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Current treatment options for metastatic adrenocortical carcinoma (ACC) have limited efficacy, despite the common use of mitotane and cytotoxic agents. This study aimed to identify novel therapeutic options for ACC. An extensive drug screen was conducted to identify compounds with potential activity against ACC cell lines. We further investigated the mechanism of action of the identified compound, TAK-243, its synergistic effects with current ACC therapeutics, and its efficacy in ACC models including patient-derived organoids and mouse xenografts. TAK-243, a clinical ubiquitin-activating enzyme (UAE) inhibitor, showed potent activity in ACC cell lines. TAK-243 inhibited protein ubiquitination in ACC cells, leading to the accumulation of free ubiquitin, activation of the unfolded protein response, and induction of apoptosis. TAK-243 was found to be effluxed out of cells by MDR1, a drug efflux pump, and did not require Schlafen 11 (SLFN11) expression for its activity. Combination of TAK-243 with current ACC therapies (e.g., mitotane, etoposide, cisplatin) produced synergistic or additive effects. In addition, TAK-243 was highly synergistic with BCL2 inhibitors (Navitoclax and Venetoclax) in preclinical ACC models including patient-derived organoids. The tumor suppressive effects of TAK-243 and its synergistic effects with Venetoclax were further confirmed in a mouse xenograft model. These findings provide preclinical evidence to support the initiation of a clinical trial of TAK-243 in patients with advanced-stage ACC. TAK-243 is a promising potential treatment option for ACC, either as monotherapy or in combination with existing therapies or BCL2 inhibitors., Significance: ACC is a rare endocrine cancer with poor prognosis and limited therapeutic options. We report that TAK-243 is active alone and in combination with currently used therapies and with BCL2 and mTOR inhibitors in ACC preclinical models. Our results suggest implementation of TAK-243 in clinical trials for patients with advanced and metastatic ACC., (© 2024 The Authors; Published by the American Association for Cancer Research.)

PARP inhibitor (PARPi)-resistant BRCA-mutant (BRCAm) high-grade serous ovarian cancer (HGSOC) represents a new clinical challenge with unmet therapeutic needs. Here, we performed a quantitative high-throughput drug combination screen that identified the combination of an ATR inhibitor (ATRi) and an AKT inhibitor (AKTi) as an effective treatment strategy for both PARPi-sensitive and PARPi-resistant BRCAm HGSOC. The ATRi and AKTi combination induced DNA damage and R loop-mediated replication stress (RS). Mechanistically, the kinase domain of AKT1 directly interacted with DHX9 and facilitated recruitment of DHX9 to R loops. AKTi increased ATRi-induced R loop-mediated RS by mitigating recruitment of DHX9 to R loops. Moreover, DHX9 was upregulated in tumors from patients with PARPi-resistant BRCAm HGSOC, and high coexpression of DHX9 and AKT1 correlated with worse survival. Together, this study reveals an interaction between AKT1 and DHX9 that facilitates R loop resolution and identifies combining ATRi and AKTi as a rational treatment strategy for BRCAm HGSOC irrespective of PARPi resistance status., Significance: Inhibition of the AKT and ATR pathways cooperatively induces R loop-associated replication stress in high-grade serous ovarian cancer, providing rationale to support the clinical development of AKT and ATR inhibitor combinations. See related commentary by Ramanarayanan and Oberdoerffer, p. 793., (©2024 American Association for Cancer Research.)

Background: There is mixed evidence about the relations of current versus past cancer with severe COVID-19 outcomes and how they vary by patient and cancer characteristics., Methods: Electronic health record data of 104,590 adult hospitalized patients with COVID-19 were obtained from 21 United States health systems from February 2020 through September 2021. In-hospital mortality and ICU admission were predicted from current and past cancer diagnoses. Moderation by patient characteristics, vaccination status, cancer type, and year of the pandemic was examined., Results: 6.8% of the patients had current (n = 7,141) and 6.5% had past (n = 6,749) cancer diagnoses. Current cancer predicted both severe outcomes but past cancer did not; adjusted odds ratios (aOR) for mortality were 1.58 [95% confidence interval (CI), 1.46-1.70] and 1.04 (95% CI, 0.96-1.13), respectively. Mortality rates decreased over the pandemic but the incremental risk of current cancer persisted, with the increment being larger among younger vs. older patients. Prior COVID-19 vaccination reduced mortality generally and among those with current cancer (aOR, 0.69; 95% CI, 0.53-0.90)., Conclusions: Current cancer, especially among younger patients, posed a substantially increased risk for death and ICU admission among patients with COVID-19; prior COVID-19 vaccination mitigated the risk associated with current cancer. Past history of cancer was not associated with higher risks for severe COVID-19 outcomes for most cancer types., Impact: This study clarifies the characteristics that modify the risk associated with cancer on severe COVID-19 outcomes across the first 20 months of the COVID-19 pandemic. See related commentary by Egan et al., p. 3., (©2022 The Authors; Published by the American Association for Cancer Research.)

