Objective We examined whether past use of hormone therapy influences the effects of raloxifene on the risk of new vertebral fracture, cardiovascular events, or breast cancer.

Study Design The Multiple Outcomes of Raloxifene Evaluation (MORE) trial examined vertebral fracture incidence as the primary endpoint, breast cancer incidence as a secondary endpoint. Cardiovascular events were collected as secondary safety endpoints.

Population: The MORE trial enrolled 7705 postmenopausal women. Of the 7682 women who reported their previous HT use status, 29% used HT before screening.

Outcomes Measured Separate logistic regression models analyzed the relationships between prior HT use and the risk of vertebral fracture, cardiovascular events, or breast cancer. Interaction terms with P<.10 were considered to be statistically significant. Confidence intervals for relative risks (RR) were calculated using the Mantel-Haenszel method.

Results Raloxifene 60 mg/d, the clinically approved dose for osteoporosis prevention and treatment, reduced the risk of vertebral fractures by 54% (RR=0.46) and 29% (RR=0.71) in women with and without prior HT use, respectively (interaction P=.05). A lower incidence of invasive breast cancer in women with prior HT use (RR=0.23) and in women without prior HT use [RR=0.31; interaction P=.60] was observed in women receiving raloxifene (pooled doses). Irrespective of prior HT use, women treated with raloxifene (pooled doses) had no change in incidence of cardiovascular events (interaction P=.56).
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Conclusions: The risk of vertebral fractures was lower in women treated with raloxifene, regardless of prior HT use, but there was a suggestion that the effect was greater in women who had used HT. Women randomized to receive raloxifene exhibited a decreased incidence of invasive breast cancer, compared with women receiving placebo. No change occurred in the incidence of cardiovascular events, regardless of prior HT use.

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Estrogen-containing hormone therapies (HT) have been used to alleviate menopausal symptoms and to prevent chronic diseases common to postmenopausal women, including osteoporosis and cardiovascular disease. (1,2) In this analysis, we use the abbreviation "HT" to refer to postmenopausal hormone therapies, either estrogen alone or combined with progestin.

Based on the findings of the randomized, double-blind Women's Health Initiative (WHI) study involving estrogen-progestin, (3) the Food and Drug Administration (FDA) recommends using HT to treat moderate to severe symptoms of vulvar and vaginal atrophy and vasomotor symptoms associated with the menopause, and to prevent postmenopausal osteoporosis. (4) When HT is prescribed only to prevent osteoporosis in women without menopausal symptoms, the FDA recommends that other approved, non-estrogen therapies be considered and that HT be used at the lowest dose for the shortest duration to achieve treatment goals. (4) Many postmenopausal women have chosen to discontinue HT in light of these recommendations. (5) However, discontinuing HT may increase bone resorption and accelerate bone loss, (6,7) which, if untreated, places women at risk for osteoporotic fractures.

The serum estrogen receptor modulator (SERM) raloxifene is not an estrogen, a progestin, or a hormone, (8) but it binds to the estrogen receptor to exert effects in the skeletal and cardiovascular systems and in breast tissue. (9) In the 4-year Multiple Outcomes of Raloxifene Evaluation (MORE) osteoporosis treatment trial of postmenopausal women, raloxifene 60 mg/d, the approved dose for postmenopausal osteoporosis prevention and treatment, increased bone mineral density (BMD) and significantly reduced the risk for new vertebral fractures with sustained efficacy. (10) With the declining use of long-term HT, (5) it is clinically relevant and important to determine whether a history of HT use has any influence on the effects of other antiresorptive agents, such as raloxifene, which may be subsequently used for postmenopausal osteoporosis prevention and treatment. The objective of this analysis is to determine the effects of raloxifene on BMD, and the risks of vertebral fractures, cardiovascular events, and breast cancer in postmenopausal women who did or did not use HT prior to screening for the MORE osteoporosis study.

* MATERIALS AND METHODS

Subjects and treatment

Details on subject recruitment and follow-up, and complete inclusion and exclusion criteria, were previously described for the MORE study. (11) The trial examined the incidence of osteoporotic fractures as a primary endpoint and the incidence of breast cancer as a prespecified secondary endpoint, and it collected reports of cardiovascular events as a secondary safety endpoint.

