- Email: [email protected]
Outcome and Medial Presentation of Breast Cancer: European Institute of Oncology Experience
Original Study
Outcome and Medial Presentation of Breast Cancer: European Institute of Oncology Experience Emilia Montagna,1 Vincenzo Bagnardi,2,3 Nicole Rotmensz,3 Giuseppe Viale,4,5 Giuseppe Cancello,1 Antonella Palazzo,1 Viviana Galimberti,6 Paolo Veronesi,6 Alberto Luini,6 Mauro G. Mastropasqua,4 Barbara Santillo,3 Aron Goldhirsch,7 Marco Colleoni1 Abstract To our knowledge, for the first time, in the present study the role of medial localization was studied according the selected tumor subtypes. The results show that medial presentation is an adverse prognostic factor irrespective of breast cancer subtype. Background: No analyses have investigated the prognostic role of medial presentation in breast cancer patients on disease-free survival (DFS) and overall survival according to immunohistochemically-defined subtypes. Patients and Methods: We collected information from the institutional clinical database on consecutive breast cancer patients who underwent conservative surgery at the European Institute of Oncology, Milan, Italy, between 1994 and 2008. We compared the outcomes of patients with medial breast cancer with those of patients with nonmedial tumors observed at the institution during the same period. Results: Among 7369 evaluable patients, 2254 (24%) had their primary tumors in medial quadrants and 7015 (76%) in other areas. Five-year DFS was 84.7% and 86.6% (P ¼ .008) in patients with medial and nonmedial disease, respectively. In multivariate analysis, medial location was correlated with greater risk of recurrence (hazard ratio [HR], 1.23; 95% confidence interval [CI], 1.11-1.35; P < .0001) and death (HR, 1.27; 95% CI, 1.09-1.49; P ¼ .0028). Conclusion: Medial presentation is an adverse prognostic factor for breast cancer patients. Clinical Breast Cancer, Vol. 15, No. 6, 440-7 ª 2015 Elsevier Inc. All rights reserved. Keywords: Luminal, Position, Subtypes, Triple negative, Tumor
Introduction The site of presentation within the breast is not considered in recent guidelines for optimal tailoring of adjuvant therapies in breast cancer patients.1 However, the location of primary breast cancer can 1
Division of Medical Senology, European Institute of Oncology, Milan, Italy Department of Quantitative Methods and Statistics, University of Milan-Bicocca, Milan, Italy 3 Division of Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy 4 Department of Pathology, European Institute of Oncology, Milan, Italy 5 School of Medicine, University of Milan, Milan, Italy 6 Division of Senology, European Institute of Oncology, Milan, Italy 7 Program of Senology (Breast Health), European Institute of Oncology, Milan, Italy 2
Submitted: Apr 6, 2015; Revised: Jun 25, 2015; Accepted: Jul 5, 2015; Epub: July 10, 2015 Address for correspondence: Emilia Montagna, MD, Division of Medical Senology, European Institute of Oncology, Via Ripamonti 435, Milan, Italy Fax: þ39 02 574829212; e-mail contact: [email protected]
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affect outcome. Several studies have reported that the medial presentation of breast cancer is correlated with worse outcome compared with nonmedial disease,2-7 although some studies failed to find any influence of tumor location on disease recurrence and survival.8-10 Several limitations such as short follow-up, limited number of patients, and selection bias might affect the findings in these studies. Different subtypes of breast cancer patients have been identified using gene expression profiling.11 A pragmatic surrogate of molecular intrinsic subtypes using immunohistochemical and in situ hybridization assays is commonly adopted in current practice.12 The different subtypes identified as luminal A, luminal B, HER2-positive, and triple-negative have different outcomes.11 No analyses have previously evaluated the effect of medial position of breast cancer according to different subtypes. The aim of the present study was to assess the outcome in terms of disease-free
1526-8209/$ - see frontmatter ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clbc.2015.07.003
Table 1 Continued
Table 1 Patient Characteristics Characteristic Total
Medial, n (%)
Lateral/Central/ Other, n (%)
2254 (100)
7015 (100)
Year of Surgery Earlier than 1998
P
Medial, n (%)
Lateral/Central/ Other, n (%)
Nil
82 (3.6)
262 (3.7)
Characteristic Adjuvant CT/HT
.691
.654
19 (0.8)
53 (0.8)
HT
1418 (62.9)
4310 (61.4)
1998-2001
505 (22.4)
1648 (23.5)
CT
270 (12)
864 (12.3)
2002-2004
864 (38.3)
2621 (37.4)
HT-CT
484 (21.5)
2005-2007
866 (38.4)
2693 (38.4)
Age at Time of Surgery, Years <35
73 (3.2)
268 (3.8)
35-50
845 (37.5)
2655 (37.8)
51-65
936 (41.5)
2900 (41.3)
>65
400 (17.7)
1192 (17)
Premenopausal
953 (42.3)
3063 (43.7)
Postmenopausal
1301 (57.7)
3952 (56.3)
Menopausal Status
Histology 1836 (81.5)
Lobular
187 (8.3)
665 (9.5)
Mixed/other
231 (10.2)
808 (11.5)
Abbreviations: CT ¼ chemotherapy; ELIOT ¼ intraoperative radiotherapy with electrons; HT ¼ hormonaltherapy; PVI ¼ peritumoral vascular invasion.
.249
survival (DFS), overall survival (OS), and locoregional recurrence of patients treated conservatively with quadrantectomy and (in almost all cases) radiotherapy for medial breast carcinoma. We compared the outcome of these patients with outcomes of the larger number of patients with nonmedial (lateral, central, or other) breast cancer treated at the same institution during the same period. Specifically, we evaluated the prognostic role of medial presentation according to selected immunohistochemically-defined subtypes.