Background: How 5-alpha reductase inhibitor (5-ARI) use influences prostate cancer mortality is unclear. The objective of this study was to determine whether men taking 5-ARIs with regular health care access have increased prostate cancer mortality., Methods: We undertook two analyses in the Health Professionals Follow-up Study examining 5-ARI use, determined by biennial questionnaires, and prostate cancer. A cohort analysis followed 38,037 cancer-free men for prostate cancer incidence from 1996 through January 2017 and mortality through January 2019. A case-only analysis followed 4,383 men with localized/locally advanced prostate cancer for mortality over a similar period. HRs and 95% confidence intervals (CI) were calculated for prostate cancer incidence and mortality., Results: Men using 5-ARIs underwent more PSA testing, prostate exams and biopsies. Over 20 years of follow-up, 509 men developed lethal disease (metastases or prostate cancer death). Among men initially free from prostate cancer, 5-ARI use was not associated with developing lethal disease [HR, 1.02; 95% confidence interval (CI), 0.71-1.46], but was associated with reduced rates of overall and localized disease (HR, 0.71; 0.60-0.83). Among men diagnosed with prostate cancer, there was no association between 5-ARI use and cancer-specific (HR, 0.78; 95% CI, 0.48-1.27) or overall survival (HR, 0.88; 95% CI, 0.72-1.07)., Conclusions: Men using 5-ARIs were less likely to be diagnosed with low-risk prostate cancer, without increasing long-term risk of lethal prostate cancer or cancer-specific death after diagnosis., Impact: Our results provide evidence that 5-ARI use is safe with respect to prostate cancer mortality in the context of regular health care access. See related commentary by Hamilton, p. 1259., (©2022 American Association for Cancer Research.)

Background: Racial disparities in prostate cancer incidence and mortality rates are considerable. We previously found in the Health Professionals Follow-up Study (HPFS) that African-American men had an 80% higher prostate cancer risk than White men. With 21 additional years of follow-up and four-fold increase in cases, we undertook a contemporary analysis of racial differences in prostate cancer incidence and mortality in HPFS., Methods: For 47,679 men, we estimated HRs and 95% confidence intervals (CI) for the association between race and risk of prostate cancer through 2016 using Cox proportional hazards regression. Multivariable models (mHR) were adjusted for lifestyle, diet, family history, and PSA screening collected on biennial questionnaires., Results: 6,909 prostate cancer cases were diagnosed in White, 89 in African-American, and 90 in Asian-American men. African-Americans had higher prostate cancer incidence (mHR = 1.31; 95% CI, 1.06-1.62) and mortality (mHR = 1.67; 95% CI, 1.00-2.78), and lower PSA screening prevalence than White men. The excess risk was greater in the pre-PSA screening era (HR = 1.68; 95% CI, 1.14-2.48) than the PSA screening era (HR = 1.20; 95% CI, 0.93-1.56). Asian-Americans had lower prostate cancer risk (mHR = 0.74; 95% CI, 0.60-0.92), but similar risk of fatal disease compared with white men., Conclusions: Racial differences in prostate cancer incidence and mortality in HPFS are not fully explained by differences in lifestyle, diet, family history, or PSA screening., Impact: Additional research is necessary to address the disproportionately higher rates of prostate cancer in African-American men., (©2022 American Association for Cancer Research.)

