Chemotherapy plus tamoxifen better than tamoxifen alone for postmenopausal women at high-risk of breast cancer relapse

December 10, 2009

Addition of chemotherapy to standard tamoxifen treatment for postmenopausal women with node-positive* breast cancer significantly improves disease-free survival, and this benefit is maximised when the tamoxifen follows chemotherapy. These are the conclusions of an Article published Online First (www.thelancet.com) and in an upcoming edition of The Lancet, by Professor Kathy S Albain, Cardinal Bernadin Cancer Center, Loyola University Chicago Stritch School of Medicine, Maywood, IL, USA, and colleagues.

A second Article by Professor Albain and colleagues, published at the same time Online First in The Lancet Oncology, shows that a commonly-used prognostic test (the 21-gene recurrence assay) can predict whether these patients (from the same study) will benefit from the addition of chemotherapy to tamoxifen--and find that those with a high recurrence score are more likely to benefit from adjuvant chemotherapy, while those with low scores might not benefit--which could save these patients from the toxic effects of chemotherapy.

The Lancet Oncology study is being presented at the CTRC-AACR San Antonio Breast Cancer Symposium, TX, USA, at the embargo time above. The Lancet study will also be mentioned during this presentation.

The Lancet study gives the 10-year results of a phase 3, randomised trial (SWOG-8814), which assessed postmenopausal women with hormone-receptor positive, node-positive breast cancer. Two main objectives were tested. The primary outcome was whether disease free survival was longer with chemotherapy (cyclophospamide, doxorubicin, and fluorouracil [CAF]) given every four weeks for six cycles, plus 5 years of daily tamoxifen than with tamoxifen alone; and whether disease free survival was longer with CAF followed by tamoxifen (CAF-T) than with CAF plus concurrent tamoxifen (CAFT). Secondary endpoints were overall survival and toxicity. Patients were assigned to the tamoxifen only, CAF-T, and CAFT groups in a ratio of 2:3:3.

The researchers found that of 1588 randomised women, 1477 (95%) were eligible for the final analysis. After a maximum follow-up of 13 years (median 9 years), at 10 years 60% of women treated with CAF-T were free of recurrence or death due to any cause, compared with 53% on CAFT and only 48% on tamoxifen alone. The proportions of women alive at 10 years were 68%, 62% and 60%, respectively, for CAF-T, CAFT and tamoxifen. An analysis that adjusted for important prognostic factors showed that women in the combined CAF-T/CAFT groups were 24% less likely to experience a breast cancer recurrence or death than those given tamoxifen alone, and 17% more likely to survive. The difference between CAF-T and CAFT was not statistically significant, although the data favoured CAF-T. Various adverse events were more frequent in the chemotherapy groups than the tamoxifen only group. These included depleted white blood cell count (neutropenia), congestive heart failure, leukaemia, and thromboembolism.

The authors say: "We found that adjuvant treatment with a combination of CAF chemotherapy plus tamoxifen significantly improved disease-free survival compared with tamoxifen alone in post-menopausal women with node-positive, hormone-receptor-positive breast cancer. This advantage was greater in women with four or more positive nodes and in younger postmenopausal women--aged under 65 years--although benefit cannot be ruled out for women with one to three positive nodes or for older women."

They add: "The magnitude of benefit for disease-free survival when CAF was added to tamoxifen seemed greater when this drug followed chemotherapy than when it was given concurrently."

They conclude: "We believe that for postmenopausal women with few comorbidities who have a substantial risk of recurrence or death based on the prognostic profile of their tumour, the risk-benefit balance favours anthracycline-based chemotherapy followed by tamoxifen. However, characteristics of the tumour should also be factored into the risk-benefit ratio. This study shows the necessity of long-term follow-up of adjuvant therapies to determine the outcomes of treatment."

In a Comment which accompanies The Lancet paper, Professor Michael Gnant and Professor Guenther G Steger, Medical University of Vienna, Austria, say: "In SWOG-8814 and other adjuvant trials, overall benefit is mainly accounted for by the high-risk subgroup of patients...patients at low risk of relapse might not benefit at all from adjuvant chemotherapy."

They conclude: "'First, do not harm' remains the main principle in medicine. To be able to follow this rule, we need to better understand the biology of breast cancer. The mistake of 'one treatment fits all' can only be ameliorated when we critically review trial designs of adjuvant breast oncology. Selection of precisely defined cohorts for phase 3 trials is necessary, despite pressure to the contrary by scientific ambition, pragmatism, and demands of industry."

In The Lancet Oncology study, Albain and colleagues analysed the effectiveness of the 21-gene recurrence score assay in predicting whether or not node-positive breast cancer patients would benefit from the addition of adjuvant chemotherapy to standard tamoxifen treatment.

The 21-gene recurrence score assay is a test done on breast tumour specimens that analyses important genes that determine the behaviour of an individual cancer and whether the dominant biology of the tumour is aggressive or not. It has been utilised in clinical practice for several years in lymph node negative breast cancer to select which patients need chemotherapy, This is the first study to determine if this test can define a group of women with node-positive disease--for whom the default is to give chemotherapy due to the higher risk--who may not need chemotherapy at all.

Throughout the SWOG-8814 study, patients had the option of having specimens 'banked' for future determination of potential biological markers predictive of prognosis and treatment outcome. The specimens were banked, in effect, a decade before the 21-gene test was discovered. In this study, the effect of recurrence score on disease-free survival was assessed for the CAF-T group versus the tamoxifen only group. A total of 367 specimens were analysed, representing 40% of the patients in these groups.

The researchers found that there was no apparent benefit of chemotherapy to patients in the CAF-T group with a low recurrence score (<18), while those with a high-recurrence score (>31) experienced significant improvements in disease-free survival. The recurrence score-treatment interaction was strongest in the first 5 years of follow-up but its predictive effect lasted for 10 years. Also, the same lack of apparent chemotherapy benefit for lower recurrence scores was observed for women with 1-3 positive nodes as well as those with 4 or more nodes.

The authors conclude: "The recurrence score is prognostic for tamoxifen-treated patients with positive nodes and predicts significant benefit of CAF in tumours with a high recurrence score. A low recurrence score identifies women who might not benefit from anthracycline-based chemotherapy, despite positive nodes."

In a Reflection and Reaction comment which accompanies The Lancet Oncology paper, Dr Fabrice Andre and Dr Suzette Delaloge, Department of Medical Oncology and Unit INSERM U981, Institut Gustave Roussy, Villejuif, France, say that although the 21-gene recurrence score assay is clearly a prognostic tool, more studies are needed to better define its indications. They add that the cost of the kit limits its use in low-income and middle-income countries.
-end-
For Professor Kathy S Albain, Cardinal Bernadin Cancer Center, Loyola University Chicago Stritch School of Medicine, Maywood, IL, USA, please contact Jim Ritter, Media Relations, Loyola University. T) +1 (708) 216-3200 E) jritter@lumc.edu / kalbain@lumc.edu

Professor Michael Gnant, Medical University of Vienna, Austria. T) +43 699 100 65 280 E) michael.gnant@meduniwien.ac.at

Dr Fabrice Andre, Department of Medical Oncology and Unit INSERM U981, Institut Gustave Roussy, Villejuif, France. T) +33 142114371 E) fandre@igr.fr

For The Lancet Article and Comment, see: http://press.thelancet.com/tlalbain.pdf

For The Lancet Oncology Article and Reflection and Reaction, see: http://press.thelancet.com/tloalbain.pdf

Notes to editors: *Node positive breast cancer is breast cancer which has spread to the lymph nodes under the arm.

Lancet

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