5542 (79)
Patients and Methods <.001
PT pT1
1754 (77.8)
pT2
491 (21.8)
1786 (25.5)
5188 (74)
pT3
9 (0.4)
41 (0.6) <.001
Positive Lymph Nodes, n None
1539 (68.3)
4389 (62.6)
1-3
556 (24.7)
1873 (26.7)
4
159 (7.1)
753 (10.7)
52 (2.3)
176 (2.5)
1513 (67.1)
4744 (67.6)
689 (30.6)
2095 (29.9)
Grade Unknown 1-2 3
.562
Subtype St Gallen 2013
.84
Luminal A
852 (37.8)
2559 (36.5)
Luminal B (HER2)
906 (40.2)
2899 (41.3)
Luminal B (HER2þ)
192 (8.5)
598 (8.5)
HER2þ
98 (4.3)
303 (4.3)
206 (9.1)
656 (9.4)
1773 (78.7)
5373 (76.6)
Moderate
335 (14.9)
1086 (15.5)
Extensive
146 (6.5)
556 (7.9)
2254 (100)
7015 (100)
Triple-negative PVI Absent
.047
Radiotherapy Performed/Proposed No Yes, standard Yes, ELIOT
e .268
39 (1.7)
158 (2.3)
1677 (74.4)
5146 (73.4)
538 (23.9)
1711 (24.4)
Patients We collected information from the institutional clinical database on consecutive breast cancer patients treated at the European Institute of Oncology (EIO), Milan, Italy, between 1994 and 2008. This use of data was approved by the institutional review board. Data on the patient’s medical history, concurrent diseases, type of surgery, histopathological features, and results of any staging procedures (blood chemistry, hematological values, bone scan, chest film, and upper abdominal ultrasound examination) were reviewed. We identified patients with early breast cancer (pT1-3 pN0-3 M0) who underwent conservative surgery with sentinel lymph node biopsy or complete axillary dissection. We excluded from the current analysis patients with distant disease at presentation or patients treated with neoadjuvant therapy. We used the larger number of patients with nonmedial breast cancer observed at the same institution during the same period as the comparator group. After final surgery, all cases were discussed during the weekly multidisciplinary meeting attended by surgeons, medical oncologists, radiation oncologists, and pathologists. Women were usually followed up with physical examination every 6 months and mammography with or without breast ultrasound (US) annually. In symptomatic cases or when clinically indicated, bone scan, chest x-ray, liver US, or computed tomography scans were also performed.
Treatments
Surgery Quadrantectomy
1579 (22.5)
.531
.042
Ductal
P
The decision for adjuvant systemic treatment was made on the basis of biological features, staging, comorbidities, and patient preference.1,13,14 For patients with luminal A disease, adjuvant endocrine therapy alone according to menopausal status was prescribed (tamoxifen or aromatase inhibitor) for a duration of 5 years in postmenopausal patients. Premenopausal patients were advised to have a combination of tamoxifen for 5 years with gonadotropinreleasing hormone analogues for at least 2 years.
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Outcome and Medial Presentation of BC: EIO Experience For patients with luminal B tumors, chemotherapy (an anthracycline combination for 4 cycles) was administered before the hormonal program. Patients with triple-negative disease were advised to undergo chemotherapy for 6 cycles including an alkylating agent (ie, classical cyclophosphamide, methotrexate, fluorouracil). In case of HER2 overexpression and/or amplification, trastuzumab was combined with adjuvant therapy starting from 2004. Postoperative breast irradiation was proposed to all patients.
Pathology and Immunohistochemistry This was a single-institution study. All patients had pathological evaluation performed after extensive sampling of the surgical specimens. Immunostaining for estrogen receptor (ER) and progesteron receptor (PgR), HER2 protein, and Ki-67 antigen were performed on consecutive tissue sections, as previously reported.15 The following primary antibodies were used: the monoclonal antibody (MAb) to ER (Dako, Glostrup, Denmark at 1/100 dilution), the MAb to PgR (Dako, 1/800), the MIB-1 MAb to the Ki-67 antigen (Immunotech, Marseille, France, 1/1200), and the polyclonal antiserum (Dako, 1/ 3200) to the HER2 protein. Only nuclear reactivity was taken into account for ER, PgR, and Ki-67 antigen, whereas only an intense and complete membrane staining in > 10% of the tumor cells qualified for HER2 overexpression (3þ). The results for ER, PgR, and Ki-67 were recorded as the percentage of immunoreactive cells over at least 2000 neoplastic cells. The value of 20% for Ki-67 labeling index was used as a cutoff in distinguishing tumors with a low (< 20%) and high (> 20%) proliferative fraction.
Statistical Analysis Differences in the distribution of subject characteristics according to site of primary tumor (medial vs. lateral, central, or other) were evaluated using the c2 test. The end points evaluated were invasive DFS and OS. DFS was defined as the time from surgery to events such as relapse (including ipsilateral breast recurrence), appearance of a second primary cancer (including contralateral breast cancer), or
death, whichever occurred first. OS was defined as the time from surgery until the date of death (from any cause). The DFS and OS functions were estimated using the KaplaneMeier method. The log-rank test was used to assess differences between groups. The hazard ratios (HRs) in comparisons of medial presentation versus lateral, central, or other presentation were estimated using a Cox proportional hazards multivariable model, controlled for menopausal status, number of positive lymph nodes, tumor size, perivascular invasion, and biological subtype. All of the analyses were carried out using the SAS software (SAS Institute, Cary, NC). P values .05 were deemed statistically significant. All reported P values were 2-sided.
Results Of the 12,628 patients treated with conservative surgery at EIO between 1994 and 2008, we excluded patients who underwent surgery after neoadjuvant therapy (n ¼ 729), patients with metastatic disease at presentation (n ¼ 110), with incomplete biological features or follow-up data (n ¼ 2520) leaving 9269 selected for the present study. A total of 2254 (24%) patients had their primary tumors in a medial location and 7015 (76%) patients had their primary tumors in other breast quadrants. Table 1 shows the patient characteristics according to the site of primary tumor: medial versus nonmedial. Patients with medial presentation were more likely to have small tumor size (78% vs. 74%) and axillary lymph node-negative disease (68% vs. 63%) compared with patients with nonmedial cancers. The other patient characteristics, including the prevalence of the immunohistological subtypes, were not significantly different according to site of tumor. The median follow-up was 8.3 years. The KaplaneMeier curves for DFS in the study population, according to site of breast cancer, is shown in Figure 1A. A worse outcome was reported for patients with medial tumors versus those with nonmedial disease. Five-year DFS was 84.7% and 86.6% (P ¼ .0081) in patients with medial and nonmedial disease, respectively. Patients with nonmedial tumors continued to have better DFS during later follow-up with
Figure 1 (A) Disease-Free Survival and (B) Overall Survival for the 9269 Patients Evaluated According to Site of Primary Tumor
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Clinical Breast Cancer December 2015
Emilia Montagna et al 10-year DFS of 73.4% compared with 70.2% in the medial group. Figure 1B shows the OS for the 2 groups. Five- and 10-year OS were 95.1% and 87.7% in the medial group compared with 95.7% and 89.8% in patients with nonmedial disease (P ¼ .19). Of the 2254 patients with medial tumors, 24.3% had an event, compared
with 21.8% among 7015 patients with other site tumor locations. In the medial and nonmedial groups 7.7% and 6.2% had a locoregional recurrence (P ¼ .013); distant recurrence was reported in 8.7% of the medial group and in 7.4% of the nonmedial group (P ¼ .047).
