JNCI Journal of the National Cancer Institute Advance Access published November 11, 2008 EDITORIALS Breast Cancer Prevention Using Calcium and Vitamin D: A Bright Future?
Despite aggressive treatment and screening efforts, breast cancer the risk of breast cancer among postmenopausal women. Breast remains the second leading cause of cancer-related deaths among cancer incidence was a prospectively planned secondary endpoint women in the United States ( 1 ). Because of the large number of in the WHI study. This trial had a large number of racially diverse women dying from this disease and the toxicity of breast cancer women who maintained relatively good adherence to the study treatments, recent efforts have focused on identifying effective can-
protocol. Despite the meticulous design, careful control, and ade-
cer preventive agents. These efforts have led to the development of
quate adherence, Chlebowski et al. report that calcium and vitamin
antiestrogen agents, such as tamoxifen and raloxifene, which pre-
D supplementation did not reduce the incidence of breast cancer.
vent approximately 50% of invasive breast cancers in women who
Previous groups ( 17 , 18 ) have reported the results of the other
are at high risk for breast cancer. However, the use of these agents
components of the WHI study. In these studies, there was a small
for breast cancer prevention has been limited by their toxicity.
but statistically signiﬁ cant increase in hip bone density, suggesting
A large amount of evidence exists to indicate that vitamin D the possibility of a clinically relevant effect of CaD supplementa-
may be a particularly promising cancer preventive agent. Vitamin
tion. Analysis of this WHI data also demonstrated that there was
D is a fat-soluble vitamin that is essential for bone formation and no decrease in hip bone fractures or colorectal cancer incidence, calcium homeostasis. The potential link between vitamin D levels
which were the other primary and secondary endpoints of the trial
and reduced cancer incidence was suggested by results from epide-
( 17 , 18 ). These results, along with the results presented in this issue
miological studies by Garland et al., Giovannucci, and others ( 2 – 5 )
( 16 ), suggest that women who received the CaD in this trial did not
and by recent data suggesting a strong association between low experience the predicted beneﬁ ts of calcium and vitamin D supple-vitamin D levels and increased colon cancer risk ( 6 ). Several case –
mentation — a reduction in bone fractures, colon cancer, and breast
control and cohort studies support an inverse relationship between
vitamin D intake and breast cancer incidence ( 7 – 11 ); however,
Should these negative results discourage the use of calcium and
other studies show either no association or an association with vitamin D in future breast cancer prevention studies? Not neces-increased breast cancer risk ( 10 , 12 – 14 ). In addition, recent studies
sarily. Although Chlebowski et al. ( 16 ) did not ﬁ nd a statistically
found that vitamin D deﬁ ciency was linked to poor outcomes in signiﬁ cant association between calcium and vitamin D supplemen-patients with early breast cancer ( 15 ).
tation and reduced incidence of breast cancer, there could be sev-
It is against this backdrop that Chlebowski et al. ( 16 ) report the
eral important confounders at play. The ﬁ rst confounder is that of
results of a randomized controlled clinical trial evaluating the variable baseline vitamin D levels. The authors measured the base-breast cancer preventive effect of vitamin D and calcium supple-
line level of plasma 25-hydroxyvitamin D and compared this level
mentation. This study, which was compiled from the calcium plus
with self-reported vitamin D intake. There was a large overlap of
vitamin D (CaD) arm of the Women’s Health Initiative (WHI), baseline self-reported vitamin D intake across the plasma 25-randomly assigned 36 282 postmenopausal women to receive daily
hydroxyvitamin D quintiles, suggesting that factors besides intake
doses of either 1000 mg calcium with 400 IU vitamin D3 supple-
(such as sunlight exposure, body mass index, metabolism, physical
mentation or placebo and were followed up for an average of 7 activity, and genetic factors) have a stronger inﬂ uence on plasma years. To maximize participation and size, the WHI trial had over-
25-hydroxyvitamin D than just intake quantity alone.
