Citations

Carriers of germline mutations in DNA mismatch repair (MMR) genes are at increased risk of several cancers including colorectal and gynecologic cancers (Lynch syndrome). There is no substantial evidence that these mutations are associated with an increased risk of cervical cancer. A total of 369 families with at least one carrier of a mutation in a MMR gene (133 MLH1, 174 MSH2, 35 MSH6 and 27 PMS2) were ascertained via population cancer registries or via family cancer clinics in Australia, New Zealand, Canada, and USA. Personal and family histories of cancer were obtained from participant interviews. Modified segregation analysis was used to estimate the hazard ratio (incidence rates for carriers relative to those for the general population), and age‐specific cumulative risks of cervical cancer for carriers. A total of 65 cases of cervical cancer were reported (including 10 verified by pathology reports). The estimated incidence was 5.6 fold (95% CI: 2.3–13.8; p = 0.001) higher for carriers than for the general population with a corresponding cumulative risk to 80 years of 4.5% (95% CI: 1.9–10.7%) compared with 0.8% for the general population. The mean age at diagnosis was 43.1 years (95% CI: 40.0–46.2), 3.9 years younger than the reported USA population mean of 47.0 years (p = 0.02). Women with MMR gene mutations were found to have an increased risk of cervical cancer. Due to limited pathology verification we cannot be certain that a proportion of these cases were not lower uterine segment endometrial cancers involving the endocervix, a recognized cancer of Lynch syndrome.

Direct Pulmonary Vein Ablation With Stenosis Prevention TherapyIntroductionThe dominant location of electrical triggers for initiating atrial fibrillation (AF) originates from the muscle sleeves inside pulmonary veins (PVs). Currently, radiofrequency ablation (RFA) is performed outside of the PVs to isolate, rather than directly ablate these tissues, due to the risk of intraluminal PV stenosis.MethodsIn 4 chronic canine experiments, we performed direct PV muscle sleeve RFA ± postablation drug‐coated balloon (DCB) treatment with paclitaxel/everolimus. Of the 4 PVs, 2 PVs were ablated and treated with DCB, 1 PV was ablated without DCB treatment (positive control), and 1 PV was left as a negative control. Local electrograms were assessed in PVs for near‐field signals and were targeted for ablation. After 12–14 weeks survival, PVs were interrogated for absence of near‐field PV potentials, and each PV was assessed for stenosis.ResultsAll canines survived the study period without cardiorespiratory complications, and remained ambulatory. In all canines, PVs that were ablated and treated with DCB remained without any significant intraluminal stenosis. In contrast, PVs that were ablated and not treated with DCB showed near or complete intraluminal stenosis. At terminal study, PV potentials remained undetectable. A blinded, histologic analysis demonstrated that ablated PVs without DCB treatment had extensive thrombus, fibrin, mineralization, and elastin disruption.ConclusionOur chronic canine data suggest that direct PV tissue ablation without subsequent stenosis is feasible with the use of postablation DCBs.

