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Journal of Clinical Oncology, Vol 23, No 36 (December 20), 2005: pp. 9437-9439 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.04.3554
In Reply:The National Cancer Research Institute and the University of Genoa, Genoa, Italy The letter by Dr Demonty raises a number of issues that are relevant both to clinical practice and from the ethical and social points of view. The first issue regards lack of survival benefits from the use of aromatase inhibitors (AIs) to manage early breast cancer. As Dr Demonty outlines, none of the AIs adjuvant trials reported a survival benefit yet,1-5 except for the MA 17 trial that, on the basis of a retrospective unplanned analysis, reported a significant survival benefit in the subgroup of node-positive women.6 Dr Demonty’s observation is formally correct under this point of view, though he forgot to mention our previous trial on switching with low-dose aminogluthetimide, which showed both overall and breast cancer–specific survival benefits.7 Since all trials with AIs have shown that the use of these drugs upfront as an alternative to tamoxifen, or in a sequence following a few years or even five years of tamoxifen, can alter the natural history of early breast cancer, indeed one should ask why most of them have failed to show a survival benefit as well. From the speculative point of view, there might be several reasons: (1) the gain obtained by AIs might be overweighted by treatment associated lethality; (2) the gain achieved by AIs use in the adjuvant setting consists mainly in improving local control and in preventing controlateral breast cancer and both these situations are likely to translate just in a small survival gain and only in the long run; (3) independently of the type of the benefit, most of the trials available so far have been reported when follow-up time was short. Though some of them enrolled large numbers of patients, relatively small numbers of deaths have been observed so far in each individual trial. So most trials are too early to allow reliable mortality analysis. The results of the pooled analysis of both the trials performed by our group1,7 (this analysis had been planned on a prospective basis when we designed the second trial) prompt us to believe that, basically, the third hypothesis might be the most appropriate. This pooled analysis (the results of which will form the object of a separate paper) included the mortality data coming from the October 2004 analysis of each one of these trials in October 2004. The results of the updated analysis of the Italian Tamoxifen Anastrozole (ITA) trial formed the object of a poster presentation at the last American Society of Clinical Oncology meeting in Orlando, Fl, May 13-17, 2005.8 Overall, 828 patients were included into the pooled analysis. All of them were postmenopausal and most of them were estrogen-receptor positive and node positive. The whole cohort of women had been followed for a median time of 68 months (range, 1 to 141) since they had been randomly assigned to continue receiving tamoxifen, following 2 to 3 years of treatment with this antiestrogen, for a total of 5 years (n = 415) or to be switched to an AI (either aminogluthetimide or anastrozole) for a comparable period of time. As it is shown in Figure 1, both trials show a comparable benefit in overall and breast cancer related mortality in favor of the women switched to the AI. Lack of statistical significance of some of the ratios is clearly related to the number of deaths (as graphically represented by the size of the squares) which, in turn, is clearly related to the duration of median follow-up time (which was 104 months for the Gruppo per la Ricerca sulla Chemo-Ormonoterapia Adiuvante (GROCTA) 04 trial, but only 52 months for the ITA trial) since the size of the two trials is comparable.
The results of our pooled analysis are in agreement with those of a meta-analysis of published AIs trials, that have been recently presented at the 9th Nottingham International Breast Cancer Conference (Nottingham, United Kingdom; September 13-16, 2005; R. Gray, personal communication) that also showed overall and breast cancer specific survival benefits in favor of the women randomly assigned to receive an aromatase inhibitor in those previous trials. If one considers that the median follow-up time of most of the AIs trials does not exceed 36 months and that the great majority of the women enrolled onto these trials had a low-intermediate risk of relapse (most of the women were node negative and in some cases entry was restricted to those with G1-G2 tumors) and a high chance to benefit from tamoxifen therapy (most of the women were both estrogen-receptor and progesterone-receptor positive) it is quite reasonable to expect that a few more years are required for all these trials to show a survival benefit as well. Yet it is still possible that the mortality gain will benefit mainly (or exclusively) some patient subgroups rather than the entire population of postmenopausal women with early breast cancer. The first one of our previous assumptions is strictly correlated with the second concern raised by Dr Demonty relative to the safety of long-term treatment with AIs, in particular in respect to cardiovascular morbility. While there is no doubt that AIs might affect lipid metabolism in a different way than tamoxifen,9,10 it is still impossible to ascertain whether and how few years of treatment with these kinds of drugs can impact with cardiovascular lethality, that as punctually recognized by Dr Demonty, is the most common cause of mortality worldwide.11 Unfortunately none of the AIs trials provide enough information about factors, like smoking, diet, obesity, hypertension, lifestyle, and inherited metabolic conditions, that are also involved in the pathogenesis of cardiac diseases and that can play a major role as confounding factors in mortality