Breast Cancer |

Optimizing the Antihormonal Treatment and Prevention of Breast Cancer

 May 30, 2008 Viewed: 3374

Is Prevention Better Than Cure?

The antihormonal therapy of breast cancer has probably reached its zenith, but the application of SERMs for the chemoprevention of breast cancer is providing a new dimension for the consideration of public health.  Despite progress in the treatment of breast cancer,  prevention remains a viable strategy.  In the 1970’s laboratory studies showed that tamoxifen prevented carcinogen induced rat mammary cancer, probably via an ER mediated mechanism47).  Gradually, this work was translated to clinical trial and the results demonstrated that tamoxifen would be a useful agent to test as a chemo-preventative22).  The NSABP-1 trial subsequently showed that in high risk women, tamoxifen significantly decreased the risk of breast cancer by 50%  in pre and postmenopausal volunteers. Tamoxifen is approved in the United States for risk reduction of breast cancer in high risk pre-menopausal and postmenopausal women.  Despite the fact that chemoprevention is a pioneering application for tamoxifen, there are justifiable concerns about toxic side effects.  The side effects (primarily venous thrombosis and endometrial cancer, though the incidence is small) have limited the use of tamoxifen by primary care practitioners.  Nevertheless, it must be stressed that the side effects are limited to postmenopausal women.

There are no significant increases in endometrial cancer and thrombosis in postmenopausal women.

Tamoxifen remains the chemo-preventative agent of choice in this risk group48,  49).  To address the issue of side effects (e.g. endometrial cancer) with tamoxifen, a noval SERM strategy was devised.  If SERMs can prevent bone loss and prevent recurrent cancer at the same time50, 51), why not develop a SERM to prevent osteoporosis and prevent breast cancer at the same time?  This evidenced based hypothesis52)  has now been evaluated with the application of raloxifene to prevent osteoporosis.  Breast cancer and endometrial cancer are reduced when raloxifene is used to treat osteoporosis53,  54).  It is now possible to state that thou-
sands of women treated with raloxifene to prevent osteoporosis will have significant reductions in their breast cancer incidence49, 55, 56).  Based on the successful evaluation of raloxifene as an osteoporosis drug, raloxifene was then targeted to postmenopausal women at high risk for breast cancer.

The studies of tamoxifen and raloxifene (STAR) trial was designed to compare and contrast tamoxifen and raloxifene for the reduction in the incidence of breast cancer in high risk women and to improve the side effect profiles57).  The results of the trial demonstrated that the SERMs are equivalent in the prevention of invasive breast cancer, but it appears that tamoxifen is slightly better in preventing noninvasive breast cancer.  Nevertheless,  the results do not reach statistical significance.  The side effect profile of raloxifene is better than tamoxifen.  Raloxifene treated women have a reduced incidence of endometrial cancer, hysterectomies,  cataracts and cataract surgery.

Overall, raloxifene can be stated to be an effective agent to reduce breast cancer risk in postmenopausal women.

It is important to emphasize that no other classes of hormonal therapy have been evaluated successfully for prevention other than SERMs.

Aromatase inhibitors are slightly superior to SERMs for patients with breast cancer.  Unfortunately, aromatase inhibitors cannot be used in premenopausal women.  Therefore, the future consideration for the aromatase inhibitors is the balance of side effects between SERMs and aromatase inhibitors.  The side effect profile of osteoporosis, fractures,  and musculoskeletal pain in high risk patients will be addressed by an international clinical trial by the International Breast Intervention Study (IBIS II).  Anastrazole is being evaluated for prevention in high risk post menopausal women.

The study involves 6,000 women who will be randomized to receive anastrazole or placebo.  Another group of 4,000 women with locally excised DCIS will be randomized to receive anastrazole or tamoxifen.  After 5 years of treatment,  rates of breast cancer and side effect profiles will be examined between the groups58).  The important trial (P4)  to compare and contrast raloxifene with the aromatase inhibitor letrozole is being conducted by the National Surgical Adjuvant Breast and Bowel Project (NSABP).  These data will not be available until 2014.

