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Disseminated tumor cells and the risk of locoregional recurrence in nonmetastatic breast cancer
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
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]
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Background: In early breast cancer patients, bone marrow (BM)-disseminated tumor cells (DTCs) were associated
original article
Annals of Oncology
patients and methods
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results Six hundred and twenty-one patients with stage I–III BC were eligible for the study. The median follow-up was 56 months (range 1–100). Patient characteristics, tumor characteristics and locoregional treatments are shown in Table 1. In addition to surgery of the primary tumor and axillary lymph nodes (sentinel lymph node or axillary lymph node dissection), treatment of disseminated cancer cells combined locoregional (radiotherapy) and systemic (chemotherapy and hormone therapy) treatments. Surgical treatment consisted of radical modified mastectomy (27%) or breast-conserving wide tumor excision (73%). Axillary lymph node dissection was carried out in 68% of patients. Ninety-two percent of patients (n = 573) received adjuvant radiotherapy as previously described. Neoadjuvant and adjuvant chemotherapy (mostly anthracycline based) was administered to 19% and 48% of patients, respectively (BM aspiration was carried out at diagnosis before any chemotherapy). Sixty-five percent of patients received endocrine therapy: tamoxifen or aromatase inhibitors (after 2003) were used in hormonal receptor-positive patients according to their menopausal status. As previously reported, the BM DTC detection rate was 15.1% (Table 1). There was no significant association between DTC detection and any of the patient or treatment characteristics, even for axillary lymph node dissemination of cancer cells (P = 0.78, Table 1). The median follow-up was 56 months (range 1–100). Eighteen patients (2.9%) without any previous or concurrent distant metastases experienced locoregional relapse (17 LR and 1 RR). In nine patients, multimetastatic relapse was accompanied by synchronous or metachronous tumor growth in the breast, chest wall or regional lymph nodes: these events were not taken into account in the analysis. Correlations between LRFS and patient characteristics are shown in Table 2. Of note, in the whole population, BM DTC detection was an independent prognostic factor for LRFS on univariate (Figure 1A) and multivariate analysis [P < 0.0001, relative risk 5.1, 95% confidence interval (CI) 2.0–13.0, Table 2]. In BM DTC-positive patients, LRFS was longer when patients received adjuvant hormone therapy (P = 0.03, relative risk 11.5, 95% CI 1.26–106) and radiotherapy to SCN/IMN (P = 0.055, relative risk 4.8, 95% CI 0.97–24.4) on multivariate analysis (Table 3). In contrast, in BM DTC-negative patients, lymphovascular invasion was the only significant prognostic factor for LRFS (P = 0.048, relative risk 3.3, 95% CI 1.1–11.7).
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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
had to be proven histologically. Metastasis-associated locoregional tumor growth, i.e. locoregional tumor growth occurring after or concurrently (<2 months interval) to distant metastases, were not included in this analysis. LRFS time was measured from the date of surgery until the date of LR or RR (or last follow-up). Differences between categorical variables were analyzed by chi-square tests or Fisher’s exact test. LRFS curves were plotted according to the Kaplan–Meier method. Statistical significance between survival curves was assessed using the log-rank test. Multivariate analyses were carried out by the Cox proportional hazards model. To test the main study hypothesis that the therapeutic benefit of different radiotherapy fields may vary according to BM DTC status, an interaction term combining treatment arm and BM DTC status was added to the Cox proportional hazards model. Its significance was tested using a likelihood ratio test.
original article
Annals of Oncology
Table 1. Patient characteristics, treatments and DTC detection rates
Table 2. Patient characteristics, treatments and locoregional recurrence
Characteristic or treatment Number of patients DTC detection rate (%)
Patient characteristic or treatment
103 518
17.5 14.7
321 172 124
17.4 12.2 12.9
295 324
15.6 14.8
514 75 32
14.4 16.0 30.0
203 235 163
14.8 14.9 15.3
495 116
14.3 17.3
412 189
13.6 18.0
527 94
– –
449 165
14.9 15.1
572 48
14.8 18.7
568 42
14.9 21.5
277 332
15.5 15.4
116 496
15.5 15.3
372 237
15.3 15.6
346 275
15.6 14.5
404 210 621
14.8 16.2 15.1
DTC detection rate was not correlated with any patient characteristic or treatment. Due to missing data, some numbers do not add to 621. DTC, disseminated tumor cell; HR status, hormone receptor status (positive when estrogen and/or progesterone receptors were positive); BM, bone marrow; RT, radiotherapy; CW, chest wall; SCN, supraclavicular node; IMN, internal mammary node.
1838 | Bidard et al.