The use of Bruton tyrosine kinase (BTK) inhibitors to block B-cell receptor (BCR)-dependent NF-κB activation in lymphoid malignancies has been a major clinical advance, yet acquired therapeutic resistance is a recurring problem. We modeled the development of resistance to the BTK inhibitor ibrutinib in the activated B-cell (ABC) subtype of diffuse large B-cell lymphoma, which relies on chronic active BCR signaling for survival. The primary mode of resistance was epigenetic, driven in part by the transcription factor TCF4. The resultant phenotypic shift altered BCR signaling such that the GTPase RAC2 substituted for BTK in the activation of phospholipase Cγ2, thereby sustaining NF-κB activity. The interaction of RAC2 with phospholipase Cγ2 was also increased in chronic lymphocytic leukemia cells from patients with persistent or progressive disease on BTK inhibitor treatment. We identified clinically available drugs that can treat epigenetic ibrutinib resistance, suggesting combination therapeutic strategies., Significance: In diffuse large B-cell lymphoma, we show that primary resistance to BTK inhibitors is due to epigenetic rather than genetic changes that circumvent the BTK blockade. We also observed this resistance mechanism in chronic lymphocytic leukemia, suggesting that epigenetic alterations may contribute more to BTK inhibitor resistance than currently thought. See related commentary by Pasqualucci, p. 555 . This article is highlighted in the In This Issue feature, p. 549 ., (©2021 American Association for Cancer Research.)

Background: The TMPRSS2:ERG gene fusion and PTEN loss are two of the most common somatic molecular alterations in prostate cancer. Here, we investigated the association of prediagnostic-circulating metabolomics and prostate cancer defined by ERG or PTEN status to improve understanding of these etiologically distinct molecular prostate cancer subtypes., Methods: The study was performed among 277 prostate cancer cases with ERG status, 211 with PTEN status, and 294 controls nested in the Health Professionals Follow-up Study (HPFS) and the Physicians' Health Study (PHS). We profiled 223 polar and non-polar metabolites using LC-MS in prediagnostic plasma specimens. We applied enrichment analysis and multinomial logistic regression models to identify biological metabolite classes and individual metabolites associated with prostate cancer defined by ERG or PTEN status., Results: Compared with noncancer controls, sphingomyelin ( P : 0.01), ceramide ( P : 0.04), and phosphatidylethanolamine ( P : 0.03) circulating levels were enriched among ERG-positive prostate cancer cases. Sphingomyelins ( P : 0.02), ceramides ( P : 0.005), and amino acids ( P : 0.02) were enriched among tumors exhibiting PTEN-loss; unsaturated diacylglycerols ( P : 0.003) were enriched among PTEN-intact cases; and unsaturated triacylglycerols were enriched among both PTEN-loss ( P : 0.001) and PTEN-intact ( P : 0.0001) cases. Although several individual metabolites identified in the above categories were nominally associated with ERG or PTEN-defined prostate cancer, none remained significant after accounting for multiple testing., Conclusions: The molecular process of prostate carcinogenesis may be distinct for men with different metabolomic profiles., Impact: These novel findings provide insights into the metabolic environment for the development of prostate cancer., (©2021 American Association for Cancer Research.)

High-grade serous ovarian carcinoma (HGSOC) is the most lethal gynecologic malignancy in industrialized countries and has limited treatment options. Targeting ataxia-telangiectasia and Rad3-related/cell-cycle checkpoint kinase 1 (CHK1)-mediated S-phase and G 2 -M-phase cell-cycle checkpoints has been a promising therapeutic strategy in HGSOC. To improve the efficacy of CHK1 inhibitor (CHK1i), we conducted a high-throughput drug combination screening in HGSOC cells. PI3K/mTOR pathway inhibitors (PI3K/mTORi) showed supra-additive cytotoxicity with CHK1i. Combined treatment with CHK1i and PI3K/mTORi significantly attenuated cell viability and increased DNA damage, chromosomal breaks, and mitotic catastrophe compared with monotherapy. PI3K/mTORi decelerated fork speed by promoting new origin firing via increased CDC45, thus potentiating CHK1i-induced replication stress. PI3K/mTORi also augmented CHK1i-induced DNA damage by attenuating DNA homologous recombination repair activity and RAD51 foci formation. High expression of replication stress markers was associated with poor prognosis in patients with HGSOC. Our findings indicate that combined PI3K/mTORi and CHK1i induces greater cell death in HGSOC cells and in vivo models by causing lethal replication stress and DNA damage. This insight can be translated therapeutically by further developing combinations of PI3K and cell-cycle pathway inhibitors in HGSOC. SIGNIFICANCE: Dual inhibition of CHK1 and PI3K/mTOR pathways yields potent synthetic lethality by causing lethal replication stress and DNA damage in HGSOC, warranting further clinical development., (©2020 American Association for Cancer Research.)

