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Prediction of axillary lymph node status in male breast carcinoma
original articles
Annals of Oncology Annals of Oncology 24: 370–376, 2013 doi:10.1093/annonc/mds283 Published online 9 October 2012
Prediction of axillary lymph node status in male breast carcinoma C. Vaysse1, J. Sroussi1, P. Mallon1, J. G. Feron1, A. L. Rivain1, C. Ngo1, C. Belichard1, S. Lasry1, J. Y. Pierga2, B. Couturaud1, A. Fitoussi1, F. Laki1, V. Fourchotte1, S. Alran1, Y. Kirova3, A. VincentSalomon4, X. Sastre-Garau4, B. Sigal-Zafrani4, R. Rouzier1 & F. Reyal1* Departments of 1Surgery; 2Medical Oncology; 3Radiotherapy; 4Biology of Tumors, Institut Curie, Paris, France
Background: To evaluate whether predictive factors of axillary lymph node metastasis in female breast cancer (BC) are similar in male BC.
Patients and methods: From January 1994 to May 2011, we recorded 80 non-metastatic male BC treated at Institut Curie (IC). We analysed the calibration and discrimination performance of two nomograms [IC, Memorian SloanKettering Cancer Center (MSKCC)] originally designed to predict axillary lymph node metastases in female BC. Results: About 55% and 24% of the tumours were pT1 and pT4, respectively. Nearly 46% demonstrated axillary lymph node metastasis. About 99% were oestrogen receptor positive and 94% HER2 negative. Lymph node status was the only significant prognostic factor of overall survival (P = 0.012). The area under curve (AUC) of IC and MSKCC nomograms were 0.66 (95% CI 0.54–0.79) and 0.64 (95% CI 0.52–0.76), respectively. The calibration of these two models was inadequate. Conclusions: Multi-variate models designed to predict axillary lymph node metastases for female BC were not effective in our male BC series. Our results may be explained by (i) small sample size (ii) different biological determinants influencing axillary metastasis in male BC compared with female BC. Key words: calibration, discrimination, male breast cancer, metastasis axillary lymph node, nomogram
introduction Male breast cancer (BC) is a rare disease, accounting for <1% of all BCs and <1% of all annual cancer deaths in men, in Western countries [1] (http://seer.cancer.gov/csr/1975_2004/ results_merged/sect_04_breast.pdf ). Randomized controlled clinical trials of BC therapy in men are not practical given the small number of cases diagnosed. Consequently, therapy provided to men with BC is extrapolated from results of clinical trials on female populations [2]. Axillary staging is a key step in BC management because nodal status correlates significantly with overall survival and determines therapeutic decision-making. Many predictors of axillary lymph node metastases have been previously suggested in female BC including tumour size, tumour grade, tumour location, presence of lymphatic/vascular invasion, high MIB-1 index, age at diagnosis, S phase, oestrogen receptor (ER) status, progesteron receptor (PR) status and HER2 status [3–12]. The Memorial Sloan-Kettering Cancer Center (MSKCC) and Institute Curie (IC) Cancer Center have developed and validated in large and independent BC series two multi-variate *Correspondence to: Dr F. Reyal, Department of Surgery, Institut Curie, 26 rue d’Ulm, 75005 Paris, France. Tel: +33-615-271-980; Fax: +33-153-104-037; E-mail: fabien. [email protected]
models to predict metastatic axillary lymph node in female patients with BC [12, 13]. The aim of this work was to evaluate and compare the performance in terms of discrimination and calibration of these nomograms on a male BC population. Our aim was to establish if the subtle interactions between significant predictive factors in MSKCC and IC nomograms are transposable to a male BC population.
patients and methods patients male population We identified 99 men with an initial diagnosis of breast carcinoma without distant metastases, treated at the IC (Paris, France) from January 1994 to May 2011.
female population Our previously published dataset [12] consisted of 615 females with earlystage breast carcinoma treated in 2008 at the IC (Paris, France).
surgical procedure Inclusion criteria were patients with infiltrating breast carcinoma treated initially with mastectomy or breast conserving surgery and axillary lymph
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Received 8 May 2012; revised 29 May 2012; accepted 5 July 2012
original articles
Annals of Oncology node exploration. Sentinel node (SN) biopsy was performed with blue patent dye, radioisotope or a combination as previously described, in conjunction with recommendations of the French Health Authority’. Axillary lymph node dissection (ALND) was performed intra-operatively if the SN was positive by frozen section. ALND was performed at a second operation if isolated tumour cells, micro or macro metastases were identified in the SN post-operatively by haematoxylin-eosin staining or immunohistochemistry. Exclusion criteria were (i) patients receiving neoadjuvant treatment (chemotherapy, hormonal therapy, targeted therapy or radiotherapy), (ii) locoregional recurrence, (iii) distant metastatic disease, (iv) surgical specimens with a final pathology report of ductal carcinoma in situ (DCIS) and (v) missing data.
