Alcohol and risk of breast cancer in postmenopausal women: an analysis of etiological heterogeneity by multiple tumor characteristics.

Alcohol consumption is an established risk factor for breast cancer. Whether associations vary by specific tumor characteristics independent of other characteristics is unclear. We evaluated the association between alcohol consumption and breast cancer risk in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial cohort (54,562 women aged 55-74 years recruited at 10 US screening centers between 1993 and 2001; median follow-up, 8.9 years; 1,905 invasive breast cancer cases). Hazard ratios and 95% confidence intervals for subtypes defined by histological type and estrogen receptor (ER)/progesterone receptor (PR) status were calculated with standard Cox models. A novel 2-stage Cox model assessed heterogeneity in risk for individual tumor characteristics while adjusting for others. Significant trends across categories of alcohol consumption were observed, with hazard ratios for those consuming 7 or more drinks per week versus never drinkers as follows: for estrogen receptor-positive (ER+) cancer, 1.48 (95% confidence interval (CI): 1.19, 1.83); for progesterone receptor-positive (PR+) cancer, 1.64 (95% CI: 1.31, 2.06); for ER+/PR+ cancer, 1.63 (95% CI: 1.30, 2.05); and for mixed ductal/lobular cancer, 2.51 (95% CI: 1.20, 5.24). For ER+ and PR+ cancers, trends were significant for ductal and mixed ductal/lobular types. PR status explained the positive association with ER status (for ER status, Pheterogeneity=0.70 after adjustment for PR status). Alcohol consumption was not associated with all breast cancer subtypes. Future work should emphasize large collaborative studies, precise definition of subtypes, and adjustment for correlated tumor characteristics.

Modified Gleason grade of prostatic adenocarcinomas detected in the PLCO cancer screening trial.

PURPOSE: We determined the modified Gleason grade of prostatic adenocarcinomas detected in PLCO to assess grade distribution and compare modified Gleason grades of cancer detected in the intervention arm (organized annual screening) vs the control arm (opportunistic screening). MATERIALS AND METHODS: Modified Gleason grading was performed in 859 radical prostatectomy cases by a single urological pathologist. We compared the proportion of cases with high grade disease in the screened arm vs the control arm by logistic regression analysis. RESULTS: In the intervention arm a modified Gleason score of 5, 6, 7 (3+4), 7 (4+3), 8, 9 and 10 was assigned in 3.6%, 43.3%, 39%, 7.4%, 3.5%, 3.2% and 0.1% of cases, respectively. In the control arm a modified Gleason score of 5, 6, 7 (3+4), 7 (4+3), 8, 9 and 10 was assigned in 3.0%, 35.7%, 46.4%, 7.1%, 5.4%, 1.9% and 0.5% of cases, respectively, after correcting for high grade disease over sampling. A high grade modified Gleason score of 7 or greater was detected in 53% of cases in the intervention arm vs 61.3% in the control arm after correction (p=0.019). The median modified Gleason score was 7 (3+4) in each arm. CONCLUSIONS: A significant percent of cancers in each arm had a component of high grade disease. The modified Gleason grade of prostate cancers detected by organized annual screening was slightly lower than the modified grade of those detected by opportunistic screening. This is an expected consequence of more intensive screening.

Long-term disease-specific functioning among prostate cancer survivors and noncancer controls in the prostate, lung, colorectal, and ovarian cancer screening trial.

PURPOSE: Within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO), we assessed the long-term disease-specific functioning among prostate cancer (PCa) survivors versus noncancer controls, the impact of trial arm (screening/usual care) on functioning, and the effect of treatment modality on functioning. PATIENTS AND METHODS: PCa survivors (n = 529), 5 to 10 years postdiagnosis, were frequency-matched to noncancer controls (n = 514) for race, screening center, year of enrollment, and trial arm. Participants completed a telephone interview regarding PCa-specific symptomatology. Weights accounted for patient selection from the five PLCO screening centers. Propensity-score methods were used to balance groups of interest with respect to demographic and medical characteristics. RESULTS: Weighted linear regression analyses revealed poorer sexual and urinary function among PCa survivors compared with noncancer controls (P < .001). Trial arm was not significantly related to any outcome (P > .31). Compared with radical prostatectomy patients (n = 201), radiation-therapy patients (n = 110) reported better sexual (P < .05) and urinary (P < .001) functioning but poorer bowel outcomes (P < .05). Survivors who received treatment combinations including androgen deprivation (n = 207) reported significantly poorer hormone-related symptoms compared with radical prostatectomy patients (P < .05). CONCLUSION This study demonstrated the persistence of clinically significant, long-term PCa treatment-related sexual and urinary adverse effects up to 10 years postdiagnosis. To our knowledge, this was the first comparison of prostate-related dysfunction among screened survivors versus screened noncancer controls and indicated that these long-term problems were attributable to PCa treatment and not to aging or comorbidities. Finally, differences in long-term adverse effects between treatment modalities are particularly relevant for patients and clinicians when making treatment decisions.

