Tailoring a tailored treatment: the importance of fine-tuning on the patient
Authors: C. Tondini, R. Labianca
Journal: Annals of Oncology (2005)

Until very recently, 5 years of oral tamoxifen has been the standard of care for adjuvant hormonal treatment of post-menopausal women with endocrine-responsive early breast cancer (EBC) [1.Early Breast Cancer Trialists' Collaborative Group. Tamoxifen for early breast cancer: an overview of the randomised trials.Lancet. 1998; 351: 1451-1467Abstract Full Text Full Text PDF PubMed Scopus (3896) Google Scholar, 2.Early Breast Cancer Trialists’ Collaborative Group. Tamoxifen for early breast cancer. Cochrane Database Syst Rev 2001; 1: CD000486.Google Scholar]. Now things are changing. In January of this year [3.Winer E.P. Hudis C. Burstein H.J. et al.American Society of Clinical Oncology technology assessment on the use ofaromatase inhibitors as adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer: status report 2004.J Clin Oncol. 2005; 23: 619-629Crossref PubMed Scopus (770) Google Scholar], the ASCO Technology Assessment Panel issued an updated recommendation on the use of aromatase inhibitors (AIs) in this setting. The Panel's conclusions state that ‘The Panel believes that optimal adjuvant hormonal therapy for a postmenopausal woman with receptor-positive breast cancer includes an aromatase inhibitor as initial therapy or after treatment with tamoxifen. Women with breast cancer and their physicians must weigh the risks and benefits of all therapeutic options.’ This recommendation has been issued on the basis of early data coming from randomised clinical trials comparing different strategies that include an AI in the treatment of these women. Research strategies have ranged from head-to-head comparison of an AI with tamoxifen in the ATAC study [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 (Arimidex Tamoxifen Alone or in Combination) trial efficacy and safety update analyses.Cancer. 2003; 98: 1802-1810Crossref PubMed Scopus (732) Google Scholar] and in the prime core analysis of the BIG1-98 study (B. Thurliman, personal communication), to switching to an AI after 2–3 years of adjuvant tamoxifen in the IES study [5.Coombes R.C. Hall E. Gibson L.J. et al.Intergroup Exemestane Study. A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer.N Engl J Med. 2004; : 3501081-3501092Google Scholar], ABCSG/ARNO study (R. Jakesz, personal communication) and ITA study [6.Boccardo F. Switching trial of adjuvant tamoxifen with an aromatase inhibitor in postmenopausal patients with breast cancer.Clin Breast Cancer. 2004; 5: S13-S17Abstract Full Text PDF PubMed Scopus (10) Google Scholar], to extending treatment with an AI beyond 5 years of tamoxifen in the MA.17 study [7.Goss P.E. Ingle J.N. 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. 2003; 349: 1793-1802Crossref PubMed Scopus (1655) Google Scholar, 8.Goss P.E. Changing clinical practice extending the benefits of adjuvant endocrine therapy in breast cancer.Semin Oncol. 2004; 31: 15-22Crossref PubMed Scopus (7) Google Scholar]. Available data, with a follow-up ranging from 24 to 68 months, are quite consistent with the fact that introducing an AI in the adjuvant treatment of these women at any of the tested time points (at the beginning or after 5 or fewer years of adjuvant tamoxifen) can significantly improve outcome, mainly event-free and recurrence-free survival. Significant improvements in overall survival have yet to emerge, with the exception of a pre-defined subgroup analysis of N+ patients in the MA.17 study [8.Goss P.E. Changing clinical practice extending the benefits of adjuvant endocrine therapy in breast cancer.Semin Oncol. 2004; 31: 15-22Crossref PubMed Scopus (7) Google Scholar]. Relative risk reductions for relapse (including distant relapse) have ranged from approximately 25% to 40%, with absolute risk reductions in the range 2.5%–4.9%. But a better anti-tumour activity was not the only benefit expected with AIs. From studies in the advanced setting, it was clear that AIs lack some of the most bothering and life-threatening toxicity of tamoxifen, namely the endometrial toxicity (including second cancers) and the pro-thrombotic effect. On the other hand, some oestrogen deprivation effects were likely to emerge, and they did. These include musculoskeletal and joint symptoms (polyarthralgia, muscle pain), osteoporosis with increased fracture risk, and possibly vaginal discomfort (mainly dryness, as opposed to vaginal discharge or bleeding typical of tamoxifen). Therefore, all prospective studies have been designed to monitor pre-specified toxicities, including hot flushes, nausea and vomiting, diarrhoea, mood disturbances, arthralgia, vaginal bleeding or discharge, endometrial thickening and endometrial cancer, osteoporosis and fractures, venous thrombo-emebolic events, cardiovascular or cerebrovascular ischaemic events, cataracts. All randomised comparisons confirm that, apart from a significantly increased percentage of musculoskelatal complaints and a clear