Age (years) <45 ‡45 cT 1 2 3/4 pN 0 1 Histology Ductal Lobular Other Tumor grade 1 2 3 HR status Positive Negative LVI No Yes BM DTC Negative Positive Surgery Lumpectomy Mastectomy RT (all modalities) Yes No Breast/CW RT Yes No Boost RT Yes No Axillary RT Yes No SCN and IMN RT Yes No Chemotherapy Yes No Hormone therapy Yes No
5.8 2.3
0.037
0.079
2.4 4.1 2.4
0.78
Ni
3.4 2.5
0.46
Ni
3.1 2.7 0
0.96
Ni
2.4 2.9 3.7
0.81
Ni
2.6 4.3
0.32
Ni
2.7 3.7
0.50
Ni
1.9 8.5
<0.0001
2.9 3.0
0.98
Ni
2.6 6.2
0.11
Ni
2.6 7.1
0.07
Ni
2.9 3.0
0.93
Ni
2.6 3.0
0.73
Ni
2.7 3.4
0.48
Ni
3.2 2.5
0.83
Ni
2.0 4.7
0.037
0.060
0.0006
2.4 (0.9–6.4)
5.1 (2.0–13.0)
2.4 (0.9–6.2)
CI, confidence interval; Ni, not included in multivariate analysis; HR, hormone receptor; LVI, lymphovascular invasion; BM, bone marrow; RT, radiotherapy; CW, chest wall; SCN, supraclavicular node; IMN, internal mammary node.
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Age (years) <45 ‡45 cT 1 2 3/4 pN 0 1 Histology Ductal Lobular Other Tumor grade 1 2 3 HR status Positive Negative Tumor emboli No Yes BM DTC Negative Positive Surgery Lumpectomy Mastectomy RT (all modalities) Yes No Breast/CW RT Yes No Boost RT Yes No Axillary RT Yes No SCN and IMN RT Yes No Chemotherapy Yes No Hormone therapy Yes No Total
Locoregional Locoregional recurrence-free survival recurrence Univariate Multivariate (%) analysis analysis P value P Relative risk value (95% CI)
Annals of Oncology
A significant interaction test between BM DTC status and SCN/ IMN radiotherapy for LRFS (P = 0.028) confirmed that the impact of SCN/IMN radiotherapy on LRFS was almost restricted to BM DTC-positive patients. Importantly, the site of BM aspirates (sternum or iliac crest) did not influence these results.
discussion In this prospective study, BM DTC detection in 94 of 621 early breast cancer patients (15%) was the only significant prognostic factor independently associated with shorter LRFS. Using a clinically relevant definition of locoregional recurrence, this study confirms our initial report describing not only BM DTCassociated systemic but also locoregional relapses [6]. To our
Volume 20 | No. 11 | November 2009
knowledge, no other published series has reported a significant association between the presence of breast cancer cells disseminated in the BM and breast cancer locoregional recurrences [1, 4, 15]. As for overall survival, most discrepancies between published series are due to BM DTC detection technical issues (reviewed in [5]). Technically, the present study was conducted according to the current guidelines for BM DTC detection proposed by an interlaboratory working party [16, 17]. In the Oslo series, the other large series meeting these detection guidelines, breast cancers were smaller (pT1 rate 61% versus 40% here), breastconserving surgery was carried out less frequently (31% versus 72% here) and fewer patients received adjuvant radiotherapy (47% versus 96% here) [18]. The Oslo series therefore presented a lower risk of locoregional relapse, which could explain the lack of association between BM DTC detection and LRFS. Most relapses reported in the present series were LR, i.e. relapses in the breast or chest wall. The biological basis for LR in BM DTC-positive patients is not fully understood. However, cancer cells which have escaped the primary tumor before locoregional treatment have been reported to recirculate within the body [19]. This secondary seeding of DTC could be guided to the primary tumor area by chemoattractants released during the post-surgery and post-radiotherapy locoregional wound-healing processes [20]. BM (and all other tissues in which tumor cells disseminate) may therefore act as a tumor cell reservoir in which disseminated cancer cells escape locoregional treatment [1]. In their new microenvironment, BM DTCs have been described to undergo a dormancy process, which causes a relative chemoresistance of these noncycling tumor cells [21]. Effective adjuvant systemic treatments should therefore include cycle-independent therapy such as hormone therapy. Indeed, our results show a benefit from adjuvant hormone therapy; however, this treatment was used in the majority of hormone receptor-positive tumors, preventing any conclusion about the respective effects of hormone-receptor status and hormone therapy. Bisphosphonates, which act on bone remodeling, might also be used as they have been reported to prevent metastatic relapse in BM DTC-positive patients [22]. In the overall population included in this nonrandomized study, neither radiotherapy nor chemotherapy was associated with a lower risk of locoregional recurrence. Strikingly, in addition to adjuvant hormonal therapy, the present analysis indicates that the BM DTC-positive subgroup may benefit from larger irradiation fields, including IMN and SCN. As SCN and IMN irradiation were coupled in our clinical practice, it is difficult to conclude whether irradiation of only one of these two areas, or both, is responsible for this result. Noteworthy, no significant association was found between BM DTC detection and axillary lymph node involvement, which was the main indication for IMN/SCN irradiation; this indicates that IMN irradiation might play a more important role in preventing locoregional relapse in BM DTC-positive patients. This observation gives support to the hypothesis of a possible alternate lymphatic dissemination in breast cancers that have given rise to BM DTC [23]. Several comparative studies have already described that dissemination in BM and axillary lymph nodes could be two opposite, or at least distinct,
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Figure 1. Locoregional recurrence-free survival (LRFS) according to bone marrow-disseminated tumor cell (BM DTC) status (A; P < 0.0001) and supraclavicular node/internal mammary node irradiation (B). (The yintercept corresponds to 50% LRFS.) The number of patients at risk is reported below each curve.
