Ann Oncol -- eLetters for Rodenhuis et al., 0 (2006) 11

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original article:
S. Rodenhuis, M. Bontenbal, Q. G. C. M. van Hoesel, W. M. Smit, M. A. Nooij, E. E. Voest, E. van der Wall, P. Hupperets, H. van Tinteren, J. L. Peterse, M. J. van de Vijver, and E. G. E. de Vries for the Netherlands Working Party on Autologous Transplantation in Solid Tumours
Efficacy of high-dose alkylating chemotherapy in HER2/neu-negative breast cancer
Ann Oncol 2006; 0: mdl001v1 [Abstract] [PDF]

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Role of intensified primary chemotherapy in HR-negative and any HER2-status LABC patients.: Maria Teresa Ionta, Francesco Atzori, Bruno Massidda (22 January 2007)

Role of intensified primary chemotherapy in HR-negative and any HER2-status LABC patients. 22 January 2007

Maria Teresa Ionta,
Medical Oncologyst
University of Cagliari, Italy (09100),
Francesco Atzori, Bruno Massidda
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Re: Role of intensified primary chemotherapy in HR-negative and any HER2-status LABC patients.

Hormone receptors (HR) and human epidermal growth factor 2 (HER2) as is well known are the most important predictive factors in breast cancer tumors. HER2-negative tumour with lack of expression of both HR (identified as triple negative phenotype o Basal like-array subtype), as well as HER2-array subtype (mostly HER2-positive/ HR-negative phenotype) carry a poorer prognosis after conventional chemotherapy [1,2] than luminal subtype( mostly HER2-negative/HR-positive), despite their high intrinsic chemosensibility [3]. In a recent retrospective analysis of CALGB group, Berry et al.[4], it has been shown that the benefit of increasing chemotherapy aggressiveness was largely confined to the ER-negative subset of patients. This suggests that both HER2 and Basal-like subtypes could benefit by improvements in chemotherapy [1]. Nevertheless, the use of high-dose chemotherapy in these subsets of patients is viewed with skepticism. The study of Rodhenhuis et al.[5], published in Annals of Oncology in January 2006, updated the results of a prospective trial of 885 stage III primary breast cancer patients (mostly <50 years and HR-positive) who were randomly assigned to receive 5 courses of FE90C (as conventional arm) or 4 courses of the same regimen followed by high-dose chemotherapy (HDC) with cyclophosphamide (6 g/m2), thiotepa (480 mg/m2) and carboplatin (1600 mg/m2), followed by tamoxifen and RT in both arms. At a median follow -up of 87 months, there was a trend for a better relapse-free survival (RFS) in the HDC arm (p=0.076) whereas no significant difference was observed in OS (p= 0.22). Interestingly, only patients with HER2- negative tumors(621) significantly benefited from HDC compared with conventional arm (RFS 71.5% vs. 59,1% p=0.002; OS 78.2% vs. 71.0% p= 0.02 ), whereas patients with HER2-positive tumors did not. Patients with triple negative tumors showed a benefit from the HDC as large as all HER2-negative patients (p= 0.12). We report the results of 50 out of 72 consecutive T4-LABC patients, assessable for both hormone receptor and HER2 by IHC (77 % T4abc; 23 % T4d; 42% ER-negative; 72% PR-negative; 88 % axillary nodes involvement) median age 51 (32-68), 40% <50 years, treated with primary PEV chemotherapy (cisplatin 50 mg/m2; epirubicin 100 mg/m2; vinorelbine 25 mg/m2). The same regimen was administered in two different schedules: a total number of 4 courses once every 3 weeks for the first 19 patients (as standard group) and 6 courses every 2 weeks plus filgrastim for the subsequent 31 patients (as intensified group); the entire treatment for both groups lasted 12 weeks. All 50 patients received adjuvant CMF, RT and tamoxifen ±LH-RH if indicated; 39 out of 50 patients (78%) were HER2- negative, of whom 12 patients ( 31%) were triple negative,13 patients (33%) were HER2-negative/ER-positive/ PR-negative and 14 patients (36%) were HER2-negative/HR-positive;11 out of 50 patients (22%) were HER2- positive, 8 of whom (73%) were HER2-positive/HR-negative.All the subgroups were well balanced in both treatment arms. At a median follow- up of 91 months (range 58-123) a trend for a better DFS was observed in the entire population treated with the intensified regimen compared to the standard regimen (68% vs. 21%),in the HER2-negative (64% vs. 23%) as well as in the HER2-positive (78% vs. 0%).Patients with both HR-negative tumors, irrespective of HER2-status, obtained the higher benefit from dose-dense intensified regimen (p= 0.002); no benefit from intensified regimen was observed for patients with HER2-negative and both HR-positive tumors in terms of either DFS (29% vs. 29%) as well as OS (71% vs 71%).
It is well known that pathological complete remission both in breast and in axilla (pCR) after primary chemotherapy is strongly associated with better outcome and usually is considered as a surrogate marker of survival. In our study overall 10 pCR (20%) have been observed of whom 9 in intensified group (29%) whereas only 1 in standard group (5%). Interestingly, in the intensified group, patients with triple negative tumors had 57% of pCR rate, patients with HER2-negative/ER- positive/PR-negative tumors had 25% of pCR rate, patients with HER2- negative tumors and both HR-positive had 14% of pCR rate; patients with HER2-positive tumors and both HR-negative had 33% of pCR rate. Therefore, both HER2-negative and HER2-positive tumors resulted highly sensible to the intensified chemotherapy treatment, when associated with HR- negative. Our results are consistent with the findings reported by Rouzier et al. [3] that showed a 45% of pCR rate in both basal-like array-subtype (as triple negative) and HER2-array subtype (mostly HR-negative) and only 6% in luminal tumors(mostly HER2-neg,HR-pos) in breast cancer patients treated with anthracycline and taxane-based primary chemotherapy. In multivariate analysis only age <50 years and estrogen-receptor negative status were identified as independent variables associated with higher pCR. Rodenhuis et al.[5] concluded that all HER2-negative tumors, irrespective of HR status, may benefit from high-dose alkylating agents,including,unexpectedly, HER2-negative/HR-positive tumors. The authors explain this finding as an endocrine effect due to ovarian ablation, more common after HDC than after conventional chemotherapy, rather than the direct cytotoxicity of the treatment. If the justification above reported was accepted, should an endocrine therapy with high castration effect be used? In fact, this approach could lead the patients to achieve the same benefit by avoiding the multiple inconveniences of an HDC treatment. In conclusion, we are confident that the use of alkylating agents would yet represent a valid alternative option in the treatment of HER2- negative tumors as described by Pritchard et al.[2] Nevertheless further randomized studies are necessary to confirm the real benefits of HDC in HER2-negative and over-expression of ER and PR receptors.
References
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. Pritchard KJ, Shepherd LE, O’Malley FP et al. (2006) HER2 and responsiveness of breast cancer to adjuvant chemotherapy. National Cancer Institute of Canada Clinical Trials Group NEJM 354(20) :2103- 2111.
3. Rouzier R, Perou CM, SymmansWF et al. (2005) Breast cancer molecular Subtype respond differently to preoperative chemotherapy. Clin Cancer Res 11(16):5678-5685.
4. Berry DA, Cirrincione C, Henderson C et al. (2006) Estrogen-Receptor status and outcomes of modern chemotherapy for patients with node-positive breast cancer. JAMA 295: 1658-1667.
5. 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.
Conflict of Interest:
None declared