Researchers enrolled 7705 women up to 80 years of age who were at least 2 years postmenopausal, and who had osteoporosis as defined by radiographically apparent vertebral fractures at baseline or BMD criteria. Women were randomly assigned to receive raloxifene 60 or 120 mg/d, or an identically appearing placebo. (11) All women received daily supplements of calcium (500 mg) and vitamin D (400 to 600 IU). An ethical review board at each site approved the MORE study protocol. All women gave written informed consent to participate in the study in accordance with the ethical principles stated in the Declaration of Helsinki.

Breast cancer is the second leading cause of cancer deaths in women today (after lung cancer) and is the most common cancer among women, excluding non-melanoma skin cancers. According to the World Health Organization, more than 1.2 million people will be diagnosed with breast cancer this year worldwide. The American Cancer Society estimates that in 2004, approximately 215,990 women in the United States will be diagnosed with invasive breast cancer (stages I-IV). Another 59,390 women will be diagnosed with in situ breast cancer, a very early form of the disease. Though much less common, breast cancer also occurs in men. An estimated 1450 cases will be diagnosed in men in 2004. A woman's lifetime chance of developing breast cancer is now listed as one in eight. There are four types of Western medical treatment for breast cancer currently considered standard: surgery, radiation, chemotherapy, and hormone therapy. Which treatment a woman will receive depends on her particular condition and personal wishes. However, treatment in most last-stage cases will include chemotherapy. Because chemotherapy is a systemic treatment affecting the cells in the entire body, it typically causes side effects, such as nausea and hair loss to name the two most infamous. In China, Chinese herbal medicinals are routinely used to manage and mitigate such chemotherapy side effects as well as to improve outcomes and increase length of life. In issue #5, 2004 on pages 270-272 of the Shan Dong Zhong Yi Za Zhi (Shandong Journal of Chinese Medicine), Wang Xing-chun et al. published an article titled, "A Clinical Study on the Treatment of Late Stage Breast Cancer with Xiao Chai Hu Tang (Minor Bupleurum Decoction) Combined with Chemotherapy." Because this study is indicative of how Chinese doctors are integrating traditional Chinese and modern Western medicines in the treatment of breast cancer, a summary of its main points is presented below.

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Cohort description

Altogether, there were 60 patients with late stage breast cancer enrolled in this study. These 60 patients were randomly divided into two groups, a so-called treatment group and a control or comparison group. All had been treated with surgery and had distant metastases. After surgery, all experienced recurrence or metastasis. These women's Karnvosky score was 60 points or more, and all had a three month or more projected survival time. Diagnosis and follow-up studies were carried out by X-ray, ultrasound, MRI, CT scan, and bone ETC. In the four weeks prior to the commencement of this study, none of the women had had any chemotherapy. Blood signs and liver and kidney function were normal, EKG was normal, and heart enzymes were basically normal. In terms of Karnovsky scores, pathology staging, TNM staging, sites of metastases, and whether the woman was receiving initial or repeat therapy, the women in both groups were statistically quite comparable. (These statistics were all included in the original Chinese article.)

Treatment method

Members of both groups received the CAF protocol. This consisted of 400mg/[m.sup.2] of cytotoxin (CTX) from days 1-8, 40mg/[m.sup.2] of adriomyacin (ADM) day one, and 300mg/[m.sup.2] of 5-flourouracil (5-FU) on days 2-5, with 21 days equaling one round of treatment. One week before the commencement of this protocol, the members of the treatment group also received Xiao Chai Hu Tang, which was continued through the length of this study. Xiao Chai Hu Tang consisted of:

Chai Hu (Radix Bupleuri)
Huang Qin (Radix Scutellariae Baicalensis)
Ban Xia (Rhizoma Pinelliae Ternatae)
Dang Shen (Radix Codonopsitis Pilosulae)
Da Zao (Fructus Zizyphi Jujubae)
Sheng Jiang
(uncooked Rhizoma Zingiberis Officinalis)
Gan Cao (Radix Glycyrrhizae Uralensis)

Seventy-eight point two grams of herbal medicinals were used to make each 200ml of medicinal liquid, and 200ml of this liquid were administered orally each time, two times per day (i.e., BID). Treatment was continued for three whole courses for both groups of patients.