Abstract Introduction: Current models to predict breast cancer risk do not differentiate risk for estrogen receptor (ER) positive and negative breast cancer (BC), despite growing evidence that these tumors are biologically very different. We hypothesized that women with ER+ BC cancers have different clinical risk factors and histologic findings on prior benign breast biopsies than those with ER- BC. Methods: After IRB approval, we examined associations of age at benign biopsy and histologic features of the benign biopsy with ER status of incident BCs within the Mayo Benign Breast Disease Cohort. Benign biopsy slides were reviewed for extent of lobular involution and degree of epithelial proliferation by a single breast pathologist blinded to BC events. Invasive BCs occurring within 15 years after benign biopsy were classified as ER+ if ER staining was >1%. BC case-only associations with ER status were evaluated using multivariate logistic regression. Full-cohort hazard ratios (HR) and 95% confidence intervals (CI) for risk of ER-specific subtypes were estimated using Cox proportion hazards regression. Results: Among 13,410 women undergoing a benign breast biopsy from 1967-2001, 656 invasive BCs (459 ER+, 106 ER, 106 unknown) occurred within 15 years. Women who developed ER+ and ER- BCs were similar in age at the time of their prior benign breast biopsy (p=0.34). Although benign biopsies in women who later developed ER+ BC were more likely to show complete involution (23% vs 15% for ER- BC), this was not statistically significant (p=0.06). However, the degree of epithelial proliferation was significantly associated with ER status of later BCs (p=0.001), with ER+ BCs more likely than ER- BCs to have had a prior biopsy with atypical hyperplasia (16% vs 8%), and ER+ BCs less likely than ER- BCs to have had a prior biopsy with proliferative disease without atypia (33% vs 52%); this association remained after multivariate adjustment (p=0.003). We further pursued the association of epithelial proliferation with differential risk of ER+ and ER- BC in our overall cohort of 13,410 women (Table 1). Compared to women with non-proliferative disease, women with proliferative disease +/- atypia had ∼2-fold hazard ratios for ER- BC, whereas hazard ratios for ER+ BC were higher in women with atypical hyperplasia (∼4-fold) compared to proliferative disease. Hazard Ratio of ER+ and ER- BC within 15 years of BBD based upon degree of epithelial proliferation at benign biopsyCancer TypeGroupNN EventsHazard Ratio (95% CI)p-valueInvasive ER- ≤15 yearsNP8478421.00 (ref)<0.0001 PD4229542.63 (1.76, 3.93) AH70382.60 (1.22, 5.54) Invasive ER+ ≤15 yearsNP84782321.00 (ref)<0.0001 PD42291511.33 (1.09, 1.64) AH703744.41 (3.39, 5.73) NP=nonproliferative disease, PD=proliferative disease without atypia; AH=atypical hyperplasia Conclusion: ER+ and ER- breast cancers appear to have different features on prior benign breast biopsy, with atypical hyperplasia showing increased risk for both types of breast cancer, but a greater risk for ER+ tumors. Citation Format: Amy C Degnim, Derek C Radisky, Robert A Vierkant, Ryan D Frank, Marlene H Frost, Vernon S Pankratz, Celine M Vachon, Tanya L Hoskin, Julie M Cunningham, Chen Wang, Jean-Pierre Kocher, Teresa M Allers, Joanne L Johnson, Tina J Hieken, Karthik Ghosh, Lynn C Hartmann, Daniel W Visscher. Histologic features of benign breast biopsy tissue and association with ER positive and ER negative breast cancer in the Mayo BBD cohort study [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 P6-10-06.

