ONLINE DRIVERS MEDIA

Which of the dirty dozen of supplements and foodstuffs in todays SuppVersity review can really help you to make sure, youre not the one out of those nine men who develops prostate cancer?

Supplements that are supposed to protect you from developing prostate cancer and/or agents that may help patients with existing prostate issues are - obviously - in high demand. And as W. Merkle points out in a recent article in the German science journal Urologe using them - even if they may not be as effective as some patients may believe - makes sense: from a psychological perspective, alone (Merkle. 2014).

Taking a pill with selenium, for example, has been shown to alleviate some of the side effects of chemotherapy. General protective effects against prostate cancer, on the other hand, have not been established. In fact, the most recent studies rather suggest that "supplementation did not benefit men with low selenium status but increased the risk of high-grade PCa among men with high selenium status" (Kristal. 2014).
Luckily, there are other supplements with more promising data. Supplements that will actually complement, a healthy diet and active lifestyle, the two pillars of all (not just prostate) cancer protection. Supplements like...

• Curcumin - As a SuppVersity reader youve probably already expected to see the curcumin on the list. Its potent anti-inflammatory effects and more specifically its ability to target multiple inflammatory pathways, which include NF-KappaB, COX2, STAT3 and high levels of CRP, Prostaglandins and TNF-alpha make it a particularly valuable anti-tumor agent of which Guo et al. observed in a recent study that it will induce cell cycle arrest and apoptosis of prostate cancer cells by regulation the expression of IkappaBalpha, c-Jun and androgen receptor (Guo. 2013)
• Genistein - Just like curcumin, genistein acts on NF-KappaB (Adjakly. 2013). In addition it will upregulate a protein called miR-574- 3p that will have cancer cells "kill themselves" (go into apopotosis; Chiyomaru. 2013). In addition scientists have found genistein to support the efficiacy of Cabazitaxel which is used for the treatment of hormone-refractory prostate cancer.
• Pomegranate - Pomegranate extracts or rather its ingredients, i.e. ellagic acid, caffeic acid, luteolin and punicic acic, have been shown to inhibit the proliferation and induce apoptosis in prostate cancer cells (NCI. 2013).

  Figure 1: If you look at the actual increase in apoptotic cancer cells in response to the pomegranate treatment, it is obvious that some patients (e.g. #53) benefited more than others (Pantuck et al. 2006)

  A clinical trial by Pantuck et al. (2006) was also able to show that the time it takes for the PSA levels, an albeit debatable marker of prostate cancer risk, to double decreased significantly, when the subjects, men with rising PSA after surgery or radiotherapy, were treated with 8 ounces of pomegranate juice daily (Wonderful variety, 570 mg total polyphenol gallic acid equivalents) until disease progression. Unfortunately, a more recent study by Stenner-Liewen et al. (2013) could not confirm these effects. 
• Brassica vegetables (cruciferous vegetables) - While general vegetable intake is already associated with a -39% reduced risk of developing extraprostatic prostate cancer (cancer, eating tons of cruciferous vegetable, it was the intake of broccoli and cauliflower that made the biggest impact in a 2007 study by Kirsh et al.
  
  

  Even if they dont protect you from prostate cancer broccoli & co will inhibit myostatin and could help you to grow more muscle... well, at least theoretically, you know about the difference between the petri dish and the real world, so dont expect monster gains | more.

  As it is usually the case the evidence is yet ambiguous. In a 2002 review of the evidence, Kristal, et al. found that of the six studies they could clearly interpret, only three reported statistically significant reduced risks (P < 0.05), while one reported a borderline significant reduced risk (P = 0.06). Against that background Verhoeven et al. are right, when they say: " Further epidemiological research should separate the anticarcinogenic effect of brassica vegetables from the effect of vegetables in general" (Verhoeven. 1996).
  
  More recently, Joseph et al. found that the existing differences in the epidemiological data may be due to genetic polymorphisms due to which only men with a certain genetic polymorphisms in glutathione S-transferases M1 and T1 will benefit from eating tons of cruciferous veggies (Joseph. 2004).
• Green tea - Green tea is good for everything, right? Well unless its not loaded with toxic molecules (see previous SuppVersity article) this may in fact be right. Convincing evidence from human trials is albeit scarce. What we do have are rodent studies like the ones that were conducted with TRAMP mice, which model closely mirrors the pathogenesis of human prostate cancer.
  
