Squamous cell carcinoma of the breast, are there two entities with distinct prognosis? A series of 39 patients.

PURPOSE: Squamous cell carcinoma (SCC) of the breast is a rare entity of breast cancer, with a very poor prognosis, and whose pathophysiology is still unwell established. Therapeutic management is very heterogeneous due to its incomplete understanding. Nevertheless, it seems that two histological entities can be distinguished: pure SCC close to the cutaneous origin, and metaplastic squamous breast cancer (MSBC). The aim of this study is therefore to assess the difference in survival according to the histological type (SCC or MSBC) and to describe the demographic, clinical, and therapeutic characteristics of the two underlying populations. METHODS: Our data came from a monocentric retrospective series of 39 patients treated between 1985 and 2018 at the Gustave Roussy Institute (France) for a breast SCC. RESULTS: Of the 39 patients included, 64% had MSBC and 36% had a pure form. The overall and recurrence-free survival at 3 years [CI 95%] was 72.3% [56.9%; 87.0%] and 67.2% [51.2%; 83.2%], respectively. The overall 3-year survival of patients with MSBC was significantly lower than that with pure SCC: HR [CI 95%] 9.5 [1.2; 73.1], p = 0.008. The 3-year recurrence-free survival of patients with MSBC was also poorer: HR [CI 95%] 11.9 [1.6; 90.7], p = 0.002. Patients with MSBC also tended to be younger, have a large lesion size, and be more metastatic. CONCLUSION: The histological nature of SCC seems to bring fundamental new elements to the therapeutic management as it impacts recurrence and survival. It should therefore be better characterized at diagnosis in order to possibly adapt treatments.

Prognostic and predictive value of tumor-infiltrating lymphocytes in two phase III randomized adjuvant breast cancer trials.

BACKGROUND: Tumor-infiltrating lymphocytes (TILs) are emerging as strong prognostic factor for early breast cancer patients, especially in the triple-negative subtype. Here, we aim to validate previous findings on the prognostic role of TIL in the context of two randomized adjuvant trials and to investigate whether lymphocyte infiltrates can predict benefit from adjuvant anthracyclines. PATIENTS AND METHODS: A total of 816 patients enrolled and treated at the Gustave Roussy in the context of two multicentric randomized trials comparing adjuvant anthracyclines versus no chemotherapy were included in the present analysis. Primary end point was overall survival (OS). Hematoxilin and eosin slides of primary tumors were retrieved and evaluated for the percentage of intratumoral (It) and stromal (Str) TIL. Each case was also defined as high-TIL or low-TIL breast cancer adopting previously validated cutoffs. RESULTS: TIL were assessable for 781 of 816 cases. High-TIL cases were more likely grade 3 and estrogen receptor (ER)-negative (P < 0.001). In multivariate analysis, both continuous It-TIL and Str-TIL were strong prognostic factors for OS [hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.77-0.95 P = 0.003; HR 0.89, 95% CI 0.81-0.96, P = 0.005 for It-TIL and Str-TIL, respectively]. The prognostic effect of continuous TIL was limited to triple-negative and HER2-positive patients. Ten-year OS rates were: 89% and 68% for triple-negative high-TIL and low-TIL, respectively (HR 0.44, 95% CI 0.18-1.10, P = 0.07) and 78% and 57% for HER2-positive high-TIL versus low-TIL, respectively (HR 0.46, 95% CI 0.20-1.11, P = 0.08). Either continuous or binary TIL variables did not predict for the efficacy of anthracyclines. Test for interaction P value was not significant in the whole study population and in subgroups (ER+/HER2-, HER2+, ER-/HER2-). CONCLUSIONS: We confirmed the prognostic role of TIL in triple-negative early breast cancer and suggested a prognostic impact in HER2+ patients as well. Basing on our data, TIL should not be used as a parameter to select patients for anthracyclines chemotherapy.

Prognostic value of tumor-infiltrating lymphocytes on residual disease after primary chemotherapy for triple-negative breast cancer: a retrospective multicenter study.

