Showing papers on "Breast cancer published in 2002"

Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from the Women's Health Initiative randomized controlled trial

Abstract: Context Despite decades of accumulated observational evidence, the balance of risks and benefits for hormone use in healthy postmenopausal women remains uncertain Objective To assess the major health benefits and risks of the most commonly used combined hormone preparation in the United States Design Estrogen plus progestin component of the Women's Health Initiative, a randomized controlled primary prevention trial (planned duration, 85 years) in which 16608 postmenopausal women aged 50-79 years with an intact uterus at baseline were recruited by 40 US clinical centers in 1993-1998 Interventions Participants received conjugated equine estrogens, 0625 mg/d, plus medroxyprogesterone acetate, 25 mg/d, in 1 tablet (n = 8506) or placebo (n = 8102) Main outcomes measures The primary outcome was coronary heart disease (CHD) (nonfatal myocardial infarction and CHD death), with invasive breast cancer as the primary adverse outcome A global index summarizing the balance of risks and benefits included the 2 primary outcomes plus stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture, and death due to other causes Results On May 31, 2002, after a mean of 52 years of follow-up, the data and safety monitoring board recommended stopping the trial of estrogen plus progestin vs placebo because the test statistic for invasive breast cancer exceeded the stopping boundary for this adverse effect and the global index statistic supported risks exceeding benefits This report includes data on the major clinical outcomes through April 30, 2002 Estimated hazard ratios (HRs) (nominal 95% confidence intervals [CIs]) were as follows: CHD, 129 (102-163) with 286 cases; breast cancer, 126 (100-159) with 290 cases; stroke, 141 (107-185) with 212 cases; PE, 213 (139-325) with 101 cases; colorectal cancer, 063 (043-092) with 112 cases; endometrial cancer, 083 (047-147) with 47 cases; hip fracture, 066 (045-098) with 106 cases; and death due to other causes, 092 (074-114) with 331 cases Corresponding HRs (nominal 95% CIs) for composite outcomes were 122 (109-136) for total cardiovascular disease (arterial and venous disease), 103 (090-117) for total cancer, 076 (069-085) for combined fractures, 098 (082-118) for total mortality, and 115 (103-128) for the global index Absolute excess risks per 10 000 person-years attributable to estrogen plus progestin were 7 more CHD events, 8 more strokes, 8 more PEs, and 8 more invasive breast cancers, while absolute risk reductions per 10 000 person-years were 6 fewer colorectal cancers and 5 fewer hip fractures The absolute excess risk of events included in the global index was 19 per 10 000 person-years Conclusions Overall health risks exceeded benefits from use of combined estrogen plus progestin for an average 52-year follow-up among healthy postmenopausal US women All-cause mortality was not affected during the trial The risk-benefit profile found in this trial is not consistent with the requirements for a viable intervention for primary prevention of chronic diseases, and the results indicate that this regimen should not be initiated or continued for primary prevention of CHD

Gene expression profiling predicts clinical outcome of breast cancer

Abstract: Breast cancer patients with the same stage of disease can have markedly different treatment responses and overall outcome. The strongest predictors for metastases (for example, lymph node status and histological grade) fail to classify accurately breast tumours according to their clinical behaviour. Chemotherapy or hormonal therapy reduces the risk of distant metastases by approximately one-third; however, 70-80% of patients receiving this treatment would have survived without it. None of the signatures of breast cancer gene expression reported to date allow for patient-tailored therapy strategies. Here we used DNA microarray analysis on primary breast tumours of 117 young patients, and applied supervised classification to identify a gene expression signature strongly predictive of a short interval to distant metastases ('poor prognosis' signature) in patients without tumour cells in local lymph nodes at diagnosis (lymph node negative). In addition, we established a signature that identifies tumours of BRCA1 carriers. The poor prognosis signature consists of genes regulating cell cycle, invasion, metastasis and angiogenesis. This gene expression profile will outperform all currently used clinical parameters in predicting disease outcome. Our findings provide a strategy to select patients who would benefit from adjuvant therapy.

