Christelle Faure

Regulatory T Cells Recruited through CCL22/CCR4 Are Selectively Activated in Lymphoid Infiltrates Surrounding Primary Breast Tumors and Lead to an Adverse Clinical Outcome

Immunohistochemical analysis of FOXP3 in primary breast tumors showed that a high number of tumor-infiltrating regulatory T cells (Ti-Treg) within lymphoid infiltrates surrounding the tumor was predictive of relapse and death, in contrast to those present within the tumor bed. Ex vivo analysis showed that these tumor-infiltrating FOXP3(+) T cells are typical Treg based on their CD4(+)CD25(high)CD127(low)FOXP3(+) phenotype, their anergic state on in vitro stimulation, and their suppressive functions. These Ti-Treg could be selectively recruited through CCR4 as illustrated by (a) selective blood Treg CCR4 expression and migration to CCR4 ligands, (b) CCR4 down-regulation on Ti-Treg, and (c) correlation between Ti-Treg in lymphoid infiltrates and intratumoral CCL22 expression. Importantly, in contrast to other T cells, Ti-Treg are selectively activated locally and proliferate in situ, showing T-cell receptor engagement and suggesting specific recognition of tumor-associated antigens (TAA). Immunohistochemical stainings for ICOS, Ki67, and DC-LAMP show that Ti-Treg were close to mature DC-LAMP(+) dendritic cells (DC) in lymphoid infiltrates but not in tumor bed and were activated and proliferating. Furthermore, proximity between Ti-Treg, CD3(+), and CD8(+) T cells was documented within lymphoid infiltrates. Altogether, these results show that Treg are selectively recruited within lymphoid infiltrates and activated by mature DC likely through TAA presentation, resulting in the prevention of effector T-cell activation, immune escape, and ultimately tumor progression. This study sheds new light on Treg physiology and validates CCR4/CCL22 and ICOS as therapeutic targets in breast tumors, which represent a major health problem.

Is surgical biopsy mandatory in case of atypical ductal hyperplasia on 11-gauge core needle biopsy? a retrospective study of 300 patients

BACKGROUND Atypical ductal hyperplasia (ADH) is diagnosed in 4% to 10% of directional vacuum-assisted stereotactic biopsies (DVABs) performed for microcalcifications. Since the underestimation rate varies from 7% to 36%, surgical excision is still recommended, although some authors have tried to identify a subset of patients who can be spared surgery. METHODS AND RESULTS In this study, we analyzed a retrospective series of 300 patients with ADH on 11-gauge DVAB. The only 4 events that occurred (3%) in 135 of 184 patients (61%) who were followed may not be due to underestimation. Comparing the diagnoses on DVAB and surgical excisions for 116 patients (39%), we identified 3 subsets of patients: no underestimation (size <6 mm and complete removal), low rate of 4% (< or =2 foci ADH in microcalcifications either <6 mm with incomplete removal or > or =6 mm and <21 mm), and high rate of 36% to 38% (>2 foci ADH in microcalcifications either <6 mm with incomplete removal or > or =6 mm and <21 mm, lesion size > or =21 mm). CONCLUSIONS Our results suggest that strict follow-up can be a safe option for the first 2 groups of patients, but that surgical excision is mandatory for patients from the third group.

Body weight change in women receiving adjuvant chemotherapy for breast cancer: a French prospective study.

BACKGROUND & AIMS Adjuvant chemotherapy has frequently been associated with weight gain after breast cancer diagnosis. We aimed to prospectively evaluate body weight variations in French patients with early breast cancer. METHODS This prospective observational study included 272 breast cancer patients who were candidates for adjuvant chemotherapy. Weight and body mass index were measured at baseline visit, then at 9 and 15 months from baseline (6 and 12-month post-chemotherapy). At baseline visit, information on the benefits of weight gain prevention and healthy diet was given by a dietician. Univariate logistic regression was performed to test the association between weight gain and potential predictive factors. RESULTS Thirty percent of patients gained weight during the year before diagnosis, 26% were overweight and 15% were obese. At one year, the mean weight change was +1.5kg (SD=4.1) and +2.3% (SD=6.0); 60% of the cohort had gained weight, with a median increase of 3.9kg (SD=3.0) and 5.9% (SD=4.4). Reported weight gain during the year before diagnosis appears to be the only factor associated with the absence of post-chemotherapy weight gain (OR=0.54, 95% CI [0.31-0.95], p=0.034). CONCLUSION Body weight increased in the post-chemotherapy period in French breast cancer survivors, even when given dietary recommendations. Appropriate weight management interventions with nutritional follow-up and physical activity programs are needed.

