HOW TO PREVENT CANCERS

Last week new data were released adding to the evidence on the harmful effects of hormone therapy on breast cancer incidence and mortality (story). This timely report released in October when so much media attention focuses on breast cancer detection, treatment and prevention, brings further evidence to show how hormones cause breast cancer. Here I put these results in some perspective of findings from studies over the past 20 years.

Numerous studies that have evaluated trends in breast cancer over time consistently show that since the result of the Women’s Health Initiative were published in 2002 rates of breast cancer have declined in parallel with the drop in use of combination estrogen plus progestin (Prempro). Combination therapy, estrogen plus progestin, causes breast cancer and is classified as a carcinogen by the IARC (International Agency for Research on Cancer 2007). Strong evidence that use of hormone therapy can act as a late promoter of cancer in women comes from evidence relating unopposed estrogen and endometrial cancer. With the acknowledgment of this cause and effect relation in the 1970s, a sharp drop in estrogen prescribing led to a parallel rapid decrease in incidence of endometrial cancer (Austin and Roe 1982). Uptake of estrogen plus progestin therapy was somewhat slow, and epidemiologic data in the US were limited in their ability to separate effects of combination therapy from that of unopposed estrogen. However, by 1995 prospective data from the Nurses’ Health Study indicated that estrogen plus progestin therapy was not protective against breast cancer and the increase in risk may be greater than for estrogen alone (Colditz, Hankinson et al. 1995). Furthermore, mortality from breast cancer was significantly elevated in women who had used hormones prior to diagnosis. Estrogen alone remained the treatment of choice for women without a uterus. Between the mid-1970s and the mid-1980s, incidence of estrogen receptor-positive tumors increased an average of 131% in the population-based tumor registry of Kaiser Permanente in the United States (Portland, OR), perhaps implicating hormonal factors in the rising incidence of breast cancer (Glass and Hoover 1990).

Epidemiologic studies (Ross, Paganini-Hill et al. 2000; Schairer, Lubin et al. 2000) during the 1990s show that combination E&P therapy significantly increased risk, and that this was most evident among leaner women who would have lower starting estrogen levels prior to use of postmenopausal hormone therapy. Recommendations based on these findings were for women to avoid progestins if possible (Willett, Colditz et al. 2000). A broad range of epidemiologic studies continue to support the causal relation between combination E&P and total breast cancer. Meanwhile, some investigators focused on the increase in lobular cancer (Li, Weiss et al. 2000; Li, Anderson et al. 2003) – these tumors are predominantly estrogen receptor positive and so would reflect a signal from hormone therapy more precisely than the more common form of breast cancer, ductal cancer, that is estrogen receptor positive only about 70 percent of the time. Overall, studies of receptor positive tumors show that combination therapy clearly increases risk (Glass and Hoover 1990).

In 2002, the Women’s Health Initiative confirmed the epidemiologic findings relating combination hormone therapy to increased risk for breast cancer. In this trial there was substantial non-adherence to therapy, which would reduce the ability of the study to detect an effect. In fact some 40% of the women randomized to take estrogen plus progestin (PremPro), stopped taking the drug. The independent Data Safety Monitoring Board stopped the trial early due to the adverse effect of therapy on breast cancer (Rossouw, Anderson et al. 2002). The results were consistent with the HERS trial and epidemiologic data showing an increase in risk of breast cancer in the initial 2 to 5 years of use. Importantly, risk increased significantly with duration of use; the longer a woman used hormones the greater her risk of breast cancer.

Based on data from the San Francisco mammography registry, prescribing of E&P peaked in 1999. Before publication of HERS the use of hormone therapy was increasing at 1% per quarter, but declined by 1% per quarter after the publication (Haas, Kaplan et al. 2004). This decline in prescribing continued until the publication of the WHI in 2002, at which point a more substantial decline of 18% per quarter was observed. The peak and decline through 1999 to 2002 is concordant with the HERS report (Hulley, Grady et al. 1998) in 1998 showing a significant increase in CHD in the first year of therapy among women with prevalent coronary disease, and in addition, no long-term benefit in reducing CHD (Grady, Herrington et al. 2002). The growing epidemiologic evidence published since 2000 on the adverse effects of combination therapy on breast cancer added further evidence against the use of this therapy. Bases on the level of use of combination hormone therapy in California, Tina Clarke and colleagues estimate that 11 percent of all breast cancer was being caused by use of hormone therapy (Clarke, Purdie et al. 2006). Since risk increases with duration of use, this estimate of the proportion of cancers caused by hormone therapy is likely conservative.