A Gene-Expression Signature as a Predictor of Survival in Breast Cancer

Abstract: Background A more accurate means of prognostication in breast cancer will improve the selection of patients for adjuvant systemic therapy. Methods Using microarray analysis to evaluate our previously established 70-gene prognosis profile, we classified a series of 295 consecutive patients with primary breast carcinomas as having a gene-expression signature associated with either a poor prognosis or a good prognosis. All patients had stage I or II breast cancer and were younger than 53 years old; 151 had lymph-node–negative disease, and 144 had lymph-node–positive disease. We evaluated the predictive power of the prognosis profile using univariable and multivariable statistical analyses. Results Among the 295 patients, 180 had a poor-prognosis signature and 115 had a good-prognosis signature, and the mean (±SE) overall 10-year survival rates were 54.6±4.4 percent and 94.5±2.6 percent, respectively. At 10 years, the probability of remaining free of distant metastases was 50.6±4.5 percent in the group with a...

Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer.

Abstract: Background In 1976, we initiated a randomized trial to determine whether lumpectomy with or without radiation therapy was as effective as total mastectomy for the treatment of invasive breast cancer. Methods A total of 1851 women for whom follow-up data were available and nodal status was known underwent randomly assigned treatment consisting of total mastectomy, lumpectomy alone, or lumpectomy and breast irradiation. Kaplan–Meier and cumulative-incidence estimates of the outcome were obtained. Results The cumulative incidence of recurrent tumor in the ipsilateral breast was 14.3 percent in the women who underwent lumpectomy and breast irradiation, as compared with 39.2 percent in the women who underwent lumpectomy without irradiation (P<0.001). No significant differences were observed among the three groups of women with respect to disease-free survival, distant-disease–free survival, or overall survival. The hazard ratio for death among the women who underwent lumpectomy alone, as compared with those wh...

Endogenous sex hormones and breast cancer in postmenopausal women: reanalysis of nine prospective studies.

Abstract: Background: Reproductive and hormonal factors are involved in the etiology of breast cancer, but there are only a few prospective studies on endogenous sex hormone levels and breast cancer risk We reanalyzed the worldwide data from prospective studies to examine the relationship between the levels of endogenous sex hormones and breast cancer risk in postmenopausal women Methods: We analyzed the individual data from nine prospective studies on 663 women who developed breast cancer and 1765 women who did not None of the women was taking exogenous sex hormones when their blood was collected to determine hormone levels The relative risks (RRs) for breast cancer associated with increasing hormone concentrations were estimated by conditional logistic regression on case–control sets matched within each study Linear trends and heterogeneity of RRs were assessed by two-sided tests or chi-square tests, as appropriate Results: The risk for breast cancer increased statistically significantly with increasing concentrations of all sex hormones examined: total estradiol, free estradiol, non-sex hormone-binding globulin (SHBG)-bound estradiol (which comprises free and albumin-bound estradiol), estrone, estrone sulfate, androstenedione, dehydroepiandrosterone, dehydroepiandrosterone sulfate, and testosterone The RRs for women with increasing quintiles of estradiol concentrations, relative to the lowest quintile, were 142 (95% confidence interval [CI] = 104 to 195), 121 (95% CI = 089 to 166), 180 (95% CI = 133 to 243), and 200 (95% CI = 147 to 271; Ptrend<001); the RRs for women with increasing quintiles of free estradiol were 138 (95% CI = 094 to 203), 184 (95% CI = 124 to 274), 224 (95% CI = 153 to 327), and 258 (95% CI = 176 to 378; Ptrend<001) The magnitudes of risk associated with the other estrogens and with the androgens were similar SHBG was associated with a decrease in breast cancer risk (P trend = 041) The increases in risk associated with increased levels of all sex hormones remained after subjects who were diagnosed with breast cancer within 2 years of blood collection were excluded from the analysis Conclusion: Levels of endogenous sex hormones are strongly associated with breast cancer risk in postmenopausal women [J Natl Cancer Inst 2002;94:606–16]

Prophylactic Oophorectomy in Carriers of BRCA1 or BRCA2 Mutations

Abstract: Background Data concerning the efficacy of bilateral prophylactic oophorectomy for reducing the risk of gynecologic cancer in women with BRCA1 or BRCA2 mutations are limited. We investigated whether this procedure reduces the risk of cancers of the coelomic epithelium and breast in women who carry such mutations. Methods A total of 551 women with disease-associated germ-line BRCA1 or BRCA2 mutations were identified from registries and studied for the occurrence of ovarian and breast cancer. We determined the incidence of ovarian cancer in 259 women who had undergone bilateral prophylactic oophorectomy and in 292 matched controls who had not undergone the procedure. In a subgroup of 241 women with no history of breast cancer or prophylactic mastectomy, the incidence of breast cancer was determined in 99 women who had undergone bilateral prophylactic oophorectomy and in 142 matched controls. The length of postoperative follow-up for both groups was at least eight years. Results Six women who underwent proph...

