Disseminated tumor cells and the risk of locoregional recurrence in ...

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Jun 25, 2009 - Results: BM DTCs were detected in 94 of 621 stage I–III breast cancer ... In early-stage breast cancer patients, ..... Slade MJ, Coombes RC.
original article

Annals of Oncology 20: 1836–1841, 2009 doi:10.1093/annonc/mdp200 Published online 25 June 2009

Disseminated tumor cells and the risk of locoregional recurrence in nonmetastatic breast cancer F.-C. Bidard1 , Y. M. Kirova2 , A. Vincent-Salomon3, S. Alran4, Y. de Rycke5, B. Sigal-Zafrani3, X. Sastre-Garau3, L. Mignot1, A. Fourquet2 & J.-Y. Pierga1,6* Departments of 1Medical Oncology; 2Radiation Oncology; 3Pathology; 4Surgery; 5Statistics, Institut Curie, Paris, France and 6University Paris Descartes, Paris, France

Received 26 December 2008; revised 6 March 2009; accepted 9 March 2009

original article

Background: In early breast cancer patients, bone marrow (BM)-disseminated tumor cells (DTCs) were associated with distant metastasis and locoregional recurrence. Our aim was to determine whether BM DTC detection could be related to specific locoregional dissemination of cancer cells, according to radiotherapy volumes. Patients and methods: The relationship between locoregional recurrence-free survival (LRFS) and DTC detection was evaluated according to the various locoregional volumes irradiated after surgery. Results: BM DTCs were detected in 94 of 621 stage I–III breast cancer patients (15%) and were not associated with axillary node status. Eighteen patients (2.9%) experienced locoregional recurrence (median follow-up 56 months), of whom eight (44%) were initially BM DTC positive. BM DTC detection was the only prognostic factor for LRFS [P = 0.0005, odds ratio = 5.2 (2.0–13.1), multivariate analysis]. In BM DTC-positive patients, a longer LRFS was observed in those who were given adjuvant hormone therapy (P = 0.03) and radiotherapy to supraclavicular nodes (SCNs)/internal mammary nodes (IMNs) (P = 0.055) (multivariate analysis; interaction test: P = 0.028). Conclusions: The presence of DTC in BM may be associated with a different pattern of locoregional cancer cell dissemination and influences LRFS. The possible reseeding of the primary cancer area by DTC could be prevented by systemic hormone therapy but also by SCN/IMN irradiation. Key words: bone marrow micrometastasis, breast cancer, disseminated tumor cells, internal mammary nodes, locoregional recurrence

background Hematogenous dissemination can occur independently or after initial lymphatic spread: cancer cells can then be detected in blood as circulating tumor cells and in bone marrow (BM) as disseminated tumor cells (DTCs) (also called micrometastasis) [1]. In early-stage breast cancer patients, circulating tumor cell detection has been reported to be associated with a poorer prognosis [2]. However, some technical issues remain unresolved [3]. In all studies conducted with an adequate detection method, BM DTC had an independent impact on metastasis-free and overall survival of early breast cancer patients [4, 5]. BM DTC could reflect a more advanced metastatic process and their detection may be a more reliable marker of the risk of metastatic relapse. In the prospective Institut Curie breast cancer micrometastasis series, BM DTC detection was also an independent prognostic factor for locoregional recurrence-free survival (LRFS) [6]. *Correspondence to: Prof. J. Y. Pierga, Institut Curie, 26 rue d’Ulm, 75005 Paris, France. Tel: +33-01-44-32-42-07; Fax: +33-01-53-10-40-41; E-mail: [email protected]  

Both authors contributed equally to this work.

Prevention of these locoregional recurrences is the major purpose of adjuvant radiotherapy. Ionizing radiation can be delivered to several ipsilateral areas: breast (or chest wall after mastectomy), axillary lymph nodes, supraclavicular nodes (SCNs) and internal mammary nodes (IMNs). Following breast-conserving surgery for early breast cancer, breast irradiation significantly decreases the rate of in-breast local recurrence (LR) [7–9]. The benefit of adjuvant radiotherapy to the chest wall has been controversial for many years. However, recently published data show that radiotherapy regimens produced moderate but definite reductions not only in breast cancer mortality but also overall mortality [7, 8]. Apart from the main dissemination route which involves axillary lymph nodes and SCNs, some authors have reported that cancer cell dissemination to the IMNs occurs in up to 20% of patients with operable breast cancer and affects the long-term survival [7, 9]. However, IMN irradiation remains controversial due to its potential toxicity. The purpose of this study was to evaluate the role of radiotherapy in preventing LR in patients, according to their BM DTC status.