BACKGROUND: There is a need to develop surrogates for treatment efficacy in the neoadjuvant setting to speed-up drug development and stratify patients according to outcome. Preclinical studies showed that chemotherapy induces an antitumor immune response. In order to develop new surrogates for drug efficacy, we assessed the prognostic value of tumor-infiltrating lymphocytes (TIL) on residual disease after neoadjuvant chemotherapy (NACT) in patients with triple-negative breast cancer (TNBC). PATIENTS AND METHODS: Three hundred four TNBC patients with residual disease after NACT were retrospectively identified in three different hospitals. Hematoxylin and eosin-stained slides from surgical postchemotherapy specimens were evaluated for intratumoral (It-TIL) and stromal (Str-TIL) TIL. Cases were classified as High-TIL if It-TIL and/or Str-TIL >60%. RESULTS: TIL were assessable for 278 cases. Continuous It-TIL and Str-TIL variables were strong prognostic factors in the multivariate model, both for metastasis-free [hazard ratio (HR) 0.86, 95% confidence interval (CI) 0.77-0.96, P = 0.01 and HR 0.85, 95% CI 0.75-0.98, P = 0.02 for Str-TIL and It-TIL, respectively] and overall survival (HR 0.86, 95% CI 0.77-0.97, P = 0.01 and HR 0.86, 95% CI 0.75-0.99, P = 0.03 for Str-TIL and It-TIL, respectively). The 5-year overall survival rate was 91% (95% CI 68% to 97%) for High-TIL patients (n = 27) and 55% (95% CI 48% to 61%) for Low-TIL patients (HR 0.19, 95% CI 0.06-0.61, log-rank P = 0.0017). The major prognostic impact of TIL was seen for patients with large tumor burden following NACT (residual tumor >2 cm and/or node metastasis). In all but one High-TIL case, It-TIL and Str-TIL values were lower on the prechemotherapy sample. CONCLUSIONS: The presence of TIL in residual disease after NACT is associated with better prognosis in TNBC patients. This parameter may represent a new surrogate of drug efficacy to test investigational agents in the neoadjuvant setting and a new prognostic marker to select patients at high risk of relapse.

Pure and mixed mucinous carcinoma of the breast: fine needle aspiration cytology findings and review of the literature.

OBJECTIVE: Mucinous (colloid) breast carcinoma accounts for 1-6% of all breast cancer. It comprises pure mucinous tumours and mixed infiltrating ductal carcinomas with a mucinous component. As this latter mixed form has a worse prognosis than pure colloid carcinoma, making this diagnosis on fine needle aspiration cytology (FNAC) might influence the choice of treatment. METHODS: We report a consecutive series of 22 cases consisting of 17 mixed and five pure mucinous carcinomas diagnosed by cytology and verified on histopathology. Patients underwent FNAC at the one-stop clinic of our institution during a 7-year period of time. Cytological findings were evaluated by a semi-quantitative method and included percentage of smear surface occupied by mucin, shape of cell groupings, size and outline of tumour nuclei as well as presence or absence of nucleolus. RESULTS: Three of five pure mucinous carcinomas displayed at least two of the following features: abundant mucin, small nuclei and/or regular nuclear outlines. Sparse mucin, large nuclei, irregular nuclear outlines or the presence of nucleoli were found in 7 out of 17 mixed mucinous carcinomas but not in pure tumours. CONCLUSION: Cytopathological identification of patients with pure mucinous carcinomas may be performed in a limited number of cases.

Breast Cancer Index predicts pathological complete response and eligibility for breast conserving surgery in breast cancer patients treated with neoadjuvant chemotherapy.

BACKGROUND: The aim of neoadjuvant chemotherapy is to increase the likelihood of successful breast conservation surgery (BCS). Accurate identification of BCS candidates is a diagnostic challenge. Breast Cancer Index (BCI) predicts recurrence risk in estrogen receptor+lymph node-breast cancer. Performance of BCI to predict chemosensitivity based on pathological complete response (pCR) and BCS was assessed. METHODS: Real-time RT-PCR BCI assay was conducted using tumor samples from 150 breast cancer patients treated with neoadjuvant chemotherapy. Logistical regression and c-index were used to assess predictive strength and additive accuracy of BCI beyond clinicopathologic factors. RESULTS: BCI classified 42% of patients as low, 35% as intermediate and 23% as high risk. Low BCI risk group had 98.4% negative predictive value (NPV) for pCR and 86% NPV for BCS. High versus low BCI group had a 34 and 5.8 greater likelihood of achieving pCR and BCS, respectively (P=0.0055; P=0.0022). BCI increased c-index for pCR (0.875-0.924; P=0.017) and BCS prediction (0.788-0.843; P=0.027) beyond clinicopathologic factors. CONCLUSIONS: BCI significantly predicted pCR and BCS beyond clinicopathologic factors. High NPVs indicate that BCI could be a useful tool to identify breast cancer patients who are not eligible for neoadjuvant chemotherapy. These results suggest that BCI could be used to assess both chemosensitivity and eligibility for BCS.