analysis. However, so far none of the AI studies have reported an increase in breast cancer unrelated mortality with the exception of the Breast International Group 1-98 trial, which showed a small increase in the incidence of cardiac ischemic deaths.5 In the pooled analysis of our two AI adjuvant trials, there was indeed a nonsignificant difference in respect to breast cancer unrelated mortality between groups, but this favored the women switched to aminogluthetimide or anastrozole (13 deaths v 22). In particular, we recorded five cardiovascular deaths among the women in this group as compared with 11 in the group of women who continued to receive tamoxifen. Nonetheless, we agree that no definite conclusions can be drawn at the moment about long-term safety of AI treatment in the adjuvant setting, even in view of the fact that at least in women at higher risk of relapse, breast cancer unrelated deaths usually do occur later than breast cancer deaths (in the previously mentioned pooled analysis of our two AI trials, 50% of breast cancer unrelated deaths occurred 8 years or more after random assignment). On the other hand, several years had to elapse between the first report on the estrogen-like-effect of tamoxifen on the endometrium12 and the first report on an increased risk of endometrial cancer in women receiving this antiestrogen as their adjuvant treatment.13 Nonetheless, the carcinogenic effects of tamoxifen did not stop clinicians from going on to use this drug that, as Dr Demonty recalled, still represents a valuable therapeutic option for the management of early breast cancer, even outside the third world countries. The third point raised by Demonty concerns the wide geographical variation in the standards of care, which in turn involve a number of pharmacoeconomic, social, political, and ethical issues. All of these issues deserve an appropriate forum in which they can be debated. However, these problems commonly exist in the decision making regarding the usage of other treatments in oncology (comparable considerations are likely to be applied to the use of anthracyclines or taxanes in early breast cancer) and with other widespread medical diseases (like AIDS). It is clear that in principle the cost of drugs should be comparable in all countries, and that pharmaceutical companies should probably agree to offer antitumor drugs at a lower cost to low-income countries, similar to what has occurred for some anti-AIDS drugs. The relevant question is whether the use of AIs in early breast cancer should be mandatorily considered in any patient. In our opinion, this recommendation applies only to postmenopausal women candidates who are receiving adjuvant hormone therapy and who are not suitable for being treated with, or become intolerant to, tamoxifen. Otherwise, AIs should represent a possible alternative, most suitable for selective groups of women. We have no doubt that in a few years the trials already completed and those still going on, together with biomolecular and pharmacogenomics studies, will help us in decision making more than present algorithms and models do. In the meanwhile, a careful evaluation of the benefits and costs of introducing an AI in the management of any individual patient should be part of the decision making process. In fact, no one of the strategies tested so far (upfront use, sequencing, switch-ing, extended use) can be regarded as the panacea for all women. Authors’ Disclosures of Potential Conflicts of Interest
Although all authors completed the disclosure declaration, the following author or immediate family members 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 discription 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) $10,000–99,000 (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. 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 350:1081-1092, 2004 3. Howell A, Cuzick J, Baum M, et al: 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[CrossRef][Medline] 4. Jakesz R, Jonat W, Gnant M, et al: Switching of postmenopausal women with endocrine-responsive early breast cancer to anastrozole after 2 years’ adjuvant tamoxifen: Combined results of ABCSG trial 8 and ARNO 95 trial. Lancet 366:455-462, 2005[CrossRef][Medline] 5. Thurlimann B, Keshaviah A, Mouridsen H, 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. Amer Soc Clin Oncol 511, 2005 6. Goss PE, Ingle JN, Martino S, et al: Update 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. Amer Soc Clin Oncol 847, 2004 7. Boccardo F, Rubagotti A, Amoroso D, et al: Sequential tamoxifen and aminogluthetimide versus tamoxifen alone in the adjuvant treatment of postmenopausal breast cancer patients: Results of an Italian cooperative study. J Clin Oncol 19:4209-4215, 2001 8. Boccardo F, Rubagotti A, Puntoni M, et al: Switching to anastrozole (ANA) vs continued tamoxifen (TAM) treatment of early breast cancer (EBC). Updated results of the Italian tamoxifen anastrozole (ITA) trial. Amer Soc Clin Oncol Poster discussion 526, 2005 9. Sawada S, Sato K: Effect of anastrozole and tamoxifen on serum lipid levels in Japanese postmenopausal women with early breast cancer. Breast Cancer Res Treat 82:S31, 2003(suppl 1; abstr 143) 10. Wojtacki J, Lesniewski-Kmak K, Kruszewski WJ: Anastrozole therapy does not compromise lipid metabolism in breast cancer patients previously treated with tamoxifen. Breast Cancer Res Treat 76:S75, 2002 (suppl 1; abstr 262) 11. World Health Report 2003: www.who.int. 12. Boccardo F, Bruzzi P, Rubagotti A, et al: Estrogen-like action of tamoxifen on vaginal epithelium in breast cancer patients. Oncology 38:281-285, 1981[CrossRef][Medline] 13. Fornander T, Rutqvist LE, Cedemark B, et al: Adjuvant tamoxifen in early breast cancer: Occurrence of new primary cancers. Lancet 1:117-120, 1989[Medline]
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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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