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Originally published as JCO Early Release 10.1200/JCO.2008.18.7062 on January 21 2009 © 2009 American Society of Clinical Oncology.
Postmastectomy Radiotherapy: Will the Selective Use of Postmastectomy Radiotherapy Study End the Debate?Department of Radiotherapy, The Netherlands Cancer Institute, Amsterdam, the Netherlands
Department of Clinical Oncology, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom
Department of Radiotherapy, Academic Medical Centre, Amsterdam, the Netherlands
Beatson Oncology Centre, Western Infirmary, Glasgow, United Kingdom
Department of Pathology, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom
University of Edinburgh Endocrine Cancer Unit, Western General Hospital, Edinburgh, United Kingdom
Department of Pathology, Academic Medical Centre, Amsterdam, the Netherlands
Department of Radiation Oncology, Centre Oscar Lambret, Lille and Henri Mondor Hospital, Créteil, University of Paris 12, France
Department of Radiotherapy, Royal Marsden Hospital, Surrey, United Kingdom
Department of Clinical Oncology, Velindre NHS Trust, United Kingdom To the Editor: In their editorial entitled "One to three versus four or more positive nodes and postmastectomy radiotherapy: Time to end the debate," Marks, Zang, and Proznitz1 present the case for postmastectomy radiotherapy (PMRT) in all node-positive breast cancer patients, regardless of the number of affected nodes. However, we do not share their conclusion that the PMRT debate is now closed. Issues to be considered include target volume definition, the local recurrence risk postmastectomy, new estimates of overall survival benefits from PMRT in clinical trials, and new biologic approaches. The first issue is the extent of the target volume for PMRT. In the Gebski et al2 meta-analysis, the criterion to determine an adequate target volume was the inclusion of axillary radiotherapy. Considering the extremely low risk of axillary recurrence after adequate axillary dissection and the fact that the axillary fields are responsible for increasing the toxicity of PMRT (lung, brachial plexus, shoulder function, and arm edema), it is unknown whether full locoregional radiation gives additional benefit beyond chest wall radiation alone.3 In Selective Use of Post Mastectomy Radiotherapy (SUPREMO), a Medical Research Council/European Organisation for Research and Treatment of Cancer Breast International Group (BIG) 2-04 study, the role of postmastectomy chest wall irradiation without inclusion of the regional areas is investigated in the intermediate-risk group (defined as T1N1, T2N1, or T2N0 with grade 3 or vascular invasion).4 This international trial recruits patients from four continents and aims to provide data applicable to the global breast cancer population. Second, locoregional recurrence risks in node-positive patients after mastectomy and current systemic therapies without radiotherapy are no longer as high as those reported by the Early Breast Cancer Trialists' Collaborative Group for women treated several decades ago.5,6 Better attention to surgical technique in the axilla and widespread adoption of adjuvant anthracyclines, taxanes, trastuzumab, and hormonal therapy are responsible for substantial reductions in local recurrence rates.7–16 We estimate the local relapse risk of intermediate-risk patients is currently in the range of 5% to 15%,6 and that further reductions with PMRT may be too small to justify this treatment, especially if cardiac tissue is included in the treatment volume. Third, the authors correctly question the artificial cutoff at four or more positive nodes as an indication for PMRT. Alternatively, nodal ratios which have been shown to have prognostic value might be a more relevant parameter to determine local recurrence risk.17 There is evidence, however, that prognostic indicators such as nodal parameters may not be predictive of the survival effects derived from adjuvant radiotherapy. In addition to the studies mentioned in the Marks et al editorial, studies by other authors, such as the elegant analyses of van de Steene et al,18,19 have demonstrated a consistently greater relative improvement in survival in trials with a better overall survival of the patients, leading to a larger ratio of survival benefit to improvement in local control than the "one in four rule" (one life saved for four local recurrences prevented) derived from the Early Breast Cancer Trialists' Collaborative Group overview.5 Finally, there is accumulating evidence that biologic factors, including genetic alterations and gene expression profiles in the tumor, will be able to predict the response to both adjuvant radiotherapy and chemotherapy. Similar to the concept of the European Organisation for Research and Treatment of Cancer BIG 3-04 trial, known as the Micro-Array In Node-Negative Disease May Avoid Chemotherapy trial,20 which uses molecular genetic analysis of the tumor to select patients who could avoid adjuvant chemotherapy (recently extended to include N1 disease), it is important to identify molecular markers which can guide treatment strategy for adjuvant radiotherapy. One of the most important aspects of the SUPREMO study is the translational research of the TRANS-SUPREMO substudy. Recent data suggest that patients with human epidermal growth factor receptor 2 (HER-2) –positive and basal tumors have a higher risk for locoregional recurrence as compared with luminal A type tumors.21 Kyndi et al22,23 have analyzed the molecular features of tumors in a subgroup analysis of the Danish Breast Cancer Cooperative Group 82 B and C trials. Hormone receptor–negative, HER-2–positive tumors did not seem to benefit from PMRT, whereas the patients with more favorable biologic features had both a lower local relapse rate and a greater improvement in overall survival from PMRT. These observations suggest the biology is more complex than previously appreciated. In the new era of biologic tumor classification, the