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Background: Since the development of anti Trop2 antibody-drug conjugates (ADC), Trop2 has been validated as a major therapeutic target for antibody-drug conjugates in metastatic triple-negative breast cancer (TNBC). However, very few data have been reported regarding the prognostic implication, or clinicopathological variables, associated with Trop2 expression levels in early TNBC. Our aim was to evaluate Trop2 expression and its prognostic value in a retrospective series of patients with non-metastatic TNBC and a long follow-up, characterized for Basal-like (BL) or molecular apocrine-like (MA) IHC profiles as well as TILs infiltrate, PDL1 expression and PIK3CA/PTEN mutations. Patients and methods: The analysis was performed in a series of 228 patients with non-metastatic TNBC treated in our center between 2002 and 2012 arrayed on 6 TMA. BL and MA profiles were defined as IHC CK5/6 and/or EGFR expression, and Androgen-receptor and FOXA1 IHC expression, respectively. Trop2 expression levels were tested for their association with baseline clinicopathological variables, and for Relapse-Free Survival (RFS) and Overall survival (OS). Trop2 IHC level of expression was evaluated using the ENZ-ABS380 mouse monoclonal antibody and the methodology described by Bardia et al. (Annals of Oncology, 2021) to quantify the membrane signal. First, we established a score grid, according to staining intensity (no labeling: 0; weak labeling: 1; moderate labeling: 2; strong labeling: 3). Then, for each sampled core, the percentage of labeled invasive tumor cells in each intensity was reported. The overall membrane expression was then calculated using the H-Score method (3 x % of cells with labeling intensity 3 + 2 x % of cells with intensity 2 + 1 x % of cells with intensity 1). The scores obtained ranged from 0 to 300. Results: Median age was 58.2 years (range 28.5-89.1). 43.9% of tumors were classified pT1 and 63.5% pN0. 83.8% of patients had ductal carcinomas. Histological grade 1-2 represented 22.7% of all tumors. A BL phenotype was observed in 68.1% of cases, and an MA profile in 39.4% of the cases. Adjuvant chemotherapy (ACT) was delivered in 74% of patients. We observed low Trop2 expression (H-Score < 100) in 12.3% of the cases (28/228 samples), moderate Trop2 expression (H-Score 100-200) in 28.9% of the cases (66/228 samples), and strong Trop2 expression (H-Score >200) in 58.8% of the cases (134/228 samples). We only identified 3 tumors without any Trop2 expression. Regarding baseline clinicopathological correlations, Trop2 levels were only found significantly associated with pT stage, pT1 tumors displaying more frequently high Trop2 scores compared to tumors >= pT2 (p=0.002). No significant correlation was found between Trop2 expression levels and HER2 levels (0 vs. 1+/2+), BL or MA status. With a median follow-up of 9.7 years, Trop2 levels were not associated with RFS nor OS in univariate analysis. In multivariate analysis, poor RFS was associated with classical variables in the early TNBC setting: tumors >=T2 stage (Hazard Ratio (HR) 2.13, p=0.02), N+ status (HR 3.51, p< 0.001), while high (>5%) TILs infiltration levels (HR 0.54, p=0.03) and adjuvant chemotherapy use (HR 0.49, p=0.007) were associated with improved RFS. Conclusions: Trop2 is expressed in nearly all early TNBC cases, and Trop2 levels of expression, while associated with T stage, did not impact survival in this population. These results are consistent with the ones reported in the metastatic setting in the ASCENT trial. Trop2 level of expression appearing homogeneous distributed in all the clinicopathological subtypes of TNBC, advocating for the evaluation of combined treatments with anti-Trop2 ADCs and dedicated targeted therapies in specific TNBC subgroups. Citation Format: William Jacot, Marie-Christine Chateau, Simon Thezenas, Séverine Guiu, Nelly Firmin, Florence Boissière-Michot. Prognostic value of Trop2 expression levels in non-metastatic triple-negative breast cancer and correlation with other biomarkers [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-11-17.

BACKGROUND: Colorectal cancer (CRC) patients have a better prognosis if metastases are resectable. Initially, unresectable liver-only metastases can be converted to resectable with chemotherapy plus a targeted therapy. We assessed which of chemotherapy doublet (2-CTx) or triplet (3-CTx), combined with targeted therapy by RAS status, would be better in this setting. METHODS: PRODIGE 14 was an open-label, multicenter, randomised Phase 2 trial. CRC patients with initially defined unresectable liver-only metastases received either, 2-CTx (FOLFOX or FOLFIRI) or 3-CTx (FOLFIRINOX), plus bevacizumab/cetuximab by RAS status. The primary endpoint was to increase the R0/R1 liver-resection rate from 50 to 70% with the 3-CTx. RESULTS: Patients (n = 256) were mainly men with an ECOG PS of 0, and a median age of 60 years. In total, 109 patients (42.6%) had RAS-mutated tumours. After a median follow-up of 45.6 months, the R0/R1 liver-resection rate was 56.9% (95% CI: 48–66) with the 3-CTx versus 48.4% (95% CI: 39–57) with the 2-CTx (P = 0.17). Median overall survival was 43.4 months with 3-CTx versus 40 months with 2-CTx. CONCLUSION: We failed to increase from 50 to 70% the R0/R1 liver-resection rate with the use of 3-CTx combined with bevacizumab or cetuximab by RAS status in CRC patients with initially unresectable liver metastases.

We hypothesized that perioperative FOLFOX (5-fluorouracil, leucovorin, oxaliplatin) might be used as an alternative to standard FLOT (docetaxel, 5-fluorouracil, leucovorin, and oxaliplatin) in patients with locally advanced oesogastric adenocarcinomas (OGA), particularly those with frailties.We reviewed the charts of 61 consecutives patients treated with FOLFOX for resectable OGA to estimate overall survival, recurrence-free survival, and safety.The median follow-up was 69.7 (range=3.6-97.9) months. Few patients experienced grade 3 adverse events during the preoperative (n=6; 10%) and postoperative (n=6; 16%) phases. One patient experienced a fatal grade 5 adverse events (cardiogenic shock). Median overall survival was 51.7 months [95% confidence interval (CI)=31.6-93.2 months] and the 5-year survival rate was 44.4% (95% CI=30.3%-57.5%).Regarding its comparable efficacy and its favourable toxicity profile, perioperative FOLFOX is a reasonable alternative to FLOT for frail patients with resectable OGA.

