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The production of estrogen from androgen via the estrogen biosynthesis pathway is catalyzed by aromatase P450 (CYP19). To assess the association between breast cancer risk and a polymorphism at codon 39 Trp/Arg of the encoding gene, a case-control study was conducted at Aichi Cancer Center Hospital in Japan. Subjects were 248 histologically confirmed breast cancer patients and 603 hospital controls without cancer. Odds ratios (OR) and 95% confidence intervals (95% CI) were determined by logistic regression analysis. The allele frequency among controls was 3.8% for the C allele, and the OR (95% CI) of the polymorphism relative to TT genotype was 1.21 (0.69-2.14) for TC/CC genotypes combined. There was no association between CYP19 gene polymorphism and breast cancer risk in the study group as a whole, but homozygous and heterozygous carriers of the variant Arg allele showed a significantly increased risk of breast cancer among premenopausal women with a late age at first full-term pregnancy (OR 7.31, 95% CI 1.88-28.5) or a high body mass index (OR 2.77, 95% CI 1.12-6.87). Additional larger studies should be done to confirm that the rare CYP19 variant increases the risk of breast cancer among premenopausal Japanese women.

Chemicals known to disrupt the endocrine system of animal models are assessed for their potential impact on the health of menopausal and postmenopausal women. These "endocrine disrupters" consist of two groups of compounds - man-made and naturally occurring. There is some evidence to suggest that the naturally occurring phytoestrogens, derived from plant material, may have some beneficial effects on menopausal symptoms and the risk of breast cancer, cardiovascular disease and osteoporosis. Further studies are required to confirm these possibilities. Some man-made environmental pollutants appear to increase the risk of breast cancer, although again the evidence is inconclusive. Mechanistic experiments indicate that these chemicals interact with oestrogen receptors and alter metabolism in a number of different ways, some of which may be important in postmenopausal women. Further investigation of the differences in mode of action between the man-made and the natural endocrine disrupters may lead to important insights into their effects on women's health.

Objectives: To determine the incidence and characteristics of prostate cancer in men with spinal cord injury (SCI). Little is known about the characteristics of prostate cancer in men with SCI, because prostate cancer screening is not aggressively performed in this population., Methods: In one fiscal year, 648 men with SCI older than age 50 years were actively enrolled with the SCI service, 20,949 able-bodied men older than age 50 years were actively enrolled in the outpatient clinic database, and 945 patients with prostate cancer were in the cancer registry at our facility. These three databases were cross-referenced for prostate cancer diagnosis and stage and compared with the presence of SCI., Results: Of the 648 patients with SCI, 12 patients with a prostate cancer diagnosis that preceded their injury were excluded. Of the remaining 636 patients, 11 (1.7%) had been diagnosed with prostate cancer since their injury. In contrast, of the 20,949 able-bodied men older than age 50 years seen at our facility in fiscal year 1999, 919 (4.4%) had prostate cancer. Of the patients with SCI and prostate cancer, 7 (63.6%) had locally advanced (Stage T3) or metastatic prostate cancer compared with 267 (29.1%) in the able-bodied population (P = 0.012)., Conclusions: Although the proportion of patients with a prostate cancer diagnosis was greater in the able-bodied patients, the prostate cancer detected in the patients with SCI tended to be of a more advanced stage and grade. The difference was likely a result of the decreased use of prostate cancer screening in this population.

This program looked at extended adjuvant therapy options in breast cancer, focusing on adjuvant therapies in women who are postmenopausal with advanced breast cancer and disease progression following traditional antiestrogen therapy. Aromatase inhibitors and novel approaches to managing hormone-dependent breast cancer were covered, as well as associated nursing implications.

Objective: To determine if male breast carcinogenesis was similar to its more common female counterpart, we compared incidence patterns among men and women with breast cancer., Methods: Breast cancer records were obtained from the SEER database. Women were stratified by age < 50 and > or = 50 years to simulate premenopausal and postmenopausal breast cancer., Results: Age-adjusted incidence trends were stable among men but increased among women. Male to female breast cancer ratio was higher for blacks than for whites. Favorable prognostic factors reflective of tumor biology (nuclear grade and hormone receptor expression) were more common for men and postmenopausal women than for premenopausal women. For example, low nuclear grade, estrogen and progesterone receptor-positive expression were more common among men and postmenopausal women than among premenopausal women. The age-specific incidence rate curve for men increased steadily for all ages with a constant slope. On the other hand, age-specific rates for women increased rapidly until age 50 years then rose at a slower rate for postmenopausal women. Age-frequency distribution for male breast cancer was unimodal, with peak incidence at age 71 years. Age-frequency distribution for women was bimodal with early-onset and late-onset incidence at 52 and 71 years, respectively., Conclusions: Gender-specific incidence trends differed, most likely reflective of female-related changes in surveillance and/or reproductive risk factors. On the other hand, similar prognostic factor profiles reflective of tumor biology, age-specific incidence rate patterns, and age-frequency distributions suggested that male breast cancer was more like postmenopausal than premenopausal female breast cancer.

The incidence of gynecologic tumors in the Province of Sassari in the period 1992-2000 has been studied in order to estimate their value and to make a comparison with the data of the period 1974-83. The analysis of our data regarding the period 1992-2000, if compared with those of the previous period 1974-83, showed a change in the percentage distribution of all gynecologic tumors, with an increase in the incidence of malignant tumors of the ovary (from 17.1% to 28.0%) and a reduction in the incidence of endometrial carcinoma (from 52.1% to 45.0%). Cervix cancer seemed stationary with a mild reduction (from 26.8% to 23.0%). The data showed, with regard to the incidence per 100,000, an increase of endometrial carcinoma (19.05 per 100,000 vs 11.99 per 100,000) and malignant ovarian tumor (11.99 per 100,000 vs 3.95 per 100,000). Our data reported a worrying increase of hormonal-dependent tumors in North Sardinia such as endometrial and ovarian cancer with the highest increase in malignant ovarian tumors. In comparison to the previous period we confirmed a historically low incidence of cervical and external genitalia tumors (vulva and vagina) in North Sardinia.

