Fifty women developed cancers other than skin cancer. The risk for cancer in the calcium-plus vitamin-D group was less than half that in the placebo group (RR 0.4; P=0.013). The calcium only group had no statistically significant risk reduction. Researchers adjusted for the possibility that cancers detected during the first year of the study, had been present but silent at baseline, and analyzed these separately. Relative risk for cancer in the calcium/vitamin D group was lower than in the placebo control subjects 0.2 (P< 0.005), and the risk reduction for the calcium only group was not statistically significant.

Women in the calcium plus vitamin D group had higher serum vitamin D levels that correlated with lower cancer risk, both at baseline and at one year. Adherence to the study doses was 86%.

Lappe JM, et al. Vitamin D and calcium supplementation reduces cancer risk: Results of a randomized trial. Am J Clin Nut 2007; Jun;85(6):1586-1591

Commentary: The only other randomized trial of vitamin D and cancer was the Women’s Health Initiative, which used a lower dose of vitamin D (400 IU) and women with a lower baseline vitamin D status. The WHI reported no significant effect of the vitamin D intervention on colorectal cancer incidence but did observe a significant inverse relation between baseline vitamin D levels and cancer risk, as in this study. It’s reassuring to see that the benefits of higher than recommended dosing of vitamin D is catching on. It is estimated that about 60% of women in the U.S. are vitamin D deficient, no what part of the country they live in. The current adult daily recommendations for vitamin D in women 51 to 70 is
400 IU -800 IU per day. Supplement doses up to 2000 IU are considered safe and to be without significant risk for adverse events. Many practitioners are advising even higher doses, but I would recommend this only after assessment for medical need, serum testing, and evaluation for risk of side effects.

Calcium and Vitamin D Intake and Risk for Breast Cancer

The relationship between vitamin D and breast cancer was prospectively assessed among 10,000 premenopausal and 20,000 postmenopausal women who were enrolled in the Women’s Health Study. Intake of calcium and vitamin D was determined from self-reported questionnaires about diet and vitamin use.

During an average follow-up of 10 years, the overall incidence of invasive breast cancer was 2.6% among premenopausal women and 3.6% among postmenopausal women. Among premenopausal women, the hazard ratio for developing breast cancer was 0.61 for women in the highest versus lowest quintiles of calcium use and 0.65 for vitamin D intake. No benefit was seen for these nutrient intakes and breast cancer risk in postmenopausal women.

Lin J et al. Intakes of calcium and vitamin D and breast cancer risk in women. Arch Intern Med 2007, May 28; 167(10):1050-1059.

Commentary: This is a very large, prospective study, which once again demonstrates important findings for vitamin D, at least for premenopausal women. A higher intake of calcium and vitamin D was associated with a lower risk for breast cancer among premenopausal women, but not for postmenopausal women. While the hazard ratio was large, the absolute reduction in risk was small. Being a population based study using only self-reported questionnaires, the usefulness of the findings in this study are limited, especially since the amount of vitamin D and calcium was recorded only once at baseline. In addition, there could easily be other variables that explain the findings. Nonetheless, it supports the trend to advise women about adequate intakes of calcium and vitamin D, both in the diet and in supplement form.

The main outcome was a recurrence of breast cancer, a new primary breast cancer, or death from any cause. After an average follow-up of a 7.3 years , there were no differences in breast cancer events or all-cause mortality between women in the two dietary groups despite the treatment group eating 65% more vegetables, 25% more fruit, 30% more fiber and 13% less fat.

16.7% of the women in the dietary intervention group developed an invasive breast cancer event and 10.1% died vs. 16.9% in the regular diet group with 10.3% having died.

Pierce J, et al. Influence of a diet very high in vegetables, fruits, and fiber and low in fat on prognosis following treatment for breast cancer. JAMA 2007;298(3):289-298.