original article
original article
Annals of Oncology
Table 3. Prognostic factors of locoregional recurrence in DTC-positive and -negative patients Characteristic
DTC2 Locoregional recurrence, n relapses/n at risk (%)
LRFS Univariate analysis P value
Multivariate analysis P value Relative risk (95% CI)
5/76 (7) 3/18 (17)
0.15
Ni
3/85 (4) 7/442 (2)
0.18
5/56 (9) 1/21 (5) 2/16 (12)
0.64
Ni
3/265 (1) 6/151 (4) 1/108 (1)
0.18
5/46 (11) 3/48 (6)
0.50
Ni
5/249 (2) 5/276 (2)
0.79
Ni
8/442 (2) 2/63 (3) 0/22 (0)
0.51
0.81
3/30 (10) 3/35 (9) 2/25 (8)
0.94
Ni
2/173 (1) 4/200 (2) 4/138 (3)
0.55
4/72 (6) 4/20 (20)
0.04
0.68
9/424 (2) 1/96 (1)
0.48
7/56 (12) 1/34 (3)
0.16
Ni
4/356 (1) 6/155 (4)
0.048
6/67 (9) 2/25 (8)
0.85
Ni
7/382 (2) 3/140 (2)
0.87
6/85 (7) 2/9 (22)
0.14
Ni
9/487 (2) 1/39 (3)
0.67
6/85 (7) 2/9 (22)
0.14
Ni
9/483 (2) 1/33 (3)
0.59
2/43 (5) 6/51 (12)
0.21
Ni
6/234 (2) 4/281 (1)
0.34
2/18 (11) 6/76 (8)
0.46
Ni
1/98 (1) 9/418 (2)
0.40
2/57 (4) 6/37 (16)
0.03
0.055
8/315 (3) 2/200 (1)
0.30
4/54 (7) 4/40 (10)
0.67
Ni
7/292 (2) 3/235 (1)
0.49
1/60 (2) 7/34 (21) 8/94 (9)
0.0009
0.03
7/344 (2) 3/176 (2) 10/527 (2)
0.87
8/72 (11) 0/12 (0) 0/10 (0)
1.3 (0.3–6.0)
4.8 (0.97–24)
11.5 (1.3–106)
LRFS Univariate analysis P value Relative risk (95% CI)
3.3 (1.1–12)
Multivariate analysis was not carried out in the DTC-negative subgroup, as only one characteristic was associated with LRFS on univariate analysis. DTC, disseminated tumor cell; LRFS, locoregional recurrence-free survival; CI, confidence interval; Ni, not included in multivariate analysis; HR status, hormone receptor status (positive when estrogen and/or progesterone receptors were positive); LVI, lymphovascular invasion; RT, radiotherapy; CW, chest wall; SCN, supraclavicular node; IMN, internal mammary node.
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Age (years) <45 ‡45 cT 1 2 3/4 pN 0 1 Histology Ductal Lobular Other Tumor grade 1 2 3 HR status Positive Negative LVI No Yes Surgery Lumpectomy Mastectomy RT (all modalities) Yes No Breast/CW RT Yes No Boost RT Yes No Axillary RT Yes No SCN and IMN RT Yes No Chemotherapy Yes No Hormone therapy Yes No Total
DTC+ Locoregional recurrence, n recurrences/n at risk (%)
Annals of Oncology
funding Institut Curie micrometastasis incitative research program funded by individual grants.
acknowledgements This study has been presented in part as a poster discussion at the 2008 San Antonio Breast Cancer Symposium
references 1. Pantel K, Brakenhoff RH, Brandt B. Detection, clinical relevance and specific biological properties of disseminating tumour cells. Nat Rev Cancer 2008; 8: 329–340. 2. Ignatiadis M, Xenidis N, Perraki M et al. Different prognostic value of cytokeratin19 mRNA positive circulating tumor cells according to estrogen receptor and HER2 status in early-stage breast cancer. J Clin Oncol 2007; 25: 5194–5202. 3. Slade MJ, Coombes RC. The clinical significance of disseminated tumor cells in breast cancer. Nat Clin Pract Oncol 2007; 4: 30–41. 4. Braun S, Vogl FD, Naume B et al. A pooled analysis of bone marrow micrometastasis in breast cancer. N Engl J Med 2005; 353: 793–802.
