Breast Neoplasms: Cuzick J

Visvanathan K, Chlebowski RT, Hurley P, Col NF, Ropka M, Collyar D, Morrow M, Runowicz C, Pritchard KI, Hagerty K, Arun B, Garber J, Vogel VG, Wade JL, Brown P, Cuzick J, Kramer BS, Lippman SM, Anonymous00092. · Cancer Policy and Clinical Affairs, 2318 Mill Rd, Suite 800, Alexandria, VA 22314, USA. · J Clin Oncol. · Pubmed #19470930 No free full text.

Abstract: PURPOSE To update the 2002 American Society of Clinical Oncology guideline on pharmacologic interventions for breast cancer (BC) risk reduction. METHODS A literature search identified relevant randomized trials published since 2002. Primary outcome of interest was BC incidence (invasive and noninvasive). Secondary outcomes included BC mortality, adverse events, and net health benefits. An expert panel reviewed the literature and developed updated consensus guidelines. Results Seventeen articles met inclusion criteria. In premenopausal women, tamoxifen for 5 years reduces the risk of BC for at least 10 years, particularly estrogen receptor (ER) -positive invasive tumors. Women < or = 50 years of age experience fewer serious side effects. Vascular and vasomotor events do not persist post-treatment across all ages. In postmenopausal women, raloxifene and tamoxifen reduce the risk of ER-positive invasive BC with equal efficacy. Raloxifene is associated with a lower risk of thromboembolic disease, benign uterine conditions, and cataracts than tamoxifen in postmenopausal women. No evidence exists establishing whether a reduction in BC risk from either agent translates into reduced BC mortality. Recommendations In women at increased risk for BC, tamoxifen (20 mg/d for 5 years) may be offered to reduce the risk of invasive ER-positive BC, with benefits for at least 10 years. In postmenopausal women, raloxifene (60 mg/d for 5 years) may also be considered. Use of aromatase inhibitors, fenretinide, or other selective estrogen receptor modulators to lower BC risk is not recommended outside of a clinical trial. Discussion of risks and benefits of preventive agents by health providers is critical to patient decision making.

Forbes JF, Cuzick J. · No affiliation provided · Med J Aust. · Pubmed #16274343 links to  free full text

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Cuzick J. · No affiliation provided · J Natl Cancer Inst. · Pubmed #15769997 links to  free full text

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Cuzick J. · No affiliation provided · J Natl Cancer Inst. · Pubmed #11353776 links to  free full text

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Cuzick J, Otto F, Baron JA, Brown PH, Burn J, Greenwald P, Jankowski J, La Vecchia C, Meyskens F, Senn HJ, Thun M. · Cancer Research UK Centre for Epidemiology, Mathematics, and Statistics, Queen Mary University of London, London UK. · Lancet Oncol. · Pubmed #19410194 No free full text.

Abstract: Evidence clearly shows a chemopreventive effect for aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) on colorectal cancer and probably other cancer types; however, data on the risk-benefit profile for cancer prevention are insufficient and no definitive recommendations can be made. Aspirin has emerged as the most likely NSAID for use in chemoprevention because of its known cardiovascular benefit and available safety and efficacy data. Other traditional NSAIDs, particularly sulindac, and selective COX-2 inhibitors are now given to patients at high risk of colorectal cancer, although these drugs do not provide cardioprotection. More studies of aspirin and cancer prevention are needed to define the lowest effective dose, the age at which to initiate therapy, the optimum treatment duration, and the subpopulations for which the benefits of chemoprevention outweigh the risks of adverse side-effects. Although it might be possible to answer some of these questions with longer follow-up of existing clinical trials, randomised controlled trials with new study designs will be needed. Future projects should investigate the effects of aspirin treatment on multiple organ systems. Cancers of interest are colorectal, breast, prostate, lung, stomach, and oesophageal. The main side-effect of aspirin is peptic ulcers; therefore coadministration of aspirin with a proton-pump inhibitor is an attractive option and is under investigation in the AspECT trial.

