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.

Challenging single- and multi-probesets gene expression signatures of pathological complete response to neoadjuvant chemotherapy in breast cancer: experience of the REMAGUS 02 phase II trial.

This study was designed to identify predictive signatures of pathological complete response (pCR) in breast cancer treated by taxane-based regimen, using clinicopathological variables and transcriptomic data (Affymetrix Hgu133 Plus 2.0 devices). The REMAGUS 02 trial (n = 153,training set) and the publicly available M.D. Anderson data set (n = 133, validation set) were used. A re-sampling method was applied. All predictive models were defined using logistic regression and their classification performances were tested through Area Under the Curve (AUC) estimation. A stable set of 42 probesets (31 genes) differentiate pCR or no pCR samples. Single-or 2-probesets signatures, mainly related to ER pathway, were equally predictive of pCR with AUC greater then 0.80. Models including probesets associated with ESR1, MAPT, CA12 or PIGH presented good classification performances. When clinical variables were entered into the model, only CA12 and PIGH, remained informative (p = 0.05 and p = 0.005) showing that a combination of a few genes provided robust and reliable prediction of pCR.

Brachytherapy for isolated tongue metastasis of renal clear cell carcinoma.

INTRODUCTION: Tongue metastasis of renal cell carcinoma (RCC) is rare. Treatment is hindered by the proximity of anatomic structures involved in swallowing, speech and mastication. It is, moreover, radioresistant. CASE REPORT: We report a case of inaugural isolated tongue metastasis, where biopsy redirected diagnosis to RCC. To avoid potentially mutilating excision in a metastatic disease of poor prognosis, treatment was local, consisting in interstitial brachytherapy, enabling a high dose (65Gy) to be delivered. Despite initially complete response, recurrence at 10.5months required salvage surgery. DISCUSSION AND CONCLUSION: Brachytherapy allowed a higher dose to be delivered than with external beam radiation therapy, previously reported for similar cases. This dose, which can usually be expected to ensure local control in 90% of squamous cell carcinomas of the tongue, obtained 10months' response, insufficient to avoid salvage surgery.

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 elasticity: principles, technique, results: an update and overview of commercially available software.

Breast ultrasound elasticity evaluation has become a routine tool in addition to diagnostic ultrasound during the last five years. Two elasticity evaluation modes are currently available: free-hand elastography and shear-wave elastography (SWE). Most of the commercially available elastography scanners have specific procedures which must be understood by the users. Free-hand elastography usually displays qualitative imaging such as an elastogram, but most of the companies now use it to quantify the relative stiffness between a lesion and the surrounding breast tissue. SWE is a new mode theoretically independent of the sonographer which displays more quantitative information, and can be useful for characterizing breast lesions. Recent studies on elastography suggest that elasticity imaging can increase B-mode accuracy and specificity in differentiating benign and malignant breast lesions. This functional imaging mode could help reduce the number of biopsies performed for benign breast lesions. This review gives a detailed description of the main commercially available systems and the results of current applications in the evaluation of breast elasticity.

Array CGH and PIK3CA/AKT1 mutations to drive patients to specific targeted agents: a clinical experience in 108 patients with metastatic breast cancer.

Breast cancer includes high number of molecular entities targetable by specific agents. In this study, array CGH and PIK3CA/AKT1 mutations were used to drive patients into targeted therapy. A prospective molecular analysis was offered to metastatic breast cancer patients for whom samples were collected prospectively or retrospectively either from frozen or paraffin-embedded tissue. Analyses were performed using array CGH (Agilent platform) and PIK3CA (exon 10 and 21) and AKT1 mutations were explored by standard Sanger sequencing. One hundred and eight patients were included. Good quality CGH was obtained in 79% cases and was better for frozen samples. Genomic alterations were identified in 50% of patients including 11 PIK3CA and 8 AKT1 mutations. Eighteen treatments (17 patients) were administered according to their molecular profile with evidence of activity in nine. Reasons for not providing a genomic-driven treatment included absence of progressive disease (38%), investigator's choice (9%), rapid PD (19%), and no drug access (21%). Array CGH correctly identified Her2 status in 97% cases; failures were related to low % of tumour cells. Our study showed that array CGH is feasible in the context of daily practice and, in combination with PIK3CA/AKT1 mutations, identifies a significant number of actionable molecular alterations that allow driving patients into specific targeted agents.

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.

[Accelerated partial breast irradiation: bifractionated 40Gy in one week. A French pilot phase II study]. / Étude pilote française de phase II d'irradiation partielle accélérée du sein conformationnelle tridimensionnelle bi-fractionnée hebdomadaire de 40Gy.