tumour samples
Value, N Age (years), median (range) Body mass index, median (range) Medical history (%) High blood pressure Diabetes Tobacco Dyslipidemia Myocardial infarction Family history of breast cancer (%) BRCA mutation analysis (%) BRCA1 mutation (%) BRCA2 mutation (%) No mutation (%) In process
Baseline characteristics were compared between groups using chi-square or Fisher’s exact tests for categorical variables and Student’s t-tests for continuous variables. The MSKCC nomogram was obtained from the unit’s website (http://nomograms.mskcc.org/Breast/ BreastSLNodeMetastasisPage.aspx). The probability of SN metastases was calculated using the following variables: age at diagnosis, tumour size, special tumour type, tumour location, LVI, multi-focality, tumour type and grade, ER status and PR status [13]. The IC nomogram was obtained from FR and Y. de Rycke. A Java web-based interface is available at www. cancerdusein.curie.fr. The probability of SN metastases was calculated using the following variables: age at diagnosis, ER status and HER2 status interaction (ERpos HER2neg|ERpos HER2pos|ERneg HER2neg|ERneg HER2pos), LVI and tumour size. The model performance was quantified with respect to discrimination and calibration. Discrimination (i.e. whether the relative ranking of individual predictions is in the correct order) was quantified with the area under the receiver operating characteristic curve. Calibration (i.e. agreement between observed outcome frequencies and predicted probabilities) was studied with graphical representations of the relationship between the observed outcome frequencies and the predicted probabilities (calibration curves): the grouped proportions versus mean predicted probability in groups defined by deciles and the logistic calibration were represented. Well-calibrated models have an intercept α = 0 and a slope β = 1. Therefore, a sensible measure of calibration is a likelihood ratio statistic testing the null hypothesis that α = 0 and β = 1. The statistic has a χ 2 distribution with 2 df (unreliability [U] statistic). We also evaluated average errors [Eaver] and maximal errors [Emax] between predictions and observations obtained from a calibration curve. Discrimination and calibration analysis were performed for each nomogram on the whole population and on particular subgroups based on the pathological tumour classification (Whole population|pT4 Exclusion|pT4 only). These analyses were performed using R software (http://cran.r-project.org).
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19 (23.8) 7 (8.7) 29 (36.2) 11 (13.7) 7 (8.7) 16 (91.3) 42 (52.5) 2 (6.9) 7 (24.2) 20 (68.9) 13
Table 2. Pathological characteristics and adjuvant treatment Pathological features
statistical analysis
63 (24–88) 24.7 (14.9–41.0)
Value, N
pTNM classification (%) pT1 pT2 pT3 pT4 Tumour size (mm), median (range) Histological type (%) Invasive ductal carcinoma Invasive papillary carcinoma Invasive lobular carcinoma Tumour grade, Elston Ellis (%) Grade 1 Grade 2 Grade 3 Mitotic index (%) Low Intermediate High Lympho vascular invasion (%) Oestrogen receptor positive status (IHC) (%) Progesteron receptor positive status (IHC) (%) HER2 positive status (IHC) (%) Axillary lymph node metastasis (%) Treatment (%) Mastectomy Sentinel node biopsy Axillary lymph node dissection Adjuvant treatment Radiotherapy Chemotherapy Hormonal therapy Tamoxifen Aromatase inhibitor LH-RH agonist
44 (55.0) 16 (20.0) 1 (1.2) 19 (23.8) 18 (5–60) 77 (96.3) 2 (2.5) 1 (1.2) 13 (16.2) 43 (53.8) 24 (30.0) 29 (36.3) 24 (30.0) 27 (33.7) 33 (41.3) 79 (98.8) 64 (84.2) 4 (5.6) 37 (46.3) 78 (97.5) 20 (25) 67 (84) 73 (91.3) 58 (72.5) 39 (48.8) 69 (86.3) 61 (88.4) 26 (32.5) 1 (1.5)
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The following histological features were collected: histological type, tumour size, histological grade according to the Elston–Ellis grading system, mitotic index, lympho-vascular invasion (LVI), ER/PR and HER2 status, quantity of SN’s retrieved and number of positive SN’s. Cases were considered positive for ER and PR according to the standardized guidelines using 10% threshold of positive nuclei per carcinomatous duct. The determination of HER2 over-expression status was determined according to the American Society of Clinical Oncology Guidelines [14]. The clinical and pathological data were extracted from the IC prospective BC database.
Table 1. Patient’s clinical characteristics
original articles ethics statement The registration process of patients at the IC in this cohort was appropriate according to the French National Committee on Computers and Liberties (CNIL, Commission nationale de l’informatique et des libertés). Patients gave informed written consent before being registered in the cohort. The study was approved by the BC study group and the comity of clinical research study of the IC.
Annals of Oncology
results patient characteristics We identified 99 male patients with breast carcinoma at the IC from January 1994 to May 2011. There were a total of 19 patients excluded based on our criteria previously described; (i) DCIS (7), (ii) synchronous distant metastatic status at time
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Figure 1. ROCs for the Institut Curie and Memorian Sloan-Kettering Cancer Center nomograms on overall population (80), population excluding locally advanced tumor ( pT4. 61) and pT4 exclusively (19).
| Vaysse et al.
