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Originally published as JCO Early Release 10.1200/JCO.2009.23.8691 on August 10 2009 © 2009 American Society of Clinical Oncology.
Reply to L.C. PanasciUniversity of Alberta, Edmonton, Alberta, Canada
Cross Cancer Institute, Edmonton, Alberta, Canada
Genetic Pathology Evaluation Centre, Vancouver Coastal Health Research Institute, British Columbia Cancer Agency; and University of British Columbia, Vancouver, British Columbia, Canada
Lineberger Comprehensive Cancer Center; and Departments of Genetics and Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC
Inserm U590; Hospices Civils de Lyon; and Université Lyon, Lyon, France
Burnham Institute for Medical Research, La Jolla, CA
Inserm U590; and Centre Léon Bérard, Lyon, France
Cancer International Research Group, Paris, France
sanofi-aventis, Paris, France
Cross Cancer Institute, Edmonton, Alberta, Canada
Hospital Universitario San Carlos, Madrid, Spain
Lynn Cancer Center, Boca Raton, FL We are indebted to Panasci1 for raising the important question of whether treatment with docetaxel, doxorubicin, and cyclophosphamide (TAC) removed the difference in outcomes between luminal B (estrogen receptor [ER] positive and/or progesterone receptor [PR] positive and either human epidermal growth factor receptor 2 [HER2] positive and/or Ki67high) and luminal A (ER positive and/or PR positive and not HER2 positive or Ki67high) patients in our study.2 We must preface our response with the caveat that because we do not have the corresponding genetic analyses of these study patients, this unplanned subset analysis actually became an analysis of Ki-67 in ER-positive patients and should not be interpreted as a gold-standard definition of luminal A and luminal B. To answer this question, we proceeded in a step-wise fashion by first testing for an interaction between the two luminal subgroups and treatment with TAC or fluorouracil, doxorubicin, and cyclophosphamide (FAC) only in patients who received adjuvant tamoxifen after completion of chemotherapy. As listed in Table 1, using a Cox model, there was a statistically significant interaction between luminal type and treatment (P = .0073). A similar result was seen in a model that incorporated an adjustment for proven covariates, including tumor size, overall histologic grade, extensive vascular invasion, and number of involved lymph nodes (data not shown). As expected, the disease-free survival (DFS) of luminal B patients was significantly better with TAC treatment (HR, 0.56; P = .0007). Although the data suggested that luminal A patients treated with tamoxifen seemed to have worse DFS when treated with TAC, this difference was not statistically significant (HR, 2.33; P = .087).
Because the Breast Cancer International Research Group 001 trial protocol did not include trastuzumab, we then defined a modified luminal B population (ie, luminal BHER2neg; ER positive and/or PR positive and Ki67high but not HER2 positive) by removing the HER2-positive patients. Repeating the interaction analysis (Table 1) between treatment and luminal subgroups using the luminal BHER2neg patients, we saw a similar and statistically significant interaction (P = .0063), despite the loss of power that occurred by reducing the sample size. The model run with adjustments for the covariates was also significant (data not shown). To directly compare the DFS of the luminal A and luminal BHER2neg subgroups by treatment, we employed the Cox model with Kaplan-Meier curves (Fig 1). Because the two luminal groups differed in their response to FAC, a comparison of the DFS of luminal BHER2neg and luminal A patient groups treated with FAC yielded a highly significant difference (P = .0007). In contrast, there is, as Panasci1 suggested, no significant difference between the DFS of luminal BHER2neg and luminal A patients treated with TAC (P = .93).
When the DFS of the best treatment response in either group of patients was compared with luminal BHER2neg patients treated with TAC and luminal A patients treated with FAC, we saw a nonsignificant trend (P = .07) for improved DFS in FAC-treated luminal A patients over TAC-treated luminal BHER2neg patients, suggestive of biologic differences in prognosis and benefit from adjuvant therapy in the luminal subgroups. Thus, the answer to the question raised by Panasci1 is that there is a suggestion that TAC treatment in luminal BHER2neg patients results in DFS nearly, but perhaps not completely, equivalent to that of luminal A patients treated with FAC or TAC. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description 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. Employment or Leadership Position: Emmanuelle Magherini, sanofi-aventis (C) Consultant or Advisory Role: Judith Hugh, sanofi-aventis (U); John Mackey, sanofi-aventis (C); Miguel Martin, sanofi-aventis (C) Stock Ownership: Charles Perou, University Genomics; Emmanuelle Magherini, sanofi-aventis Honoraria: John Mackey, sanofi-aventis; Miguel Martin, sanofi-aventis; Charles Vogel, sanofi-aventis Research Funding: Judith Hugh, sanofi-aventis; Torsten Nielsen, sanofi-aventis; Charles Dumontet, sanofi-aventis Expert Testimony: None Other Remuneration: None REFERENCES
1. Panasci LC: Breast cancer subtypes and response to docetaxel in node-positive breast cancer: Use of an immunohistochemical definition in the BCIRG 001 trial. J Clin Oncol 27:e111; 2009. 2. Hugh J, Hanson J, Cheang MC, et al: Breast cancer subtypes and response to docetaxel in node-positive breast cancer: Use of an immunohistochemical definition in the BCIRG 001 trial. J Clin Oncol 27:1168–1176, 2009.
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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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