Anthracyclines in Early Breast Cancer
http://www.100md.com
《新英格兰医药杂志》
To the Editor: The observation that adjuvant chemotherapy with cyclophosphamide, epirubicin, and fluorouracil (CEF) yielded survival results superior to those obtained with cyclophosphamide, methotrexate, and fluorouracil (CMF) in premenopausal women with stage 2 breast cancer led to widespread implementation of CEF chemotherapy in Canada.1 Pritchard and colleagues (May 18 issue)2 analyzed outcomes according to whether the primary tumor expressed human epidermal growth factor receptor type 2 (HER2) and concluded that amplification of the HER2 gene in breast-cancer cells is associated with clinical responsiveness to anthracycline-containing chemotherapy.2 A more widely applicable conclusion, however, is that for the majority of premenopausal women with stage 2 breast cancer (i.e., those with HER2-negative tumors), chemotherapy with CMF is as effective as chemotherapy with CEF. The authors suggest that future patients with HER2-negative tumors "could" be treated with a less toxic regimen than CEF. Considering the substantially greater acute and long-term toxic effects of CEF3 and the virtual superimposability of the survival curves2 for patients with HER2-negative tumors treated with CEF and such patients who were treated with CMF, the statement by Piccart-Gebhart3 in the accompanying editorial that the results of Pritchard et al. are not likely to influence current clinical practice is perplexing. Why the reluctance to abandon CEF in its present form for these patients?
Kenneth S. Wilson, M.D.
Pacific Oncology Partnership
Victoria, BC V8R 5K4, Canada
kwilsonmd@telus.net
References
Levine MN, Pritchard KI, Bramwell VH, et al. Randomized trial comparing cyclophosphamide, epirubicin, and fluorouracil with cyclophosphamide, methotrexate, and fluorouracil in premenopausal women with node-positive breast cancer: update of National Cancer Institute of Canada Clinical Trials Group MA5. J Clin Oncol 2005;23:5166-5170.
Pritchard KI, Shepherd L, O'Malley FP, et al. HER2 and responsiveness of breast cancer to adjuvant chemotherapy. N Engl J Med 2006;354:2103-2111.
Piccart-Gebhart MJ. Anthracyclines and the tailoring of treatment for early breast cancer. N Engl J Med 2006;354:2177-2179.
The authors reply: Wilson's letter reflects our view of the interpretation and potential implementation of our data. We believe that the comment by Piccart-Gebhart, that these results are not likely to influence current clinical practice, reflected the issue of interpreting these data in an environment in which trastuzumab is now commonly given as adjuvant therapy to all women with tumors that overexpress HER2. We believe that these are two different issues. Piccart-Gebhart et al. reported that in patients who received anthracycline-containing chemotherapy regimens such as CEF; cyclophosphamide, doxorubicin, and fluorouracil; or cyclophosphamide and doxorubicin in the Herceptin Adjuvant (known as HERA) trial,1 the subsequent addition of a year of trastuzumab therapy yielded benefits similar to those found among patients who received other types of chemotherapy. We would interpret these data to suggest that patients who have tumors that overexpress HER2 can obtain relatively greater benefit from CEF than from CMF and can then obtain additional benefit from the subsequent use of trastuzumab. In short, we agree with Wilson.
Kathleen I. Pritchard, M.D.
Toronto Sunnybrook Regional Cancer Centre
Toronto, ON M4N 3M5, Canada
kathy.pritchard@sunnybrook.ca
Vivien H. Bramwell, M.B., B.S.
Tom Baker Cancer Centre
Calgary, AB T2N 4N2, Canada
Mark N. Levine, M.D.
McMaster Medical Centre
Hamilton, ON L8V 1C3, Canada
for the National Cancer Institute of Canada Clinical Trials Group
References
Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 2005;353:1659-1672.
The editorialist replies: The reluctance to abandon adjuvant therapy with CEF in women with HER2-negative breast cancer is based on the following: HER2-negative breast cancer is a heterogeneous disease, the complexity of which has been appreciated only recently in the light of the results of high-throughput gene-expression profiling.1 It is plausible that one subgroup of HER2-negative cancers benefits from anthracyclines. The old way in which our clinical trials were designed does not allow this possibility to be ruled out a posteriori. When one considers the bulk of data correlating HER2 status and the outcome of adjuvant chemotherapy, and not just data from the Canadian trial, a small benefit from anthracyclines in HER2-negative breast cancer cannot be ruled out. New data reinforce the link between aberrations in the topoisomerase II gene and the outcome of adjuvant chemotherapy with anthracyclines. Some of these data originate from the Canadian trial itself.2,3,4 It seems mandatory to dissect this relationship further, since it makes more sense to make treatment recommendations related to the target gene than to a surrogate marker.
Martine J. Piccart-Gebhart, M.D., Ph.D.
Jules Bordet Institute
1000 Brussels, Belgium
References
Sotiriou C, Neo SY, McShane LM, et al. Breast cancer classification and prognosis based on gene expression profiles from a population-based study. Proc Natl Acad Sci U S A 2003;100:10393-10398.
Knoop A, Knudsen H, Balslev E, et al. TOP2A aberrations as predictive and prognostic marker in high-risk breast cancer patients: a randomized DBCG Trial (DBCG89D). J Clin Oncol 2006;24:11s-11s.
