Cancer Australia

Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 100-month analysis of the ATAC trial

September, 2008

Commentary by Dr Jacquie Chirgwin

The article

The Arimidex, Tamoxifen, Alone or in Combination (ATAC) Trialists’ Group. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 100-month analysis of the ATAC trial. Lancet Oncol 2008;9(1):45-53

Reviewer

Dr Jacquie Chirgwin is a medical oncologist at the Box Hill Hospital and Maroondah Hospital, Victoria.

Summary

Abbreviations

Aromatase Inhibitor (AI); Arimidex, Tamoxifen, Alone or in Combination (ATAC); Confidence Interval (CI); Contralateral Breast Cancer (CBC); Disease-Free Survival (DFS); Hazard Ratio (HR); Incidence Rate Ratios (IRR); Overall Survival (OS); Time To Distant Recurrence (TTDR); Time To Recurrence (TTR)

Study design

The ATAC trial is a randomised controlled trial comparing anastrozole and tamoxifen for treatment of breast cancer in postmenopausal women. The trial includes a total of 6241 women (intention to treat population) of which 5216 had hormone receptor-positive breast cancer (anastrozole n=2618; tamoxifen n = 2598). This article reports long-term results of the trial, with a median follow-up of 100 months (range 0–126 months). The primary outcome was disease-free survival (DFS) and safety and tolerability. Secondary outcomes included contralateral breast cancer (CBC), overall survival (OS), time to recurrence (TTR), time to distant recurrence (TTDR) and time to breast cancer death. Adverse events were also reported (N=6186 for safety analysis).

Findings

Those treated with anastrozole had a significant improvement in DFS, TTR, TTDR and CBC compared to those treated with tamoxifen, see Table 1. No statistically significant difference in the number of deaths between the treatment groups was reported.

Table 1. Results of ATAC trial

The lower recurrence rate for anastrozole compared to tamoxifen was maintained after treatment was finished. At 5 years, the absolute DFS benefit (absolute difference) among the hormone receptor-positive population was 2.8% (HR: 0.77; 95% CI: 0.65,0.91; p=0.002) and at 9 years the absolute benefit increased to 4.8% (HR: 0.76; 95% CI: 0.67, 0.87; p=0.0001).

While undergoing treatment, patients in the anastrozole arm had higher rates of fracture episodes compared to those on tamoxifen (IRR: 1.55; 95% CI: 1.31, 1.83; p<0.0001) however this association disappeared once treatment was stopped (IRR: 1.03, 95% CI: 0.81, 1.31; p=0.79).

Conclusion

This study shows long-term efficacy of anastrozole compared with tamoxifen as initial adjuvant treatment for postmenopausal women with hormone receptor-positive, early breast cancer, in terms of DFS and TTDR but not overall survival. In addition, a significant ‘carryover’ effect of anastrozole was demonstrated.

Commentary

The recent ATAC update, in the Lancet Oncology, concludes with the following statement: “The current analysis, at a median follow up of 100 months, extends and strengthens the evidence for the use of 5 years of anastrozole as initial adjuvant endocrine treatment for postmenopausal women with hormone receptor positive breast cancer.” I have to disagree.

The report provides very little data to extend or strengthen the argument for initial use of anastrazole as adjuvant treatment. Although the data does support anastrozole as an option for initial adjuvant endocrine treatment, the longer follow up disappointingly has not provided any new evidence to support this as the preferred or best option, and has provided few answers to the outstanding questions which surround endocrine adjuvant treatment in this patient population. The new report does however provide reassurance that the increased loss in bone density ceases once the anastrazole is ceased, although it appears that there is a “carry over” therapeutic effect after treatment cessation, as there is for tamoxifen.

What does this article add to existing clinical evidence in this area?

A median of over 8 years of follow up is reported in this article. This includes information on over 6,000 women and over 46,000 women-years of follow up. Despite the large amount of data available, few of the unanswered questions posed by the NBCC Recommendations for Aromatase inhibitors as adjuvant endocrine therapy¹ have been addressed by this additional analysis.

There are, however, some things that are clear:

1. The study confirms a significant DFS benefit of anastrozole over tamoxifen.
2. The size of the DFS benefit has increased (since the time point when the anastrozole and tamoxifen were ceased) from 2.8% to 4.8% indicating a “carryover” effect, as has been demonstrated previously for tamoxifen.²
3. There is a statistically significant improvement in Time To Distant Relapse (TTDR), although there is no increase in Overall Survival (OS), and very likely never will be. This may in part be due to the average age of the population (72 years), for whom competing causes of death are significant.
4. There is no statistical difference in risk of death.
5. The risk of predefined SAE’s are reduced for anastrozole compared to tamoxifen.
6. Although the fracture rate is increased by 55% during treatment with anastrozole, this increased risk disappears once treatment is completed.
7. There appears to be no increase in ischaemic heart disease on anastrozole.
8. The risk of CVA is greater on tamoxifen than anastrozole.

How adequate was the methodology used in addressing the aim of the study?

This is one of the largest adjuvant trials undertaken (and was the largest at the time it was initially reported). However there are some aspects of the methodology which may influence interpretation.

Firstly, the study contains more than 16% of patients with hormone receptor-negative disease or unknown hormone receptor status, and hormone receptor positive status has not been centrally verified for the analysis. It is known that hormone receptor status is not consistently reproducible on local testing.³ Aromatase inhibitors are only effective in patients with hormone receptor-positive breast cancer.

