Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Suitable trial designs and cohorts for preventive breast cancer agents

Nature Reviews Clinical Oncology volume 10, pages 677–687 (2013)Cite this article

Subjects

Key Points

  • Several selective oestrogen receptor (ER) modulators and the aromatase inhibitor exemestane have been shown to reduce the incidence of ER-positive breast cancer by >50%

  • However, acceptance of these agents in the clinic is low because benefit:risk ratios are difficult to predict on an individual level and the number-needed-to-treat (NNT) is high even in 'at-risk' cohorts

  • In the future, biomarkers to assess both risk and treatment efficacy will be needed to lower the NNT in the prevention setting; similarly, communication of risk and benefit estimates must be improved

  • To accelerate prevention research, standardized biomarker validation studies are needed and definitive prevention trials should include novel end points in addition to breast cancer incidence

  • Identification of suitable biomarkers and models developed using these approaches will help reduce the size of cohorts and follow-up durations needed in prevention studies and improve patient acceptance

Abstract

Effective chemoprevention of oestrogen receptor (ER)-positive breast cancer has been shown convincingly using several selective ER modulators and the aromatase inhibitor exemestane. Although these agents are well tolerated and the numbers needed-to-treat in the prevention setting are similar to other established preventive interventions, uptake has been poor in clinical practice because of difficulties in visualizing risk, predicting individual outcomes and measuring treatment benefit. In addition, new agents targeting ER-negative breast cancer are urgently needed. The development of new agents is hampered by the lack of suitable biomarkers and targets, as well as regulatory and financial considerations. Establishing breast cancer chemoprevention in standard clinical practice will require advances in many different fields, including biomarker research, the development of more powerful tools to predict and communicate the risks and benefits of treatments and establishing innovative trial designs. Furthermore, changes in regulatory procedures could reduce the size and cost of trials needed in the prevention setting. Identification of biomarkers for risk and efficacy that are easily accessible, such as blood-based biomarkers, will be key to future chemoprevention strategies.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2: The ABC paradigm of chemoprevention.

Similar content being viewed by others

References

  1. Estimated cancer incidence, mortality, prevalence and disability-adjusted life years (DALYs) worldwide in 2008. International Agency for Research Against Cancer [online], (2008).

  2. Mortality from breast cancer, age-standardised rate (World), all ages. International Agency for Research Against Cancer [online], (2011).

  3. Bleyer, A. & Welch, H. G. Effect of three decades of screening mammography on breast-cancer incidence. N. Engl. J. Med. 367, 1998–2005 (2012).

    Article  CAS  PubMed  Google Scholar 

  4. Sporn, M. B. Approaches to prevention of epithelial cancer during the preneoplastic period. Cancer Res. 36, 2699–2702 (1976).

    CAS  PubMed  Google Scholar 

  5. Cuzick, J. & Baum, M. Tamoxifen and contralateral breast cancer. Lancet 2, 282 (1985).

    Article  CAS  PubMed  Google Scholar 

  6. Fisher, B. & Redmond, C. New perspective on cancer of the contralateral breast: a marker for assessing tamoxifen as a preventive agent. J. Natl Cancer Inst. 83, 1278–1280 (1991).

    Article  CAS  PubMed  Google Scholar 

  7. Powles, T. et al. Interim analysis of the incidence of breast cancer in the Royal Marsden Hospital tamoxifen randomised chemoprevention trial. Lancet 352, 98–101 (1998).

    Article  CAS  PubMed  Google Scholar 

  8. Antoniou, A. et al. Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: a combined analysis of 22 studies. Am. J. Hum. Genet. 72, 1117–1130 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Antoniou, A. C. et al. RAD51 135G-->C modifies breast cancer risk among BRCA2 mutation carriers: results from a combined analysis of 19 studies. Am. J. Hum. Genet. 81, 1186–1200 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Clemons, M., Loijens, L. & Goss, P. Breast cancer risk following irradiation for Hodgkin's disease. Cancer Treat. Rev. 26, 291–302 (2000).

    Article  CAS  PubMed  Google Scholar 

  11. Goss, P. E. & Sierra, S. Current perspectives on radiation-induced breast cancer. J. Clin. Oncol. 16, 338–347 (1998).

    Article  CAS  PubMed  Google Scholar 

  12. Liu, P. H., Wang, J. D. & Keating, N. L. Expected years of life lost for six potentially preventable cancers in the United States. Prev. Med. 56, 309–313 (2013).