Study outcomes

Study outcomes were based on WHO criteria for cancer. CR meant complete remission, i.e., complete disappearance of lesions within the area treated. PR meant partial remission or a more than 50% decrease in lesions within the treated area. NC meant no change, i.e., less than a 50% decrease or less than a 25% increase in lesions within the treated area, and PD meant a more than 25% increase of a lesion in treated area or new lesions within treated area. Based on these criteria, outcomes were divided between treatment and comparison groups and between those receiving initial treatment and repeat treatment. There were seven patients in the treatment group who received initial treatment. Of these, there were two CRs, four PRs, one NC, and no PDs, with a CR + PR rate of 85.7%. In the comparison group, there were nine cases receiving initial treatment. Among these, there was one CR, five PRs, one NC, and two PDs, with a Cr + PR rate of only 66.7%. In the treatment group, there were 23 patients who received repeat therapy. Of these, there were five CRs, 11 PRs, five NCs, and two PDs, for a CR + PR rate of 69.6%. In the comparison group, there were 21 cases who received repeat treatment. Among these, there were two CRs, eight PRs, six NCs, and five PDs, with a CR + PR rate of only 47.6%. Therefore, the combined Chinese-Western medical protocol was judged more effective than the chemotherapy alone (P + 0.05). Further, the mean remission time in the treatment group was 9.7 months as compared to only 6.9 months in the comparison group.

Breast cancer advocates are tired of hearing the same old risk factors repeated every October. Many advocates are pushing to rename October, "Breast Cancer Industry Awareness Month," because the industries that control all the information about breast cancer risk factors, and manufacture drugs used to treat breast cancer, also produce pesticides which are increasingly suspected of contributing to the rise of breast cancer. For example, the Zeneca Corporation, formerly a subsidiary of Imperial Chemical Industries of Great Britain, makes tamoxifen (Nolvadex), the controversial yet most widely prescribed breast cancer drug in the world. Less known is the fact that Zeneca also manufactures the pesticide, acetochlor (a carcinogenic herbicide), and along with other organochlorine pesticides is increasingly implicated as a causal factor in the rising incidence of breast cancer. Four years ago annual sales for tamoxifen reached 500 million dollars. Sales for acetochlor brought in another 300 million dollars. (1)

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The Zeneca Corporation was praised in a March 8, 1996, article in The New York Times because their stock "was soaring" after they merged with Sandoz and Ciba-Geigy, two of Switzerland's big drug makers. Zeneca has also been buying up cancer clinics around the country. Cancer prevention certainly would not be in the best interests of their stockholders. (1)

"Breast Cancer Awareness Month" was the brainchild of the Zeneca Corporation, which pays for and controls all the radio and TV spots, all the pamphlets, and all the information related to October as "Breast Cancer Awareness Month," with no mention of environmental risk factors, toxic pesticides, or chemical pollutants. Women are urged to get a yearly mammogram touting early detection as their best protection. There is no mention that all the mammography equipment is made by the General Electric Corporation, which is heavily invested in the nuclear industry. There is no mention that repeated mammograms might actually damage DNA in breast tissue, and increase a women's risk of developing breast cancer at a later time in her life. (2)

Mammograms for women between the ages of 40 and 49 with no symptoms may increase deaths from breast cancer within ten years after the first screening, as reported in the October 2003 Journal of the National Cancer Institute (JNCI). (3) However, baseline mammograms are still being promoted for younger women. New findings indicate that mammogram screening for women over age 50 does not result in lower breast cancer deaths. Danish scientists, Ole Olson and Peter Gotzsche looked at all the published studies of screening mammography and found the studies which reported the highest benefit to women, were the most flawed in their methods, whereas studies like the large Canadian study that reported no benefits from mammography were the most reliable. They did find the use of screening mammography led to more aggressive treatment (30% more mastectomies and lumpectomies). "The additional surgeries did NOT translate into more lives saved." (4)

Insurance companies willingly pay for yearly mammograms but balk at paying for less risky thermograms, which use heat sensitive technology to detect a troubling situation years before a tumor is large enough to show up in a mammogram.

