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Cancer Epidemiology Biomarkers & Prevention

Background: Few studies have evaluated whether adherence to dietary recommendations is associated with mortality among cancer survivors. In breast cancer survivors, we examined how postdiagnosis Healthy Eating Index (HEI)-2005 scores were associated with all-cause and cause-specific mortality.

Methods: Our prospective cohort study included 2,317 postmenopausal women, ages 50 to 79 years, in the Women's Health Initiative's Dietary Modification Trial (n = 1,205) and Observational Study (n = 1,112), who were diagnosed with invasive breast cancer and completed a food frequency questionnaire after being diagnosed. We followed women from this assessment forward. We used Cox proportional hazards models to estimate multivariate-adjusted HRs and 95% confidence intervals (CI) for death from any cause, breast cancer, and causes other than breast cancer, according to HEI-2005 quintiles.

Results: Over 9.6 years, 415 deaths occurred. After adjustment for key covariates, women consuming better quality diets had a 26% lower risk of death from any cause (HRQ4:Q1, 0.74; 95% CI, 0.55–0.99; Ptrend = 0.043) and a 42% lower risk of death from non–breast cancer causes (HRQ4:Q1, 0.58; 95% CI, 0.38–0.87; Ptrend = 0.011). HEI-2005 score was not associated with breast cancer death (HRQ4:Q1, 0.91; 95% CI, 0.60–1.40; Ptrend = 0.627). In analyses stratified by tumor estrogen receptor (ER) status, better diet quality was associated with a reduced risk of all-cause mortality among women with ER+ tumors (n = 1,758; HRQ4:Q1, 0.55; 95% CI, 0.38–0.79; Ptrend = 0.0009).

Conclusion: Better postdiagnosis diet quality was associated with reduced risk of death, particularly from non–breast cancer causes.

Impact: Breast cancer survivors may experience improved survival by adhering to U.S. dietary guidelines. Cancer Epidemiol Biomarkers Prev; 23(4); 575–83. ©2014 AACR.

Background: Although fertility drugs stimulate ovulation and raise estradiol levels, their effect on breast cancer risk remains unresolved.

Methods: An extended follow-up was conducted among a cohort of 12,193 women evaluated for infertility between 1965 and 1988 at five U.S. sites. Follow-up through 2010 was achieved for 9,892 women (81.1% of the eligible population) via passive as well as active (questionnaires) means. Cox regression determined HRs and 95% confidence intervals (CI) for fertility treatments adjusted for breast cancer risk factors and causes of infertility.

Results: During 30.0 median years of follow-up (285,332 person-years), 749 breast cancers were observed. Ever use of clomiphene citrate among 38.1% of patients was not associated with risk (HR = 1.05; 95% CI, 0.90–1.22 vs. never use). However, somewhat higher risks were seen for patients who received multiple cycles, with the risk for invasive cancers confirmed by medical records being significantly elevated (HR = 1.69; 95% CI, 1.17–2.46). This risk remained relatively unchanged after adjustment for causes of infertility and multiple breast cancer predictors. Gonadotropins, used by 9.6% of patients, mainly in conjunction with clomiphene, showed inconsistent associations with risk, although a significant relationship of use with invasive cancers was seen among women who remained nulligravid (HR = 1.98; 95% CI, 1.04–3.60).

Conclusions: Although the increased breast cancer risk among nulligravid women associated with gonadotropins most likely reflects an effect of underlying causes of infertility, reasons for the elevated risk associated with multiple clomiphene cycles are less clear.

Impact: Given our focus on a relatively young population, additional evaluation of long-term fertility drug effects on breast cancer is warranted. Cancer Epidemiol Biomarkers Prev; 23(4); 584–93. ©2014 AACR.

Background: This study aimed to evaluate the association of recurrent molecular alterations in prostate cancer, such as ERG rearrangements and phosphatase and tensin homolog gene (PTEN) deletions, with oncologic outcomes in patients with prostate cancer treated with brachytherapy.