    Article  PubMed  Google Scholar 

  13. Dupont, W. D. & Page, D. L. Risk factors for breast cancer in women with proliferative breast disease. N. Engl. J. Med. 312, 146–151 (1985).

    Article  CAS  PubMed  Google Scholar 

  14. Hartmann, L. C. et al. Benign breast disease and the risk of breast cancer. N. Engl. J. Med. 353, 229–237 (2005).

    Article  CAS  PubMed  Google Scholar 

  15. Degnim, A. C. et al. Stratification of breast cancer risk in women with atypia: a Mayo cohort study. J. Clin. Oncol. 25, 2671–2677 (2007).

    Article  PubMed  Google Scholar 

  16. Warnberg, F., Yuen, J. & Holmberg, L. Risk of subsequent invasive breast cancer after breast carcinoma in situ. Lancet 355, 724–725 (2000).

    Article  CAS  PubMed  Google Scholar 

  17. Bodian, C. A., Perzin, K. H. & Lattes, R. Lobular neoplasia. Long term risk of breast cancer and relation to other factors. Cancer 78, 1024–1034 (1996).

    Article  CAS  PubMed  Google Scholar 

  18. Boyd, N. F. et al. Quantitative classification of mammographic densities and breast cancer risk: results from the Canadian National Breast Screening Study. J. Natl Cancer Inst. 87, 670–675 (1995).

    Article  CAS  PubMed  Google Scholar 

  19. Zhang, Y. et al. Bone mass and the risk of breast cancer among postmenopausal women. N. Engl. J. Med. 336, 611–617 (1997).

    Article  CAS  PubMed  Google Scholar 

  20. Toniolo, P. G. et al. A prospective study of endogenous estrogens and breast cancer in postmenopausal women. J. Natl Cancer Inst. 87, 190–197 (1995).

    Article  CAS  PubMed  Google Scholar 

  21. Byrne, C. et al. Mammographic features and breast cancer risk: effects with time, age, and menopause status. J. Natl Cancer Inst. 87, 1622–1629 (1995).

    Article  CAS  PubMed  Google Scholar 

  22. Schairer, C. et al. Menopausal estrogen and estrogen-progestin replacement therapy and breast cancer risk. JAMA 283, 485–491 (2000).

    Article  CAS  PubMed  Google Scholar 

  23. Magnusson, C. et al. Body size in different periods of life and breast cancer risk in post-menopausal women. Int. J. Cancer 76, 29–34 (1998).

    Article  CAS  PubMed  Google Scholar 

  24. Hsieh, C. C., Trichopoulos, D., Katsouyanni, K. & Yuasa, S. Age at menarche, age at menopause, height and obesity as risk factors for breast cancer: associations and interactions in an international case-control study. Int. J. Cancer 46, 796–800 (1990).

    Article  CAS  PubMed  Google Scholar 

  25. Cauley, J. A. et al. Elevated serum estradiol and testosterone concentrations are associated with a high risk for breast cancer. Study of Osteoporotic Fractures Research Group. Ann. Intern. Med. 130, 270–277 (1999).

    Article  CAS  PubMed  Google Scholar 

  26. Gail, M. H. et al. Projecting individualized probabilities of developing breast cancer for white females who are being examined annually. J. Natl Cancer Inst. 81, 1879–1886 (1989).

    Article  CAS  PubMed  Google Scholar 

  27. Fisher, B. et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J. Natl Cancer Inst. 90, 1371–1388 (1998).

    Article  CAS  PubMed  Google Scholar 

  28. Vogel, V. G. et al. Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial. JAMA 295, 2727–2741 (2006).

    Article  CAS  PubMed  Google Scholar 

  29. Cuzick, J. et al. First results from the International Breast Cancer Intervention Study (IBIS-I): a randomised prevention trial. Lancet 360, 817–824 (2002).

    Article  CAS  PubMed  Google Scholar 

  30. Goss, P. E. et al. Exemestane for breast-cancer prevention in postmenopausal women. N. Engl. J. Med. 364, 2381–2391 (2011).

    Article  CAS  PubMed  Google Scholar 

  31. Cuzick, J. et al. Selective oestrogen receptor modulators in prevention of breast cancer: an updated meta-analysis of individual participant data. 381, 1827–1834 Lancet (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Tyrer, J., Duffy, S. W. & Cuzick, J. A breast cancer prediction model incorporating familial and personal risk factors. Stat. Med. 23, 1111–1130 (2004).

    Article  PubMed  Google Scholar 

  33. Claus, E. B., Risch, N. & Thompson, W. D. Autosomal dominant inheritance of early-onset breast cancer. Implications for risk prediction. Cancer 73, 643–651 (1994).