lapping groups, including a dietary modiﬁ cation (DM) group, a
A second potential confounder is the high level of calcium and
vitamin D self-supplementation (up to 1000 mg of calcium and
hormone therapy (HT) group, and a CaD group, which was added
1000 IU of vitamin D) that was allowed during the study. This
in the second year of the study. As a result, 69% of women in the
“outside of study” supplementation led to 15% of placebo patients
calcium with vitamin D trial were also part of the DM group, 54%
“dropping in” to the active treatment component of the study.
were part of the HT group, and 14% had participated in both the DM and the HT trials ( 17 ). Furthermore, in this trial, personal use of calcium and vitamin D was permitted in both the supplementa-
Affiliations of authors: Department of Molecular and Cellular Biology (CS),
Lester and Sue Smith Breast Center and Department of Medicine (PB), Baylor
Chlebowski et al. should be congratulated for successfully com-
pleting such a large and sophisticated trial. The well-designed and
Correspondence to: Powel H. Brown, MD, PhD, Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, BCM 600, Houston, TX
well-executed randomized, double-blinded, placebo-controlled 77030 (e-mail: [email protected] ). trial with a nested case – control study is unrivaled in its scope and DOI: 10.1093/jnci/djn390 complexity. This current study tested the hypothesis that 1000 mg/
The Author 2008. Published by Oxford University Press. All rights reserved.
day calcium plus 400 IU vitamin D3 supplementation would reduce
For Permissions, please e-mail: [email protected].
1562 Editorials | JNCI
Such “outside of study” supplementation, sometimes at levels more addition, future trials may need to be carefully controlled for diet, than twice the trial dose, may have diminished the observed differ-
sunlight exposure, HT, and physical activity. Finally, such trials
ence in breast cancer incidence between the placebo and CaD arms.
may require earlier initiation and longer duration. Given the long
Another very important issue is the dose of vitamin D given in
latency of breast cancer, longer follow-up times may be needed to
this trial. Recent reports suggest that higher doses of vitamin D evaluate the effect of vitamin D on breast cancer incidence. (1000 – 2000 IU/day) may be required to prevent cancer ( 19 ). It is
Because preclinical, epidemiological, and clinical trial results of
possible that doses sufﬁ cient to prevent osteoporosis are not sufﬁ -
vitamin D supplementation are conﬂ icting, additional studies will
cient to prevent cancer. The results of this trial suggest that a dose
be needed to determine whether vitamin D plus calcium will pre-
of 400 IU of vitamin D could be insufﬁ cient to prevent breast vent breast cancer. However, this article by Chlebowski et al. cancer ( 16 ) or colon cancer ( 17 ).
offers an important ﬁ rst step in addressing this issue. Future clini-
Another important aspect of this trial is the age of the study cal trials should address the above questions to help determine
population. The women in the WHI trial were postmenopausal whether higher doses of vitamin D supplements will be cancer and aged 50
– 79 years. Previous epidemiological studies preventive. The potential health beneﬁ ts of vitamin D and calcium
( 8 , 10 , 14 , 20 ) have not shown a clear association between vitamin may yet still have a bright future. D intake and breast cancer in postmenopausal women (relative risks [RRs] = 0.55 to 1.3); however, results from epidemiological
studies of premenopausal women ( 10 , 14 ) suggest that vitamin D 1. American Cancer Society. Breast Cancer Facts & Figures 2007–2008 . intake may prevent breast cancer in these women (RRs = 0.65 to
Atlanta : American Cancer Society, Inc ; 2008 .