Cummings SR, Tice JA, Bauer S, Browner WS, Cuzick J, Ziv E, Vogel V, Shepherd J, Vachon C, Smith-Bindman R, Kerlikowske K. · San Francisco Coordinating Center, California Pacific Medical Center Research Institute, 94107, USA. · J Natl Cancer Inst. · Pubmed #19276457 No free full text.

Abstract: BACKGROUND: It is uncertain whether evidence supports routinely estimating a postmenopausal woman's risk of breast cancer and intervening to reduce risk. METHODS: We systematically reviewed prospective studies about models and sex hormone levels to assess breast cancer risk and used meta-analysis with random effects models to summarize the predictive accuracy of breast density. We also reviewed prospective studies of the effects of exercise, weight management, healthy diet, moderate alcohol consumption, and fruit and vegetable intake on breast cancer risk, and used random effects models for a meta-analyses of tamoxifen and raloxifene for primary prevention of breast cancer. All studies reviewed were published before June 2008, and all statistical tests were two-sided. RESULTS: Risk models that are based on demographic characteristics and medical history had modest discriminatory accuracy for estimating breast cancer risk (c-statistics range = 0.58-0.63). Breast density was strongly associated with breast cancer (relative risk [RR] = 4.03, 95% confidence interval [CI] = 3.10 to 5.26, for Breast Imaging Reporting and Data System category IV vs category I; RR = 4.20, 95% CI = 3.61 to 4.89, for >75% vs <5% of dense area), and adding breast density to models improved discriminatory accuracy (c-statistics range = 0.63-0.66). Estradiol was also associated with breast cancer (RR range = 2.0-2.9, comparing the highest vs lowest quintile of estradiol, P < .01). Most studies found that exercise, weight reduction, low-fat diet, and reduced alcohol intake were associated with a decreased risk of breast cancer. Tamoxifen and raloxifene reduced the risk of estrogen receptor-positive invasive breast cancer and invasive breast cancer overall. CONCLUSIONS: Evidence from this study supports screening for breast cancer risk in all postmenopausal women by use of risk factors and breast density and considering chemoprevention for those found to be at high risk. Several lifestyle changes with the potential to prevent breast cancer should be recommended regardless of risk.

Sherrill B, Amonkar M, Wu Y, Hirst C, Stein S, Walker M, Cuzick J. · RTI Health Solutions, Biometrics, Research Triangle Park, NC 27709-2194, USA. · Br J Cancer. · Pubmed #19002178 No free full text.

Abstract: The relationship between overall survival (OS) and disease progression end points has been demonstrated in colorectal, colon, and non-small cell lung cancers. We assessed the association between OS and time-to-progression (TTP) or progression-free survival (PFS) in metastatic breast cancer (MBC) studies. A literature search retrieved all randomised controlled trials since 1994 in patients with MBC in which OS and either TTP or PFS were reported. Summary data on trial and patient characteristics were abstracted. Study effect sizes were derived as the ratio of median progression (or survival) times, which approximates the hazard ratio. Effects were centred at zero for regression analyses weighted by sample size. Numerous treatments were represented in 67 studies (17 081 patients). Modeling showed a positive association between outcomes for progression and survival (R(2)=0.30) with a slope of 0.32 (P<0.001) and a non-significant intercept. Thus, a treatment effect on TTP/PFS translated into a concordant effect on OS, but with attenuated effect size. Similar results were found in models of subsets and sensitivity analyses. These results demonstrate that treatment effects on progression end points in MBC trials are expected to result in treatment differences on OS that are smaller yet consistently in the same direction.

Cuzick J. · Cancer Research UK Centre for Epidemiology, Mathematics and Statistics, Wolfson Institute of Preventive Medicine, Queen Mary, University of London, Charterhouse Square, London, UK. · Eur J Cancer. · Pubmed #18783940 No free full text.

Abstract: Hormone replacement therapy (HRT) has had a chequered history ever since its initial use to manage menopausal symptoms. It is clear that it has many other effects and here we review its impact on the risk of breast cancer. A clear risk is seen for current uses of combined oestrogen/progestagen pills, but this returns to normal shortly after treatment cessation. The role of oestrogen only replacement therapy is less clear, but most studies find a weaker, but still positive, association in current users. Recent sharp reductions in HRT use have been correlated with declines in breast cancer incidence in the USA, but not so clearly elsewhere.