The most recent report from the Women’s Health Initiative, addressing mortality from breast cancer, shows that risk is elevated among the women who took estrogen plus progestin therapy (study). Investigators followed participants for 11 years. Among the 16,000 women in the study those randomized to estrogen plus progestin had twice as many deaths from breast cancer as seen in the women who took placebo. This, of course, is counter to the substantial marketing effort by the manufacturers who have been shown to have ghost written articles for gynecologists to advocate for hormone therapy as safe since it only causes “good cancers” that respond adequately to treatment. This literature and the academic physicians paid to write for the industry are summarized by Dr. Fugh-Berman and is available online (article). She summarizes evidence from industry documents showing how the pharmaceutical company Wyeth used ghostwritten medical journal articles to mitigate the perceived risks of breast cancer associated with hormone therapy. The WHI results published last week confirm previous epidemiologic data on the mortality effect of hormone therapy and rule the reassurance from the industry as only a marketing ploy not a truthful message for women.

With the evidence at hand, use of hormone therapy for menopausal symptoms should be extremely limited, if used at all. Combination therapy is more harmful than unopposed estrogen and is not indicated for women who do not have a uterus. As we have noted previously, hormone levels within a woman after menopause are directly related to risk of breast cancer. Weight loss through energy restriction and increase in physical activity is the best natural way to reduce these hormone levels and significantly reduce risk of breast cancer (related post).

Breast cancer prevention means taking action now. We talked about awareness earlier this week and have discussed drug strategies to reduce risk of breast cancer in high risk or postmenopausal women. But for every woman there are things to do now to lower risk.

1. be active - increase your level of physical activity
2. maintain a healthy weight
3. cut down on the amount of alcohol you drink

The LA Times has a provocative new article out that seems to rail against breast cancer awareness month.

What are the criticisms?
- Since the breast cancer awareness campaign started, age-adjusted rates have remained largely flat.



- Talking about "breast cancer" ignores all of the research done to date that shows there are many different types of breast cancers, with very different etiologies and treatment paths. In particular, screening likely has very different effectiveness for different types of breast cancers.

- Promoting early detction, as the campaign does, leads to unnecessary diagnostic testing and treatment. (it is interesting to note that the major sponsor of breast cancer awareness month is a chemotherapy drug maker)

So is it time for the message to be changed? We addressed this, to some extent, in a previous CNiC post - when we talked about the "campaign" to list your bra color on social networking sites to promote breast cancer awareness.

Instead of focusing on awareness of the second most common cancer among women, why not focus energies to something more specific - like increasing enrollment in research studies and clinical trials, as advocated by Dr. Love, Avon and their Army of Women, which has opportunities for breast cancer survivors, those without cancer but who may have an increased risk, and individuals with no cancer history. OR, by focusing on primary prevention of cancer - not just early detection.

And breast cancer is preventable -- maintaining a healthy weight, participating in regular physical activity, and avoiding excess alcohol intake all reduce risk. Research shows that losing weight reduces the risk of overweight and obese women, so it isn't too late to start.

	Raloxifene	Tamoxifen
Invasive breast cancer prevented	15	20
Noninvasive breast cancer prevented	16	20
Endometrial cancer caused	0	2.25
Thromboembolic events caused	2.47	3.3
Benefit to risk ratio	31 vs. 2.47 or 13:1	40 vs. 5.55 or 7:1

Soy foods have been studied a great deal for their potential protection against a range of chronic conditions, including breast and prostate cancer, heart disease, osteoporosis, and menopausal symptoms.

It’s not known exactly how a diet rich in soy results in such benefits. It could be due to some of the individual components of soy, such as isoflavones which have some qualities similar to naturally occurring hormones. Or it could be the collective make up of soy, all its components together, which have the beneficial effects.

Because most pre-menopausal symptoms are linked to dropping levels of the hormone estrogen, it’s been considered that soy, and the insoflavones it contains, could help mimic natural estrogen and therefore quell things like hot flashes. Current evidence, though, suggests that soy intake actually has little impact on hormone levels. Still, research also suggest that a diet rich in soy may reduce menopausal symptoms (1).

The potential cardiovascular benefits from higher soy intake may be due to soy’s being a healthier replacement for some higher fat choices. Soy has only about 20 percent of its calories from fat, which is predominantly “healthy” polyunsaturated fat (2), whereas chicken can have nearly half of its calories from fat, and beef can have as much as 80 percent of its calories from fat, much of it in the form of “unhealthy” saturated fat. Studies looking at the relationship between soy intake and heart disease suggest that a diet rich in soy can improve blood pressure, blood cholesterol, and insulin levels (3).