Background The CARMENA trial in patients with metastatic renal cell carcinoma (mRCC) demonstrated that treatment with sunitinib alone was noninferior to cytoreductive nephrectomy (CN) followed by sunitinib (nephrectomy⬜sunitinib). Objective The objective of this study was to provide updated overall survival (OS) outcomes of CARMENA and assess whether some subgroups may still benefit from upfront CN. Design, setting, and participants CARMENA was a phase III trial in 450 patients with mRCC enrolled from 2009 to 2017. Intervention Patients in the intention-to-treat population received nephrectomy⬜sunitinib (standard of care [SOC]; n = 226) or sunitinib alone (n = 224). Outcome measurements and statistical analysis Primary endpoint was OS, assessed using an updated data cut-off (October 2018; median OS event-free follow-up, 36.6 mo). Patients were reclassified by risk using International Metastatic RCC Database Consortium (IMDC) criteria. Results and limitations Sunitinib alone was noninferior to nephrectomy⬜sunitinib (hazard ratio [HR], 0.97; 95% confidence interval, 0.79⬜1.19; p = 0.8) and demonstrated longer median OS (19.8 mo vs 15.6 mo, respectively). For patients with two or more IMDC risk factors, OS was significantly longer with sunitinib alone than with nephrectomy⬜sunitinib (31.2 mo vs 17.6 mo, respectively; HR, 0.65; p = 0.03). For patients with one IMDC risk factor, OS was longer for nephrectomy⬜sunitinib versus sunitinib alone although not significantly (31.4 mo vs 25.2 mo; HR, 1.30; p = 0.2). The post hoc nature of the subgroup analyses may limit their interpretation. Conclusions Sunitinib alone was noninferior compared with nephrectomy⬜sunitinib, suggesting that CN should not be considered SOC in patients with mRCC requiring systemic treatment. Certain subgroups, including patients with one IMDC risk factor, may still benefit from upfront CN. Patient summary We assessed the survival of patients with metastatic kidney cancer in a clinical trial. Patients treated with sunitinib on its own had the same survival as patients who had surgery before sunitinib treatment. We conclude that surgery may not be necessary for some patients with metastatic kidney cancer.

This study looked at whether epidermal growth factor receptor inhibition by the monoclonal antibody panitumumab could increase the efficacy of standard chemotherapy in advanced urothelial cancer. Results were disappointing, with higher toxicity and no improvement in efficacy in the combination arm. Background: Epidermal growth factor receptor (EGFR) overexpression is frequent and associated with poor outcome in urothelial carcinoma. EGFR inhibition could improve the antitumor activity of chemotherapy. Patients and Methods: Patients with advanced, treatment-naive, histologically confirmed advanced urothelial carcinoma and no HRAS or KRAS mutation in the primary tumor received dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (dd-MVAC) without or with the anti-EGFR monoclonal antibody panitumumab (Pmab). A randomized (1:2) phase II design was used with progression-free survival (PFS) as the primary endpoint. Results: Ninety-seven eligible patients were randomized; 96 patients were evaluable for toxicity and 87 for efficacy. The median PFS were 6.8 months (95% confidence interval [CI], 6.3-9.2) for dd-MVAC and 5.7 months (95% CI, 4.6-6.4 months) for dd-MVAC+Pmab. For both immunohistochemical and molecular definition of basal/squamous-like (BASQ) tumors, no difference was observed in objective response rates or PFS between the two arms in BASQ and non-BASQ tumors. Conclusion: dd-MVAC+Pmab was associated with more serious adverse events and no improvement in efficacy outcomes.

Background The diagnosis of breast cancer (BC)-related leptomeningeal metastases (LM) relies on the detection of tumor cells in cerebrospinal fluid (CSF) using conventional cytology (gold standard). However, the sensitivity of this technique is low. Our goal was to evaluate whether circulating tumor cell (CTC) detection in CSF using the CellSearch® system could be used for LM diagnosis. Methods This prospective, monocentric study included adult patients with suspected BC-related LM. The clinical sensitivity and specificity of CTC detection in CSF for LM diagnosis were calculated relative to conventional CSF cytology. Results Forty-nine eligible patients were included and 40 were evaluable (CTC detection technical failure: n = 8, eligibility criteria failure: n = 1). Cytology was positive in 18/40 patients. CTCs were detected in these 18 patients (median: 5824 CTC, range: 93 to 45052) and in 5/22 patients with negative cytology (median: 2 CTC, range: 1 to 44). The detection of ≥1 CSF CTC was associated with a clinical sensitivity of 100% (95% CI, 82.4–100) and a specificity of 77.3% (95% CI, 64.3–90.3) for LM diagnosis. HER2+ CTCs were detected in the CSF of 40.6% of patients with HER2− BC (median: 500 CTC, range: 13 to 28 320). Conclusions The clinical sensitivity of CTC detection in CSF with the CellSearch® system for LM diagnosis is higher than that of CSF cytology. CTC detection in patients with negative cytology, however, must be further investigated. The finding of HER2+ CTCs in patients with HER2− BC suggests that the HER2 status of LM should be evaluated to increase the treatment opportunities for these patients.

Background : In France, home parenteral nutrition (HPN) is managed by two parallel healthcare systems : in approved specialist centers (HPN > 12 weeks), and outside of these approved specialist centers (HPN

Background: Immediate implant reconstruction after a skin sparing or a nipple sparing mastectomy is an attractive option made easier by the use of mesh to cover the lower implant pole. Acellular dermal matrices (ADM) have been widely used and described in the literature. A titanium-coated polypropylene mesh (TCPM) is an alternative to ADM but only few clinical data have been published. Methods: 209 patients who underwent single or bilateral immediate implant breast reconstruction after conservative mastectomies using TCPM were retrospectively evaluated accounting for 260 procedures. We analyzed short-term outcomes and surgical complications. Univariate and multivariable logistic regression analyses were performed to evaluate the predictive character of patients and procedure-related characteristics on postoperative complications. Major complications were defined as implant loss and implant replacement by an expander. Results: Among 260 mastectomies, 170 were skin-sparing mastectomies, 66 nipple-sparing mastectomies and 24 skin-reducing mastectomies with an inferior deepithelialized dermal flap associated with TCPM. The median age was 52.5 years (range: 25-84), 26.3% of patients were smokers and 21.3% had previously received radiotherapy. The overall complication rate was 34.6% and major complications occurred in 8.9% of cases. Implant infection occurred in 8.8%, delayed wound healing in 20.8% and skin or nipple areola complex necrosis in 2.7% of cases. In univariate analyses, smoking, a high breast weight and implant infection occurrences were associated with major complications. Risk factors for implant infection were high body mass index (BMI), smoking, a high breast and implant weight and long drainage duration. Risk factors for delayed wound healing were smoking, a high breast and implant weight and skin reducing mastectomies. Cutaneous abdominal flap was reported as a protective factor for delayed wound healing and implant infection probably allowed by a tension-free closure. In multivariable analysis, smoking and a high breast weight were independently correlated with postoperative complication occurrence. Major complications were associated with smoking and implant infection while an inferior deepithelialized dermal flap associated with TCPM was reported as a protective factor. Conclusion: Titanium-coated polypropylene mesh (TCPM) in immediate breast reconstruction reported acceptable complication rates. Cutaneous abdominal flap and an inferior deepithelialized dermal flap associated with TCPM may help reducing the complication rate particularly when complication risk factors are present. Tension-free closure and careful handle of the cutaneous flap during mastectomy could help reducing the complication rate. Citation Format: Laure Delmond, Flavie Sire, Simon Thezenas, Philippe Rouanet, Pierre-Emmanuel Colombo, Anne Mourregot, Marian Gutowski. Immediate implant-based breast reconstruction using a titanium-coated polypropylene mesh (TiLOOP Bra): Complication rates and risk factors in a single-institution experience [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-20-16.

