a significantly lower risk of recurrence (HR=0.23, 95% CI [0.06, 0.87], p=0.031). Patients with the highest quartile of monocytes were also at a lower risk for recurrence (HR= 0.17, 95% CI [0.11, 0.72] p=0.02). This effect was magnified in subgroup analysis among patients with hormone negative (n=125, p=0.017) and grade 3 (n=155, p=0.02) breast cancer. Patients in the highest quartile of both lymphocytes and monocytes had similarly lower recurrence rates (HR=0.24, 95% CI [0.08, 0.88] p=0.034). In subgroup analysis with regard to lifestyle factors, association of higher monocytes with lower recurrence was most significant among those consuming alcohol (n=237, p=0.005). Subgroup analysis of alcohol use was unremarkable for lymphocytes, as was subgroup analysis of smoking history (n=144) for lymphocytes and monocytes. In patients with BMI>30, lower lymphocytes were more strongly associated with recurrence (n=144, p=0.04); conversely, in patients with BMI Conclusion: Higher recurrence rates are observed in patients with early stage breast cancer who have low-normal lymphocyte and monocyte counts at time of diagnosis. This association is stronger in subgroups of patient with high BMI and who consume alcohol, known risk factors for breast cancer. Citation Format: Eric G Xie, Maya M Lapinski, Sarah Talamantes, Kala Visvanathan, Antonio Wolff, Cesar Santa-Maria. Association of circulating immune cells with lifestyle factors, and recurrence and mortality in patients with early stage breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-04-16.

BACKGROUND: Epidemiologic studies have consistently observed reduced ovarian cancer risks with higher parity and oral contraceptive use. Increased risks with younger age at menarche and older age at menopause have also been reported. Furthermore, it has been demonstrated that an acute pro-inflammatory environment is created following ovulation at the surface of the ovary and within the distal fallopian tube, whereby both are bathed in follicular fluid containing inflammatory cytokines, reactive oxygen species, and steroids, creating a DNA damage-rich environment and thereby supporting the possible role of incessant ovulation in ovarian carcinogenesis. Consistent with this, greater lifetime ovulatory cycles (LOC) have been associated with increased ovarian cancer risk in numerous studies, however the etiologic heterogeneity of this association has not been resolved. It is difficult to measure LOCs directly, but estimates of the cumulative sum of a woman's ovulatory cycles can be obtained through mathematical algorithms that calculate the time between menopause and menarche (menstrual span) and subtract anovulatory cycles, i.e., durations of oral contraceptive use and pregnancy. AIM: To investigate the association of LOC and its components with ovarian cancer (overall and by histotype) using prospective individual-level data from the Ovarian Cancer Cohort Consortium (OC3). METHODS: We analyzed data from 23 prospective cohort studies including 3,866 ovarian cancer cases diagnosed among 618,175 naturally menopausal women. Cases included 2288 serous, 352 endometrioid, 210 mucinous, and 137 clear cell tumors, and 879 other epithelial/unknown tumors. We evaluated associations between LOC, individual components of LOC (menstrual span, pregnancy, oral contraceptive use), and ovarian cancer using Cox regression stratified by study and adjusted for potential confounders; histotype analyses were conducted using competing-risks Cox regression. RESULTS: In models evaluating the overall LOC effect (without adjustment for component factors), women in the 90th percentile of LOC (>511) were almost twice as likely to be diagnosed with ovarian cancer during follow-up than women in the 10th percentile ( CONCLUSIONS: In this large prospective analysis of pooled cohort study data we observed positive associations between increased LOC and risk of serous, endometrioid, and clear cell tumors, independent of the associations with individual LOC components. Our data provide support for the hypothesis that incessant ovulation contributes to the etiology of these ovarian cancer histotypes, and further supports the etiologic heterogeneity of ovarian cancers. Citation Format: Britton Trabert, Mary K. Townsend, Renée T. Fortner, Kala Visvanathan, Shelley S. Tworoger, Nicolas Wentzensen, on behalf of the Ovarian Cancer Cohort Consortium (OC3). LIFETIME NUMBER OF OVULATORY CYCLES ARE DIFFERENTIALLY ASSOCIATED WITH OVARIAN CANCER HISTOTYPES: AN ANALYSIS FROM THE OVARIAN CANCER COHORT CONSORTIUM (OC3) [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr DP-014.