Polymorphisms in DNA repair genes and associations with cancer risk.

Abstract: Common polymorphisms in DNA repair genes may alter protein function and an individual's capacity to repair damaged DNA; deficits in repair capacity may lead to genetic instability and carcinogenesis. To establish our overall understanding of possible in vivo relationships between DNA repair polymorphisms and the development of cancer, we performed a literature review of epidemiological studies that assessed associations between such polymorphisms and risk of cancer. Thirty studies of polymorphisms in OGG1, XRCC1, ERCC1, XPC, XPD, XPF, BRCA2, and XRCC3 were identified in the April 30, 2002 MEDLINE database (National Center for Biotechnology Information. PubMed Database: http://www.ncbi.nlm.nih.gov/entrez). These studies focused on adult glioma, bladder cancer, breast cancer, esophageal cancer, lung cancer, prostate cancer, skin cancer (melanoma and nonmelanoma), squamous cell carcinoma of the head and neck, and stomach cancer. We found that a small proportion of the published studies were large and population-based. Nonetheless, published data were consistent with associations between: (a) the OGG1 S326C variant and increased risk of various types of cancer; (b) the XRCC1 R194W variant and reduced risk of various types of cancer; and (c) the BRCA2 N372H variant and increased risk of breast cancer. Suggestive results were seen for polymorphisms in other genes; however, small sample sizes may have contributed to false-positive or false-negative findings. We conclude that large, well-designed studies of common polymorphisms in DNA repair genes are needed. Such studies may benefit from analysis of multiple genes or polymorphisms and from the consideration of relevant exposures that may influence the likelihood of cancer in the presence of reduced DNA repair capacity.

Revision of the American Joint Committee on Cancer Staging System for Breast Cancer

Abstract: PURPOSE: To revise the American Joint Committee on Cancer staging system for breast carcinoma. MATERIALS AND METHODS: A Breast Task Force submitted recommended changes and additions to the existing staging system that were (1) evidence-based and/or consistent with widespread clinical consensus about appropriate diagnostic and treatment standards and (2) useful for the uniform accrual of outcome information in national databases. RESULTS: Major changes included the following: size-based discrimination between micrometastases and isolated tumor cells; identifiers to indicate usage of innovative technical approaches; classification of lymph node status by number of involved axillary lymph nodes; and new classifications for metastasis to the infraclavicular, internal mammary, and supraclavicular lymph nodes. CONCLUSION: This revised staging system will be officially adopted for use in tumor registries in January 2003.

Risk-reducing salpingo-oophorectomy in women with a BRCA1 or BRCA2 mutation.

Abstract: Background Risk-reducing salpingo-oophorectomy is often considered by carriers of BRCA mutations who have completed childbearing. However, there are limited data supporting the efficacy of this approach. We prospectively compared the effect of risk-reducing salpingo-oophorectomy with that of surveillance for ovarian cancer on the incidence of subsequent breast cancer and BRCA-related gynecologic cancers in women with BRCA mutations. Methods All women with BRCA1 or BRCA2 mutations identified during a six-year period were offered enrollment in a prospective follow-up study. A total of 170 women 35 years of age or older who had not undergone bilateral oophorectomy chose to undergo either surveillance for ovarian cancer or risk-reducing salpingo-oophorectomy. Follow-up involved an annual questionnaire, telephone contact, and reviews of medical records. The time to cancer in the two groups was compared by Kaplan–Meier analysis and a Cox proportional-hazards model. Results During a mean follow-up of 24.2 months...