molecular features of a tumor may provide better discriminators of which patients are likely to benefit from PMRT. However, the trial patients in the Danish studies were not treated with anthracyclines, taxanes, or HER2 inhibition, so we should be cautious to extrapolate the data to current practice. It is critical to evaluate such biologic features in a prospective randomized trial with contemporary systemic therapy to derive in particular prognostic and predictive assays for local recurrence risk and radiosensitivity, respectively.24 We can then move on from 20th-century criteria and paradigms such as nodal status to 21st-century concepts of individual treatment tailoring based on biology. We hope these areas of uncertainty will encourage patients with one to three involved axillary nodes, supported by their surgical, medical and radiation oncologists, to participate in the BIG 2-04 SUPREMO trial.25 AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. REFERENCES
1. Marks LB, Zeng J, Prosnitz LR: One to three versus four or more positive nodes and postmastectomy radiotherapy: Time to end the debate. J Clin Oncol 26:2075–2077, 2008. 2. Gebski V, Lagleva M, Keech A, et al: Survival effects of postmastectomy adjuvant radiation therapy using biologically equivalent doses: A clinical perspective. J Natl Cancer Inst 98:26–38, 2006. 3. Poortmans P: Evidence based radiation oncology: Breast cancer. Radiother Oncol 84:84–101, 2007.[CrossRef][Medline] 4. Kunkler IH, Canney P, van TG, et al: Elucidating the role of chest wall irradiation in ‘intermediate-risk’ breast cancer: The MRC/EORTC SUPREMO trial. Clin Oncol (R Coll Radiol) 20:31–34, 2008.[Medline] 5. Favourable and unfavourable effects on long-term survival of radiotherapy for early breast cancer. An overview of the randomised trials—Early Breast Cancer Trialists' Collaborative Group. Lancet 355:1757–1770, 2000.[CrossRef][Medline] 6. Recht A, Gray R, Davidson NE, et al: Locoregional failure 10 years after mastectomy and adjuvant chemotherapy with or without tamoxifen without irradiation: Experience of the Eastern Cooperative Oncology Group. J Clin Oncol 17:1689–1700, 1999. 7. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival. An overview of the randomised trials. Lancet 365:1687–1717, 2005.[CrossRef][Medline] 8. Coates AS, Keshaviah A, Thurlimann B, et al: Five years of letrozole compared with tamoxifen as initial adjuvant therapy for postmenopausal women with endocrine-responsive early breast cancer: Update of study BIG 1-98. J Clin Oncol 25:486–492, 2007. 9. Coombes RC, Kilburn LS, Snowdon CF, et al: Survival and safety of exemestane versus tamoxifen after 2-3 years' tamoxifen treatment (Intergroup Exemestane Study): A randomised controlled trial. Lancet 369:559–570, 2007.[CrossRef][Medline] 10. Forbes JF, Cuzick J, Buzdar A, et al: Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 100-month analysis of the ATAC trial. Lancet Oncol 9:45–53, 2008.[CrossRef][Medline] 11. Goss PE, Ingle JN, Martino S, et al: Efficacy of letrozole extended adjuvant therapy according to estrogen receptor and progesterone receptor status of the primary tumor: National Cancer Institute of Canada Clinical Trials Group MA.17. J Clin Oncol 25:2006–2011, 2007. 12. Levine MN, Bramwell VH, Pritchard KI, et al: Randomized trial of intensive cyclophosphamide, epirubicin, and fluorouracil chemotherapy compared with cyclophosphamide, methotrexate, and fluorouracil in premenopausal women with node-positive breast cancer: National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 16:2651–2658, 1998.[Abstract] 13. Romond EH, Perez EA, Bryant J, et al: Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 353:1673–1684, 2005. 14. Smith I, Procter M, Gelber RD, et al: 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: A randomised controlled trial. Lancet 369:29–36, 2007.[CrossRef][Medline] 15. Thürlimann B, Keshaviah A, Coates AS, et al: A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med 353:2747–2757, 2005. 16. Ward S, Simpson E, Davis S, et al: Taxanes for the adjuvant treatment of early breast cancer: Systematic review and economic evaluation. Health Technol Assess 11:1–144, 2007.[Medline] 17. Woodward WA, Vinh-Hung V, Ueno NT, et al: Prognostic value of nodal ratios in node-positive breast cancer. J Clin Oncol 24:2910–2916, 2006. 18. Van de Steene J, Soete G, Storme G: Adjuvant radiotherapy for breast cancer significantly improves overall survival: The missing link. Radiother Oncol 55:263–272, 2000.[CrossRef][Medline] 19. Van de Steene J, Vinh-Hung V, Cutuli B, et al: Adjuvant radiotherapy for breast cancer: Effects of longer follow-up. Radiother Oncol 72:35–43, 2004.[CrossRef][Medline] 20. Cardoso F, Van't VL, Rutgers E, et al: Clinical application of the 70-gene profile: The MINDACT trial. J Clin Oncol 26:729–735, 2008. 21. Nguyen PL, Taghian AG, Katz MS, et al: Breast cancer subtype approximated by estrogen receptor, progesterone receptor, and HER-2 is associated with local and distant recurrence after breast-conserving therapy. J Clin Oncol 26:2373–2378, 2008. 22. Kyndi M, Overgaard M, Nielsen HM, et al: High local recurrence risk is not associated with large survival reduction after postmastectomy radiotherapy in high-risk breast cancer: A subgroup analysis of DBCG 82 b&c. Radiother Oncol [epub ahead of print on May 7, 2008]. 23. Kyndi M, Sorensen FB, Knudsen H, et al: Estrogen receptor, progesterone receptor, HER-2, and response to postmastectomy radiotherapy in high-risk breast cancer: The Danish Breast Cancer Cooperative Group. J Clin Oncol 26:1419–1426, 2008. 24. Nuyten DS, Kreike B, Hart AA, et al: Predicting a local recurrence after breast-conserving therapy by gene expression profiling. Breast Cancer Res 8:R62; 2006.[CrossRef][Medline] 25. National Health Service Scotland. MRC Supremo Trial. www.supremo-trial.com.
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Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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