Women with a family member who had breast cancer, or who themselves have had breast cancer, are considered to be of high risk and are therefore urged more strongly to get yearly mammograms. I vividly recall attending a conference on breast cancer at which a soft spoken young woman addressed this problem by asking how ethical was it to urge women of high risk to purposefully expose themselves to radiation of the breast, when radiation exposure is the only proven cause of breast cancer. A good point, indeed. A wiser approach would be to help these women, and all women, learn about environmental risk factors and provide them with information on ways to reduce or eliminate many unnecessary toxic exposures. Promoting alternative diagnostic tools to mammography would also be of great benefit.

The controlled media information that accompanies "Breast Cancer Awareness Month" carefully avoids mentioning pesticides and other chemical toxins as risk factors for breast cancer. The time has come for women to ask the hard question. Is "Breast Cancer Awareness Month" really about protecting women's health, or is it more about protecting corporate wealth? There is very little profit in disease prevention and breast cancer has become big business.

Every year the American Cancer Society and National Cancer Institute, supported by the petro-chemical-pharma-medical complex drag out the same old risk factors for breast cancer--age, family history, personal history, early menarche/late menopause, late pregnancy/no pregnancy. (These risk factors are discussed in more detail in "Breast Cancer Awareness Month: A Look at the Environment," TLfDP #195, Oct 1999, and can be read on the Google web site by clicking on "Rose Marie Williams.") The connection to estrogen is emphasized as though women's bodies were intentionally designed to sabotage themselves. Breast cancer advocates are tired of this myopic explanation, and are looking at the big picture of how environmental exposures may be interfering with estrogen production and function, and are finding many plausible explanations.

Women who are diagnosed with breast cancer at a young age or at an advanced stage of breast cancer at any age are more likely to die from the cancer than from art other causes of death combined, according to an Aug 31, 2004, news release from the National Institutes of Health (NIH). A new study by scientists at the National Cancer Institute (NCI), part of the NIH, reports that the probability of death from breast cancer varies significantly according to stage, tumor size, estrogen receptor (ER) status, and age at diagnosis in both African American and Caucasian patients.

To calculate the probabilities of death from breast cancer versus all other causes combined among breast cancer patients, researchers analyzed data from NCI's Surveillance, Epidemiology and End Results program for more than 400,000 patients who were diagnosed with breast cancer between 1973 and 2000. They calculated probabilities of death from breast cancer and all other causes combined during a 28-year follow-up period according to stage and age at diagnosis and during an 11-year follow-up period according to tumor size and ER status for a subset of patients.

The researchers found that patients with breast cancer who had ER-negative tumors were more likely to die from the cancer than patients with ER-positive tumors. Additionally, patients with larger tumors were more likely to die from the cancer than were patients with smatter tumors. The probability of death from breast cancer was greater than that from all other causes for patients who were diagnosed with localized breast cancer when they were younger than 50 years of age. The same is true for patients diagnosed with localized breast cancer before age 60 or with distant disease (ie, cancer that has spread to distant organs or distant lymph nodes) at any age.

As age at breast cancer diagnosis increased, the risk of death from other causes increased, and the risk of death from breast cancer generally decreased. Even among older patients, however, breast cancer still accounted for significant mortality.

The researchers also found that mortality from breast cancer generally was higher in African American patients than in Caucasian patients. According to the researchers, these results are consistent with those of other analyses that have shown generally poorer breast cancer survival in African American patients than in Caucasian patients. The NCI researchers suggest that this may be due to differences in treatment and to a higher prevalence of obesity and obesity-related health conditions in African American patients, among other factors.

By the President of the United States of America

A Proclamation

During National Breast Cancer Awareness Month, we raise awareness of this deadly disease, encourage early detection, and support research to find a cure.

Prevention and early detection are key to winning the right against breast cancer. Although the exact cause of the disease is unknown, factors that can affect the risk of developing cancer include age, general health, and family history. This year, estimates are that over 200,000 women will be diagnosed with breast cancer. Regular screening for breast cancer continues to be the most effective way to detect this disease early and to save lives, and mammograms are the best screening tool we currently have. Women should talk to their health care providers about their breast cancer risk.

To improve the quality of life and find a cure for those affected by breast cancer, we are learning more about its causes. The National Institutes of Health has invested an estimated $700 million this year alone on breast cancer research and will spend more next year. The Centers for Disease Control and Prevention has devoted over $200 million this year and more next year for an early detection program that promotes mammograms and helps low-income women afford screenings for breast and cervical cancer. The Department of Defense also invested approximately $150 million for its Breast Cancer Research program in 2004. This funding will help lead to better treatments for cancer patients and new hope for countless Americans and their families. We salute breast cancer survivors for their courage and perseverance. Their courageous battle against cancer is an inspiration to countless Americans, and their willingness to share their stories and experiences helps spread awareness and offers hope and comfort to cancer patients across the country. Together with health care professionals, researchers, and family members, we can improve the lives of those suffering from this disease and win the fight against breast cancer.

Now, Therefore, I, George W. Bush, President of the United States of America, by virtue of the authority vested in me by the Constitution and laws of the United States, do hereby proclaim October 2004 as National Breast Cancer Awareness Month. I call upon Government officials, businesses, communities, health care professionals, educators, volunteers, and all the people of the United States to continue our Nation's strong commitment to controlling and curing breast cancer.

In Witness Whereof, I have hereunto set my hand this first day of October, in the year of our Lord two thousand four, and of the Independence of the United States of America the two hundred and twenty-ninth.

Results of a Finnish cohort study showed an association between antibiotic use and breast cancer risk in women younger than 50 years. Given the high prevalence of breast cancer and the widespread use of antibiotics, Velicer and colleagues performed a case-control study to determine whether an association exists between breast cancer risk and antibiotic use.

Patients with newly diagnosed primary breast cancer were identified, along with matched control patients. Data on antibiotic use were obtained from pharmacy records. Two measures of antibiotic exposure were employed: the cumulative number of days of antibiotic use and the total number of antibiotic prescriptions for each study participant. Antibiotic use was categorized as low, moderate, or high. Detailed information about risk factors for breast cancer was available for study enrollees. In a substudy, a chart review allowed investigators to ascertain the indications for antibiotic use.

For all eight antibiotic classes considered, increasing cumulative days of use were associated with increased risk of incident breast cancer. For categories of increasing days of use (i.e., zero, one to 50, 51 to 100, 101 to 500, 501 to 1,000, and 1,001 or more days), the odds ratios for breast cancer were 1.00, 1.45, 1.53, 1.68, 2.14, and 2.07. Similar results were found when the number of antibiotic prescriptions was the focus of the analysis. In addition, a strong association was noted between antibiotic use and death from breast cancer. None of these results was affected when adjusting for demographic and breast cancer risk variables.The authors conclude that there is an association between increasing antibiotic use as measured by cumulative number of days and prescriptions, and increased risk of incident breast cancer. The findings apply to pre- and post-menopausal women. In a sub-analysis, indication for antibiotic use was not associated with breast cancer risk, but because of the small size of the subset, indication may play a role. The study, which controlled for many risk factors, could not ascertain whether the association of antibiotic use and cancer risk is causal, or whether antibiotic use is related to some other cause (such as a weakened immune system) or medical indication.

Animal models have revealed that calorie restriction extends life and protects against tumors, including mammary carcinogenesis. In humans, breast tissue appears to be particularly susceptible to carcinogenic processes in early life and before the first pregnancy. Michels and Ekbom conducted a retrospective cohort study of the impact of caloric restriction on the development of breast cancer. Specifically, they studied women with anorexia nervosa severe enough to require hospitalization to determine if these women had a lower incidence of breast cancer than was expected in the general population.

The authors used data from several Swedish Registries to find woman who were hospitalized for anorexia before age 40 between 1965 and 1998. Of the 7,303 women identified, 31 were excluded because of a cancer diagnosis before discharge. A standardized incidence ratio calculated the observed number of first primary cancer cases as a ratio to the number of cases expected. The modifying relationship of parity on breast cancer incidence was assessed by dividing dividing women into parous and nulliparous groups.

In this cohort, 52 women were identified with any type of cancer during 96,887 person-years of follow-up between 1965 and 2000. The standardized incidence ratio for breast cancer was 0.47 among women who were diagnosed with anorexia before 40 years of age. These women had a 53 percent lower incidence of breast cancer than women in the Swedish general population. None of the women with anorexia diagnosed before 20 years of age developed breast cancer. The number of expected cases was 2.7. In the group including women aged 20 to 29 years, the actual and expected cases were 4.0 versus 6.4, respectively. In the group aged 30 to 39 years, there were 3.0 actual cases and 5.7 expected cases. In the 73 percent of women who remained nulliparous, the standardized incidence ratio for breast cancer was 0.77 during 78,984 person-years of follow-up; the ratio was 0.24 during 17,903 person-years of follow-up in the parous group. The reduced incidence of breast cancer in these groups was 23 percent in nulliparous women and 76 percent in parous women.

The authors found a significant decrease in breast cancer incidence in the cohort of women with a hospital discharge diagnosis of anorexia compared with the Swedish general population, with additional protection conferred by subsequent pregnancy. These findings are consistent with observations that in developing countries where food is scarce but there is a high birth rate, women have a lower incidence of breast cancer than in affluent countries.

The impact of caloric restriction in the early period of breast development may be particularly important, as may differentiation of breast tissue during pregnancy in conferring a protective effect. The authors call for further research to determine if the lower incidence of breast cancer associated with anorexia is due to caloric restriction on breast cell development, to amenorrhea and lack of estrogen, or to a decreased level of growth factors.

A diet high in fruit and vegetables and low in fat is hypothesized to improve breast cancer prognosis and decrease risk of recurrence. Armed with the knowledge that women with breast cancer are highly motivated to make lifestyle changes, and that women with cancer-prevention knowledge are more likely to make changes in their diet, several intervention trials have been established with the goal of helping women with breast cancer make healthful dietary changes. Many women appear to be aware of this dietary advice, as several recent nonintervention studies have found that breast cancer survivors report they have increased their intake of fruits and vegetables while decreasing their fat intake. The present study had two aims. First, the researchers intended to quantify changes in dietary intake after breast cancer diagnosis using data from a food frequency questionnaire administered at two points in time. Intake of kilocalories, macronutrients, and fruit and vegetable servings 1 year before breast cancer diagnosis was compared with intake l-year postdiagnosis and relevant demographic and treatment factors were evaluated. Second, comparisons were made between self-reported change in fruit, vegetable, and fat intake and change in intake of these items as measured by repeated food frequency questionnaires.

The subjects included 260 New Mexico women, part of a larger, population-based, prospective cohort study of breast cancer prognosis called the Health, Eating, Activity, and Lifestyle study. This study enrolled women with newly diagnosed breast cancer between August 1996 and March 1999. A short dietary screener was collected on all women, and a food frequency questionnaire Was added part of the way through the study as additional funding made this possible.
Two-year change scores for kilocalories, macronutrients, and fruit and vegetable servings were calculated and tested for difference from zero. Amount of change in fruit and vegetable servings and fat intake were calculated using food frequency data from women who reported increasing their intake of fruits and vegetables or decreasing their intake of fat after diagnosis.

Small but significant decreases in intake of total energy and macronutrients were found 2 years postdiagnosis, with younger women reporting the greatest decreases. Fat as a percentage of diet increased over this period. There was no change in mean intake of fruit and vegetable servings. There is agreement between change as measured by food frequency questionnaire and change reported by more global questions on dietary habits; however, the amount of change measured was small. Women reporting an increase in fruit and vegetable intake post-diagnosis described an increase of one-quarter serving of fruit and one-third serving of vegetables per day.

In conclusion, breast cancer diagnosis results in modest dietary changes. Small changes in fruit and vegetable consumption suggest that efforts are needed to encourage increased consumption of these foods. Women who report increasing fruit and vegetable servings after breast cancer diagnosis report intakes that are, on average, still below the recommended five servings per day. For this reason, dietary intervention efforts should be targeted toward all women, not merely those who report no increase in fruit and vegetable consumption.