Obesity increases the risk of certain cancer types, e.g., cancer of the endometrium, colon and gallbladder. For some other cancer forms, e.g., prostate cancer, the association is less clear. We examined the association between body mass index (BMI) and hormone-dependent tumors, utilizing a cohort of 21,884 Swedish twins born during 1886-1925. Information about BMI at different ages and potential confounding factors was collected prospectively. The Swedish Cancer Registry was used to identify cases of cancer in the prostate (n = 666), breast (n = 607), corpus uteri (n = 150) and ovary (n = 118) during 1969-1997. The material was analyzed as a traditional cohort and with co-twin control analyses that allow for control of genetic influences. Obesity (BMI >/=30 kg/m(2)) at baseline was positively associated with cancer in the corpus uteri [relative risk (RR) = 3.03, 95% confidence interval (CI) 1.82-5.03], as was BMI at age 25, independently of BMI at baseline. Increased risk was also found for breast cancer but only in older women (>/=70 years). Overweight at age 25 was associated with decreased risk of breast cancer (RR = 0.51, 95% CI 0.33-0.78). No association was found for prostate cancer. We conclude that age is an important effect modifier of cancer risk associated with obesity and that obesity and overweight in young adult life may affect cancer risk also later in life., (Copyright 2003 Wiley-Liss, Inc.)

Breast cancer is by far the most frequent cancer among women worldwide. Its determinants include reproductive events, exogenous and endogenous hormone levels and metabolism, exposures, such as radiation and chemicals, and genetics. This paper will review available evidence from all of these areas, exploring the occurrence of cancer, risk factors for occurrence and the hormonal milieu that underlies it.

The great variety of different types of human malignancies and the equally variable individual history of physical activity militate against finding any simple relationship between the risk of developing cancer and physical activity. Due to an obvious lack of prospective randomized trials, any evidence for a correlation is currently based on cohort and case control studies. Furthermore, the study results are sometimes inconsistent, and only for selected cancers, the available data are sufficient to draw any conclusions, resulting in a level of evidence of 2-3 (level of recommendation 'B'). Thus, a convincing risk reduction was found for colon cancer (40-50%) and estrogen-dependent malignancies such as breast (40-50%) and endometrial cancer (35-40%). Risk reduction is likely for some others, e. g. ovarian, lung or prostate cancer; but no definite conclusions can be drawn for hematological malignancies. Plausible explanations for reduction of the individual's cancer risk by increased physical activity are currently available for estrogen dependent cancers (breast, ovarian, endometrial) and colon cancers. The currently available data allow the recommendation of adopting a 'healthy life style' including physical activity for prevention of certain cancers., (Copyright 2003 S. Karger GmbH, Freiburg)

Chemotherapy was traditionally perceived to be ineffective for prostate cancer and was only administered to patients with symptomatic hormone-refractory disease. Although previous reviews have confirmed this belief, recent studies have demonstrated significant antitumor activity with chemotherapy regimens. This article highlights the preliminary results of recent studies involving chemohormonal therapy.

Menopause is arguably the most important phase of a woman's social, physiologic, and personal life. Approximately 1.3 million women reach this age in the United States annually. In the past decade, numerous studies have correlated breast cancer and the use of ERT (estrogen replacement therapy) or HRT (hormone replacement therapy) in menopausal women. Whether this is an actual increase in the creation of new cancers or a result of a diagnostic or other bias has yet to be determined. Even more uncertainty surrounds the use of hormones once breast cancer is diagnosed. Previously, once a woman was diagnosed with an estrogen-dependent tumor, ERT and HRT were simply forbidden. As discussed herein, that is no longer the case.

Marine fatty acids, particularly the long-chain eicosapentaenoic and docosahexaenoic acids, have been consistently shown to inhibit the proliferation of breast and prostate cancer cell lines in vitro and to reduce the risk and progression of these tumors in animal experiments. However, whether a high consumption of marine fatty acids can reduce the risk of these cancers or other hormone-dependent cancers in human populations is unclear. Focusing primarily on the results of cohort and case-control studies, we reviewed the current epidemiologic literature on the intake of fish and marine fatty acids in relation to the major hormone-dependent cancers. Despite the many epidemiologic studies that have been published, the evidence from those studies remains unclear. Most of the studies did not show an association between fish consumption or marine fatty acid intake and the risk of hormone-related cancers. Future epidemiologic studies will probably benefit from the assessment of specific fatty acids in the diet, including eicosapentaenoic and docosahexaenoic acids, and of the ratio of these to n-6 fatty acids, dietary constituents that have not been examined individually very often.

A novel mechanistic hypothesis is proposed which suggests that hyperhomocysteinemia is a risk factor for the development of estrogen-induced hormonal cancer in humans. Mechanistically, hyperhomocysteinemia may exert its pathogenic effects largely through metabolic accumulation of intracellular S-adenosyl-L-homocysteine, a strong non-competitive inhibitor of the catechol-O-methyltransferase-mediated methylation metabolism of endogenous and exogenous catechol estrogens (mainly 2-hydroxyestradiol and 4-hydroxyestradiol). While a strong inhibition of the methylation metabolism of 2-hydroxyestradiol would decrease the formation of 2-methoxyestradiol (an antitumorigenic endogenous metabolite of 17beta-estradiol), an inhibition of the methylation of 4-hydroxyestradiol would lead to accumulation of this hormonally-active and strongly procarcinogenic catechol estrogen metabolite. Both of these effects resulting from inhibition of the methylation metabolism of catechol estrogens would facilitate the development of estrogen-induced hormonal cancer in the target organs. This hypothesis also predicts that adequate dietary intake of folate, vitamin B6, and vitamin B12 may reduce hyperhomocysteinemia-associated risk for hormonal cancer. Experimental studies are warranted to determine the relations of hyperhomocysteinemia with the altered circulating or tissue levels of 4-hydroxyestradiol and 2-methoxyestradiol and also with the altered risk for estrogen-induced hormonal cancer.