pro-osteoporotic effect of all AIs with a potential detrimental effect on the incidence of osteoporotic bone fractures, the overall tolerability profile is in favour of AIs. Overall, serious adverse events (SAE) and study withdrawal due to SAE have been more common with tamoxifen than with aromatase inhibitors. However, we must not forget that net results observed in a large population of subjects may be the result of a mixture of great benefit, smaller benefit, no benefit and, possibly, some detrimental effect. The final effect (nil, benefit or detriment) observed in a study is a result of different effects obtained in subgroups of patients that might respond differently to study treatments. Subgroup analysis is a dangerous attitude, accepted to some extent when predefined in the study design [9.Brookes S.T. Whitley E. Peters T.J. et al.Subgroup analyses in randomised controlled trials: quantifying the risks of false-positives and false-negatives.Health Tech Assess. 2001; 5: 1-56Crossref PubMed Scopus (364) Google Scholar]. However, we can attempt not to oversee discordant treatment effects in certain type of patients [10.Bonetti M. Gelber R.D. Patterns of treatment effects in subsets of patients in clinical trials.Biostatistics. 2004; 5: 465-481Crossref PubMed Scopus (141) Google Scholar]. We must remember that when we want to transfer clinical trials finding to our practice, we want to be able to tailor our treatment decision to the patient in front of us and not to a general population [11.Gelber R.D. Bonetti M. Castiglione-Gertsch M. Coates A.S. Goldhirsch A. International Breast Cancer Study Group (IBCSG) Tailoring adjuvant treatments for the individual breast cancer patient.Breast. 2003; 12: 558-568Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar]. At the recent 2005 St. Gallen meeting, investigators from the BIG Collaboration released the first Primary Core Analysis of the BIG1-98 study, namely the head-to-head upfront comparison of letrozole and tamoxifen in the adjuvant treatment of endocrine responsive EBC (data from the switch arms of this study will be available in a few years). Efficacy and tolerability data were well in line with all other studies presented so far. However, investigators also reported a slight excess of non-breast cancer deaths in the letrozole arm (3.1% versus 1.8%). This excess was apparently imputable to an excess in cerebrovascular accidents (7 versus 1) and cardiac accidents (26 versus 13). In this preliminary analysis, detailed information was not available about the precise type of accident (most likely ischaemic) nor of possible related risk factors. Of interest, the average age of patients with vascular accidents was approximately a decade higher than the average age for the whole study (B. Thurliman, personal communication). These data have created some worry. Is this an isolated finding? Maybe not. In the recently updated ATAC study [12.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. 2005; 365: 60-62Abstract Full Text Full Text PDF PubMed Scopus (2017) Google Scholar], the overall better tolerability of anastrozole was confirmed. In this study, however, there was a slight non-significant excess in ischaemic cardiovascular accidents (4.1% versus 3.4%; RR 1.23, 95% CI 0.95–1.6) with anastrozole, but less ischaemic cerebrovascular accidents than with tamoxifen. Both differences did not even approach statistical significance. In the IES study, the authors have reported a slight excess of myocardial infarctions (fatal and non-fatal) in the exemestane group (20 versus eight cases) and an overall excess of non-breast cancer mortality due to cardiac and vascular events (28 versus 19 cases) (R. C. Coombes, personal communication). In this study, although the average age was similar, all myocardial infarctions happened in women with at least one known risk factor. Finally, in the MA.17 study, where letrozole was compared with a no-treatment arm, the incidence of cardiovascular events was no higher for the letrozole arm than for the placebo arm (5.8% versus 5.6%) (P. Goss, personal communication). These data, although worrying, must be interpreted with caution. On one hand, it must be stressed that tamoxifen treatment, although potentially harmful for blood clotting, has been shown to ameliorate the serum lipid profile [13.Wasan K.M. Ramaswamy M. Haley J. et al.Administration of long-term tamoxifen therapy modifies the plasma lipoprotein-lipid concentration and lipid transfer protein I activity in postmenopausal women with breast cancer.J Pharm Sci. 1997; 86: 876-879Abstract Full Text PDF PubMed Scopus (26) Google Scholar, 14.Guetta V. Lush R.M. Figg W.D. et al.Effects of the antiestrogen tamoxifen on low-density lipoprotein concentrations and oxidation in postmenopausal women.Am J Cardiol. 