Secondly, there is no information presented on endocrine treatment after relapse. It would be interesting to investigate the duration and identity of all endocrine treatment during the course of each patient’s breast cancer. This would include the capture of details of any extended adjuvant endocrine treatments these patients may have received, which is also not reported. These details may have an impact on outcomes, especially overall survival.

What are the implications of this study for clinical practice in Australia?

In Australia a considerable proportion of patients would receive upfront adjuvant treatment with aromatase inhibitors. This is despite the lack of an overall survival advantage for this approach. The lack of OS benefit also technically means that there can be no real determination of cost:benefit ratio, despite what has been published.^4,5 There is a demonstrated OS benefit for the strategy of switching treatment from tamoxifen to an aromatase inhibitor after 2-3 years.^6,7 However the ATAC study provides no additional information on the relative merits of these two approaches despite claiming to add further evidence for the upfront use of AIs.

The results indicate that patients who do not receive upfront AI are not more likely to die overall. However there are slightly more deaths numerically attributed to breast cancer on tamoxifen (for hormone receptor-positive patients, 269 vs 245). Anastrozole treated patients appear to have numerically more deaths from non-breast cancer causes. There were 242 deaths for tamoxifen and 279 for anastrozole – a 15% increase (although this is only 8% if only hormone receptor-positive patients are included). However this difference was not statistically significant.

More information will be available for guiding clinical decisions when the BIG 1-98 adjuvant letrozole reports results for the sequence arms. Results from TransATAC studies are awaited and may deliver the information needed to identify proteomic or genomic markers that will allow us to focus the use of anastrozole on those who will really benefit from it. It is quite possible still, that tamoxifen may be superior for some patients and AIs superior for others (and the difference may be as straightforward as CYP2D6 phenotype⁸). For many patients, delaying recurrence is a valuable outcome, and it is reasonable to assume that upfront AI is valuable for this purpose, although it has not been shown to improve overall survival. Many factors will need to be taken into consideration when discussing AIs with patients, including patient preferences, cost and side effects.

References

1. National Breast Cancer Centre. Recommendations for aromatase inhibitors as adjuvant endocrine therapy for post-menopausal women with hormone receptor-positive early breast cancer. Camperdown, NSW: NBCC, 2006.

2. Early Breast Cancer Trials Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for Early Breast Cancer on recurrence and 15 year survival: an overview of the randomized trials. Lancet 2005;366(9472):1687-717.

3. Francis GD, Dimech M, Giles L, Hopkins A. Frequency and reliability of oestrogen receptor, progesterone receptor and HER2 in breast carcinoma determined by immunohistochemistry in Australasia: results of the RCPA Quality Assurance Program. J Clin Pathol 2007;60(11):1277-83. Epub 26 Jan 2007.

4. Mansel R, Locke G, Fallowfield L, et al. Cost Effectiveness analysis of Anastrozole vs.Tamoxifen in adjuvant therapy for early stage breast cancer in the UK: the 5 year completed treatment analysis of the ATAC trial. Br J Cancer 2007;97(2):152-61.

5. Tannock IF. Can we afford the future: effectiveness or cost effectiveness as the criterion for introducing new therapies for breast cancer. European Breast Cancer Conference, April 2008, Abstract 1, EJC 6(7):51.

6. Coombes RC, Kilburn LS, Snowden CF, et al. Intergroup Exemestane Study Survival and safety of Exemestane versus Tamoxifen after 2-3 years Tamoxifen treatment (IES): a randomized controlled trial. Lancet 2007;369(9561):559-70.

7. Jonat W, Gnant M, Boccardo F, et al. Effectiveness of switching from adjuvant Tamoxifen to Anastrozole in postmenopausal women with hormone sensitive early stage breast cancer: a meta-analysis. Lancet Oncology 2006;7(12):991-6.

8. Punglia R, Burstein H, Winer E, Weeks, J. Pharmacogenomic Variation of CYP2D6 and the Choice of Optimal Adjuvant Endocrine Therapy for Postmenopausal Breast Cancer: A modelling Analysis. J Natl Cancer Inst 2008;100:642-8

acknowledgement

National Breast and Ovarian Cancer Centre (NBOCC) acknowledges the contributions of Associate Professor Fran Boyle, member of NBOCC’s Board of Directors, and Dr Catherine Shannon, member of NBOCC’s Clinical Expert Advisory Panel, in reviewing this issue of Clinical Update – Breast Cancer.

Editor: Alison Pearce, Program Manager, National Breast and Ovarian Cancer Centre.
Editorial Committee: Mr John Collins - Surgeon, Ms Jo Keyser - Specialist Breast Nurse, Dr Warwick Lee - Radiologist, A/Prof Liz Lobb – Senior Research Fellow, Dr Sue-Anne McLachlan - Medical Oncologist, Dr Sally Meade - Breast Surgeon, Dr Sue Pendlebury - Radiation Oncologist, A/Prof Martin Stockler - Medical Oncologist.

Disclaimer

Clinical Update - Breast Cancer is produced by National Breast and Ovarian Cancer Centre (NBOCC) and is intended to provide health professionals with timely expert commentary on new research in breast cancer. Commentaries included in Clinical Update - Breast Cancer do not replace recommendations included in NBOCC clinical practice guidelines.

Information contained in Clinical Update - Breast Cancer is not intended to be used as substitute for an independent health professional's advice. NBOCC does not accept any liability for any injury, loss or damage incurred by use of or reliance on the information contained in Clinical Update - Breast Cancer. NBOCC develops material based on the best available evidence however cannot guarantee and assumes no legal liability or responsibility for the currency or completeness of the information.