Contrary to expectation based on studies examining pre-diagnostic intakes, our results suggest that among prostate cancer patients, overall intakes of milk and dairy products are not associated with a greater risk of lethal prostate cancer. We observed decreased risk of lethal disease among men with higher intakes of post-diagnostic low-fat dairy intake, and increased risk of lethal prostate cancer among men with higher intakes of whole milk.
Evidence linking milk and dairy intake with risk of total prostate cancer incidence are inconclusive, but some data support a link with incidence of high stage, high grade, and/or fatal prostate cancer(4
). Furthermore, some studies support a link between low-fat milk intake and risk of total prostate cancer, whereas other studies support an association for whole milk. Secondary data analysis from randomized clinical trials, and prior analyses from this cohort, have suggested that calcium intake is related to lower risk of PSA screening-detected low-grade prostate cancer, but positively related to risk of advanced disease(41
). In light of this, our finding of an inverse association between low-fat dairy intake and risk of lethal prostate cancer should be interpreted with caution. Moreover, there was no apparent trend when considering the individual hazard ratios of the different quintiles of low-fat dairy intake (). In addition, even though biochemical recurrence is an imprecise predictor of prostate cancer death (56
), we found no inverse association between milk and dairy intake and risk of progression when biochemical and clinical recurrence was considered the endpoint. Although we were able to control for several known or suspected risk factors for prostate cancer progression, high intake of low-fat dairy products may be a marker for some other lifestyle factor which in turn has a protective effect on lethal prostate cancer. There could also be residual confounding due to measurement error of some factors we were able to control for. It is also possible, however, that high intake of low-fat dairy products after a prostate cancer diagnosis has a true protective effect on risk of lethal disease. Factors or mechanisms that act after diagnosis and treatment are likely different from those that act early in prostate carcinogenesis. Rather than exerting effects on the primary tumor cells, factors operating after diagnosis and treatment presumably have effects on circulating tumors cells or micro-metastases, or on their target organs such as the bones. For instance, high post-diagnostic calcium and vitamin D intake from milk and other dairy foods could potentially decrease, rather than increase, metastatic growth by suppressing the levels of parathyroid hormone (PTH) and lowering the rate of bone resorption(58
), factors that may influence skeletal metastases and progression in prostate cancer(60
We found an increased risk of lethal prostate cancer among men with the highest versus lowest whole milk intake. A factor abundant in whole milk that may increase prostate cancer progression is saturated fat. High saturated fat intake has been associated with an increased risk of prostate cancer and a higher risk of biochemical recurrence after prostatectomy(48
). However, we found no positive association between intake of total high fat dairy products and risk of lethal prostate cancer, or biochemical recurrence and clinical progression. In addition, on average, less than 10% of the total amount of dairy fat consumed by the men in this cohort came from whole milk. Taken together, these findings suggest that some component in whole milk other than saturated fat may be associated with an increased risk of progression. It is also possible that the positive association between whole milk intake and risk of progression in our study is explained by residual confounding due to measurements error of potential confounding factors or unmeasured potential confounding factors, or by chance.
As exploratory analyses, we investigated if the association between milk and dairy intake and prostate cancer endpoints differed by Gleason score or median age at diagnosis. There was some evidence of an increased risk of lethal prostate cancer, as well as biochemical recurrence and clinical progression, among men with high skim and low-fat milk intake and total milk intake and Gleason score <7 tumors, and at the same time a decreased the risk among men with Gleason score ≥7 tumors. It is unclear what mechanism or factor would create such a pattern, and this interaction needs to be confirmed in other studies as it may have been due to chance. Also, we found no strong evidence in favor of an interaction between milk and dairy intake and median age at diagnosis.
In our previous study among 1,202 men diagnosed with prostate cancer between 1986 and 1996, we found a suggestion of an 30% increased risk of progression (HR 1.30; 95% CI: 0.93-1.83), defined primarily by biochemical recurrence, among men with the highest versus lowest post-diagnostic total milk intake(49
). With additional follow-up, we did not find that total milk intake is associated with an increased risk of prostate cancer progression; the HR in the current study was 0.89 (95% CI: 0.58-1.37) for lethal prostate cancer, and 1.08 (95% CI: 0.84-1.39) for biochemical recurrence and clinical progression (i.e., the endpoint in the current study comparable to the endpoint used in the previous study). Part of these discrepancies in the point estimates may be explained by biochemical recurrence being an imprecise proxy for lethal prostate cancer. Moreover, the previous study included men diagnosed with local or regional disease, whereas our current analysis included only men with apparently localized disease at diagnosis. Thus, the previous and the current study are not fully comparable in terms of inclusion criteria, cohort size, number of endpoints, or time period of follow-up. The new cases included in the present analysis were mainly PSA-detected and therefore diagnosed at an earlier stage in the natural history of prostate cancer, which could explain some of the difference in the current findings. It should be noted, however, that in the previous study we did not examine low fat/skim milk and whole milk separately; this distinction appeared to be important in our current analyses.
There are several strengths and limitations to consider in interpreting our findings. To define stage at cancer diagnosis, we relied on medical records and to some extent on self report (<6%). This could have led to inclusion of some men with extra-prostatic disease at diagnosis. However, any misclassification of stage is likely unrelated to dairy intake and thus it is unlikely that such bias should have any effect on the risk estimates. Another limitation of this study is that we were unable to investigate finer categories, in terms of fat content, of milk intake in relation to risk of prostate cancer progression because of the phrasing of the questions in the food frequency questionnaires. We were for example unable to separate intake of 2% fat milk from intake of other skim and low-fat milk products. This precluded us from indentifying potentially informative associations in finer categories of milk intake. In addition, the participants were predominately Caucasian, and therefore our findings may not be generalizable to other ethnic groups. Strengths of this study include the prospective design, complete long follow-up (up to 20 years), validated repeated follow-up questionnaires, and large number of lethal endpoints. We used repeated measurements of intake of milk and other dairy foods, which allowed us to evaluate potential changes in dairy (as well as adjust for measurement error).
In summary, with the exception of whole milk, our results suggest that overall milk and dairy intakes after diagnosis are not associated with a greater risk of distant metastases and prostate cancer death.