  In these mice EGCG, one of the main catechins in green tea, decreased the proliferation of prostate cancer cells and reduced the PSA levels. Scientists believe that these effects are mainly mediated by the effects EGCG has on the growth promoting proteins ERK1/2. Unfortunately, the same rodent studies also suggest that it is probably too late for many of you to start drinking green tea, now, because said beneficial effects are only observed in young, not in old TRAMP mice (Donald. 2012).

• Coffee is for the ladies, too! Studies show significantly reduced risks of breast cancer with 5+ cups of coffee. Tee and cacao help, as well | more

  Coffee - Obviously I am biased, when it comes to coffee. I still hope you believe me when I say that drinking 5+ cups of coffee per day has been associated with significantly reduced risk of prostate cancer in what is probably the most large-scale meta-analysis of the topic today.
  
  In their meta-analsis of 12 peer-reviewed case-control studies, Lu et al. calculated a 4% risk reduction for Europeans who consumed five or more cups of coffee and Americans who consumed 4 or more regular cups of coffee (equ. to approximately 400-500mg of caffeine). Moreover, the scientist found "a significant inverse association in all categories of prostate cancer except Gleason <7 grade" in both the "fixed-effects model" and the "random-effects model" (Lu. 2014).
  
  Wilson et al. also report an inverse association between coffee consumption and the incidence of highly malignant prostate cancer (Wilson. 2013). This means that drinking coffee is not only going to reduce your overall risk of developing prostate and other cancers (Geybels. 2013), it will also increase your chance that in the unfortunate case you still develop cancer, its going to be a benign and treatable form of prostate cancer.
• Lignans (e.g. from flaxseed) - While many of you will probably know them as "bad anti-androgens", there is little doubt that lignans from flax and other foodstuff inhibit cancer growth. What is particularly interesting about these agents is that they dont work via the "regular" NF-kappaB pathway but inhibit the expression of the vascular endothelial growth favtor (VEGF; cf. Azrad. 2013).
• Lycopene - Its the bright red carotene and carotenoid pigment and phytochemical that gives tomatoes and other red fruits and vegetables, such as red carrots, watermelons, gac, and papayas, although not in strawberries, red bell peppers, or cherries their color.
  
  Based on the currently available evidence it appears to help not just with prostate, but also with pancreatic, intestinal and lung cancer (Giovannucci. 1999). In that, it makes a particularly effective adjunct to classic cancer therapy (Tang. 2011).

  Figure 2: Prostate cancer risk w/ high vs. low intakes of the given antioxidants according to XRCC1 genotype (Goodman. 2006)

  Unfortunately, the data is ambigious... as usual. Unlike for other agents, it does yet appear as if scientists have already identified a certain gene, i.e. XRCC1, which appears to determine whether you do or do not benefit from the consumption of increased amounts of tomato lycopene (Goodman. 2006).
  
  In view of the fact that certain genotypes actually increase their prostate cancer risk specifically if they are consuming both, a high amount of lycopene and vitamin E (alpha-tocopherol), the latest Cochrane Review on the protective effects of lycopene against prostate cancer considers the evidence for "preliminary" and "insufficient" (Ilic. 2011).
• Fish oil / omega-3 - In spite of the fact that the media jumped at the finding of the SELECT trial (learn more) that claimed that selenium would be bad, while a high fish consumption or rather a high amount of omega-3s in the blood would protect you against prostate cancer, a close re-analysis of the data you can read up on at the website of the Life Extension Foundation indicates that this was all media hype.
  
  With a de facto difference of only 0.18% the difference was... well, youd say a joke, scientists would say "within the margin of statistical error" and thus by no means significant. If you take an even closer look at the data, it would even seem as if omega-3 fatty acids would increase the risk of prostate cancer.
• Resveratrol - If you look at the existing evidence you will be surprised to find studies that indicate that resveratrol increases (Klink. 2013) and studies that show that it inhibits prostate cancer growth (Iguchi. 2012; Kai. 2011).
  
  Again, it took a closer look at the data and another experiment to find out what really was going on: a dose-dependent effect with increased risk with low and decreased risk with high doses of resveratrol (Benitez. 2007). Bad news: With the current low biovailable oral resveratrol preparations youre likely to end up in the "increased risk" resveratrol exposure zone.
• Selenium - While I have mentioned it in the introduction already, its certainly worth taking a closer look at what selenium is actually supposed to do.
  
