Annals of Oncology Advance Access originally published online on September 13, 2006
Annals of Oncology 2007 18(1):202-203; doi:10.1093/annonc/mdl306
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© 2006 European Society for Medical Oncology
letters to the editor |
High-dose chemotherapy for triple negative breast cancer
1 Istituto Oncologico Romagnolo, Department of Oncology and Hematology, Santa Maria delle Croci Hospital, Ravenna
2 Istituto Oncologico Romagnolo, Department of Oncology, Pierantoni Hospital, Forli, Italy
* (E-mail: ugo_degiorgi{at}yahoo.com)
Triple negative (HER2-negative and hormone receptors negative) breast carcinomas are biologically aggressive [1]. It has been suggested that they respond to chemotherapy better than other types of breast cancer, but prognosis remains very poor, if treated by conventional chemotherapy [1].
In a study recently published in Annals of Oncology, Rodenhuis et al. [2] updated and reanalysed results of a prospective randomised trial that compared five courses of FEC (fluorouracil, epirubicin and cyclophosphamide) with four courses of the same regimen followed by a single shot of high-dose chemotherapy (HDC) with cyclophosphamide (6 g/m2), thiotepa (480 mg/m2) and carboplatin (1600 mg/m2) in high-risk breast cancer showing that HER2-negative tumours benefited from HDC, while HER2-positive tumours did not. They examined the results in HER2-negative patients with negative hormone receptors (triple negative tumours) showing that the advantage for the HDC arm is as large as in HER2-negative receptor-positive patients, where an endocrine effect could have contributed to the benefit of HDC due to a major number of women becoming post-menopausal in the HDC arm. However, authors concluded that a subgroup of breast cancer exists ‘that is specifically sensitive to high-doses of alkylating agents, mainly characterized by the absence of HER2 amplification’, even if the endocrine-related confounding effect of HDC in positive hormone receptor patients needs to be considered.
A retrospective analysis of the WSG AM 01 randomised trial has recently been presented that tried to identify patient subgroups with maximum benefit from HDC [3]. The study compared two courses of accelerated epirubicin and cyclophosphamide (EC) followed by two courses of a HDC consisting of standard-dose epirubicin (90 mg/m2) and high doses of cyclophosphamide (3 g/m2) and thiotepa (400 mg/m2) with a dose-dense conventional regimen consisting of four identical cycles of EC followed by three cycles of accelerated cyclophosphamide, methotrexate and fluorouracil (CMF) in patients with more than nine positive lymph nodes. The largest benefit from HDC was reported for younger patients with triple negative tumours. Most of these patients could be attributed by K-means clustering to basal-like type and an undefined proliferative group characterised mainly by the absence of specifying markers.
Although retrospective analyses, both studies showed the efficacy of HDC chemotherapy based on cyclophosphamide and thiotepa in triple negative tumours.
In a phase II feasibility study, we investigated a high-dose dense chemotherapy regimen consisting of a mobilising course with epirubicin and paclitaxel plus filgrastim, followed by three HDC courses with epirubicin (150 mg/m2), preceded by dexrazoxane and paclitaxel (400 mg/m2) every 16–19 days in high-risk breast cancer patients. Overall, 58 of 70 enrolled patients [median age 51 years (range 34–60), median number of positive nodes 15 (range 4–38)] were evaluated for HER2 status by IHC. HER2 positivity, scored as 3+, was observed in 17 cases (29%), while HER2 negativity, scored as 0, 1+ and 2+, was observed in 41 cases (71%). After a median follow-up time of 36 months from surgery (range 18–76 months), a continuously disease-free status was reported in nine of 17 (53%) patients with HER2-positive tumours and 28 of 41 (68%) with HER2-negative tumours. Within the latter subgroup, a disease-free status was reported in six of 10 (60%) patients with negative hormone receptors (triple negative tumours) and 22 of 31 (71%) with positive hormone receptors. Our preliminary results with high-doses of epirubicin and paclitaxel must be considered with caution because of selection bias, small number of patients, short follow-up period and the absence of FISH testing. However, to date our data in triple negative tumours appear similar to those reported in other series with conventional doses of these drugs [1]. Tumours with topoisomerase II
(TOP2A) gene amplification are more sensitive to epirubicin escalated-dose and dose-intensity [4]. However, TOP2A amplification occurs only in 30%–40% of tumours with HER2 amplification, while it is reported in 1%–10% of HER2-negative tumours [4, 5]. It is then possible that epirubicin escalated-dose and dose-intensity could not contribute to the benefit of HDC regimens in the largest part of triple negative breast cancer.
Rodenhuis et al. concluded that ‘for HER2-negative tumours, HDC should remain the subject of clinical studies’. We feel that their results and recent data including gene expression profiles suggest that HDC based on alkylating agents could be effective in triple negative tumours and needs more investigation in this subset of breast cancer.
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1. Brenton JD, Carey LA, Ahmed AA, Caldas C. (2005) Molecular classification and molecular forecasting of breast cancer: ready for clinical application? J Clin Oncol 23:7350–7360.
2. Rodenhuis S, Bontenbal M, van Hoesel QGCM, et al. (2006) Efficacy of high-dose alkylating chemotherapy in HER2/neu-negative breast cancer. Ann Oncol 17:588–596.
3. Nitz UA, Gluz O, Herr A, et al. (2006) Retrospective analysis of WSG AM01 tandem high dose chemotherapy trial in high risk primary breast cancer: A hypothesis generating study. Proc Am Soc Clin Oncol 24:665 (Abstr).
4. Tanner M, Isola J, Wiklund T, et al. (2006) Topoisomerase II alpha 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 24:2428–2436.
5. Knoop AS, Knudsen H, Balslev E, et al. (2005) Retrospective analysis of topoisomerase IIa amplifications and deletions as predictive markers in primary breast cancer patients randomly assigned to cyclophosphamide, methotrexate, and fluorouracil or cyclophosphamide, epirubicin, and fluorouracil: Danish Breast Cancer Cooperative Group. J Clin Oncol 23:7483–7490.
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