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Originally published as JCO Early Release 10.1200/JCO.2005.03.904 on July 11 2005 © 2005 American Society of Clinical Oncology.
Aromatase Inhibitors in Adjuvant Therapy of Breast Cancer: Before, Instead of, or Beyond TamoxifenToronto Sunnybrook Regional Cancer Centre, Toronto, Ontario, Canada
The trial by Boccardo et al,1 which is published in this issue of the Journal of Clinical Oncology, represents the fourth published randomized trial of an adjuvant aromatase inhibitor used either instead of2-4 or after 2 to 3 or 5 years of tamoxifen.5 Before these data became available, 5 years of adjuvant tamoxifen had been considered standard based on the results of individual trials6 and the Early Breast Cancer Trialists' Collaborative Group Overview.7 These trials showed that 5 years of tamoxifen therapy, compared with either 2 years of tamoxifen or none, was associated with greatly improved relapse-free and overall survival. Several trials of 5 years compared with indefinite tamoxifen8,9 or 5 years compared with 10 years of tamoxifen therapy10 subsequently suggested that longer therapy might be less beneficial, whereas one small trial suggested the opposite conclusion.11 The Oxford Overview Database, including data from the ongoing randomized ATOM (Adjuvant Tamoxifen or More)12 and ATLAS (Adjuvant Tamoxifen Longer Against Shorter; C. Davies, personal communication, April 2004) trials of 5 compared with 10 years of tamoxifen, has not yet shown any clear significant difference between 5 years of tamoxifen therapy and more prolonged tamoxifen (http://www.ctsu.ox.ac.uk/ However, it is well known that women with a previous diagnosis of breast cancer have a long-term ongoing risk of breast cancer recurrence. Data from the long-term follow-up of a group of Eastern Cooperative Oncology Group trials13 and from the Oxford Overview7 have shown that there are as many recurrences during years 6 through 15 after primary surgery as between years 1 through 5 in both women treated with tamoxifen and controls. The estimated recurrence risk beyond year 5 is approximately 4% per year for women with node-positive disease at the time of primary surgery and approximately 2% per year for women with node-negative disease. Consideration of these data before the design of the current group of adjuvant endocrine trials strongly suggested that additional therapy beyond 5 years of tamoxifen could prove useful. Now, for women nearing completion of 5 years of tamoxifen, the decision to consider additional years of endocrine therapy with an aromatase inhibitor seems fairly straightforward. Issues for discussion should include the risk of recurrence over the next 5 years based on prior nodal status and other risk factors. Patients should be informed of the efficacy of letrozole in reducing recurrence risk and, in the subset of node-positive women, in increasing overall survival.14 This information, together with a review of the potential short-, intermediate-, and long-term side effects of this aromatase inhibitor, should allow clinicians and patients to make a relatively informed choice regarding the desirability of this treatment. Although the MA-17 trial of 5 years of letrozole compared with placebo after tamoxifen for 5 years has, to date, a median follow-up of only 2.5 years, more data will be forthcoming. Such data should be available before the women we are currently starting on letrozole after 5 years of tamoxifen reach that 2.5-year point. Thus, more mature information regarding efficacy and longer term side effects can be provided as patients move through these phases of treatment. Currently, it seems that the added benefit of letrozole year by year, compared with the previous year, remains constant, at least through the first 3 to 4 years of therapy. Furthermore, women from the MA-17 trial who have completed 5 years of letrozole will be offered the opportunity to undergo another random assignment between a further 5 years of letrozole or placebo, thus producing data on the value of 5 compared with 10 years of such treatment. However, there are no data from randomized trials comparing shorter durations of letrozole with 5 years of letrozole or with placebo. The Arimidex, Tamoxifen Alone or in Combination (ATAC) trial, which now has 5 years of follow-up on virtually every patient, has shown sustained disease-free survival benefit for women treated with anastrozole for 5 years compared with 5 years of tamoxifen alone.2,4 In addition, less mature results from the Breast International Group (BIG) I-98 study have shown improved disease-free survival for women who were randomly assigned to receive letrozole compared with tamoxifen for 5 years.15,16 The main differences in recurrence seem to occur during years 1 to 3 of the additional therapy but are maintained and somewhat increased over subsequent years, at least as far as the data have become available.15 Thus, for the woman contemplating the initiation of endocrine therapy after primary surgery for breast cancer, the choice of an aromatase inhibitor would seem preferable, at least during the first 5 years of therapy. But then what? Is 5 years of therapy