    Article  CAS  PubMed  Google Scholar 

  34. Chen, W. Y., Rosner, B. & Colditz, G. A. Moving forward with breast cancer prevention. Cancer 109, 2387–2391 (2007).

    Article  PubMed  Google Scholar 

  35. Surveillance Epidemiology and End Results. National Cancer Institute [online], (2013).

  36. Breast Cancer Risk Assessment Tool. National Cancer Institute [online], (2011).

  37. Baker, S. G. & Kramer, B. S. Evaluating a new marker for risk prediction: decision analysis to the rescue. Discov. Med. 14, 181–188 (2012).

    PubMed  Google Scholar 

  38. Cauley, J. A. et al. Continued breast cancer risk reduction in postmenopausal women treated with raloxifene: 4-year results from the MORE trial. Multiple outcomes of raloxifene evaluation. Breast Cancer Res. Treat. 65, 125–134 (2001).

    Article  CAS  PubMed  Google Scholar 

  39. LaCroix, A. Z. et al. Breast cancer incidence in the randomized PEARL trial of lasofoxifene in postmenopausal osteoporotic women. J. Natl Cancer Inst. 102, 1706–1715 (2010).

    Article  CAS  PubMed  Google Scholar 

  40. Powles, T. J. et al. Breast cancer incidence in postmenopausal women with osteoporosis or low bone mass using arzoxifene. Breast Cancer Res. Treat. 134, 299–306 (2012).

    Article  CAS  PubMed  Google Scholar 

  41. Freedman, A. N. et al. Benefit/risk assessment for breast cancer chemoprevention with raloxifene or tamoxifen for women age 50 years or older. J. Clin. Oncol. 29, 2327–2333 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Key, T., Appleby, P., Barnes, I., Reeves, G. & Endogenous Hormones and Breast Cancer Collaborative Group. Endogenous sex hormones and breast cancer in postmenopausal women: reanalysis of nine prospective studies. J. Natl Cancer Inst. 94, 606–616 (2002).

    Article  CAS  PubMed  Google Scholar 

  43. Blair, I. A. Analysis of estrogens in serum and plasma from postmenopausal women: past present, and future. Steroids 75, 297–306 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Stanway, S. J., Purohit, A. & Reed, M. J. Measurement of estrone sulfate in postmenopausal women: comparison of direct RIA and GC-MS/MS methods for monitoring response to endocrine therapy in women with breast cancer. Anticancer Res. 27, 2765–2767 (2007).

    CAS  PubMed  Google Scholar 

  45. Mikkelsen, A. L., Borggaard, B. & Lebech, P. E. Results of serial measurement of estradiol in serum with six different methods during ovarian stimulation. Gynecol. Obstet. Invest. 41, 35–40 (1996).

    Article  CAS  PubMed  Google Scholar 

  46. Fiers, T. et al. Development of a highly sensitive method for the quantification of estrone and estradiol in serum by liquid chromatography tandem mass spectrometry without derivatization. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 893–894, 57–62 (2012).

    Article  CAS  PubMed  Google Scholar 

  47. Polyak, K. Heterogeneity in breast cancer. J. Clin. Invest. 121, 3786–3788 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Jung, S. et al. Fruit and vegetable intake and risk of breast cancer by hormone receptor status. J. Natl Cancer Inst. 105, 219–236 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Ursin, G. et al. Mammographic density and breast cancer in three ethnic groups. Cancer Epidemiol. Biomarkers Prev. 12, 332–338 (2003).

    PubMed  Google Scholar 

  50. Boyd, N. F. et al. Mammographic densities as a criterion for entry to a clinical trial of breast cancer prevention. Br. J. Cancer 72, 476–479 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Boyd, N. F. et al. Mammographic density and the risk and detection of breast cancer. N. Engl. J. Med. 356, 227–236 (2007).

    Article  CAS  PubMed  Google Scholar 

  52. Chen, J. et al. Projecting absolute invasive breast cancer risk in white women with a model that includes mammographic density. J. Natl Cancer Inst. 98, 1215–1226 (2006).

    Article  PubMed  Google Scholar 

  53. Ursin, G., Pike, M. C., Spicer, D. V., Porrath, S. A. & Reitherman, R. W. Can mammographic densities predict effects of tamoxifen on the breast? J. Natl Cancer Inst. 88, 128–129 (1996).