Background Breast cancer (BC) is the most frequent cause of leptomeningeal metastases (LM). LM diagnosis is confirmed by the detection of tumor cells in the cerebrospinal fluid (CSF) using conventional cytology (gold standard). However, even with optimal CSF sample volume and time to the analysis, the sensitivity of this technique is low, demanding repeated samples. Here, we aimed to evaluate the value of circulating tumor cell (CTC) detection in CSF using the CellSearch® system for LM diagnosis. Materials and Methods This prospective, monocentric study included adult BC patients with suspected LM (clinical and/or radiological signs). CSF samples from 1-3 lumbar puncture(s) were analyzed: protein level, conventional cytology (60 drops), and CTC detection with the CellSearch® system (60 drops, first lumbar puncture only). Sensitivity (Se) and specificity (Sp) were calculated, using the results of the conventional cytology as the gold-standard. Results Forty-nine eligible patients were included (Jan 2017-Jan 2020): median age 51.8, 95.9% women, 20.4% HER2+ BC, 93.8% previously diagnosed with metastatic BC, 89.8% with clinical symptoms. Among them, 40 were evaluable (CTC detection failure: n=8, eligibility criteria failure: n=1). Median sample volume was 3.0 mL for conventional cytology samples (median time to analysis: 22min) and 3.3 mL for CTC samples. Of the 40 evaluable patients, 18 had a positive cytology (on CSF sample n=°1/n°2: n=16/n=2) and were therefore diagnosed with LM using the gold-standard method. Protein level was elevated in 88.2% of these patients, compared with 45.1% of patients with negative CSF cytology (p=0.005). CTCs were detected in these 18 patients (median 5824 CTCs, range 93-45052). CTCs were also detected in 5/22 patients with a negative cytology (median 2 CTCs, range 1-44). Among them, one patient (44 CTCs) was diagnosed with a cytologically-proven LM 9 months later, while there was no further argument for LM in the other 4 patients’ history (1-3 CTC), who died of the extra-cerebral disease after a median time of 5.2 months (range 0.9-25.9). The detection of at least one CTC in CSF was associated with a Se of 100.0% (IC95% 82.4-100) and a Spe of 77.3% (IC95% 64.3-90.3) for the diagnosis of LM. Considering the number of CTC as a quantitative value, we determined the cut-off maximizing the Youden index using the ROC analysis (93 CTC). The detection of at least 93 CTC in CSF was associated with a Se and a Spe of 100.0% for the diagnosis of LM (area under the curve [AUC]: 1.0). Conclusion CTCs were detected with the CellSearch® system in all patients diagnosed with a cytologically-proven LM, as well as in a few patients without a cytological confirmation of LM. The prognosis of these patients with CSF cytology-/CTCs+ needs to be further investigated in a larger cohort. Citation Format: Amélie Darlix, Stéphane Pouderoux, Simon Thezenas, Alexis Bievelez, William Jacot, Laure Cayrefourcq, Nicolas Menjot-de-Champfleur, Cristina Leaha, Catherine Alix-Panabières. Detection of circulating tumor cells in cerebrospinal fluid for patients with suspected breast cancer leptomeningeal metastases: A prospective study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-01-12.

Objective Time to adjuvant treatment could have an impact on cancer prognosis. It is possible that robotic surgery lengthens the healing time of vaginal cuff after minimally invasive hysterectomy. The objective of this study was to state the impact of time to RT (TTR) on prognosis in endometrial carcinoma (EC) patients and to assess variables associated with TTR. Study design We conducted a multicentric retrospective study in two cancer centers. We included EC patients, between January 1996 and January 2016. We searched variables associated with TTR and impact of TTR on end-points: local recurrence-free survival, metastatic-free survival, event-free survival and overall survival. Results 329 patients were included and 279 were analyzed for TTR impact. Robotic surgery was associated with shorter TTR (8 weeks, 8.9 w for laparotomy, 9.2 w for laparoscopy). Pelvic lymphadenectomy, para-aortic lymphadenectomy, discussion in multidisciplinary meeting and treatment center was independently associated with TTR. No impact of TTR was shown on metastatic-free survival, event-free survival and overall survival but there was a trend of a decreased local recurrence rate in case of prolonged TTR (HRcontinuous variable = 1.08; CI95 %: 0.97–1.2). Conclusion Our study did not show any impact of treatment delay on survival end-points although prolonged TTR could moderate the benefit of radiotherapy on local control rate. Surgical route was not associated with TTR, particularly robot-associated laparoscopy did not lengthen treatment delay. TTR seems dependent of health-care organization and could represent a quality criterion of EC care for institutions.

The management of patients with colorectal cancer (CRC) and potentially resectable liver metastases (LM) requires quick assessment of mutational status and of response to pre-operative systemic therapy. In a prospective phase II trial (NCT01442935), we investigated the clinical validity of circulating tumor cell (CTC) and circulating tumor DNA (ctDNA) detection. CRC patients with potentially resectable LM were treated with first-line triplet or doublet chemotherapy combined with targeted therapy. CTC (Cellsearch&reg, ) and Kirsten RAt Sarcoma (KRAS) ctDNA (droplet digital polymerase chain reaction (PCR)) levels were assessed at inclusion, after 4 weeks of therapy and before LM surgery. 153 patients were enrolled. The proportion of patients with high CTC counts (&ge, 3 CTC/7.5mL) decreased during therapy: 19% (25/132) at baseline, 3% (3/108) at week 4 and 0/57 before surgery. ctDNA detection sensitivity at baseline was 91% (N=42/46) and also decreased during treatment. Interestingly, persistently detectable KRAS ctDNA (p = 0.01) at 4 weeks was associated with a lower R0/R1 LM resection rate. Among patients who had a R0/R1 LM resection, those with detectable ctDNA levels before liver surgery had a shorter overall survival (p &lt, 0.001). In CRC patients with limited metastatic spread, ctDNA could be used as liquid biopsy tool. Therefore, ctDNA detection could help to select patients eligible for LM resection.