Breast Cancer Screening: A Summary of the Evidence for the U.S. Preventive Services Task Force

Abstract: Study Selection: Eight randomized, controlled trials of mammography and 2 trials evaluating breast self-examination were included. One hundred fifty-four publications of the results of these trials, as well as selected articles about the test characteristics and harms associated with screening, were examined. Data Extraction: Predefined criteria were used to assess the quality of each study. Meta-analyses using a Bayesian randomeffects model were conducted to provide summary relative risk estimates and credible intervals (CrIs) for the effectiveness of screening with mammography in reducing death from breast cancer. Data Synthesis: For studies of fair quality or better, the summary relative risk was 0.84 (95% CrI, 0.77 to 0.91) and the number needed to screen to prevent one death from breast cancer after approximately 14 years of observation was 1224 (CrI, 665 to 2564). Among women younger than 50 years of age, the summary relative risk associated with mammography was 0.85 (CrI, 0.73 to 0.99) and the number needed to screen to prevent one death from breast cancer after 14 years of observation was 1792 (CrI, 764 to 10 540). For clinical breast examination and breast self-examination, evidence from randomized trials is inconclusive. Conclusions: In the randomized, controlled trials, mammography reduced breast cancer mortality rates among women 40 to 74 years of age. Greater absolute risk reduction was seen among older women. Because these results incorporate several rounds of screening, the actual number of mammograms needed to prevent one death from breast cancer is higher. In addition, each screening has associated risks and costs.

Annual Report to the Nation on the status of cancer, 1973–1999, featuring implications of age and aging on U.S. cancer burden

Abstract: BACKGROUND The American Cancer Society, the National Cancer Institute, the North American Association of Central Cancer Registries (NAACCR), the National Institute on Aging (NIA), and the Centers for Disease Control and Prevention, including the National Center for Health Statistics (NCHS) and the National Center for Chronic Disease Prevention and Health Promotion, collaborated to provide an annual update on cancer occurrence and trends in the United States. This year's report contained a special feature focusing on implications of age and aging on the U.S. cancer burden. METHODS For 1995 through 1999, age-specific rates and age-adjusted rates were calculated for the major cancers using incidence data from the Surveillance, Epidemiology, and End Results Program, the National Program of Cancer Registries, and the NAACCR, and mortality data from NCHS. Joinpoint analysis, a model of joined line segments, was used to examine 1973–1999 trends in incidence and death rates by age for the four most common cancers. Deaths were classified using the eighth, ninth, and tenth revisions of the International Classification of Diseases. Age-adjusted incidence and death rates were standardized to the year 2000 population, which places more emphasis on older persons, in whom cancer rates are higher. RESULTS Across all ages, overall cancer death rates decreased in men and women from 1993 through 1999, while cancer incidence rates stabilized from 1995 through 1999. Age-specific trends varied by site, sex, and race. For example, breast cancer incidence rates increased in women aged 50-64 years, whereas breast cancer death rates decreased in each age group. However, a major determinant of the future cancer burden is the demographic phenomenon of the aging and increasing size of the U.S. population. The total number of cancer cases can be expected to double by 2050 if current incidence rates remain stable. CONCLUSIONS Despite the continuing decrease in cancer death rates and stabilization of cancer incidence rates, the overall growth and aging of the U.S. population can be expected to increase the burden of cancer in our nation. Cancer 2002;94:2766–92. © 2002 American Cancer Society. DOI 10.1002/cncr.10593

Quality of Life in Long-Term, Disease-Free Survivors of Breast Cancer: a Follow-up Study

Abstract: Background: Women with breast cancer are the largest group of female survivors of cancer. There is limited information about the long-term quality of life (QOL) in diseasefree breast cancer survivors. Methods: Letters of invitation were mailed to 1336 breast cancer survivors who had participated in an earlier survey and now were between 5 and 10 years after their initial diagnosis. The 914 respondents interested in participating were then sent a survey booklet that assessed a broad range of QOL and survivorship concerns. All P values were two-sided. Results: A total of 817 women completed the follow-up survey (61% response rate), and the 763 disease-free survivors in that group, who had been diagnosed an average of 6.3 years earlier, are the focus of this article. Physical well-being and emotional well-being were excellent; the minimal changes between the baseline and follow-up assessments reflected expected age-related changes. Energy level and social functioning were unchanged. Hot flashes, night sweats, vaginal discharge, and breast sensitivity were less frequent. Symptoms of vaginal dryness and urinary incontinence were increased. Sexual activity with a partner declined statistically significantly between the two assessments (from 65% to 55%, P = .001). Survivors with no past systemic adjuvant therapy had a better QOL than those who had received systemic adjuvant therapy (chemotherapy, tamoxifen, or both together) (physical functioning, P = .003; physical role function, P = .02; bodily pain, P = .01; social functioning, P = .02; and general health, P = .03). In a multivariate analysis, past chemotherapy was a statistically significant predictor of a poorer current QOL (P = .003). Conclusions: Long-term, disease-free breast cancer survivors reported high levels of functioning and QOL many years after primary treatment. However, past systemic adjuvant treatment was associated with poorer functioning on several dimensions of QOL. This information may be useful to patients and physicians who are engaging in discussion of the risks and benefits of systemic adjuvant therapy. [J Natl Cancer Inst 2002;94:39–49]

