The BIG news from San Antonio Breast Cancer Symposium 2008

Dr Henning Mouridsen presented the BIG 1-98 results last week at the 31st Annual San Antonio Breast Cancer Symposium. The outcomes were hotly discussed amongst the delegates.

The Breast International Group (BIG) 1-98 is a randomised, phase 3, double blind trial comparing two adjuvant endocrine therapy regimens, tamoxifen and letrozole, in post-menopausal women with hormone receptor positive breast cancer. Eligible participants were randomised to receive monotherapy with letrozole or tamoxifen for five years or sequential therapy with letrozole for two years followed by tamoxifen for three years, or tamoxifen for two years followed by letrozole for three years.¹

The first results were published in December 2005 in the New England Journal of Medicine¹ after a median follow up of just over two years. When comparing the groups allocated to receive letrozole initially with those assigned to receive tamoxifen initially, the results showed that the primary endpoint, disease free survival, was significantly greater with letrozole compared to tamoxifen (P=0.003), and especially in reducing recurrence at distant sites (P=0.001). The cumulative incidence of breast cancer relapse was significantly reduced with letrozole compared to tamoxifen. The cumulative incidence of second, non-breast cancers was similar between groups.¹

Sub-group analysis revealed letrozole to have a greater effect than tamoxifen in patients that received chemotherapy, did not receive radiotherapy, and those with axillary lymph node involvement. The beneficial effect of letrozole on disease free survival was not altered by the profiles of oestrogen receptor positive, progesterone receptor positive, or both.¹

Patients receiving letrozole experienced fewer thromboembolic events, vaginal bleeding, endometrial biopsies and endometrial cancers, however they did experience a greater rate of bone fractures and low grade hypercholesterolaemia. While the overall incidence of adverse cardiovascular events (grade 3, 4, or 5) was similar between the two groups more women in the letrozole group experienced cardiac events (P<0.001).¹

The increased rate of bone fractures is associated with the mechanism of action of aromatase inhibitors.¹ These drugs act by inhibiting the conversion of androgens to estrogens and consequently reduce the levels of estrogen in tissue and plasma.^2,3 New approaches are needed to reduce this risk. It is believed that the increased cholesterol levels seen in participants taking letrozole may in part be due to the cholesterol lowering effects of tamoxifen.⁴ The authors agree with a statement issued by the American Society of Clinical Oncology in 2005 that the information available currently is insufficient to fully determine the effect that aromatase inhibitors such as letrozole have on cardiovascular disease.⁵ In part it may be due to protective effects on the arteries conferred by tamoxifen.⁶

An update of the study, limited to those 4972 patients receiving monotherapy, was issued in 2007, in the Journal of Clinical Oncology.⁷ Essentially this was confirmed the primary core analysis. The five year disease free survival estimates were 84.0% and 81.1% for letrozole and tamoxifen, respectively. Subgroup analysis, however, did not reveal any apparent differences in the relative efficacy. In particular no significant differences were seen with nodal involvement or progesterone receptor status.⁷

Adverse events were similar to previous reports. More patients receiving letrozole discontinued treatment early as a result of an adverse event (12.3% of patients on letrozole and 11.1% of patients on tamoxifen), while more patients receiving tamoxifen discontinued treatment early due to disease progression (7.9% of patients on letrozole and 11.5% of patients on tamoxifen). Hence the incidence, severity, type and duration of side effects experienced by patients as well as treatment efficacy are undoubtedly relevant factors in treatment selection.⁷

The current results presented at the symposium are presented after a median follow up time of 71 months and served to answer the question: is a sequence of agents superior to letrozole monotherapy?⁸

The results suggest an improved overall survival for patients receiving letrozole (HR=0.87, 95% CI=0.75-1.02, p=0.08, 76 months median follow-up). Sequential treatments did not result in improved disease free survival compared to letrozole alone. Trends support the use of letrozole initially in patients with a higher risk of relapse.⁸

The presenters concluded that:⁸

Overall survival is superior with letrozole compared to tamoxifen;
Adjuvant endocrine therapy should begin with letrozole especially for those patients where early risk of recurrence is high; and
Following two years of treatment with letrozole, patients can be switched to tamoxifen if required.