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5. Vincent-Salomon A, Bidard FC, Pierga JY. Bone marrow micrometastasis in breast cancer: review of detection methods, prognostic impact and biological issues. J Clin Pathol 2008; 6: 570–576. 6. Bidard FC, Vincent-Salomon A, Gomme S et al. Disseminated tumor cells of breast cancer patients: a strong prognostic factor for distant and local relapse. Clin Cancer Res 2008; 14: 3306–3311. 7. Clarke M, Collins R, Darby S et al. Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005; 366: 2087–2106. 8. Gebski V, Lagleva M, Keech A et al. Survival effects of postmastectomy adjuvant radiation therapy using biologically equivalent doses: a clinical perspective. J Natl Cancer Inst 2006; 98: 26–38. 9. Veronesi U, Cascinelli N, Bufalino R et al. Risk of internal mammary lymph node metastases and its relevance on prognosis of breast cancer patients. Ann Surg 1983; 198: 681–684. 10. Pierga JY, Bonneton C, Vincent-Salomon A et al. Clinical significance of immunocytochemical detection of tumor cells using digital microscopy in peripheral blood and bone marrow of breast cancer patients. Clin Cancer Res 2004; 10: 1392–1400. 11. ICRU Report 50 et ICRU Report 62 (Supplement to ICRU Report 50). Prescribing, Recording and Reporting Photon Beam Therapy. Bethesda, MD: 1999. 12. Campana F, Kirova YM, Rosenwald JC et al. Breast radiotherapy in the lateral decubitus position: a technique to prevent lung and heart irradiation. Int J Radiat Oncol Biol Phys 2005; 61: 1348–1354. 13. Kirova YM, Servois V, Campana F et al. CT-scan based localization of the internal mammary chain and supra clavicular nodes for breast cancer radiation therapy planning. Radiother Oncol 2006; 79: 310–315. 14. Kirova YM, Campana F, Fournier-Bidoz N et al. Postmastectomy electron beam chest wall irradiation in women with breast cancer: a clinical step toward conformal electron therapy. Int J Radiat Oncol Biol Phys 2007; 69: 1139–1144. 15. Riethdorf S, Pantel K. Disseminated tumor cells in bone marrow and circulating tumor cells in blood of breast cancer patients: current state of detection and characterization. Pathobiology 2008; 75: 140–148. 16. Borgen E, Pantel K, Schlimok G et al. A European interlaboratory testing of three well-known procedures for immunocytochemical detection of epithelial cells in bone marrow. Results from analysis of normal bone marrow. Cytometry B Clin Cytom 2006; 70: 400–409. 17. Fehm T, Braun S, Muller V et al. A concept for the standardized detection of disseminated tumor cells in bone marrow from patients with primary breast cancer and its clinical implementation. Cancer 2006; 107: 885–892. 18. Wiedswang G, Borgen E, Karesen R et al. Detection of isolated tumor cells in bone marrow is an independent prognostic factor in breast cancer. J Clin Oncol 2003; 21: 3469–3478. 19. Norton L, Massague J. Is cancer a disease of self-seeding? Nat Med 2006; 12: 875–878. 20. Karnoub AE, Weinberg RA. Chemokine networks and breast cancer metastasis. Breast Dis 2006; 26: 75–85. 21. Aguirre-Ghiso JA. Models, mechanisms and clinical evidence for cancer dormancy. Nat Rev Cancer 2007; 7: 834–846. 22. Diel IJ, Solomayer EF, Costa SD et al. Reduction in new metastases in breast cancer with adjuvant clodronate treatment. N Eng J Med 1998; 339: 357–363. 23. Woelfle U, Cloos J, Sauter G et al. Molecular signature associated with bone marrow micrometastasis in human breast cancer. Cancer Res 2003; 63: 5679–5684. 24. Naume B, Zhao X, Synnestvedt M et al. Presence of bone marrow micrometastasis is associated with different recurrence risk within molecular subtypes of breast cancer. Mol Oncol 2007; 1: 160–171. 25. Punglia RS, Morrow M, Winer EP, Harris JR. Local therapy and survival in breast cancer. N Engl J Med 2007; 356: 2399–2405.
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processes [24]. These results indicate that BM DTC should be investigated in future trials to confirm that BM DTC screening is reliable to assess the indication for SCN and IMN radiotherapy [13, 25]. Seventeen of the 18 locoregional recurrences observed in this study were LR, showing the influence of extended lymph node irradiation on breast or chest wall recurrences. A possible explanation for the efficacy of extended radiotherapy in BM DTC-positive patients on SCN and IMN is that this treatment may prevent local reseeding from DTC located in BM and/or in these lymph nodes. Of note, these results were independent of the site of BM sampling, which was mainly the posterior iliac crest, which is not irradiated during adjuvant radiotherapy. However, as radiation fields (especially for IMN and SCN) include a part of BM, it cannot be excluded that this modality may have decreased cell dissemination, recirculation and finally locoregional recurrence. As this study was not randomized and as radiotherapy was delivered to patients at higher risk of distant metastatic relapse, no conclusions can be drawn concerning the efficacy of extended radiotherapy to prevent distant metastatic relapse. Moreover, our results are based on a very low level of locoregional relapse; longer follow-up is therefore necessary to evaluate the role of radiotherapy in the prevention of distant metastases. We also suggest that the presence of BM DTC in early breast cancer patients may be associated with a different pattern of locoregional cancer cell dissemination and strongly influences LRFS. The main message of our study is still the low local relapse frequency of DTC-negative patients as compared with DTC-positive patients and that DTC positivity might be a selection criterion for adjuvant radiotherapy as the possible reseeding of the primary cancer area by BM DTC could be prevented by SCN/IMN irradiation.