Low-penetrance susceptibility to breast cancer due to CHEK2(*)1100delC in noncarriers of BRCA1 or BRCA2 mutations

Abstract: Mutations in BRCA1 and BRCA2 confer a high risk of breast and ovarian cancer, but account for only a small fraction of breast cancer susceptibility. To find additional genes conferring susceptibility to breast cancer, we analyzed CHEK2 (also known as CHK2), which encodes a cell-cycle checkpoint kinase that is implicated in DNA repair processes involving BRCA1 and p53 (refs 3,4,5). We show that CHEK2(*)1100delC, a truncating variant that abrogates the kinase activity, has a frequency of 1.1% in healthy individuals. However, this variant is present in 5.1% of individuals with breast cancer from 718 families that do not carry mutations in BRCA1 or BRCA2 (P = 0.00000003), including 13.5% of individuals from families with male breast cancer (P = 0.00015). We estimate that the CHEK2(*)1100delC variant results in an approximately twofold increase of breast cancer risk in women and a tenfold increase of risk in men. By contrast, the variant confers no increased cancer risk in carriers of BRCA1 or BRCA2 mutations. This suggests that the biological mechanisms underlying the elevated risk of breast cancer in CHEK2 mutation carriers are already subverted in carriers of BRCA1 or BRCA2 mutations, which is consistent with participation of the encoded proteins in the same pathway.

Postmenopausal Hormone Replacement Therapy: Scientific Review

Abstract: ContextAlthough postmenopausal hormone replacement therapy (HRT) is widely used in the United States, new evidence about its benefits and harms requires reconsideration of its use for the primary prevention of chronic conditions.ObjectiveTo assess the benefits and harms of HRT for the primary prevention of cardiovascular disease, thromboembolism, osteoporosis, cancer, dementia, and cholecystitis by reviewing the literature, conducting meta-analyses, and calculating outcome rates.Data SourcesAll relevant English-language studies were identified in MEDLINE (1966-2001), HealthSTAR (1975-2001), Cochrane Library databases, and reference lists of key articles. Recent results of the Women's Health Initiative (WHI) and the Heart and Estrogen/progestin Replacement Study (HERS) are included for reported outcomes.Study Selection and Data ExtractionWe used all published studies of HRT if they contained a comparison group of HRT nonusers and reported data relating to HRT use and clinical outcomes of interest. Studies were excluded if the population was selected according to prior events or presence of conditions associated with higher risks for targeted outcomes.Data SynthesisMeta-analyses of observational studies indicated summary relative risks (RRs) for coronary heart disease (CHD) incidence and mortality that were significantly reduced among current HRT users only, although risk for incidence was not reduced when only studies that controlled for socioeconomic status were included. The WHI reported increased CHD events (hazard ratio [HR], 1.29; 95% confidence interval [CI], 1.02-1.63). Stroke incidence but not mortality was significantly increased among HRT users in the meta-analysis and the WHI. The meta-analysis indicated that risk was significantly elevated for thromboembolic stroke (RR, 1.20; 95% CI, 1.01-1.40) but not subarachnoid or intracerebral stroke. Risk of venous thromboembolism among current HRT users was increased overall (RR, 2.14; 95% CI, 1.64-2.81) and was highest during the first year of use (RR, 3.49; 95% CI, 2.33-5.59) according to a meta-analysis of 12 studies. Protection against osteoporotic fractures is supported by a meta-analysis of 22 estrogen trials, cohort studies, results of the WHI, and trials with bone density outcomes. Current estrogen users have an increased risk of breast cancer that increases with duration of use. Endometrial cancer incidence, but not mortality, is increased with unopposed estrogen use but not with estrogen with progestin. A meta-analysis of 18 observational studies showed a 20% reduction in colon cancer incidence among women who had ever used HRT (RR, 0.80; 95% CI, 0.74-0.86), a finding supported by the WHI. Women symptomatic from menopause had improvement in certain aspects of cognition. Current studies of estrogen and dementia are not definitive. In a cohort study, current HRT users had an age-adjusted RR for cholecystitis of 1.8 (95% CI, 1.6-2.0), increasing to 2.5 (95% CI, 2.0-2.9) after 5 years of use.ConclusionsBenefits of HRT include prevention of osteoporotic fractures and colorectal cancer, while prevention of dementia is uncertain. Harms include CHD, stroke, thromboembolic events, breast cancer with 5 or more years of use, and cholecystitis.