At the symposium, a UK oncologist questioned if the small, non significant trends for letrozole superiority over tamoxifen justified the increased costs associated with the use of aromatase inhibitors. The presenter cut short this question on the basis that they believed it to be irrelevant. However, given that the data presented at San Antonio breast Cancer symposium is highly relevant to people in developing countries such as India and China, and relevant to second world countries such as the United Kingdom, the cost issue is actually an important factor. Not only are the direct costs of treatment important but also indirect costs such as the treatment of osteoporosis, its complications and hospitalisation from osteoporotic crush fractures

The general consensus among many of the Australian delegates was that this is one of many studies that suggest benefit for a switch strategy.^9,10,11,12

References

Thurlimann B, Keshaviah Aparna, 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. A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Eng J Med 2005; 353: 2747-2757.
Osborne CK. Tamoxifen in the treatment of breast cancer. N Engl J Med 1998; 339: 1609-1618.
Smith IE, Dowsett M. Aromatase inhibitors in breast cancer. N Engl J Med 2003; 348: 2431-2442.
Herrington DM, Klein KP. Effects of SERMs on important indicators of cardiovascular health: lipoproteins, hemostatic factors, and endothelial function. Womens Health Issues 2001; 11: 95-102.
Winer EP, Hudis C, Burstein HJ, Wolff AC, Pritchard KI, Ingle JN, Chlebowski RT, Gelber R, Edge SB, Gralow J, Cobleigh MA, Mamounas EP, Goldstein LJ, Whelan TJ, Powles TJ, Bryant J, Perkins C, Perotti J, Braun S, Langer AS, Browman GP, Somerfield MR. American Society of Clinical Oncology technology assessment on the use of aromatase inhibitors as adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer: status report 2004. J Clin Oncol 2005; 23: 619-629.
Braithwaite RS, Chlebowski RT, Lau J, George S, Hess R, Col NF. Meta-analysis of vascular and neoplastic events associated with tamoxifen. J Gen Intern Med 2003; 18: 937-947.
Coates AS, Keshaviah A, Thurlimann B, Mouridsen H, Mauriac L, Forbes JF, Paridaens R, Castiglione-Gertsch M, Gelber RD, Colleoni M, Lang I, Del Mastro L, Smith I, Chirgwin J, Nogaret JM, Peinkowski T, Wardley A, Jakobsen EH, Price KN, Goldhirsch A. Five years of letrozole compared with tamoxifen as initial adjuvant therapy for postmenopausal women with endocrine-responsive early breast cancer: update of study BIG 1-98. J Clin Oncol 2007; 25: 486-492.
Mouridsen H. Letrozole monotherapy vs tamoxifen monotherapy or vs letrozole in sequence with tamoxifen for postmenopausal women with endocrine-responsive early breast cancer [Powerpoint presentation]. Presented at the San Antonia Breast Cancer Symposium. Retrieved December 15, 2008, from http://sabcs08.m2usa.com/previewer.html
Smith IE, Dowsett M. Aromatase inhibitors in breast cancer. N Engl J Med 2003; 348: 2431-2442.
Mouridsen H, Gershanovich M, Sun Y, Perez-Carrion R, Boni C, Monnier A, Apffelstaedt J, Smith R, Sleeboom HP, Janicke F, Pluzanska A, Dank M, Becquart, D, Bapsy PP, Salminen E, Snyder R, Lasssus M, Verbeek A, Staffler B, Chaudri-Ross HA, Dugan M. Superior efficacy of letrozole versus tamoxifen as first-line therapy for postmenopausal women with advanced breast cancer: results of a phase III study of the International Letrozole Breast Cancer Group. J Clin Oncol 2001;19:2596-606. [Erratum, J Clin Oncol 2001;19:3302.]
Mouridsen H, Gershanovich M, Sun Y, Perez-Carrion R, Boni C, Monnier A, Apffelstaedt J, Smith R, Sleeboom HP, Janicke F, Pluzanska A, Dank M, Becquart, D, Bapsy PP, Salminen E, Snyder R, Chaudri-Ross H, Lang R, Wyld P, Bhatnagar A. Phase III study of letrozole versus tamoxifen as first-line therapy of advanced breast cancer in postmenopausal women: analysis of survival and update of efficacy from the International Letrozole Breast Cancer Group. J Clin Oncol 2003; 21: 2101-2109.
Ellis MJ, Coop A, Singh B, Mauric L, Llonber-Cussac A, Janicke F, Miller WR, Evans DB, Dugan M, Brady C, Quebe-Fehling E, Borgs M. Letrozole is more effective neoadjuvant endocrine therapy than tamoxifen for ErbB-1 and/or ErbB-2-positive primary breast cancer: evidence from a phase III randomized trial. J Clin Oncol 2001;19: 3808-3816.