Howell A, Bundred NJ, Cuzick J, Allred DC, Clarke R. · CRC Department Medical Oncology, University of Manchester Christie Hospital and Holt Radium Inst., Manchester, UK. · Adv Exp Med Biol. · Pubmed #18497044 No free full text.

Abstract: The data from observational studies and clinical trials indicates that it is possible to prevent BC for prolonged periods using various endocrine manipulations. Ovarian suppression is thought to give lifelong protection and recent data indicate that the effectiveness of Tam continues after cessation of treatment at 5-8 years. It is clear from three randomised trials that SERMs prevent ERalpha+ tumors only in women at increased risk and at population risk of BC entered into these trials. The data from the Ral trials also suggests that this agent appears less effective than Tam in preventing DCIS. This is surprising since a large proportion of DCIS is ERalpha+. Equally surprising is the effectiveness of oophorectomy and Tam in mutation carriers, particularly BRCA1, which is associated with ERalpha+ tumors. The fact that ERT can be given without apparently abrogating the effect of oophorectomy and also to naturally postmenopausal women without increasing BC risk suggests that cyclical estrogen or estrogen + progestin are important for BC initiation and/or progression. The question arises whether the information we have concerning the responsiveness of ERalpha+ cells in TDLU, premalignant lesions, and invasive cancers give an indication of the targets for endocrine prevention. Data summarised in Table 1 indicate that TDLU are responsive to estrogen, ED, and SERMs/SERDs in premenopausal women and there may be the targets for the preventative effect of early oophorectomy particularly in BRCA1 carriers where we have demonstrated endocrine responsiveness of TDLU, which at this heterozygote stage are ERalpha+. The decline in numbers of atypical lobules in breasts without invasive cancer suggests that these are targets for the 'preventive' effect of the menopause, as suggested by Wellings. The data also suggest that ERalpha+ DCIS is responsive to estrogen and ED supporting premalignant lesions is a target as does the data from the NSABP P1 trial indicating a marked preventive effect of Tam in women previously diagnosed with atypical ductal hyperplasia and a preventative effect on CIS.

Cuzick J. · Cancer Research UK, Centre for Epidemiology, Mathematics and Statistics, Wolfson Institute of Preventive Medicine, Charterhouse Square, London EC1M 6BQ, UK. · Breast. · Pubmed #18367396 No free full text.

Abstract: This paper describes the clinical evidence for using the aromatase inhibitors (AIs), anastrozole, letrozole and exemestane, as adjuvant therapy for postmenopausal women with early breast cancer. Efficacy data for AIs are reviewed across different treatment strategies (initial, switched, sequenced or extended adjuvant therapy). Although trials are still ongoing, AIs have demonstrated superiority over tamoxifen in terms of disease-free survival and recurrence as initial therapy, and benefits in overall survival in switched or extended strategies. However, comparisons of efficacy data across trials are confounded by methodological differences between trials. To address this problem, mathematical models have been developed which allow for inter-trial comparisons. Results from these models indicate that initial adjuvant therapy with an AI is superior to initial therapy with tamoxifen, and suggest that initial AI therapy is better than starting tamoxifen and then switching to an AI. Further clinical trials are needed to ascertain the optimal length of treatment with an AI.

Santen RJ, Boyd NF, Chlebowski RT, Cummings S, Cuzick J, Dowsett M, Easton D, Forbes JF, Key T, Hankinson SE, Howell A, Ingle J, Anonymous00119. · Department of Internal Medicine/Endocrinology, University of Virginia Health System, Box 801416, Charlottesville, Virginia 22908, USA. · Endocr Relat Cancer. · Pubmed #17639036 links to  free full text