Modulation of ER phosphorylation on serine 118 by endocrine therapy: a new surrogate marker for efficacy.

BACKGROUND: Phosphorylation of serine 118 (ser118) has been reported to be involved in the activation of estrogen receptor (ER). In the present study, we evaluated whether endocrine therapy modulated ER phosphorylation on ser118. PATIENTS AND METHODS: We carried out a tissue microarray that included 80 primary breast tumors obtained before the administration of endocrine therapy. A second tissue microarray included 52 tumors obtained after endocrine therapy from the same patients. Immunostainings were carried out for ER, Pser118ER, Her2, insulin growth factor receptor (IGFR), p21-activated kinase 1 (PAK1), pMAPK, bcl2 and progesterone receptor. RESULTS: Pser118ER staining was higher in Her2- (P = 0.06), IGFR- (P = 0.0002) and pMAPK-expressing tumors (P = 0.001). The level of ER phosphorylation was not different according to the occurrence of clinical tumor response (P = 0.16). Pser118ER expression was significantly reduced by endocrine therapy. The mean Pser118ER score was 163 [standard deviation (SD) 81] before endocrine therapy and 80 (SD 90) after endocrine therapy (P = 0.0001, paired t-test). The magnitude of Pser118ER decrease was higher in tumors that responded to endocrine therapy (mean decrease 128, SD 86) as compared with refractory tumors (mean decrease 38, SD 130) (P = 0.017, t-test). CONCLUSION: These findings suggest that endocrine therapy modulates ER on ser118. Pser118ER immunostaining could be used as surrogate marker to monitor treatment efficacy.

Efficacy of adjuvant chemotherapy according to Prion protein expression in patients with estrogen receptor-negative breast cancer.

BACKGROUND: Prion protein (PrPc) has been previously reported to be associated with resistance to proapoptotic stimuli. We evaluated whether the expression of PrPc was associated with the resistance to adjuvant chemotherapy in patients with estrogen receptor (ER) -negative breast cancer. PATIENTS AND METHODS: The expression of PrPc by primary tumors was assessed by immunohistochemistry in a series of 756 patients included in two randomized trials that compared anthracycline-based chemotherapy to no chemotherapy. The PrPc expression was correlated with ER expression and the benefit of adjuvant chemotherapy was assessed according to PrPc expression in patients with ER-negative tumors. RESULTS: Immunostaining analysis showed that PrPc was mainly expressed by myoepithelial cells in normal breast tissue. Tissue microarray analysis from 756 breast tumors showed that PrPc was associated with ER-negative breast cancer subsets (P < 0.001). Adjuvant chemotherapy was not associated with a significant risk reduction for death in patients with ER-negative/PrPc-positive disease [adjusted hazard ratio (HR) for death = 0.98, 95% confidence interval (CI) 0.45-2.1, P = 0.95], while it decreased the risk for death (HR = 0.39, 95% CI 0.2-0.74, P = 0.004) in patients with ER-negative/PrPc-negative tumors. CONCLUSION: These data indicate that ER-negative/PrPc-negative phenotype is associated with a high sensitivity to adjuvant chemotherapy.

[Nipple areola complex conservation in immediate breast reconstruction: prospective study of 66 cases]. / Conservation aréolo-mamelonnaire en reconstruction mammaire immédiate: étude prospective de 66 cas.

OBJECTIVE OF THE STUDY: Our objective is to define a sub-group of patients in whom skin-sparing mastectomy with immediate reconstruction and preservation of the nipple-areola complex is technically and oncologically feasible without increasing the risk of complications and local recurrence. PATIENTS AND METHODS: Between September 1999 and December 2005, 66 patients presenting an in situ and/or invasive breast carcinoma justifying a mastectomy underwent immediate breast reconstruction preserving the skin and nipple-areolar complex. RESULTS: After a median follow-up of 37 months, definitive conservation of the nipple-areolar complex with good esthetic results was achieved in 71% of the cases. CONCLUSION: This preliminary study provides encouraging results in a selected patient population but requires a longer term follow-up in order to draw definitive conclusions on the oncological safety preserving the nipple-areolar complex.