Much of the interest in the links between soy intake and cancer risk is motivated by the historically low breast and prostate cancer risk among Asians, whose diets are traditionally high in soy. Detailed reviews by Wu and colleagues shows that at high intakes typical of Asian diets, soy is significantly related to a reduced risk for breast cancer, and the effect may be strongest for high intake in childhood and adolescence. A meta-analysis found that diets with high amounts of soy (20 mg per day of isoflavone) in Asian women was associated with a decreased risk for breast cancer, compared to Asian women consuming lower amounts (5 mg daily) (4). What this means for most American women is unclear. Studies in the US have typically not found a link between soy intake and breast cancer, but this could largely be due to widely different diets between the two regions. The highest intake in the US is typically 80 percent below the lowest intake in Asia (0.3 mg isoflavones/day in the US versus 25-50 mg isoflavones/day in Asia, which is equivalent to 1 g of soy food versus 80-160 g of soy food). Should diets shift to resemble those of Asia, it’s more than likely that studies would begin to reveal breast cancer benefits with soy as well.

Looking at the data on soy and prostate cancer, a number of studies show benefits from a higher intake of soy and soy-products. Soy milk intake was shown to be inversely related to risk of prostate cancer among US men in the Seventh Day Adventist Cohort study (5). As soy milk consumption went up, the risk of prostate cancer went down. A similar relationship has been seen between total soy intake and the risk of prostate cancer in other cohort and case-control studies (6), even though the amount of the effect on risk varied a bit from study to study. The only potential evidence that soy might increase the risk of prostate cancer comes from research of fermented soy (Miso), which has been positively related to risk in some studies.

Overall, there is currently little evidence that a diet high in soy is bad for health, and a growing body of evidence that it could have substantial health benefits. Realizing such potential benefits though, would likely take intake levels beyond what most people in the US typically eat.


Literature cited:

1. Kurzer, M.S., Soy consumption for reduction of menopausal symptoms. Inflammopharmacology, 2008. 16(5): p. 227-9.
2. van Ee, J.H., Soy constituents: modes of action in low-density lipoprotein management. Nutr Rev, 2009. 67(4): p. 222-34.
3. Carlson, S., et al., Effects of botanical dietary supplements on cardiovascular, cognitive, and metabolic function in males and females. Gend Med, 2008. 5 Suppl A: p. S76-90.
4. Wu, A.H., et al., Epidemiology of soy exposures and breast cancer risk. Br J Cancer, 2008. 98(1): p. 9-14.
5. Jacobsen, B.K., S.F. Knutsen, and G.E. Fraser, Does high soy milk intake reduce prostate cancer incidence? The Adventist Health Study (United States). Cancer Causes Control, 1998. 9(6): p. 553-557.
6. Jian, L., Soy, isoflavones, and prostate cancer. Mol Nutr Food Res, 2009. 53(2): p. 217-26.

We know from studies of leukemia and some other cancers that people who were exposed to certain factors (such as to radiation) while in the womb (in utero) can have a greater risk of cancer as children and adults. More recently, interest has shifted from large one-time exposures to carcinogens (such as to atomic bomb radiation) to other more subtle factors, such as: older maternal age, maternal obesity, maternal pre-eclampsia during childbirth, higher child birthweight, and certain infections. Each of these factors is thought to alter a mother’s estrogen levels, which may in turn prime cells in the baby’s body for future cancer risk. On top of its possible effect on estrogen levels, a high birthweight may also be associated with in utero exposure to high levels of growth hormones, which like estrogen, can increase later risk of cancer.

A recent review of the research on this topic found that higher birthweight was associated with a fairly small increase in the risk of breast cancer, especially in premenopausal women. Specifically, the paper found that a 2.2 pound (1 kilogram) increase in birthweight raised the risk of breast cancer later in life by about 15 percent (study link) (1). This means that women who weighed, for example, 10 pounds at birth, had a 15 percent higher risk of breast cancer compared to women who weighed 7 pounds, 13 ounces.

Literature cited
1. Xue, F. and K.B. Michels, Intrauterine factors and risk of breast cancer: a systematic review and meta-analysis of current evidence. Lancet Oncol, 2007. 8(12): p. 1088-100.

A new study of adolescent diet and subsequent risk of precursor lesions for breast cancer shows that women who had higher intake of fiber earlier in life have lower cancer risk. Data from the Nurses' Health Study show that women in the highest quintile of adolescent fiber intake had a 25% lower risk of proliferative benign breast disease. This significant reduction in risk was seen regardless of the source of fiber.