Abstract: The majority of candidates for breast cancer prevention have not accepted tamoxifen because of the perception of an unfavorable risk/benefit ratio and the acceptance of raloxifene remains to be determined. One means of improving this ratio is to identify women at very high risk of breast cancer. Family history, age, atypia in a benign biopsy, and reproductive factors are the main parameters currently used to determine risk. The most powerful risk factor, mammographic density, is not presently employed routinely. Other potentially important factors are plasma estrogen and androgen levels, bone density, weight gain, age of menopause, and fracture history, which are also not currently used in a comprehensive risk prediction model because of lack of prospective validation. The Breast Cancer Prevention Collaborative Group (BCPCG) met to critically examine and prioritize risk factors that might be selected for further testing by multivariate analysis using existing clinical material. The BCPCG reached a consensus that quantitative breast density, state of the art plasma estrogen and androgen measurements, history of fracture and height loss, BMI, and waist-hip ratio had sufficient priority for further testing. As a practical approach, these parameters could be added to the existing Tyrer-Cuzick model which encompasses factors included in both the Claus and Gail models. The BCPCG analyzed potentially available clinical material from previous prospective studies and determined that a large case/control study to evaluate these new factors might be feasible at this time.

Howell A, Clarke RB, Evans G, Bundred N, Cuzick J, Santen R, Allred C. · CRUK Department of Medical Oncology, Christie Hospital, University of Manchester, UK. · Recent Results Cancer Res. · Pubmed #17302193 No free full text.

Abstract: Estrogen deprivation (ED) either as a result of a natural or artificial menopause or the use of aromatase inhibitors in postmenopausal women results in a reduction of the incidence of breast cancer. Two major clinical trials of this approach comparing anastrozole or exemestane with placebo are currently in progress to test their efficacy for prevention. Reduction of contralateral breast lesions by at least 50% compared with tamoxifen indicate this approach has promise. The target lesion within the breast for ED is not known but we argue that hyperplastic enlarged lobular units (HELUs) as well as more advanced lesions are good candidates. A major problem for ED is de novo or acquired resistance to its effectiveness. We discuss potential mechanisms of resistance including high concentrations of tissue estrogens, increase in growth factor, and signal transduction pathways within the epithelial cell and activation of paracrine pathways from breast adipocytes, macrophages and fibroblasts. It may be possible to increase effectiveness of ED by additional preventive agents or by lifestyle alterations.

Buzdar A, Chlebowski R, Cuzick J, Duffy S, Forbes J, Jonat W, Ravdin P. · University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. · Curr Med Res Opin. · Pubmed #16870082 No free full text.

Abstract: BACKGROUND: Over the past few years, data have been published concerning the relative efficacy and safety profiles of tamoxifen and the aromatase inhibitors (AIs) in the adjuvant therapy setting for women with early hormone receptor-positive breast cancer. Recently, debate has centred around trials which have studied primary tamoxifen and AI therapy, switching and sequencing strategies and extended adjuvant therapy. METHODS: Here, a group of 24 breast cancer experts review efficacy and safety data from the recent major trials investigating tamoxifen and the third-generation AIs in postmenopausal women, which have challenged the perception of tamoxifen as optimum adjuvant endocrine therapy. Data from the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial, Breast International Group (BIG) 1-98 study, National Cancer Institute of Canada MA 17 trial, Intergroup Exemestane Study (IES), Italian Tamoxifen Anastrozole (ITA) trial, Austrian Breast and Colorectal Cancer Study Group (ABCSG) Trial 8 and Arimidex-Nolvadex (ARNO) 95 are considered to provide a rational interpretation of the impact of these data on current practice, and to highlight areas where further investigation is needed. CONCLUSION: We can be confident that AIs represent superior adjuvant endocrine treatment to tamoxifen in postmenopausal women, either as initial therapy or as an alternative for women who have started adjuvant therapy with tamoxifen. However, there remain issues regarding the best way to use AIs, such as the optimal length of AI treatment and how a sequence of tamoxifen followed by an AI compares with AI monotherapy; these will require further data to resolve.