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original articles
Annals of Oncology
follow-up
nomograms were 0.66 (95% CI 0.54–0.79) and 0.64 (95% CI 0.52–0.76), respectively. In the subgroup of patients without pT4 tumours (61 patients), the AUC of IC and MSKCC were 0.65 (95% CI 0.51–0.79) and 0.65 (95% CI 0.51–0.79), respectively. In the subgroup of patients with only pT4 tumours (19 patients), the AUC of IC and MSKCC were 0.63 (95% CI 0.31–0.95) and 0.57 (95% CI 0.26–0.89), respectively (Table 3). The discrimination of the two nomograms failed to validate the statistical hypotheses in the pT4 subgroup. calibration
Calibration plots are given in Figure 2. Probability of SN metastatic involvement in pT4 subgroup was significantly under-estimated by both nomograms. The average difference (Eaver) between predicted and observed probabilities ranged from 10% to 24% and the maximal difference (Emax) ranged from 35% to 36% within pT4 subgroup. The two nomograms are established for patients with clinical negative axilla to predict sentinel lymph node status. Twenty patients were clinically node positive, and 40 were node negative. The discrimination of the two nomograms failed to validate the statistical hypotheses in both subgroups. sample size issue
The median follow-up was 56 months (range = 2–200). Fiveyear metastasis-free survival (MFS) was 87.5% (95% CI 89– 100). Eleven (13.8%) patients developed a recurrence and among them, 10 (12.5%) had a distant metastasis (bone, pulmonary or liver). Five patients had simultaneously a locoregional recurrence. ‘One patient had only an axillary node recurrence’. A total of 11 deaths were identified; 5 deaths were related to cancer and 6 deaths were related to another cause. Information was missing for four patients. Five-year MFS was 96.3% (95% CI 89–100) for patients without axillary lymph node metastasis and 78.0% (95% CI 64–95) for patients with axillary metastasis. The axillary lymph node status (P = 0.012) was found to be the only significant factor related to distant metastasis and overall survival.
As the IC and MSKCC performance were lower than expected even if significant [ published validations of these two nomograms showed higher performances: IC validation set AUC with 0.73 and MSKCC with 0.754], we hypothesize a small sample size issue as we analysed a cohort of 80 males breast carcinoma only [12, 13]. In an attempt to resolve this issue, we performed an iterative sampling (10 000) of 61 samples out of a series of 615 early-stage female breast carcinomas and quantified for each predictor (IC and MSKCC) their discrimination performance with the area under the receiver operating characteristic curve. It shows that a similar or lower performance in terms of discrimination was identified in 20% of the 10 000 re-sampling procedures (Figure 3).
performance of the MSKCC and IC nomograms to predict axillary lymph node status
discussion The aim of this study was to determine if predictive factors of BC axillary lymph node metastasis as defined in a female population were the same in a male population. As series of male breast carcinoma are scarce, we applied two nomograms
discrimination
Receiver Operating Characteristic (ROC) curves are plotted in Figure 1. The area under curves (AUC) of the IC and MSKCC
Table 3. Performance analysis of the IC and MSKCC in a set of 80 male breast cancer patients Overall population (n = 80) IC MSKCC Discrimination AUC 95% CI P Calibration U:p Eaver (%) Emax (%)
0.66 0.54–0.79 0.006 0.35 13 18
0.64 0.52–0.76 0.014 0.168 10 14
pT4 excluded (n = 61) IC MSKCC 0.65 0.51–0.79 0.024 0.12 11 21
0.65 0.51–0.79 0.024 0.234 22 19
pT4 only (n = 19) IC 0.63 0.31–0.95 0.202 0.039 24 35
MSKCC 0.57 0.26–0.89 0.31 0.077 10 36
IC, Institut Curie; MSKCC, Memorian Sloan-Kettering Cancer Center; AUC, area under curve.
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of diagnosis (5), (iii) neo-adjuvant chemotherapy treatment (2) and (iv) missing data (5). The patient characteristics, namely, median age at surgery, BMI, co-morbidities and BRCA mutation status are summarized in Table 1. Regarding surgical procedures, 78 (97.5%) patients underwent mastectomy and 2 patients had a partial mastectomy for initial diagnosis of gynaecomastia. ALND was performed in 67 (83.7%) patients (as a first procedure in 60 patients). SN biopsy was performed in 20 (25.0%) patients. Positive SN biopsy was identified in seven patients who proceeded to ALND. Pathological examination of the surgical specimens showed that 44 of the tumours were pT1 (55.0%) and 19 were pT4 (23.8%), according to the pTNM classification. There were 37 (46.3%) patients showing axillary lymph node metastasis. Tumours were ER positive in 79 (98.8%) patients and PR positive in 64 (84.2%) patients. There were 68 of 72 patients (94.4%) HER2 negative (eight patients had incomplete data). Seventy-three (91.3%) patients received an adjuvant treatment (chemotherapy and/or hormonal therapy and/or radiotherapy, Table 2).
original articles that have been build and validated in large independent female BC series on a male BC population. Pathological features were very similar to other male BC studies [15–18]. We observed a large proportion of pT4 (23.8%) breast carcinoma. The male mammary gland stand rudimentary after puberty compared with female. Its small
Annals of Oncology
volume could explain an important proportion of pT4 tumour in this setting. This diagnosis was made after full pathological examination of the surgical specimen. Pre-surgical clinical examination diagnosed only six (7.5%) patients with a T4 BC. Cutuli et al. found 217 (47.4%) pT1, 91 (20%) pT2 and 150 (32.8%) pT3/T4 tumours in a multi-centric series of 489 male
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Figure 2. AUC and P value for the Institut Curie and Memorian Sloan-Kettering Cancer Center nomograms on overall population (80 patients), population excluding locally advanced tumour ( pT4, 61 patients) and pT4 exclusively (19 patients).
| Vaysse et al.