Overall Summary
When treating patients with ER positive breast cancer,  there are many new choices available for patients.  Recurrent cancer which is SERM resistant and side effects such as venous thrombosis and endometrial cancer prompted investigation into aromatase inhibitors. Currently, clinical trials indicate that aromatase inhibitors should be used for initial hormonal therapy.  One must keep in mind that although aromatase inhibitors are superior for prevention of recurrence,  some patients still get recurrent breast cancer and the absolute difference between aromatase inhibitors and tamoxifen is a small percentage when comparing individual studies.  Furthermore,  the BIG trial is the only trial that stratified patients into node negative and node positive patients in terms of disease free survival rates.  Letrozole was significantly more beneficial with node positive patients, and there was no difference between node negative patients.  If fractures,  bone pain and other side effects are intolerable,  tamoxifen is still a viable option for prevention of recurrence,  especially in node negative patients with no uterus and without a history of clotting.  In node positive patients, aromatase inhibitors are probably the best initial treatment option. Treatment for recurrent cancer should be tailored for individual patients based on disease characteristics and tolerance of side effects such as osteopenia and musculoskeletal pain, cardiac risk, risk of venous thrombosis, and risk of uterine cancer.  For the future, prevention of breast cancer remains the most ideal situation and a significant number of patients will continue to benefit from the use of tamoxifen or raloxifene, with an additional benefit of maintaining bone density.  The era of multifunctional medicines has arrived.

Acknowledgements
Supported by 5T32CA10365-03 (RRP)  and by the Department of Defense Breast Program under award number BC050277 Center of Excellence (Views and opinions of, and endorsements by the author(s) do not reflect those of the US Army or the Department of Defense) (VCJ),  SPORE in Breast Cancer CA 89018 (VCJ),  R01 GM067156 (VCJ), FCCC Core Grant NIH P30 CA006927 (VCJ),  the Avon Foundation and the Weg Fund of Fox Chase Cancer Center (VCJ).