Abstract Objective: Contralateral PM (CPM) and Bilateral PM (BPM) markedly decrease, but do not completely eliminate the possibility of development of a new BC on the side of the PM. Given the relative infrequency of its occurrence, little is known about the clinical characteristics, presentation, and management of patients who develop BC after PM. Our aim was to review our institutional experience of BC occurring after PM. Methods: Between 1960 and 1993, 1,065 women underwent BPM and 1,643 women with unilateral BC treated with therapeutic mastectomy underwent a CPM. Medical records were reviewed and study-specific questionnaires were sent to all women at 10 years and 20 years after PM. BC after PM included locoregional invasive BC or DCIS on the side of the PM. Results: Thirteen patients who underwent BPM developed BC after PM. Twelve patients who underwent CPM developed a subsequent BC on the side of the CPM. The median follow-up time from PM was 22 years (range 3-34). Detailed clinical characteristics of BC after PM are shown in Table 1. Presentations included: disease limited to the axilla without evidence of a local primary 4 (16%); synchronous local and axillary disease 1 (4%); synchronous local disease and distant metastases 4 (16%); clinically isolated local disease 17 (68%). Characteristics of BC Following PM All Patients (n=25)BPM Cohort (n=13)CPM Cohort (n=12)Median age at diagnosis of BC after PM56 (range 38-81)58 (range 38-71)54 (range 39-81)Median time to development of BC after PM (years)7 (range 1-25)6 (range 2-25)8 (range 1-21)Presentation Self-detected abnormality23 (92%)12 (92%)11 (92%)Screening mammogram1 (4%)02 (16%)Not known1 (4%)1 (8%)0Local disease only17 (68%)10 (77%)7 (58%)-Sub-areolar7 (41%)6 (40%)1 (8%)-UOQ/axillary tail2 (12%)02 (16%)-Lower/inframmamary crease2 (12%)1 (10%)1(8%)Chest wall or unspecified6 (35%)3 (30%)3 (25%)Local & regional (axillary) disease1 (4%01 (8%)Axillary BC without evidence of local primary4 (16%)1 (8%)3 (25%)Synchronous local and distant disease3 (12%)2 (15%)1 (8%) Of the 17 patients with isolated local disease, 11 (65%) underwent a completion/redo mastectomy, local excision of the tumor was performed in 5 (29%), and surgical management was unknown in 1 (6%). Ten of 17 (59%) underwent axillary lymph node dissection, 1 (6%) underwent sentinel lymph node biopsy, 1 did not undergo axillary staging, and axillary management was unknown in 5 (29%). Median tumor size was 0.9 cm (range 0.3-3.5) and only 1 of 17 (6%) patients was confirmed to have pathologic nodal involvement. Twelve of 17 (71%) received some type of adjuvant therapy: chemotherapy and/or endocrine therapy 3 (18%); radiotherapy 2 (12%); both 5 (29%); none 5 (29%). With a median follow-up of 7 years since diagnosis of local BC after PM, there has been one isolated local recurrence and 2 distant recurrences as first event. Conclusion: BC can occur after PM. With rising rates of PM, understanding management of BC after PM is important. Most common presentation is local disease and can be managed with resection with consideration of adjuvant therapy. Multidisciplinary management of these cases is needed. Citation Format: Robert W Mutter, Tanya L Hoskin, Marlene H Frost, Joanne L Johnson, Lynn C Hartmann, Judy C Boughey. Breast cancer (BC) following prophylactic mastectomy (PM), a clinical entity: Presentation, management, and outcomes [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 P5-12-05.

Abstract Introduction: AI-induced joint symptoms negatively impact drug adherence and quality of life. Based on observations that n-3 polyunsaturated fatty acids (PUFAs) have anti-inflammatory effects and that the mechanism of AI-induced joint symptoms may be partly due to inflammation, we hypothesized that women taking more n-3 PUFAs are less likely to develop AI-induced joint symptoms. Methods: We conducted a randomized, double-blind, placebo-controlled study comparing n-3 PUFA vs placebo in postmenopausal breast cancer patients starting adjuvant AIs. Participants were randomized to n-3 supplements [2.58 g eicosapentaenoic acid + 1.74 g docosahexaenoic acid/day; Marine Nutriceuticals, Mt. Bethel, PA] vs matched placebo for 24 weeks (wks). Primary endpoints was feasibility; secondary outcomes were self-reported symptoms as assessed by the Brief Pain Inventory short form (BPI-SF), Functional Assessment of Cancer Treatment, Breast & Endocrine Symptoms (FACTB-ES), and Stanford's Health Assessment and Disability Index (HAQ) at baseline prior to AI receipt, 12 and 24 wks. Compliance and toxicity were evaluated monthly. Serial peripheral blood n-3 PUFA levels and inflammatory cytokines (IL-6, TNFR2, IL-17) were drawn. MRI of hands/wrists was performed in selected patients