International audience; Few data are currently available regarding the efficacy and safety of T-DM1 in breast cancer (BC) patients with unselected brain metastases (BM), since most clinical trials have excluded BM patients or have only included highly selected patients. HER2 + BC patients with BM treated with T-DM1 in 5 French centers were included in this retrospective study. Clinical management was performed according to the product guidelines. Efficacy was evaluated recording tumor response rates, progression-free (PFS) and overall survival, treatment compliance, and safety. Thirty nine patients received T-DM1, among whom 82 % presented with concomitant extra-cerebral disease. Median number of previous metastatic chemotherapy and HER2-directed targeted therapy regimens was 2 (range 0-8) and 1 (0-7), respectively. Thirty six patients had received BM loco-regional treatment (72 % whole-brain radiation therapy). After a median follow-up of 8.1 months (1.4-39.6), 24 patients had progressed (first site of progression: brain 14; meningeal 2; outside of the central nervous system 5; both intra- and extra-cerebral 3), 12 patients had died (disease progression), and 27 patients were still alive. Median number of T-DM1 cycles was 8 (1-43). There were 17 partial responses (44 %) and 6 patients achieved disease stabilization (59 % clinical benefit rate). Median PFS was 6.1 months (95 %CI 5.2-18.3), with one- and two-year PFS rates of 33 and 17 %, respectively. Treatment was well tolerated, without unexpected toxicities, treatment delay, or dose reduction. In this retrospective study, T-DM1 appeared to be an effective and well-tolerated therapeutic option in unselected HER2 + BC patients with BM. These findings require a prospective validation.

The impact of serum vitamin D levels on rate of pathologic complete response (pCR) after neoadjuvant chemotherapy in 144 patients with operable breast cancer was retrospectively investigated. Low serum vitamin D levels were associated with not attaining a pCR. Further study of vitamin D supplementation as a means to improve pCR rates is warranted. INTRODUCTION: There has been increasing interest in the potential benefit of vitamin D in improving breast cancer outcome. Preclinical studies suggest that vitamin D enhances chemotherapy-induced cell death. We investigated the impact of serum vitamin D levels during neoadjuvant chemotherapy (NAC) on the rates of achieving pathologic complete response (pCR) after breast cancer NAC. PATIENTS AND METHODS: Patients from 1 of 2 Iowa registries who had serum vitamin D level measured before or during NAC were included. French patients enrolled onto a previous study of the impact of NAC on vitamin D and bone metabolism were also eligible for this study. Vitamin D deficiency was defined as < 20 ng/mL. pCR was defined as no residual invasive disease in breast and lymph nodes. A Firth penalized logistic regression multivariable model was used. RESULTS: The study included 144 women. There was no difference between the French and Iowan cohorts with regard to age at diagnosis (P .20), clinical stage (P=.22), receptor status (P = .32), and pCR rate (P = .34). French women had lower body mass index (mean 24.8 vs. 28.8, P

International audience; BACKGROUND Cytoreductive nephrectomy has been the standard of care in metastatic renal-cell carcinoma for 20 years, supported by randomized trials and large, retrospective studies. However, the efficacy of targeted therapies has challenged this standard. We assessed the role of nephrectomy in patients with metastatic renal-cell carcinoma who were receiving targeted therapies. METHODS In this phase 3 trial, we randomly assigned, in a 1: 1 ratio, patients with confirmed metastatic clear-cell renal-cell carcinoma at presentation who were suitable candidates for nephrectomy to undergo nephrectomy and then receive sunitinib (standard therapy) or to receive sunitinib alone. Randomization was stratified according to prognostic risk (intermediate or poor) in the Memorial Sloan Kettering Cancer Center prognostic model. Patients received sunitinib at a dose of 50 mg daily in cycles of 28 days on and 14 days off every 6 weeks. The primary end point was overall survival. RESULTS A total of 450 patients were enrolled from September 2009 to September 2017. At this planned interim analysis, the median follow-up was 50.9 months, with 326 deaths observed. The results in the sunitinib-alone group were noninferior to those in the nephrectomy-sunitinib group with regard to overall survival (stratified hazard ratio for death, 0.89; 95% confidence interval, 0.71 to 1.10; upper boundary of the 95% confidence interval for noninferiority

International audience; PURPOSE:Intermediate-risk early breast cancer (EBC) is a heterogeneous group in which adjuvant chemotherapy decision proves to be difficult. Clinical and pathological criteria are sometimes insufficient to determine the best therapeutic options, and validated biomarkers such as uPA/PAI-1, are needed to contribute to the decision-making. The objective of this study was to evaluate the clinical outcome of an unselected ER+/HER2- pN0 EBC cohort of patients in whom the routine clinical decision process included a prospective uPA/PAI-1 determination.METHOD:This monocentric retrospective study included 520 patients who underwent curative surgery in our institute between 2006 and 2011. Adjuvant therapeutic strategy was decided based on clinical-pathological data, altogether with a routine prospective determination of uPA/PAI-1 tumor levels using fresh, extemporaneously sampled tissue. We evaluated the correlation between uPA/PAI-1 levels, clinical-pathological variables, and the patient's outcome (relapse-free survival, RFS, and overall survival, OS).RESULT:Median follow-up was 5.4 years. The 5- and 10-year RFS rates were ,respectively, 95 and 89%, and the five-year OS rate was 96.3%. Forty percent of tumors had low uPA/PAI-1 levels. Seventy-five percent of patients with low uPA/PAI-1 levels did not receive chemotherapy, when 25% did. Sixty percent of patients with high uPA and/or PAI-1 levels received chemotherapy, while 40% did not. No statistical significant correlation was found between the uPA/PAI-1 levels and RFS or OS.CONCLUSION:The personalization of the patients' treatment using uPA/PAI-1 tumor levels allows the reversion of the well-known poor prognostic impact of high uPA/PAI-1 levels and strongly supports the use of this biomarker in clinical practice.