with an aromatase inhibitor enough? What would be the risk of recurrence after discontinuation of this treatment? Could tamoxifen after 5 years of an adjuvant aromatase inhibitor be useful? Should additional years of an aromatase inhibitor be added, and should it be a different aromatase inhibitor or the same one? We have no further data regarding any of these questions, and there is no plan to randomly assign women beyond 5 years of any therapy in the ATAC or BIG trials to allow for further treatment comparisons. More recently, this field of study has been further advanced by compelling data,3,18,19 including the article by Boccardo et al,1 suggesting that, in women who have completed 2 to 3 years of tamoxifen as adjuvant therapy, a switch to either exemestane3 or anastrozole1,18 for a total treatment duration of 5 years is associated with a significant disease-free survival benefit. In these trials, however, the total duration of therapy was 5 years, with no suggestion of what therapy should be administered beyond that time. The situation is made somewhat more complex by comparisons of short-, intermediate-, and long-term toxicities between the aromatase inhibitors and tamoxifen. It is clear that tamoxifen is associated with an increased rate of development of endometrial cancer, deep vein thrombosis, and pulmonary emboli and perhaps strokes,18 all of which seem to be increased with increasing duration of tamoxifen treatment. In comparison, the aromatase inhibitors seem to carry no increased risk of endometrial cancer, deep vein thrombosis, or pulmonary emboli compared with placebo.5 However, aromatase inhibitors are associated in every trial with small but often significant increases in reports or findings of osteoporosis or fracture and an increased incidence of musculoskeletal complaints. These musculoskeletal symptoms vary from mild and tolerable to quite severe, but they probably occur in only approximately an additional 5% to 10% of patients compared with placebo.5 These toxicity profiles, which are clearly defined from a wide variety of randomized trial data, should allow clinicians and women to make informed choices. However, there remain concerns about longer term effects, particularly in bone, where the most serious sequelae of osteoporosis, such as hip fracture, may occur only after many years of follow-up. Ongoing monitoring of these issues will be crucial in optimizing treatment in this setting. In the meantime, can one usefully compare trials, as Boccardo et al1 have suggested, and conclude that aromatase inhibitors may be more useful administered after 2 to 3 years of tamoxifen than when administered from the time of primary surgery for a full 5 years? Can one draw conclusions regarding which, if any, of the aromatase inhibitors are superior in either efficacy or toxicity? Such cross-trial comparisons are fraught with peril, with the possibility of different patient selection, different compliance to treatment, different follow-up schedules, and different criteria for collection of various end points. Thus, these indirect comparisons should be viewed with a great deal of caution. Nonetheless, there are many who believe, based on the currently available clinical and preclinical data, that there may be some beneficial effect of priming the tumor with tamoxifen before using an aromatase inhibitor. But what about the women who recur during the first 2 to 3 years of tamoxifen therapy who would not have recurred if administered an aromatase inhibitor, as supported by the ATAC data? Clearly, for them, this would not be a beneficial trade-off. Furthermore, the women who recur within the first 2 years after surgery and who probably have more aggressive disease are excluded from the population who are randomly assigned after 2 years of tamoxifen therapy in the Intergroup Exemestane Study and Italian Tamoxifen Anastrozole trials. Fortunately, the upcoming additional results of the BIG 1-98 trial will go far in answering these questions. The BIG 1-98 trial is a four-arm study of adjuvant endocrine therapy in which 5 years of letrozole is compared with 5 years of tamoxifen, with 2 to 3 years of tamoxifen followed by 2 to 3 years of letrozole, and with 2 to 3 years of letrozole followed by 2 to 3 years of tamoxifen, for a total of 5 years of treatment in all four arms.16 If patients remain on their treatments through the entire schedule of therapy, a good deal of worthwhile data examining these options will become available to us. Similarly, the ongoing National Cancer Institute of Canada Clinical Trials Group MA-27 trial comparing anastrozole to exemestane as first-line adjuvant therapy will provide direct comparative data between at least two of the currently available aromatase inhibitors. A number of other questions still remain unresolved. What should we suggest to women who have completed 5 years of an aromatase inhibitor or 2 to 3 years of tamoxifen followed by an aromatase inhibitor for a total of 5 years of therapy? Given the current data, it is unclear what, if any, therapy we should recommend in this setting. Therefore, it is important for us to undertake trials with additional randomizations beyond 5 years of