Background- The ability to consistently detect cell-free tumor-specific DNA in peripheral blood of patients with metastatic breast cancer provides the opportunity to detect changes in tumor burden and to monitor response to treatment. Studies of cell-free DNA in the peripheral blood of breast cancer patients suggest that methylated DNA markers in serum or plasma could be used for detection of advanced disease, monitoring of therapeutic response, and for early detection of disease recurrence. Methods- A genome-wide serum DNA methylome array (Illumina HumanMethylation27 BeadChip) analysis was conducted on cell-free circulating DNA in serum from women with stage IV recurrent breast cancer, and 232 key CpG loci were identified. Methylation for this panel of 10 gene loci was evaluated using our newly developed cMethDNA assay to detect miniscule amounts of methylated DNA in Training and Test sets of sera from a total of 112 women (n = 55 normal, n = 57 metastatic breast cancer). The clinical sensitivity and specificity of the assay, along with technical reproducibility, was determined. To evaluate the concordance of DNA methylation patterns, the 10 gene panel was tested on 22 DNA sets of primary tumor, metastases and serum from the same patient. Finally, the ability of cMethDNA to monitor response to therapy was evaluated in 28 patients with metastatic disease. Results- A normal laboratory threshold of 7 cumulative methylation units was set and assay parameters were locked, based on Receiver Operating Characteristic (ROC) analyses of DNA from 300 ul of patient sera in the Training set (normal, n = 28; cancer, n = 24; 92% sensitivity, 96% specificity, and AUC = 0.950). Evaluation of the Test set of patient sera (normal, n = 27; cancer n = 33) resulted in detection of metastatic breast cancer with 91% sensitivity, 100% specificity, and AUC = 0.994 (0.984-1.005, p Conclusion- Together, our data suggest that the cMethDNA test 1) can detect tumor DNA shed into blood, 2) reflect the methylation alterations typical of the primary tumor and its metastatic lesions, and 3) reflect response to treatment after chemotherapy. Next, we will test the clinical utility of cMethDNA in independent clinical trial sample sets where it's complementary and independent roles will be examined against CA15.3 and CTC assays. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-06-01.

Author(s): Barton, V; Armeson, K; Hampras, S; Ferris, LK; Visvanathan, K; Rollison, D; Alberg, AJ | Abstract: BackgroundSome reports suggest a history of keratinocyte carcinoma (KC) may be associated with increased mortality. The high prevalence of KC makes the possibility of associated subsequent mortality from other causes important from a clinical and public health perspective. However, the variable methods and findings of existing studies leave the overall significance of these results uncertain. To provide clarity, we conducted a systematic review to characterize the evidence on the associations of KC with: 1) all-cause mortality, 2) cancer-specific mortality, and 3) cancer survival.MethodsBibliographic databases were searched through February 2016. Studies were included if adequate data were provided to estimate mortality ratios in patients with- vs.-without KC. Data were abstracted from the studies that met inclusion criteria.ResultsFor all-cause mortality, a significant increased risk was observed for patients with a history of squamous cell carcinoma (SCC) (relative risk estimates (RR) 1.25 and 1.30), whereas no increased risk was observed for patients with a history of basal cell carcinoma (BCC) (RRs 0.96 and 0.97). In one study, cancer-specific mortality was increased for patients with a KC history (RR 1.28; 95% CI 1.22-1.34). With few exceptions, across multiple types of cancer BCC and SCC were consistently associated with poorer survival from second primary malignancies.ConclusionMultiple studies support an association between KC and fatal outcomes; the associations tend to be more potent for SCC than BCC. Additional investigation is needed to more precisely characterize these associations and elucidate potential underlying mechanisms.