Proteomics and Bioinformatics Approaches for Identification of Serum Biomarkers to Detect Breast Cancer

Abstract: Background: Surface-enhanced laser desorption/ionization (SELDI) is an affinity-based mass spectrometric method in which proteins of interest are selectively adsorbed to a chemically modified surface on a biochip, whereas impurities are removed by washing with buffer. This technology allows sensitive and high-throughput protein profiling of complex biological specimens. Methods: We screened for potential tumor biomarkers in 169 serum samples, including samples from a cancer group of 103 breast cancer patients at different clinical stages [stage 0 (n = 4), stage I (n = 38), stage II (n = 37), and stage III (n = 24)], from a control group of 41 healthy women, and from 25 patients with benign breast diseases. Diluted serum samples were applied to immobilized metal affinity capture Ciphergen ProteinChip® Arrays previously activated with Ni2+. Proteins bound to the chelated metal were analyzed on a ProteinChip Reader Model PBS II. Complex protein profiles of different diagnostic groups were compared and analyzed using the ProPeak software package. Results: A panel of three biomarkers was selected based on their collective contribution to the optimal separation between stage 0–I breast cancer patients and noncancer controls. The same separation was observed using independent test data from stage II–III breast cancer patients. Bootstrap cross-validation demonstrated that a sensitivity of 93% for all cancer patients and a specificity of 91% for all controls were achieved by a composite index derived by multivariate logistic regression using the three selected biomarkers. Conclusions: Proteomics approaches such as SELDI mass spectrometry, in conjunction with bioinformatics tools, could greatly facilitate the discovery of new and better biomarkers. The high sensitivity and specificity achieved by the combined use of the selected biomarkers show great potential for the early detection of breast cancer.

Racial and Ethnic Disparities in the Receipt of Cancer Treatment

Abstract: A disproportionate number of cancer deaths occur among racial/ethnic minorities, particularly African Americans, who have a 33% higher risk of dying of cancer than whites. Although differences in incidence and stage of disease at diagnosis may contribute to racial disparities in mortality, evidence of racial disparities in the receipt of treatment of other chronic diseases raises questions about the possible role of inequities in the receipt of cancer treatment. To evaluate racial/ethnic disparities in the receipt of cancer treatment, we examined the published literature that addressed access/use of specific cancer treatment procedures, trends in patterns of use, or survival studies. We found evidence of racial disparities in receipt of definitive primary therapy, conservative therapy, and adjuvant therapy. These treatment differences could not be completely explained by racial/ethnic variation in clinically relevant factors. In many studies, these treatment differences were associated with an adverse impact on the health outcomes of racial/ethnic minorities, including more frequent recurrence, shorter disease-free survival, and higher mortality. Reducing the influence of nonclinical factors on the receipt of cancer treatment may, therefore, provide an important means of reducing racial/ethnic disparities in health. New data resources and improved study methodology are needed to better identify and quantify the full spectrum of nonclinical factors that contribute to the higher cancer mortality among racial/ethnic minorities and to develop strategies to facilitate receipt of appropriate cancer care for all patients.

Alcohol, tobacco and breast cancer - Collaborative reanalysis of individual data from 53 epidemiological studies, including 58 515 women with breast cancer and 95 067 women without the disease