Houssami N, Cuzick J, Dixon JM. · Screening and Test Evaluation Program, School of Public Health, University of Sydney, Camperdown, NSW 2006, Australia, and Edinburgh Breast Unit, Western General Hospital, Edinburgh, Scotland. · Med J Aust. · Pubmed #16515434 links to  free full text

Abstract: The reduction in the incidence of contralateral breast cancer in women treated with adjuvant tamoxifen provided a model for prevention using endocrine agents. Oestrogen-receptor-positive cancer can be prevented with tamoxifen, but side effects limit its clinical utility, and the risk-benefit ratio is not sufficiently high to routinely recommend tamoxifen as a preventive agent. Agents being evaluated in prevention trials include raloxifene and the aromatase inhibitors; these are expected to be at least as effective as tamoxifen and to have fewer side effects. Core needle biopsy (providing histological information) and high-resolution breast ultrasound enhance preoperative assessment of breast cancer. Mammography remains the only screening test shown to reduce breast cancer deaths in randomised trials. Magnetic resonance imaging may have a role in screening women with inherited mutations of the breast cancer genes. Sentinel lymph node biopsy accurately assesses lymph node status and is associated with less morbidity than axillary dissection. Where the biopsy is negative (no histologic evidence of metastases), no further axillary treatment is necessary. Breast reconstruction after mastectomy can produce good cosmetic results, especially where autologous tissue is used. Myocutaneous flaps using latissimus dorsi or transverse rectus abdominus muscles are increasingly popular. Adjuvant trastuzumab therapy in patients whose tumours overexpress HER2 (growth factor receptor) can reduce recurrence rates and improve survival. Neoadjuvant endocrine therapy (as an initial treatment before surgery) is an underutilised treatment in postmenopausal women with oestrogen-receptor-positive large operable or locally advanced cancers. It makes more patients suitable for surgery and offers others the choice of breast conservation.

Cuzick J, Sasieni P, Howell A. · Cancer Research UK Centre for Epidemiology, Mathematics and Statistics, Wolfson Institute of Preventive Medicine, Barts and the London, Queen Mary's School of Medicine and Dentistry, Charterhouse Square, London EC1M 6BQ, UK. · Br J Cancer. · Pubmed #16434989 links to  free full text

Abstract: A number of trials have studied the value of aromatase inhibitors (AIs) for the adjuvant treatment of early hormone-responsive postmenopausal breast cancer. Three different AIs have been used and they have been compared as initial treatment (two trials) or after 2-3 years of tamoxifen (four trials), in both cases against a standard arm of 5 years of tamoxifen. In addition, two trials have evaluated AIs against no treatment after 5 years of tamoxifen. In all circumstances, the AIs have demonstrated superior efficacy. However, no results are currently available for the key question, that is - is it better to start initially with an AI or use it sequentially after 2 years of tamoxifen? Here, we review the trial results and present two models, which address this issue. The models clearly show that early treatment with an AI is superior to using it after 5 years of tamoxifen. They also favour an upfront strategy to sequencing after 2 years of tamoxifen, but in this case the differences are small and model-dependent. A key question is whether AIs have substantially better efficacy than tamoxifen for ER-positive-PgR-negative tumours, where the data are currently contradictory. A mechanism explaining why greater efficacy might be so is proposed. Further results from ongoing trials will be needed to resolve this issue.

Cuzick J. · Wolfson Institute of Preventive Medicine, St. Bartholomew's Medical School, London, UK. · Drugs Today (Barc). · Pubmed #16034487 No free full text.

Abstract: Recent trials have indicated that the aromatase inhibitors (anastrozole, letrozole, exemestane) are more effective than tamoxifen, the standard adjuvant treatment for estrogen receptor-positive breast cancer, both in adjuvant and first-line advanced settings. This paper reviews the mode of action and the main clinical trials done with anastrozole, the only aromatase inhibitor currently licensed for use in the adjuvant setting in estrogen receptor-positive tumors. Results from studies using anastrozole as a first-line treatment in advanced disease strongly suggest that this drug should now be considered as an alternative first-line therapy to tamoxifen in postmenopausal women with estrogen receptor-positive advanced breast cancer. As a second-line treatment in tamoxifen failures, anastrozole has shown a better survival rate and a better side-effect profile than megestrol acetate. Similarly, the use of anastrozole in the adjuvant setting has shown a significantly prolonged disease-free survival time and improved tolerability compared to tamoxifen in postmenopausal breast cancer survivors.

