Michael J, Howard LE, Markt SC, et al. Early-life alcohol intake and high-grade prostate cancer: results from an equal access, racially diverse biopsy cohort. Am Assoc Cancer Res (Phila). 2018.
To test the association between early-life alcohol consumption and prostate cancer diagnosis, including tumor aggressiveness at time of diagnosis.
Men aged 49 to 89 at the Veterans Affairs (VA) Medical Center in Durham, North Carolina undergoing a prostate biopsy between January 2007 and January 2018. Only men with a prostate-specific antigen (PSA) test within 12 months prior to enrollment and no history of prostate cancer, who also completed the questionnaire and consented to a prostate biopsy, were included in the study.
Study Parameters Assessed
Questionnaire, which included demographic, medical and lifestyle characteristics, number of alcoholic drinks per week for each decade of life, and number of cigarettes per day for each decade of life; weight and height to calculate BMI; digital rectal examination (DRE) findings; prostate volume; serum PSA level; prostate cancer grade from biopsy using the Epstein 5-grade system.
Patient characteristics were summarized based on alcohol consumption at ages 15 to 19 using Kruskal-Wallis test for continuous variables and chi-squared test for categorical variables. Logistic regression was used to test the association between alcohol consumption and prostate cancer grade at diagnosis and association between alcohol consumption and prostate cancer by race; white vs non-white; P values <0.05 were considered statistically significant. Statistical analyses were performed using SAS v9.4.
Biopsy was performed on 1,221 (77%) of the 1,595 eligible men. Biopsy results were missing on 12 men, 528 men did not complete the questionnaire, and 31 men were missing covariates, leaving a study cohort of 650 participants. Age at biopsy ranged from 49 to 89 years old and 47% were white. Median PSA was 5.7 ng/mL. From ages 15 to 19, 317 (49%) men reported not drinking, 279 (43%) reported 1 to 6 drinks per week, and 54 (8%) reported ≥7 drinks per week. Men who reported ≥7 drinks per week at 15 to 19 years old also reported more smoking pack-years (P<0.001). Half of the 650 participants (n=325) were diagnosed with prostate cancer; 238 were grade 1 or 2, and 88 were grade 3, 4, or 5.
Results of statistical analyses included the following:
- There was no association between alcohol intake at ages 15 to 19 and odds of prostate cancer diagnosis; P=0.57 and P=0.76, respectively.
- 1 to 6 drinks per week at ages 20 to 29, 1 to 6 drinks per week at ages 30 to 39 and ages 40 to 49, and ≥7 drinks per week at ages 30 to 39 and 40 to 49 were associated with increased odds of prostate cancer diagnosis.
- ≥7 drinks per week was not significantly associated with prostate cancer for ages 30 to 39 and 40 to 49.
- There was no association between alcohol intake and odds of low-grade prostate cancer at ages 15 to 19, and not with any other decade of life.
- ≥7 drinks per week at ages 15 to 19 was significantly associated with increased odds of high-grade prostate cancer, with a significant trend across categories of increasing alcohol intake (P=0.020). Similar trends were seen for ages 20 to 29 (P=0.034), ages 30 to 39 (P=0.19), and ages 40 to 49 (P=0.007).
- Current alcohol consumption was not significantly associated with high-grade prostate cancer diagnosis.
- There was no difference in associations between alcohol consumption and overall prostate cancer diagnosis between white and non-white men.
- The middle tertile for cumulative lifetime alcohol consumption was associated with a moderate increase in overall and low-grade prostate cancer diagnosis but this trend was not significant. Men in the highest tertile of cumulative lifetime alcohol consumption had increased risk of high-grade prostate cancer diagnosis (odds ratio [OR]: 3.20) compared to the lowest tertile, with a significant trend for high-grade prostate cancer diagnosis (P=0.003).
Male military veterans with heavier alcohol consumption earlier in life were more likely to be diagnosed with high-grade prostate cancer when compared to men without early-life consumption. Higher cumulative alcohol consumption in tertiles was also associated with increased odds of high-grade prostate cancer. Current level of alcohol consumption did not correlate with either overall or high-grade prostate cancer diagnosis.
What are the risk factors for developing prostate cancer? According to the United Kingdom’s National Health Service, risk factors include age over 50, African-Caribbean or African ethnicity, family history of a male relative who developed prostate cancer before age 60 or a close female relative with breast cancer, obesity, and a high-calcium diet.1 The Mayo Clinic cites age, race (higher risk and more advanced and aggressive in black men), family history of prostate cancer or breast cancer, and obesity.2 Alcohol is not currently on these lists, but this study suggests it could be.
We know that life choices can affect risk for many cancers: sedentarism and colon cancer, smoking and lung cancer, and obesity and breast cancer, to name a few.