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Annals of Oncology
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Figure 3. AUC of the ROCs and P values calculated on 10 000 samples of 80 patients from a population of female patients with BC.
axillary lymph node involvement for breast cancer tumours in males compared to females patients’. After puberty, the male gland is rudimentary and essentiality concentred in retro-areolar. More pT4 tumours are observed compared with female BCs with nipple and/or thoracic chest involvement [18, 43]. This anatomic difference could explain a larger proportion of metastasis axillary lymph nodes compared with female BCs. To determine if sample size is a viable explanation, we tested these two nomograms on 10 000 random samples of 61 female BC patients drawn from a 615 early-stage female breast carcinoma independent dataset and showed that 20% of these 10 000 samples would lead to an AUC inferior or equal to 0.6. This, therefore, does not exclude the possibility that the results in the male population are due to a small sample size. However, some evidence supports the hypothesis of a different biological behaviour between male and female BC in terms of axillary lymph node metastasis. We reported in ER positive HER2 positive male BC a rate of 50% of metastatic lymph node when tumour size was >20 mm. This rate was independent of the tumour size. The situation is different for female BC, for which the lymph node metastasis risks were proportional to tumour size [12]. This suggests a different biological mechanism in male BC. Our study has several limitations. It is retrospective by nature, including patients managed according to recommendation for female BC and the number of patients was small as a result of strict inclusion criteria. However, given the low incidence of these tumours, it is the first study that compares nomograms already validated on female BC to evaluate the prediction of lymph nodes metastasis on male BC. Our conclusions suggest a different biology for male BC compared with female BC within ER positive HER2 negative subgroup, probably due to different intrinsic cellular and molecular properties. However, small sample size may also be a factor. A larger prospective study with genetic molecular
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breast carcinomas. They observed only 2%, 5% and 22% of local, regional and distant metastatic recurrences, respectively, with a median follow-up of 58 months [18]. Our population of male BC revealed that 98.8% of tumours were positive for at least one hormone receptor; this figure is similar to the current literature. In previous studies, the fraction of positive tumours for ER ranged from 78.9% to 94.3% and for PR ranged from 76.8% to 89.2% (supplementary Table S1, available at Annals of Oncology online) [18–27]. The few studies which analysed HER2 status demonstrated that the vast majority of the tumours were HER2 negative. The absence of overexpression was found in 44%–99% of tumours (supplementary Table S2, available at Annals of Oncology online) [2, 28–34]. Our study observed that 68 tumours were HER2 negative out of 72 tumours tested (94.4%). Only four patients (5.6%) were HER2 positive. This result was different from female BC because HER2 is amplified and over-expressed in ∼15%–20% of cases [35, 36]. Three important retrospective studies compared axillary lymph node status between male and female with BC. Anderson et al. found 42.3% and 33.1% positive axillary lymph node on 3184 male BCs and 473 327 female BCs, respectively [24]. Nahleh et al. observed 46.4% and 31.2% positive axillary lymph node on 551 male BCs and 2181 female BCs, respectively [22]. Giordano et al. showed 42.3% and 31.8% positive axillary lymph node on 995 male BCs and 149 917 female BCs, respectively [37]. The differences were statistically significant (P < 0.001), and their results were similar to ours. We found 37 of 80 patients with positive axillary lymph node (46.3%). This rate is very stable throughout most published male breast carcinoma study (supplementary Table S3, available at Annals of Oncology online) [2, 15, 16, 18–20, 22–27, 34, 37–42]. The axillary lymph node status was a significant factor that correlated with distant MFS in our study. Cutuli et al. [18] showed in a multi-variate analysis that axillary lymph node involvement and high SBR (Scarff Bloom Richardson) were statistically significant risk factors for distant metastases. Nahleh et al. [22] reported that lymph node status, age, sex and clinical stage were independent prognostic factors for survival in male breast carcinoma. Our population showed histological features, which were similar to those reported in the literature about male BC but very different from those reported in the literature about female BC. To try understanding the intrinsic biological properties of male BC related to axillary lymph node status, we tested two nomograms designed to predict the axillary lymph node status in female breast carcinoma. These two models were tested on the whole population of male BC, on the same population after exclusion of patients with pT4 tumours, and on patients with pT4 tumours only. We showed that the IC and MSKCC nomograms had an AUC equal to 0.66 (95% CI 0.54–0.79) for IC and 0.64 (0.52–0.76) for MSKCC. These results are relatively low compare to those previously published: IC validation set AUC with 0.73 (95% CI 0.68–0.78) and MSKCC with 0.754 [12, 13]. As expected, the two nomograms were inaccurate to predict the axillary lymph node status within pT4 subgroups. ‘These results may have three possible explanations: 1) different anatomy of the male breast, 2) small sample size and 3) a different biology in terms of
original articles
original articles analysis of male BC should improve our understanding of this disease.
disclosure The authors have declared no conflicts of interest.