O'Malley FP, Chia S, Tu D, et al. Prognostic and predictive value of topoisomerase II alpha in a randomized trial comparing CMF to CEF in premenopausal women with node positive breast cancer (NCIC CTG MA.5). J Clin Oncol 2006;24:11s-11s.
Tanner M, Isola J, Wiklund T, et al. Topoisomerase II gene amplification predicts favorable treatment response to tailored and dose-escalated anthracycline-based adjuvant chemotherapy in HER-2/neu-amplified breast cancer: Scandinavian Breast Group Trial 9401. J Clin Oncol 2006;24:2428-2436.
Kenneth S. Wilson, M.D.
Pacific Oncology Partnership
Victoria, BC V8R 5K4, Canada
kwilsonmd@telus.net
References
Levine MN, Pritchard KI, Bramwell VH, et al. Randomized trial comparing cyclophosphamide, epirubicin, and fluorouracil with cyclophosphamide, methotrexate, and fluorouracil in premenopausal women with node-positive breast cancer: update of National Cancer Institute of Canada Clinical Trials Group MA5. J Clin Oncol 2005;23:5166-5170.
Pritchard KI, Shepherd L, O'Malley FP, et al. HER2 and responsiveness of breast cancer to adjuvant chemotherapy. N Engl J Med 2006;354:2103-2111.
Piccart-Gebhart MJ. Anthracyclines and the tailoring of treatment for early breast cancer. N Engl J Med 2006;354:2177-2179.
The authors reply: Wilson's letter reflects our view of the interpretation and potential implementation of our data. We believe that the comment by Piccart-Gebhart, that these results are not likely to influence current clinical practice, reflected the issue of interpreting these data in an environment in which trastuzumab is now commonly given as adjuvant therapy to all women with tumors that overexpress HER2. We believe that these are two different issues. Piccart-Gebhart et al. reported that in patients who received anthracycline-containing chemotherapy regimens such as CEF; cyclophosphamide, doxorubicin, and fluorouracil; or cyclophosphamide and doxorubicin in the Herceptin Adjuvant (known as HERA) trial,1 the subsequent addition of a year of trastuzumab therapy yielded benefits similar to those found among patients who received other types of chemotherapy. We would interpret these data to suggest that patients who have tumors that overexpress HER2 can obtain relatively greater benefit from CEF than from CMF and can then obtain additional benefit from the subsequent use of trastuzumab. In short, we agree with Wilson.
Kathleen I. Pritchard, M.D.
Toronto Sunnybrook Regional Cancer Centre
Toronto, ON M4N 3M5, Canada
kathy.pritchard@sunnybrook.ca
Vivien H. Bramwell, M.B., B.S.
Tom Baker Cancer Centre
Calgary, AB T2N 4N2, Canada
Mark N. Levine, M.D.
McMaster Medical Centre
Hamilton, ON L8V 1C3, Canada
for the National Cancer Institute of Canada Clinical Trials Group
References
Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 2005;353:1659-1672.
The editorialist replies: The reluctance to abandon adjuvant therapy with CEF in women with HER2-negative breast cancer is based on the following: HER2-negative breast cancer is a heterogeneous disease, the complexity of which has been appreciated only recently in the light of the results of high-throughput gene-expression profiling.1 It is plausible that one subgroup of HER2-negative cancers benefits from anthracyclines. The old way in which our clinical trials were designed does not allow this possibility to be ruled out a posteriori. When one considers the bulk of data correlating HER2 status and the outcome of adjuvant chemotherapy, and not just data from the Canadian trial, a small benefit from anthracyclines in HER2-negative breast cancer cannot be ruled out. New data reinforce the link between aberrations in the topoisomerase II gene and the outcome of adjuvant chemotherapy with anthracyclines. Some of these data originate from the Canadian trial itself.2,3,4 It seems mandatory to dissect this relationship further, since it makes more sense to make treatment recommendations related to the target gene than to a surrogate marker.
Martine J. Piccart-Gebhart, M.D., Ph.D.
Jules Bordet Institute
1000 Brussels, Belgium
References
Sotiriou C, Neo SY, McShane LM, et al. Breast cancer classification and prognosis based on gene expression profiles from a population-based study. Proc Natl Acad Sci U S A 2003;100:10393-10398.
Knoop A, Knudsen H, Balslev E, et al. TOP2A aberrations as predictive and prognostic marker in high-risk breast cancer patients: a randomized DBCG Trial (DBCG89D). J Clin Oncol 2006;24:11s-11s.
O'Malley FP, Chia S, Tu D, et al. Prognostic and predictive value of topoisomerase II alpha in a randomized trial comparing CMF to CEF in premenopausal women with node positive breast cancer (NCIC CTG MA.5). J Clin Oncol 2006;24:11s-11s.
Tanner M, Isola J, Wiklund T, et al. Topoisomerase II gene amplification predicts favorable treatment response to tailored and dose-escalated anthracycline-based adjuvant chemotherapy in HER-2/neu-amplified breast cancer: Scandinavian Breast Group Trial 9401. J Clin Oncol 2006;24:2428-2436.