References

  1. McPherson K, Steel CM, Dixon JM: ABC of breast diseases. Breast cancer-epidemiology, risk factors, and genetics. BMJ 321(7261):624-628, 2000.
  2. Breast Cancer Facts and Figures. American Cancer Society. 2005-2006.
  3. Kols A: Breast Cancer; increasing incidence, limited options. Outlook 19:1-8, 2002.
  4. Marugame T, Kamo K, Katanoda K, Ajiki W, Sobue T: Cancer incidence and incidence rates in Japan in 2000: estimates based on data from 11 populationbased cancer registries. Jpn J Clin Oncol 36:668-675, 2006.
  5. Japanese Cancer Society:http://www. jcancer.jp/en/ screening.html. 2005.
  6. Vital Statistics of Japan: Statistics and Information Department. Minister's Secretariat, Ministry of Health, Labour and Welfare. 2001.
  7. Japanese Cancer Society: http://www .ncc.go.jp/en/ statistics/2005/index.html. 2005.
  8. Mettlin C: Global breast cancer mortality statistics. CA Cancer J Clin 49:138-144, 1999.
  9. Tung HT, Tsukuma H, Tanaka H, Kinoshita N, Koyama Y, Ajiki W, Oshima A, Koyama H: Risk factors for breast cancer in Japan, with special attention to anthropometric measurements and reproductive history. Japanese Journal of Clinical Oncology 29:137-146, 1999.
  10. Li CI, Daling JR, Malone KE: Incidence of invasive breast cancer by hormone receptor status from 1992 to 1998. J Clin Oncol 21:3-4, 2003.
  11. Anderson WF, Chatterjee N, Ershler WB, Brawley OW: Estrogen receptor breast cancer phenotypes in the Surveillance, Epidemiology, and End Results database. Breast Cancer Research and Treatment 76:27-36, 2002.
  12. Nomura Y, Tashiro H, Hamada Y, Shigematsu T: Relationship between estrogen receptors and risk fac-tors of breast cancer in Japanese pre- and postmenopausal patients. Breast Cancer Res Treat 4:37-43, 1984.
  13. Matsumoto K, Sakamoto G, Nomura Y: International comparisons concerning breast cancer and steroid receptors. Anticancer Research 6:621-624, 1986.
  14. McGuire WL, Carbone PP, Sears ME, Escher GC: Estrogen receptors in human breast cancer: an overview. In: Estrogen Receptor in Human Breast Cancer. McGuire WL, Carbone PP, Volmer EP eds Raven Press, New York. pp 1-7, 1975.
  15. Nomura Y, Kobayashi S, Takatani O, Sugano H, Matsumoto K, McGuire WL: Estrogen receptor and endocrine responsiveness in Japanese versus American breast cancer patients. Cancer Res 37:106-110, 1977.
  16. Jensen EV, Jacobson HI: Basic guides to the mechanism of estrogen action. Recent Progr Hormone Res 18:387-414, 1962.
  17. Jensen EV, Jordan VC: The estrogen receptor: a model for molecular medicine. The Dorothy P. Landon AACR Prize for Translational Research. Clin Cancer Res 9:1980-1989, 2003.
  18. Russo J, Fernandez SV, Russo PA, Fernbaugh R, Sheriff FS, Lareef HM, Garber J, Russo IH: 17-Beta-estradiol induces transformation and tumorigenesis in human breast epithelial cells. Faseb J 20:1622-1634, 2006.
  19. Cavalieri E, Chakravarti D, Guttenplan J, Hart E, Ingle J, Jankowiak R, Muti P, Rogan E, Russo J, Santen R, Sutter T: Catechol estrogen quinones as initiators of breast and other human cancers: implications for biomarkers of susceptibility and cancer prevention. Biochim Biophys Acta 1766:63-78, 2006.
  20. NCI Website: http://cancer.gov.cancertopics/under-standingcancer.
  21. EBCTCG: Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet 354:1451- 1467, 1998.
  22. Fisher B, Costantino JP, Wickerham DL, Redmond CK, Kavanah M, Cronin WM, Vogel V, Robidoux A, Dimitrov N, Atkins J, Daly M, Wieand S, Tan-Chiu E, Ford L, Wolmark N: 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.
  23. Buzdar AU, Jones SE, Vogel CL, Wolter J, Plourde P, Webster A: A phase III trial comparing anastrozole (1 and 10 milligrams), a potent and selective aromatase inhibitor, with megestrol acetate in postmenopausal women with advanced breast carcinoma. Arimidex Study Group. Cancer 79:730-739, 1997.