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Annals of Oncology
Annals of Oncology Annals of Oncology 24: 370–376, 2013 doi:10.1093/annonc/mds283 Published online 9 October 2012
Prediction of axillary lymph node status in male breast carcinoma C. Vaysse1, J. Sroussi1, P. Mallon1, J. G. Feron1, A. L. Rivain1, C. Ngo1, C. Belichard1, S. Lasry1, J. Y. Pierga2, B. Couturaud1, A. Fitoussi1, F. Laki1, V. Fourchotte1, S. Alran1, Y. Kirova3, A. VincentSalomon4, X. Sastre-Garau4, B. Sigal-Zafrani4, R. Rouzier1 & F. Reyal1* Departments of 1Surgery; 2Medical Oncology; 3Radiotherapy; 4Biology of Tumors, Institut Curie, Paris, France
Background: To evaluate whether predictive factors of axillary lymph node metastasis in female breast cancer (BC) are similar in male BC.
Patients and methods: From January 1994 to May 2011, we recorded 80 non-metastatic male BC treated at Institut Curie (IC). We analysed the calibration and discrimination performance of two nomograms [IC, Memorian SloanKettering Cancer Center (MSKCC)] originally designed to predict axillary lymph node metastases in female BC. Results: About 55% and 24% of the tumours were pT1 and pT4, respectively. Nearly 46% demonstrated axillary lymph node metastasis. About 99% were oestrogen receptor positive and 94% HER2 negative. Lymph node status was the only significant prognostic factor of overall survival (P = 0.012). The area under curve (AUC) of IC and MSKCC nomograms were 0.66 (95% CI 0.54–0.79) and 0.64 (95% CI 0.52–0.76), respectively. The calibration of these two models was inadequate. Conclusions: Multi-variate models designed to predict axillary lymph node metastases for female BC were not effective in our male BC series. Our results may be explained by (i) small sample size (ii) different biological determinants influencing axillary metastasis in male BC compared with female BC. Key words: calibration, discrimination, male breast cancer, metastasis axillary lymph node, nomogram
introduction Male breast cancer (BC) is a rare disease, accounting for <1% of all BCs and <1% of all annual cancer deaths in men, in Western countries [1] (http://seer.cancer.gov/csr/1975_2004/ results_merged/sect_04_breast.pdf ). Randomized controlled clinical trials of BC therapy in men are not practical given the small number of cases diagnosed. Consequently, therapy provided to men with BC is extrapolated from results of clinical trials on female populations [2]. Axillary staging is a key step in BC management because nodal status correlates significantly with overall survival and determines therapeutic decision-making. Many predictors of axillary lymph node metastases have been previously suggested in female BC including tumour size, tumour grade, tumour location, presence of lymphatic/vascular invasion, high MIB-1 index, age at diagnosis, S phase, oestrogen receptor (ER) status, progesteron receptor (PR) status and HER2 status [3–12]. The Memorial Sloan-Kettering Cancer Center (MSKCC) and Institute Curie (IC) Cancer Center have developed and validated in large and independent BC series two multi-variate *Correspondence to: Dr F. Reyal, Department of Surgery, Institut Curie, 26 rue d’Ulm, 75005 Paris, France. Tel: +33-615-271-980; Fax: +33-153-104-037; E-mail: fabien. [email protected]
models to predict metastatic axillary lymph node in female patients with BC [12, 13]. The aim of this work was to evaluate and compare the performance in terms of discrimination and calibration of these nomograms on a male BC population. Our aim was to establish if the subtle interactions between significant predictive factors in MSKCC and IC nomograms are transposable to a male BC population.
patients and methods patients male population We identified 99 men with an initial diagnosis of breast carcinoma without distant metastases, treated at the IC (Paris, France) from January 1994 to May 2011.
female population Our previously published dataset [12] consisted of 615 females with earlystage breast carcinoma treated in 2008 at the IC (Paris, France).
surgical procedure Inclusion criteria were patients with infiltrating breast carcinoma treated initially with mastectomy or breast conserving surgery and axillary lymph
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Received 8 May 2012; revised 29 May 2012; accepted 5 July 2012
original articles
Annals of Oncology node exploration. Sentinel node (SN) biopsy was performed with blue patent dye, radioisotope or a combination as previously described, in conjunction with recommendations of the French Health Authority’. Axillary lymph node dissection (ALND) was performed intra-operatively if the SN was positive by frozen section. ALND was performed at a second operation if isolated tumour cells, micro or macro metastases were identified in the SN post-operatively by haematoxylin-eosin staining or immunohistochemistry. Exclusion criteria were (i) patients receiving neoadjuvant treatment (chemotherapy, hormonal therapy, targeted therapy or radiotherapy), (ii) locoregional recurrence, (iii) distant metastatic disease, (iv) surgical specimens with a final pathology report of ductal carcinoma in situ (DCIS) and (v) missing data.