Commentary: This is a discouraging bit of news from those of us who work with breast cancer survivors advising them on dietary changes. It can be noted that in the WHEL study, women who had undergone chemotherapy were not included. It may be that we would see better results in women receiving chemotherapy undergoing dietary changes vs. those that don’t. In addition, with a one on one clinical practice, we would often achieve better compliance with more success in eating more vegetables, fruit, fiber and less fat. Other reports on dietary fat show that those studies that reduce fat intake to 15% -20% of total calories consumed, may not achieve results, while studies that reduce fat intake to 10%of calories and focus on fish, seeds, nuts and olive oil as a source of fats, do in fact bode well for future breast health. The current WHEL study also failed to achieve two important results in the dietary intervention group — there was no reduction in total calories and no difference in weight loss, two important influences on breast health.

While many dietary factors have been shown to have influence on risks of breast cancer in observational studies, these relatively small changes in vegetable, fruit and fat intake in the WHEL study, did not make much difference. The message here: we need to eat even more vegetables and fruits, lower fat to 10% and focus on the good fats, eat less in general and do a better job of managing our weight. Sigh…..

Lappe J, et al. Â Vitamin D and calcium supplementation reduces cancer risk: Results of a randomized trial. Â Am J Clin Nut 2007; une 85: 1586-1591

Lin J et al.  Intakes of calcium and vitamin D and breast cancer risk in women. Arch Intern Med 2007, May 28; 167:1050-1059.

Rebbeck T, Troxel A, Norman S, et al. A retrospective case-control study of the use of hormone-related supplements and association with breast cancer. Int. J. Cancer 2007; 120:1523-1528.

Comments: Women included in the study were those with a first primary, invasive, breast cancer of stage I, II, III, of any grade and any tissue type (ductal, lobular, mucinous, papillary, mixed.) Women with ductal carcinoma in situ or lobular carcinoma in situ were excluded.

This is not the first study that has indicated anti-proliferative, anti-estrogenic effects of black cohosh on breast cancer cells, especially estrogen receptor (ER) positive breast cancer cells. In the current study, black cohosh and/or Remifemin persisted irrespective of ER status. On the other hand, the effect of black cohosh and/or Remifemin varied by progesterone receptor (PR) status. The effect was significant in PR positive tumors but not in PR negative tumors. This suggests that PR status may be related to the protective effects of black cohosh on the breast.

While the researchers in this study, incorrectly describe black cohosh as containing phytoestrogens, this study is yet one more positive finding on the safety of black cohosh for breast cancer survivors with menopausal symptoms.

Comparing the incidence rates in 2001 with the rates in 2004, but not including this rapidly changing period from mid-2002 to mid- 2003, showed that the annual decrease in breast cancer incidence was only present in women who were 50 or older. During that time period, there was an increase of 1.3% in breast cancer incidence in women under age 50 (95% CI, -3.1 to 5.8), a decrease of 11.8% for women between 50 and 69 (95% CI, 9.2 to 14.5) , and a decrease of 11.1% for women 70 and older (95% CI 7.9 to 14.2). The compelling question is, why this sharp drop, followed by a stabilization at a lower rate in women 50 and older?

As best I can tell, there are potentially, several explanations: 1. A decline in hormone use since the first report of the Women’s Health Initiative (WHI). 2. A decrease in the rate of screening mammograms. 3. A possible decrease in the rates of annual exams in women 50 and older due to discontinuing HRT 4. An error in the NCI Surveilance, Epidemiology, and End Results (SEER) data. 5. A possible general decrease in the rates of cancers in general 6. Some possible positive influence on the rates of breast cancer. A little closer examination of each of these is important.

One possible explanation that has been posed, is a reporting flaw in the SEER data. This is considered to be unlikely due to there being no significant change in the incidence of any other cancer other than breast cancer during this period. In addition, all nine SEER registries showed the same trend.