Management of patients diagnosed with atypical ductal hyperplasia by vacuum-assisted core biopsy: a prospective assessment of the guidelines used at our institution

BACKGROUND Because of underestimation, surgical excision is recommended for atypical ductal hyperplasia diagnosed on directional vacuum-assisted biopsies. The following guidelines have been established according to our retrospective study published in 2008: excision for lesions ≥ 21 mm, follow-up for lesions <6 mm with complete removal of microcalcifications, and follow-up or excision for 6 to 21-mm lesions with respectively less or >2 atypical ductal hyperplasia foci. METHODS AND RESULTS These guidelines were assessed in a prospective series of 124 patients with a median follow-up of 30 months. Conformity rate was 92%. Upgrading was 28% (15 of 53 patients) for conformed surgery and absent for surgery performed beyond the scope of guidelines. For the patients with benign result at surgery (n = 38) or just followed (n = 61), 3 cancers occurred in either breast at 1 to 3 years. CONCLUSIONS These convenient guidelines can safely spare surgery for a subset of patients. However, annual mammographic follow-up is recommended since the risk of subsequent cancer remains high for both breasts.

Surgical Management of Benign and Borderline Phyllodes Tumors of the Breast.

Phyllodes tumors (PT) are uncommon fibroepithelial breast neoplasms and there is currently no clear consensual treatment for these tumors. The aim of our study was to evaluate the surgical management and outcome of benign and borderline PT. We retrospectively assessed 76 cases of benign or borderline PT managed at the Leon Berard comprehensive cancer center in Lyon, France between July 2003 and December 2013. The mean age at diagnosis was 37.9 years and the median follow‐up was 58 months. Seventy‐five patients (99%), with a mean tumor size of 27 mm, underwent a breast‐conserving procedure. The tumor margins were considered positive (when the tumor was present at the inked surgical section) in seven of 76 cases (9%) and negative in 65 out of 76 cases (86%). We observed the presence of small negative surgical margins <10 mm in 89% and <1 mm in 71% of the patients. Although no re‐excision was performed to increase these margins, we did not see any increase in the local recurrence rate (4%) when compared to recurrence rates reported in the literature. We thus suggest that systematic revision surgery for close or positive surgical margins for benign PT should not be systematically performed. However, as recurrences occur within 2 years of initial excision, we recommend a regular clinical and imaging follow‐up especially during this period for which patients compliance is essential.

Traitements adjuvants dans le cancer du sein : impact du résultat du curage axillaire en cas de micrométastase ou de cellules tumorales isolées dans le ganglion sentinelle

Prognostic signification of micrometastases ou isolated tumor cells (ITC) has not yet been clearly precised. Management of the axilla in case of micrometastases or ITC depends on the local pratices: no surgical completion or axillary lymph node dissection (ALND). Axillary lymph node status is the most important prognostic factor in patients with breast cancer; morbidity of ALND is now well known whereas its therapeutic benefit has not been demonstrated. This study is based on a retrospective database of 1375 patients who underwent sentinel node (SN) biopsy for breast cancer. In case of micrometastase or ITC in SN with completion axillary dissection, we examined if non-sentinel lymph node status has changed the indications of adjuvant treatments (chimiotherapy or radiotherapy). The results of our study show that non-sentinel lymph node status modify systemic therapy for a very few patients (less than 4% concerning chimiotherapy and less than 15% concerning radiotherapy).

[Axillary lymph node metastases with an occult breast: About 16 cases from a cohort of 7770 patients].

OBJECTIVES Isolated axillary lymph node metastases is an unusual clinical presentation of breast carcinoma. We studied its different issues. METHODS This study is a follow-up study of 16patients, treated between 1996 and 2012, presenting with axillary metastases with an occult breast carcinoma, which could not be identified by physical examination nor by a conventional imaging or a breast MRI. Clinical characteristics, histological analysis, treatment, monitoring and five-year survival rate were studied. RESULTS The incidence of this kind of breast cancer was 0.20%. A breast MRI was performed in 75% of the patients. The histology of these tumors showed a rate of hormono-sensibility of 50% and an HER2 overexpression of 44%. Sixty-nine percent of the patients had no breast surgery or radiotherapy; global five-year survival rate for these women was 77.4%±11.5. CONCLUSION The survival rates of this study should lead the practitioner to choose a less aggressive breast therapy. Moreover, the histological characteristics explain the high metastatic potential of these tumors, and relate them to the HER2+ subclass of gene expression patterns of breast carcinomas.