Methods: Ninety-two men underwent I-125 brachytherapy with a 145 Gy delivered dose between 2000 and 2008. Pretreatment prostate biopsies were analyzed by immunohistochemistry (IHC) and FISH for ERG rearrangement and overexpression, PTEN deletion, and expression loss. Univariable and multivariable Cox-regression analyses evaluated association of ERG and PTEN status with biochemical recurrence (BCR).

Results: Within a median follow-up of 73 months, 11% of patients experienced BCR. Of 80 samples with both IHC and FISH performed for ERG, 46 (57.8%) demonstrated rearrangement by FISH and 45 (56.3%) by IHC. Of 77 samples with both IHC and FISH for PTEN, 14 (18.2%) had PTEN deletion by FISH and 22 (28.6%) by IHC. No significant associations were found between ERG, PTEN status, and clinicopathologic features. Patients with concurrent ERG rearrangement and PTEN deletion demonstrated significantly worse relapse-free survival rates compared with those with ERG or PTEN wild type (P < 0.01). In multivariable Cox regression analysis adjusted for the effects of standard clinicopathologic features, combined ERG rearranged and PTEN deletion was independently associated with BCR (HR = 2.6; P = 0.02).

Conclusions: Concurrent ERG rearrangement and PTEN loss was independently associated with time to BCR in patients undergoing brachytherapy. Future studies are needed to validate prostate cancer molecular subtyping for risk stratification.

Impact: Identifying patients in the ERG-rearranged/PTEN-deleted molecular subclass may improve treatment personalization. Cancer Epidemiol Biomarkers Prev; 23(4); 594–600. ©2014 AACR.

Background: Individuals with a strong family history of colorectal cancer have significant risk for colorectal cancer, although adherence to colonoscopy screening in these groups remains low. This study assessed whether a tailored telephone counseling intervention can increase adherence to colonoscopy in members of high-risk families in a randomized, controlled trial.

Methods: Eligible participants were recruited from two national cancer registries if they had a first-degree relative with colorectal cancer under age 60 or multiple affected family members, which included families that met the Amsterdam criteria for hereditary non-polyposis colon cancer (HNPCC), and if they were due for colonoscopy within 24 months. Participants were randomized to receive a tailored telephone intervention grounded in behavioral theory or a mailed packet with general information about screening. Colonoscopy status was assessed through follow-up surveys and endoscopy reports. Cox proportional hazards models were used to assess intervention effect.

Results: Of the 632 participants (ages 25–80), 60% were female, the majority were White, non-Hispanic, educated, and had health insurance. Colonoscopy adherence increased 11 percentage points in the tailored telephone intervention group, compared with no significant change in the mailed group. The telephone intervention was associated with a 32% increase in screening adherence compared with the mailed intervention (HR, 1.32; P = 0.01).

Conclusions: A tailored telephone intervention can effectively increase colonoscopy adherence in high-risk persons. This intervention has the potential for broad dissemination to healthcare organizations or other high-risk populations.

Impact: Increasing adherence to colonoscopy among persons with increased colorectal cancer risk could effectively reduce incidence and mortality from this disease. Cancer Epidemiol Biomarkers Prev; 23(4); 601–10. ©2014 AACR.

Background: Prior studies suggested that glycans were differentially expressed in patients with ovarian cancer and controls. We hypothesized that glycan-based biomarkers might serve as a diagnostic test for ovarian cancer and evaluated the ability of glycans to distinguish ovarian cancer cases from matched controls.

Methods: Serum samples were obtained from the tissue-banking repository of the Gynecologic Oncology Group, and included healthy female controls (n = 100), women diagnosed with low malignant potential (LMP) tumors (n = 52), and epithelial ovarian cancers (EOC) cases (n = 147). Cases and controls were matched on age at enrollment within ±5 years. Serum samples were analyzed by glycomics analysis to detect abundance differences in glycan expression levels. A two-stage procedure was carried out for biomarker discovery and validation. Candidate classifiers of glycans that separated cases from controls were developed using a training set in the discovery phase and the classification performance of the candidate classifiers was assessed using independent test samples that were not used in discovery.