Breast cancer is a major cause of female morbidity and mortality worldwide. In this review, we discuss the hormonal and genetic risk factors associated with breast cancer development and describe the currently available models for predicting an individual woman's risk. We highlight three more sophisticated surrogate markers of life-time oestrogen exposure (plasma oestradiol, mammographic breast density, bone mineral density) and propose that these may be used to improve estimates of a woman's absolute risk.

Prostate cancer is disease in which the mortality rate is highly variable among populations. An increasing risk with migratory changes suggests that some environmental factor or factors influence prostate cancer risk. It is well established that the prostate is hormonally influenced. Carcinogenesis is a process of malignant transformation evolving over time, involving cellular growth and division. There is evidence suggesting that androgenic influences over a period time encourages the process of prostate carcinogenesis. Studies of prostate biology support the concept that dihydrotestosterone is the principal androgen responsible for both normal and hyperplastic growth of the prostate gland. It may be that androgen causes prostate carcinogenesis. Suppression of dihydrotestosterone synthesis may inhibit carcinogenic transformation. Some preclinical and clinical observations support this hypothesis. A placebo controlled randomized trial using finasteride, an inhibitor of 5-alpha-reductase, the enzyme that converts testosterone to dihydrotestosterone, is ongoing. The endpoint of this trial is reduction of prostate cancer incidence.

Steroid-hormone dependent cancers, including those of the breast, prostate and colon, are leading causes of morbidity and mortality in western countries. In rural Asian areas, these diseases are relatively uncommon. Dietary factors, including low consumption of fruit, vegetables and soy in the west have been shown in various epidemiologic studies as reasons for these differences. This review discusses flavonoids, one component of these plant foods that is being investigated for their role in chemoprevention. Epidemiological, in vitro, animal and human studies shall be explored to look at mechanisms involved, including steroid hormone activity, effects on cell growth, antioxidant activities, inhibition of chemical carcinogenesis and influences on modulators of cancer risk. Although the in vitro and animal models point to several pathways by which flavonoids may reduce incidence of these cancers, the clinical data are still relatively lacking. More research is needed to determine how best to use foods containing these compounds to reduce steroid hormone-dependent cancer risk.

Excessive estrogen stimulation unopposed by progesterone strongly predisposes to endometrial cancer. Because the antiproliferative effect of progesterone requires the progesterone receptor (PR), which exists in two isoforms, PR-A and -B, we reasoned that variants in the PR gene may predispose to endometrial cancer. We found six variable sites, including four polymorphisms in the hPR gene and five common haplotypes. One promoter region polymorphism, +331G/A, creates a unique transcription start site. Biochemical assays showed that the +331G/A polymorphism increases transcription of the PR gene, favoring production of hPR-B in an endometrial cancer cell line. Using a case-control study nested within the Nurses' Health Study cohort, we observed a statistically significant association between the +331G/A polymorphism and the risk of endometrial cancer, which was even greater in overweight women carriers. After including a second population of controls, these associations remained intact. Our findings suggest that the +331G/A hPR gene polymorphism may contribute to endometrial cancer risk by increasing expression of the hPR-B isoform.

It has been reported that age-specific breast cancer rates vary by estrogen receptor and progesterone receptor status. We report breast cancer rates for age-at-diagnosis, stage-at-diagnosis, histological grade and type by estrogen (ER) and progesterone (PgR) receptor status in six major racial/ethnic groups. The average annual age-adjusted rates for breast cancers with estrogen receptor positive (ER+), ER-, progesterone receptor positive (PgR+), PgR-, ER+PgR+, ER+PgR-, ER-PgR+ and ER-PgR- are determined from 123,732 breast cancers with known ER status, diagnosed from 1992 to 1998 from 11 Surveillance, Epidemiology, and End Results (SEER) cancer registries. For each racial/ethnic group, their ER+ (ER+PgR+ and ER+PgR-) age-specific rates increased with age (but at a slower pace after ages 50-54) while their ER- (ER- PgR+ and ER-PgR-) age-specific rates did not increase after ages 50-54. The rank orders of the rates among the racial/ethnic groups varied by ER/PgR status. The stage I rates were greater than the stage II rates for the ER/PgR groups except for ER- and ER- PgR- cancers. The grade 2 (moderately differentiated) rates were greater than the grades 3 and 4 (poorly differentiated and undifferentiated cancers) rates for ER+ cancers, but not for ER- cancers. These results suggest that although breast cancer is a disease with enormous heterogeneity, the multiple types of breast cancer can be separated into distinct subgroups by their ER status, and perhaps by their ER/PgR status, and their cancer characteristics may be important in understanding the multiple nature of breast cancer.

Visible light of sufficient intensity inhibits melatonin biosynthesis and numerous experimental studies suggest that melatonin may protect against cancer. From a public health point of view it is important to verify or falsify the hypothesis that artificial light - or even sunlight itself - suppresses melatonin production sufficiently to increase the risk of developing cancers of internal organs. Since humans are exposed universally, even small risk elevations could lead to numerous cases. Recent epidemiological studies of people exposed to anthropogenic light-at-night in the course of shift work and first evaluations of natural light experiments in blind people and in residents of the Arctic are compatible with the possibility that light can influence - at least hormone- dependent - cancer developments via melatonin. To systematically investigate the effect of geographically different light intensities on melatonin production in man, a pan-European study is suggested. Further epidemiological investigations can contribute to the understanding of the patho-physiological relationships between light, melatonin and human biology.