Four loci have been associated with pancreatic cancer through genome-wide association studies (GWAS). Pathway-based analysis of GWAS data is a complementary approach to identify groups of genes or biological pathways enriched with disease-associated single-nucleotide polymorphisms (SNPs) whose individual effect sizes may be too small to be detected by standard single-locus methods. We used the adaptive rank truncated product method in a pathway-based analysis of GWAS data from 3851 pancreatic cancer cases and 3934 control participants pooled from 12 cohort studies and 8 case-control studies (PanScan). We compiled 23 biological pathways hypothesized to be relevant to pancreatic cancer and observed a nominal association between pancreatic cancer and five pathways (P < 0.05), i.e. pancreatic development, Helicobacter pylori lacto/neolacto, hedgehog, Th1/Th2 immune response and apoptosis (P = 2.0 × 10(-6), 1.6 × 10(-5), 0.0019, 0.019 and 0.023, respectively). After excluding previously identified genes from the original GWAS in three pathways (NR5A2, ABO and SHH), the pancreatic development pathway remained significant (P = 8.3 × 10(-5)), whereas the others did not. The most significant genes (P < 0.01) in the five pathways were NR5A2, HNF1A, HNF4G and PDX1 for pancreatic development; ABO for H.pylori lacto/neolacto; SHH for hedgehog; TGFBR2 and CCL18 for Th1/Th2 immune response and MAPK8 and BCL2L11 for apoptosis. Our results provide a link between inherited variation in genes important for pancreatic development and cancer and show that pathway-based approaches to analysis of GWAS data can yield important insights into the collective role of genetic risk variants in cancer.

Background BRCA 1/2 mutation carriers are encouraged to have their ovaries removed by age 40 to reduce cancer risk and prolong survival. Given the recency of genetic testing, it will be some years before robust estimates are available of the long term adverse effects. In the meantime data from the general population can help inform women and providers about potential adverse effects so that preventive strategies can be implemented. Bone loss accelerates following natural menopause and oophorectomy before age 45 is a known risk factor for osteoporosis. However there is limited data quantifying the effects of bilateral oophorectomy on bone mineral density (BMD), an early sensitive marker of osteoporosis. Methods: We evaluated the associations of oophorectomy with arthritis and BMD in NHANES III, a nationally representative survey conducted 1988–1994. For analysis we included women aged 40 years and older with no history of cancer who reported a bilateral oophorectomy or intact ovaries. Women were asked if a doctor told them they had arthritis. Femoral neck BMD was measured by dual energy x-ray (DXA). Osteoporosis was defined as BMD (g/m2) more than 2.5 standard deviations below the mean of white women aged 20–29 years. Survey weights were used to account for the complex survey design. Odds Ratios (OR) for arthritis and osteoporosis were estimated using logistic regression. Oophorectomy status was categorized intact ovaries, oophorectomy Results: The sample size was 4039 for the arthritis analysis and 3660 for the BMD analysis. Women with oophorectomy were more likely to report arthritis than women with intact ovaries (45.4% vs. 32.1% p Conclusions: The prevalence of arthritis and osteoporosis were significantly greater in women who reported bilateral oophorectomy. Results were most profound among women whose oophorectomy was performed before age 45 and among women who never used HRT. These results suggest that women who undergo oophorectomy for cancer prevention should be closely monitored for osteoporosis over the long term. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-11-01.

BACKGROUND: Underdeveloped countries reported 882,900 new cases of breast cancer and 324,000 deaths in 2012, likely to be a gross underestimation according to recent reports. Often, mammography screening is not available, primary care services are limited, and pathology and treatment services are available only in the regional hospitals. Because of the lack of access to diagnostic and treatment services, it is estimated that more than 90% of patients with breast cancer never present for medical treatment. To address this situation, an accurate, easy-to-perform diagnostic test appropriate for use in remote clinics is desperately needed. Johns Hopkins (JH) and Cepheid partnered to translate a robust Quantitative Multiplex Methylation-Specific PCR (QM-MSP) assay to an automated, cartridge-based system that provides quantitative measures of DNA methylation within hours of fine needle aspiration or core biopsy of image-detected suspicious lesions. METHODS: With a goal of discriminating malignant from benign breast disease with high sensitivity and specificity, we evaluated 24 breast cancer-specific DNA methylation markers (selected through comprehensive methylome analysis) in 119 invasive ductal carcinomas and 186 benign breast tissues. QM-MSP was performed on sections of formalin-fixed paraffin-embedded (FFPE) tissues to quantify DNA methylation. The dynamic range and performance of quantitative methylation detection was tested using a subset of 9 genes in the cartridge-based system. RESULTS: QM-MSP was performed in a Training set consisting of 93 tissues [n=43 IDC, n=50 benign lesions (25 usual ductal hyperplasia, UDH, and 25 papilloma)] from the US. We selected 9 DNA markers significantly (p CONCLUSIONS: We identified a panel of methylated DNA markers that discriminate malignant from benign breast lesions and built a prototype automated cartridge-based assay with promising sensitivity and specificity for breast cancer. Such an assay has the potential to aid in specimen triage in the pathology lab and provide fast, low cost and accurate diagnosis of breast cancer in LMIC settings. Citation Format: Fackler MJ, Downs BM, Mercado-Rodriguez C, Cimino-Mathews A, Chen C, Yuan J, Cope LM, Kohlway A, Kocmond K, Lai E, Weidler J, Visvanathan K, Umbricht CB, Harvey S, Wolff AC, Bates M, Sukumar S. An automated DNA methylation assay (QM-MSP) for rapid breast cancer diagnosis in underdeveloped countries [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P6-03-07.