using a 3 Tesla dedicated wrist coil at baseline and treatment end. Results: Forty-four women were enrolled and randomized to study drug; 42 received ≥1 cycle (4 wks) of treatment; 36 had ≥1 post treatment evaluation at wk 12 or 24. Median age was 59.5 (range 43-76); history of prior taxane (n=15, 34%). The two groups’ baseline characteristics were similar. Overall, 93% and 88% of patients took >80% of the placebo and n-3 PUFA doses, respectively. Baseline erythrocyte n-3 PUFA was similar for both groups (6.6% ± 1.6%, 7.2% ±1.9%, p=0.20), but higher in the n-3 PUFA arm by wk 24 (6.5%±1.0% vs 15.0%±3.3%, p<0.001). Most toxicities were grade 1; the n-3 PUFA arm had only 1 (2.5%) grade 3 toxicity (diarrhea). The n-3 PUFA arm reported lower mean BPI-SF scores after treatment [(-.0.28/ -0.25 at week 12/24); but not statistically significant compared to placebo (p=0.494 and 0.601)]. Based on BPI-SF, the n-3 PUFA arm reported less interference of pain symptoms compared to placebo at 12 weeks (-.72, p=0.08). This arm also had a decreased walking, activity and working (WAW) score on BPI-SF at 12 weeks (-.81 p=0.05), and reported significantly greater pain relief from medications at 12 (p=0.043) and 24 weeks (p=0.011). Both arms had similar baseline and wk 24 serum IL-6 levels; levels decreased from baseline to wk 24 in the n-3 PUFA arm (-0.54±0.25, p=0.048). There was a non-significant trend (p= 0.2) toward decreased wrist inflammation by MRI imaging at 24 wks in the n-3 PUFA arm. Conclusions: This is the first randomized pilot study to show that n-3 PUFA supplementation to prevent AI-induced joint symptoms is feasible and well tolerated. There is preliminary evidence that this intervention may help reduce the burden of AI-induced arthralgias. OSU Study #11022; ClinicalTrials.gov Identifier: NCT01478477. Grants from the National Cancer Institute (CA037447-26) to the Alliance for Clinical Trials in Oncology supported this pilot study. Citation Format: Maryam B Lustberg, Tonya Orchard, Xueliang Pan, Raquel Reinbolt, Amanda Logan, Joanne Lester, Rachel M Layman, Erin Macrae, Ewa Mrozek, Bhuvaneswari Ramaswamy, Robert Wesolowski, Michael Berger, Michael Knopp, Charles Loprinzi, Charles L Shapiro, Lisa Yee. Prevention of aromatase Inhibitor (AI)-induced joint symptoms with omega-3 fatty acid supplementation: A randomized placebo-controlled pilot study [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 P1-09-03.

Abstract Background: Genome-wide association studies have identified multiple genetic variants associated with prostate cancer risk which explain a substantial proportion of familial relative risk. These variants can be used to stratify individuals by their risk of prostate cancer. Methods: We genotyped 25 prostate cancer susceptibility loci in 40,414 individuals and derived a polygenic risk score (PRS). We estimated empirical odds ratios (OR) for prostate cancer associated with different risk strata defined by PRS and derived age-specific absolute risks of developing prostate cancer by PRS stratum and family history. Results: The prostate cancer risk for men in the top 1% of the PRS distribution was 30.6 (95% CI, 16.4–57.3) fold compared with men in the bottom 1%, and 4.2 (95% CI, 3.2–5.5) fold compared with the median risk. The absolute risk of prostate cancer by age of 85 years was 65.8% for a man with family history in the top 1% of the PRS distribution, compared with 3.7% for a man in the bottom 1%. The PRS was only weakly correlated with serum PSA level (correlation = 0.09). Conclusions: Risk profiling can identify men at substantially increased or reduced risk of prostate cancer. The effect size, measured by OR per unit PRS, was higher in men at younger ages and in men with family history of prostate cancer. Incorporating additional newly identified loci into a PRS should improve the predictive value of risk profiles. Impact: We demonstrate that the risk profiling based on SNPs can identify men at substantially increased or reduced risk that could have useful implications for targeted prevention and screening programs. Cancer Epidemiol Biomarkers Prev; 24(7); 1121–9. ©2015 AACR.

