NATAP: Red Meat & Prostate Cancer

[Guest guest]

"In summary, this collaborative analysis of worldwide data on IGFs and their main binding proteins and prostate cancer risk demonstrates that the higher the circulating level of IGF-I, the greater the subsequent risk for prostate cancer. Given the need to identify modifiable risk factors for prostate cancer (36), the current results suggest IGF-I as a possible candidate because it is both associated with the disease and is potentially modifiable through its association with many dietary and lifestyle factors (37–40)."39. Giovannucci E, Pollak M, Liu Y, Platz EA, Majeed N, Rimm EB, et al. Nutritional predictors of insulin-like growth factor I and their relationships to cancer in men. Cancer Epidemiol Biomarkers Prev. 2003;12:84-9. [PMID: 12582016].[Abstract/Free Full Text]In summary, a diet high in protein and minerals in middle-aged to elderly men was associated with higher plasma IGF-I and IGF-I:IGFBP-3. The influence of such a diet on overall health in aging individuals, including cancer risk, requires additional study......The major sources of animal protein, including milk, fish, and poultry, but not red meat, as well as total vegetable protein, were associated with an increase in IGF-I levels.....The dietary factors most closely related to high IGF-I and IGF-I:IGFBP-3 ratios included high intake of fish, poultry, and total milk, the most important sources of essential amino acids and minerals. These findings were similar to the Nurses’ Health Study analysis (18) , which found milk and fish but not red meat associated with higher IGF-I levels. Both animal and plant sources of protein were independently related to IGF-I, strongly indicating that protein, and not a correlate, was the actual factor. The lack of an association between red meat intake and plasma IGF-I was somewhat surprising, because red meat is an important source of protein and some minerals. Some potential contributing factors were that red meat consumption was relatively low in this health conscious population, and men consuming lower intakes of red meat tended to eat more fish and slightly less mineral intake overall. Supporting this supposition, in this population, red meat intake was only moderately correlated with total protein intake (r = 0.18) but inversely correlated with mineral intake (r = -0.11)....Another important finding of our study is that cow milk may increase IGF-I levels, but when we controlled for protein and minerals, milk was no longer a significant factor. In a recent randomized intervention study of 204 healthy men and women 55–85 years of age, individuals who consumed three servings per day of nonfat or 1% fat milk for 12 weeks had a statistically significant 10% increase in serum IGF-I levels compared with those who consumed no milk (17) . Milk contains IGF-I, regardless of treatment of the cows with recombinant bovine somatotropin for milk production, but whether intact growth factor can be absorbed with milk and increase circulating IGF-I levels is unknown (24, 25, 26) . Some recent animal data indicate that some IGF-I can be absorbed intact from milk (27) , but most experts do not believe that IGF-I would retain bioactivity if ingested p.o. because of rapid proteolysis in the upper gut (24 , 25) . Our findings from multivariate models suggest that the major influence of milk on IGF-I levels is likely related to its nutrient content, although we cannot exclude the possibility of additional increases in IGF-I induced by milk intake from recombinant bovine somatotropin-treated cows.40. NE, Appleby PN, Davey GK, Key TJ. Hormones and diet: low insulin-like growth factor-I but normal bioavailable androgens in vegan men. Br J Cancer. 2000;83:95-7. [PMID: 10883675].[Medline]Mean serum insulin-like growth factor-I was 9% lower in 233 vegan men than in 226 meat-eaters and 237 vegetarians (P = 0.002). Vegans had higher testosterone levels than vegetarians and meat-eaters, but this was offset by higher sex hormone binding globulin, and there were no differences between diet groups in free testosterone, androstanediol glucuronide or luteinizing hormoneInsulin-like Growth Factors, Their Binding Proteins, and Prostate Cancer Risk: Analysis of Individual Patient Data from 12 Prospective Studies