Main drug-metabolizing enzyme systems in human breast tumors and peritumoral tissues.

In an attempt to better understand breast tumors sensitivity or resistance to anticancer drugs, the main drug-metabolizing enzyme systems were evaluated in both breast tumors and their corresponding peritumoral tissues in 12 patients. The following enzymes were assayed by Western blot: cytochromes P-450 (1A1/A2, 2B1/B2, 2C8-10, 2E1, 3A4); glutathione S-transferases (GST-alpha, -mu, and -pi); and epoxide hydrolase. The activity of the following enzymes or cofactor were determined by spectrophotometric or fluorometric assays: GST; total glutathione; UDP-glucuronosyltransferase; beta-glucuronidase; sulfotransferase; and sulfatase. Results showed the absence of all probed cytochromes P-450 in both tumoral and peritumoral tissues. GST activity was significantly (P < 0.05) higher in tumors (mean +/- SD, 399 +/- 362 nmol/min/mg) than in corresponding peritumoral tissues (86 +/- 67). The GST isoenzymes GST-mu and GST-pi (determined by immunoblotting) were also higher in tumors than in corresponding peritumoral tissues (3- and 5-fold, respectively). Both GST-mu and GST-pi levels were significantly correlated with GST activity. GST-alpha was not detected in either tumoral or peritumoral tissues. Glutathione levels in tumors (22 +/- 23 nmol/mg protein) were not statistically different from peritumoral tissues (11 +/- 12). Epoxide hydrolase was expressed at similar levels in tumors and peritumoral tissues. The glucuronide-forming enzyme UDP-glucuronosyltransferase was 5-fold lower in tumors (0.1 +/- 0.2 nmol/h/mg) than in peritumoral tissues (0.5 +/- 1), whereas the opposite was observed for the hydrolytic enzyme beta-glucuronidase, which was 6-fold higher in tumors (736 +/- 1392 nmol/h/mg) compared to peritumoral tissues (125 +/- 75). No difference was noted between tumoral and peritumoral tissues for sulfotransferase (1 +/- 2 nmol/h/mg), but the corresponding hydrolytic enzyme (sulfatase) was 2-fold higher in tumoral tissues (14 +/- 15 nmol/h/mg) than in peritumoral tissues (6 +/- 2). In conclusion, several differences were observed between human breast tumors and peritumoral tissues for many conjugating enzymes (GST-mu, GST-pi, and UDP-glucuronosyltransferase) and hydrolytic enzymes (sulfatase and beta-glucuronidase). These noteworthy differences between tumoral and peritumoral tissues with regard to their main drug-metabolizing enzymes could play a role in the relative drug sensitivity or insensitivity of human breast cancer tissues to chemotherapeutic agents and could be potential targets for chemotherapeutic interventions.

Loss of heterozygosity, allele silencing and decreased expression of p73 gene in breast cancers: prevalence of alterations in inflammatory breast cancers.

The p73 gene is a p53 homologue located at 1p36-33, a region submitted to deletions in breast cancer (BC) and putatively imprinted. To study whether p73 was associated with breast carcinogenesis, loss of heterozygosity (LOH), allele expression and transcript levels were assessed in 59 BC, including 39 BC presenting no inflammatory symptoms (NBC) and 20 inflammatory BC (IBC). IBC is a rare but aggressive form of cancer with a very poor prognosis. Normal breast epithelium (BE) and lymphocytes from patients were used as controls. StyI polymorphism generating GC and/or AT alleles was used to select 22 heterozygous patients. p73 LOH was significantly higher in IBC than in NBC [five of eight cases (62%) versus two of 14 cases (14%); Fisher's exact test, P=0.05]. p73 was biallelically expressed in all BE. In contrast, 12 of 16 (75%) BC were monoallelically expressed, showing that allele silencing was significantly associated with breast carcinogenesis (P=0.012), AT being the preferential silent allele (10 out of 12 tumours). p73 mRNA levels in NBC and IBC were two- and threefold lower than in BE, respectively, suggesting that decreased expression could be related to tumour aggressiveness. In conclusion, LOH, allele silencing and decreased expression of the p73 gene may play a role in breast carcinogenesis.

Prognostic significance of S-phase fraction in good-risk, node-negative breast cancer patients.