Adjuvant systemic therapy along with screening have been key to the observed improvements in disease-free and overall survival (DFS/OS) in breast cancer. Improvements in overall survival already take into account therapy related toxicities that can result in death. However, this measure alone does not adequately capture the impact on health-related quality of life. Therefore, it is important to examine the prevalence, frequency and short/long-term impact of therapy-related toxicities, identify patients who might be at greatest risk. Ultimately decisions regarding expected therapy benefits (relative and absolute percentage improvements in DFS/OS) must be made against a background of known potential harms. For many patients with early breast cancer (EBC), their risk of recurrence is not zero but is small. At the same time, for many therapies for early stage breast cancer, the risk of serious side effects is small but is not zero. As we better understand the long-term side effects of adjuvant chemotherapy and targeted therapy, it becomes critical to integrate our growing understanding of breast cancer biology with standard high-quality histopathologic measures to better identify the patients most likely to benefit from the various options for combined multimodality therapy. Hence, we must strive against the notion of recommending adjuvant systemic chemotherapy “just in case.” This article focuses on the long-term side effects of adjuvant chemotherapy in patients with EBC.

Several studies have associated polymorphisms in the androgen receptor gene with the risk of developing hormone-dependent cancers. A highly polymorphic (CAG)n repeat in exon 1 encodes a polyglutamine tract of varying length. The determination of the number of CAG repeats in the androgen receptor has typically been performed on denaturing polyacrylamide gels with autoradiographic or fluorescent detection of differently sized alleles. Samples run on a capillary electrophoresis-based ABI Prism® 310 Genetic Analyzer gave anomalous results when internal standards supplied by the manufacturer were used. Here we report a modified procedure for androgen receptor allele size determination that can be used on an automated capillary electrophoresis-based DNA sequencer equipped with the appropriate software. The assay is very precise, comparable to DNA sequencing, and is compatible with the latest generation of automated DNA sequencers.

It is well documented that tumor cells undergo dramatic genetic and epigenetic changes during initial establishment as cell lines and in subsequent serial passaging, and that the resultant cell lines may have evolved significantly from the primary tumors from which they were derived. This has potential implications due to their widespread use in drug response experiments and studies of genomic function. One approach to optimizing the design of such cell line studies is to identify and use the cell lines that faithfully recapitulate critical features of primary tumors. To evaluate the epigenetic fidelity of breast cancer cell lines in the context of primary tumors, we performed methylation profiling of 55 well-characterized breast cancer cell lines on the Illumina HumanMethylation27 BeadChip platform, and compared them to publicly available methylation profiles of primary breast tumors. We found that the DNA methylation profiles of breast cancer cell lines largely retain the features that characterize primary tumors, although there are crucial differences as well. We describe these similarities and differences between primary tumors and breast cancer cell lines in detail, and develop a quantitative measure of similarity that is used to score each cell line with respect to how faithfully its methylation profile mirrors that of primary tumors.

Isolated intracranial Rosai Dorfman disease (sinus histiocytosis with massive lymphadenopathy) is rare. We present a 26-year-old male who presented with left focal motor seizures becoming secondarily generalized of one-year duration. Clinically and radiologically patient was diagnosed to have a right parietal convexity meningioma. However on histopathological examination a final diagnosis of intracranial Rosai Dorfman disease was rendered.