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
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.
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Background: In early breast cancer patients, bone marrow (BM)-disseminated tumor cells (DTCs) were associated
original article
Annals of Oncology
patients and methods
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results Six hundred and twenty-one patients with stage I–III BC were eligible for the study. The median follow-up was 56 months (range 1–100). Patient characteristics, tumor characteristics and locoregional treatments are shown in Table 1. In addition to surgery of the primary tumor and axillary lymph nodes (sentinel lymph node or axillary lymph node dissection), treatment of disseminated cancer cells combined locoregional (radiotherapy) and systemic (chemotherapy and hormone therapy) treatments. Surgical treatment consisted of radical modified mastectomy (27%) or breast-conserving wide tumor excision (73%). Axillary lymph node dissection was carried out in 68% of patients. Ninety-two percent of patients (n = 573) received adjuvant radiotherapy as previously described. Neoadjuvant and adjuvant chemotherapy (mostly anthracycline based) was administered to 19% and 48% of patients, respectively (BM aspiration was carried out at diagnosis before any chemotherapy). Sixty-five percent of patients received endocrine therapy: tamoxifen or aromatase inhibitors (after 2003) were used in hormonal receptor-positive patients according to their menopausal status. As previously reported, the BM DTC detection rate was 15.1% (Table 1). There was no significant association between DTC detection and any of the patient or treatment characteristics, even for axillary lymph node dissemination of cancer cells (P = 0.78, Table 1). The median follow-up was 56 months (range 1–100). Eighteen patients (2.9%) without any previous or concurrent distant metastases experienced locoregional relapse (17 LR and 1 RR). In nine patients, multimetastatic relapse was accompanied by synchronous or metachronous tumor growth in the breast, chest wall or regional lymph nodes: these events were not taken into account in the analysis. Correlations between LRFS and patient characteristics are shown in Table 2. Of note, in the whole population, BM DTC detection was an independent prognostic factor for LRFS on univariate (Figure 1A) and multivariate analysis [P < 0.0001, relative risk 5.1, 95% confidence interval (CI) 2.0–13.0, Table 2]. In BM DTC-positive patients, LRFS was longer when patients received adjuvant hormone therapy (P = 0.03, relative risk 11.5, 95% CI 1.26–106) and radiotherapy to SCN/IMN (P = 0.055, relative risk 4.8, 95% CI 0.97–24.4) on multivariate analysis (Table 3). In contrast, in BM DTC-negative patients, lymphovascular invasion was the only significant prognostic factor for LRFS (P = 0.048, relative risk 3.3, 95% CI 1.1–11.7).
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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
had to be proven histologically. Metastasis-associated locoregional tumor growth, i.e. locoregional tumor growth occurring after or concurrently (<2 months interval) to distant metastases, were not included in this analysis. LRFS time was measured from the date of surgery until the date of LR or RR (or last follow-up). Differences between categorical variables were analyzed by chi-square tests or Fisher’s exact test. LRFS curves were plotted according to the Kaplan–Meier method. Statistical significance between survival curves was assessed using the log-rank test. Multivariate analyses were carried out by the Cox proportional hazards model. To test the main study hypothesis that the therapeutic benefit of different radiotherapy fields may vary according to BM DTC status, an interaction term combining treatment arm and BM DTC status was added to the Cox proportional hazards model. Its significance was tested using a likelihood ratio test.
original article
Annals of Oncology
Table 1. Patient characteristics, treatments and DTC detection rates
Table 2. Patient characteristics, treatments and locoregional recurrence
Characteristic or treatment Number of patients DTC detection rate (%)
Patient characteristic or treatment
103 518
17.5 14.7
321 172 124
17.4 12.2 12.9
295 324
15.6 14.8
514 75 32
14.4 16.0 30.0
203 235 163
14.8 14.9 15.3
495 116
14.3 17.3
412 189
13.6 18.0
527 94
– –
449 165
14.9 15.1
572 48
14.8 18.7
568 42
14.9 21.5
277 332
15.5 15.4
116 496
15.5 15.3
372 237
15.3 15.6
346 275
15.6 14.5
404 210 621
14.8 16.2 15.1
DTC detection rate was not correlated with any patient characteristic or treatment. Due to missing data, some numbers do not add to 621. DTC, disseminated tumor cell; HR status, hormone receptor status (positive when estrogen and/or progesterone receptors were positive); BM, bone marrow; RT, radiotherapy; CW, chest wall; SCN, supraclavicular node; IMN, internal mammary node.