ls of Internal Medicine7 October 2008 | Volume 149 Issue 7 | Pages 461-471 W. Roddam, DPhil; Naomi E. , DPhil; Appleby, MSc; J. Key, DPhil; Luigi Ferrucci, MD; H. Ballentine , MD; E. Metter, MD; Chu Chen, PhD; Noel S. Weiss, MD; Annette Fitzpatrick, PhD; Ann W. Hsing, PhD; V. Lacey, Jr, PhD; Kathy Helzlsouer, MD; Sabina Rinaldi, PhD; Elio Riboli, MD; Rudolf Kaaks, PhD; Joop A.M.J.L. Janssen, MD; Mark F. Wildhagen, PhD; Fritz H. Schröder, MD; A. Platz, ScD; Pollak, MD; Giovannucci, MD; Schaefer, PhD; P. Quesenberry, Jr., PhD; ph H. Vogelman, DEE; Gianluca Severi, PhD; Dallas R. English, PhD; Graham G. Giles, PhD; Pär Stattin, MD; Göran Hallmans, MD; Mattias Johansson, PhD; June M. Chan, ScD; Gann, MD; E. Oliver, PhD; Jeff M. Holly, PhD; Donovan, PhD; François Meyer, MD; Isabelle Bairati, MD; and Pilar Galan, MDEditors' Notes

Context

    * Insulin-like growth factors (IGFs) and IGF binding proteins may be associated with some cancers.

Contribution

    * This reanalysis of individual patient data from 12 studies of the association between IGFs and IGF binding proteins and prostate cancer suggests that higher levels of serum IGF-I are associated with higher risk for prostate cancer.

Caution

    * The 12 studies varied in the types of patients they studied and in how they measured IGFs.

Implication

    * High IGF-I levels seem to be a risk factor for prostate cancer.

—The EditorsABSTRACTBackground:  Some, but not all, published results have shown an association between circulating blood levels of some insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) and the subsequent risk for prostate cancer.

Purpose: To assess the association between levels of IGFs and IGFBPs and the subsequent risk for prostate cancer.

Data Sources: Studies identified in PubMed, Web of Science, and CancerLit.

Study Selection: The principal investigators of all studies that published data on circulating concentrations of sex steroids, IGFs, or IGFBPs and prostate cancer risk using prospectively collected blood samples were invited to collaborate.

Data Extraction: Investigators provided individual participant data on circulating concentrations of IGF-I, IGF-II, IGFBP-II, and IGFBP-III and participant characteristics to a central data set in Oxford, United Kingdom.

Data Synthesis: The study included data on 3700 men with prostate cancer and 5200 control participants. On average, case patients were 61.5 years of age at blood collection and received a diagnosis of prostate cancer 5 years after blood collection. The greater the serum IGF-I concentration, the greater the subsequent risk for prostate cancer (odds ratio [OR] in the highest vs. lowest quintile, 1.38 [95% CI, 1.19 to 1.60]; P < 0.001 for trend). Neither IGF-II nor IGFBP-II concentrations were associated with prostate cancer risk, but statistical power was limited. Insulin-like growth factor I and IGFBP-III were correlated (r = 0.58), and although IGFBP-III concentration seemed to be associated with prostate cancer risk, this was secondary to its association with IGF-I levels. Insulin-like growth factor I concentrations seemed to be more positively associated with low-grade than high-grade disease; otherwise, the association between IGFs and IGFBPs and prostate cancer risk had no statistically significant heterogeneity related to stage or grade of disease, time between blood collection and diagnosis, age and year of diagnosis, prostate-specific antigen level at recruitment, body mass index, smoking, or alcohol intake.

Limitations: Insulin-like growth factor concentrations were measured in only 1 sample for each participant, and the laboratory methods to measure IGFs differed in each study. Not all patients had disease stage or grade information, and the diagnosis of prostate cancer may differ among the studies.