Cuzick J. · Centre of Epidemiology, Mathematics & Statistics, Wolfson Institute of Preventive Medicine, Charterhouse Square, London EC1M 6BQ, United Kingdom. · J Clin Oncol. · Pubmed #15755971 No free full text.

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Cuzick J. · Department of Epidemiology, Mathematics and Statistics, Cancer Research UK, Wolfson Institute of Preventive Medicine, Charterhouse Square, London, EC1M 6BQ, UK. · Surg Oncol. · Pubmed #14998562 No free full text.

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Cuzick J. · Cancer Research UK, Department of Epidemiology, Mathematics and Statistics, Wolfson Institute of Preventive Medicine, Charterhouse Square, London ECIM 6BQ. · Recent Results Cancer Res. · Pubmed #12903846 No free full text.

Abstract: Current prevention trials have shown that tamoxifen can reduce the incidence of breast cancer by about 30%-40% in high-risk women, but that the risk of thromboembolic disease and endometrial cancer are increased about twofold. An alternative approach for postmenopausal women is to use an aromatase inhibitor to reduce oestrogen to very low levels. Data from the ATAC adjuvant trial indicate that the aromatase inhibitor anastrozole is more effective than tamoxifen in reducing recurrence and preventing new contralateral tumours, and also has a more favourable side-effect profile. This has led us to launch a new prevention trial--IBIS-II--in 6,000 high-risk postmenopausal women comparing anastrozole against placebo. A parallel trial will compare anastrozole against tamoxifen in 4,000 women with locally excised DCIS.

Cuzick J, Powles T, Veronesi U, Forbes J, Edwards R, Ashley S, Boyle P. · Cancer Research UK, London, UK. · Lancet. · Pubmed #12559863 No free full text.

Abstract: BACKGROUND: Early findings on the use of tamoxifen or raloxifene as prophylaxis against breast cancer have been mixed; we update available data and overview the combined results. METHODS: All five randomised prevention trials comparing tamoxifen or raloxifene with placebo were included. Relevant data on contralateral breast tumours and side-effects were included from an overview of adjuvant trials of tamoxifen versus control. FINDINGS: The tamoxifen prevention trials showed a 38% (95% CI 28-46; p<0.0001) reduction in breast-cancer incidence. There was no effect for breast cancers negative for oestrogen receptor (ER; hazard ratio 1.22 [0.89-1.67]; p=0.21), but ER-positive cancers were decreased by 48% (36-58; p<0.0001) in the tamoxifen prevention trials. Age had no apparent effect. Rates of endometrial cancer were increased in all tamoxifen prevention trials (consensus relative risk 2.4 [1.5-4.0]; p=0.0005) and the adjuvant trials (relative risk 3.4 [1.8-6.4]; p=0.0002); no increase has been seen so far with raloxifene. Venous thromboembolic events were increased in all tamoxifen studies (relative risk 1.9 [1.4-2.6] in the prevention trials; p<0.0001) and with raloxifene. Overall, there was no effect on non-breast-cancer mortality; the only cause showing a mortality increase was pulmonary embolism (six vs two). INTERPRETATION: The evidence now clearly shows that tamoxifen can reduce the risk of ER-positive breast cancer. New approaches are needed to prevent ER-negative breast cancer and to reduce the side-effects of tamoxifen. Newer agents such as raloxifene and the aromatase inhibitors need to be evaluated. Although tamoxifen cannot yet be recommended as a preventive agent (except possibly in women at very high risk with a low risk of side-effects), continued follow-up of the current trials is essential for identification of a subgroup of high-risk, healthy women for whom the risk-benefit ratio is sufficiently positive.

Cuzick J, Anonymous00027. · Department of Mathematics, Statistics, and Epidemiology, Imperial Cancer Research Fund, London, United Kingdom. · Ann N Y Acad Sci. · Pubmed #11795344 No free full text.