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Age (years) <45 ‡45 cT 1 2 3/4 pN 0 1 Histology Ductal Lobular Other Tumor grade 1 2 3 HR status Positive Negative LVI No Yes BM DTC Negative Positive Surgery Lumpectomy Mastectomy RT (all modalities) Yes No Breast/CW RT Yes No Boost RT Yes No Axillary RT Yes No SCN and IMN RT Yes No Chemotherapy Yes No Hormone therapy Yes No
5.8 2.3
0.037
0.079
2.4 4.1 2.4
0.78
Ni
3.4 2.5
0.46
Ni
3.1 2.7 0
0.96
Ni
2.4 2.9 3.7
0.81
Ni
2.6 4.3
0.32
Ni
2.7 3.7
0.50
Ni
1.9 8.5
<0.0001
2.9 3.0
0.98
Ni
2.6 6.2
0.11
Ni
2.6 7.1
0.07
Ni
2.9 3.0
0.93
Ni
2.6 3.0
0.73
Ni
2.7 3.4
0.48
Ni
3.2 2.5
0.83
Ni
2.0 4.7
0.037
0.060
0.0006
2.4 (0.9–6.4)
5.1 (2.0–13.0)
2.4 (0.9–6.2)
CI, confidence interval; Ni, not included in multivariate analysis; HR, hormone receptor; LVI, lymphovascular invasion; BM, bone marrow; RT, radiotherapy; CW, chest wall; SCN, supraclavicular node; IMN, internal mammary node.
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Age (years) <45 ‡45 cT 1 2 3/4 pN 0 1 Histology Ductal Lobular Other Tumor grade 1 2 3 HR status Positive Negative Tumor emboli No Yes BM DTC Negative Positive Surgery Lumpectomy Mastectomy RT (all modalities) Yes No Breast/CW RT Yes No Boost RT Yes No Axillary RT Yes No SCN and IMN RT Yes No Chemotherapy Yes No Hormone therapy Yes No Total
Locoregional Locoregional recurrence-free survival recurrence Univariate Multivariate (%) analysis analysis P value P Relative risk value (95% CI)
Annals of Oncology
A significant interaction test between BM DTC status and SCN/ IMN radiotherapy for LRFS (P = 0.028) confirmed that the impact of SCN/IMN radiotherapy on LRFS was almost restricted to BM DTC-positive patients. Importantly, the site of BM aspirates (sternum or iliac crest) did not influence these results.
discussion In this prospective study, BM DTC detection in 94 of 621 early breast cancer patients (15%) was the only significant prognostic factor independently associated with shorter LRFS. Using a clinically relevant definition of locoregional recurrence, this study confirms our initial report describing not only BM DTCassociated systemic but also locoregional relapses [6]. To our
Volume 20 | No. 11 | November 2009
knowledge, no other published series has reported a significant association between the presence of breast cancer cells disseminated in the BM and breast cancer locoregional recurrences [1, 4, 15]. As for overall survival, most discrepancies between published series are due to BM DTC detection technical issues (reviewed in [5]). Technically, the present study was conducted according to the current guidelines for BM DTC detection proposed by an interlaboratory working party [16, 17]. In the Oslo series, the other large series meeting these detection guidelines, breast cancers were smaller (pT1 rate 61% versus 40% here), breastconserving surgery was carried out less frequently (31% versus 72% here) and fewer patients received adjuvant radiotherapy (47% versus 96% here) [18]. The Oslo series therefore presented a lower risk of locoregional relapse, which could explain the lack of association between BM DTC detection and LRFS. Most relapses reported in the present series were LR, i.e. relapses in the breast or chest wall. The biological basis for LR in BM DTC-positive patients is not fully understood. However, cancer cells which have escaped the primary tumor before locoregional treatment have been reported to recirculate within the body [19]. This secondary seeding of DTC could be guided to the primary tumor area by chemoattractants released during the post-surgery and post-radiotherapy locoregional wound-healing processes [20]. BM (and all other tissues in which tumor cells disseminate) may therefore act as a tumor cell reservoir in which disseminated cancer cells escape locoregional treatment [1]. In their new microenvironment, BM DTCs have been described to undergo a dormancy process, which causes a relative chemoresistance of these noncycling tumor cells [21]. Effective adjuvant systemic treatments should therefore include cycle-independent therapy such as hormone therapy. Indeed, our results show a benefit from adjuvant hormone therapy; however, this treatment was used in the majority of hormone receptor-positive tumors, preventing any conclusion about the respective effects of hormone-receptor status and hormone therapy. Bisphosphonates, which act on bone remodeling, might also be used as they have been reported to prevent metastatic relapse in BM DTC-positive patients [22]. In the overall population included in this nonrandomized study, neither radiotherapy nor chemotherapy was associated with a lower risk of locoregional recurrence. Strikingly, in addition to adjuvant hormonal therapy, the present analysis indicates that the BM DTC-positive subgroup may benefit from larger irradiation fields, including IMN and SCN. As SCN and IMN irradiation were coupled in our clinical practice, it is difficult to conclude whether irradiation of only one of these two areas, or both, is responsible for this result. Noteworthy, no significant association was found between BM DTC detection and axillary lymph node involvement, which was the main indication for IMN/SCN irradiation; this indicates that IMN irradiation might play a more important role in preventing locoregional relapse in BM DTC-positive patients. This observation gives support to the hypothesis of a possible alternate lymphatic dissemination in breast cancers that have given rise to BM DTC [23]. Several comparative studies have already described that dissemination in BM and axillary lymph nodes could be two opposite, or at least distinct,
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Figure 1. Locoregional recurrence-free survival (LRFS) according to bone marrow-disseminated tumor cell (BM DTC) status (A; P < 0.0001) and supraclavicular node/internal mammary node irradiation (B). (The yintercept corresponds to 50% LRFS.) The number of patients at risk is reported below each curve.