International audience; CONTEXT:Cancer-associated cachexia is correlated with survival, side-effects, and alteration of the patients' well-being.OBJECTIVES:We implemented an institution-wide multidisciplinary supportive care team, a Cancer Nutrition Program (CNP), to screen and manage cachexia in accordance with the guidelines and evaluated the impact of this new organization on nutritional care and funding.METHODS:We estimated the workload associated with nutrition assessment and cachexia-related interventions and audited our clinical practice. We then planned, implemented, and evaluated the CNP, focusing on cachexia.RESULTS:The audit showed a 70% prevalence of unscreened cachexia. Parenteral nutrition was prescribed to patients who did not meet the guideline criteria in 65% cases. From January 2009 to December 2011, the CNP team screened 3078 inpatients. The screened/total inpatient visits ratio was 87%, 80%, and 77% in 2009, 2010, and 2011, respectively. Cachexia was reported in 74.5% (n = 2253) patients, of which 94.4% (n = 1891) required dietary counseling. Over three years, the number of patients with artificial nutrition significantly decreased by 57.3% (P < 0.001), and the qualitative inpatients enteral/parenteral ratio significantly increased: 0.41 in 2009, 0.74 in 2010, and 1.52 in 2011. Between 2009 and 2011, the CNP costs decreased significantly for inpatients nutritional care from 528,895€ to 242,272€, thus financing the nutritional team (182,520€ per year).CONCLUSION:Our results highlight the great benefits of implementing nutritional guidelines through a physician-led multidisciplinary team in charge of nutritional care in a comprehensive cancer center.

International audience; PURPOSE: Concomitant treatment with radiation therapy and cisplatin (CDDP) remains the gold standard for bladder preservation in the treatment of muscle-invasive bladder cancer (MIBC). We present the long-term results of a phase 1 clinical trial to assess the association of twice-weekly gemcitabine with CDDP and radiation therapy in this setting. METHODS AND MATERIALS: Patients with pT2-pT4N0M0 MIBC without hydronephrosis or diffuse carcinoma in situ were enrolled in this study. After maximal transurethral resection of the bladder tumor, patients received concomitant radiation therapy (63 Gy in 1.8 fractions) and chemotherapy (CDDP 20 mg/m²/day over 4 days every 21 days and gemcitabine twice a week). The starting dose of gemcitabine was 15 mg/m² with dose escalation to 20, 25, and 30 mg/m². The primary endpoint was the maximum tolerated dose (MTD). Secondary endpoints included toxicity and tumor control. RESULTS: Fourteen patients were enrolled. Dose-limiting toxicity occurred in 2 patients treated with 30 mg/m² gemcitabine (grade 4 thrombocytopenia and severe impairment of World Health Organization performance status, respectively). Nine patients received the complete chemoradiation therapy protocol. The recommended dose of gemcitabine was 25 mg/m². The median follow-up time was 53 months, and the overall and disease-specific 5-year survival rates were 62% and 77%, respectively. Among the patients who received the complete treatment, bladder-intact survival was 76% at 5 years, and the median overall survival was 69.6 months. CONCLUSIONS: This regimen was well tolerated. The gemcitabine MTD was 25 mg/m². Bladder preservation and disease control were promising. A multicenter phase 2 randomized trial is ongoing.

We currently have limited knowledge of the involvement of long non-coding RNAs (lncRNAs) in normal cellular processes and pathologies. Here, we identify and characterize SNHG5 as a stable cytoplasmic lncRNA with up-regulated expression in colorectal cancer. Depletion of SNHG5 induces cell cycle arrest and apoptosis in vitro and limits tumour outgrowth in vivo, whereas SNHG5 overexpression counteracts oxaliplatin-induced apoptosis. Using an unbiased approach, we identify 121 transcript sites interacting with SNHG5 in the cytoplasm. Importantly, knockdown of key SNHG5 target transcripts, including SPATS2, induces apoptosis and thus mimics the effect seen following SNHG5 depletion. Mechanistically, we suggest that SNHG5 stabilizes the target transcripts by blocking their degradation by STAU1. Accordingly, depletion of STAU1 rescues the apoptosis induced after SNHG5 knockdown. Hence, we characterize SNHG5 as a lncRNA promoting tumour cell survival in colorectal cancer and delineate a novel mechanism in which a cytoplasmic lncRNA functions through blocking the action of STAU1., Several lncRNAs have been linked to cancer. Here, the authors identify SNHG5 as a long non-coding RNA promoting proliferation and survival of colorectal cancer cells by protecting specific mRNAs from STAU1-mediated degradation.

Introduction et but de l’etude Les consequences secondaires a la radiochimiotherapie curative dans les cancers des VADS sont d’ordre physique et psychosocial, incluant une diminution de la tolerance a l’effort et de la qualite de vie. Le patient rentre alors dans un cercle vicieux du deconditionnement qui, in fine, majore sa vulnerabilite aux traitements et degrade sa tolerance a l’effort et sa qualite de vie. Les activites physiques adaptees (APA) et une prise en charge nutritionnelle individualisee sont des strategies coherentes pour inverser ce cercle vicieux. Materiel et methodes Soixante-dix patients avec un cancer des VADS non metastatique etaient randomises dans le groupe « APA » ou « controle » entre juillet 2012 et novembre 2015 dans 4 centres de soins regionaux. Le groupe « APA » participait a des seances de 55 minutes d’ElectroStimulation (ES) du quadriceps, 3 fois par semaine durant toute la duree du traitement, suivi de 3 mois d’ergocycle a domicile (3 seances par semaine de 45 minutes). Les deux groupes beneficiaient d’un suivi nutritionnel selon les recommandations [Nutrition clinique et metabolisme 2012 ;26(4) :149–164]. Des evaluations ont ete realisees avant traitement (V0), a la fin du traitement oncologique (V1) et 3 mois apres la fin du traitement (V2). Les mesures portaient sur : 1) la tolerance a l’effort (temps d’endurance), 2) le nombre de pas par jour (mesures actimetriques), 3) la qualite de vie (SF-36, QLQC30). On considerait comme succes (critere d’efficacite principal) un patient qui augmentait son taux d’endurance initial de 40 % ou plus a V2. Resultats et analyse statistique En moyenne, l’observance aux seances d’ES etait de 87 % et pour l’ergocycle de 51 %. L’intervention APA ameliorait la tolerance a l’effort d’au moins 40 % chez 68 % des patients (IC95 % [48–84) vs 27 % (IC95 % [16–48]) dans les groupes « APA » vs « controle » respectivement (p ≤ 0,05)[T.S1].[PB2]. L’evolution mediane du temps d’endurance entre V0 et V2 etait de +27 % vs −43 % dans les groupes « APA » vs « controle » respectivement (p = 0,001). Des effets significatifs etaient observes sur le nombre de pas moyen realise par jour : 4050 (V0) a 4096 (V2) dans le groupe « APA » vs 4010 (V0) a 3257 (V2) dans le groupe « controle » (p = 0,003). Les analyses de qualite de vie n’objectivaient aucun effet positif ou negatif. Conclusion L’etude NUTRIMOUV a permis de montrer qu’une intervention APA couplee a une prise en charge nutritionnelle adaptee etait faisable dans cette population. De plus, cette prise en charge ameliorait la tolerance a l’effort sans modification de la qualite de vie. Les effets observes etaient principalement en lien avec l’utilisation de l’ergocycle. En effet, l’ES pendant le traitement n’avait pas d’impact positif sur le temps d’endurance des patients. Une etude de phase III comparative serait justifiee pour valider ces resultats.