endocrine treatment because past experience would suggest that these women will remain at a relatively high risk of recurrence and that additional treatment with prolonged aromatase inhibitors, tamoxifen, or other new endocrine agents, such as the selective estrogen receptor downregulators, may be beneficial. It is crucial that we design studies to collect this information immediately; otherwise, an increasing number of women will pass through these treatment windows and will by necessity choose further therapy or none, without the help of data from randomized trials. In the meantime, clear explanations of the additional benefits made available by the aromatase inhibitors and of the associated short-, intermediate-, and long-term side effects must be offered to all women in these treatment settings. Furthermore, close follow-up, particularly with regard to bone effects, will be required for another decade before the long-term safety of these agents can be assured. Author's Disclosures of Potential Conflicts of Interest The following author or their immediate family members has indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C)
REFERENCES
1. Boccardo F, Rubagotti A, Puntoni M, et al: Switching to anastrozole versus continued tamoxifen treatment of early breast cancer: Preliminary results of the Italian Tamoxifen Anastrozole trial. J Clin Oncol 23: 5138-5147, 2005 2. The Arimidex, Tamoxifen Alone or in Combination 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: 2131-2139, 2002[CrossRef][Medline]
3. Coombes RC, Hall E, Gibson LJ, 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: 1081-1091, 2004 4. Baum M, Buzdar A, Cuzick J, et al: Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early-stage breast cancer: Results of the ATAC trial efficacy and safety update analysis. Cancer 98: 1802-1810, 2003[CrossRef][Medline]
5. Goss PE, Ingle JN, Martino S, et al: A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med 349: 1793-1802, 2003
6. Fisher B, Redmond C, Brown A, et al: Adjuvant chemotherapy with and without tamoxifen in the treatment of primary breast cancer: 5-year results from the National Surgical Adjuvant Breast and Bowel Project Trial 34. J Clin Oncol 4: 459-471, 1986 7. Early Breast Cancer Trialists' Collaborative Group: Tamoxifen for early breast cancer: An overview of the randomised trials. Lancet 351: 1451-1467, 1998[CrossRef][Medline] 8. Stewart HJ, Forrest AP, Everington D, et al: Randomised comparison of 5 years of adjuvant tamoxifen with continuous therapy for operable breast cancer: The Scottish Cancer Trials Breast Group 299. Br J Cancer 74: 297-299, 1996[Medline]
9. Stewart DJ, Prescott RJ, Forrest PM: Scottish adjuvant tamoxifen trial: A randomized study updated to 15 years. J Natl Cancer Inst 93: 456-462, 2001
10. Fisher B, Dignam J, Bryant AJS, et al: Five versus more than five years of tamoxifen for lymph node negative breast cancer: Updated findings from the National Surgical Adjuvant Breast and Bowel Project B-14. J Natl Cancer Inst 93: 684-690, 2001
11. Tormey DC, Gray R, Falkson HC: Postchemotherapy adjuvant tamoxifen therapy beyond five years in patients with lymph node-positive breast cancer: Eastern Cooperative Oncology Group. J Natl Cancer Inst 88: 1828-1833, 1996 12. Earl H, Gray R, Kerr D, et al: The optimal duration of adjuvant tamoxifen treatment for breast cancer remains uncertain: Randomize into aTTom. Clin Oncol (R Coll Radiol) 9: 141-143, 1997
13. Saphner T, Tormey DC, Gray R: Annual hazard rates of recurrence for breast cancer after primary therapy. J Clin Oncol 14: 2738-2746, 1996 14. Goss PE, Ingle JN, Martino S, et al: Updated analysis of the NCIC CTG Ma.17 randomized placebo (P) controlled trial of letrozole (L) after five years of tamoxifen in postmenopausal women with early stage breast cancer. J Clin Oncol 22: 88s, 2004 (suppl, abstr 3641)[CrossRef] 15. Thurlimann BJ, Keshaviah A, Mouridson H, et al: BIG 1-98: Randomized double-blind phase III study to evauate letrozole (L) vs. tamoxifen (T) as adjuvant endocrine therapy for post-menopausal women with receptor-positive breast cancer. Proc Am Soc Clin Oncol 23: 16s, 2005 (abstr 511; suppl) 16. Thurlimann BJ: The Breast. Presented at the Primary Therapy in Early Breast Cancer Conference, St Gallen, Switzerland, January 26-29, 2005 (abstr S4) 17. Howell A: Completed treatment analysis: Anastrozole demonstrates superior efficacy and tolerability compared with tamoxifen. Breast Cancer Res Treat 88: 57, 2004 (abstr 1)[CrossRef] 18. Coombes RC, Hall E, Snowdon CF, et al: The Intergroup Exemestane Study: A randomized trial in postmenopausal patients with early breast cancer who remain disease-free after two to three years of tamoxifen—Updated survival analysis. Breast Cancer Res Treat 88: 57, 2004 (abstr 3) 19. Jakesz R, Kaufmann M, Gnant M, et al: Benefits of switching postmenopausal women with hormone-sensitive early breast cancer to anastrozole after two years adjuvant tamoxifen: Combined results from 3,123 women enrolled in the ABCSG Trial 8 and the ARNO 95 Trial. Breast Cancer Res Treat 88: 57, 2004 (abstr 2)
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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