Background: The association between male pattern baldness and prostate cancer has been inconsistent. We prospectively investigated the association between baldness at age 45 and prostate cancer risk in the Health Professionals Follow-up Study (HPFS), focusing on clinical and molecular markers., Methods: Baldness was self-reported on the 1992 questionnaire using the modified Norwood-Hamilton scale prior to diagnosis. We estimated HRs between baldness and prostate cancer risk among 36,760 men, with follow-up through 2014. We also investigated whether baldness was associated with prostate cancer defined by tumor protein expression of androgen receptor and the presence of the TMPRSS2:ERG fusion., Results: During 22 years, 5,157 prostate cancer cases were identified. Fifty-six percent of the men had either frontal or vertex baldness. No significant associations were found between baldness and prostate cancer risk. Among men younger than 60 years, there was a statistically significant association between frontal and severe vertex baldness and overall prostate cancer (HR: 1.74; 95% confidence interval: 1.23-2.48). Baldness was not significantly associated with expression of molecular subtypes defined by AR and TMPRSS2:ERG IHC of prostate tumors., Conclusions: This study showed no association between baldness at age 45 and prostate cancer risk, overall or for clinical or molecular markers. The association between baldness and overall prostate cancer among younger men is intriguing, but caution is warranted when interpreting this finding., Impact: The null findings from this large cohort study, together with previous literature's inconclusive findings across baldness patterns, suggest that baldness is not a consistent biomarker for prostate cancer risk or progression., (©2020 American Association for Cancer Research.)

Purpose: Statins are associated with lower risk of aggressive prostate cancer, but lethal prostate cancer is understudied and contributing mechanisms are unclear. We prospectively examined statins and lethal prostate cancer risk in the Health Professionals Follow-up Study (HPFS), tested associations with molecular subtypes, and integrated gene expression profiling to identify putative mechanisms., Experimental Design: Our study included 44,126 men cancer-free in 1990, followed for prostate cancer incidence through 2014, with statin use recorded on biennial questionnaires. We used multivariable Cox regression to examine associations between statins and prostate cancer risk overall, by measures of clinically significant disease, and by ERG and PTEN status. In an exploratory analysis, age-adjusted gene set enrichment analysis identified statin-associated pathways enriched in tumor and adjacent normal prostate tissue., Results: During 24 years of follow-up, 6,305 prostate cancers were diagnosed and 801 (13%) were lethal (metastatic at diagnosis or metastatic/fatal during follow-up). Relative to never/past use, current statin use was inversely associated with risk of lethal prostate cancer [HR, 0.76; 95% confidence interval (CI), 0.60-0.96] but not overall disease. We found a strong inverse association for risk of PTEN-null cancers (HR, 0.40; 95% CI, 0.19-0.87) but not PTEN-intact cancers (HR, 1.18; 95% CI, 0.95-1.48; P heterogeneity = 0.01). Associations did not differ by ERG. Inflammation and immune pathways were enriched in normal prostate tissue of statin ever ( n = 10) versus never users ( n = 103)., Conclusions: Molecular tumor classification identified PTEN and inflammation/immune activation as potential mechanisms linking statins with lower lethal prostate cancer risk. These findings support a potential causal association and could inform selection of relevant biomarkers for statin clinical trials., (©2019 American Association for Cancer Research.)