Experiments were carried out on straight cylindrical supersonic exhaust diffusers (SED) using cold nitrogen and hot rocket exhaust gases as driving fluids, in order to evaluate the effects of the ratios of the SED area to rocket nozzle throat area (Ad/At), SED area to rocket nozzle exit area (Ad/Ac), SED length to its diameter (L/D) and specific heat ratio of the driving gases (K) on the minimum starting pressure ratio, (Po/Pa)st, of SED. The rocket nozzle and SED starting transients were also simulated in the models. The study reveals that (Po/Pa)st increases monotonically with increase in (Ad/At) and k. One-dimensional normal shock relations were used in predicting the (Po/Pa)st since the compression in long ducts is basically a normal shock process. Predicted values of (Po/Pa)st were validated with experimental data. SED efficiency factors(?ns) were arrived at based on one-dimensional normal shock relations. ?ns goes down at higher values of (Ad/Ac). (Po/Pa)st is lower for lower k values for the same (Ad/At). Cylindrical SEDs exhibit no hysteresis. The results of this investigation were utilised in validating the design of high altitude test (HAT) facility for testing the third stage motor (PS-3) of Polar Satellite Launch Vehicle (PSLV). The simulation of starting transients in the model revealed that the HAT facility shall not be operated in the unstarted phase, because the rocket nozzle may fail due to violent oscillations of the vacuum chamber pressure. These experimental data were also utilised for designing a SED for PS-3 sub-scale motor, the results of which are covered in this paper. The accuracy of measurements are within a range of � 0.4%. Error analysis of the data were carried out and are presented in Appendix A.Experiments were carried out on straight cylindrical supersonic exhaust diffusers (SED) using cold nitrogen and hot rocket exhaust gases as driving fluids, in order to evaluate the effects of the ratios of the SED area to rocket nozzle throat area (Ad/At), SED area to rocket nozzle exit area (Ad/Ae), SED length to its diameter (L/D) and specific heat ratio of the driving gases (k) on the minimum starting pressure ratio, (Po/Pa)st, of SED. The rocket nozzle and SED starting transients were also simulated in the models. The study reveals that (Po/Pa)st increases monotonically with increase in (Ad/At) and k. One-dimensional normal shock relations were used in predicting the (Po/Pa)st since the compression in long ducts is basically a normal shock process. Predicted values of (Po/Pa)st were validated with experimental data. SED efficiency factors (?ns) were arrived at based on one-dimensional normal shock relations. ?ns goes down at higher values of (Ad/Ae). (Po/Pa)st is lower for lower k values for the same (Ad/At). Cylindrical SEDs exhibit no hysteresis. The results of this investigation were utilized in validating the design of high altitude test (HAT) facility for testing the third stage motor (PS-3) of Polar Satellite Launch Vehicle (PSLV). The simulation of starting transients in the model revealed that the HAT facility shall not be operated in the unstarted phase, because the rocket nozzle may fail due to violent oscillations of the vacuum chamber pressure. These experimental data were also utilized for designing a SED for PS-3 sub-scale motor, the results of which are covered in this paper. The accuracy of measurements are within a range of �0.4%. Error analysis of the data were carried out and are presented in Appendix A.