  In their 2011 review of the literature, Rizky Abdulah et al. didnt just highlight the many different molecular pathways, by which selenium could protect you from developing cancer, they also point out that the type of selenium supplement used could be of critical importance with respect to the success of your efforts to avoid the development of cancer. In that,...

  In rodents selenium acts as corrosion inhibitor in the brain | learn more

  "[...] methylselenol is believed to be the critical metabolite in selenium chemoprevention. Since methylselenol is highly reactive, methylselenol precursors such as Semet and Se-mSC are important both in in vitro and in vivo experiments. Semet and Se-mSC conversion to methylselenol, however, requires enzymatic conversion by the enzyme ?-lyase, which is 800 times less prevalent in human tissues than in mouse tissues.

  This may explain why the results of Semet and Se-mSC anticancer studies in humans were not as impressive as in vivo experiments. Although researchers have now turned to other Se compounds such as mSeA, which do not need enzymatic conversion to methylselenol, or selenite, which does not need to be converted to methylselenol for its anticancer properties, more substantial research on selenium compound metabolism in human tissues is necessary." (Abdulah. 2011)

  In other words, as of now, we dont know which form of selenium we actually have to use in human trials to generate similar impressive results as they have been observed in rodents.
  
  And as if that wasnt already "bad" enough, a meta-analysis of intervention studies by Hurst et al. (2012) indicates that there is a very narrow "band" of serum concentrations, where selenium is actually good for you! When your selenium level passes 170 ng/ml the tumor-protective effect disappears and - worst case scenario - your risk increases. So remember: More does certainly not help more!
• Silibin (from milk thistle) - You probably think of milk thistle as a "liver supplement". In fact, its main active constituent will yet also reduce the efficacy of osteoclast cytokines and reduce the concentration of RANKL-ligands. Thus it will regulate the NF-?B und AP1 levels in cells and inhibit the proliferation, invasion and migration of metastatic prostate cancer (Ting. 2011; Chen. 2012) 
• Vitamin D - Believe it or not: There are things vitamin D3 cannot do! One of this things is to protect you prostate cancer. Thats the prerogative of active vitamin D aka calciferol. In rodent studies and studies on human cell lines calciferol and multiple analogs of active vitamin D have shown to be promising drugs for prostate cancer protection, though (Tokar. 2005).
  
  

  Underestimated Vitamin D Sources: Eggs, Chicken, Pork, Fish & Dairy Contain Ready-Made 25OHD | more

  Since simply popping tons of vitamin D3 is (luckily) without effect on the levels of calciferol (otherwise you would run the risk of being calcified from the currently prevalent abuse of vitamin D3 supplements), using vitamin D3 is less effective, but not useless.
  
  In 2010, for example, Woo et al. observed that the time it took for the PSA levels of prostate cancer patients to double was significantly reduced, when the subjects received 2,000 IU of vitamin D3 per day (Woo. 2005) - an effect of which previous in vitro studies suggest that it could be due to the local conversion of D3 to active vitamin D in prostate cancer cells (Tokar. 2005).
• Vitamin E - Needless to say that vitamin E has gotten a bad rep ever since scientists observed an increased risk when they gave the subjects of the SELECT trial vitamin E (learn more). Still, as long as you stay away from "classic" vitamin E and buy one of the still expensive tocotrienol supplements (or eat red palm oil), you can expect an anti-proliferative effect of the vitamins E (Conte. 2004; Srivastava. 2006)

References:

• Abdulah, Rizky, et al. "Molecular targets of selenium in prostate cancer prevention (Review)." International journal of oncology 39.2 (2011): 301-309. 
• Andersson, Swen-Olof, et al. "Lifestyle factors and prostate cancer risk: a case-control study in Sweden." Cancer Epidemiology Biomarkers & Prevention 5.7 (1996): 509-513.
• Azrad, Maria, et al. "Flaxseed-derived enterolactone is inversely associated with tumor cell proliferation in men with localized prostate cancer." Journal of medicinal food 16.4 (2013): 357-360.
• Benitez, Dixan A., et al. "Mechanisms Involved in Resveratrol?Induced Apoptosis and Cell Cycle Arrest in Prostate Cancer—Derived Cell Lines." Journal of andrology 28.2 (2007): 282-293. 
• Chen, Rongxin, et al. "The significance of MMP-9 over MMP-2 in HCC invasiveness and recurrence of hepatocellular carcinoma after curative resection." Annals of surgical oncology 19.3 (2012): 375-384.
• Chiyomaru, Takeshi, et al. "Genistein up-regulates tumor suppressor microRNA-574-3p in prostate cancer." PloS one 8.3 (2013): e58929. 
• Conte, Carmela, et al. "??Tocotrienol Metabolism and Antiproliferative Effect in Prostate Cancer Cells." Annals of the New York Academy of Sciences 1031.1 (2004): 391-394.
• Donald, J. L. "Plasma metabolic profiling reveals age-dependency of systemic effects of green tea polyphenols in mice with and without prostate cancer." Molecular BioSystems 6.10 (2010): 1911-1916.
• Geybels, Milan S., et al. "Coffee and tea consumption in relation to prostate cancer prognosis." Cancer Causes & Control 24.11 (2013): 1947-1954. 
• Giovannucci, Edward. "Tomatoes, tomato-based products, lycopene, and cancer: review of the epidemiologic literature." Journal of the National Cancer Institute 91.4 (1999): 317-331.
• Guo H, Xu YM, Ye ZQ, Yu JH, Hu XY. "Curcumin induces cell cycle arrest and apoptosis of prostate cancer cells by regulating the expression of IkappaBalpha, c-Jun and androgen receptor." Pharmazie 68.6 (2013):431-4.
• Hurst, Rachel, et al. "Selenium and prostate cancer: systematic review and meta-analysis." The American journal of clinical nutrition 96.1 (2012): 111-122.
• Iguchi, Kazuhiro, et al. "Antiandrogenic activity of resveratrol analogs in prostate cancer LNCaP cells." Journal of andrology 33.6 (2012): 1208-1215. 
• Joseph, Michael A., et al. "Cruciferous vegetables, genetic polymorphisms in glutathione S-transferases M1 and T1, and prostate cancer risk." Nutrition and cancer 50.2 (2004): 206-213.
• Kai, Li, and Anait S. Levenson. "Combination of resveratrol and antiandrogen flutamide has synergistic effect on androgen receptor inhibition in prostate cancer cells." Anticancer research 31.10 (2011): 3323-3330.
• Kirsh, Victoria A., et al. "Prospective study of fruit and vegetable intake and risk of prostate cancer." Journal of the National Cancer Institute 99.15 (2007): 1200-1209.
• Klink, Joseph C., et al. "Resveratrol worsens survival in SCID mice with prostate cancer xenografts in a cell?line specific manner, through paradoxical effects on oncogenic pathways." The Prostate 73.7 (2013): 754-762.
• Kristal, Alan R., et al. "Baseline selenium status and effects of selenium and vitamin E supplementation on prostate cancer risk." Journal of the National Cancer Institute 106.3 (2014): djt456.
• Lu, Yu, et al. "Coffee consumption and prostate cancer risk: an updated meta-analysis." Cancer Causes & Control 25.5 (2014): 591-604. 
• Merkle, W. "Prostatakarzinomprophylaxe durch Nahrungsergänzungsmittel." Der Urologe (2014): 1-7.
• NCI (2013) Pomegranate: prostate cancer, nutrition and dietary supplements (PDQ). NCI, Bethesda. http://www.cancer.gov
• Ornish, Dean, et al. "Intensive lifestyle changes may affect the progression of prostate cancer." The Journal of urology 174.3 (2005): 1065-1070.
• Pantuck, Allan J., et al. "Phase II study of pomegranate juice for men with rising prostate-specific antigen following surgery or radiation for prostate cancer." Clinical Cancer Research 12.13 (2006): 4018-4026.
• Putnam, Shannon D., et al. "Lifestyle and anthropometric risk factors for prostate cancer in a cohort of Iowa men." Annals of epidemiology 10.6 (2000): 361-369.
• Stenner-Liewen, Frank, et al. "Daily Pomegranate Intake Has No Impact on PSA Levels in Patients with Advanced Prostate Cancer-Results of a Phase IIb Randomized Controlled Trial." Journal of Cancer 4.7 (2013): 597. 
• Srivastava, Janmejai K., and Sanjay Gupta. "Tocotrienol-rich fraction of palm oil induces cell cycle arrest and apoptosis selectively in human prostate cancer cells." Biochemical and biophysical research communications 346.2 (2006): 447-453.
• Tang, Yaxiong, et al. "Lycopene enhances docetaxels effect in castration-resistant prostate cancer associated with insulin-like growth factor I receptor levels." Neoplasia 13.2 (2011): 108-119. 
• Ting, Harold, Gagan Deep, and Rajesh Agarwal. "Molecular mechanisms of silibinin-mediated cancer chemoprevention with major emphasis on prostate cancer." The AAPS journal 15.3 (2013): 707-716. 
• Tokar, Erik J., and Mukta M. Webber. "Chemoprevention of prostate cancer by cholecalciferol (vitamin D3): 25-hydroxylase (CYP27A1) in human prostate epithelial cells." Clinical & experimental metastasis 22.3 (2005): 265-273.
• Verhoeven, Dorette T., et al. "Epidemiological studies on brassica vegetables and cancer risk." Cancer Epidemiology Biomarkers & Prevention 5.9 (1996): 733-748.
• Wilson, Kathryn M., et al. "Coffee and risk of prostate cancer incidence and mortality in the Cancer of the Prostate in Sweden Study." Cancer Causes & Control 24.8 (2013): 1575-1581.
• Woo, Tony Choon Seng, et al. "Pilot study: potential role of vitamin D (cholecalciferol) in patients with PSA relapse after definitive therapy." Nutrition and cancer 51.1 (2005): 32-36.