Pancreatic cancer risk: associations with meat-derived carcinogen intake in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) cohort.

BACKGROUND: Epidemiological studies report positive associations between high-temperature cooked meat intake and pancreatic cancer. We assessed associations between dietary intake of heterocyclic amines (HCAs) and benzo(a)pyrene (BaP)-mutagens formed in meat cooked at high temperatures-and incident exocrine pancreatic cancer in a prospective cohort. METHODS: The 62 581 subjects randomized to screening in the Prostate, Lung, Colorectal, and Ovarian Screening Trial (PLCO) who completed an initial dietary survey that assessed meat intake, cooking methods, and doneness preferences defined the cohort. Subjects were surveyed annually for incident cancers through 2007. A National Cancer Institute research database (CHARRED) was used to estimate HCA and BaP intake and a Mutagenic Activity Index (MAI) from survey data. Proportional hazard ratios (HRs) for risk of pancreatic cancer were estimated from multi-variate Cox regression models by quintile of intake, with the lowest quintile as the referent. RESULTS: During follow-up (median: 10 yr), 248 cases of exocrine pancreatic cancer were confirmed. Preferences for well and very well done meat were generally associated with increased risks. Significant elevations in pancreatic cancer risk were found in upper quintiles of MAI, and individual mutagens 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (DiMeIQx) and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx). Compared to the lowest quintile of MAI, the third and fifth quintiles brought HRs of 1.86 (1.22, 2.85) and 1.87 (1.16, 3.02), respectively. These three exposures exhibited significant (P-trend: 0.01-0.03) positive trends in risk as their levels increased CONCLUSION: Consuming well-done meat cooked at high temperatures, which contains high mutagen levels, appears to confer increased risk of pancreatic cancer.

Serum prostate-specific antigen hemodilution among obese men undergoing screening in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial.

BACKGROUND: Previous studies have shown an inverse relationship between prostate-specific antigen (PSA) concentration and body mass index (BMI). It has been recently proposed that this relationship may be explained by the larger plasma volume of obese men diluting a fixed amount of PSA (hemodilution effect). We examined this hypothesis in a cohort of men enrolled in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. METHODS: Of 38,349 men ages 55 to 74 years randomized in PLCO to receive annual PSA and digital rectal examination screening, 28,380 had a baseline PSA, complete demographic information, and no prostate cancer diagnosis within 6 years from baseline. Self-reported height and weight were used to calculate BMI and to estimate plasma volume. PSA mass was estimated as PSA concentration times plasma volume. Multivariable linear regression models were used to investigate the relationship between PSA concentration, plasma volume, PSA mass, and BMI. RESULTS: PSA concentration significantly decreased with increasing BMI (P<0.001); mean PSA values were 1.27, 1.25, 1.18, and 1.07 ng/mL among normal (BMI, 18.5-25), overweight (BMI, 25-30), obese (BMI, 30-35), and morbidly obese (BMI, >35) men, respectively. However, plasma volume also increased with increasing BMI and PSA mass showed no association with BMI, with mean values of 3.78, 3.95, 3.97, and 3.82 microg across the four BMI categories (P=0.10). CONCLUSIONS: This study confirms earlier findings that the inverse relationship between PSA concentration and BMI may be explained by a hemodilution effect. These findings could have implications for prostate cancer screening in large men.

Prostate cancer screening in the Prostate, Lung, Colorectal and Ovarian cancer screening trial: update on findings from the initial four rounds of screening in a randomized trial.

OBJECTIVE: To describe the results of the first four rounds (T0-T3) of prostate cancer screening in the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial (designed to determine the value of screening in the four cancers), that for prostate cancer is evaluating whether annual screening with prostate-specific antigen (PSA) and a digital rectal examination (DRE) reduces prostate cancer-specific mortality. SUBJECTS AND METHODS: In all, 38 349 men aged 55-74 years were randomized to undergo annual screening with PSA (abnormal >4.0 ng/mL) and a DRE. The follow-up of abnormal screening results was at the discretion of subjects' physicians. PLCO staff obtained records related to diagnostic follow-up of positive screen results. RESULTS: Compliance with screening decreased slightly from 89% at baseline to 85% at T3. Both PSA positivity rates (range 7.7-8.8% at T0-T3) and DRE positivity rates (range 6.8-7.6% at T0-T3) were relatively constant over time. The positive predictive value (PPV) of a PSA level of >4.0 ng/mL decreased from 17.9% at T0 to 10.4-12.3% at T1-T3; the PPV for DRE (in the absence of a positive PSA test) was constant over time (2.9-3.6%). Cancer was diagnosed in 1902 men (4.9%). Screen-detected cancers at T0 (549) were more likely to be clinical stage III/IV (5.8%) and to have a Gleason score of 7-10 (34%) than screen-detected cancers at T1-T3 (1.5-4.2% stage III/IV and 24-27% Gleason score 7-10 among 1054 cases). CONCLUSION: The present findings on serial prostate screening are similar to those reported from other multi-round screening studies. Determining the effect of PSA screening on prostate cancer mortality awaits further follow-up.

Melanoma, thyroid, cervical, and colon cancer risk after use of fertility drugs.

OBJECTIVE: This study was undertaken to evaluate melanoma, thyroid, colon, and cervical cancer risks after clomiphene or gonadotropins. STUDY DESIGN: Retrospective cohort of 8422 women (155,527 women-years) evaluated for infertility (1965-1988). Through 1999, cancers were ascertained by questionnaire, cancer and death registries. Poisson regression estimated adjusted rate ratios (RRs). RESULTS: Clomiphene use did not significantly increase risk of melanoma (RR=1.66; 95% CI, 0.9-3.1), thyroid (RR=1.42; 95% CI, 0.5-3.7), cervical (RR=1.61; 95% CI, 0.5-4.7), or colon cancer (RR=0.83; 95% CI, 0.4-1.9). We found no relationship between clomiphene dose or cycles of use and cancer risk at any site. Clomiphene use may impart stronger effects on risks of melanoma (RR=2.00; 95% CI, 0.9-4.6) and thyroid cancer among women who remained nulliparous (RR=4.23; 95% CI, 1.0-17.1). Gonadotropins did not increase cancer risk for these sites. CONCLUSION: Fertility drugs do not appear to have strong effects on these cancers. Nonetheless, follow-up should be pursued to assess long-term risks and to monitor effects among women who remain nulliparous.

Causes of infertility as predictors of subsequent cancer risk.

BACKGROUND: Although studies have found elevated risks of certain cancers linked to infertility, the underlying reasons remain unclear. METHODS: In a retrospective cohort study of 12,193 U.S. women evaluated for infertility between 1965 and 1988, 581 cases of cancer were identified through 1999. We used standardized incidence ratios (SIRs) to compare cancer risk with the general population. Analyses within the cohort estimated rate ratios (RRs) associated with infertility after adjusting for other risk predictors. RESULTS: Infertility patients demonstrated a higher cancer risk than the general population (SIR = 1.23; 95% confidence interval [CI] = 1.1-1.3), with nulligravid (primary infertility) patients at even higher risk (1.43; 1.3-1.6). Particularly elevated risks among primary infertility patients were observed for cancers of the uterus (1.93) and ovaries (2.73). Analyses within the cohort revealed increased RRs of colon, ovarian, and thyroid cancers, and of melanomas associated with endometriosis. Melanomas were linked with anovulatory problems, whereas uterine cancers predominated among patients with tubal disorders. When primary infertility patients with specific causes of infertility were compared with unaffected patients who had secondary infertility, endometriosis was linked with distinctive excesses of cancers of the colon (RR = 2.40; 95% CI = 0.7-8.4), ovaries (2.88; 1.2-7.1), and thyroid (4.65; 0.8-25.6) cancers, as well as melanomas (2.32; 0.8-6.7). Primary infertility due to anovulation particularly predisposed to uterine cancer (2.42; 1.0-5.8), and tubal disorders to ovarian cancer (1.61; 0.7-3.8). Primary infertility associated with male-factor problems was associated with unexpected increases in colon (2.85; 0.9-9.5) and uterine (3.15; 1.0-9.5) cancers. CONCLUSIONS: The effects of infertility may extend beyond gynecologic cancers. Thyroid cancers and melanomas deserve specific attention, particularly with respect to endometriosis.

Ovarian cancer risk associated with varying causes of infertility.

OBJECTIVE: To evaluate the risk of ovarian cancer as related to underlying causes of infertility. DESIGN: Retrospective observational cohort study. SETTING: Five large reproductive endocrinology practices. PATIENT(S): A total of 12,193 women evaluated for infertility between 1965 and 1988. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Ovarian cancer ascertained through 1999. RESULT(S): With 45 identified ovarian cancers, this cohort of infertility patients demonstrated a significantly higher rate of ovarian cancer than the general female population (standardized incidence ratio [SIR] = 1.98; 95% confidence interval [CI], 1.4-2.6). The risk was higher for patients with primary infertility (SIR = 2.73) than for those with secondary infertility (SIR = 1.44), and it was particularly high for patients who never subsequently conceived (SIR = 3.33). Women with endometriosis had the highest risk (SIR = 2.48; 95% CI, 1.3-4.2), with a further elevated risk among those with primary infertility (4.19, 2.0-7.7). Comparisons among the infertile women, which allowed calculation of rate ratios (RRs) after adjustment for multiple factors, also showed links with endometriosis. Compared with women with secondary infertility without endometriosis, patients with primary infertility and endometriosis had a RR of 2.72 (95% CI, 1.1-6.7). CONCLUSION(S): Determination of ovarian cancer risk should take into account the type of infertility (primary vs. secondary) and underlying causes. Further study of endometriosis may provide insights into ovarian carcinogenesis.

Breast cancer risk associated with ovulation-stimulating drugs.

BACKGROUND: Despite the recognized role of hormones in the aetiology of breast cancer, there has been little evaluation of hormonal preparations used to treat infertility. METHODS: A retrospective cohort study of 12,193 women evaluated for infertility between 1965 and 1988 at five clinical sites identified 292 in situ and invasive breast cancers in follow-up through 1999. Standardized incidence ratios (SIRs) compared breast cancer risks with those of the general population. Analyses within the cohort estimated rate ratios (RRs) associated with medications after adjustment for other breast cancer predictors. RESULTS: Infertile patients had a significantly higher breast cancer risk than the general population [SIR = 1.29, 95% confidence interval (CI) 1.1-1.4]. Analyses within the cohort showed adjusted RRs of 1.02 for clomiphene citrate and 1.07 for gonadotrophins, and no substantial relationships to dosage or cycles of use. Slight and non-significant elevations in risk were seen for both drugs after > or = 20 years of follow-up (RRs = 1.39 for clomiphene and 1.54 for gonadotrophins). However, the risk associated with clomiphene for invasive breast cancers was statistically significant (RR = 1.60, 95% CI 1.0-2.5). CONCLUSIONS: Although there was no overall increase in breast cancer risk associated with use of ovulation-stimulating drugs, long-term effects should continue to be monitored.

Ovarian cancer risk after the use of ovulation-stimulating drugs.

OBJECTIVE: To assess the long-term effects of ovulation-stimulating drugs on the risk of ovarian cancer. METHODS: A retrospective cohort study of 12,193 eligible study subjects (median age 30 years) who were evaluated for infertility during the period of 1965-1988 at 5 clinical sites identified 45 subsequent ovarian cancers in follow-up through 1999. Standardized incidence ratios compared the risk of cancer among the infertile patients to the general population, whereas analyses within the cohort allowed the derivation of rate ratios for drug usage compared with no usage after adjustment for other ovarian cancer predictors. RESULTS: The infertility patients had a significantly elevated ovarian cancer risk compared with the general population (standardized incidence ratio 1.98, 95% confidence intervals [CI] 1.4, 2.6). When patient characteristics were taken into account and risks assessed within the infertile women, the rate ratios associated with ever usage were 0.82 (95% CI 0.4, 1.5) for clomiphene and 1.09 (95% CI 0.4, 2.8) for gonadotropins. There were higher, albeit nonsignificant, risks with follow-up time, with the rate ratios after 15 or more years being 1.48 (95% CI 0.7, 3.2) for exposure to clomiphene (5 exposed cancer patients) and 2.46 (95% CI 0.7, 8.3) for gonadotropins (3 exposed cancer patients). Although drug effects did not vary by causes of infertility, there was a slightly higher risk associated with clomiphene use among women who remained nulligravid, based on 6 exposed patients (rate ratio 1.75; 95% CI 0.5, 5.7). CONCLUSION: The results of this study generally were reassuring in not confirming a strong link between ovulation-stimulating drugs and ovarian cancer. Slight but nonsignificant elevations in risk associated with drug usage among certain subgroups of users, however, support the need for continued monitoring of long-term risks. LEVEL OF EVIDENCE: II-2