A feasible explanation might be related to a major decrease in the rate of screening mammography. For 2003, there was a decrease of 3.2% in the rate of screening mammograms between the ages of 50 and 65, compared with the year 2000. Another aspect of this influence, might be that there could be a change in the frequency and pattern of screening mammograms in women who formerly used hormone replacement therapy (HRT), and now do not. Women who receive HRT, are likely to also receive annual mammograms. Once they discontinue HRT, might they also discontinue doing annual mammograms, as well as go to the doctor less frequently for breast exams? Basically, breast cancers going undetected. Although I do think that in fact, women who discontinue HRT, do initially delay their annual screening mammograms and visits to the doctors, we have no published data showing a decrease in mammographic screening in women who discontinue HRT. In addition, women who discontinue HRT, who are 50 and older, are also disinclined to receive annual exams, especially now since they are being told they do not need an annual pap smear.

The decrease in breast cancer incidence began in mid-2002, and occurred shortly after the publication of the first report of the Women’s Health Initiative in July of 2002, which demonstrated a slight increase in the risk of breast cancer after 4 years of use. By the end of 2002, the use of conventional HRT, declined by approximately 38% in the U.S. and there were 20 million fewer prescriptions written in 2003 than in 2002. , The total number of prescriptions for Premarin and PremPro, the two most common forms of HRT, saw a steep decline starting in 2002, and especially in 2003. 62 million prescriptions were written in 2000, 61 million in 2001, 47 million in 2002, 27 million in 2003, 21 million in 2004, and 18 million in 2005. The periods of sharpest decline appeared to start in 2002 and then also in 2003.

What about some positive influence on the rates of breast cancer? Could there have been something that emerged starting in 2003? Drugs such as tamoxifen, raloxifene, nonsteroidal antiinflammatories and statins have certainly increased dramatically, and there is some evidence for the beneficial effects of these medications on the overall risk of breast cancer. However, it appears that none of these medications had a significant increased change in use during the period from 2000 to 2004. Increased utilization of vitamin D or green tea or soy products might also deserve some thought. While there is some data as to the potential positive influence of these on breast health and even reducing the risk of breast cancer, we do not have any data on increased utilization of these products distinctly in this period of 2002 to 2003.

Women who were in the Women’s Health Initiative PremPro arm when the study was discontinued, are being followed for clinical outcomes, and a report of this will likely be published later in 2007. This report will shed additional evidence related to the influence of discontinuation of HRT on the incidence of breast cancer.

Experts on the topic of HRT and breast cancer are hesitating to render any final opinion on this report while also admitting that “the ultimate understanding of the effect of cessation of hormone-replacement therapy will be complex; it will probably depend on more than one mechanism and will be affected in different ways by various forms of postmenopausal hormone-replacement therapy.”

Additional time will reveal another interesting aspect of this: will the appearance of clinically detectable tumors by mammography only be delayed, rather than an actual long term reduction in breast cancer incidence. Removing HRT may only slightly or temporarily slow the growth of tumors that already exist. If this is the case, then as the use of HRT stabilizes at a certain utilization rate, then the incidence of breast cancer would rise again.

It is my humble opinion that since the WHI and many other studies demonstrate only a slight increase in the rates of breast cancer after combined conjugated equine estrogens and progestins for 5 years or more, that any decrease in the rates of breast cancer seen in 2003, immediately post WHI, is associated with withdrawal of an agent that can slightly increase the growth of an already pre-existing tumor.

1. Ravdin P, Cronin K, Howlander N, Chlebowski R, Berry D. A sharp decrease in breast ancer incidence in the United States in 2003. Breast Cancer Res Treat 2006; 100: Suppl: S2, a abstract.
2. Ravdin P, Cronin K, Howlader N, et al. The decrease in breast-cancer incidence in 2003 in the United States. NEJM 2007;365;16:1670-1674.
3. Rossouw J, Anderson G, Prentice R, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA 2002; 288: 321-333.
4. Buist D, Newton K, Miglioretti D, et al. Hormone therapy prescribing patterns in the United States. Obstet Bynecol 2004; 104:1042-1050.
5. Hersh A, Stefanick M, Stafford R. National use of postmenopausal hormone therapy: annual trends and response to recent evidence. JAMA 2004;291:47-53.
6. Drug Topics. Drugs by units in the United States ion specific years. (Accessed March 29, 2007, at http://www.drugtopics.com/drugtopics/.)