Figure 2 Disease-Free Survival According to Site of Primary Tumor and Histological Subtype
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Outcome and Medial Presentation of BC: EIO Experience Figures 2 and 3 show DFS and OS curves in a comparison of medial and nonmedial primary sites according to immunohistological subtype. The results show that medial presentation is an
adverse prognostic factor irrespective of breast cancer subtype. The heterogeneity test of the effect of medial presentation among different subtypes was not statistically significant for DFS and OS.
Figure 3 Overall Survival According to Site of Primary Tumor and Histological Subtype
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Clinical Breast Cancer December 2015
Emilia Montagna et al Moreover, we analyzed the interaction on medial presentation and tumor size. The adverse prognostic effect of medial presentation was confirmed in large and small tumor size as shown in Figure 4.
Multivariate Analysis The independent association between biological and clinical variables and the risk of recurrence and death in the whole series of patients were analyzed. The results, obtained using Cox
proportional hazard regression analysis, are shown in Table 2. In multivariate analysis we confirmed the prognostic role of classical clinical and biological features that correlated with greater risk of worse outcome such as larger tumor size, and positive nodal involvement. Moreover, the medial tumor presentation was associated with greater risk of recurrence (HR, 1.23; 95% confidence interval [CI], 1.11-1.35; P < .0001) and death (HR, 1.27; 95% CI, 1.09-1.49; P ¼ .0028).
Figure 4 Interaction Between Tumor Size and Medial Presentation in Terms of Disease-Free Survival and Overall Survival
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Outcome and Medial Presentation of BC: EIO Experience Table 2 Multivariate Analysis DFS
OS
HR (95% CI)
P
HR (95% CI)
Site, Medial versus Central/Lateral/Other
1.23 (1.11-1.35)
<.0001
1.27 (1.09-1.49)
.0028
Menopausal Status, Post- versus Premenopausal
1.34 (1.22-1.46)
<.0001
1.91 (1.64-2.22)
<.0001
2 versus 1
1.53 (1.39-1.69)
<.0001
1.94 (1.67-2.25)
<.0001
3 versus 1
2.05 (1.33-3.17)
.0012
2.84 (1.55-5.19)
.0007
1-3 versus none
1.29 (1.16-1.43)
<.0001
1.43 (1.19-1.70)
<.0001
4 versus none
2.28 (2.00-2.61)
<.0001
3.31 (2.72-4.03)
<.0001
Moderate versus absent
1.15 (1.02-1.30)
.0206
1.22 (1.01-1.48)
.0361
Extensive versus absent
1.32 (1.14-1.53)
.0002
1.52 (1.22-1.88)
.0002
Luminal B HER2 versus luminal A
1.51 (1.35-1.69)
<.0001
1.68 (1.38-2.05)
<.0001
Luminal B HER2þ versus luminal A
1.72 (1.47-2.01)
<.0001
1.74 (1.33-2.29)
<.0001
HER2 versus luminal A
2.21 (1.84-2.66)
<.0001
2.60 (1.95-3.46)
<.0001
Triple-negative versus luminal A
2.08 (1.79-2.42)
<.0001
3.28 (2.59-4.16)
<.000
Variable
P
PT
Positive LNs, n
PVI
Subtype (St Gallen 2013)
þ
Abbreviations: DFS ¼ disease-free survival; OS ¼ overall survival; PVI ¼ peritumoral vascular invasion.
Discussion
446
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The identification of clinicopathological features that might play a prognostic role in breast cancer patients is a key issue for improved patient care. In the present study, on the basis of a prospective and quality controlled database, the medial site of presentation, compared with nonmedial disease, was associated with greater risk of recurrence and death in breast cancer patients. These results retained their statistical significance after the adjustment for other prognostic factors. The magnitude of the adverse prognostic effect associated with medial presentation was similar to that reported by the International Breast Cancer Study Group (IBCSG).5 In our study, the HR was 1.23 for DFS and 1.27 for OS compared with a HR of 1.22 and 1.24 in the IBCSG analysis. However, significant differences in outcome were present between our study and that of the IBCSG. In the current series, 10-year DFS and OS for patients with medial tumors were 70.2% and 87.7% compared with 46% and 59% in the previous report. These differences are likely because all patients of the current study were treated with conservative surgery, compared with only 18% in the previous study, and that they had smaller tumors (77% of them had tumor size < 2 cm vs. 46%) and more often node-negative disease (68% vs. 44%). More importantly, however, the outcome differences might be explained by the improvement in tailored adjuvant treatments during the years of reference. The IBCSG study included patients treated from 1978 to 1993, and our analysis concerned patients treated more recently (1994-2008) when new chemo-, hormonal, and radiotherapy programs were available. The poorer outcome of medial breast cancer compared with the primary sites might be because of understaging of the disease, specifically by failing to detect occult spread to the internal mammary chain (IMC). Some authors reported that sentinel node biopsy
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of IMC has a limited prognostic effect and other studies showed the utility of IMC biopsy.16-18 Unknown IMC status and the absence of radiotherapy to the IMC field could result in a worse outcome of medial disease. Recently an Early Breast Cancer Trialists’ Collaborative Group meta-analysis reported that radiotherapy after mastectomy (and axillary dissection) including IMC reduced recurrence and breast cancer mortality in women with 1-3 positive lymph nodes.19 Moreover, 3 randomized studies, focused on the role of IMC irradiation were published or presented. Two trials tested the effect of additional IMC and supraclavicular node irradiation,20,21 and 1 trial tested the effect of additional IMC irradiation only.22 The primary end point was OS for all studies. The patients included had more frequently node-positive disease or medial or central tumors and received adjuvant chemotherapy. The randomized French trial did not show any benefit for IMC irradiation, but it was underpowered.22 The European Organization for Research and Treatment of Cancer (EORTC) 22922-10925 study randomized more than 4000 patients, with extended followup (10.9 years).20 The Canadian study, MA20, included more than 1000 patients treated with conservative surgery.21 The latter 2 studies reported a survival benefit for patients with IMC and supraclavicular node irradiation. Moreover the EORTC trial reported a benefit of DFS and metastasis-free survival (HR, 0.89 and 0.86, respectively). The Canadian study showed that additional regional nodal irradiation reduced the risk of locoregional (HR, 0.59; P ¼ .02) and distant recurrence (HR, 0.64; P ¼ .002).21 The EORTC and MA20 studies did not report a significant increase in cardiac or lung toxicity, although the follow-up in MA20 (62 months) was insufficient to exclude late toxicities. Because the magnitude of the benefit is limited, the accurate identification of candidate patients for IMC irradiation is still debated, although the size of medial tumors could represent a useful
Emilia Montagna et al criterion. The current study on the prognostic role of breast cancer location reports on the largest series of patients with mature followup, detailed clinical and biological information, and data of adjuvant treatment received in recent years. Moreover, to our knowledge, for the first time, the role of medial localization was studied according to the selected tumor subtypes. The heterogeneity test result on the effect of medial presentation among different subtypes show that the medial presentation is an adverse prognostic factor for breast cancer patients irrespective of breast cancer subtype However, the prognostic implications of medial presentation might have a role in the definition of adjuvant program, with particular regard to radiation therapy.