Results: The patterns of glycans showed discriminatory power for distinguishing EOC and LMP cases from controls. Candidate glycan-based biomarkers developed on a training set (sensitivity, 86% and specificity, 95.8% for distinguishing EOC from controls through leave-one-out cross-validation) confirmed their potential use as a detection test using an independent test set (sensitivity, 70% and specificity, 86.5%).

Conclusion: Formal investigations of glycan biomarkers that distinguish cases and controls show great promise for an ovarian cancer diagnostic test. Further validation of a glycan-based test for detection of ovarian cancer is warranted.

Impact: An emerging diagnostic test based on the knowledge gained from understanding the glycobiology should lead to an assay that improves sensitivity and specificity and allows for early detection of ovarian cancer. Cancer Epidemiol Biomarkers Prev; 23(4); 611–21. ©2014 AACR.

Background: To date, common genetic variants in approximately 70 loci have been identified for breast cancer via genome-wide association studies (GWAS). It is unknown whether rare variants in these loci are also associated with breast cancer risk.

Methods: We investigated rare missense/nonsense variants with minor allele frequency (MAF) ≤5% located in flanking 500 kb of each of the index single-nucleotide polymorphism (SNP) in 67 GWAS loci. Included in the study were 3,472 cases and 3,595 controls from the Shanghai Breast Cancer Study. Both single marker and gene-based analyses were conducted to investigate the associations.

Results: Single marker analyses identified 38 missense variants being associated with breast cancer risk at P < 0.05 after adjusting for the index SNP. SNP rs146217902 in the EDEM1 gene and rs200340088 in the EFEMP2 gene were only observed in 8 cases (P = 0.004 for both). SNP rs200995432 in the EFEMP2 gene was associated with increased risk with an OR of 6.2 [95% confidence interval (CI), 1.4–27.6; P = 6.2 x 10–3]. SNP rs80358978 in the BRCA2 gene was associated with 16.5-fold elevated risk (95% CI, 2.2–124.5; P = 2.2 x 10–4). Gene-based analyses suggested eight genes associated with breast cancer risk at P < 0.05, including the EFEMP2 gene (P = 0.002) and the FBXO18 gene (P = 0.008).

Conclusion: Our results identified associations of several rare coding variants neighboring common GWAS loci with breast cancer risk. Further investigation of these rare variants and genes would help to understand the biologic mechanisms underlying the associations.

Impact: Independent studies with larger sample size are warranted to clarify the relationship between these rare variants and breast cancer risk. Cancer Epidemiol Biomarkers Prev; 23(4); 622–8. ©2014 AACR.

Background: Results from prospective studies on the association between urinary levels of melatonin and risk of postmenopausal breast cancer have been mixed. Several although not all studies have found lower urinary levels of melatonin in women who developed breast cancer compared with cancer-free women.

Methods: We examined the association between urinary levels of melatonin and breast cancer risk in postmenopausal women in a case–control study nested in the Women's Health Initiative Observational Cohort. Levels of 6-sulfatoxymelatonin were measured in first morning voids from 258 women who later developed breast cancer and from 515 matched controls. Multivariable conditional logistic regression was used to calculate ORs and 95% confidence intervals (CI).

Results: Fully adjusted risk estimates of breast cancer, relative to the lowest quartile level of creatinine-adjusted melatonin, were 1.07 (95% CI, 0.67–1.71), 1.26 (95% CI, 0.79–2.01), and 1.25 (95% CI, 0.78–2.02) for women in the second, third, and highest quartile (Ptrend = 0.27). Comparable results for cases diagnosed less than four years after urinary collection and matched controls were 1.0, 1.25 (95% CI, 0.51–3.06), 1.85 (95% CI, 0.75–4.57), and 1.94 (95% CI, 0.75–5.03; Ptrend = 0.11). Melatonin levels and breast cancer were not associated in cases diagnosed four or more years after urinary collection and matched controls (Ptrend = 0.89).

Conclusions: We found no evidence that higher urinary levels of melatonin are inversely associated with breast cancer risk in postmenopausal women.