    Article  CAS  PubMed  Google Scholar 

  54. Atkinson, C., Warren, R., Bingham, S. A. & Day, N. E. Mammographic patterns as a predictive biomarker of breast cancer risk: effect of tamoxifen. Cancer Epidemiol. Biomarkers Prev. 8, 863–866 (1999).

    CAS  PubMed  Google Scholar 

  55. Cuzick, J., Warwick, J., Pinney, E., Warren, R. M. & Duffy, S. W. Tamoxifen and breast density in women at increased risk of breast cancer. J. Natl Cancer Inst. 96, 621–628 (2004).

    Article  CAS  PubMed  Google Scholar 

  56. Cigler, T. et al. Effects of the steroidal aromatase inhibitor exemestane on mammographic breast density and other end-organ functions [abstract]. Breast Cancer Res. Treat. 106 (Suppl.), a1026 (2007).

    Google Scholar 

  57. Cigler, T. et al. A randomized, placebo-controlled trial (NCIC CTG MAP.2) examining the effects of exemestane on mammographic breast density, bone density, markers of bone metabolism and serum lipid levels in postmenopausal women. Breast Cancer Res. Treat. 126, 453–461 (2011).

    Article  CAS  PubMed  Google Scholar 

  58. Cigler, T. et al. A placebo-controlled trial examining the effects of letrozole on mammographic breast density and bone and lipid metabolism [abstract]. Breast Cancer Res. Treat. 106 (Suppl.), a2082 (2007).

    Google Scholar 

  59. Vachon, C. M. et al. Longitudinal trends in mammographic percent density and breast cancer risk. Cancer Epidemiol. Biomarkers Prev. 16, 921–928 (2007).

    Article  PubMed  Google Scholar 

  60. Vachon, C. M. et al. Mammographic breast density response to aromatase inhibition. Clin. Cancer Res. 19, 2144–2153 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Vidi, P. A., Leary, J. F. & Lelièvre, S. A. Building risk-on-a-chip models to improve breast cancer risk assessment and prevention. Integr. Biol. (Camb.) 5, 1110–1118 (2013).

    Article  CAS  Google Scholar 

  62. Wang, W. & Srivastava, S. Strategic approach to validating methylated genes as biomarkers for breast cancer. Cancer Prev. Res. (Phila.) 3, 16–24 (2010).

    Article  Google Scholar 

  63. Fabian, C. J. et al. Short-term breast cancer prediction by random periareolar fine-needle aspiration cytology and the Gail risk model. J. Natl Cancer Inst. 92, 1217–1227 (2000).

    Article  CAS  PubMed  Google Scholar 

  64. Shaaban, A. M., Sloane, J. P., West, C. R. & Foster, C. S. Breast cancer risk in usual ductal hyperplasia is defined by estrogen receptor-alpha and Ki-67 expression. Am. J. Pathol. 160, 597–604 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  65. King, B. L. & Love, S. M. The intraductal approach to the breast: raison d'être. Breast Cancer Res. 8, 206 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  66. Chaiwun, B. & Thorner, P. Fine needle aspiration for evaluation of breast masses. Curr. Opin. Obstet. Gynecol. 19, 48–55 (2007).

    Article  PubMed  Google Scholar 

  67. Stomper, P. C., Budnick, R. M. & Stewart, C. C. Use of specimen mammography-guided FNA (fine-needle aspirates) for flow cytometric multiple marker analysis and immunophenotyping in breast cancer. Cytometry 42, 165–173 (2000).

    Article  CAS  PubMed  Google Scholar 

  68. Bondeson, L. & Lindholm, K. Prediction of invasiveness by aspiration cytology applied to nonpalpable breast carcinoma and tested in 300 cases. Diagn. Cytopathol. 17, 315–320 (1997).

    Article  CAS  PubMed  Google Scholar 

  69. Akhtar, M., Bakry, M., al-Jeaid, A. S. & McClintock, J. A. Electron. microscopy of fine-needle aspiration biopsy specimens: a brief review. Diagn. Cytopathol. 8, 278–282 (1992).

    Article  CAS  PubMed  Google Scholar 

  70. Henry-Stanley, M. J. & Stanley, M. W. Processing of needle rinse material from fine-needle aspirations rarely detects malignancy not identified in smears. Diagn. Cytopathol. 8, 538–540 (1992).