2. 3. 4.
5. 6. 7. 8.
Conclusion The current study showed that medial presentation has a prognostic role in breast cancer patients. This factor should be considered for optimal tailoring of adjuvant therapies.
Clinical Practice Points Some studies failed to find any influence of tumor location on
9. 10. 11. 12.
disease recurrence and survival in breast cancer patients. No analyses have investigated on the prognostic role of medial
presentation in breast cancer patients according to immunohistochemically defined subtypes. The current study on the prognostic role of breast cancer location reports on the largest series of patients with mature followup, detailed clinical and biological information, and data of adjuvant treatment received in recent years. In the present study, the medial site of presentation, compared with nonmedial disease, was associated with greater risk of recurrence and death in breast cancer patients. The negative effect of medial disease could be taken into account for the prescription of adjuvant program with particular regard to radiation therapy.
13. 14.
15. 16. 17. 18. 19.
Disclosure The authors have stated that they have no conflicts of interest.
20. 21.
References 1. Goldhirsch A, Winer EP, Coates AS, et al. Panel members personalizing the treatment of women with early breast cancer: highlights of the St Gallen
22.
International Expert Consensus on the Primary Therapy of Early Breast Cancer. Ann Oncol 2013; 24:2206-23. Lohrisch C, Jackson J, Jones A, Mates D, Olivotto IA. Relationship between tumor location and relapse in 6,781 women with early invasive breast cancer. J Clin Oncol 2000; 18:2828-35. Gaffney DK, Tsodikov A, Wiggins CL. Diminished survival in patients with inner versus outer quadrant breast cancers. J Clin Oncol 2003; 21:467-72. Fowble B, Solin LJ, Schultz DJ, Weiss MC. Breast recurrence and survival related to primary tumor location in patients undergoing conservative surgery and radiation for early-stage breast cancer. Int J Radiat Oncol Biol Phys 1992; 23: 933-9. Colleoni M, Zahrieh D, Gelber RD, et al. Site of primary tumor has a prognostic role in operable brest cancer: the International Breast Cancer study group experience. J Clin Oncol 2005; 23:1390-400. Zucali R, Mariani L, Marubini E, et al. Early breast cancer: evaluation of the prognostic role of the site of the primary tumor. J Clin Oncol 1998; 16:1363-6. Brautigam E, Track C, Seewald DH, et al. Medial tumor localization in breast cancer an unappreciated risk factor? Strahlenther Onkol 2009; 185:663-8. Sigurdson E, Boraas M, Torosian M, Goldstein L. Internal mammary node irradiation neither decreases distant metastases nor improves survival in stage I and II breast cancer. Int J Radiat Oncol Biol Phys 2000; 47:883-94. Janni W, Rack B, Sommer H, et al. Intra-mammary tumor location does not influence prognosis but influences the prevalence of axillary lymph-node metastases. J Cancer Res Clin Oncol 2003; 129:503-10. Vitucci C, Tirelli C, Graziano F, et al. Results of conservative surgery for limitedsized infiltrating brest cancer analysis of 962 tested patients:24 years of experience. J Surg Oncol 2000; 74:108-15. Perou CM, Sørlie T, Eisen MB, et al. Molecular portraits of human breast tumours. Nature 2000; 406:747-52. Nielsen TO, Parker JS, Leung S, et al. A comparison of PAM50 intrinsic subtyping with immunohistochemistry and clinical prognostic factors in tamoxifen-treated estrogen receptor-positive breast cancer. Clin Cancer Res 2010; 16:5222-32. Goldhirsch A, Glick JH, Gelber RD, et al. Meeting highlights: International Consensus Panel on the Treatment of Primary Breast Cancer. J Natl Cancer Inst 1998; 90:1601-8. Goldhirsch A, Wood WC, Coates AS, et al. Strategies for subtypes: dealing with the diversity of breast cancer—highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2011. Ann Oncol 2011; 22:1736-47. Colleoni M, Orvieto E, Nolè F, et al. Prediction of response to primary chemotherapy for operable breast cancer. Eur J Cancer 1999; 35:574-9. Johnson N, Soot L, Nelson J, Franzini MD. Sentinel node biopsy and internal mammary lymphatic mapping in breast cancer. Am J Surg 2000; 179:386-8. Cong BB, Qiu PF, Wang YS. Internal mammary sentinel lymph node biopsy: minimally invasive staging and tailored internal mammary radiotherapy. Ann Surg Oncol 2014; 21:2119-21. Veronesi U, Arnone P, Veronesi P, et al. The value of radiotherapy on metastatic internal mammary nodes in breast cancer. Results on a large series. Ann Oncol 2008; 19:1553-60. EBCTCG (Early Breast Cancer Trialists’ Collaborative Group), McGale P, Taylor C, et al. Effect of radiotherapy after mastectomy and axillary surgery on 10-year recurrence and 20-year breast cancer mortality: meta-analysis of individual patient data for 8135 women in 22 randomised trials. Lancet 2014; 383: 2127-35. Poortmans PM, Collette S, Kirkove C, et al. Internal mammary and medial supraclavicular irradiation in breast cancer. N Engl J Med 2015; 373:317-27. Whelan TJ, Olivotto IA, Parulekar WR, et al. Regional nodal irradiation in early stage breast cancer. N Engl J Med 2015; 373:307-16. Hennequin C, Bossard N, Servagi-Vernat S, et al. Ten-year survival results of a randomized trial of irradiation of internal mammary nodes after mastectomy. Int J Radiat Oncol Biol Phys 2013; 86:860-6.