Background: Breast cancer is hormone related, as are cancers of the endometrium, ovary, and prostate. Several studies have suggested that higher extracellular levels of androgens are associated with breast cancer risk, while biological evidence indicates that androgens are protective. The codon 49 alanine to threonine substitution (A49T), codon 89 valine to leucine substitution (V89L) and TA repeat polymorphisms of the steroid 5alpha-reductase type II (SRD5A2) gene are considered functional with respect to enzyme activity converting testosterone into dihydrotestosterone. To test the hypothesis that these three polymorphisms are associated with risk of breast cancer, a case-control study was conducted with patients of Aichi Cancer Center Hospital., Methods: The cases were 237 patients histologically diagnosed with breast cancer, and the controls were 185 noncancer outpatients. DNA from peripheral blood was genotyped by PCR methods., Results: The threonine allele of A49T was not found in our subjects. Compared with the V/V genotype of V89L, the L/L genotype was associated with a decreased risk (crude odds ratio [OR] = 0.61, 95% confidence interval [CI] = 0.36-1.05). This was also the case for the TA(9/9) genotype, with an OR of 0.58 (95% CI = 0.13-2.63) relative to TA(0/0). Among women with the TA(0/0) genotype, however, the OR for the L/L genotype was 0.46 (95% CI = 0.24-0.88) compared with the V/V genotype, and those with the V/V and TA(0/0) genotypes had the highest risk. The haplotype with the L and TA(9) repeat alleles was not found., Conclusion: This study is the first to our knowledge focusing on Japanese women, suggesting that SRD5A2 polymorphisms might have an association with breast cancer risk. Further large-sample studies will be required to confirm the association and to assess any interactions with environmental factors.

Reproductive history is a consistent risk factor for human breast cancer. Epidemiological studies have repeatedly demonstrated that early age of first pregnancy is a strong protective factor against breast cancer and provides a physiologically operative model to achieve a practical mode of prevention. In rodents, the effects of full-term pregnancy can be mimicked by a three-week exposure to low doses of estrogen and progesterone. Neither hormone alone is sufficient to induce protection. The cellular and molecular mechanisms that underlie hormone-induced refractoriness are largely unresolved. Our recent studies have demonstrated that an early cellular response that is altered in hormone-treated mammary cells is the initial proliferative burst induced by the chemical carcinogen methylnitrosourea. The decrease in proliferation is also accompanied by a decrease in the ability of estrogen receptor-positive cells to proliferate. RNA expression of several mammary cell-cycle-related genes is not altered in hormone-treated mice; however, immunohistochemical assays demonstrate that the protein level and nuclear compartmentalization of the p53 tumor suppressor gene are markedly upregulated as a consequence of hormone treatment. These results support the hypothesis that hormone stimulation, at a critical period in mammary development, results in cells with persistent changes in the intracellular regulatory loops governing proliferation and response to DNA damage. A corollary to this hypothesis is that the genes affected by estrogen and progesterone are independent of alveolar differentiation-specific genes. Suppressive subtractive hybridization-PCR methods have identified several genes that are differentially expressed as a consequence of prior estrogen and progesterone treatment. Future experiments are aimed at determining the mechanisms of hormone-induced upregulation of p53 protein expression as part of the overall goal of identifying and functionally characterizing the genes responsible for the refractory phenotype.

Background: Ethnicity, when it is used to mean shared genetic inheritance within a group, has become one of the most important factors in determining prostate carcinoma risk. Genetic polymorphisms were hypothesized to be the probable explanation for differences in risk among ethnic groups. The authors evaluated the association between polymorphisms in genes involved in the androgen biosynthesis and metabolism pathway and the risk of prostate carcinoma., Methods: Two hundred twenty-six patients with the pathologic diagnosis of sporadic prostate tumor and 156 healthy matched (age, ethnic group) male controls from a large epidemiologic cohort were genotyped for previously described polymorphisms in the androgen receptor (AR), 5alpha-reductase type II (SRD5A2), p450c17 (CYP17), and aromatase (CYP19) genes. The different polymorphisms in prostate carcinoma patients also were analyzed according to age of onset, preoperative prostate-specific antigen level, tumor stage, and tumor grade., Results: The distribution of the tetranucleotide simple tandem repeat polymorphism (STRP) in intron 4 of CYP19 was significantly different in control and cancer patients (P = 0.012). The 171 allele and the 187 allele were associated with prostate carcinoma risk (P = 0.05 and P = 0.045, respectively). Conversely, no association was observed between prostate carcinoma risk and the other polymorphisms studied as follow: the CAG repeat in exon 1 of AR, the (TA)n dinucleotide repeat polymorphism in the 3' untranslated region, and the A49T or V89L substitutions in SDR5A2, the single base pair (bp) (a T to C transition) polymorphism that creates an additional Sp1-type (CCACC box) promoter site in CYP17. In prostate carcinoma patients, CAG repeats of AR, and TA repeats of SDR5A2 are associated with age of onset (P = 0.05 and P < 0.001, respectively)., Conclusions: The association between the 171-bp allele of CYP19 and prostate carcinoma risk suggests that aromatase could be used as a new indicator for prostate carcinoma prevention in men of White French ethnogeographic origin. Conversely, it is possible that an individual carries both a high- and a low-risk marker (e.g., CYP17 A2 allele and V89L in SRD5A2) resulting in no overall difference in risk observed across the population. For these reasons, the development of a polygenic model, incorporating multiple loci from the individual genes may maximize the chance of identifying individuals with high-risk genotypes., (Copyright 2001 American Cancer Society.)

Background: Previous studies provide evidence that breast cancers occurring in different age and ethnic groups are not evenly distributed with regard to their biologic, pathologic and clinical characteristics. We evaluated the distributions of 11 pathological and biological variables between African-American (AA) and white patients and between three different age groups (20-39, 40-59 and 60-74 years). We examined whether racial differences existed across levels of age., Methods: Data were obtained from the Carolina Breast Cancer Study (CBCS), a population-based, case-control study of breast cancer in North Carolina. Eighty hundred and sixty one women with a first diagnosis of invasive breast cancer participated in Phase I of the CBCS. Diagnostic paraffin blocks were obtained from 807 cases. One representative block was scored for histologic type and grade (architectural, nuclear, mitotic and overall). Medical chart review yielded tumor size, lymph node status, distant metastases, stage, hormone receptor status (ER/PR) and DNA ploidy., Results: Pathologically advanced tumors (large size, high grade, high stage, ER/PR negative) were significantly more common in young and AA women. Racial differences varied by age. Among younger, AAs and whites differed only with respect to ER/PR status, while among older women AAs and whites differed only with respect to stage at diagnosis., Conclusions: The results of this study confirm the presence of poorer prognosis breast cancer among AA and younger women. They also highlight the need for age and race to be considered together when evaluating pathologic and biologic characteristics of disease and when making inferences regarding tumor aggressiveness.