PURPOSE: Formalin-fixed, paraffin-embedded tissues from axillary node-negative breast cancer patients were analyzed by flow cytometry to determine the prognostic significance of DNA ploidy and S-phase fraction (SPF). PATIENTS AND METHODS: All patients were registered on a good-risk control arm of an intergroup clinical trial. They had small- to intermediate-sized (less than 3 cm), estrogen receptor (ER)-positive tumors and received no adjuvant therapy after modified radical mastectomy or total mastectomy with low axillary-node sampling. The median follow-up was 4.8 years. RESULTS: Assessable ploidy results were obtained from 92% of the 298 specimens studied (51% diploid, 49% aneuploid), and SPFs were assessable for 83% of the tumors. SPFs for diploid tumors ranged from 0.7% to 11.9% (median, 3.6%), compared with a range of 1.2% to 26.7% (median, 7.6%) for aneuploid tumors (P less than .0001). No significant differences in disease-free or overall survival were observed between patients with diploid and aneuploid tumors. Using different SPF cutoffs by ploidy status (4.4% for diploid, 7.0% for aneuploid), patients with low SPFs had significantly longer disease-free survival rates than patients with high SPFs (P = .0008). The actuarial 5-year relapse rates were 15% and 32% for patients with low (n = 142) and high SPFs (n = 105), respectively. Similar relationships between SPF and clinical outcome were observed for patients with diploid tumors (P = .053) and for patients with aneuploid tumors (P = .0012). CONCLUSION: S-phase fraction provides additional prognostic information for predicting disease-free survival for axillary node-negative breast cancer patients with small, ER-positive tumors.

Strategies for cancer gene therapy using adenoviral vectors.

Modification of tumor cells using gene transfer either to enhance host immunity or to act directly on tumor cells is being intensively studied in animal models. Remarkable results have yielded to approved clinical protocols in the treatment of cancer patients using this approach. Several methods of gene delivery have been developed. This article is particularly devoted to the interest of the use of adenoviral vectors in the different strategies of cancer gene therapy.

Breast radiological cases: training with BIRADS classification.

The American College of Radiology has established guidelines for outcomes monitoring known as the Breast Imaging Reporting and Data System. The last edition of the BIRADS classification includes mammography, but also ultrasonography and MRI. Radiologists must be used to the BIRADS lexicon and the BIRADS assessment, in order to clarify mammography reports and to facilitate communication with the other physicians. This work is a training on 20 mammography cases to be familiar with the BIRADS classification.

The poor responsiveness of infiltrating lobular breast carcinomas to neoadjuvant chemotherapy can be explained by their biological profile.

The aim of this study was to determine the chemosensitivity of infiltrating lobular breast carcinoma (ILC) in comparison with infiltrating ductal carcinoma (IDC). Between 1987 and 1995, 457 patients with invasive T2>3 cm-T4 breast carcinomas were treated with primary chemotherapy (CT), surgery, radiation therapy. Clinical response, the possibility of breast preservation, pathological response and survival were evaluated according to the histological type. In order to evaluate the biological differences between ILC and IDC patients and their implication with regard to tumour chemosensitivity, additional immunohistochemical stainings (oestrogen receptor (ER), Bcl2, p53, c-erbB-2 and Ki67) were performed on 129 pretherapeutical specimens. 38 (8.3%) ILC were diagnosed by core needle biopsy before CT. ILC was an independent predictor of a poor clinical response (P=0.02) and ineligibility for breast-conserving surgery after neoadjuvant chemotherapy (P=0.03). Histological and biological factors predicting a poor response to CT (histological grade, ER, Ki67 and p53 status) were more frequent in ILC than in IDC patients. After a median follow-up of 98 months (range: 3-166), the low chemosensitivity of ILC did not result in a survival disadvantage. Our results demonstrate that ILC achieved a lower response to CT than IDC because of their immunohistochemical profile. Preoperative CT did not allow a high rate of conservative treatment for ILC and therefore the use of neoadjuvant CT for ILC patients should be questioned.

p53 mediated tumor cell response to chemotherapeutic DNA damage: a preliminary study in matched pairs of breast cancer biopsies.

