Etude LYMPHOREC. Réponse immunitaire intra-tumorale à la radiothérapie préopératoire pour des cancers du rectum de stades II-III: nouveau paramètre pronostic de la survie des patients

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[Various aspects of intestinal tuberculosis.]

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Prognostic value of androgen receptor and FOXA1 co-expression in non-metastatic triple negative breast cancer and correlation with other biomarkers

International audienceBACKGROUND: In luminal androgen receptor (AR) tumours, FOXA1 may direct AR to sites occupied by ER in luminal tumours, thus stimulating proliferation.METHODS: AR and FOXA1 expression were evaluated by immunohistochemistry in 333 non-metastatic triple-negative breast cancers (TNBC). Positivity threshold was set at ≥ 1% staining. Lymphocytic infiltration, PD-L1expression, PIK3CA mutations, PTEN defects and BRCA1 promoter methylation were assessed.RESULTS: AR + /FOXA1 + tumours (42.4%) were more frequently: found in older patients, lobular, of lower nuclear grade, with more frequently PIK3CA mutations; exhibited less frequently BRCA1 promoter methylation, defects of PTEN and PD-L1 expression than others. Recurrence-free and overall survivals were significantly lower for AR + /FOXA1 + TNBC (median follow-up: 7.8 years).CONCLUSIONS: AR + /FOXA1 + expression defines a luminal-like TNBC subgroup affected with a worse outcome compared to other TNBC and a higher risk of late recurrences. This subgroup appears enriched in PIK3CA mutations, suggesting a role for PI3K inhibitors in this subgroup

Tumoral lymphocyte immune response to preoperative radiotherapy in locally advanced rectal cancer as a prognostic factor for survival: the LYMPHOREC study

Présentation PosterInternational audienceBackground: Short-course preoperative radiotherapy (sc-preopRT) and long-course preoperative radiotherapy (lc-preopRT) followed by total mesorectal excision (TME) are worldwide standards of care in locally advanced T3–4 N0 or N1 rectal adenocarcinoma. It is now well established that the host immune system participates in the elimination of tumor cells and that significant tumor infiltration by T-cells (LT), such as CD8+, is associated with a better prognosis. In colorectal tumors, the infiltration of Treg FoxP3+ is also described as a prognostic factor associated with better survival. We aimed to investigate the impact of the immune response to preoperative RT on progression-free survival (PFS) and overall survival (OS) in rectal cancer managed with TME.Material and Methods: We analyzed data for 237 patients with rectal cancer who underwent TME between 1995 and 2007 after neo-adjuvant treatment with preoperative RT with or without CT in 3 French centers. The LYMPHOREC study was approved by the French national review boards and independent ethics committee (CPP, CCTIRS and the CNIL). Our primary objective was to assess the impact of the immune infiltration of the tumor or tumor site (in cases with complete response) by CD8+ and FoxP3+ lymphocytes after sc-preopRT or lc-preopRT with or without CT on progression-free survival (PFS) and overall survival (OS). Our secondary objectives were to assess changes in the quantities of these lymphocyte infiltrations with respect to the type of preoperative RT (with vs without chemotherapy) or the dose fractionation scheme (≤2Gy vs >2Gy/fraction). These second analyses were performed with 133 patients from whom one biopsy sample was collected. A biopsy-based pretherapeutic lymphocyte infiltration was thus evaluated.Results: In univariate analysis, TNM stage, the delay between surgery and RT, CD8+, FoxP3+ and the ratio CD8+/FoxP3+ were significantly correlated with survival outcomes while chemotherapy as a component of preoperative radiotherapy was not. In multivariate analysis, when adjusted for clinical and treatment-related variables, tumor infiltration by FoxP3 lymphocytes after treatment significantly correlated with PFS (p=0.007). Variations in the CD8/FoxP3 ratio inside the epithelial tissue from before to after preoperative RT correlated with PFS and OS (p=0.049 and p=0.024, respectively). Interestingly, the dose per fraction (<2Gy vs. ≥2Gy) significantly influenced the CD8/FoxP3 ratio after treatment (p=0.027) with a lower ratio with hypofractionated RT.Conclusions: Patients with rectal cancer who had a significant decrease in the CD8/FoxP3 ratio after preoperative radiotherapy had better survival outcomes. The CD8/FoxP3 ratio needs to be validated prospectively. The immune response to preoperative RT may guide physicians in the decision to give adjuvant treatment to patients with rectal cancer

Coexpression of androgen receptor and FOXA1 in nonmetastatic triple-negative breast cancer: ancillary study from PACS08 trial

International audienceAim: Microarray studies identified a subgroup of molecular apocrine tumors (estrogen receptor [ER] negative/androgen receptor [AR] positive) that express luminal genes including FOXA1. FOXA1 may direct AR to sites normally occupied by ER in luminal tumors, inducing an estrogen-like gene program that stimulated proliferation. Materials & methods: Expression of AR and FOXA1 was evaluated by immunohistochemistry in 592 patients with nonmetastatic triple-negative breast cancer (TNBC). Results: Coexpression of AR and FOXA1 was found in 15.2% of patients. These tumors were more frequently lobular, found in older patients and exhibited a lower nuclear grade and a greater degree of node involvement. They less often exhibited lymphocytic infiltrate, pushing margins, syncytial architecture, central fibrosis or necrosis. Conclusion: TNBC with coexpression of AR and FOXA1 seems to behave like luminal tumors with a morphological profile distinct from other TNBC. These biomarkers could be useful to identify a subgroup of TNBC and could have future therapeutic implications

Prognostic relevance at 5 years of the early monitoring of neoadjuvant chemotherapy using (18)F-FDG PET in luminal HER2-negative breast cancer.