ª The Author 2009. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]

original article

Annals of Oncology

patients and methods Accrual in the Breast Cancer Micrometastasis Project was open at the Institut Curie (Paris, France) from November 1998 to September 2005. Patient characteristics were recorded prospectively in Institut Curie medical files. The eligibility criteria for the study were female patients over the age of 18 with histologically proven nonmetastatic adenocarcinoma of the breast, no previous malignancy other than treated in situ carcinoma of the cervix or nonmelanoma skin cancer and no bilateral breast cancers. The routine diagnostic work-up included bilateral mammography, tumor biopsy, chest X-rays, abdominal ultrasound, bone scan, blood sampling and clinical examination. Apart from the usual tumor characteristics, HER2 status was not taken into account in our study as it was assessed retrospectively at metastatic relapse. All samples were obtained with the patient’s written informed consent, after approval by the regional ethics committee. Surgery, radiotherapy, chemotherapy and hormone therapy were delivered according to the institutional guidelines. BM sampling (iliac crest or sternum aspirates were done before the surgery or before the start of a neoadjuvant chemotherapy), processing and mononuclear cell staining using the pancytokeratin mAb A45-B/B3 (Micromet, Munich, Germany and Chromavision, San Juan, CA) have been described previously [6, 10]. BM aspirates were classified by a trained pathologist according to the results of the European Working Group for standardization of tumor cell detection: cytokeratin-positive cells with atypical cytology features were the only cells to be classified as BM DTC. The results of the analysis remained unknown to both patients and clinicians. Neoadjuvant chemotherapy was allowed. During surgery, axillary lymph node dissection was carried out with radical modified mastectomy and also when lymph nodes were clinically involved and/or after a positive sentinel lymph node biopsy. Tumor-free margins had to be at least 3 mm. After surgery, adjuvant chemotherapy and/or hormone therapy was delivered when recommended by institutional guidelines. Adjuvant and neoadjuvant chemotherapy were based on anthracycline regimens for all patients: FEC100 regimen [5-fuorouracil (5-FU) 500 mg/m2, epirubicin 100 mg/m2 and cyclophosphamide 500 mg/m2 on day 1, every 21 days] or FAC60 regimen (5-FU 500 mg/m2, doxorubicin 60 mg/m2 and cyclophosphamide 500 mg/m2). High-risk patients (node-positive or locally advanced tumors) also received docetaxel (Taxotere, Sanofi-Aventis, Paris, France). Radiotherapy was delivered after surgery using high-energy photons of a cobalt unit and/or linear accelerator. Normofractionated radiotherapy delivered a total dose of 50 Gy to the whole breast and/or chest wall in 5–6 weeks (five fractions per week, 25 fractions) followed, when indicated, by a boost to the tumor bed. Radiotherapy complied with the recommendations of reports 29 and 50 of the International Commission on Radiation Units [11]. After breast-conserving surgery, a standard tangential field technique or a previously reported isocentric lateral technique [12] was used. Post-mastectomy adjuvant irradiation was indicated for lymph node-positive tumors at initial presentation, tumors >40 mm, clinically multiple tumors and vascular invasion and young patients. The prescribed dose was 50 Gy in 25 fractions to the chest wall. When regional lymph node irradiation was indicated (mostly for patients with axillary node involvement), SCNs and axillary regions were treated by photons, whereas the IMN region was treated by a mixed photon-electron technique. The axilla was irradiated only in cases with massive lymph node involvement (>50% after axillary lymph node dissection). This technique and the limits of IMN and SCNs have been previously described [13, 14]. During follow-up, clinical examination was carried out every 6 months with annual bilateral mammography at the Institut Curie. For this study, LR was defined as ipsilateral recurrence of the breast or chest wall; regional recurrence (RR) was defined as lymph node (axillary, supraclavicular or IMN) recurrence in irradiated and nonirradiated regions. All recurrences

Volume 20 | No. 11 | November 2009

had to be proven histologically. Metastasis-associated locoregional tumor growth, i.e. locoregional tumor growth occurring after or concurrently (