Dont fall for someone who overgeneralizes, misreports or -interprets study results to tell you that healthy mid-range testosterone levels were a major trigger of cancer development.

I just got an email from my good friend Carl Lanore who hosts the Super Human Radio Show I am sure you have already seen in the sidebar of the SuppVersity. He pointed me towards the results of a recent study from the Copenhagen University Hospital saying "Adel have you seen this? Im sure the media will be all over it." Since Carl is usually pretty good at identifying things that "news" make headlines, I would like to leapfrog the mass media craze before any of you consider cutting off their best parts to end up in the allegedly healthy depth of quasi zero testosterone.

You have no clue what I am talking about? Well, I am about to elaborate. You just have to stay with me for the rest of a comparatively long, but insightful (I promise) analysis of the study and related contemporary evidence.
So, where do I begin?  The "mass media compatible message" of the abstract (and this is usually not even as far as most headline producers read) says: Having normal testosterone levels increases your risk of dying from cancer before your time by at least 30%! The more testosterone, the likelier you will pass away before your expiry date."

Well, as I said, this is the mainstream interpretation. And interpretation anyone could identify as being fundamentally flawed by simply reading the abstract carefully. In fact, you dont even have to read the whole 268 words! It would suffice to read the end of the first line of the result section, where it says:

"For risk of early death after cancer, for men [...]" (Ørsted. 2014)

Did you notice it? There is an "after cancer" in this sentence. This means, your risk of dying, if you develop cancer is increased, if [whatever follows]. Now, that which follows is ...

• if you are in the 2nd quartile, your risk will be increased by 30%,
• if you are in the 3rd quartile, your risk will be increased by 31%,
• if you are in the 4th quartile, your risk will be increased by 52% and
• if you are in the 5th quartile, your risk will be increased by 80%.

So, if you happen to be unlucky enough to develop cancer and your testosterone levels are high there is in fact an increased risk you could die from cancer.

So testosterone is still bad, right? Yes, but anything that is "anabolic", i.e. promotes the growth of all cells in your body is "bad" for someone who has cancer. Guess what chemotherapy will to do your testosterone levels and the amount of other pro-anabolic factors in your body? It will wreak havoc on your testes (Wallace. 1997), reduce their size to that of dried raisins, increase your risk of gynecomastia and reduce your testosterone levels to exactly those 6-10 nmol/L (Whitehead. 1982) of which the previously cited study by Ørsted et al. found that they are associated with the least risk of dying from already existing cancer in your body.

Figure 1: If you look at a random assemble of the myriad of risk associations that have been established for low T, the results of the study at hand do no longer appear to be that frightening - right?

A result that conceals the established negative effects of having low testosterone (see Figure 1) or depressing it which androgen deprivation therapy which may reduce the testosterone levels to the allegedly desirable range, but is associated with a 350% (!) increased risk of dieing from cardiovascular disease in prostate cancer patients (Tsai. 2007). I guess this should make you reconsider the "usefulness" of low testosterone levels.

But there is also an increase in cancer risk, no?