International audiencePURPOSE: The objective of this study was to evaluate, in the luminal human epidermal growth factor receptor 2 (HER2)-negative breast cancer subtype, the prognostic value of tumour glucose metabolism at baseline and of its early changes during neoadjuvant chemotherapy (NAC). METHODS: This prospective study included 61 women with hormone-sensitive HER2-negative breast cancer treated with NAC. (18)F-Fluorodeoxyglucose (FDG) positron emission tomography (PET) was performed at baseline. Hepatic activity was used as a reference to distinguish between low metabolic and hypermetabolic tumours. In hypermetabolic tumours, a PET exam was repeated after the first course of NAC. The relative change in the maximum standardized uptake value of the tumour (∆SUV) was calculated. RESULTS: Nineteen women had low metabolic luminal breast cancers at baseline, correlated with low proliferation indexes. Forty-two women had hypermetabolic tumours, corresponding to more proliferative breast cancers with higher Ki-67 expression (p = 0.017) and higher grade (p = 0.04). The median follow-up period was 64.2 months (range 11.5-93.2). Thirteen women developed recurrent disease, nine of whom died. Worse overall survival was associated with larger tumour size [>5 cm, hazard ratio (HR) = 6.52, p = 0.009] and with hypermetabolic tumours achieving a low metabolic response after one cycle of NAC (ΔSUV < 16 %, HR = 10.63, p = 0.004). Five-year overall survival in these poor responder patients was 49.2 %. Overall survival in women with low metabolic tumours or hypermetabolic/good response tumours was 100 and 96.15 %, respectively. CONCLUSION: In luminal HER2-negative breast tumours, tumour metabolism at baseline and changes after the first course of NAC are early surrogate markers of patients' survival. A subgroup of women with hypermetabolic/poorly responding tumours, correlated with poor prognosis at 5 years, can be identified early. These results may guide future studies by tailoring the NAC regimen to the metabolic response

Genomic and transcriptomic comparison of post-radiation versus sporadic sarcomas

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Exosomes are nanovesicles released by all cells that can be found in the blood. A key point for their use as potential biomarkers in cancer is to differentiate tumour-derived exosomes from other circulating nanovesicles. Heat shock protein-70 (HSP70) has been shown to be abundantly expressed by cancer cells and to be associated with bad prognosis. We previously showed that exosomes derived from cancer cells carried HSP70 in the membrane while those from non-cancerous cells did not. In this work, we opened a prospective clinical pilot study including breast and lung cancer patients to determine whether it was possible to detect and quantify HSP70 exosomes in the blood of patients with solid cancers. We found that circulating exosomal HSP70 levels, but not soluble HSP70, reflected HSP70 content within the tumour biopsies. Circulating HSP70 exosomes increased in metastatic patients compared to non-metastatic patients or healthy volunteers. Further, we demonstrated that HSP70-exosome levels correlated with the disease status and, when compared with circulating tumour cells, were more sensitive tumour dissemination predictors. Finally, our case studies indicated that HSP70-exosome levels inversely correlated with response to the therapy and that, therefore, monitoring changes in circulating exosomal HSP70 might be useful to predict tumour response and clinical outcome.

International audienceExosomes are nanovesicles released by all cells that can be found in the blood. A key point for their use as potential biomarkers in cancer is to differentiate tumour-derived exosomes from other circulating nanovesicles. Heat shock protein-70 (HSP70) has been shown to be abundantly expressed by cancer cells and to be associated with bad prognosis. We previously showed that exosomes derived from cancer cells carried HSP70 in the membrane while those from non-cancerous cells did not. In this work, we opened a prospective clinical pilot study including breast and lung cancer patients to determine whether it was possible to detect and quantify HSP70 exosomes in the blood of patients with solid cancers. We found that circulating exosomal HSP70 levels, but not soluble HSP70, reflected HSP70 content within the tumour biopsies. Circulating HSP70 exosomes increased in metastatic patients compared to non-metastatic patients or healthy volunteers. Further, we demonstrated that HSP70-exosome levels correlated with the disease status and, when compared with circulating tumour cells, were more sensitive tumour dissemination predictors. Finally, our case studies indicated that HSP70-exosome levels inversely correlated with response to the therapy and that, therefore, monitoring changes in circulating exosomal HSP70 might be useful to predict tumour response and clinical outcome