Conclusion: High circulating IGF-I concentrations are associated with a moderately increased risk for prostate cancer.Prostate cancer is one of the most common types of cancer in men, yet few risk factors for the disease, other than age, race, and a family history, have been established (1, 2). Insulin-like growth factors (IGFs) and their associated binding proteins (IGFBPs) have been the subject of many epidemiologic investigations of prostate cancer because they are known to help regulate cell proliferation, differentiation, and apoptosis (3). Although results from some, but not all, studies suggest an association between IGFs and IGFBPs and prostate cancer risk, there has been much uncertainty about its consistency and magnitude. A previous meta-analysis that included only 3 prospective studies suggested that high levels could be associated with more than a 2-fold increase in risk (4), although recent studies have suggested the risk is lower. Furthermore, given that these peptides are correlated with each other, uncertainty remains about any observed relationships. The individual studies are rarely large enough to allow proper mutual adjustment for these correlated factors, and they are insufficiently powered to investigate the consistency of their findings in key subgroups (for example, stage and grade of disease). Such analyses are important because studies have suggested that IGF-I might be more associated with advanced than with localized disease (5, 6).

The Endogenous Hormones and Prostate Cancer Collaborative Group was established to conduct collaborative reanalyses of individual data from prospective studies on the relationships between circulating levels of sex hormones and IGFs and subsequent prostate cancer risk. Results for the sex hormones have been reported elsewhere and show no statistically significant relation between androgen or estrogen levels in men and the subsequent risk for prostate cancer (7). We report results for concentrations of IGFs and IGFBPs.Discussion

This collaborative analysis of individual data from 12 studies found that increasing levels of circulating IGF-I were statistically significantly associated with a moderately increased risk for subsequent prostate cancer. Insulin-like growth factor binding protein III concentrations were also associated with an increased risk, but IGFBP-III is correlated with IGF-I, and the association was no longer evident after adjustment for IGF-I. Neither IGF-II nor IGFBP-II was associated with risk for prostate cancer, although these analyses were based on much less information than that for IGF-I and IGFBP-III. Further adjustment for potential confounding variables made little difference to any of the risk estimates. The association of serum IGF-I levels was somewhat stronger for low-grade than high-grade cancer, but this could be due to chance.

This collaborative analysis includes information from 12 of the 13 prospective studies that published information on IGFs, IGFBPs, and prostate cancer. The only study that we did not include had 100 case patients with prostate cancer (20) and reported no association between IGF-I or IGFBP-III levels and prostate cancer risk. We also include further unpublished data from the Health Professionals Follow-up Study. After the database was closed for analysis, 3 further studies with 141, 727, and 96 case patients of prostate cancer have been published (23–25). One reported a small association between IGF-I and prostate cancer risk (23), 1 reported no association (25), and 1 reported an association of a similar magnitude to our collaboration (24). Including these additional studies in the collaboration would not have materially changed our results, and our findings therefore provide a reliable summary of the totality of the evidence on the association between IGF and IGFBP levels and prostate cancer risk.

The increase in prostate cancer risk associated with serum IGF-I concentration is thought to be related to the mitogenic and antiapoptotic effects of IGF-I (3, 26–28). The overall bioactivity of IGF-I is the result of a series of complex interactions among IGF-I, its binding proteins, and their cellular receptors. More than 90% of circulating IGF-I is bound to IGFBP-III and an acid-labile subunit, which cannot transfer from the circulation to the target tissues. A decrease in circulating levels of IGFBP-III has been suggested to result in a relative increase in bioactive IGF-I. Thus, a decreased IGFBP-III concentration might perhaps be expected to be associated with an increased risk for prostate cancer. However, recent in vitro experiments have shown that IGFBP-III can modulate the effects of IGF-I and, under some conditions, enhance the proliferative effects of IGFs (28, 29).