Abstract: Alcohol and tobacco consumption are closely correlated and published results on their association with breast cancer have not always allowed adequately for confounding between these exposures. Over 80% of the relevant information worldwide on alcohol and tobacco consumption and breast cancer were collated, checked and analysed centrally. Analyses included 58515 women with invasive breast cancer and 95067 controls from 53 studies. Relative risks of breast cancer were estimated, after stratifying by study, age, parity and, where appropriate, women's age when their first child was born and consumption of alcohol and tobacco. The average consumption of alcohol reported by controls from developed countries was 6.0 g per day, i.e. about half a unit/drink of alcohol per day, and was greater in ever-smokers than never-smokers, (8.4 g per day and 5.0 g per day, respectively). Compared with women who reported drinking no alcohol, the relative risk of breast cancer was 1.32 (1.19 - 1.45, P < 0.00001) for an intake of 35 - 44 g per day alcohol, and 1.46 (1.33 - 1.61, P < 0.00001) for greater than or equal to 45 g per day alcohol. The relative risk of breast cancer increased by 7.1% (95% CI 5.5-8.7%; P<0.00001) for each additional 10 g per day intake of alcohol, i.e. for each extra unit or drink of alcohol consumed on a daily basis. This increase was the same in ever-smokers and never-smokers (7.1 % per 10 g per day, P < 0.00001, in each group). By contrast, the relationship between smoking and breast cancer was substantially confounded by the effect of alcohol. When analyses were restricted to 22 255 women with breast cancer and 40 832 controls who reported drinking no alcohol, smoking was not associated with breast cancer (compared to never-smokers, relative risk for ever-smokers= 1.03, 95% CI 0.98 - 1.07, and for current smokers=0.99, 0.92 - 1.05). The results for alcohol and for tobacco did not vary substantially across studies, study designs, or according to 15 personal characteristics of the women; nor were the findings materially confounded by any of these factors. If the observed relationship for alcohol is causal, these results suggest that about 4% of the breast cancers in developed countries are attributable to alcohol. In developing countries, where alcohol consumption among controls averaged only 0.4 g per day, alcohol would have a negligible effect on the incidence of breast cancer. In conclusion, smoking has little or no independent effect on the risk of developing breast cancer; the effect of alcohol on breast cancer needs to be interpreted in the context of its beneficial effects, in moderation, on cardiovascular disease and its harmful effects on cirrhosis and cancers of the mouth, larynx, oesophagus and liver. (C) 2002 Cancer Research UK.

Endocrine-responsive breast cancer and strategies for combating resistance.

Abstract: Deaths from breast cancer have fallen markedly over the past decade due, in part, to the use of endocrine agents that reduce the levels of circulating oestrogens or compete with oestrogen for binding to its receptor. However, many breast tumours either fail to respond or become resistant to endocrine therapies. By understanding the mechanisms that underlie this resistance, we might be able to develop strategies for overcoming or bypassing it.

Clinical Characteristics of Individuals With Germline Mutations in BRCA1 and BRCA2: Analysis of 10,000 Individuals

Abstract: PURPOSE: To assess the characteristics that correlate best with the presence of mutations in BRCA1 and BRCA2 in individuals tested in a clinical setting. PATIENTS AND METHODS: The results of 10,000 consecutive gene sequence analyses performed to identify mutations anywhere in the BRCA1 and BRCA2 genes (7,461 analyses) or for three specific Ashkenazi Jewish founder mutations (2,539 analyses) were correlated with personal and family history of cancer, ancestry, invasive versus noninvasive breast neoplasia, and sex. RESULTS: Mutations were identified in 1,720 (17.2%) of the 10,000 individuals tested, including 968 (20%) of 4,843 women with breast cancer and 281 (34%) of 824 with ovarian cancer, and the prevalence of mutations was correlated with specific features of the personal and family histories of the individuals tested. Mutations were as prevalent in high-risk women of African (25 [19%] of 133) and other non-Ashkenazi ancestries as those of European ancestry (712 [16%] of 4379) and were significantly l...

Fasting Insulin and Outcome in Early-Stage Breast Cancer: Results of a Prospective Cohort Study

Abstract: PURPOSE: Insulin, a member of a family of growth factors that includes insulin-like growth factor (IGF)-I and IGF-II, exerts mitogenic effects on normal and malignant breast epithelial cells, acting via insulin and IGF-I receptors. Because of this and because of its recognized association with obesity, an adverse prognostic factor in breast cancer, we examined the prognostic associations of insulin in early-stage breast cancer. PATIENTS AND METHODS: A cohort of 512 women without known diabetes, who had early-stage (T1 to T3, N0 to N1, and M0) breast cancer, was assembled and observed prospectively. Information on traditional prognostic factors and body size was collected, and fasting blood was obtained. RESULTS: Fasting insulin was associated with distant recurrence and death; the hazard ratios and 95% confidence intervals (CI) for those in the highest (> 51.9 pmol/L) versus the lowest (< 27.0 pmol/L) insulin quartile were 2.0 (95% CI, 1.2 to 3.3) and 3.1 (95% CI, 1.7 to 5.7), respectively. There was some...