Strategies for reducing the occurrence of prostate cancers will be critical in limiting the morbidity and mortality of this disease. The long latency period of prostate tumors and improved understanding of prostate carcinogenesis suggest opportunities for effective preventive measures. Because androgen is integral to prostatic carcinogenesis, several preventive strategies under investigation target the androgen axis. Epidemiologic and basic studies implicate dietary factors in prostate cancer development and suggest that altering diet may influence prostate cancer risk and progression. Many of the micronutrients with preventive potential have antioxidant properties; cellular defenses against oxidative stresses are likely to be crucial in reducing prostate carcinogenesis. This article summarizes the current status and opportunities in prostate cancer prevention.

Background: The tendency for breast cancer to form multiple lesions is important to consider when planning breast-conserving surgery. However, many unknowns remain regarding the pathology and prognosis of multiple breast cancer, and therefore it is clinically significant to investigate its clinicopathological properties., Methods: Over the past 25 years, in the period between April 1972 and March 1997, we investigated the clinicopathological findings including the 5-year and 10-year survival rates of 66 patients treated for unilateral multiple breast cancer., Results: Of the total of 1,334 female patients with unilateral breast cancer who underwent curative surgery at our hospital, we identified 66 (5.0%) patients with unilateral multiple cancer. The incidence of such cancer has been higher in recent years. Of the 66 patients, 50 (75.8%) were premenopausal, and the remaining patients were postmenopausal, but multiple cancer among postmenopausal women is a recent phenomenon. The ER positivity rate of the main lesion in patients with multiple breast cancer was 69.2% and that of PgR was 50.0%. The 5-and 10-year overall survival rate in all 66 patients with multiple breast cancer was 90.8% and 79.7%, respectively., Conclusion: In the past, multiple breast cancer was frequently identified in premenopausal women. However, the current findings indicate that its incidence among postmenopausal women has increased in recent years. In addition, prognoses were comparable for patients with multiple or solitary breast cancer, a relevant finding in the planning of breast-conserving surgery.

The mutation of the p53 gene is a common phenomenon in numerous human tumors including breast cancer. It leads to an accumulation of nonfunctioning p53 protein in the cell nuclei, which can be detected by immunohistochemical techniques. In breast cancer overexpression of mutated p53 protein has been correlated to a poor prognosis. Our study is an immunohistochemical analysis of p53 in 82 cases of breast cancer in young (< or = 30 years old) Kuwaiti women, correlating it with histopathological grade, lymph node status, estrogen (ER) and progesterone receptor (PgR) content, tumor cell proliferation (immunostaining for Ki-67) and expression of c-erbB-2 oncoprotein. p53 immunostaining was found in 47 (57.32%) of the carcinomas. 65% of them displayed positive immunostaining for c-erbB-2. 63.7% of tumors with p53 overexpression were aneuploid. 64.8% of the p53 positive tumors were node positive. 93.5% of the p53 immunopositive carcinomas were ER-negative, and in 95.7% of this subclass of patients no PgR could be detected. The vast majority of p53 positive carcinomas were grade III (76.6%), 21.3% were grade II and 2.1% grade I, but neither tumor grade or tumor size showed a correlation with p53 expression. A significant negative correlation between ER- and PgR-content (p = 0.006) and immunostaining for p53 was observed. Our study provided evidence that the association of negative hormone receptor status and positivity for p53 immunostaining points to a greater tumor aggressiveness.

A healthy cardiovascular system, with minimal arteriosclerosis, good endothelial function and well-compensated ventricular function has been observed at advanced ages, and linked to a healthy lifestyle. This has consisted of a plant-based diet, low in salt and fat, with monounsaturates as the principal fat. Other healthy lifestyle factors include regular physical activity (farming and traditional dance) and minimal tobacco use. The associated negative risk factors are low homocysteine, healthy cholesterol profile (Total:HDL ratio less than 3.5) and reasonable blood pressures throughout the life cycle. Hormone-dependent cancers including breast, ovary, prostate and colon and osteoporotic complications, such as hip fracture rates, are also less frequent compared to the west. Protective factors may include high anti-oxidant consumption, mainly flavonoids and carotenoids, through a high vegetable (e.g., onions) and soy intake. Related biological observations include low lipid peroxide, high superoxide dismutase activity and high serum hydroxyproline, a marker of bone formation. Dehydroepiandrosterone (DHEA) and its hormonal byproducts testosterone and oestrogen appear to be high in Okinawan serum compared with age-matched Americans, possibly reflecting a slower age-associated decline in the sex hormone axis in Okinawans. This may be linked to better cardiovascular and overall health. Further study is needed to delineate the reasons behind the impressive cardiovascular and overall health of the Okinawans.

Breast cancer rarely occurs in women below the age of 35 years. Data from various sources indicate that diagnosis at such an age is associated with a dire prognosis mainly because of a more aggressive presentation. Although the effect of chemotherapy for premenopausal patients is substantial, recent evidence on 2233 patients suggested that very young women with endocrine-responsive tumors had a statistically significantly higher risk of relapse than older premenopausal patients with such tumors. In contrast, results for younger and older premenopausal patients were similar if their tumors were classified as endocrine nonresponsive. Information from studies on 7631 patients who were treated with chemotherapy alone in trials of three major U.S. cooperative groups showed a similar interaction between the effect of age and steroid hormone receptor status of the primary tumor. Better treatments for very young patients are required and may involve ovarian function suppression in addition to other endocrine agents in patients with endocrine responsive tumors and a more precise investigation of chemotherapy and its timing, duration, and intensity in those with endocrine nonresponsive tumors. Very young women with this disease are faced with personal, family, professional, and quality-of-life issues, which further complicate the phase of treatment decision making. The development of more effective therapies for younger patients requires tailored treatment investigations and cannot rely on information predominantly contributed from older premenopausal women.