Our study showed a modest correlation between IGF-I and IGFBP-III levels, reflecting the fact that growth hormone largely controls synthesis of both peptides and IGF-I is bound and stabilized by IGFBP-III. After mutual adjustment, the increased risk between IGF-I and prostate cancer remained, whereas the association with IGFBP-III was attenuated. This suggests that the association of IGFBP-III with prostate cancer risk is secondary to the association with IGF-I. In addition, the association of IGFBP-III and prostate cancer risk had statistically significant heterogeneity among studies, which may reflect differences in the assays used by different studies (Appendix Table, shows detailed descriptions of laboratory methods). It has been suggested that different assays may have different specificities for the intact and the nonintact, proteolytically cleaved forms of IGFBP-III; furthermore, specificities may have changed over time owing to recalibration, making comparisons among methods (and hence studies) difficult to interpret (30).No obvious biological mechanism can explain the apparent stronger association of IGF-I with low-grade than high-grade disease, and this may be a chance finding. The distinction between low- versus high-grade cancer is unlikely to represent 2 distinct types of disease, and prostate cancer grading has varied considerably over time, making interpretation of this finding difficult (31). Studies with uniform procedures for grading cancer are needed to investigate this finding further.

We found no evidence that high circulating levels of IGF-II or IGFBP-II are related to an increased risk for prostate cancer, although with few case patients, statistical power was limited (we had approximately 80% power to detect an OR of 1.7).

Detection of localized prostate cancer has increased substantially since the introduction of the PSA test in the late 1980s (32). The mix of a growing proportion of early, localized cancers with a decreasing number of advanced cancers can lead to difficulty in the interpretation of studies, particularly because some early-stage PSA-detected cancers never progress to clinical disease (33). The lead time associated with PSA testing (number of years earlier the tumor is detected by testing) has been estimated to be as high as 12 years in men age 55 years (34). We did not have detailed information on each participant's PSA screening history or on which of the tumors were PSA detected. However, the lack of any detectable heterogeneity in risk estimates, according to tumor characteristics, suggests that the introduction of PSA testing and differences in its use in various populations are unlikely to have unduly influenced the associations.

Our study has several limitations. The analysis relies on measurement of IGF in only 1 sample at 1 time point. These single measures provide an imperfect estimate of a man's usual hormonal status and are influenced both by within-person errors and analytic errors. However, because both types of error are likely to lead to attenuation of the relationship between IGF concentration and risk, this would imply that the true association between IGF-I and prostate cancer risk may be greater. Although a single IGF measurement has been shown to reliably reflect average exposure over a few years (16), whether it also adequately reflects lifetime exposure is unknown. Insulin-like growth factors play a major role in growth during childhood (35), and circulating IGF concentration during this period could also be an important exposure window for subsequent prostate cancer development.

A further limitation is that many of the studies did not record information on the clinical diagnosis of cancer, such as basis of diagnosis, biopsy protocol, or staging criteria, or on how these may have changed over time. However, with no evidence of heterogeneity among studies and stability in the estimates with year of diagnosis, such differences are unlikely to have had a major influence on the results. Furthermore, some of the studies were based within randomized trials, and the participants may therefore have benefited from closer investigation and clinical follow-up. However, after excluding these studies, we obtained essentially the same results. Finally, the IGF levels vary among studies, which may be mostly due to differences in assay methods (Appendix Table). Our method of analysis allows for this by defining study quintiles of hormone concentration and pooling study specific estimates of ORs. This method assumes that the quintiles are similar among studies, and if this assumption is not true, estimates of the OR may be biased. However, because heterogeneity was not evident among studies and the distributions of IGF-I concentration were not expected to differ greatly among the men in the different studies, this assumption seems reasonable.

In summary, this collaborative analysis of worldwide data on IGFs and their main binding proteins and prostate cancer risk demonstrates that the higher the circulating level of IGF-I, the greater the subsequent risk for prostate cancer. Given the need to identify modifiable risk factors for prostate cancer (36), the current results suggest IGF-I as a possible candidate because it is both associated with the disease and is potentially modifiable through its association with many dietary and lifestyle factors (37–40).