0.89). Furthermore, given long latency of breast cancer, many of the
2. Garland C , Shekelle RB , Barrett-Connor E , Criqui MH , Rossof AH , Paul
O . Dietary vitamin D and calcium and risk of colorectal cancer: a 19-year
postmenopausal women in the WHI trial may have already devel-
prospective study in men . Lancet . 1985 ; 1 ( 8424 ): 307 – 309 .
oped premalignant breast lesions or cryptic breast cancers at the 3. Giovannucci E . Vitamin D and cancer incidence in the Harvard cohorts . time of study enrollment. If vitamin D is effective as a cancer
Ann Epidemiol . 2008 ; doi:10.1016/j.annepidem.2007.12.002.
preventive agent only before breast cells become cancerous, then
4. Kampman E , Giovannucci E , van’t Veer P , et al . Calcium, vitamin D,
the vitamin D taken by women with existing, undetected breast
dairy foods, and the occurrence of colorectal adenomas among men and women in two prospective studies . Am J Epidemiol . 1994 ; 139 ( 1 ): 16 – 29 .
cancers would not prevent the progression of these cryptic can-
5. Bostick RM , Potter JD , Sellers TA , McKenzie DR , Kushi LH , Folsom
cers. Indeed, the results reported by Chlebowski et al. show that
AR . Relation of calcium, vitamin D, and dairy food intake to incidence of
140 women developed cancer within the ﬁ rst year of the trial;
colon cancer among older women. The Iowa Women’s Health Study . Am
these women may have had in situ noninvasive breast cancers or
J Epidemiol . 1993 ; 137 ( 12 ): 1302 – 1317 .
small, undetected invasive breast cancers before the trial began. In
6. Otani T , Iwasaki M , Sasazuki S , Inoue M , Tsugane S . Plasma vitamin D
and risk of colorectal cancer: the Japan Public Health Center-Based
addition, 26% of women who developed breast cancer during the
Prospective Study . Br J Cancer . 2007 ; 97 ( 3 ): 446 – 451 .
trial were diagnosed with cancer within 2 years of trial initiation.
7. Lowe LC , Guy M , Mansi JL , et al . Plasma 25-hydroxy vitamin D concen-
It is interesting that the cumulative hazard lines begin to separate
trations, vitamin D receptor genotype and breast cancer risk in a UK
between the supplemented and placebo groups in the last 2 years
Caucasian population . Eur J Cancer . 2005 ; 41 ( 8 ): 1164 – 1169 .
of the trial (although this difference is not statistically signiﬁ cant).
8. McCullough ML , Rodriguez C , Diver WR , et al . Dairy, calcium, and
vitamin D intake and postmenopausal breast cancer risk in the Cancer
This result suggests that vitamin D plus calcium supplementation
Prevention Study II Nutrition Cohort . Cancer Epidemiol Biomarkers Prev .
is effective only at early stages of breast carcinogenesis. To inves-
tigate this hypothesis, it would be particularly useful to determine
9. Braga C , La Vecchia C , Negri E , Franceschi S , Parpinel M . Intake of
whether these lines further separate with continued follow-up.
selected foods and nutrients and breast cancer risk: an age- and menopause-
Should we then abandon further study of vitamin D as a breast
speciﬁ c analysis . Nutr Cancer . 1997 ; 28 ( 3 ): 258 – 263 .
10. Lin J , Manson JE , Lee IM , Cook NR , Buring JE , Zhang SM . Intakes of
cancer prevention agent? Given the extensive preclinical data
calcium and vitamin D and breast cancer risk in women . Arch Intern Med .
showing a cancer preventative effect of vitamin D ( 21 , 22 ), to do so
may be premature. We should ﬁ rst attempt to answer several ques-
11. Abbas S , Linseisen J , Chang-Claude J . Dietary vitamin D and calcium
tions not answered by the current study. Could vitamin D have a
intake and premenopausal breast cancer risk in a German case-control
different cancer preventive effect on premenopausal vs postmeno-
study . Nutr Cancer . 2007 ; 59 ( 1 ): 54 – 61 .
12. Levi F , Pasche C , Lucchini F , La Vecchia C . Dietary intake of selected
pausal women? Should vitamin D be used earlier in the course of
micronutrients and breast-cancer risk . Int J Cancer . 2001 ; 91 ( 2 ): 260 – 263 .
breast carcinogenesis, ie, at a younger age? Did concomitant HT,
13. Potischman N , Swanson CA , Coates RJ , et al . Intake of food groups and
which may increase the risk of developing breast cancer, affect the
associated micronutrients in relation to risk of early-stage breast cancer .
results of the study? Did DM with a low-fat, high fruit and vege-
Int J Cancer . 1999 ; 82 ( 3 ): 315 – 321 .
table diet vs no DM affect the response to vitamin D and calcium?