Yes, there is. According to the scientists it is (I quote) "1.07 (95% CI 0.98–1.18) and 1.06 (0.93–1.22) for men and women" if you compare say a man with 10nmol/L to a man with 20nmol/L. Now, as far as I can remember a 95% confidence interval, which is what you see in brackets, i.e. for men 0.98-1.18, defines the range in which the chance that the hypothesis that is tested, i.e. "testosterone influences the risk of prostate cancer" has a 5% chance of not being bullocks... ah, I mean statistical significant.
So, the scientists are 95% sure that a 2x higher testosterone level will be associated with a 2% decrease and 18% increase in... does this ring a bell? Yeah, thats not exactly a reliable prediction considering the fact that the researchers adjusted for smoking status, cumulative smoking, body mass index, alcohol consumption, level of education, and level of income for men and women, but "forgot" to adjust for...

• family history of cancer, which is one of the, if not the main correlate of your risk of developing various cancer, such as prostate cancer (1000% increase, no typo | Steinberg. 1990), colon cancer (up to 59% risk increase depending on the region | Slattery. 1994) or breast cancer (145% risk increase with first-degree relative having breast cancer | Slattery. 1993) 
• diabetes, which has been found to be associated with a 60% increase in colorectal cancer risk in patients who have been diagnosed with diabetes 10+ years ago (La Vecchia. 1997), a
• the level of visceral fat, where high levels (relative to total body fat) are associated with 850% increased risk of breast cancer (Schapira. 1994) and up to 1000% increased prostate cancer risk (Hafe. 2004)
• low sleep duration and quality, which has been associated with an increased risk of developing almost every form of cancer you can think of (Blask. 2009), including 60% increased breast cancer risk for women working the "graveyard shift" (Davis. 2001)

I could go on with all sorts of nutritional factors, medication (specifically hormonal contraceptives) the amount of exercise, the area you live in, your year of birth and hundreds of other factors that have previously been associated with an increase of cancer risk, but I guess the above should suffice to make you less confident that a "confidence interval" of 0.98–1.18 in men and 0.93–1.22 in women was enough to make the claim that "having a high testosterone level would [mechanistically!] trigger the development of cancer.
References:

• Araujo, Andre B., et al. "Endogenous testosterone and mortality in men: a systematic review and meta-analysis." The Journal of Clinical Endocrinology & Metabolism 96.10 (2011): 3007-3019.
• Blask, David E. "Melatonin, sleep disturbance and cancer risk." Sleep medicine reviews 13.4 (2009): 257-264.
• Davis, Scott, Dana K. Mirick, and Richard G. Stevens. "Night shift work, light at night, and risk of breast cancer." Journal of the national cancer institute 93.20 (2001): 1557-1562.
• Garavello, Werner, et al. "Family history and the risk of oral and pharyngeal cancer." International journal of cancer 122.8 (2008): 1827-1831.
• Hafe, Pedro, et al. "Visceral fat accumulation as a risk factor for prostate cancer." Obesity research 12.12 (2004): 1930-1935.
• La Vecchia, Carlo, et al. "Diabetes mellitus and colorectal cancer risk." Cancer Epidemiology Biomarkers & Prevention 6.12 (1997): 1007-1010.
• Morgentaler, Abraham. "Testosterone and prostate cancer: an historical perspective on a modern myth." european urology 50.5 (2006): 935-939.
• Raynaud, Jean-Pierre. "Prostate cancer risk in testosterone-treated men." The Journal of steroid biochemistry and molecular biology 102.1 (2006): 261-266.
• Roddam, Andrew W., et al. "Endogenous sex hormones and prostate cancer: a collaborative analysis of 18 prospective studies." Journal of the National Cancer Institute 100.3 (2008): 170-183.
• Slattery, Martha L., and Richard A. Kerber. "A comprehensive evaluation of family history and breast cancer risk: the Utah Population Database." Jama 270.13 (1993): 1563-1568.
• Slattery, Martha L., and Richard A. Kerber. "Family history of cancer and colon cancer risk: the Utah Population Database." Journal of the National Cancer Institute 86.21 (1994): 1618-1626.
• Schapira, David V., et al. "Visceral obesity and breast cancer risk." Cancer 74.2 (1994): 632-639.
• Shores, Molly M., et al. "Low serum testosterone and mortality in male veterans." Archives of internal medicine 166.15 (2006): 1660-1665.
• Stattin, Pär, et al. "High levels of circulating testosterone are not associated with increased prostate cancer risk: a pooled prospective study." International journal of cancer 108.3 (2004): 418-424.
• Steinberg, G. D., Carter, B. S., Beaty, T. H., Childs, B. and Walsh, P. C. (1990), Family history and the risk of prostate cancer. Prostate, 17: 337–347. doi: 10.1002/pros.2990170409 
• Tsai, Henry K., et al. "Androgen deprivation therapy for localized prostate cancer and the risk of cardiovascular mortality." Journal of the National Cancer Institute 99.20 (2007): 1516-1524. 
• Ujpál, Márta, et al. "Diabetes and Oral Tumors in Hungary Epidemiological correlations." Diabetes care 27.3 (2004): 770-774.
• Wallace, Euan M., et al. "Effects of chemotherapy-induced testicular damage on inhibin, gonadotropin, and testosterone secretion: a prospective longitudinal study." The Journal of Clinical Endocrinology & Metabolism 82.9 (1997): 3111-3115.
• Whitehead, E., et al. "The effects of Hodgkins disease and combination chemotherapy on gonadal function in the adult male." Cancer 49.3 (1982): 418-422.