4508 Background: Carmena was a randomized phase III trial, testing the benefit of CN followed by sunitinib (arm A) vs sunitinib alone (arm B), with stratification by MSKCC risk groups in 450 mRCC patients. Based on this trial, CN is not anymore recommended in mRCC (NEJM, Mejean et al, 2018). However there are questions about which patients could still benefit from CN, especially in intermediate risk group. In the present study, we investigated different subgroups from the Carmena trial to answer these questions. Methods: Carmena trial was initially stratified according to MSKCC risk groups. For the purpose of this analysis, we reclassified the patients based on IMDC risk groups. We also analyzed patients with one metastatic site vs more than one, as well as patients with secondary nephrectomy in arm B. Overall survival (OS) was the primary endpoint. Results: With a updated median FU of 61.5 months (mo), the median OS by ITT analysis was 15.6 vs 19.8 mo in arm A and B respectively stratified on MSKCC (HR 0.933 ; 95% CI [0.76- 1.15]) / stratified on IMDC (HR 0.957 ; 95% CI [0.78- 1.18]). Using IMDC risk group factors, 58.6% patients were intermediate and 41.4 % were poor risk. When looking at intermediate risk group only, 48.1% had only one risk factor (interval between diagnosis and treatment < 1y), with a median OS of 30.5 and 25.2 mo in arm A and B respectively (HR 1.24 [0.81 – 1.90]). By contrast, 51.9 % had two risk factors (mostly low hemoglobin, high corrected calcium or neutrophils), with a median OS of 16.6 and 31.2 mo in arm A and B respectively (HR 0.61 [0.41 – 0.91] p = 0.015). Regarding number of metastatic sites, 33% had only one metastatic site. Median OS was 23.6 and 22.7 mo in arm A and B respectively (HR 1.08 [0.75 – 1.57]. Finally, 40 patients had a secondary nephrectomy in arm B, with median OS of 48.5 mo [CI 95%: 27.9-64.4] vs 15.7 mo [CI 95%: 13.3-20.5] in patients who never had surgery. Conclusions: With longer FU, Carmena trial confirms that CN is not superior to sunitinib alone in ITT population, both with MSKCC and IMDC risk groups. However for patients with only one IMDC risk factor, CN might be beneficial. Number of metastatic site is not helpful to define good candidates for surgery. Finally, patients with secondary nephrectomy have very long OS, supporting this strategy. Clinical trial information: NCT00930033.

Introduction Brain metastases (BM) from breast cancer are associated with poor prognosis. This study was made to determine the prognostic influence of breast cancer biological subtypes, and to define the best therapeutic options in this setting, with a special focus on the HER2-positive population. Patients and methods Breast cancer patients with known hormone receptors (HR) and HER2 status presenting with BM treated between 1995 and 2010 in our two institutions were considered for this retrospective study. Results 250 patients were included. The study population consisted of 25.6% patients categorized as triple-negative (HR−/HER2−), 30.8% as HR+/HER2− and 43.6% as HER2+ breast cancer. Median overall survival (OS) was 8.9 months (95% CI, 6.9–10.3 months). Cerebral progression remained the most frequent cause of death (57.1%). On multivariate analysis, HER2 positivity and the RPA score were the two most important prognostic factors. Local treatment (surgery or stereotactic radiotherapy) and chemotherapy were significantly associated with an increased survival. On multivariate analysis of the RPA1-2 population, local treatment and chemotherapy were independent prognostic factors in addition to biological subtypes, RPA class, liver metastases and clinical signs of intra-cranial hypertension. Anti-HER2 therapies administered after BM diagnosis significantly and independently increased OS. Median OS in patients receiving both trastuzumab and lapatinib after BM diagnosis was significantly better than that the one of patients receiving only one of the 2 targeted therapies (25.7 vs. 9.6 months, p Conclusions Biological subtypes are independent prognostic determinants. Chemotherapy and targeted therapies positively affect the prognosis after first BM.

IF 9.269; International audience; Background: We prospectively detected circulating tumor DNA (ctDNA) and circulating tumor cells (CTC) levels in patients (pts) included in the PRODIGE14-ACCORD21-METHEP2 randomized phase II trial.Methods: The trial enrolled colorectal cancer pts with potentially resectable liver metastases & no prior treatment; the primary endpoint was the rate of R0/R1 liver metastases resection achieved by 1st line regimen (targeted therapies & bi- vs tri-chemotherapy; Ychou, ASCO 2016). Blood samples were collected at inclusion, after 1 month of therapy and before any liver metastases surgery. CTCs (CellSearch) & ctDNA (ddPCR, BioRad) were detected in an experienced laboratory (Inst. Curie).Results: 153 pts had at least one blood analysis. High CTC count (≥3 CTC/7.5ml) was detected in 25/132 pts (19%) at baseline and associated with synchronous...

International audience; PurposeThe present study examined patient self-reports of descriptions, experiences and consequences of meal disturbances and food preferences within a cultural context (i.e., French meal traditions) in various treated cancer patients along their disease trajectory.MethodsOver 800 questionnaires were sent to 20 cancer treatment centres in France. During a 9-month period, 255 questionnaires were received from five centres. Inclusion criteria included those French patients over 18 years of age, could read and understand French, had an Eastern Cooperative Oncology Group score between 0 and 2, experienced treatment-induced nutrition changes and/or had decreased oral intake. Dietetic staff assessed clinical characteristics while patients completed a 17-item questionnaire.ResultsThe majority of patients were diagnosed with breast, gastro-intestinal (GI) tract and head and neck cancers (62 %). Half of the patients (49 %) experienced weight loss >5 %. The main treatment-induced side effects were fatigue, nausea, dry mouth, hypersensitivity to odors and GI tract transit disorders. These discomforts affected eating and drinking in 83 % of patients, inducing appetite loss and selected food aversion. Food preference appeared heterogeneous. Food taste, odor and finally appearance stimulated appetite. Finally, dietary behaviors and satisfaction were driven by the extent to which food was enjoyed.ConclusionsDuring oncologic treatments, eating and drinking were affected in more than three-quarters of patients. As recommended by practice guidelines, nutritional assessment and follow-up are required. Personalized nutritional counseling should include the role of the family, patient’s meal traditions, and food habits.