14. Shin MH , Holmes MD , Hankinson SE , Wu K , Colditz GA , Willett WC .
Intake of dairy products, calcium, and vitamin D and risk of breast cancer .
Is 400 IU of supplemented vitamin D too low of a dose to prevent
J Natl Cancer Inst . 2002 ; 94 ( 17 ): 1301 – 1311 .
15. Goodwin P , Ennis M , Pritchard KI , Koo J , Hood N . Frequency of vitamin
These questions should drive the design of future vitamin D
D (Vit D) deﬁ ciency at breast cancer (BC) diagnosis and association with
cancer prevention trials. It is particularly important that future tri-
risk of distant recurrence and death in a prospective cohort study of T1-3,
als evaluate higher doses of vitamin D. With such a high percent-
N0 – 1, M0 BC . Paper presented at the annual meeting of ASCO; May 30, 2008; Chicago, IL. J Clin Oncol . 2008 ; abstract 511 , 15s (Part 1 of 2) : 9s .
age of pre- and postmenopausal women taking vitamin D and 16. Chlebowski RT , Johnson KC , Kooperberg C , et al . Calcium plus vitamin
calcium supplements, future trials will likely need to compare
D supplementation and the risk of breast cancer
“standard dose” supplements with “high dose” supplements. In
JNCI | Editorials 1563
17. Wactawski-Wende J , Kotchen JM , Anderson GL , et al . Calcium plus
20. Robien K , Cutler GJ , Lazovich D . Vitamin D intake and breast cancer risk
vitamin D supplementation and the risk of colorectal cancer . N Engl J
in postmenopausal women: the Iowa Women’s Health Study
Med . 2006 ; 354 ( 7 ): 684 – 696 .
Causes Control . 2007 ; 18 ( 7 ): 775 – 782 .
18. Jackson RD , LaCroix AZ , Gass M , et al . Calcium plus vitamin D supple-
21. Mehta RG , Moriarty RM , Mehta RR , et al . Prevention of preneoplastic
mentation and the risk of fractures . N Engl J Med . 2006 ; 354 ( 7 ): 669 – 683 .
mammary lesion development by a novel vitamin D analogue, 1alpha-
19. Gorham ED , Garland CF , Garland FC , et al . Optimal vitamin D status
hydroxyvitamin D5 . J Natl Cancer Inst . 1997 ; 89 ( 3 ): 212 – 218 .
for colorectal cancer prevention: a quantitative meta analysis . Am J Prev
22. Lipkin M , Newmark HL . Vitamin D, calcium and prevention of breast
Med . 2007 ; 32 ( 3 ): 210 – 216 .
cancer: a review . J Am Coll Nutr . 1999 ; 18 (5 suppl): 392S – 397S .
1564 Editorials | JNCI
LAWS OF TRINIDAD AND TOBAGO ANTIBIOTICS ACT CHAPTER 30:02 18 of 1948 Current Authorised Pages LAWS OF TRINIDAD AND TOBAGO 2 Chap. 30:02 Antibiotics Index of Subsidiary Legislation Importation of Antibiotics Preparations Order … … … …Approved Pharmaceutical Firms Order … … … …Antibiotics (Conditions for Use) Order (LN 29/1989) … … … Note on the ab
Christoph Berger, Publications Original Papers: 1a. Berger Ch, Holzach P, Matter P. Die Skidaumenverletzung beim Kind. Helv Chir Acta 1993;60:615- 1b. Berger Ch, Holzach P, Matter P. Die Skidaumenverletzung beim Kind. Z Unfallchir Versicherungsmed 1993 Suppl 1:222-231. 2. Berger C, Uehlinger J, Ghelfi D, Blau N, Fanconi S. Comparison of C-reactive protein and white blood cell