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Outcome and Medial Presentation of Breast Cancer: European Institute of Oncology Experience Emilia Montagna,1 Vincenzo Bagnardi,2,3 Nicole Rotmensz,3 Giuseppe Viale,4,5 Giuseppe Cancello,1 Antonella Palazzo,1 Viviana Galimberti,6 Paolo Veronesi,6 Alberto Luini,6 Mauro G. Mastropasqua,4 Barbara Santillo,3 Aron Goldhirsch,7 Marco Colleoni1 Abstract To our knowledge, for the first time, in the present study the role of medial localization was studied according the selected tumor subtypes. The results show that medial presentation is an adverse prognostic factor irrespective of breast cancer subtype. Background: No analyses have investigated the prognostic role of medial presentation in breast cancer patients on disease-free survival (DFS) and overall survival according to immunohistochemically-defined subtypes. Patients and Methods: We collected information from the institutional clinical database on consecutive breast cancer patients who underwent conservative surgery at the European Institute of Oncology, Milan, Italy, between 1994 and 2008. We compared the outcomes of patients with medial breast cancer with those of patients with nonmedial tumors observed at the institution during the same period. Results: Among 7369 evaluable patients, 2254 (24%) had their primary tumors in medial quadrants and 7015 (76%) in other areas. Five-year DFS was 84.7% and 86.6% (P ¼ .008) in patients with medial and nonmedial disease, respectively. In multivariate analysis, medial location was correlated with greater risk of recurrence (hazard ratio [HR], 1.23; 95% confidence interval [CI], 1.11-1.35; P < .0001) and death (HR, 1.27; 95% CI, 1.09-1.49; P ¼ .0028). Conclusion: Medial presentation is an adverse prognostic factor for breast cancer patients. Clinical Breast Cancer, Vol. 15, No. 6, 440-7 ª 2015 Elsevier Inc. All rights reserved. Keywords: Luminal, Position, Subtypes, Triple negative, Tumor
Introduction The site of presentation within the breast is not considered in recent guidelines for optimal tailoring of adjuvant therapies in breast cancer patients.1 However, the location of primary breast cancer can 1
Division of Medical Senology, European Institute of Oncology, Milan, Italy Department of Quantitative Methods and Statistics, University of Milan-Bicocca, Milan, Italy 3 Division of Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy 4 Department of Pathology, European Institute of Oncology, Milan, Italy 5 School of Medicine, University of Milan, Milan, Italy 6 Division of Senology, European Institute of Oncology, Milan, Italy 7 Program of Senology (Breast Health), European Institute of Oncology, Milan, Italy 2
Submitted: Apr 6, 2015; Revised: Jun 25, 2015; Accepted: Jul 5, 2015; Epub: July 10, 2015 Address for correspondence: Emilia Montagna, MD, Division of Medical Senology, European Institute of Oncology, Via Ripamonti 435, Milan, Italy Fax: þ39 02 574829212; e-mail contact: [email protected]
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affect outcome. Several studies have reported that the medial presentation of breast cancer is correlated with worse outcome compared with nonmedial disease,2-7 although some studies failed to find any influence of tumor location on disease recurrence and survival.8-10 Several limitations such as short follow-up, limited number of patients, and selection bias might affect the findings in these studies. Different subtypes of breast cancer patients have been identified using gene expression profiling.11 A pragmatic surrogate of molecular intrinsic subtypes using immunohistochemical and in situ hybridization assays is commonly adopted in current practice.12 The different subtypes identified as luminal A, luminal B, HER2-positive, and triple-negative have different outcomes.11 No analyses have previously evaluated the effect of medial position of breast cancer according to different subtypes. The aim of the present study was to assess the outcome in terms of disease-free
1526-8209/$ - see frontmatter ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clbc.2015.07.003
Table 1 Continued
Table 1 Patient Characteristics Characteristic Total
Medial, n (%)
Lateral/Central/ Other, n (%)
2254 (100)
7015 (100)
Year of Surgery Earlier than 1998
P
Medial, n (%)
Lateral/Central/ Other, n (%)
Nil
82 (3.6)
262 (3.7)
Characteristic Adjuvant CT/HT
.691
.654
19 (0.8)
53 (0.8)
HT
1418 (62.9)
4310 (61.4)
1998-2001
505 (22.4)
1648 (23.5)
CT
270 (12)
864 (12.3)
2002-2004
864 (38.3)
2621 (37.4)
HT-CT
484 (21.5)
2005-2007
866 (38.4)
2693 (38.4)
Age at Time of Surgery, Years <35
73 (3.2)
268 (3.8)
35-50
845 (37.5)
2655 (37.8)
51-65
936 (41.5)
2900 (41.3)
>65
400 (17.7)
1192 (17)
Premenopausal
953 (42.3)
3063 (43.7)
Postmenopausal
1301 (57.7)
3952 (56.3)
Menopausal Status
Histology 1836 (81.5)
Lobular
187 (8.3)
665 (9.5)
Mixed/other
231 (10.2)
808 (11.5)
Abbreviations: CT ¼ chemotherapy; ELIOT ¼ intraoperative radiotherapy with electrons; HT ¼ hormonaltherapy; PVI ¼ peritumoral vascular invasion.
.249
survival (DFS), overall survival (OS), and locoregional recurrence of patients treated conservatively with quadrantectomy and (in almost all cases) radiotherapy for medial breast carcinoma. We compared the outcome of these patients with outcomes of the larger number of patients with nonmedial (lateral, central, or other) breast cancer treated at the same institution during the same period. Specifically, we evaluated the prognostic role of medial presentation according to selected immunohistochemically-defined subtypes.