    Article  CAS  PubMed  Google Scholar 

  71. Shidham, V. B., Pandit, A. W., Rao, R. N., Basir, Z. & Shidham, A. Tissue Harvester with Functional Valve (THFV): Shidham's device for reproducibly higher specimen yield by fine needle aspiration biopsy with easy to perform steps. BMC Clin. Pathol. 7, 2 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  72. Yang, J. H. et al. Effect of core-needle biopsy vs fine-needle aspiration on pathologic measurement of tumor size in breast cancer. Arch. Surg. 140, 125–128 (2005).

    Article  PubMed  Google Scholar 

  73. Fabian, C. J., Kimler, B. F., Mayo, M. S. & Khan, S. A. Breast-tissue sampling for risk assessment and prevention. Endocr. Relat. Cancer 12, 185–213 (2005).

    Article  CAS  PubMed  Google Scholar 

  74. Easton, D. F. et al. Genome-wide association study identifies novel breast cancer susceptibility loci. Nature 447, 1087–1093 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Stacey, S. N. et al. Common variants on chromosome 5p12 confer susceptibility to estrogen receptor-positive breast cancer. Nat. Genet. 40, 703–706 (2008).

    Article  CAS  PubMed  Google Scholar 

  76. Stacey, S. N. et al. Common variants on chromosomes 2q35 and 16q12 confer susceptibility to estrogen receptor-positive breast cancer. Nat. Genet. 39, 865–869 (2007).

    Article  CAS  PubMed  Google Scholar 

  77. Ingle, J. N. et al. Selective estrogen receptor modulators and pharmacogenomic variation in ZNF423 regulation of BRCA1 expression: individualized breast cancer prevention. Cancer Discov. 3, 812–825 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Darabi, H. et al. Breast cancer risk prediction and individualised screening based on common genetic variation and breast density measurement. Breast Cancer Res. 14, R25 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  79. Dite, G. S. et al. Using SNP genotypes to improve the discrimination of a simple breast cancer risk prediction model. Breast Cancer Res. Treat. 139, 887–896 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Kelloff, G. J. et al. Risk biomarkers and current strategies for cancer chemoprevention. J. Cell. Biochem. 25 (Suppl.), 1–14 (1996).

    Article  CAS  Google Scholar 

  81. Boone, C. W., Bacus, J. W., Bacus, J. V., Steele, V. E. & Kelloff, G. J. Properties of intraepithelial neoplasia relevant to cancer chemoprevention and to the development of surrogate end points for clinical trials. Proc. Soc. Exp. Biol. Med. 216, 151–165 (1997).

    Article  CAS  PubMed  Google Scholar 

  82. Dunn, B. K., Jegalian, K. & Greenwald, P. Biomarkers for early detection and as surrogate endpoints in cancer prevention trials: issues and opportunities. Recent Results Cancer Res. 188, 21–47 (2011).

    Article  CAS  PubMed  Google Scholar 

  83. Rutqvist, L. E. et al. Contralateral primary tumors in breast cancer patients in a randomized trial of adjuvant tamoxifen therapy. J. Natl Cancer Inst. 83, 1299–1306 (1991).

    Article  CAS  PubMed  Google Scholar 

  84. Veronesi, U. et al. Prevention of breast cancer with tamoxifen: preliminary findings from the Italian randomised trial among hysterectomised women. Italian Tamoxifen Prevention Study. Lancet 352, 93–97 (1998).

    Article  CAS  PubMed  Google Scholar 

  85. Martino, S. et al. Effect of raloxifene on incidence of invasive breast cancer in postmenopausal women stratified by baseline serum estradiol: results of the Continuing Outcomes Relevant to Evista (CORE) trial [abstract]. Breast Cancer Res. Treat. 88 (Suppl.), a22 (2004).

    Google Scholar 

  86. Powles, T. J., Ashley, S., Tidy, A., Smith, I. E. & Dowsett, M. Twenty-year follow-up of the Royal Marsden randomized, double-blinded tamoxifen breast cancer prevention trial. J. Natl Cancer Inst. 99, 283–290 (2007).

    Article  CAS  PubMed  Google Scholar 

  87. Fisher, B. et al. Tamoxifen for the prevention of breast cancer: current status of the National Surgical Adjuvant Breast and Bowel Project P-1 study. J. Natl Cancer Inst. 97, 1652–1662 (2005).

    Article  CAS  PubMed  Google Scholar 

  88. Veronesi, U. et al. Tamoxifen for the prevention of breast cancer: late results of the Italian Randomized Tamoxifen Prevention Trial among women with hysterectomy. J. Natl Cancer Inst. 99, 727–737 (2007).

    Article  CAS  PubMed  Google Scholar 

  89. Barrett-Connor, E. et al. Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women. N. Engl. J. Med. 355, 125–137 (2006).