original article
original article
Annals of Oncology
Table 3. Prognostic factors of locoregional recurrence in DTC-positive and -negative patients Characteristic
DTC2 Locoregional recurrence, n relapses/n at risk (%)
LRFS Univariate analysis P value
Multivariate analysis P value Relative risk (95% CI)
5/76 (7) 3/18 (17)
0.15
Ni
3/85 (4) 7/442 (2)
0.18
5/56 (9) 1/21 (5) 2/16 (12)
0.64
Ni
3/265 (1) 6/151 (4) 1/108 (1)
0.18
5/46 (11) 3/48 (6)
0.50
Ni
5/249 (2) 5/276 (2)
0.79
Ni
8/442 (2) 2/63 (3) 0/22 (0)
0.51
0.81
3/30 (10) 3/35 (9) 2/25 (8)
0.94
Ni
2/173 (1) 4/200 (2) 4/138 (3)
0.55
4/72 (6) 4/20 (20)
0.04
0.68
9/424 (2) 1/96 (1)
0.48
7/56 (12) 1/34 (3)
0.16
Ni
4/356 (1) 6/155 (4)
0.048
6/67 (9) 2/25 (8)
0.85
Ni
7/382 (2) 3/140 (2)
0.87
6/85 (7) 2/9 (22)
0.14
Ni
9/487 (2) 1/39 (3)
0.67
6/85 (7) 2/9 (22)
0.14
Ni
9/483 (2) 1/33 (3)
0.59
2/43 (5) 6/51 (12)
0.21
Ni
6/234 (2) 4/281 (1)
0.34
2/18 (11) 6/76 (8)
0.46
Ni
1/98 (1) 9/418 (2)
0.40
2/57 (4) 6/37 (16)
0.03
0.055
8/315 (3) 2/200 (1)
0.30
4/54 (7) 4/40 (10)
0.67
Ni
7/292 (2) 3/235 (1)
0.49
1/60 (2) 7/34 (21) 8/94 (9)
0.0009
0.03
7/344 (2) 3/176 (2) 10/527 (2)
0.87
8/72 (11) 0/12 (0) 0/10 (0)
1.3 (0.3–6.0)
4.8 (0.97–24)
11.5 (1.3–106)
LRFS Univariate analysis P value Relative risk (95% CI)
3.3 (1.1–12)
Multivariate analysis was not carried out in the DTC-negative subgroup, as only one characteristic was associated with LRFS on univariate analysis. DTC, disseminated tumor cell; LRFS, locoregional recurrence-free survival; CI, confidence interval; Ni, not included in multivariate analysis; HR status, hormone receptor status (positive when estrogen and/or progesterone receptors were positive); LVI, lymphovascular invasion; RT, radiotherapy; CW, chest wall; SCN, supraclavicular node; IMN, internal mammary node.
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Age (years) <45 ‡45 cT 1 2 3/4 pN 0 1 Histology Ductal Lobular Other Tumor grade 1 2 3 HR status Positive Negative LVI No Yes Surgery Lumpectomy Mastectomy RT (all modalities) Yes No Breast/CW RT Yes No Boost RT Yes No Axillary RT Yes No SCN and IMN RT Yes No Chemotherapy Yes No Hormone therapy Yes No Total
DTC+ Locoregional recurrence, n recurrences/n at risk (%)
Annals of Oncology
funding Institut Curie micrometastasis incitative research program funded by individual grants.
acknowledgements This study has been presented in part as a poster discussion at the 2008 San Antonio Breast Cancer Symposium
references 1. Pantel K, Brakenhoff RH, Brandt B. Detection, clinical relevance and specific biological properties of disseminating tumour cells. Nat Rev Cancer 2008; 8: 329–340. 2. Ignatiadis M, Xenidis N, Perraki M et al. Different prognostic value of cytokeratin19 mRNA positive circulating tumor cells according to estrogen receptor and HER2 status in early-stage breast cancer. J Clin Oncol 2007; 25: 5194–5202. 3. Slade MJ, Coombes RC. The clinical significance of disseminated tumor cells in breast cancer. Nat Clin Pract Oncol 2007; 4: 30–41. 4. Braun S, Vogl FD, Naume B et al. A pooled analysis of bone marrow micrometastasis in breast cancer. N Engl J Med 2005; 353: 793–802.