5542 (79)
Patients and Methods <.001
PT pT1
1754 (77.8)
pT2
491 (21.8)
1786 (25.5)
5188 (74)
pT3
9 (0.4)
41 (0.6) <.001
Positive Lymph Nodes, n None
1539 (68.3)
4389 (62.6)
1-3
556 (24.7)
1873 (26.7)
4
159 (7.1)
753 (10.7)
52 (2.3)
176 (2.5)
1513 (67.1)
4744 (67.6)
689 (30.6)
2095 (29.9)
Grade Unknown 1-2 3
.562
Subtype St Gallen 2013
.84
Luminal A
852 (37.8)
2559 (36.5)
Luminal B (HER2)
906 (40.2)
2899 (41.3)
Luminal B (HER2þ)
192 (8.5)
598 (8.5)
HER2þ
98 (4.3)
303 (4.3)
206 (9.1)
656 (9.4)
1773 (78.7)
5373 (76.6)
Moderate
335 (14.9)
1086 (15.5)
Extensive
146 (6.5)
556 (7.9)
2254 (100)
7015 (100)
Triple-negative PVI Absent
.047
Radiotherapy Performed/Proposed No Yes, standard Yes, ELIOT
e .268
39 (1.7)
158 (2.3)
1677 (74.4)
5146 (73.4)
538 (23.9)
1711 (24.4)
Patients We collected information from the institutional clinical database on consecutive breast cancer patients treated at the European Institute of Oncology (EIO), Milan, Italy, between 1994 and 2008. This use of data was approved by the institutional review board. Data on the patient’s medical history, concurrent diseases, type of surgery, histopathological features, and results of any staging procedures (blood chemistry, hematological values, bone scan, chest film, and upper abdominal ultrasound examination) were reviewed. We identified patients with early breast cancer (pT1-3 pN0-3 M0) who underwent conservative surgery with sentinel lymph node biopsy or complete axillary dissection. We excluded from the current analysis patients with distant disease at presentation or patients treated with neoadjuvant therapy. We used the larger number of patients with nonmedial breast cancer observed at the same institution during the same period as the comparator group. After final surgery, all cases were discussed during the weekly multidisciplinary meeting attended by surgeons, medical oncologists, radiation oncologists, and pathologists. Women were usually followed up with physical examination every 6 months and mammography with or without breast ultrasound (US) annually. In symptomatic cases or when clinically indicated, bone scan, chest x-ray, liver US, or computed tomography scans were also performed.
Treatments
Surgery Quadrantectomy
1579 (22.5)
.531
.042
Ductal
P
The decision for adjuvant systemic treatment was made on the basis of biological features, staging, comorbidities, and patient preference.1,13,14 For patients with luminal A disease, adjuvant endocrine therapy alone according to menopausal status was prescribed (tamoxifen or aromatase inhibitor) for a duration of 5 years in postmenopausal patients. Premenopausal patients were advised to have a combination of tamoxifen for 5 years with gonadotropinreleasing hormone analogues for at least 2 years.
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Outcome and Medial Presentation of BC: EIO Experience For patients with luminal B tumors, chemotherapy (an anthracycline combination for 4 cycles) was administered before the hormonal program. Patients with triple-negative disease were advised to undergo chemotherapy for 6 cycles including an alkylating agent (ie, classical cyclophosphamide, methotrexate, fluorouracil). In case of HER2 overexpression and/or amplification, trastuzumab was combined with adjuvant therapy starting from 2004. Postoperative breast irradiation was proposed to all patients.
Pathology and Immunohistochemistry This was a single-institution study. All patients had pathological evaluation performed after extensive sampling of the surgical specimens. Immunostaining for estrogen receptor (ER) and progesteron receptor (PgR), HER2 protein, and Ki-67 antigen were performed on consecutive tissue sections, as previously reported.15 The following primary antibodies were used: the monoclonal antibody (MAb) to ER (Dako, Glostrup, Denmark at 1/100 dilution), the MAb to PgR (Dako, 1/800), the MIB-1 MAb to the Ki-67 antigen (Immunotech, Marseille, France, 1/1200), and the polyclonal antiserum (Dako, 1/ 3200) to the HER2 protein. Only nuclear reactivity was taken into account for ER, PgR, and Ki-67 antigen, whereas only an intense and complete membrane staining in > 10% of the tumor cells qualified for HER2 overexpression (3þ). The results for ER, PgR, and Ki-67 were recorded as the percentage of immunoreactive cells over at least 2000 neoplastic cells. The value of 20% for Ki-67 labeling index was used as a cutoff in distinguishing tumors with a low (< 20%) and high (> 20%) proliferative fraction.
Statistical Analysis Differences in the distribution of subject characteristics according to site of primary tumor (medial vs. lateral, central, or other) were evaluated using the c2 test. The end points evaluated were invasive DFS and OS. DFS was defined as the time from surgery to events such as relapse (including ipsilateral breast recurrence), appearance of a second primary cancer (including contralateral breast cancer), or
death, whichever occurred first. OS was defined as the time from surgery until the date of death (from any cause). The DFS and OS functions were estimated using the KaplaneMeier method. The log-rank test was used to assess differences between groups. The hazard ratios (HRs) in comparisons of medial presentation versus lateral, central, or other presentation were estimated using a Cox proportional hazards multivariable model, controlled for menopausal status, number of positive lymph nodes, tumor size, perivascular invasion, and biological subtype. All of the analyses were carried out using the SAS software (SAS Institute, Cary, NC). P values .05 were deemed statistically significant. All reported P values were 2-sided.
Results Of the 12,628 patients treated with conservative surgery at EIO between 1994 and 2008, we excluded patients who underwent surgery after neoadjuvant therapy (n ¼ 729), patients with metastatic disease at presentation (n ¼ 110), with incomplete biological features or follow-up data (n ¼ 2520) leaving 9269 selected for the present study. A total of 2254 (24%) patients had their primary tumors in a medial location and 7015 (76%) patients had their primary tumors in other breast quadrants. Table 1 shows the patient characteristics according to the site of primary tumor: medial versus nonmedial. Patients with medial presentation were more likely to have small tumor size (78% vs. 74%) and axillary lymph node-negative disease (68% vs. 63%) compared with patients with nonmedial cancers. The other patient characteristics, including the prevalence of the immunohistological subtypes, were not significantly different according to site of tumor. The median follow-up was 8.3 years. The KaplaneMeier curves for DFS in the study population, according to site of breast cancer, is shown in Figure 1A. A worse outcome was reported for patients with medial tumors versus those with nonmedial disease. Five-year DFS was 84.7% and 86.6% (P ¼ .0081) in patients with medial and nonmedial disease, respectively. Patients with nonmedial tumors continued to have better DFS during later follow-up with
Figure 1 (A) Disease-Free Survival and (B) Overall Survival for the 9269 Patients Evaluated According to Site of Primary Tumor
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Emilia Montagna et al 10-year DFS of 73.4% compared with 70.2% in the medial group. Figure 1B shows the OS for the 2 groups. Five- and 10-year OS were 95.1% and 87.7% in the medial group compared with 95.7% and 89.8% in patients with nonmedial disease (P ¼ .19). Of the 2254 patients with medial tumors, 24.3% had an event, compared
with 21.8% among 7015 patients with other site tumor locations. In the medial and nonmedial groups 7.7% and 6.2% had a locoregional recurrence (P ¼ .013); distant recurrence was reported in 8.7% of the medial group and in 7.4% of the nonmedial group (P ¼ .047).