Abstract: The available results from breast cancer chemoprevention trials are reviewed. Four trials using tamoxifen have been performed, of which three have reported efficacy results. A fifth trial using raloxifene has also been published. The largest tamoxifen trial shows approximately a 50% reduction in breast cancer incidence in the short term, but the two smaller trials have not found any incidence reduction. Greater agreement exists for side effects: thromboembolic disease and endometrial cancers are raised about 2- to 3-fold when tamoxifen is used for 5 years. The possible reasons for the discrepancy in breast cancer reduction are explored. A review of trial parameters does not clearly explain this difference, and a metanalysis indicates that all results are compatible with a 42% reduction in short-term incidence. Several important questions remain about the clinical implication of this result, including the effect on mortality, the appropriate risk groups for chemoprevention, and the long-term effects on incidence. Continued follow-up of these trials is crucial for resolving these issues.

Cuzick J. · Department of Methematics, Statistics and Epidemiology, Imperial Cancer Research Fund, London, UK. · Breast Cancer Res. · Pubmed #11250718 links to  free full text

Abstract: The available results from breast cancer chemoprevention trials are reviewed. Four trials using tamoxifen have been performed, of which three have reported efficacy results. A fifth trial using raloxifene has also been reported. The largest tamoxifen trial showed approximately 50% reduction in breast cancer incidence in the short term, but the two smaller trials did not find any reduction. Greater agreement exists for side effects; incidences of thromboembolic disease and endometrial cancers are raised approximately threefold when tamoxifen is used for 5 years. The possible reasons for the discrepancy in breast cancer reduction are explored. A review of trial parameters does not clearly explain this difference, and a meta-analysis indicates that all results are compatible with a 40% reduction in short-term incidence. Several important questions remain regarding the clinical implications of this result, including the effect on mortality, the appropriate risk groups for chemoprevention and the long-term effects on incidence. Continued follow up of these trials is crucial for resolving these issues.

Cuzick J, Howell A. · Imperial Cancer Research Fund Statistics and Epidemiology Unit, 61 Lincoln's Inn Fields, WC2A 3PX, London, UK. · Eur J Cancer. · Pubmed #11056318 No free full text.

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Cuzick J. · Department of Mathematics, Statistics and Epidemiology, Imperial Cancer Research Fund, London, U.K. · Eur J Cancer. · Pubmed #10711235 No free full text.

Abstract: Much progress has been made in cancer screening over the past decade, but a great deal more needs to be done if screening is to make a major impact on worldwide cancer mortality. Where fully implemented, cytological screening for cervical precursor lesions has had a major impact on mortality. However, the cost and required infrastructure levels are high, and new approaches are needed if screening is to be effective in the developing world. Testing for the human papillomavirus and automated liquid based cytology offer great promise to improve quality, reduce overall cost and make screening more viable generally. Breast screening has been less successful, although useful mortality benefits have been achieved in women aged over 50 years. Full implementation in countries that can afford it will save lives, but radical new approaches will be needed to conquer breast cancer. Colorectal cancer screening offers the best hope of a major reduction in cancer mortality over the next decade. Less certainty exists about screening for other major cancers such as lung, prostate and ovary, but a range of potential approaches merit investigation.

Cuzick J. · Department of Mathematics, Statistics and Epidemiology, Imperial Cancer Research Fund, London, U.K. · Eur J Cancer. · Pubmed #10505025 No free full text.

Abstract: Much progress has been made in cancer screening over the past decade, but a great deal more needs to be done if screening is to make a major impact on worldwide cancer mortality. Where fully implemented, cytological screening for cervical precursor lesions has had a major impact on mortality. However, the cost and required infrastructure levels are high, and new approaches are needed if screening is to be effective in the developing world. Testing for the human papillomavirus and automated liquid based cytology offer great promise to improve quality, reduce overall cost and make screening more viable generally. Breast screening has been less successful, although useful mortality benefits have been achieved in women aged over 50 years. Full implementation in countries that can afford it will save lives, but radical new approaches will be needed to conquer breast cancer. Colorectal cancer screening offers the best hope of a major reduction in cancer mortality over the next decade. Less certainty exists about screening for other major cancers such as lung, prostate and ovary, but a range of potential approaches merit investigation.