tumour samples
Value, N Age (years), median (range) Body mass index, median (range) Medical history (%) High blood pressure Diabetes Tobacco Dyslipidemia Myocardial infarction Family history of breast cancer (%) BRCA mutation analysis (%) BRCA1 mutation (%) BRCA2 mutation (%) No mutation (%) In process
Baseline characteristics were compared between groups using chi-square or Fisher’s exact tests for categorical variables and Student’s t-tests for continuous variables. The MSKCC nomogram was obtained from the unit’s website (http://nomograms.mskcc.org/Breast/ BreastSLNodeMetastasisPage.aspx). The probability of SN metastases was calculated using the following variables: age at diagnosis, tumour size, special tumour type, tumour location, LVI, multi-focality, tumour type and grade, ER status and PR status [13]. The IC nomogram was obtained from FR and Y. de Rycke. A Java web-based interface is available at www. cancerdusein.curie.fr. The probability of SN metastases was calculated using the following variables: age at diagnosis, ER status and HER2 status interaction (ERpos HER2neg|ERpos HER2pos|ERneg HER2neg|ERneg HER2pos), LVI and tumour size. The model performance was quantified with respect to discrimination and calibration. Discrimination (i.e. whether the relative ranking of individual predictions is in the correct order) was quantified with the area under the receiver operating characteristic curve. Calibration (i.e. agreement between observed outcome frequencies and predicted probabilities) was studied with graphical representations of the relationship between the observed outcome frequencies and the predicted probabilities (calibration curves): the grouped proportions versus mean predicted probability in groups defined by deciles and the logistic calibration were represented. Well-calibrated models have an intercept α = 0 and a slope β = 1. Therefore, a sensible measure of calibration is a likelihood ratio statistic testing the null hypothesis that α = 0 and β = 1. The statistic has a χ 2 distribution with 2 df (unreliability [U] statistic). We also evaluated average errors [Eaver] and maximal errors [Emax] between predictions and observations obtained from a calibration curve. Discrimination and calibration analysis were performed for each nomogram on the whole population and on particular subgroups based on the pathological tumour classification (Whole population|pT4 Exclusion|pT4 only). These analyses were performed using R software (http://cran.r-project.org).
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19 (23.8) 7 (8.7) 29 (36.2) 11 (13.7) 7 (8.7) 16 (91.3) 42 (52.5) 2 (6.9) 7 (24.2) 20 (68.9) 13
Table 2. Pathological characteristics and adjuvant treatment Pathological features
statistical analysis
63 (24–88) 24.7 (14.9–41.0)
Value, N
pTNM classification (%) pT1 pT2 pT3 pT4 Tumour size (mm), median (range) Histological type (%) Invasive ductal carcinoma Invasive papillary carcinoma Invasive lobular carcinoma Tumour grade, Elston Ellis (%) Grade 1 Grade 2 Grade 3 Mitotic index (%) Low Intermediate High Lympho vascular invasion (%) Oestrogen receptor positive status (IHC) (%) Progesteron receptor positive status (IHC) (%) HER2 positive status (IHC) (%) Axillary lymph node metastasis (%) Treatment (%) Mastectomy Sentinel node biopsy Axillary lymph node dissection Adjuvant treatment Radiotherapy Chemotherapy Hormonal therapy Tamoxifen Aromatase inhibitor LH-RH agonist
44 (55.0) 16 (20.0) 1 (1.2) 19 (23.8) 18 (5–60) 77 (96.3) 2 (2.5) 1 (1.2) 13 (16.2) 43 (53.8) 24 (30.0) 29 (36.3) 24 (30.0) 27 (33.7) 33 (41.3) 79 (98.8) 64 (84.2) 4 (5.6) 37 (46.3) 78 (97.5) 20 (25) 67 (84) 73 (91.3) 58 (72.5) 39 (48.8) 69 (86.3) 61 (88.4) 26 (32.5) 1 (1.5)
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The following histological features were collected: histological type, tumour size, histological grade according to the Elston–Ellis grading system, mitotic index, lympho-vascular invasion (LVI), ER/PR and HER2 status, quantity of SN’s retrieved and number of positive SN’s. Cases were considered positive for ER and PR according to the standardized guidelines using 10% threshold of positive nuclei per carcinomatous duct. The determination of HER2 over-expression status was determined according to the American Society of Clinical Oncology Guidelines [14]. The clinical and pathological data were extracted from the IC prospective BC database.
Table 1. Patient’s clinical characteristics
original articles ethics statement The registration process of patients at the IC in this cohort was appropriate according to the French National Committee on Computers and Liberties (CNIL, Commission nationale de l’informatique et des libertés). Patients gave informed written consent before being registered in the cohort. The study was approved by the BC study group and the comity of clinical research study of the IC.
Annals of Oncology
results patient characteristics We identified 99 male patients with breast carcinoma at the IC from January 1994 to May 2011. There were a total of 19 patients excluded based on our criteria previously described; (i) DCIS (7), (ii) synchronous distant metastatic status at time
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Figure 1. ROCs for the Institut Curie and Memorian Sloan-Kettering Cancer Center nomograms on overall population (80), population excluding locally advanced tumor ( pT4. 61) and pT4 exclusively (19).