PURPOSE: Since 2009, accelerated partial breast irradiation (APBI) in North America has been allowed to be used for selected group of patients outside a clinical trial according to the ASTRO consensus statement. In France, accelerated partial breast irradiation is still considered investigational, several clinical trials have been conducted using either intraoperative (Montpellier) or Mammosite(®) (Lille) or brachytherapy modality (PAC GERICO/FNCLCC). Here, we report the original dosimetric results of this technique. PATIENTS AND METHODS: Since October 2007, Institut Gustave-Roussy has initiated a phase II trial using 3D-conformal accelerated partial breast irradiation (40 Gy in 10 fractions BID in 1 week). Twenty-five patients with pT1N0 breast cancer were enrolled and were treated by two minitangent photons beams (6MV) and an "en face" electron beam (6-22 MeV). RESULTS: The mean clinical target volume and planning target volume were respectively 15.1cm(3) (range: 5.2-28.7 cm(3)) and 117 cm(3) (range: 52-185 cm(3)). The planning target volume coverage was adequate with at least a mean of 99% of the volume encompassed by the isodose 40 Gy. The mean dose to the planning target volume was 41.8 Gy (range: 41-42.4 Gy). Dose inhomogeneity did not exceed 5%. Mean doses to the ipsilateral lung and heart were 1.6 Gy (range: 1.0-2.3 Gy) and 1.2 Gy (range: 1.0-1.6 Gy), respectively. CONCLUSION: The 3D conformal accelerated partial breast irradiation using two minitangent and "en face" electron beams using a total dose of 40 Gy in 10 fractions BID over 5 days achieves appropriate planning target volume coverage and offers significant normal-tissue sparing (heart, lung). Longer follow-up is needed to evaluate the tissue tolerance to this radiation dose.

Lobular and ductal carcinomas of the breast have distinct genomic and expression profiles.

Invasive ductal carcinomas (IDCs) and invasive lobular carcinomas (ILCs) are the two major pathological types of breast cancer. Epidemiological and histoclinical data suggest biological differences, but little is known about the molecular alterations involved in ILCs. We undertook a comparative large-scale study by both array-compared genomic hybridization and cDNA microarray of a set of 50 breast tumors (21 classic ILCs and 29 IDCs) selected on homogeneous histoclinical criteria. Results were validated on independent tumor sets, as well as by quantitative RT-PCR. ILCs and IDCs presented differences at both the genomic and expression levels with ILCs being less rearranged and heterogeneous than IDCs. Supervised analysis defined a 75-BACs signature discriminating accurately ILCs from IDCs. Expression profiles identified two subgroups of ILCs: typical ILCs ( approximately 50%), which were homogeneous and displayed a normal-like molecular pattern, and atypical ILCs, more heterogeneous with features intermediate between ILCs and IDCs. Supervised analysis identified a 75-gene expression signature that discriminated ILCs from IDCs, with many genes involved in cell adhesion, motility, apoptosis, protein folding, extracellular matrix and protein phosphorylation. Although ILCs and IDCs share common alterations, our data show that ILCs and IDCs could be distinguished on the basis of their genomic and expression profiles suggesting that they evolve along distinct genetic pathways.

[Diagnosis of HER2 gene amplification in breast carcinoma]. / Diagnostic de l'amplification du gène HER2 dans les cancers du sein Le point de vue génétique.

Amplification of the HER2 gene, mapping to 17q21.1, is present in about 20 % of breast carcinomas. Amplification leads to an overexpression of the protein that made it possible to develop a targeted therapy by the monoclonal antibody trastuzumab (Herceptin). A good response to the treatment requires a stringent assessment of the gene status in tumours; only patients whose tumour shows a high expression of the protein or an amplification of the gene are eligible. Cases with intermediate level expression are checked by in situ hybridization, mainly by FISH, to identify amplifications in this subset of tumours. Results are sometimes difficult to interpret due to the frequent aneuploidy of the tumours. Moreover, copy number cut-offs of the gene for defining an amplification are variable according to the studies. A tumour is considered now as amplified when showing more than six HER2 copies per nucleus, or a ratio HER2 to centromere 17 greater than 2.2. The phenomenon of HER2 amplification in breast cancers is discussed in this paper, and distinguished from gene overrepresentation. It is recommended that tumours showing six to seven copies of HER2 are assessed with a kit including the centromere 17. Clusters of signals are characteristic of amplifications. The process designed for the assessment of HER2 is a model of strategies that will be used for the evaluation of markers involved in future targeted therapies.

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.

Specimen radiography as predictor of resection margin status in non-palpable breast lesions.

AIM: This study aimed to evaluate the role of specimen radiography in predicting margin status for non-palpable breast malignancies. METHODS: We retrospectively reviewed the clinical and pathological data together with specimen radiographs of 164 women with ductal carcinoma in situ, who were referred to our centre between January 1997 and December 2000. In all cases microcalcifications were discovered on mammography. Lesions were localized preoperatively using a guide-wire. Specimen radiography findings and clinicopathological data were correlated with pathological findings. RESULTS: Findings comprised 122 pure ductal carcinomas in situ (74%) and 42 mixed carcinomas, both infiltrating and in situ (26%). On the specimen radiographs, the lesions were close (<1mm) to one edge of the lumpectomy in 34 (21%) cases. Histologically, there were 103 positive resection margins (<1mm, 63%) and only 61 negative margins (> or =1mm, 37%). On univariate analysis, factors associated with positive resection margins were found to be distance from microcalcifications to edge of lesion on specimen radiographs, and radiological multifocality. On multivariate analysis (logistic regression), a radiological margin <5mm and multifocality were the only risk factors for close histological margins. Radiological margins were not associated with surgical findings. CONCLUSION: Our results demonstrate that there is a correlation between specimen radiographs and histological results. The clinical relevance of this should be evaluated in a prospective study.