Background: Accumulating evidence suggests that dietary acrylamide intake is not associated with the risk of most cancers in humans. However, a meta-analysis of five epidemiologic studies found a suggestion of an increased risk of kidney cancer with higher dietary acrylamide intake. Methods: We investigated this association in the prospective Health Professionals Follow-up Study (HPFS; 1986-2014) and Nurses' Health Study (NHS; 1980-2014) cohorts. Dietary acrylamide intake was calculated on the basis of 46 acrylamide-containing foods reported on food frequency questionnaires completed every 4 years. The associations with the incidence of total and fatal renal cell carcinoma (RCC; n = 292/84 HPFS, n = 337/87 NHS) during more than two decades of follow-up were assessed using Cox proportional hazards models adjusting for potential confounders. Results: There was no association between cumulative average or baseline acrylamide intake and the risk of total or fatal RCC risk in men or women. Acrylamide intake was also not associated with RCC risk among never-smokers, nor was it associated with the risk of clear cell RCC. Conclusions: Dietary acrylamide was not associated with risk of RCC in two long-term prospective cohorts with repeated measures of dietary intake. Impact: This analysis of RCC adds to the body of evidence that dietary acrylamide is not an important cancer risk factor in humans. Cancer Epidemiol Biomarkers Prev; 27(8); 979-82. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Background: The largest molecular subtype of primary prostate cancer is defined by the TMPRSS2:ERG gene fusion. Few studies, however, have investigated etiologic differences by TMPRSS2:ERG status. Because the fusion is hormone-regulated and a man's hormonal milieu varies by height and obesity status, we hypothesized that both may be differentially associated with risk of TMPRSS2:ERG -defined disease. Methods: Our study included 49,372 men from the prospective Health Professionals Follow-up Study. Participants reported height and weight at baseline in 1986 and updated weight biennially thereafter through 2009. Tumor ERG protein expression (a TMPRSS2:ERG marker) was immunohistochemically assessed. We used multivariable competing risks models to calculate HRs and 95% confidence intervals (CIs) for the risk of ERG-positive and ERG-negative prostate cancer. Results: During 23 years of follow-up, we identified 5,847 incident prostate cancers, among which 913 were ERG-assayed. Taller height was associated with an increased risk of ERG-positive disease only [per 5 inches HR 1.24; 95% confidence interval (CI), 1.03-1.50; P heterogeneity = 0.07]. Higher body mass index (BMI) at baseline (per 5 kg/m 2 HR 0.75; 95% CI, 0.61-0.91; P heterogeneity = 0.02) and updated BMI over time (per 5 kg/m 2 HR 0.86; 95% CI, 0.74-1.00; P heterogeneity = 0.07) were associated with a reduced risk of ERG-positive disease only. Conclusions: Our results indicate that anthropometrics may be uniquely associated with TMPRSS2:ERG -positive prostate cancer; taller height may be associated with greater risk, whereas obesity may be associated with lower risk. Impact: Our study provides strong rationale for further investigations of other prostate cancer risk factors that may be distinctly associated with subtypes. Cancer Epidemiol Biomarkers Prev; 27(2); 193-200. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Background: Relationships between fruit, vegetable, and mature bean consumption and prostate cancer risk are unclear. Methods: We examined associations between fruit and vegetable groups, specific fruits and vegetables, and mature bean consumption and prostate cancer risk overall, by stage and grade, and for prostate cancer mortality in a pooled analysis of 15 prospective cohorts, including 52,680 total cases and 3,205 prostate cancer-related deaths among 842,149 men. Diet was measured by a food frequency questionnaire or similar instrument at baseline. We calculated study-specific relative risks using Cox proportional hazards regression, and then pooled these estimates using a random effects model. Results: We did not observe any statistically significant associations for advanced prostate cancer or prostate cancer mortality with any food group (including total fruits and vegetables, total fruits, total vegetables, fruit and vegetable juice, cruciferous vegetables, and tomato products), nor specific fruit and vegetables. In addition, we observed few statistically significant results for other prostate cancer outcomes. Pooled multivariable relative risks comparing the highest versus lowest quantiles across all fruit and vegetable exposures and prostate cancer outcomes ranged from 0.89 to 1.09. There was no evidence of effect modification for any association by age or body mass index. Conclusions: Results from this large, international, pooled analysis do not support a strong role of collective groupings of fruits, vegetables, or mature beans in prostate cancer. Impact: Further investigation of other dietary exposures, especially indicators of bioavailable nutrient intake or specific phytochemicals, should be considered for prostate cancer risk. Cancer Epidemiol Biomarkers Prev; 26(8); 1276-87. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Little information exists on diet and prostate cancer progression. We examined the association between intakes of total red meat, processed and unprocessed red meat, poultry, fish, and eggs and prostate cancer recurrence. We conducted a prospective study of 971 men treated with radical prostatectomy for prostate cancer between 2003 and 2010. Men completed a food frequency questionnaire at diagnosis. We used logistic regression to study the association between diet and high-grade or advanced-stage disease. We used Cox models to study the risk of progression [N = 94 events, mainly prostate-specific antigen (PSA) recurrence]. Total red meat intake was marginally associated with risk of high-grade disease [Gleason ≥ 4+3; adjusted OR top vs. bottom quartile: 1.66; 95% confidence interval (CI), 0.93-2.97; P trend = 0.05], as was very high intake of eggs (OR top decile vs. bottom quartile: 1.98; 95% CI, 1.08-3.63, P trend = 0.08). Well-done red meat was associated with advanced disease (≥pT3; OR top vs. bottom quartile: 1.74, 95% CI, 1.05-2.90; P trend = 0.01). Intakes of red meat, fish, and eggs were not associated with progression. Very high poultry intake was inversely associated with progression (HR top decile vs. bottom quartile: 0.19; 95% CI, 0.06-0.63; P trend = 0.02). Substituting 30 g/d of poultry or fish for total or unprocessed red meat was associated with significantly lower risk of recurrence. Lower intakes of red meat and well-done red meat and higher intakes of poultry and fish are associated with lower risk of high grade and advanced prostate cancer and reduced recurrence risk, independent of stage and grade. Cancer Prev Res; 9(12); 933-41. ©2016 AACR., (©2016 American Association for Cancer Research.)

Background: Sleep deficiency is a major public health problem. There are limited human data on whether sleep duration or disruption are risk factors for prostate cancer., Methods: We prospectively followed 32,141 men in the Health Professionals Follow-Up Study who reported their typical sleep duration in 1987, 2000, and 2008. We identified 4,261 incident prostate cancer cases, including 563 lethal cases through 2010. Sleep disruption was assessed in 2004 among 19,639 men, with 930 prostate cancer cases (50 lethal) identified from 2004 to 2010. Cox proportional hazards models were used to evaluate the association between sleep insufficiency and risk of overall and lethal prostate cancer., Results: In 1987, 2% of men reported sleeping ≤5 hours per night. We found no association between habitual sleep duration or change in sleep duration with the risk of advanced or lethal prostate cancer. We also found no association between waking up during the night, difficulty falling asleep, or waking up too early, and risk of prostate cancer. In 2004, 6% of men reported never feeling rested when they woke up; these men had an increased risk of developing lethal prostate cancer compared with those who reported always feeling rested when they woke up (RR, 3.05; 95% CI, 1.15-8.10)., Conclusions: We found no consistent association between self-reported sleep duration or sleep disruption and any of our prostate cancer outcomes., Impact: We did not find support for a consistent association between self-reported sleep and risk of advanced or lethal prostate cancer in this large cohort of men., (©2015 American Association for Cancer Research.)

Background: The rodent carcinogen acrylamide was discovered in 2002 in commonly consumed foods. Epidemiologic studies have observed positive associations between acrylamide intake and endometrial, ovarian, and breast cancer risks, which suggest that acrylamide may have sex-hormonal effects., Methods: We cross-sectionally investigated the relationship between acrylamide intake and plasma levels of sex hormones and sex hormone-binding globulin (SHBG) among 687 postmenopausal and 1,300 premenopausal controls from nested case-control studies within the Nurses' Health Studies., Results: There were no associations between acrylamide and sex hormones or SHBG among premenopausal women overall or among never-smokers. Among normal-weight premenopausal women, acrylamide intake was statistically significantly positively associated with luteal total and free estradiol levels. Among postmenopausal women overall and among never-smokers, acrylamide was borderline statistically significantly associated with lower estrone sulfate levels but not with other estrogens, androgens, prolactin, or SHBG. Among normal-weight women, (borderline) statistically significant inverse associations were noted for estrone, free estradiol, estrone sulfate, DHEA, and prolactin, whereas statistically significant positive associations for testosterone and androstenedione were observed among overweight women., Conclusions: Overall, this study did not show conclusive associations between acrylamide intake and sex hormones that would lend unequivocal biologic plausibility to the observed increased risks of endometrial, ovarian, and breast cancer. The association between acrylamide and sex hormones may differ by menopausal and overweight status. We recommend other studies investigate the relationship between acrylamide and sex hormones in women, specifically using acrylamide biomarkers., Impact: The present study showed some interesting associations between acrylamide intake and sex hormones that urgently need confirmation., (©2013 AACR.)