Abstract Background There are several suspected environmental risk factors for non-Hodgkin lymphoma (NHL). The associations between NHL and environmental chemical exposures have typically been evaluated for individual chemicals (i.e., one-by-one). Objectives We determined the association between a mixture of 27 correlated chemicals measured in house dust and NHL risk. Methods We conducted a population-based case–control study of NHL in four National Cancer Institute–Surveillance, Epidemiology, and End Results centers—Detroit, Michigan; Iowa; Los Angeles County, California; and Seattle, Washington—from 1998 to 2000. We used weighted quantile sum (WQS) regression to model the association of a mixture of chemicals and risk of NHL. The WQS index was a sum of weighted quartiles for 5 polychlorinated biphenyls (PCBs), 7 polycyclic aromatic hydrocarbons (PAHs), and 15 pesticides. We estimated chemical mixture weights and effects for study sites combined and for each site individually, and also for histologic subtypes of NHL. Results The WQS index was statistically significantly associated with NHL overall [odds ratio (OR) = 1.30; 95% CI: 1.08, 1.56; p = 0.006; for one quartile increase] and in the study sites of Detroit (OR = 1.71; 95% CI: 1.02, 2.92; p = 0.045), Los Angeles (OR = 1.44; 95% CI: 1.00, 2.08; p = 0.049), and Iowa (OR = 1.76; 95% CI: 1.23, 2.53; p = 0.002). The index was marginally statistically significant in Seattle (OR = 1.39; 95% CI: 0.97, 1.99; p = 0.071). The most highly weighted chemicals for predicting risk overall were PCB congener 180 and propoxur. Highly weighted chemicals varied by study site; PCBs were more highly weighted in Detroit, and pesticides were more highly weighted in Iowa. Conclusions An index of chemical mixtures was significantly associated with NHL. Our results show the importance of evaluating chemical mixtures when studying cancer risk. Citation Czarnota J, Gennings C, Colt JS, De Roos AJ, Cerhan JR, Severson RK, Hartge P, Ward MH, Wheeler DC. 2015. Analysis of environmental chemical mixtures and non-Hodgkin lymphoma risk in the NCI-SEER NHL Study. Environ Health Perspect 123:965–970; http://dx.doi.org/10.1289/ehp.1408630

Abstract Background: The CpG island methylator phenotype (CIMP) represents a subset of colorectal cancers characterized by widespread aberrant DNA hypermethylation at select CpG islands. The risk factors and environmental exposures contributing to etiologic heterogeneity between CIMP and non-CIMP tumors are not known. Methods: We measured the CIMP status of 3,119 primary population-based colorectal cancer tumors from the multinational Colon Cancer Family Registry. Etiologic heterogeneity was assessed by a case–case study comparing risk factor frequency of colorectal cancer cases with CIMP and non-CIMP tumors using logistic regression to estimate the case–case odds ratio (ccOR). Results: We found associations between tumor CIMP status and MSI-H (ccOR = 7.6), BRAF V600E mutation (ccOR = 59.8), proximal tumor site (ccOR = 9; all P < 0.0001), female sex [ccOR = 1.8; 95% confidence interval (CI), 1.5–2.1], older age (ccOR = 4.0 comparing over 70 years vs. under 50; 95% CI, 3.0–5.5), and family history of CRC (ccOR = 0.6; 95% CI, 0.5–0.7). While use of NSAIDs varied by tumor CIMP status for both males and females (P = 0.0001 and P = 0.02, respectively), use of multivitamin or calcium supplements did not. Only for female colorectal cancer was CIMP status associated with increased pack-years of smoking (Ptrend < 0.001) and body mass index (BMI; Ptrend = 0.03). Conclusions: The frequency of several colorectal cancer risk factors varied by CIMP status, and the associations of smoking and obesity with tumor subtype were evident only for females. Impact: Differences in the associations of a unique DNA methylation–based subgroup of colorectal cancer with important lifestyle and environmental exposures increase understanding of the molecular pathologic epidemiology of this heavily methylated subset of colorectal cancer. Cancer Epidemiol Biomarkers Prev; 24(3); 512–9. ©2015 AACR.