Impact: Accumulating discrepancies in results across studies warrant further exploration. Cancer Epidemiol Biomarkers Prev; 23(4); 629–37. ©2014 AACR.

Background: Despite experimental evidence showing chemopreventive effects of coffee-related compounds on gastric carcinogenesis, epidemiologic studies generally do not support coffee–gastric cancer associations. Observational data are lacking among high-risk populations with sufficient regular coffee consumption.

Methods: We examined the association between caffeinated coffee intake and gastric cancer risk in a population-based cohort that enrolled 63,257 Chinese men and women ages 45 to 74 years between 1993 and 1998 in Singapore. Incident gastric cancer cases (n = 647) were identified after a mean follow-up of 14.7 years. Biomarkers of Helicobacter pylori (H. pylori) infection were measured in a subset of gastric cancer cases with blood collected before cancer diagnosis and their matched controls.

Results: In the total cohort, daily versus nondaily coffee intake was associated with a statistically nonsignificant decrease in gastric cancer risk [HR = 0.85; 95% confidence interval (CI), 0.69–1.04]. In women, the inverse association strengthened and reached statistical significance (HR = 0.63; 95% CI, 0.46–0.87). In analyses restricted to never smokers and nondrinkers of alcohol, inverse associations strengthened in the total cohort (HR = 0.69; 95% CI, 0.52–0.91) and in women (HR = 0.52; 95% CI, 0.37–0.74). There was no coffee–gastric cancer risk association among men, regardless of smoking status or alcohol consumption. Similar results were observed in the nested case–control study after adjustment for H. pylori infection.

Conclusion: Daily coffee consumption may reduce the risk of gastric cancer in high-risk populations, especially among women.

Impact: Research aimed at identifying the compounds in coffee that may protect against gastric carcinogenesis is warranted. Cancer Epidemiol Biomarkers Prev; 23(4); 638–47. ©2014 AACR.

Background: Increased physical activity is associated with decreased risk of several types of cancer, but underlying mechanisms are poorly understood. Angiogenesis, in which new blood vessels are formed, is common to adipose tissue formation/remodeling and tumor vascularization.

Methods: We examined effects of a 12-month 45 minutes/day, 5 days/week moderate-intensity aerobic exercise intervention on four serum markers of angiogenesis in 173 sedentary, overweight, postmenopausal women, 50 to 75 years, randomized to intervention versus stretching control. Circulating levels of positive regulators of angiogenesis [VEGF, osteopontin (OPN), plasminogen activator inhibitor-1 (PAI-1)], and the negative regulator pigment epithelium-derived factor (PEDF), were measured by immunoassay at baseline and 12 months. Changes were compared using generalized estimating equations, adjusting for baseline levels of analytes and body mass index (BMI).

Results: VEGF, OPN, or PAI-1 levels did not differ by intervention arm. Participants randomized to exercise significantly reduced PEDF (–3.7%) versus controls (+3.0%; P = 0.009). Reductions in fat mass were significantly associated with reductions in PAI-1 (Ptrend = 0.03; Ptrend = 0.02) and PEDF (Ptrend = 0.002; Ptrend = 0.01) compared with controls, or to those who gained any fat mass respectively. There was a significant association between decreases in VO2max, and increased reductions in PEDF (Ptrend = 0.03), compared with participants who increased their level of fitness.

Conclusions: Fat loss reduces circulating PAI-1 and PEDF. Changes in VO2max are associated with alterations in PEDF, but these associations are complex.

Impact: Unexpected reductions in PEDF with decreasing fat mass, and with decreasing VO2max, warrant further study, including examining the effects of different types and intensities of exercise; and role of dietary weight-loss with and without exercise. Cancer Epidemiol Biomarkers Prev; 23(4); 648–57. ©2014 AACR.