Figure 2 Disease-Free Survival According to Site of Primary Tumor and Histological Subtype
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Outcome and Medial Presentation of BC: EIO Experience Figures 2 and 3 show DFS and OS curves in a comparison of medial and nonmedial primary sites according to immunohistological subtype. The results show that medial presentation is an
adverse prognostic factor irrespective of breast cancer subtype. The heterogeneity test of the effect of medial presentation among different subtypes was not statistically significant for DFS and OS.
Figure 3 Overall Survival According to Site of Primary Tumor and Histological Subtype
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Emilia Montagna et al Moreover, we analyzed the interaction on medial presentation and tumor size. The adverse prognostic effect of medial presentation was confirmed in large and small tumor size as shown in Figure 4.
Multivariate Analysis The independent association between biological and clinical variables and the risk of recurrence and death in the whole series of patients were analyzed. The results, obtained using Cox
proportional hazard regression analysis, are shown in Table 2. In multivariate analysis we confirmed the prognostic role of classical clinical and biological features that correlated with greater risk of worse outcome such as larger tumor size, and positive nodal involvement. Moreover, the medial tumor presentation was associated with greater risk of recurrence (HR, 1.23; 95% confidence interval [CI], 1.11-1.35; P < .0001) and death (HR, 1.27; 95% CI, 1.09-1.49; P ¼ .0028).
Figure 4 Interaction Between Tumor Size and Medial Presentation in Terms of Disease-Free Survival and Overall Survival
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Outcome and Medial Presentation of BC: EIO Experience Table 2 Multivariate Analysis DFS
OS
HR (95% CI)
P
HR (95% CI)
Site, Medial versus Central/Lateral/Other
1.23 (1.11-1.35)
<.0001
1.27 (1.09-1.49)
.0028
Menopausal Status, Post- versus Premenopausal
1.34 (1.22-1.46)
<.0001
1.91 (1.64-2.22)
<.0001
2 versus 1
1.53 (1.39-1.69)
<.0001
1.94 (1.67-2.25)
<.0001
3 versus 1
2.05 (1.33-3.17)
.0012
2.84 (1.55-5.19)
.0007
1-3 versus none
1.29 (1.16-1.43)
<.0001
1.43 (1.19-1.70)
<.0001
4 versus none
2.28 (2.00-2.61)
<.0001
3.31 (2.72-4.03)
<.0001
Moderate versus absent
1.15 (1.02-1.30)
.0206
1.22 (1.01-1.48)
.0361
Extensive versus absent
1.32 (1.14-1.53)
.0002
1.52 (1.22-1.88)
.0002
Luminal B HER2 versus luminal A
1.51 (1.35-1.69)
<.0001
1.68 (1.38-2.05)
<.0001
Luminal B HER2þ versus luminal A
1.72 (1.47-2.01)
<.0001
1.74 (1.33-2.29)
<.0001
HER2 versus luminal A
2.21 (1.84-2.66)
<.0001
2.60 (1.95-3.46)
<.0001
Triple-negative versus luminal A
2.08 (1.79-2.42)
<.0001
3.28 (2.59-4.16)
<.000
Variable
P
PT
Positive LNs, n
PVI
Subtype (St Gallen 2013)
þ
Abbreviations: DFS ¼ disease-free survival; OS ¼ overall survival; PVI ¼ peritumoral vascular invasion.
Discussion
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The identification of clinicopathological features that might play a prognostic role in breast cancer patients is a key issue for improved patient care. In the present study, on the basis of a prospective and quality controlled database, the medial site of presentation, compared with nonmedial disease, was associated with greater risk of recurrence and death in breast cancer patients. These results retained their statistical significance after the adjustment for other prognostic factors. The magnitude of the adverse prognostic effect associated with medial presentation was similar to that reported by the International Breast Cancer Study Group (IBCSG).5 In our study, the HR was 1.23 for DFS and 1.27 for OS compared with a HR of 1.22 and 1.24 in the IBCSG analysis. However, significant differences in outcome were present between our study and that of the IBCSG. In the current series, 10-year DFS and OS for patients with medial tumors were 70.2% and 87.7% compared with 46% and 59% in the previous report. These differences are likely because all patients of the current study were treated with conservative surgery, compared with only 18% in the previous study, and that they had smaller tumors (77% of them had tumor size < 2 cm vs. 46%) and more often node-negative disease (68% vs. 44%). More importantly, however, the outcome differences might be explained by the improvement in tailored adjuvant treatments during the years of reference. The IBCSG study included patients treated from 1978 to 1993, and our analysis concerned patients treated more recently (1994-2008) when new chemo-, hormonal, and radiotherapy programs were available. The poorer outcome of medial breast cancer compared with the primary sites might be because of understaging of the disease, specifically by failing to detect occult spread to the internal mammary chain (IMC). Some authors reported that sentinel node biopsy
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of IMC has a limited prognostic effect and other studies showed the utility of IMC biopsy.16-18 Unknown IMC status and the absence of radiotherapy to the IMC field could result in a worse outcome of medial disease. Recently an Early Breast Cancer Trialists’ Collaborative Group meta-analysis reported that radiotherapy after mastectomy (and axillary dissection) including IMC reduced recurrence and breast cancer mortality in women with 1-3 positive lymph nodes.19 Moreover, 3 randomized studies, focused on the role of IMC irradiation were published or presented. Two trials tested the effect of additional IMC and supraclavicular node irradiation,20,21 and 1 trial tested the effect of additional IMC irradiation only.22 The primary end point was OS for all studies. The patients included had more frequently node-positive disease or medial or central tumors and received adjuvant chemotherapy. The randomized French trial did not show any benefit for IMC irradiation, but it was underpowered.22 The European Organization for Research and Treatment of Cancer (EORTC) 22922-10925 study randomized more than 4000 patients, with extended followup (10.9 years).20 The Canadian study, MA20, included more than 1000 patients treated with conservative surgery.21 The latter 2 studies reported a survival benefit for patients with IMC and supraclavicular node irradiation. Moreover the EORTC trial reported a benefit of DFS and metastasis-free survival (HR, 0.89 and 0.86, respectively). The Canadian study showed that additional regional nodal irradiation reduced the risk of locoregional (HR, 0.59; P ¼ .02) and distant recurrence (HR, 0.64; P ¼ .002).21 The EORTC and MA20 studies did not report a significant increase in cardiac or lung toxicity, although the follow-up in MA20 (62 months) was insufficient to exclude late toxicities. Because the magnitude of the benefit is limited, the accurate identification of candidate patients for IMC irradiation is still debated, although the size of medial tumors could represent a useful
Emilia Montagna et al criterion. The current study on the prognostic role of breast cancer location reports on the largest series of patients with mature followup, detailed clinical and biological information, and data of adjuvant treatment received in recent years. Moreover, to our knowledge, for the first time, the role of medial localization was studied according to the selected tumor subtypes. The heterogeneity test result on the effect of medial presentation among different subtypes show that the medial presentation is an adverse prognostic factor for breast cancer patients irrespective of breast cancer subtype However, the prognostic implications of medial presentation might have a role in the definition of adjuvant program, with particular regard to radiation therapy.