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original articles
Annals of Oncology
follow-up
nomograms were 0.66 (95% CI 0.54–0.79) and 0.64 (95% CI 0.52–0.76), respectively. In the subgroup of patients without pT4 tumours (61 patients), the AUC of IC and MSKCC were 0.65 (95% CI 0.51–0.79) and 0.65 (95% CI 0.51–0.79), respectively. In the subgroup of patients with only pT4 tumours (19 patients), the AUC of IC and MSKCC were 0.63 (95% CI 0.31–0.95) and 0.57 (95% CI 0.26–0.89), respectively (Table 3). The discrimination of the two nomograms failed to validate the statistical hypotheses in the pT4 subgroup. calibration
Calibration plots are given in Figure 2. Probability of SN metastatic involvement in pT4 subgroup was significantly under-estimated by both nomograms. The average difference (Eaver) between predicted and observed probabilities ranged from 10% to 24% and the maximal difference (Emax) ranged from 35% to 36% within pT4 subgroup. The two nomograms are established for patients with clinical negative axilla to predict sentinel lymph node status. Twenty patients were clinically node positive, and 40 were node negative. The discrimination of the two nomograms failed to validate the statistical hypotheses in both subgroups. sample size issue
The median follow-up was 56 months (range = 2–200). Fiveyear metastasis-free survival (MFS) was 87.5% (95% CI 89– 100). Eleven (13.8%) patients developed a recurrence and among them, 10 (12.5%) had a distant metastasis (bone, pulmonary or liver). Five patients had simultaneously a locoregional recurrence. ‘One patient had only an axillary node recurrence’. A total of 11 deaths were identified; 5 deaths were related to cancer and 6 deaths were related to another cause. Information was missing for four patients. Five-year MFS was 96.3% (95% CI 89–100) for patients without axillary lymph node metastasis and 78.0% (95% CI 64–95) for patients with axillary metastasis. The axillary lymph node status (P = 0.012) was found to be the only significant factor related to distant metastasis and overall survival.
As the IC and MSKCC performance were lower than expected even if significant [ published validations of these two nomograms showed higher performances: IC validation set AUC with 0.73 and MSKCC with 0.754], we hypothesize a small sample size issue as we analysed a cohort of 80 males breast carcinoma only [12, 13]. In an attempt to resolve this issue, we performed an iterative sampling (10 000) of 61 samples out of a series of 615 early-stage female breast carcinomas and quantified for each predictor (IC and MSKCC) their discrimination performance with the area under the receiver operating characteristic curve. It shows that a similar or lower performance in terms of discrimination was identified in 20% of the 10 000 re-sampling procedures (Figure 3).
performance of the MSKCC and IC nomograms to predict axillary lymph node status
discussion The aim of this study was to determine if predictive factors of BC axillary lymph node metastasis as defined in a female population were the same in a male population. As series of male breast carcinoma are scarce, we applied two nomograms
discrimination
Receiver Operating Characteristic (ROC) curves are plotted in Figure 1. The area under curves (AUC) of the IC and MSKCC
Table 3. Performance analysis of the IC and MSKCC in a set of 80 male breast cancer patients Overall population (n = 80) IC MSKCC Discrimination AUC 95% CI P Calibration U:p Eaver (%) Emax (%)
0.66 0.54–0.79 0.006 0.35 13 18
0.64 0.52–0.76 0.014 0.168 10 14
pT4 excluded (n = 61) IC MSKCC 0.65 0.51–0.79 0.024 0.12 11 21
0.65 0.51–0.79 0.024 0.234 22 19
pT4 only (n = 19) IC 0.63 0.31–0.95 0.202 0.039 24 35
MSKCC 0.57 0.26–0.89 0.31 0.077 10 36
IC, Institut Curie; MSKCC, Memorian Sloan-Kettering Cancer Center; AUC, area under curve.
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of diagnosis (5), (iii) neo-adjuvant chemotherapy treatment (2) and (iv) missing data (5). The patient characteristics, namely, median age at surgery, BMI, co-morbidities and BRCA mutation status are summarized in Table 1. Regarding surgical procedures, 78 (97.5%) patients underwent mastectomy and 2 patients had a partial mastectomy for initial diagnosis of gynaecomastia. ALND was performed in 67 (83.7%) patients (as a first procedure in 60 patients). SN biopsy was performed in 20 (25.0%) patients. Positive SN biopsy was identified in seven patients who proceeded to ALND. Pathological examination of the surgical specimens showed that 44 of the tumours were pT1 (55.0%) and 19 were pT4 (23.8%), according to the pTNM classification. There were 37 (46.3%) patients showing axillary lymph node metastasis. Tumours were ER positive in 79 (98.8%) patients and PR positive in 64 (84.2%) patients. There were 68 of 72 patients (94.4%) HER2 negative (eight patients had incomplete data). Seventy-three (91.3%) patients received an adjuvant treatment (chemotherapy and/or hormonal therapy and/or radiotherapy, Table 2).
original articles that have been build and validated in large independent female BC series on a male BC population. Pathological features were very similar to other male BC studies [15–18]. We observed a large proportion of pT4 (23.8%) breast carcinoma. The male mammary gland stand rudimentary after puberty compared with female. Its small
Annals of Oncology
volume could explain an important proportion of pT4 tumour in this setting. This diagnosis was made after full pathological examination of the surgical specimen. Pre-surgical clinical examination diagnosed only six (7.5%) patients with a T4 BC. Cutuli et al. found 217 (47.4%) pT1, 91 (20%) pT2 and 150 (32.8%) pT3/T4 tumours in a multi-centric series of 489 male
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Figure 2. AUC and P value for the Institut Curie and Memorian Sloan-Kettering Cancer Center nomograms on overall population (80 patients), population excluding locally advanced tumour ( pT4, 61 patients) and pT4 exclusively (19 patients).