Leiomyomata represent the most common gynecologic tumors and are responsible for over 200,000 hysterectomies per year. They are almost invariably benign and represent clonal expansion of individual myometrial cells. They can cause a variety of symptoms including menometrorrhagia, dysmenorrhea, pelvic pain, reproductive failure, and compression of adjacent pelvic viscera, or be totally asymptomatic. Leiomyomata are more common in African-American women and have a non-Mendelian inheritance pattern with up to a 50% recurrence rate after surgical removal. The therapeutic choices depend on the goals of therapy, with hysterectomy most often used for definitive treatment, and myomectomy when preservation of childbearing is desired. Intracavitary and submucous leiomyomata can be removed by hysteroscopic resection. Laparoscopic myomectomy is now technically possible but apparently with an increased risk of uterine rupture during pregnancy. Although gonadotropin-releasing hormone-agonist-induced hypogonadism can reduce the volume of leiomyomata, the severe side effects and prompt recurrences make them useful only for short-term goals such as reversing anemia or shrinking an intracavitary tumor prior to hysteroscopic resection. Nonextirpative approaches such as myolysis and uterine artery embolization are being evaluated, and may provide more options if they prove to be safe and efficacious in long-term follow-up. Ultimately, if the genetic basis for fibroid development and/or the molecular mechanism(s) of myometrial proliferation are understood, additional nonsurgical therapeutic interventions may be forthcoming. Current clinical needs are to a) determine an effective prevention strategy in genetically predisposed individuals; b) slow the growth of leiomyomata; c) identify the mechanisms of infertility; d) improve early detection; e) develop better surgical techniques; f) reduce recurrences after myomectomy; g) develop nonextirpative options; and h) evaluate their long-term results.

Uterine leiomyomata are hormonally dependent tumors that are a major source of gynecologic morbidity among women of reproductive age. Relatively few studies have attempted to identify specific risk factors for these neoplasms. In this review of epidemiologic contributions to the etiology of uterine leiomyomata, we begin by outlining methodologic issues in epidemiologic studies that arise from the fact that a large proportion of uterine leiomyomata does not come to medical attention. We then review the major findings from published epidemiologic studies, which to date have focused primarily on menstrual and childbearing history, exogenous hormone use, obesity, cigarette smoking, and other lifestyle and behavioral characteristics that may in part reflect aspects of a woman's hormonal milieu. None of the potential risk factors studied have demonstrated sufficiently consistent associations to guide decisions on the primary prevention of uterine leiomyomata. Clarifying the etiology and natural history of uterine leiomyomata will require studies designed to address methodologic issues and test hypotheses involving environmental and lifestyle influences on endocrine function, as well as on other possible etiologic mechanisms. Recent advances in molecular genetics present opportunities for epidemiologic studies of uterine leiomyomata to incorporate biomarkers of somatic changes found in these tumors and to examine inherited genetic factors related to possible causal physiologic mechanisms.

CYP17 encodes the enzyme cytochrome P-450c17 alpha, which mediates both 17 alpha-hydroxylase and 17,20-lyase in the steroid biosynthesis pathway. A polymorphism in the 5; promoter region of the CYP17 gene has been described. Steroid hormones, especially androgens, are believed to play a key role in the etiology of prostate cancer. Therefore, polymorphisms in genes involved in the androgen metabolism may affect the risk of prostate cancer. We conducted a case-control study of 63 patients with untreated histologically proven prostate cancer and 126 age-matched control men with benign prostatic hyperplasia (BPH) to determine whether a polymorphism in the CYP17 gene is associated with prostate cancer risk. This polymorphism was investigated by PCR/RFLP using DNA from lymphocytes. The transition (T-->C) in the risk allele (A2) creates a new recognition site for the restriction enzyme MspAI, which permits designation of the wildtype (A1) and the risk allele (A2). The prevalence of the A2/A2 genotype was significantly higher (P = 0.03) in the cancer group (23.8%) than in the BPH control group (9.5%). We found an increased risk in men carrying 2 A2 alleles (OR = 2.80, 95%CI = 1.02-77.76). For carrier with at least 1 A2 allele, the OR was 0.90 (95%CI = 0.43-1.89). After stratification by median age (66 years) at time of diagnosis, a marked increased risk was found in carriers of the A2/A2 genotype older than 66 years (OR = 8.93, 95%CI = 1.78-49.19, P = 0.01). Although the sample size is rather small and the controls are BPH patients, our results suggest that the CYP17A2/A2 genotype may be a biomarker for prostate cancer risk, especially for older men., (Copyright 2000 Wiley-Liss, Inc.)

Background: The use of psychotropic medications may increase the risk of hormone-related cancers in females through increased gonadotropin secretion, but the data from epidemiologic studies are limited to evaluate the hypothesis., Methods: The association between the use of psychotropic medications and cancer incidence was studied in a prospective cohort study that involves 15,270 women who participated in mammographic screening. The relative risks (RR) and 95 per cent confidence intervals (CIs) for cancer associated with the use of psychotropic medications were estimated by the Cox's proportional hazard model., Results: During an average of 7.3 years of follow-up, 1,130 incident cases of cancer were identified, including 566 breast, 67 endometrial and 47 ovarian cancers. The use of any type of psychotropic medication at baseline was associated with increased risks of breast [relative risk (RR) = 1.39, 95 per cent CI 1.11-1.74], endometrial (RR=1.71; 95 per cent CI 0.93-3.14) and ovarian (RR= 1.48, 95 per cent CI 0.69-3.16) cancers, whereas no increase in risk was observed for other cancers (RR = 1.06). When the subjects were divided by menopausal status at baseline, premenopausal women tended to have higher risk of all hormone-related cancers (RR = 1.73, 95 per cent CI 1.27-2.35) than postmenopausal women (RR=1.23, 95 per cent CI 0.94-1.62). The magnitude of the RR associated with the use of these medications did not change by length of follow-up. Analysis by type of medication did not find that the association was limited to specific types., Conclusion: The observed association needs to be confirmed in further studies based on more detailed medication history.