  24. de Ziegler D, Mattenberger C, Luyet C, Romoscanu I, Irion NF, Bianchi-Demicheli F: Clinical use of aromatase inhibitors (AI) in premenopausal women. J Steroid Biochem Mol Biol 95(1-5):121-127, 2005.
  25. Johnston S: Fulvestrant and the sequential endocrine cascade for advanced breast cancer. British J Cancer 90 Suppl 1:S15-18, 2004.
  26. Jonat W: Goserelin (Zoladex)-its role in early breast cancer in pre- and perimenopausal women. Br J Cancer 85 Suppl 2:1-5, 2001.
  27. Jordan VC: Tamoxifen: a most unlikely pioneering medicine. Nature Reviews Drug Discovery 2:205-213, 2003.
  28. Furr BJ, Jordan VC: The pharmacology and clinical uses of tamoxifen. Pharmacol Ther 25:127-205, 1984.
  29. Cole MP, Jones CT, Todd ID: A new anti-oestrogenic agent in late breast cancer. An early clinical appraisal of ICI 46474. Br J Cancer 25:270-275, 1971.
  30. Jordan VC, Allen KE: Evaluation of the antitumour activity of the non-steroidal antioestrogen monohy-droxytamoxifen in the DMBA-induced rat mammary carcinoma model. Eur J Cancer 16:239-251, 1980.
  31. Jordan VC: Use of the DMBA-induced rat mammary carcinoma system for the evaluation of tamoxifen as a potential adjuvant therapy. Reviews on Endocrine- Related Cancer (October Supplement):49-55, 1978.
  32. EBCTCG: Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 365:1687-1717, 2005.
  33. Osborne CK: Tamoxifen in the treatment of breast cancer. N Engl J Med 339:1609-1618, 1998.
  34. Howell A, Dodwell DJ, Anderson H, Redford J: Response after withdrawal of tamoxifen and progestogens in advanced breast cancer. Ann Oncol 3:611-617, 1992.
  35. Gottardis MM, Jordan VC: Development of tamoxifen-stimulated growth of MCF-7 tumors in athymic mice after long-term antiestrogen administration. Cancer Res 48:5183-8187, 1988.
  36. Jordan VC: Selective estrogen receptor modulation: concept and consequences in cancer. Cancer Cell 5:207-213, 2004.
  37. Miller WR, Dixon JM: Antiaromatase agents: preclinical data and neoadjuvant therapy. Clin Breast Cancer Suppl 1:S9-14, 2000.
  38. Buzdar AU, Jonat W, Howell A, Jones SE, Blomqvist CP, Vogel CL, Eiermann W, Wolter JM, Steinberg M, Webster A, Lee D: Anastrozole versus megestrol acetate in the treatment of postmenopausal women with advanced breast carcinoma: results of a survival update based on a combined analysis of data from two mature phase III trials. Arimidex Study Group. Cancer 83:1142-1152, 1998.
  39. Howell A, Robertson JFR, Quaresma Albano J, Aschermannova A, Mauriac L, Kleeberg UR, Vergot I, Erikstein B, Webster A, Morris C: Fulvestrant, formerly ICI 182,780, is as effective as anastrozole in postmenopausal women with advanced breast cancer progressing after prior endocrine treatment. J Clin Oncol 20:3396-3403, 2002.
  40. Osborne CK, Pippen J, Jones SE, Parker LM, Ellis M, Come S, Gertler SZ, May JT, Burton G, Dimery I, Webster A, Morris C, Elledge R, Buzdar A: Double-blind, randomized trial comparing the efficacy and tolerability of fulvestrant versus anastrozole in postmenopausal women with advanced breast cancer progressing on prior endocrine therapy: results of a North American trial. J Clin Oncol 20:3386-3395, 2002.
  41. Boccardo F, Rubagotti A, Puntoni M, Guglielmini P, Amoroso D, Fini A, Paladini G, Mesiti M, Romeo D, Rinaldini M, Scali S, Porpiglia M, Benedetto C, Restuccia N, Buzzi F, Franchi R, Massidda B, Distante V, Amadori D, Sismondi P: Switching to anastrozole versus continued tamoxifen treatment for early breast cancer: Preliminary results of the Italian Tamoxifen Anastrozole Trial. J Clin Oncol 23:5138- 5147, 2005.
  42. Coombes RC, Hall E, Gibson LJ, Paridaens R, Jassem J, Delozier T, Jones SE, Alvarez I, Bertelli G, Ortmann O, Coates AS, Bajetta E, Dodwell D, Coleman RE, Fallowfield LJ, Mickiewicz E, Andersen J, Lonning PE, Cocconi G, Stewart A, Stuart N, Snowdon CF, Carpentieri M, Massimini G, Bliss JM: 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.