2. 3. 4.
5. 6. 7. 8.
Conclusion The current study showed that medial presentation has a prognostic role in breast cancer patients. This factor should be considered for optimal tailoring of adjuvant therapies.
Clinical Practice Points Some studies failed to find any influence of tumor location on
9. 10. 11. 12.
disease recurrence and survival in breast cancer patients. No analyses have investigated on the prognostic role of medial
presentation in breast cancer patients according to immunohistochemically defined subtypes. The current study on the prognostic role of breast cancer location reports on the largest series of patients with mature followup, detailed clinical and biological information, and data of adjuvant treatment received in recent years. In the present study, the medial site of presentation, compared with nonmedial disease, was associated with greater risk of recurrence and death in breast cancer patients. The negative effect of medial disease could be taken into account for the prescription of adjuvant program with particular regard to radiation therapy.
13. 14.
15. 16. 17. 18. 19.
Disclosure The authors have stated that they have no conflicts of interest.
20. 21.
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22.
International Expert Consensus on the Primary Therapy of Early Breast Cancer. Ann Oncol 2013; 24:2206-23. Lohrisch C, Jackson J, Jones A, Mates D, Olivotto IA. Relationship between tumor location and relapse in 6,781 women with early invasive breast cancer. J Clin Oncol 2000; 18:2828-35. Gaffney DK, Tsodikov A, Wiggins CL. Diminished survival in patients with inner versus outer quadrant breast cancers. J Clin Oncol 2003; 21:467-72. Fowble B, Solin LJ, Schultz DJ, Weiss MC. Breast recurrence and survival related to primary tumor location in patients undergoing conservative surgery and radiation for early-stage breast cancer. Int J Radiat Oncol Biol Phys 1992; 23: 933-9. Colleoni M, Zahrieh D, Gelber RD, et al. Site of primary tumor has a prognostic role in operable brest cancer: the International Breast Cancer study group experience. J Clin Oncol 2005; 23:1390-400. Zucali R, Mariani L, Marubini E, et al. Early breast cancer: evaluation of the prognostic role of the site of the primary tumor. J Clin Oncol 1998; 16:1363-6. Brautigam E, Track C, Seewald DH, et al. Medial tumor localization in breast cancer an unappreciated risk factor? Strahlenther Onkol 2009; 185:663-8. Sigurdson E, Boraas M, Torosian M, Goldstein L. Internal mammary node irradiation neither decreases distant metastases nor improves survival in stage I and II breast cancer. Int J Radiat Oncol Biol Phys 2000; 47:883-94. Janni W, Rack B, Sommer H, et al. Intra-mammary tumor location does not influence prognosis but influences the prevalence of axillary lymph-node metastases. J Cancer Res Clin Oncol 2003; 129:503-10. Vitucci C, Tirelli C, Graziano F, et al. Results of conservative surgery for limitedsized infiltrating brest cancer analysis of 962 tested patients:24 years of experience. J Surg Oncol 2000; 74:108-15. Perou CM, Sørlie T, Eisen MB, et al. Molecular portraits of human breast tumours. Nature 2000; 406:747-52. Nielsen TO, Parker JS, Leung S, et al. A comparison of PAM50 intrinsic subtyping with immunohistochemistry and clinical prognostic factors in tamoxifen-treated estrogen receptor-positive breast cancer. Clin Cancer Res 2010; 16:5222-32. Goldhirsch A, Glick JH, Gelber RD, et al. Meeting highlights: International Consensus Panel on the Treatment of Primary Breast Cancer. J Natl Cancer Inst 1998; 90:1601-8. Goldhirsch A, Wood WC, Coates AS, et al. Strategies for subtypes: dealing with the diversity of breast cancer—highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2011. Ann Oncol 2011; 22:1736-47. Colleoni M, Orvieto E, Nolè F, et al. Prediction of response to primary chemotherapy for operable breast cancer. Eur J Cancer 1999; 35:574-9. Johnson N, Soot L, Nelson J, Franzini MD. Sentinel node biopsy and internal mammary lymphatic mapping in breast cancer. Am J Surg 2000; 179:386-8. Cong BB, Qiu PF, Wang YS. Internal mammary sentinel lymph node biopsy: minimally invasive staging and tailored internal mammary radiotherapy. Ann Surg Oncol 2014; 21:2119-21. Veronesi U, Arnone P, Veronesi P, et al. The value of radiotherapy on metastatic internal mammary nodes in breast cancer. Results on a large series. Ann Oncol 2008; 19:1553-60. EBCTCG (Early Breast Cancer Trialists’ Collaborative Group), McGale P, Taylor C, et al. Effect of radiotherapy after mastectomy and axillary surgery on 10-year recurrence and 20-year breast cancer mortality: meta-analysis of individual patient data for 8135 women in 22 randomised trials. Lancet 2014; 383: 2127-35. Poortmans PM, Collette S, Kirkove C, et al. Internal mammary and medial supraclavicular irradiation in breast cancer. N Engl J Med 2015; 373:317-27. Whelan TJ, Olivotto IA, Parulekar WR, et al. Regional nodal irradiation in early stage breast cancer. N Engl J Med 2015; 373:307-16. Hennequin C, Bossard N, Servagi-Vernat S, et al. Ten-year survival results of a randomized trial of irradiation of internal mammary nodes after mastectomy. Int J Radiat Oncol Biol Phys 2013; 86:860-6.
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