Objective: Over the past decades the use of fertility drugs (FDs) has greatly increased. Recently, the possible association between the use of FDs and risk of cancer has aroused great concern. In this paper, we critically review the available epidemiologic studies., Methods: We identified papers published between 1966 and 1999 that examined FDs and specific causes of subfertility in relation to the risks of cancers of the ovary, breast, endometrium and thyroid, and melanoma., Results: Although present insights into the pathogenesis of hormone-related malignancies suggest a possible association between the use of FDs and the risk of specific cancers, this has not been convincingly demonstrated in epidemiologic studies. With regard to cancer risk in relation to the cause of subfertility, the only consistent association observed is an increased risk of endometrial cancer for women with subfertility due to hormonal disorders. While positive findings in some studies on FDs and ovarian cancer risk have aroused serious concern, the associations observed in most of these reports appear to be due to bias or chance rather than being causal. The most important sources of bias are inadequate confounder control for both parity and causes of subfertility., Conclusions: To discriminate between the possible carcinogenic effects of various ovulation induction regimens, subfertility disorders, and reproductive characteristics associated with subfertility, future studies should include large populations of subfertile women with sufficient follow-up time. In such cohort studies the cause of subfertility should be measured adequately (based on medical records) and information about reproductive characteristics should be collected for all cohort members. Such studies should also include a group of subfertile women with an indication for FD use but not so treated.

In Africa breast cancer has been reported to occur frequently in young females and to show an aggressive histological and clinical picture, suggesting that this malignancy might have a different biology from this disease in Western females. To investigate this, the present study assessed by immunohistochemistry the expression of estrogen receptors (ER) and progesterone receptors (PgR) in 60 fresh frozen breast cancer tissues from indigenous Tanzanian patients. This prospective study collected tissues from routine patients treated at the Muhimbili Medical Center, Dar es Salaam, Tanzania. These markers have not been previously investigated in indigenous sub-Saharan females with breast cancer. Patients in this study expressed lower frequencies of ER (33%) and PgR (18%) as compared to literature reports including those about African-Americans. Expression of these markers, however, correlated with the demographic, clinical and histological characteristics in a similar way as observed elsewhere. A compounding effect of younger patients' age, advanced disease or late stage at hospital presentation and race in this geographical region could be responsible for the poor expression of hormonal receptors in the majority of patients as observed in this study. A surprising finding was that the proportion of hormonal receptor positive tumors increased with disease duration. In view of the low frequency of expression of hormonal markers, only 26.7% of the patients would be expected to benefit from hormonal therapy based on their expression of the hormone receptors. There is great need to undertake an inter-African study that would evaluate the hormonal status of more African women with breast cancer in different geographical regions of sub-Saharan Africa and document the true picture of their hormonal status. The outcome of these results could be important for treatment strategies for the second most common cancer among African women.

Hormone-related cancers, namely breast, endometrium, ovary, prostate, testis, thyroid and osteosarcoma, share a unique mechanism of carcinogenesis. Endogenous and exogenous hormones drive cell proliferation, and thus the opportunity for the accumulation of random genetic errors. The emergence of a malignant phenotype depends on a series of somatic mutations that occur during cell division, but the specific genes involved in progression of hormone-related cancers are currently unknown. In this review, the epidemiology of endometrial cancer and breast cancer are used to illustrate the paradigms of hormonal carcinogenesis. Then, new strategies for early detection and prevention of hormonal carcinogenesis are discussed. This includes developing polygenic models of cancer predisposition and the further development of safe and effective chemopreventives that block target sequence activity. We developed polygenic models for breast and prostate cancer after hypothesizing that functionally relevant sequence variants in genes involved in steroid hormone metabolism and transport would act together, and also interact with well-known hormonally related risk factors, to define a high-risk profile for cancer. A combination of genes each with minor variation in expressed activity could provide a degree of separation of risk that would be clinically useful as they could yield a large cumulative difference after several decades. The genes included in the breast cancer model are the 17beta-hydroxysteroid dehydrogenase 1 (HSD17B1) gene, the cytochrome P459c17alpha (CYP17) gene, the aromatase (CYP19) gene, and the estrogen receptor alpha (ER) gene. The prostate cancer model includes the androgen receptor gene (AR), steroid 5alpha-reductase type II (SRD5A2), CYP17 and the 3beta hydroxysteroid dehydrogenase (HSD3B2) gene. We present data from our multi-ethnic cohort to support these models.

Prostate cancer is the most common malignancy in males and is the second most common cause of cancer mortality in American men. Polymorphisms have been identified in two genes, the 17-hydroxylase cytochrome P450 gene (CYP17) and the steroid 5-reductase type II gene (SRD5A2) that are involved with androgen biosynthesis and metabolism. The CYP17 A2 allele contains a T-->C transition in the 5' promoter region that creates an additional Sp1-type (CCACC box) promoter site. The SRD5A2 valine to leucine (V89L) polymorphism has been correlated with lower dihydroxytestosterone levels. We tested genotypes in 108 prostate cases and 167 controls along with samples (n = 340) from several different ethnic groups. The CYP17 A2 allele (combined A1/A2 and A2/A2 genotypes) occurred at a higher frequency in Caucasian patients with prostate cancer (70%) than in Caucasian clinical control urology patients (57%), suggesting that the A2 allele may convey increased risk for prostate cancer [odds ratio (OR) = 1.7, 95% confidence interval (CI) = 1.0-3.0]. Blacks and Caucasians had a similar frequency of the A2 genotype (16 and 17%, respectively) while Taiwanese had the highest frequency (27%). The SRD5A2 leucine genotype was most frequent in Taiwanese (28%), intermediate in Caucasians (8.5%) and lowest in Blacks (2.5%). Genotypes having a SRD5A2 leucine allele were somewhat more common in prostate cancer cases (56%) than in controls (49%) (OR = 1.4, 95% CI = 0.8-2.2) but this difference was not significant. These results support the hypothesis that some allelic variants of genes involved in androgen biosynthesis and metabolism may be associated with prostate cancer risk.