    Article  CAS  PubMed  Google Scholar 

  90. Vogel, V. G. et al. Update of the National Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and Raloxifene (STAR) P-2 Trial: Preventing breast cancer. Cancer Prev. Res. (Phila.) 3, 696–706 (2010).

    Article  CAS  Google Scholar 

  91. Cummings, S. R. et al. Lasofoxifene in postmenopausal women with osteoporosis. N. Engl. J. Med. 362, 686–696 (2010).

    Article  CAS  PubMed  Google Scholar 

  92. Cummings, S. R. et al. Arzoxifene for prevention of fractures and invasive breast cancer in postmenopausal women. J. Bone Miner. Res. 26, 397–404 (2011).

    Article  CAS  PubMed  Google Scholar 

  93. Meyskens, F. L. Jr et al. Regulatory approval of cancer risk-reducing (chemopreventive) drugs: moving what we have learned into the clinic. Cancer Prev. Res. (Phila.) 4, 311–323 (2011).

    Article  Google Scholar 

  94. Familial breast cancer: classification and care of people at risk of familial breast cancer and management of breast cancer and related risks in people with a family history of breast cancer. NICE clinical guideline 164. National Institute for Health and Care Excellence [online], (2013).

  95. Buzdar, A. The ATAC ('Arimidex', Tamoxifen, Alone or in Combination) trial in postmenopausal women with early breast cancer—updated efficacy results based on a median follow-up of 47 months. Breast Cancer Res. Treat. 77, 295 (2003).

    Article  CAS  Google Scholar 

  96. van de Velde, C. J. et al. Adjuvant tamoxifen and exemestane in early breast cancer (TEAM): a randomised phase 3 trial. Lancet 377, 321–331 (2011).

    Article  CAS  PubMed  Google Scholar 

  97. Thuerlimann, B. et al. BIG 1–98: Randomized double-blind phase III study to evaluate letrozole (L) vs. tamoxifen (T) as adjuvant endocrine therapy for postmenopausal women with receptor-positive breast cancer [abstract]. J. Clin. Oncol. 23 (Suppl.), a511 (2005).

    Article  Google Scholar 

  98. Kraus, S., Naumov, I. & Arber, N. COX-2 active agents in the chemoprevention of colorectal cancer. Recent Results Cancer Res. 191, 95–103 (2013).

    Article  CAS  PubMed  Google Scholar 

  99. Lee, C. S., McNamara, D. & O'Morain, C. A. Aspirin as a chemoprevention agent for colorectal cancer. Curr. Drug Metab. 13, 1313–1322 (2012).

    Article  CAS  PubMed  Google Scholar 

  100. Brophy, J. M. Cardiovascular effects of cyclooxygenase-2 inhibitors. Curr. Opin. Gastroenterol. 23, 617–624 (2007).

    CAS  PubMed  Google Scholar 

  101. US National Library of Medicine. ClinicalTrials.gov [online], (2012).

  102. US National Library of Medicine. ClinicalTrials.gov [online], (2013).

  103. US National Library of Medicine. ClinicalTrials.gov [online], (2005).

  104. US National Library of Medicine. ClinicalTrials.gov [online], (2013).

  105. US National Library of Medicine. ClinicalTrials.gov [online], (2012).

  106. Lochhead, P. & Chan, A. T. Statins and colorectal cancer. Clin. Gastroenterol. Hepatol. 11, 109–118 (2013).

    Article  CAS  PubMed  Google Scholar 

  107. Bruno, A., Dovizio, M., Tacconelli, S. & Patrignani, P. Mechanisms of the antitumoural effects of aspirin in the gastrointestinal tract. Best Pract. Res. Clin. Gastroenterol. 26, e1–e13 (2012).

    Article  CAS  PubMed  Google Scholar 

  108. Lin, H. C. et al. Effects of metformin dose on cancer risk reduction in patients with type 2 diabetes mellitus: a 6-Year follow-up study. Pharmacotherapy http://dx.doi.org/10.1002/phar.1334.

  109. Dowsett, M. et al. Meta-analysis of breast cancer outcomes in adjuvant trials of aromatase inhibitors versus tamoxifen. J. Clin. Oncol. 28, 509–518 (2010).

    Article  CAS  PubMed  Google Scholar 

  110. van Nes, J. G. et al. Quality of life in relation to tamoxifen or exemestane treatment in postmenopausal breast cancer patients: a Tamoxifen Exemestane Adjuvant Multinational (TEAM) Trial side study. Breast Cancer Res. Treat. 134, 267–276 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Goss, P. E. et al. Randomized trial of letrozole following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: updated findings from NCIC CTG MA.17. J. Natl Cancer Inst. 97, 1262–1271 (2005).