  43. Goss PE, Ingle JN, Marino S, Robert NJ, Muss HB, Piccart MJ, Castiglione M, Tu D, Shepherd LE, Pritchard KI, Livingston RB, Davidson NE, Norton L, Perez EA, Abrams JS, Therasse P, Palmer MJ, Pater JL: A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med 349:1-10, 2003.
  44. ATAC Trialists' Group: Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomized trial. Lancet 359:2134-3139, 2002.
  45. Howell A, Cuzick J, Baum M, Buzdar A, Dowsett M, Forbes JF, Hoctin-Boes G, Houghton J, Locker GY, Tobias JS, Group AT: Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years' adjuvant treatment for breast cancer. Lancet 365:60-62, 2005.
  46. Thurlimann B, Keshaviah A, Coates AS, Mouridsen H, Mauriac L, Forbes JF, Paridaens R, Castiglione-Gertsch M, Gelber RD, Rabaglio M, Smith I, Wardly A, Price KN, Goldhirsch A, BIG (Breast International Group), Group I-C: A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med 353:2747-2757, 2005.
  47. Jordan VC: Effect of tamoxifen (ICI 46,474) on initiation and growth of DMBA- induced rat mammary carcinoma. Eur J Cancer 12:419-424, 1976.
  48. Fisher B, Costantino JP, Wickerham DL, Cecchini RS, Cronin WM, Robidoux A, Bevers TB, Kavanah MT, Atkins JN, Margolese RG, Runowicz CD, James JM, Ford LG, Wolmark N: 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.
  49. Jordan VC: Optimising endocrine approaches for the chemoprevention of breast cancer. Beyond the Study of Tamoxifen and Raloxifene (STAR) Trial. European Journal of Cancer 42:2909-2913, 2006.
  50. Jordan VC, Phelps E, Lindgren JU: Effects of antiestrogens on bone in castrated and intact female rats. Breast Cancer Res Treat 10:31-35, 1987.
  51. Gottardis MM, Jordan VC: Antitumor actions of keoxifene and tamoxifen in the N-nitrosomethylurea induced rat mammary carcinoma model. Cancer Res 47:4020-4024, 1987.
  52. Jordan VC: Chemosuppression of breast cancer with tamoxifen: laboratory evidence and future clinical investigations. Cancer Invest 6:589-595, 1988.
  53. Cummings SR, Eckert S, Krueger KA, Grady D, Powles TJ, Cauley JA, Norton L, Nickelsen T, Bjarnason NH, Morrow M, Lippman ME, Black D, Glusman JE, Costa A, Jordan VC: The effect of raloxifene on risk of breast cancer in postmenopausal women: results from the MORE randomized trial. Multiple Outcomes of Raloxifene Evaluation. JAMA 281:2189-2197, 1999.
  54. Martino S, Cauley JA, Barrett-Connor E, Powles TJ, Mershon J, Disch D, Secrest RJ, Cummings SR: For the CORE Investigators Continuing Outcomes Relevant to Evista: Breast Cancer Incidence in Postmenopausal Osteoporotic Women in a Randomized Trial of Raloxifene. J Natl Cancer Inst 96:1751-1761, 2004.
  55. Jordan VC: Chemoprevention of breast cancer with selective oestrogen-receptor modulators. Nature Reviews Cancer (in press) 2007.
  56. Jordan VC: SERMs: meeting the promise of multifunctional medicines. (Commentary). Journal of the National Cancer Institute (in press)2007.
  57. Vogel VG, Costantino JP, Wickerham DL, Cronin WM, Cecchini RS, Atkins JN, Bevers TB, Fehrenbacher L, Pajon (jr) ER, Wade I, J.L. , Robidoux A, Margolese RG, James J, Lippman SM, Runowicz CD, Ganz PA, Reis SE, McCaskill-Stevens W, Ford LG, Jordan VC, Wolmark N: The Study of Tamoxifen and Raloxifene (STAR): Report of the National Surgical Adjuvant Breast and Bowel Project P-2 Trial. JAMA 295:2727-2741, 2006.
  58. http://www. ibcsg.org/public/general-pages/trials/ open/IBIS-II/trial-IBISII.html.

Roshani R. Patel, Catherine G. N. Sharma, and V. Craig Jordan
Fox Chase Cancer Center, Philadelphia

Reprint requests to V. Craig Jordan OBE, PhD, DSc, Vice President and Research Director for Medical Science,  Alfred G.  Knudson Chair of Cancer Research,  Fox Chase Cancer Center,  333 Cottman Avenue, Philadelphia, PA 19111-2497
Email: .(JavaScript must be enabled to view this email address)

Page 4 of 4« First 2 3 4

Provided by ArmMed Media