A case-control study was carried out in Mexico City during 1995-1997 among women with epithelial ovarian cancer (84 cases) and endometrial cancer (85 cases). The control group consisted of 668 healthy women, matched according to age categories. In a multivariate analysis, the reproductive risk factors for ovarian and endometrial cancer are similar. The risk of ovarian cancer was inversely related to the number of full-term pregnancies; the odds ratio (OR) was 0.17 and the 95% confidence interval (CI) was 0.05-0.54 when comparing nulliparous women versus those with more than seven pregnancies. For endometrial cancer, a similar association was observed (OR, 0.11; 95% CI, 0.04-0.34). The use of oral contraceptive hormones was inversely associated with both ovarian (OR, 0.36; 95% CI, 0.15-0.83) and endometrial cancer risk (OR, 0.36; 95% CI, 0.14-0.90). In women with a history of more than 8.7 years without ovulation, the risk of ovarian cancer decreased four times (OR, 0.23; 95% CI, 0.10-0.50), and that of endometrial cancer decreased more than five times (OR, 0.17; 95% CI, 0.08-0.35). These two neoplasms are clearly typified as hormone dependent, and it is possible to establish that "ovulation" and "exfoliative" mechanisms jointly determine the level of risk for both ovarian and endometrial cancer.

The melatonin hypothesis states that excess exposure to environmental light may contribute to breast cancer risks via impaired pineal secretion of melatonin. A corollary, not considered previously, is that a net annual increase in oncostatic melatonin would be expected in persons who experience a light deficit during extended winter darkness periods; thus, hormone-dependent cancers should occur less frequently in people who reside north, rather than south, of the Arctic circle. Consistent with our prediction, epidemiological data indicate uniformly low risks for hormone-dependent cancers in the Arctic. The available literature on genetic, reproductive, nutritional, life-style, and environmental risk factors provides no obvious clues to the observed cancer patterns. Moreover, diurnal and 24-hour melatonin concentrations in humans living in Arctic regions were reported as high in November-January, when light intensity is low. Since these observations are consistent with our corollary and the associated prediction, we suggest that research on a melatonin-inhibited carcinogenesis in the low-risk populations of the Arctic should be pursued.

Effects of smoking on breast cancer risk remains controversial. Tar products have been claimed to increase risk, antioestrogenic effects to reduce risk. Another possibility is that associations to smoking have been confounded by diet. The increasing incidence of breast cancer from 1960 to 1994 in Sweden is parallel to that of lung cancer and the increasing proportion of female smokers. The incidence of endometrial and colon cancer was in premenopausal women negatively and in postmenopausal women positively related to the incidence of breast cancer. Possible explanations and hypotheses to the different co-variance between breast cancer and lung, endometrial and colon cancer in pre- and postmenopausal women are discussed from the perspectives of smoking, sex hormones and diet. It is concluded that the strong and specific positive relationship between breast and lung cancer in premenopausal women is compatible with the hypothesis that aromatic hydrocarbons may be involved in the causation of disease.

Breast cancer risk is increased by early menarche and late menopause, suggesting that the long duration of exposure of the breasts to the high levels of ovarian steroids in premenopausal women increases risk. Recent prospective studies have shown that postmenopausal women who develop breast cancer have significantly greater prediagnostic serum concentrations of oestradiol than postmenopausal women who remain healthy. Estimation of long-term oestradiol concentrations in premenopausal women is difficult, and few data are available from prospective studies, but these are compatible with the hypothesis that relatively high oestradiol concentrations in premenopausal women are also associated with an increase in breast cancer risk. Women in populations with low breast cancer rates have low serum oestradiol concentrations both before and after the menopause. The serum concentration of oestradiol is probably a major determinant of breast cancer risk, but more data are needed to confirm this and to investigate the possible roles of other sex hormones.

This study was undertaken to explore whether the incidence of breast tumors that overexpress HER-2/neu protein product (HER-2/neu+) is more strongly associated with oral contraceptives (OCs) and other factors than is the incidence of tumors that do not (HER-2/neu-). In a population-based sample of women <45 years, 42.9% (159 of 371) of in situ and invasive breast cancer cases were HER-2/neu+ as assessed by immunohistochemistry in archived tissue. Polytomous logistic regression was used to calculate the odds ratios (ORs) and 95% confidence intervals (CIs) for HER-2/neu+ and HER-2/neu-breast cancer, as compared with 462 population-based controls, in relation to OCs and other factors. The ratio of the ORs (HER-2/neu+ versus HER-2/neu-tumors) was used as an indicator of heterogeneity in risk. There was little heterogeneity in risk for OC use of 6 months or more by HER-2/neu status (age-adjusted ratio of ORs, 1.29; 95% CI, 0.83-2.00). Among early pill users (< or =18 years of age) heterogeneity was apparent (2.39; 95% CI, 1.08-5.30), which was attenuated in a multivariate model (1.99; 95% CI, 0.87-4.54); among cases with estrogen receptor-negative tumors, heterogeneity increased to 5-fold. For other risk factors, there was no marked heterogeneity between + and - tumors for HER-2/neu. In summary, the incidence of breast cancer among younger women in relation to OC use at an early age varied with HER-2/neu status, with the odds ratio for +tumors twice that for -tumors.

The use of hormone replacement therapy by postmenopausal women with a history of breast cancer is a subject of considerable controversy. There are no scientific studies that have appropriately examined the issue, and current practice is often based on inferences from indirect evidence, anecdotal experience, and personal bias. Our understanding of the effects of exogenous, as well as endogenous, hormones on normal and neoplastic breast tissue provides some insights but is not an appropriate basis for clinical practice. The effects of exogenous hormone replacement on the overall health of postmenopausal women, including psychosocial issues, cardiovascular risks, and the morbidity of osteoporosis, must be understood before patients can be counseled appropriately. Treatment of patients must be individualized. The rapidly expanding area of nonhormonal therapies for the treatment of postmenopausal health risks and the treatment of symptomatic complaints in postmenopausal women has already led to a reevaluation of the use of exogenous hormones among all women. A prospective randomized trial that examines the effects of hormone replacement on women with a history of breast cancer is currently underway and will provide valuable data to address these issues. The aim of this review is to outline the scientific basis for the association between estrogen and breast cancer and to provide a framework in which individualized recommendations concerning the use of hormone replacement therapy can be made for patients with breast cancer.