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5. Vincent-Salomon A, Bidard FC, Pierga JY. Bone marrow micrometastasis in breast cancer: review of detection methods, prognostic impact and biological issues. J Clin Pathol 2008; 6: 570–576. 6. Bidard FC, Vincent-Salomon A, Gomme S et al. Disseminated tumor cells of breast cancer patients: a strong prognostic factor for distant and local relapse. Clin Cancer Res 2008; 14: 3306–3311. 7. Clarke M, Collins R, Darby S et al. Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005; 366: 2087–2106. 8. Gebski V, Lagleva M, Keech A et al. Survival effects of postmastectomy adjuvant radiation therapy using biologically equivalent doses: a clinical perspective. J Natl Cancer Inst 2006; 98: 26–38. 9. Veronesi U, Cascinelli N, Bufalino R et al. Risk of internal mammary lymph node metastases and its relevance on prognosis of breast cancer patients. Ann Surg 1983; 198: 681–684. 10. Pierga JY, Bonneton C, Vincent-Salomon A et al. Clinical significance of immunocytochemical detection of tumor cells using digital microscopy in peripheral blood and bone marrow of breast cancer patients. Clin Cancer Res 2004; 10: 1392–1400. 11. ICRU Report 50 et ICRU Report 62 (Supplement to ICRU Report 50). Prescribing, Recording and Reporting Photon Beam Therapy. Bethesda, MD: 1999. 12. Campana F, Kirova YM, Rosenwald JC et al. Breast radiotherapy in the lateral decubitus position: a technique to prevent lung and heart irradiation. Int J Radiat Oncol Biol Phys 2005; 61: 1348–1354. 13. Kirova YM, Servois V, Campana F et al. CT-scan based localization of the internal mammary chain and supra clavicular nodes for breast cancer radiation therapy planning. Radiother Oncol 2006; 79: 310–315. 14. Kirova YM, Campana F, Fournier-Bidoz N et al. Postmastectomy electron beam chest wall irradiation in women with breast cancer: a clinical step toward conformal electron therapy. Int J Radiat Oncol Biol Phys 2007; 69: 1139–1144. 15. Riethdorf S, Pantel K. Disseminated tumor cells in bone marrow and circulating tumor cells in blood of breast cancer patients: current state of detection and characterization. Pathobiology 2008; 75: 140–148. 16. Borgen E, Pantel K, Schlimok G et al. A European interlaboratory testing of three well-known procedures for immunocytochemical detection of epithelial cells in bone marrow. Results from analysis of normal bone marrow. Cytometry B Clin Cytom 2006; 70: 400–409. 17. Fehm T, Braun S, Muller V et al. A concept for the standardized detection of disseminated tumor cells in bone marrow from patients with primary breast cancer and its clinical implementation. Cancer 2006; 107: 885–892. 18. Wiedswang G, Borgen E, Karesen R et al. Detection of isolated tumor cells in bone marrow is an independent prognostic factor in breast cancer. J Clin Oncol 2003; 21: 3469–3478. 19. Norton L, Massague J. Is cancer a disease of self-seeding? Nat Med 2006; 12: 875–878. 20. Karnoub AE, Weinberg RA. Chemokine networks and breast cancer metastasis. Breast Dis 2006; 26: 75–85. 21. Aguirre-Ghiso JA. Models, mechanisms and clinical evidence for cancer dormancy. Nat Rev Cancer 2007; 7: 834–846. 22. Diel IJ, Solomayer EF, Costa SD et al. Reduction in new metastases in breast cancer with adjuvant clodronate treatment. N Eng J Med 1998; 339: 357–363. 23. Woelfle U, Cloos J, Sauter G et al. Molecular signature associated with bone marrow micrometastasis in human breast cancer. Cancer Res 2003; 63: 5679–5684. 24. Naume B, Zhao X, Synnestvedt M et al. Presence of bone marrow micrometastasis is associated with different recurrence risk within molecular subtypes of breast cancer. Mol Oncol 2007; 1: 160–171. 25. Punglia RS, Morrow M, Winer EP, Harris JR. Local therapy and survival in breast cancer. N Engl J Med 2007; 356: 2399–2405.
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processes [24]. These results indicate that BM DTC should be investigated in future trials to confirm that BM DTC screening is reliable to assess the indication for SCN and IMN radiotherapy [13, 25]. Seventeen of the 18 locoregional recurrences observed in this study were LR, showing the influence of extended lymph node irradiation on breast or chest wall recurrences. A possible explanation for the efficacy of extended radiotherapy in BM DTC-positive patients on SCN and IMN is that this treatment may prevent local reseeding from DTC located in BM and/or in these lymph nodes. Of note, these results were independent of the site of BM sampling, which was mainly the posterior iliac crest, which is not irradiated during adjuvant radiotherapy. However, as radiation fields (especially for IMN and SCN) include a part of BM, it cannot be excluded that this modality may have decreased cell dissemination, recirculation and finally locoregional recurrence. As this study was not randomized and as radiotherapy was delivered to patients at higher risk of distant metastatic relapse, no conclusions can be drawn concerning the efficacy of extended radiotherapy to prevent distant metastatic relapse. Moreover, our results are based on a very low level of locoregional relapse; longer follow-up is therefore necessary to evaluate the role of radiotherapy in the prevention of distant metastases. We also suggest that the presence of BM DTC in early breast cancer patients may be associated with a different pattern of locoregional cancer cell dissemination and strongly influences LRFS. The main message of our study is still the low local relapse frequency of DTC-negative patients as compared with DTC-positive patients and that DTC positivity might be a selection criterion for adjuvant radiotherapy as the possible reseeding of the primary cancer area by BM DTC could be prevented by SCN/IMN irradiation.
original article