Abstract P2-01-01: Sentinel node surgery after neoadjuvant chemotherapy in patient with axillary node involvement: The French GANEA 2 prospective multi-institutional trial

Background Half of the patient treated with neoadjuvant chemotherapy (NAC) for a large operable breast cancer has no axillary lymph node involvement at the time of surgery. Sentinel lymph node detection (SLND), performed after NAC, must select patient who should be spared of an axillary lymph node dissection (ALND). The application of SLND for staging the axilla after NAC for patient who initially had a proven axillary lymph node involvement remains controversial because of a low detection rate (DR) and a high false negative rate (FNR). Objective The aim of GANEA 2 trial was to assess the DR and the FNR of SLND after NAC in the particular case of patients with a proven axillary lymph node involvement. Patients and Method GANEA 2 was validated by scientific and ethical national boards. Inclusion criteria: FIGO stage T2-T3 infiltrating breast carcinoma, indication of NAC, surgery (radical or conservative) after NAC and signed consent form, Exclusion criteria: inflammatory cancer, local relapse, previous surgical removal of the tumour, mental disorder, pregnancy or no contraceptive method, contra-indication to NAC, NAC interrupted due to progressive disease. Design: Diagnosis and indication to plan a NAC, control of inclusion and exclusion criteria, consent form signature, axillary sonography with fine needle cytology before NAC to select patients with a proven lymph node involvement. After NAC patients underwent both SLND, with the combined technique Blue dye and radiolabeled colloid, and complementary ALND. Pathological procedure: Pathological analysis, of sentinel and non sentinel nodes, carried out according to standard methods and classified according the last American Joint Committee staging system and Sataloff classification. Studied parameters were detection rate, false negative rate and Sataloff grading on tumor and lymph nodes. We evaluated particularly the likelihood that the FNR in patients with one or more SLN examined was greater than 10%. Patients with no lymph node involvement before NAC underwent only a SLND with an ALND only in the case of SLN macro-metastasis with a rigorous follow up. They are not part of this abstract. Results From July 2010, to February 2014, 242 patients from 19 institutions were enrolled, with a proven axillary lymph node involvement before NAC. After NAC, 1/3 had metastasis free axillary lymph node (80/142). Detection rate was 83.1% (201/242). Half of the patients with a detection failure had an involved ALND. The false negative rate was 14.2% in the whole series but 24.5% in the case of only 1 SLN resected, and 8% in case of more than 1 SLN resected. In case of involved SLN, half of the patients had involved ALND. Considering the node Sataloff scoring, 18 of the 20 false negative cases were grade C or D (n=15 grade C, metastatic disease and therapeutic effect; n = 3 grade D, metastasis and no therapeutic effect). Conclusion Among patients treated by NAC for a large operable breast cancer with proven involved lymph node before NAC, who had only 1 SLN examined, the false negative rate was 24.5%. SLND with the combined technique, provides a FNR of less than 10% only in the case of 2 or more SLN resected. Citation Format: Jean-Marc Classe, Loic Campion, Severine Alran, Christine Tunon de Lara, Pierre Francois Dupre, Christelle Faure, Nicolas Paillocher, Serge Lasry, Marie Pierre Chauvet, Gilles Houvenaeghel, Marian Gutowski, Pascaline De Blaye, Charlotte Ngo, Emmanuel Barranger, Jean Luc Veraeghe, Celine Lefebvre, Jean Francois Rodier, Virginie Bordes, Helene Charitansky, Gwenael Ferron, Pierre Gimbergues. Sentinel node surgery after neoadjuvant chemotherapy in patient with axillary node involvement: The French GANEA 2 prospective multi-institutional trial [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P2-01-01.