    Article  CAS  PubMed  Google Scholar 

  112. Davies, C. et al. Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. Lancet 381, 805–816 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Goss, P. E., Muss, H. B., Ingle, J. N., Whelan, T. J. & Wu, M. Extended adjuvant endocrine therapy in breast cancer: current status and future directions. Clin. Breast Cancer 8, 411–417 (2008).

    Article  CAS  PubMed  Google Scholar 

  114. Young, R. J. & Coleman, R. E. Zoledronic acid to prevent and treat cancer metastasis: new prospects for an old drug. Future Oncol. 9, 633–643 (2013).

    Article  CAS  PubMed  Google Scholar 

  115. Gnant, M. et al. Endocrine therapy plus zoledronic acid in premenopausal breast cancer. N. Engl. J. Med. 360, 679–691 (2009).

    Article  CAS  PubMed  Google Scholar 

  116. Ford, J. A. et al. Denosumab for treatment of bone metastases secondary to solid tumours: systematic review and network meta-analysis. Eur. J. Cancer 49, 416–430 (2013).

    Article  CAS  PubMed  Google Scholar 

  117. US National Library of Medicine. ClinicalTrials.gov [online], (2013).

  118. Wiedermann, U., Davis, A. B. & Zielinski, C. C. Vaccination for the prevention and treatment of breast cancer with special focus on Her-2/neu peptide vaccines. Breast Cancer Res. Treat. 138, 1–12 (2013).

    Article  CAS  PubMed  Google Scholar 

  119. Glimelius, B. & Lahn, M. Window-of-opportunity trials to evaluate clinical activity of new molecular entities in oncology. Ann. Oncol. 22, 1717–1725 (2011).

    Article  CAS  PubMed  Google Scholar 

  120. Kummar, S. et al. Phase 0 clinical trials: conceptions and misconceptions. Cancer J. 14, 133–137 (2008).

    Article  PubMed  Google Scholar 

  121. Coombes, R. C. et al. A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N. Engl. J. Med. 350, 1081–1092 (2004).

    Article  CAS  PubMed  Google Scholar 

  122. Napoli, M. et al. Letter to FDA opposing use of surrogate endpoints for approval of cancer prevention drugs. Center for Medical Consumers [online], (2003).

    Google Scholar 

  123. US National Institutes of Health. ClinicalTrials.gov [online], (2013).

  124. Baker, S. G. & Kramer, B. S. Surrogate endpoint analysis: an exercise in extrapolation. J. Natl Cancer Inst. 105, 316–320 (2013).

    Article  PubMed  Google Scholar 

  125. Ropka, M. E., Keim, J. & Philbrick, J. T. Patient decisions about breast cancer chemoprevention: a systematic review and meta-analysis. J. Clin. Oncol. 28, 3090–3095 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  126. Visvanathan, K. et al. American Society of Clinical Oncology clinical practice guideline update on the use of pharmacologic interventions including tamoxifen, raloxifene, and aromatase inhibition for breast cancer risk reduction. J. Clin. Oncol. 27, 3235–3258 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Waters, E. A., Cronin, K. A., Graubard, B. I., Han, P. K. & Freedman, A. N. Prevalence of tamoxifen use for breast cancer chemoprevention among U. S. women. Cancer Epidemiol. Biomarkers Prev. 19, 443–446 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Lippman, S. M. The dilemma and promise of cancer chemoprevention. Nat. Clin. Pract. Oncol. 3, 523 (2006).

    Article  PubMed  Google Scholar 

  129. Armstrong, K., Quistberg, D. A., Micco, E., Domchek, S. & Guerra, C. Prescription of tamoxifen for breast cancer prevention by primary care physicians. Arch. Intern. Med. 166, 2260–2265 (2006).

    Article  PubMed  Google Scholar 

  130. Rockhill, B., Spiegelman, D., Byrne, C., Hunter, D. J. & Colditz, G. A. Validation of the Gail et al. model of breast cancer risk prediction and implications for chemoprevention. J. Natl Cancer Inst. 93, 358–366 (2001).

    Article  CAS  PubMed  Google Scholar 

  131. Foskett, J. Constructing “high risk women”: the development and standardization of a breast cancer risk assessment tool. Sci. Technol. Human Values 29, 291–313 (2004).