In 1988 the International Agency for Research on Cancer (IARC) classified alcoholic beverages as carcinogenic.3 There is a strong association of high alcohol consumption with oral, pharyngeal, esophageal, laryngeal, breast, bowel, and liver cancers. Tobacco use increases the ability of the mouth and throat to absorb carcinogens that may be found in alcohol. This includes at least 18 known carcinogens such as acetaldehyde, acrylamide, aflatoxins, arsenic, benzene, ethanol, ethyl carbamate formaldehyde, furan, glycophosphate, lead, and others identified by IARC monograph reviews. While alcohol, which may contain many of these other carcinogens, is itself listed as a carcinogen, any lead, arsenic, acetaldehyde, cadmium, and ethyl carbamate content can be mitigated by good manufacturing practices.3
The most plausible mechanisms of alcohol consumption causing cancer include the genotoxic effects of acetaldehyde, generation of reactive oxygen species by cytochrome P450 (CYP450) 2E1, aberrant metabolism of folate and retinoids, increased estrogen, and various genetic polymorphisms that affect its metabolism.4 Alcohol also appears to be immunosuppressive, which would support both tumor progression and metastasis.
Ethanol is rapidly absorbed through the small intestine wall and is metabolized by alcohol dehydrogenases to acetaldehyde in the cytosol of liver cells. This acetaldehyde enters the mitochondria where it is oxidized by mitochondrial aldehyde dehydrogenase (ALDH) to form acetate.4 During high alcohol consumption, CYP450 2E1, which is found in peroxisomes (inside cells), catalyzes ethanol into acetaldehyde and reactive oxygen species byproducts. This latter pathway may be involved in carcinogenesis. Compared to consumption under 40 g ethanol per day, consumption of 50 g of ethanol (one-half bottle of wine, 3 beers, or 3 ounces of distilled spirits) per day increases esophageal cancer risk 2-fold to 3-fold; 80 g per day increases hepatocellular carcinoma risk 4.5-fold to 7.3-fold. Ethanol enhances catabolism of retinoic acid via CYP450 2E1 and also upregulates estrogen, and thus may favor proliferation and malignant transformation of precancerous cells.4
Alcohol is excreted in urine as ethyl glucuronide (ET), detectable above 500 ng/mL. Identification of ET is a very effective method of monitoring alcohol consumption in individuals who are being counseled to avoid alcohol. In one study, the use of 120 mL (4 ounces) of hand sanitizer containing 62% alcohol over the course of a day led to a positive urine alcohol test in 8 of 11 participants at the end of the day.5 Ethyl glucuronide can be detected 30 to 110 hours after consumption of a single beverage.6 The effect of ET on the prostate does not appear to be significant but is largely unknown.
Prior studies on the relationship between alcohol consumption and prostate cancer have been mixed. A meta-analysis published in 2000 found no association.7 Three meta-analyses from 2001, 2009, and 2012 found a modest increase in risk with increasing levels of alcohol consumption.8-10 A more recent meta-analysis found a significant relationship between quantity of alcohol consumed and overall prostate cancer risk and mortality.11 The present study found an association between early life, heavier alcohol consumption, and high-grade prostate cancer.
We know that life choices can affect risk for many cancers: sedentarism and colon cancer, smoking and lung cancer, and obesity and breast cancer, to name a few. If the results of the present study should prove true in future analyses, then all integrative practitioners have a responsibility to educate patients about the risks associated with alcohol consumption in their conversations about prostate cancer prevention.
Critiques of this study are several. This is a recall study so bias and the risks of underreporting are possible. Recall information was not collected until after prostate cancer was diagnosed, so alcohol consumption may be underestimated. In this study, 39% were excluded because they did not complete the questionnaire, leading to a high risk of selection bias. Interestingly, the excluded cohort tended to be younger and African-American, with a higher PSA at biopsy. African-Americans have an increased risk of prostate cancer so there is a very real potential for bias. Also, prostate cancer was diagnosed by a biopsy that samples less than 1% of prostate tissue. False negatives, which in this study would have been in the control group, are a clinical reality in about 35% of prostate biopsies.12 In addition, the “non-drinker” cohort used for comparison included previous drinkers who were no longer drinkers, not a pure teetotaler sample. On a positive note, 54% of the study participants were non-white. Overall this study appeared to be well-designed and well-executed and challenges were acknowledged and addressed.
In this cohort of 650 men at the Durham VA Medical Center with biopsy-proven prostate cancer, heavier consumption of alcohol at an early age significantly increased the risk of high-grade prostate cancer on diagnosis. Higher cumulative consumption of alcohol was also associated with increased odds of biopsy-proven high-grade prostate cancer. Current alcohol consumption revealed no correlation with overall prostate cancer or high-grade prostate cancer at diagnosis.