International audience; Breast cancer (BC) is the second most common cause of brain metastases (BM). Predictive factors for BM have been widely studied in metastatic BC; however, there is no known serum tumor marker to accurately predict BM. Elevated serum S100ß protein and neuron-specific enolase (NSE) could reflect the brain damages induced by BM. Matrix metalloproteinase 9 (MMP-9) is involved in tumor invasion and metastatic dissemination, including BM. Also, HER2-amplified BC were shown to have a particular tropism for central nervous system (CNS). This study evaluated the correlation of these biomarkers with the presence of BM in metastatic BC patients. In this case-control study, 88 consecutive metastatic BC patients with BM (BM group) treated in our institution (2008-2015) were retrospectively selected, based on the availability of frozen serum samples for tumor marker determination. Patients were matched by age, tumor biology and number of previous metastatic chemotherapy lines to 162 metastatic BC patients without CNS involvement (control group). Serum NSE, MMP-9 and HER2 extracellular domain (ECD) levels were significantly higher in the BM group (p = 0.0051, p = 0.0062 and p = 0.0057, respectively). In multivariate analysis, serum HER2 and MMP-9 levels accurately discriminated patients with BM: odds ratios 4.4 (p < 0.001; 95%CI: 1.9-9.6) for HER2 ECD and 3.5 (p = 0.005; 95%CI: 1.5-8.4) for MMP-9. In multivariate analysis, HER2 ECD and NSE serum levels were independent prognostic factors in patients with BM. Serum HER2 ECD and MMP-9 appear to be associated with BM in metastatic BC patients. Their predictive value for BM still needs to be evaluated in further prospective studies.

Inflammatory, angiogenic and oxidative stress markers have been explored in head and neck squamous cell carcinoma (HNSCC) patients before and during radiochemotherapy. Furthermore, the effects of an oral supplementation containing amino acids, ω-3 fatty acids, ribonucleic acids, vitamins, and antioxidants on biological markers and acute toxicities were investigated.Thirty-one patients with non-metastatic stage III or IV HNSCC treated with concomitant radiochemotherapy were recruited. A nutritional support (Oral Impact) was given during 5 days before each cycle of chemotherapy. Biological samples were collected at baseline, after 5 days of oral supplementation and before the last cycle of chemotherapy. Acute phase proteins levels, proteomic cytokines determination and urinary isoprostanes levels were used as inflammatory and oxidative stress biomarkers. Toxicities were followed up during radiochemotherapy.At baseline, median levels of inflammatory (CRP 9.8 mg/l [0.8-130.1], IL-6 4.2 pg/ml [0.7-126.5]), pro-angiogenic (VEGF 229.5 pg/ml [13.1-595.9]) and pro-oxidative stress (urinary isoprostanes 118 pmol/mmol creatinine [51-299]) markers were increased. Decrease in CRP (p = 0.002) and α-1 acid glycoprotein (p = 0.020) levels were observed after 5 days of oral supplementation. During radiochemotherapy, no significant variation of inflammatory markers was reported, and a low incidence of severe acute mucositis was noted.Stage III or IV HNSCC patients are characterised by a pro-inflammatory, pro-angiogenic and pro-oxidative status. Nutritional support could improve this inflammatory state and could prevent severe acute mucositis.

Background. Triplet chemotherapy has demonstrated manageable toxicities and a favorable response rate. The addition of cetuximab to chemotherapy can increase treatment efficacy. We evaluated the efficacy and safety of cetuximab plus 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX), the ERBIRINOX regimen, as first-line treatment in patients with unresectable metastatic colorectal cancer (mCRC). Patients and Methods. In a phase II study, treatment consisted of weekly cetuximab plus biweekly. Treatment was continued for a maximum of 12 cycles and tumor response was evaluated every four cycles. The primary efficacy criterion was the complete response (CR) rate. Results. From April 2006 to April 2008, 42 patients were enrolled. The median age was 60 years (range, 32–76 years). The median duration of treatment was 5.2 months (range, 0.7–8.5 months), and a median of nine cycles was given per patient (range, 1–12 cycles). Five patients (11.9%) showed a CR, with a median duration of 23.1 months (95% confidence interval [CI], 10.8–39.7 months). The objective response rate was 80.9% (95% CI, 65.9%–91.4%). The median overall and progression-free survival times were 24.7 months (95% CI, 22.6 months to not reached) and 9.5 months (95% CI, 7.6–10.4 months), respectively. The most frequent grade 3–4 adverse events were diarrhea (52%), neutropenia (38%), and asthenia (32%). Conclusion. The ERBIRINOX regimen appears to be effective and feasible in first-line treatment of mCRC patients. These promising results led us to initiate a multicenter, randomized, phase II trial ([Research Partnership for Digestive Oncology] PRODIGE 14) in patients with potentially resectable mCRC.

Summary Objectives The most commonly used schedules are 5-FU in combination with CDDP with or without epirubicin (ECF) or docetaxel (TCF) in treatment of MGA patients (pts), independently of HER status. We evaluated the efficacy of FOLFIRI regimen in a large retrospective series of MGA pts. Methods Two hundred and twelve pts from 13 French centers were treated with at least one cycle of FOLFIRI (irinotecan 180 mg/m 2 intravenous (i.v.) over 90 minutes on day 1 with folinic acid (FA) 400 mg/m 2 i.v. over two hours followed by 5-FU 400 mg/m 2 i.v. bolus then 5-FU 2400 mg/m 2 continuous infusion over 46 hours on day 1, repeated every 14 days). Primary tumour sites were 120 (58%) stomach and 92 (42%) gastroesophageal junction. FOLFIRI was administered as first-line in 137 (65%) pts and as later-line in 75 (35%) pts for MGA. Results There was no difference between chemonaive and not chemonaive pts treated as first-line in terms of response rate 37% (95% CI: 25–50) vs 44% (95% CI: 21–69), median PFS, 6.7 (95% CI: 5.5–9.9) vs 5.3 months (95% CI: 3.6–6.9) ( P = 0.25), and OS, 13.1 (95% CI: 11.7–18.7) vs 8.8 months (95% CI: 7.3–15.6) ( P = 0.19), respectively. There was no difference between pts treated as second or later-line in terms of response rate 20% (95% CI: 8–39) vs 22% (95% CI: 6–48), median PFS, four months (95% CI: 2.8–5.4) vs 3.5 months (95% CI: 2.3–4.5) ( P = 0.56), and OS, 10.4 months (95% CI: 5.4–14.4) vs 5.3 months (95% CI: 3.5–11.3) ( P = 0.58), respectively. The global grade 3–4 toxicities were: diarrhea 11%, vomiting 9%, neutropenia 18%, febril neutropenia 4% (one toxic death). Conclusions This retrospective study confirms the activity and good tolerance of FOLFIRI regimen in MGA as first-line as well as later-line.