The Pathology of Familial Breast Cancer: Predictive Value of Immunohistochemical Markers Estrogen Receptor, Progesterone Receptor, HER-2, and p53 in Patients With Mutations in BRCA1 and BRCA2

Abstract: PURPOSE: The morphologic and molecular phenotype of breast cancers may help identify patients who are likely to carry germline mutations in BRCA1 and BRCA2. This study evaluates the immunohistochemical profiles of tumors arising in patients with mutations in these genes. MATERIALS AND METHODS: Samples of breast cancers obtained from the International Breast Cancer Linkage Consortium were characterized morphologically and immunohistochemically using antibodies to estrogen receptor, progesterone receptor, HER-2 (c-erbB-2 oncogene), and p53 protein. RESULTS: Breast cancers in patients with BRCA1 germline mutations are more often negative for estrogen receptor, progesterone receptor, and HER-2, and are more likely to be positive for p53 protein compared with controls. In contrast, BRCA2 tumors do not show a significant difference in the expression of any of these proteins compared with controls. CONCLUSION: BRCA1 has a distinctive morphology and immunohistochemical phenotype. The combined morphologic and immu...

Polygenic susceptibility to breast cancer and implications for prevention

Abstract: The knowledge of human genetic variation that will come from the human genome sequence makes feasible a polygenic approach to disease prevention, in which it will be possible to identify individuals as susceptible by their genotype profile and to prevent disease by targeting interventions to those at risk. There is doubt, however, regarding the magnitude of these genetic effects and thus the potential to apply them to either individuals or populations. We have therefore examined the potential for prediction of risk based on common genetic variation using data from a population-based series of individuals with breast cancer. The data are compatible with a log-normal distribution of genetic risk in the population that is sufficiently wide to provide useful discrimination of high- and low-risk groups. Assuming all of the susceptibility genes could be identified, the half of the population at highest risk would account for 88% of all affected individuals. By contrast, if currently identified risk factors for breast cancer were used to stratify the population, the half of the population at highest risk would account for only 62% of all cases. These results suggest that the construction and use of genetic-risk profiles may provide significant improvements in the efficacy of population-based programs of intervention for cancers and other diseases.

Stromal Effects on Mammary Gland Development and Breast Cancer

Abstract: Breast cancer manifests itself in the mammary epithelium, yet there is a growing recognition that mammary stromal cells also play an important role in tumorigenesis During its developmental cycle, the mammary gland displays many of the properties associated with breast cancer, and many of the stromal factors necessary for mammary development also promote or protect against breast cancer Here we review our present knowledge of the specific factors and cell types that contribute to epithelial-stromal crosstalk during mammary development To find cures for diseases like breast cancer that rely on epithelial-stromal crosstalk, we must understand how these different cell types communicate with each other

Prognostic significance of elevated cyclooxygenase-2 expression in breast cancer.

Abstract: Cyclooxygenase-2 (Cox-2) expression can induce mammary tumorigenesis in transgenic mice, and selective Cox-2 inhibitors are both chemopreventive and chemotherapeutic in rat models of breast cancer. We analyzed the expression of Cox-2 protein by immunohistochemistry in tissue array specimens of 1576 invasive breast cancers. Moderate to strong (elevated) expression of Cox-2 protein was observed in 37.4% of the tumors, and it was associated with unfavorable distant disease-free survival (P < 0.0001). Elevated Cox-2 expression was associated with a large tumor size, a high histological grade, a negative hormone receptor status, a high proliferation rate (identified by Ki-67), high p53 expression, and the presence of HER-2 oncogene amplification (P < 0.0001 for all comparisons), along with axillary node metastases and a ductal type of histology (P = 0.0001 and P = 0.0017, respectively). Interestingly, association with the unfavorable outcome was especially apparent in the subgroups defined by estrogen receptor positivity, low p53 expression, and no HER-2 amplification (P < 0.0001 for all comparisons). These results indicate that elevated Cox-2 expression is more common in breast cancers with poor prognostic characteristics and is associated with an unfavorable outcome. The present findings support efforts to initiate clinical trials on the efficacy of Cox-2 inhibitors in adjuvant treatment of breast cancer.