Red (meat) breast cancer alert!

Its not the first study and I am pretty sure its not going to be the last study to link red meat and cancer, but in view of the fact that I am pretty sure that the results Maryam S Farvid and colleagues present in their latest paper in the British Journal of Medicine are going to be all over the place this week, I feel that its worth to give you an unbiased overview of the results before you are confronted with the sensational press release celebrating the newest "Harvard science" - a source people trust, one that "propagates the truth" and one that is (ab-)used by press release writers to generate the impression that each and every word they write is true.

Well the truth is that we are dealing with yet another prospective epidemiological study which does not have the power to reveal causal links between parameter (a), in this case the dietary protein sources in early adulthood and parameter (b), which is the incidence of breast cancer.
The average ignoramus will still read the headlines as "red meat" causes cancer and think of poultry, fish, eggs, legumes, and nuts as "the cure". In contrast to the red meat intake which was associated with a 22% risk increase in the 2830 documented cases of breast cancer the scientists had been collecting and following for 20 years, the a higher intake of poultry, fish, eggs, legumes, and nuts was
not just unrelated to breast cancer, in postmenopausal women, a high poultry intake was even associated with a -27% reduced breast cancer risk.

Energy intake and cancer risk expressed relative to lowest intake quintile for red meat (Farvid. 2014)

The latter observation gives rise to one of the (imho) hilarious substitute this for that equations, where the "estimating the effects of exchanging different protein sources, substituting one serving/day of legumes for one serving/day of red meat was associated with a 15% lower risk of breast cancer among all women (0.85, 0.73 to 0.98) and a 19% lower risk among premenopausal women (0.81, 0.66 to 0.99). Substituting poultry for red meat was even associated with 17% and 24% lower breast cancer risk in all and postmenopausal women.

Unlike the fooled readers of the press release, the researchers are obviously aware of the weaknesses of the study, in the discussion of the results, Farvid et al. point out that "potential limitations need to be considered":

• participants were predominantly white, educated US adults, they cannot determine whether our findings are generalizable to other race or ethnic groups
• dietary intake was assessed by food frequency questionnaires, some degree of measurement error is inevitably present, and thus to reduce measurement error they used the cumulative average of
  multiple measurements in a sensitivity analysis
• residual confounders are always of concern in any observational studies; although they adjusted for a wide range of potential confounders for breast cancer, they still could not rule out the possibility that other unmeasured or inadequately measured factors have confounded the true association
• they only estimated the effects of substitution of legumes, poultry, and other protein sources for red meat on risk of breast cancer, when trials on dietary modification would be ideal to support these substitutions

In addition, the scientists made multiple comparisons (different food groups and nutrients, premenopausal and postmenopausal subgroups, and subtype of tumors) in this analysis, and can thus not exclude the possibility of type I errors. But (sarcasm) this is not so much of concern, "the central finding of an association with red meat was [after all] a prior hypothesis." (Farvid. 2014) - In other words: What do you want people, weve just made sure we confirm our hypothesis.
Reference:

• Farvid, et al. "Dietary protein sources in early adulthood and breast cancer incidence: prospective cohort study." BMJ 2014;348:g3437 doi: 10.1136/bmj.g3437