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Annals of Oncology
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Figure 3. AUC of the ROCs and P values calculated on 10 000 samples of 80 patients from a population of female patients with BC.
axillary lymph node involvement for breast cancer tumours in males compared to females patients’. After puberty, the male gland is rudimentary and essentiality concentred in retro-areolar. More pT4 tumours are observed compared with female BCs with nipple and/or thoracic chest involvement [18, 43]. This anatomic difference could explain a larger proportion of metastasis axillary lymph nodes compared with female BCs. To determine if sample size is a viable explanation, we tested these two nomograms on 10 000 random samples of 61 female BC patients drawn from a 615 early-stage female breast carcinoma independent dataset and showed that 20% of these 10 000 samples would lead to an AUC inferior or equal to 0.6. This, therefore, does not exclude the possibility that the results in the male population are due to a small sample size. However, some evidence supports the hypothesis of a different biological behaviour between male and female BC in terms of axillary lymph node metastasis. We reported in ER positive HER2 positive male BC a rate of 50% of metastatic lymph node when tumour size was >20 mm. This rate was independent of the tumour size. The situation is different for female BC, for which the lymph node metastasis risks were proportional to tumour size [12]. This suggests a different biological mechanism in male BC. Our study has several limitations. It is retrospective by nature, including patients managed according to recommendation for female BC and the number of patients was small as a result of strict inclusion criteria. However, given the low incidence of these tumours, it is the first study that compares nomograms already validated on female BC to evaluate the prediction of lymph nodes metastasis on male BC. Our conclusions suggest a different biology for male BC compared with female BC within ER positive HER2 negative subgroup, probably due to different intrinsic cellular and molecular properties. However, small sample size may also be a factor. A larger prospective study with genetic molecular
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breast carcinomas. They observed only 2%, 5% and 22% of local, regional and distant metastatic recurrences, respectively, with a median follow-up of 58 months [18]. Our population of male BC revealed that 98.8% of tumours were positive for at least one hormone receptor; this figure is similar to the current literature. In previous studies, the fraction of positive tumours for ER ranged from 78.9% to 94.3% and for PR ranged from 76.8% to 89.2% (supplementary Table S1, available at Annals of Oncology online) [18–27]. The few studies which analysed HER2 status demonstrated that the vast majority of the tumours were HER2 negative. The absence of overexpression was found in 44%–99% of tumours (supplementary Table S2, available at Annals of Oncology online) [2, 28–34]. Our study observed that 68 tumours were HER2 negative out of 72 tumours tested (94.4%). Only four patients (5.6%) were HER2 positive. This result was different from female BC because HER2 is amplified and over-expressed in ∼15%–20% of cases [35, 36]. Three important retrospective studies compared axillary lymph node status between male and female with BC. Anderson et al. found 42.3% and 33.1% positive axillary lymph node on 3184 male BCs and 473 327 female BCs, respectively [24]. Nahleh et al. observed 46.4% and 31.2% positive axillary lymph node on 551 male BCs and 2181 female BCs, respectively [22]. Giordano et al. showed 42.3% and 31.8% positive axillary lymph node on 995 male BCs and 149 917 female BCs, respectively [37]. The differences were statistically significant (P < 0.001), and their results were similar to ours. We found 37 of 80 patients with positive axillary lymph node (46.3%). This rate is very stable throughout most published male breast carcinoma study (supplementary Table S3, available at Annals of Oncology online) [2, 15, 16, 18–20, 22–27, 34, 37–42]. The axillary lymph node status was a significant factor that correlated with distant MFS in our study. Cutuli et al. [18] showed in a multi-variate analysis that axillary lymph node involvement and high SBR (Scarff Bloom Richardson) were statistically significant risk factors for distant metastases. Nahleh et al. [22] reported that lymph node status, age, sex and clinical stage were independent prognostic factors for survival in male breast carcinoma. Our population showed histological features, which were similar to those reported in the literature about male BC but very different from those reported in the literature about female BC. To try understanding the intrinsic biological properties of male BC related to axillary lymph node status, we tested two nomograms designed to predict the axillary lymph node status in female breast carcinoma. These two models were tested on the whole population of male BC, on the same population after exclusion of patients with pT4 tumours, and on patients with pT4 tumours only. We showed that the IC and MSKCC nomograms had an AUC equal to 0.66 (95% CI 0.54–0.79) for IC and 0.64 (0.52–0.76) for MSKCC. These results are relatively low compare to those previously published: IC validation set AUC with 0.73 (95% CI 0.68–0.78) and MSKCC with 0.754 [12, 13]. As expected, the two nomograms were inaccurate to predict the axillary lymph node status within pT4 subgroups. ‘These results may have three possible explanations: 1) different anatomy of the male breast, 2) small sample size and 3) a different biology in terms of
original articles
original articles analysis of male BC should improve our understanding of this disease.
disclosure The authors have declared no conflicts of interest.
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