    Article  Google Scholar 

  132. Kaplan, C. P. et al. Breast cancer risk reduction options: awareness, discussion, and use among women from four ethnic groups. Cancer Epidemiol. Biomarkers Prev. 15, 162–166 (2006).

    Article  PubMed  Google Scholar 

  133. Savage, L. Researchers wonder why high-risk women are not taking chemoprevention drugs. J. Natl Cancer Inst. 99, 913–914 (2007).

    Article  PubMed  Google Scholar 

  134. Hux, J. E., Levinton, C. M. & Naylor, C. D. Prescribing propensity: influence of life-expectancy gains and drug costs. J. Gen. Intern. Med. 9, 195–201 (1994).

    Article  CAS  PubMed  Google Scholar 

  135. Lipkus, I. M., Klein, W. M. & Rimer, B. K. Communicating breast cancer risks to women using different formats. Cancer Epidemiol. Biomarkers Prev. 10, 895–898 (2001).

    CAS  PubMed  Google Scholar 

  136. Malenka, D. J., Baron, J. A., Johansen, S., Wahrenberger, J. W. & Ross, J. M. The framing effect of relative and absolute risk. J. Gen. Intern. Med. 8, 543–548 (1993).

    Article  CAS  PubMed  Google Scholar 

  137. Mazur, D. J. & Hickam, D. H. Patients' and physicians' interpretations of graphic data displays. Med. Decis. Making 13, 59–63 (1993).

    Article  CAS  PubMed  Google Scholar 

  138. McGettigan, P., Sly, K., O'Connell, D., Hill, S. & Henry, D. The effects of information framing on the practices of physicians. J. Gen. Intern. Med. 14, 633–642 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Tversky, A. & Kahneman, D. Judgment under uncertainty: heuristics and biases. Science 185, 1124–1131 (1974).

    Article  CAS  PubMed  Google Scholar 

  140. Woloshin, S., Schwartz, L. M., Black, W. C. & Welch, H. G. Women's perceptions of breast cancer risk: how you ask matters. Med. Decis. Making 19, 221–229 (1999).

    Article  CAS  PubMed  Google Scholar 

  141. Ancker, J. S., Senathirajah, Y., Kukafka, R. & Starren, J. B. Design features of graphs in health risk communication: a systematic review. J. Am. Med. Inform. Assoc. 13, 608–618 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  142. Edwards, A. Communicating risks through analogies. BMJ 327, 749 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  143. Hibbard, J. H. & Peters, E. Supporting informed consumer health care decisions: data presentation approaches that facilitate the use of information in choice. Annu. Rev. Public Health 24, 413–433 (2003).

    Article  PubMed  Google Scholar 

  144. Lipkus, I. M. & Hollands, J. G. The visual communication of risk. J. Natl Cancer Inst. Monogr. 1999, 149–163 (1999).

    Article  Google Scholar 

  145. Stone, E. R. et al. Foreground: background salience: explaining the effects of graphical displays on risk avoidance. Organ. Behav. Hum. Decis. Process. 90, 19–36 (2003).

    Article  Google Scholar 

  146. Bober, S. L., Hoke, L. A., Duda, R. B., Regan, M. M. & Tung, N. M. Decision-making about tamoxifen in women at high risk for breast cancer: clinical and psychological factors. J. Clin. Oncol. 22, 4951–4957 (2004).

    Article  PubMed  Google Scholar 

  147. Goldenberg, V. K. et al. Atypia in random periareolar fine-needle aspiration affects the decision of women at high risk to take tamoxifen for breast cancer chemoprevention. Cancer Epidemiol. Biomarkers Prev. 16, 1032–1034 (2007).

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Center for Oncology, Hematology and Palliative Care, Wilhelminen Hospital, Montleartstrasse 36, Vienna, A-1160, Austria

    Kathrin Strasser-Weippl

  2. Massachusetts General Hospital Cancer Center, 55 Fruit Street, Lawrence House, LRH-302, Boston, 02114, MA, USA

    Paul E. Goss

Authors
  1. Kathrin Strasser-Weippl
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Paul E. Goss
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

K. Strasser-Weippl researched data for the manuscript. Both authors made a substantial contribution to discussion of the article content, wrote the manuscript and edited it before submission.

Corresponding author

Correspondence to Paul E. Goss.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Strasser-Weippl, K., Goss, P. Suitable trial designs and cohorts for preventive breast cancer agents. Nat Rev Clin Oncol 10, 677–687 (2013). https://doi.org/10.1038/nrclinonc.2013.174

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrclinonc.2013.174

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer