Victoria A. Kirsh

A Prospective Study of Lycopene and Tomato Product Intake and Risk of Prostate Cancer

Background: Dietary lycopene and tomato products may reduce risk of prostate cancer; however, uncertainty remains about this possible association. Methods: We evaluated the association between intake of lycopene and specific tomato products and prostate cancer risk in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, a multicenter study designed to investigate cancer early detection methods and etiologic determinants. Participants completed both a general risk factor and a 137-item food frequency questionnaire at baseline. A total of 1,338 cases of prostate cancer were identified among 29,361 men during an average of 4.2 years of follow-up. Results: Lycopene intake was not associated with prostate cancer risk. Reduced risks were also not found for total tomato servings or for most tomato-based foods. Statistically nonsignificant inverse associations were noted for pizza [all prostate cancer: relative risk (RR), 0.83; 95% confidence interval (95% CI), 0.67-1.03 for ≥1 serving/wk versus < 0.5 serving/mo; Ptrend = 0.06 and advanced prostate cancer: RR, 0.79; 95% CI, 0.56-1.10; Ptrend = 0.12] and spaghetti/tomato sauce consumption (advanced prostate cancer: RR = 0.81, 95% CI, 0.57-1.16 for ≥2 servings/wk versus < 1 serving/mo; Ptrend = 0.31). Among men with a family history of prostate cancer, risks were decreased in relation to increased consumption of lycopene (Ptrend = 0.04) and specific tomato-based foods commonly eaten with fat (spaghetti, Ptrend = 0.12; pizza, Ptrend = 0.15; lasagna, Ptrend = 0.02). Conclusions: This large study does not support the hypothesis that greater lycopene/tomato product consumption protects from prostate cancer. Evidence for protective associations in subjects with a family history of prostate cancer requires further corroboration. (Cancer Epidemiol Biomarkers Prev 2006;15(1):92–8)

A prospective study of meat and meat mutagens and prostate cancer risk.

High-temperature cooked meat contains heterocyclic amines, including 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), and polycyclic aromatic hydrocarbons, such as benzo(a)pyrene (BaP). In rodents, a high intake of PhIP induces prostate tumors. We prospectively investigated the association between meat and meat mutagens, specifically PhIP, and prostate cancer risk in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Diet was assessed using a 137-item food frequency questionnaire and a detailed meat-cooking questionnaire linked to a database for BaP and the heterocyclic amines 2-amino-3,8-dimethylimidazo[4,5-b]quinoxaline (MeIQx), 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (DiMeIQx), and PhIP. During follow-up, we ascertained a total of 1,338 prostate cancer cases among 29,361 men; of these, 868 were incident cases (diagnosed after the first year of follow-up) and 520 were advanced cases (stage III or IV or a Gleason score of > or =7). Total, red, or white meat intake was not associated with prostate cancer risk. More than 10 g/d of very well done meat, compared with no consumption, was associated with a 1.4-fold increased risk of prostate cancer [95% confidence interval (95% CI), 1.05-1.92] and a 1.7-fold increased risk (95% CI, 1.19-2.40) of incident disease. Although there was no association with MeIQx and DiMeIQx, the highest quintile of PhIP was associated with a 1.2-fold increased risk of prostate cancer (95% CI, 1.01-1.48) and a 1.3-fold increased risk of incident disease (95% CI, 1.01-1.61). In conclusion, very well done meat was positively associated with prostate cancer risk. In addition, this study lends epidemiologic support to the animal studies, which have implicated PhIP as a prostate carcinogen.

Alcohol and tobacco use prediagnosis and postdiagnosis, and survival in a cohort of patients with early stage cancers of the oral cavity, pharynx, and larynx.

As more people begin to survive first cancers, there is an increased need for science-based recommendations to improve survivorship. For survivors of head and neck cancer, use of tobacco and alcohol before diagnosis predicts poorer survival; however, the role of continuing these behaviors after diagnosis on mortality is less clear, especially for more moderate alcohol consumption. Patients (n = 264) who were recent survivors of early stage head and neck cancer were asked to retrospectively report their tobacco and alcohol histories (before diagnosis), with information prospectively updated annually thereafter. Patients were followed for an average of 4.2 years, with 62 deaths observed. Smoking history before diagnosis dose-dependently increased the risk of dying; risks reached 5.4 [95% confidence interval (95% CI), 0.7-40.1] among those with >60 pack-years of smoking. Likewise, alcohol history before diagnosis dose-dependently increased mortality risk; risks reached 4.9 (95% CI, 1.5-16.3) for persons who drank >5 drinks/d, an effect explained by beer and liquor consumption. After adjusting for prediagnosis exposures, continued drinking (average of 2.3 drinks/d) postdiagnosis significantly increased risk (relative risk for continued drinking versus no drinking, 2.7; 95% CI, 1.2-6.1), whereas continued smoking was associated with nonsignificantly higher risk (relative risk for continued smoking versus no smoking, 1.8; 95% CI, 0.9-3.9). Continued drinking of alcoholic beverages after an initial diagnosis of head and neck cancer adversely affects survival; cessation efforts should be incorporated into survivorship care of these patients. (Cancer Epidemiol Biomarkers Prev 2009;18(12):3368–74)

Tumor Characteristics Associated With Mammographic Detection of Breast Cancer in the Ontario Breast Screening Program

BACKGROUND Few studies have compared the prognostic value of tumor characteristics by type of breast cancer diagnosed in the interval between mammographic screenings with screen-detected breast cancers. METHODS We conducted a case-case study within the cohort of women (n = 431 480) in the Ontario Breast Screening Program who were aged 50 years and older and were screened between January 1, 1994, and December 31, 2002. Interval cancers, defined as breast cancers diagnosed within 24 months after a negative screening mammogram, were designated as true interval cancers (n = 288) or missed interval cancers (n = 87) if they were not identified at the time of screening but were identified in retrospect. Screen-detected breast cancers (n = 450) were selected to match interval cancers. Tumors were evaluated for stage, grade, mitotic index, histology, and expression of hormone receptors and odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by conditional logistic regression. RESULTS Both true and missed interval cancers were of higher stage and grade than matched screen-detected breast cancers. However, true interval cancers had a higher mitotic index (OR = 3.13, 95% CI = 1.81 to 5.42), a higher percentage of nonductal histology (OR = 1.94, 95% CI = 1.05 to 3.59), and were more likely to be both estrogen receptor-negative (OR = 2.09, 95% CI = 1.32 to 3.30) and progesterone receptor-negative (OR = 2.49, 95% CI = 1.68 to 3.70) compared with matched screen-detected tumors. CONCLUSIONS In this study, interval cancers were of higher stage and grade compared with screen-detected cancers. True interval cancers were more likely to have additional adverse prognostic features of estrogen and progesterone receptor negativity and nonductal morphology. The findings suggest a need for more sensitive screening modalities to detect true interval breast cancers and different approaches for early detection of fast-growing tumors.

Ovarian Cancer Risk Factors by Histologic Subtype: An Analysis From the Ovarian Cancer Cohort Consortium

PURPOSE An understanding of the etiologic heterogeneity of ovarian cancer is important for improving prevention, early detection, and therapeutic approaches. We evaluated 14 hormonal, reproductive, and lifestyle factors by histologic subtype in the Ovarian Cancer Cohort Consortium (OC3). PATIENTS AND METHODS Among 1.3 million women from 21 studies, 5,584 invasive epithelial ovarian cancers were identified (3,378 serous, 606 endometrioid, 331 mucinous, 269 clear cell, 1,000 other). By using competing-risks Cox proportional hazards regression stratified by study and birth year and adjusted for age, parity, and oral contraceptive use, we assessed associations for all invasive cancers by histology. Heterogeneity was evaluated by likelihood ratio test. RESULTS Most risk factors exhibited significant heterogeneity by histology. Higher parity was most strongly associated with endometrioid (relative risk [RR] per birth, 0.78; 95% CI, 0.74 to 0.83) and clear cell (RR, 0.68; 95% CI, 0.61 to 0.76) carcinomas (P value for heterogeneity [P-het] < .001). Similarly, age at menopause, endometriosis, and tubal ligation were only associated with endometrioid and clear cell tumors (P-het ≤ .01). Family history of breast cancer (P-het = .008) had modest heterogeneity. Smoking was associated with an increased risk of mucinous (RR per 20 pack-years, 1.26; 95% CI, 1.08 to 1.46) but a decreased risk of clear cell (RR, 0.72; 95% CI, 0.55 to 0.94) tumors (P-het = .004). Unsupervised clustering by risk factors separated endometrioid, clear cell, and low-grade serous carcinomas from high-grade serous and mucinous carcinomas. CONCLUSION The heterogeneous associations of risk factors with ovarian cancer subtypes emphasize the importance of conducting etiologic studies by ovarian cancer subtypes. Most established risk factors were more strongly associated with nonserous carcinomas, which demonstrate challenges for risk prediction of serous cancers, the most fatal subtype.

The risk of breast cancer following reproductive surgery

Alteration of exposure to ovarian hormones, by eliminating or impairing the function of one or both ovaries, may affect the risk of breast cancer. To assess the relationship between reproductive surgical procedures and breast cancer risk, we conducted a retrospective cohort study involving 524,709 Ontario women who underwent tubal ligation or other salpingectomy, hysterectomy and/or ovariectomy between 1979 and 1993. Data on type and year of surgery were obtained from hospital records and linked with breast cancer diagnoses recorded in the Ontario Cancer Registry. Observed breast cancers were compared with age- and calendar-period expected rates in Ontario. A decreased risk of breast cancer was observed among women who had undergone either hysterectomy (observed/expected [O/E] = 0.87, P < 0.001) or unilateral ovariectomy (O/E = 0.74, P < 0.001). Bilateral ovariectomy and tubal ligation were associated with reduced risk when the surgery occurred before the age of 45 years, and tubal ligation was protective if performed after the age of 54 years. There was no trend in risk with increasing follow-up. Our data support the hypothesis that reduced levels of endogenous oestrogen may be protective for breast cancer in women.

Influence of Patterns of hormone replacement therapy use and mammographic density on breast cancer detection

Background: There is evidence that factors such as current hormone replacement therapy (HRT) use and mammographic density may each lower the sensitivity of mammography and are associated with a greater risk of developing an interval cancer. This study explores this relationship further by examining the influence of patterns of HRT use and the percentage of mammographic density on the detection of breast cancer by classification of interval cancer. Methods: This study uses a case-case design nested within a cohort of women screened by the Ontario Breast Screening Program between 1994 and 2002. Interval cancers, both those missed at screening but seen on retrospective review (n = 87) or true intervals without visible tumor signs at screening (n = 288) were matched to 450 screen-detected cancers. The association between the percentage of mammographic density, measured by radiologists and a computer-assisted method, and HRT use, ascertained from a mailed questionnaire, and the risk of being diagnosed with an interval cancer was estimated using conditional logistic regression. Results: A monotonic gradient of increasing risk for interval cancers was found for each 25% increase in mammographic density [odds ratio (OR), 1.77; 95% confidence intervals (95% CI), 1.07-2.95 for missed intervals and OR, 2.16; 95% CI, 1.59-2.94 for true intervals]. After adjusting for mammographic density, a significantly increased risk for true-interval cancers remained for women taking estrogen alone (OR, 1.75; 95% CI, 1.11-2.83) as well as for missed- (OR, 2.84; 95% CI, 1.32-6.13) and true-interval cancers (OR, 1.79; 95% CI, 1.10-2.90) for women taking combined HRT. Conclusions: Information on mammographic density and HRT use should routinely be collected at the time of screening. Women at risk should be made aware of the lower sensitivity of mammography and offered alternative procedures for screening. (Cancer Epidemiol Biomarkers Prev 2006;15(10):1856–63)

Estrogen and estrogen–progestin replacement therapy and risk of postmenopausal breast cancer in Canada

Objective: To examine the association between hormone replacement therapy (HRT) use and breast cancer incidence and to determine whether the association differs according to type of regimen. Method: Data were collected in Ontario from 404 incident cases and 403 age frequency-matched controls, between 1995 and 1996, using a self-administered questionnaire. Results: Multivariate analyses revealed an elevated odds ratio among long-term (≥ten years) HRT users (odds ratio (OR) = 1.80, 95% confidence interval (CI) 1.06–3.06). Risk among long-term estrogen–progestin users was substantially higher (OR = 3.48, 95% CI 1.00–12.11) than risk among long-term users of estrogen alone (OR = 1.74, 95% CI 0.93–3.24). Among both estrogen and estrogen–progestin users, positive associations were not observed for durations of use less than ten years. Conclusion: These data suggest that long-term use of HRT increases the risk of breast cancer and that estrogen–progestin therapy may be more detrimental than estrogen use alone.

Aspirin but not ibuprofen use is associated with reduced risk of prostate cancer: A PLCO Study

Background:Although most epidemiological studies suggest that non-steroidal anti-inflammatory drug use is inversely associated with prostate cancer risk, the magnitude and specificity of this association remain unclear.Methods:We examined self-reported aspirin and ibuprofen use in relation to prostate cancer risk among 29 450 men ages 55–74 who were initially screened for prostate cancer from 1993 to 2001 in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Men were followed from their first screening exam until 31 December 2009, during which 3575 cases of prostate cancer were identified.Results:After adjusting for potential confounders, the hazard ratios (HRs) of prostate cancer associated with <1 and ⩾1 pill of aspirin daily were 0.98 (95% confidence interval (CI), 0.90–1.07) and 0.92 (95% CI: 0.85–0.99), respectively, compared with never use (P for trend 0.04). The effect of taking at least one aspirin daily was more pronounced when restricting the analyses to men older than age 65 or men who had a history of cardiovascular-related diseases or arthritis (HR (95% CI); 0.87 (0.78–0.97), 0.89 (0.80–0.99), and 0.88 (0.78–1.00), respectively). The data did not support an association between ibuprofen use and prostate cancer risk.Conclusion:Daily aspirin use, but not ibuprofen use, was associated with lower risk of prostate cancer risk.

Oxidative balance score and risk of prostate cancer: Results from a case-cohort study

BACKGROUND Prostate cancer is a disease with a complex etiology. Oxidative stress has been implicated in its pathogenesis; however, few prospective studies have investigated the association between an oxidative stress/balance score and risk of prostate cancer. METHODS We investigated associations between an oxidative balance score, calculated as the summation of individual scores obtained from five pro-oxidative and eight anti-oxidative exposures, as well as each individual constituent of the score and risks of prostate cancer overall, and by clinical characteristics, in a case-cohort study (661 cases and 1864 subcohort) nested within the Canadian Study of Diet, Lifestyle, and Health cohort. Men in the lowest quintiles of each pro-oxidant exposure received a score of four (the highest score), while those in the highest quintile received a score of zero (the lowest score). In contrast, scoring for all anti-oxidants was performed in the opposite way. Total oxidative balance score was calculated by summating all individual scores of pro- and anti-oxidative variables, with higher values indicating a higher antioxidant status. RESULTS The average oxidative balance score was similar between prostate cancer cases and men in the subcohort: 25.2 and 25.3, respectively. There was no association between oxidative balance score and overall risk of prostate cancer with hazard ratios (HRs) of 1.00, 1.02, 1.03, 0.97 and 1.01 for increasing quintiles of the score (p-trend=0.71). There were also no associations for non-advanced or advanced disease, or when analysis was restricted to incident cases that arose after two years of follow-up (n=508). In general constituents of the score were not associated with prostate cancer, except for red meat intake (HR=1.44; 95%CI 1.06-1.95 comparing Q5 vs. Q1) and lycopene (HRs of 0.7-0.8 for increasing quintiles). CONCLUSION Our findings do not support an association between oxidative balance score and risks of overall prostate cancer or advanced disease.