Wild type p53 plays a crucial role in maintaining genomic stability in both normal and tumor cells in vitro. When DNA damage occurs, p53 acts as a cell cycle checkpoint and induces a cellular response that aims at restoring genomic integrity. p53 may either allow the repair of damaged DNA by inducing a transient G1 arrest or may eliminate the damaged cells by triggering apoptosis. Mutant p53 fails to mediate any of these effects. From this, a p53 status-dependent response to therapy might be expected when tumors are treated with DNA-damaging genotoxic agents: Although wild type p53-harboring tumors have an intact checkpoint that might allow them to restore genomic integrity back to a pre-exposure level, mutant p53 tumors have a corrupted checkpoint that could lead to an accelerated loss of genomic stability. Until now, no studies have been described that examine such a p53-mediated effect in vivo. The authors tested this response model in vivo comparing 32 matched biopsy pairs from patients with breast cancer before and after rigorously standardized polychemotherapy. Four of the five drugs specifically induce a wild type p53-mediated checkpoint response. Tumor tissue from matched pairs of untreated and treated biopsies of the same patient were analyzed for treatment-associated changes of p53 protein expression by immunocytochemistry and, in a few available specimens, of p53 genotype changes by polymerase chain reaction-based DNA analysis. Treatment-associated changes of the p53 immunophenotype, which the authors speculate to reflect clonal selection, occurred in 39% (12 of 31) of the specimens. One specimen was not informative. Most tumors undergoing clonal selection originally harbored mutant p53 (nine of 12), and only three of 12 tumors were wild type. This study shows that exposure to genotoxic agents is commonly associated with a change in p53 immunophenotype. Although the limited material in this cohort prevented direct analysis of genetic instability, these results suggest that tumors with altered p53 may be genomically less stable and, therefore, may be more likely to undergo treatment-induced clonal changes than wild type tumors. This study also shows that the rigorous matched sample approach, although difficult to obtain, is an important tool that allows the in vivo assessment of the tumor response to genotoxic therapy in a controlled fashion.

Quality of life after sentinel lymph node biopsy in early breast cancer.

AIM: This study assessed the effects of multiple therapeutic factors on quality of life (QOL) in the treatment of breast cancer. METHODS: We surveyed 179 recurrence-free women with early breast cancer who had undergone a sentinel lymph node procedure, between January 1999 and June 2001. Age, tumour size, breast and axillary procedure, nodal status, chemotherapy, supra-clavicular fossa radiotherapy, and hormone therapy were tested as possible factors associated with poor QOL. RESULTS: Information on QOL was obtained for 148 out of 179 patients. Age less than 55 years and chemotherapy were factors associated with impairment of physical well-being. Tumour size was associated with poor socio-familial well-being. Factors associated with altered arm subscale scores were age <55, axillary procedure, nodal status, chemotherapy and supra-clavicular fossa radiotherapy. Unexpectedly, sentinel lymph node (SLN) procedure delayed the onset of chemotherapy if the metastatic status of SLN was not diagnosed intra-operatively. CONCLUSION: Efforts are needed to improve the QOL of young patients. Axillary procedure affects only QOL related to arm morbidity.

Sentinel lymphadenectomy without systematic axillary dissection in breast cancer patients: predictors of non-sentinel lymph node metastasis.

AIMS: To identify factors predicting metastatic involvement of non sentinel axillary lymph nodes in breast cancer patients who underwent sentinel lymph node (SLN) biopsy followed by complete axillary dissection only in case of metastatic sentinel lymph node. METHODS: A prospective database including 165 breast cancer patients who underwent SLN biopsy without further complete axillary dissection in case of non-metastatic SLN was reviewed. Primary tumor size, pathologic grade, lymphatic invasion in the primary tumor, estrogen receptor status, tumor size in the SLN and number of metastatic SLNs were tested as possible predictors of metastatic involvement of non-SLN. RESULTS: The sentinel lymph node detection rate was 97% (160/165 patients). The mean number of SLNs per patient was 1.8 (range: 1-5). Fifty patients (31.3%) had a metastatic axillary SLN: 10 of the 42 patients with T1a or T1b breast tumors and 40 of the 118 patients with T1c< or = 15mm tumors. Fifteen of the 50 patients with metastatic SLN had metastatic non-SLN. Primary tumor size, tumor size in the SLN, pathologic grade, estrogen receptor status and age were not significantly associated with metastatic involvement of non-SLN. Number of metastatic SLNs fell short of reaching statistical significance (P: NS). Lymphatic invasion in the primary tumor was the only factor significantly associated with the presence of tumor in the non SLN (P<0.01). CONCLUSION: In our series, only lymphatic invasion in the primary tumor was correlated with metastases detection in the non-SLN. We could not identify a subset of patients without metastatic non-SLN in patients with metastatic SLN.