Curage axillaire après reconstruction mammaire par lambeau de grand dorsal : principes chirurgicaux et résultats

OBJECTIVES We retrospectively reviewed all the cases of axillary lymph node dissection (ALND) performed within a year after an immediate breast reconstruction procedure by a pedicled Latissimus dorsi, which is transferred to the anterior thoracic wall through an axillary funnel. Operative technical steps are described taking account of the new anatomical relationship of the axilla. METHODS We assessed postoperative immediate complications and late sequelaes. RESULTS From 1999 to 2013, 21 ALND were performed. Immediate postoperative period was free of complication in 85% of cases when following the operative steps described in this work. Partial or total necrosis of the reconstructed breast did not occur. With a median follow-up of 64 months, 6 patients (28% of the whole population) presented at least one sequelae like a feeling of heavy arm (n=2, 9%) or a lymphedema (n=3, 14%), a chronic neuropathic pain (n=4, 19%) or a limitation in the arm range of motion (n=2, 9%). CONCLUSION ALND after immediate breast reconstruction by a pedicled Latissimus dorsi is feasible and safe, without any additional postoperative complication in comparison with a classic ALND.

Abstract P4-11-23: Membranous ERα-36 expression is an independent predictor of poor prognosis in operable breast cancer

Background ERα-36 is a splice variant of ER-α with molecular weight of 36-kDa that lacks transactivation domains, and is expressed in the cytoplasm and cell membrane of ER (ERα66) negative as well as ERα66 positive breast cancer cells. It is also thought to predict resistance to tamoxifen therapy. Here we investigate its prognostic significance, its association with other clinico-pathologic factors and correlation with other biomarkers of the PI3K/AKT/mTOR pathway. Methods We studied ERα-36 expression on TMA blocks prepared from samples of 160 consecutive operable breast cancer patients who presented at CLB between 1998 and 2001. The intensity of the staining and the percentage of tumor cells stained for each biomarker (ERα-36, PI3K, pAKT, p4EBP1, pS6RP and LKB1) were integrated into a single score and a cutoff was defined for high versus low expression. Correlations were done between ERα-36 expression and the clinico-pathological parameters and other biomarkers using Pearson’s chi-square test. Kaplan-Meier method was used to estimate distant metastasis free survival (DMFS), disease free survival (DFS) and overall survival (OS) and the difference between the groups was evaluated with log-rank test. Cox regression model was used to adjust for other prognostic parameters in the multivariate analysis. Results Median age at diagnosis was 56.9 years (range: 30 to 87 years). The maximum tumor size was larger than 2 cm in 57.5% of cases and axillary lymph nodes (LN) were positive (N1a to N3) in 52.5% of cases. 16.3% of the patients had SBR grade I, 44.4% had grade II and 39.4% had grade III tumors. ERα66 was positive in 91.2%, PgR in 74.7% and HER2 was over-expressed in 15% of the cases. High ER-α36 expression in the cell membrane was observed in 65 patients (40.6%). ERα-36 expression was independent of the ERα66, PgR or HER2 expression and was not associated with age, tumor size, SBR grade or axillary LN invasion. There was no correlation between ERα-36 expression and PI3K, pAKT, p4EBP1, pS6RP or LKB1 expression. ERα-36 expression in tumor cells was a predictor of poor prognosis regarding DMFS (HR=2.02; 95% CI: 1.2 to 3.4; p=0.008), DFS (HR=1.7; 95% CI: 1.05 to 2.7; p=0.031) and OS (HR=1.8; 95% CI: 1.02 to 3.2; p=0.043). In the multivariate analysis and after adjustment for age, tumor size, SBR grade and LN invasion, ERα-36 remained an independent predictor of shorter DMFS (p=0.016) and DFS (p=0.052) in addition to SBR grade and axillary LN metastasis. The ERα-36 expression predicted shorter DMFS for patients who received tamoxifen as the only adjuvant systemic treatment (p=0.022) and also for those who received other hormonal therapy and adjuvant chemotherapy (p=0.039). Conclusion Immunohistochemically detected membranous ERα-36 expression can be a poor prognostic factor for patients with operable breast cancer that is independent from the traditional clinico-pathologic parameters and from PI3K/AKT/mTOR pathway activation status. Citation Format: Loay Kassem, Soleilmane Omarjee, Sylvie Chabaud, Emilie Lavergne, Christelle Faure, Frederic Beurrier, Olivier Tredan, Laura Corbo, Isabelle Treilleux, Muriel Le Romancer. Membranous ERα-36 expression is an independent predictor of poor prognosis in operable breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-11-23.