Background: Preliminary studies from our lab have shown that a panel of methylation markers in tissue identifies 100% of tested breast cancer and 95% of tested DCIS, and has high accuracy in cells from ductal fluid and spontaneous nipple discharge1,2. Other groups have reported on the use of a single marker or a panel of markers to detect breast cancer in serum or plasma. Cell-free DNA studies in the peripheral blood of breast cancer patients with advanced disease or with early-stage disease after completion of local therapy support the hypothesis that methylated DNA markers in serum or plasma could be used to monitor response to therapy and for long-term surveillance. Validation studies to test these hypotheses have been hampered by assay methodological issues such as the very small amount of DNA shed in the serum by tumor compared to the total DNA shed by normal cells. Methods: To overcome this problem, we developed a modified quantitative methylation-specific PCR that directly measures the number of copies of methylated DNA markers in a small aliquot of serum (Serum-QM-MSP) and robustly detects less than 25 copies of DNA in 300 µL of serum. We then conducted a genome-wide methylome analysis to identify key markers that are preferentially methylated in serum from women with breast cancer and compared the profiles to those from women with no breast cancer. We then analyzed 300 µL each of sera from 55 normal women (single time point) and 43 women with metastatic breast cancer using this newly developed panel of markers and the Serum-QM-MSP assay. We also examined changes after therapy in a subset of patients with metastatic disease. Results: Methylation markers were quantitatively detected in sera of 39 out of 43 (91% sensitive) metastatic breast cancer patients with varying tumor burdens, and not in sera of any of 55 women (100% specific) for an AUC=0.95, using a laboratory threshold of 7.2 cumulative methylation units. 28 of the 43 patients had sampling repeated 3–5 weeks after therapy started. Sera from patients whose tumors regressed and from those that had stable disease showed a quantitative reduction, while those with progressive disease showed an increase in methylation levels of several genes. Conclusion: Our results suggest that methylated DNA in serum accurately discriminates between blood samples from normal women and from metastatic breast cancer patients. Also, early changes after therapy initiation for metastatic disease may correlate with subsequent clinical outcome. Assay analytical validation studies are ongoing. Studies examining a potential role in surveillance in the adjuvant setting and therapeutic benefit in the metastatic setting are warranted. 1. Fackler MJ et al. Genome-wide methylation analysis identifies genes specific to breast cancer hormone receptor status and risk of recurrence. Cancer Res. 2011 Oct 1;71(19):6195–207. PMCID: PMC3308629. 2. Fackler MJ, et al. Hypermethylated genes as biomarkers of cancer in women with pathologic nipple discharge. Clin Cancer Res. 2009 Jun 1;15(11):3802–11. PMID: 19470737 Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-02-01.

To identify methylated gene markers of disease progression, and to better understand the biology of hormone receptor-positive and negative breast cancer, we performed a genome-wide methylation array analysis on 103 primary invasive breast cancers and 21 normal breast samples using the Illumina Infinium HumanMethylation27 array that queried 27,578 CpG loci. Estrogen/Progesterone receptor (ER)-positive tumors displayed more hypermethylated loci than ER-negative tumors. However, the hypermethylated loci in ER-negative tumors were clustered closer to the transcriptional start site compared to ER-positive tumors, suggesting tighter transcriptional regulation by these loci. An ER-classifier set of 200 CpG loci was identified, which independently partitioned primary tumors into ER-subtypes. Forty (32 novel, 8 previously known) CpG loci showed differential methylation specific to either ER-positive or ER-negative tumors; the loci interconnected several important signaling networks including estrogen metabolism, and cellular growth and proliferation. Each of the 40 ER-subtype-specific loci was validated in silico using an independent, publicly available methylome dataset from The Cancer Genome Atlas (TCGA). In addition, we identified 32 methylated CpG loci from 27 genes (17 novel, 10 known) that were significantly associated with disease progression; the majority of these loci were informative particularly in ER-negative breast cancer. Overall, the set was highly enriched in homeobox containing genes, revealing a heretofore unknown function of this gene class acting as a group to disease progression. The tissues used for the current analysis were from an institutional cohort of frozen specimens and are therefore, samples of convenience with their inherent drawbacks. Additional studies will need address the question of the precise role of methylation signatures in prognosticating outcome and predicting response to therapy. More discovery and validation will need to be performed with annotated samples from case-control studies, with more uniform standards of sample collection, such as in the context of large mature national clinical trials. To allow investigation on archival specimens, the rapid development of methods to retrieve high quality DNA from paraffin embedded tissues is imperative. Our recent success in standardizing restoration of DNA retrieved from FFPE tissues and optimizing Human Methylation 450K arrray analysis with this DNA, in collaboration with Illumina Inc., will be presented. In summary, this study has demonstrated the feasibility of distinguishing ER-subtype in breast cancers and to possibly predict outcome based on CpG DNA methylation. The study suggested pathways which may explain distinctive behaviors among ER-positive and ER-negative tumors. Of great significance, the data strongly support the validity and feasibility of upcoming studies that will, in a prospective-retrospective fashion, examine the prognostic outcome and predictive therapeutic information of methylation markers using existing clinically-annotated tissues from previously conducted prospective randomized trials. Citation Information: Cancer Prev Res 2011;4(10 Suppl):CN05-04.