1995; 76: 1072-1073Abstract Full Text PDF PubMed Scopus (61) Google Scholar] and to be potentially useful for coronary artery health [15.Braithwaite R.S. Chlebowski R.T. Lau J. George S. Hess R. Col N.F. Meta-analysis of vascular and neoplastic events associated with tamoxifen.J Gen Intern Med. 2003; 18: 937-947Crossref PubMed Scopus (300) Google Scholar]. In a recent meta-analysis of 31 tamoxifen trials including 52 929 women, tamoxifen significantly decreased myocardial infarction deaths (RR 0.62; 95% CI 0.41–0.93) and was associated with a decrease, although statistically non-significant, in myocardial infarction incidence (RR 0.90; 95% CI 0.66–1.23). It is therefore likely that when comparing with tamoxifen, the lack of a protective effect on the coronary arteries might emerge. In this issue of Annals of Oncology, Wasan et al. [16.Wasan K.M. Goss P.E. Haydn Pritchard P. et al.The influence of letrozole on serum lipid concentrations in postmenopausal women with primary breast cancer who have completed five years of adjuvant tamoxifen NCIC CTG MA.17L. Ann Oncol. 2005; 16: 707-715Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar] report on the results of a lipid metabolism companion protocol in a subgroup of 347 women out of the 5187 patients included in the MA.17 study. After a median treatment time of 2.1 years, in this group of non-hyperlipidemic women after 5 years of adjuvant treatment with tamoxifen, the results of a prospective evaluation on lipid profile have shown only a marginal and non-significant excess of unfavourable lipid profile in the letrozole-treated women at some time points. In other words, in the short term, letrozole does not appear to significantly worsen the unfavourable tamoxifen-withdrawal effect on lipid profile. This is certainly good news, but is it the end of the story? Unfortunately not. As the authors point out, these data apply only to a favourable subset of women who were normolipidemic at treatment initiation and after a prolonged period of favourable tamoxifen effect on the lipid profile, and possibly on their coronary health. They must, therefore, be considered a selected ‘low cardiovascular’ risk subgroup of post-menopausal women compared with the general population as a whole. Furthermore, at the time of the present analysis, the treatment period was relatively short with a median of 2.1 years of treatment and with only a minority of patients exceeding 36 months. Thus, an emerging worry of prolonged treatment with AI may be a potential interaction with the patient's cardiovascular risk. This story has yet to unfold. Although no significant evidence has emerged so far from any of the prospective randomised trials, the relative impact of AI and tamoxifen on coronary artery health might be significantly different. This, of course, does not necessarily mean a direct toxicity of the AIs on the heart, what we observe may be a lack of protective effect of tamoxifen on the baseline cardiovascular risk. This evidence should emerge more from studies of direct comparison between an AI arm and a tamoxifen arm, rather than from the MA.17 study. Although it is becoming indisputable that the overall toxicity profile of AIs is better than tamoxifen as a whole, this might not be true for certain subgroups of women. In the individualised clinical decision-making about appropriate endocrine adjuvant treatment for our post-menopausal patients, we must learn to accurately balance benefits and potential adverse effects of treatment. Therefore, we have a duty to fully evaluate this differential in cardiovascular side-effects. It might well turn out that for certain women (i.e. hystectomised women with cardiovascular risk factors and initial osteoporotic status) the favourable profile of AIs versus tamoxifen might be reversed. Sometimes, average benefits in large populations might induce us to oversee, as a nuisance, uncommon adverse effects. This is wrong, and the recent story about COX-2 inhibitors' cardiovascular toxicity teaches us an important lesson once again [17.Psaty B.M. Furberg C.D COX-2 inhibitors—lessons in drug safety.N Engl J Med. 2005; 352: 1133-1135Crossref PubMed Scopus (225) Google Scholar, 18.Drazen J.M COX-2 inhibitors—a lesson in unexpected problems.N Engl J Med. 2005; 352: 1131-1132Crossref PubMed Scopus (172) Google Scholar]. In the AIs story that is now being written, we must evaluate whether the benefit of using an AI as opposed to tamoxifen may vary widely across different patient populations. Tailoring decisions about adjuvant hormonal therapy requires an understanding of disease and patient characteristics that can play a role [11.Gelber R.D. Bonetti M. Castiglione-Gertsch M. Coates A.S. Goldhirsch A. International Breast Cancer Study Group (IBCSG) Tailoring adjuvant treatments for the individual breast cancer patient.Breast. 2003; 12: 558-568Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar]. Interaction between AIs, tamoxifen and cardiovascular risk has not been clarified yet. All ongoing studies should make an effort to carefully evaluate all retrospective and long-term prospective evidence of cardiovascular morbidity and mortality. Certainly, the short-term lack of unfavourable effects of letrozole on lipid-profile helps us to hope for the best.