Early-onset breast cancer (EOBC) causes substantial loss of life and productivity, creating a major burden among women worldwide. We analyzed 1,265,548 Hapmap3 single-nucleotide polymorphisms (SNP) among a discovery set of 3,523 EOBC incident cases and 2,702 population control women ages ≤ 51 years. The SNPs with smallest P values were examined in a replication set of 3,470 EOBC cases and 5,475 control women. We also tested EOBC association with 19,684 genes by annotating each gene with putative functional SNPs, and then combining their P values to obtain a gene-based P value. We examined the gene with smallest P value for replication in 1,145 breast cancer cases and 1,142 control women. The combined discovery and replication sets identified 72 new SNPs associated with EOBC (P < 4 x 10–8) located in six genomic regions previously reported to contain SNPs associated largely with later-onset breast cancer (LOBC). SNP rs2229882 and 10 other SNPs on chromosome 5q11.2 remained associated (P < 6 x 10–4) after adjustment for the strongest published SNPs in the region. Thirty-two of the 82 currently known LOBC SNPs were associated with EOBC (P < 0.05). Low power is likely responsible for the remaining 50 unassociated known LOBC SNPs. The gene-based analysis identified an association between breast cancer and the phosphofructokinase-muscle (PFKM) gene on chromosome 12q13.11 that met the genome-wide gene-based threshold of 2.5 x 10–6. In conclusion, EOBC and LOBC seem to have similar genetic etiologies; the 5q11.2 region may contain multiple distinct breast cancer loci; and the PFKM gene region is worthy of further investigation. These findings should enhance our understanding of the etiology of breast cancer. Cancer Epidemiol Biomarkers Prev; 23(4); 658–69. ©2014 AACR.

Background: Genetic background plays a role in multiple myeloma susceptibility. Several single-nucleotide polymorphisms (SNP) associated with genetic susceptibility to multiple myeloma were identified in the last years, but only a few of them were validated in independent studies.

Methods: With the aim to conclusively validate the strongest associations so far reported, we selected the polymorphisms rs2227667 (SERPINE1), rs17501108 (HGF), rs3136685 (CCR7), rs16944 (IL1B), rs12147254 (TRAF3), rs1805087 (MTR), rs1800629 (TNF-α), rs7516435 (CASP9), rs1042265 (BAX), rs2234922 (mEH), and rs1801133 (MTHFR). We genotyped them in 1,498 multiple myeloma cases and 1,934 controls ascertained in the context of the International Multiple Myeloma rESEarch (IMMEnSE) consortium, and meta-analyzed our results with previously published ones.

Results: None of the selected SNPs were significantly associated with multiple myeloma risk (P value range, 0.055–0.981), possibly with the exception of the SNP rs2227667 (SERPINE1) in women.

Conclusions: We can exclude that the selected polymorphisms are major multiple myeloma risk factors.

Impact: Independent validation studies are crucial to identify true genetic risk factors. Our large-scale study clarifies the role of previously published polymorphisms in multiple myeloma risk. Cancer Epidemiol Biomarkers Prev; 23(4); 670–4. ©2014 AACR.

Cancer prevention postdoctoral fellowships have existed since the 1970s. The National Cancer Institute facilitated a meeting by a panel of experts in April 2013 to consider four important topics for future directions for cancer prevention postdoctoral training programs: (i) future research needs; (ii) underrepresented disciplines; (iii) curriculum; and (iv) career preparation. Panelists proffered several areas needing more research or emphasis, ranging from computational science to culture. Health care providers, along with persons from nontraditional disciplines in scientific training programs such as engineers and lawyers, were among those recognized as being underrepresented in training programs. Curriculum suggestions were that fellows receive training in topics such as leadership and human relations, in addition to learning the principles of epidemiology, cancer biologic mechanisms, and behavioral science. For career preparation, there was a clear recognition of the diversity of employment options available besides academic positions, and that program leaders should do more to help fellows identify and prepare for different career paths. The major topics and strategies covered at this meeting can help form the basis for cancer prevention training program leaders to consider modifications or new directions, and keep them updated with the changing scientific and employment climate for doctoral degree recipients and postdoctoral fellows. Cancer Epidemiol Biomarkers Prev; 23(4); 679–83. ©2014 AACR.