Background: Acrylamide is a probable human carcinogen formed during cooking of starchy foods. Two large prospective cohort studies of dietary acrylamide intake and ovarian cancer risk observed a positive association, although two other studies reported no association., Methods: We measured acrylamide exposure using red blood cell acrylamide and glycidamide hemoglobin adducts among women in two large prospective cohorts: the Nurses' Health Study and Nurses' Health Study II. Between blood collection and 2010, we identified 263 incident cases of epithelial ovarian cancer, matching two controls per case. We used logistic regression models to examine the association between acrylamide exposure and ovarian cancer risk, adjusting for matching factors, family history of ovarian cancer, tubal ligation, oral contraceptive use, body mass index, parity, alcohol intake, smoking, physical activity, and caffeine intake., Results: The multivariate-adjusted relative risk (RR) of ovarian cancer comparing the highest versus lowest tertile of total acrylamide adducts was 0.79 (95% CI, 0.50-1.24, P trend = 0.08). The comparable RR of ovarian cancer among non-smokers at blood draw was 0.85 (95% CI, 0.57-1.27, P trend = 0.14). The association did not differ by tumor histology (serous invasive versus not), P for heterogeneity = 0.86. Individual adduct types (acrylamide or glycidamide) were not associated with risk., Conclusions: We observed no evidence that acrylamide exposure as measured by adducts to hemoglobin is associated with an increased risk of ovarian cancer., Impact: Our finding indicates that acrylamide intake may not increase risk of ovarian cancer.

Background: Bony metastases cause substantial morbidity and mortality from prostate cancer (PCa). The calcium-sensing receptor (CaSR) is expressed on prostate tumors and may participate in bone metastases development. We assessed whether (i) common genetic variation in CaSR was associated with PCa risk and (ii) these associations varied by calcium intake or plasma 25-hydroxyvitamin D [25(OH)D] levels., Methods: We included 1,193 PCa cases and 1,244 controls nested in the prospective Health Professionals Follow-up Study (1993-2004). We genotyped 18 CaSR single-nucleotide polymorphism (SNPs) to capture common variation. The main outcome was risk of lethal PCa (n = 113); secondary outcomes were overall (n = 1,193) and high-grade PCa (n = 225). We used the kernel machine approach to conduct a gene-level multimarker analysis and unconditional logistic regression to compute per-allele ORs and 95% confidence intervals (CI) for individual SNPs., Results: The joint association of SNPs in CaSR was significant for lethal PCa (P = 0.04); this association was stronger in those with low 25(OH)D (P = 0.009). No individual SNPs were associated after considering multiple testing; three SNPs were nominally associated (P < 0.05) with lethal PCa with ORs (95% CI) of 0.65(0.42-0.99): rs6438705; 0.65(0.47-0.89): rs13083990; and 1.55(1.09-2.20): rs2270916. The three nonsynonymous SNPs (rs1801725, rs1042636, and rs1801726) were not significantly associated; however, the association for rs1801725 was stronger in men with low 25(OH)D [OR(95%CI): 0.54(0.31-0.95)]. There were no significant associations with overall or high-grade PCa., Conclusions: Our findings indicate that CaSR may be involved in PCa progression., Impact: Further studies investigating potential mechanisms for CaSR and PCa, including bone remodeling and metastases are warranted.

Background: Acrylamide is a probable human carcinogen formed during cooking of many common foods. Epidemiologic studies on acrylamide and breast cancer risk have been null; however, positive associations with ovarian and endometrial cancers have been reported. We studied acrylamide intake and risk for breast, endometrial, and ovarian cancers in a prospective cohort study., Methods: We assessed acrylamide intake among 88,672 women in the Nurses' Health Study using food frequency questionnaires administered every 4 years. Between 1980 and 2006, we identified 6,301 cases of invasive breast cancer, 484 cases of invasive endometrial adenocarcinoma, and 416 cases of epithelial ovarian cancer. We used Cox proportional hazards models to study the association between acrylamide and cancer risk., Results: We found no association between acrylamide intake and breast cancer overall or according to estrogen and progesterone receptor status. We found an increased risk for endometrial cancer among high acrylamide consumers (adjusted relative risk for highest versus lowest quintile = 1.41; 95% CI, 1.01-1.97; P for trend = 0.03). We observed a nonsignificant suggestion of increased risk for ovarian cancer overall (relative risk, 1.25; 95% CI, 0.88-1.77; P trend = 0.12), with a significantly increased risk for serous tumors (relative risk, 1.58; 95% CI, 0.99-2.52; P trend = 0.04). Associations did not differ by smoking status., Conclusions: We observed no association between acrylamide and breast cancer. Risk for endometrial cancer and possibly ovarian cancer was greater among high acrylamide consumers., Impact: This is the second prospective study to report positive associations with endometrial and ovarian cancers. These associations should be further evaluated to inform public health policy., (©2010 AACR.)