The aim of this study was to measure the inter-observer agreement between two teams of three dermatologists and oncologists in labelling and grading the cetuximab-induced dermatological toxicities from 98 photographs performed in a cohort of 15 patients with metastatic colorectal cancer receiving cetuximab-based chemotherapy. Kappa coefficient (κ) assessed inter-observer grading agreement. Both teams defined by the same terms eight of the 13 (62%) toxic effects reported together. Discrepancies concerned the labelling of rash desquamation, hand-foot syndrome and xerosis and the grading (different and often going in the opposite direction) of various toxicities such as paronychia, xerosis, desquamation and hand-foot syndrome (κ value less than 0.40). Acneiform eruption was recognised by both teams, but the grading allocated by oncologists was lower. Our results suggested the need for a real consensus between oncologists and dermatologists for labelling and grading these dermatological toxicities. Better training of oncologists by using a dermatological atlas would improve inter-observer agreement.

LBA3 Background: Cytoreductive nephrectomy (CN) has been the standard of care in mRCC in the past twenty years, supported by randomized and large retrospective studies. However the efficacy of targeted therapies has challenged this standard. CARMENA was designed to answer the question of whether upfront CN should continue to be performed before sunitinib. Methods: CARMENA was a randomized phase III trial. Patients (pts) with synchronous mRCC, amenable to CN, were enrolled after confirmation of clear cell histology on biopsy if PS 0-1, absence of symptomatic brain metastasis, acceptable organ function and eligible for sunitinib therapy. Pts were randomized 1:1 to either CN followed by sunitinib (arm A) or sunitinib alone (arm B), and stratified by MSKCC risk groups. Sunitinib was given at 50 mg/d, 4/6wk with dose adaptation to routine practice. In arm A, sunitinib had to start 4 to 6 wk after surgery. Primary endpoint was overall survival (OS). A total of 576 pts had to be enrolled to demonstrate non inferiority hypothesis (H0: λE/λC > 1.20), with 80% power at a 1-sided significance level of 5%. Results: 450 pts were included from 9/09 to 9/17, 226 and 224 in arm A and B, respectively. Median age was 62, ECOG-PS was 0 in 56% and 1 in 44%. MSKCC risk groups were intermediate/poor in 55.6/44.4% (arm A) and in 58.5/41.5% (arm B). In arm A, 6.7% did not have CN and 22.5% never received sunitinib. In arm B, 4.9 % never received sunitinib and 17% had secondary nephrectomy. At the time of the analysis, 326 deaths have been observed with a median follow-up of 50.9 mo. OS was not inferior in arm B, overall as well as by MSKCC risk groups (table). No difference in response rate and PFS was observed. Safety of sunitinib was as expected in both arms. Conclusions: Sunitinib alone is not inferior to CN followed by sunitinib in synchronous mRCC both in intermediate and poor MSKCC risk groups. CN should not be anymore the standard of care when medical treatment is required. Clinical trial information: NCT00930033. [Table: see text]

3535Background: pts with unresectable CRLM who respond to induction CT allowing curative-intent liver surgery have longer overall survival (OS) than pts who do not. Triplet (3-) or doublets (2-) CT...

e16189Background: S-1, an oral fluoropyrimidine, combined with Irinotecan (IRI) or Oxaliplatin (OX) (biweekly schedule) was assessed in Asian populations with acceptable safety profile and efficacy...

Purpose The antiepidermal growth factor receptor antibody cetuximab shows activity in irinotecan-refractory metastatic colorectal cancer (mCRC), mainly in wild-type KRAS tumors. Cetuximab may also exert antitumor effects through antibody-dependent cell-mediated cytotoxicity (ADCC) in which antibody Fc portion interacts with Fc receptors (FcγRs) expressed by immune cells. ADCC is influenced by FcγRIIa-H131R and FcγRIIIa-V158F polymorphisms that are clinically relevant in follicular lymphoma and metastatic breast cancer treated with rituximab and trastuzumab, respectively. We investigated the association of FcγR polymorphisms and KRAS mutation with the outcome of irinotecan-refractory mCRC patients treated with cetuximab plus irinotecan. Patients and Methods Tumor and normal tissues from 69 patients were screened for KRAS mutations using a sensitive multiplex assay and genotyped for FcγRIIa and FcγRIIIa polymorphisms by direct sequencing and multiplex allele-specific polymerase chain reaction, respectively. The results were correlated with response and progression-free survival (PFS). Results KRAS mutations were associated with lower response rate (4% v 27% in nonmutated patients; P = .021) and shorter PFS (3.0 v 5.3 months; P = .021). Patients with FcγRIIa-131H/H and/or FcγIIIa-158V/V genotypes had longer PFS than 131R and 158F carriers (5.5 v 3.0 months; P = .005). The difference remained significant for mutated-KRAS patients. By multivariate analysis, KRAS mutation and FcγR combined status were independent risk factors for PFS. Conclusion Combined FcγRIIa/FcγRIIIa polymorphisms are prognostic factors for disease progression in mCRC patients treated with cetuximab plus irinotecan. As these polymorphisms are also clinically relevant in mutated-KRAS mCRC, an important role of ADCC in cetuximab efficacy is presumed.

Purpose: To investigate the clinical relevance of the recently characterized human oncoprotein cancerous inhibitor of protein phosphatase 2A (CIP2A) in human breast cancer. Experimental Design: CIP2A expression (mRNA and protein) was measured in three different sets of human mammary tumors and compared with clinicopathologic variables. The functional role of CIP2A in breast cancer cells was evaluated by small interfering RNA–mediated depletion of the protein followed by an analysis of cell proliferation, migration, anchorage-independent growth, and xenograft growth. Results: CIP2A mRNA is overexpressed (n = 159) and correlates with higher Scarff-Bloom-Richardson grades (n = 251) in samples from two independent human breast cancer patients. CIP2A protein was found to be overexpressed in 39% of 33 human breast cancer samples. Furthermore, CIP2A mRNA expression positively correlated with lymph node positivity of the patients and with the expression of proliferation markers and p53 mutations in the tumor samples. Moreover, CIP2A protein expression was induced in breast cancer mouse models presenting mammary gland–specific depletion of p53 and either BRCA1 or BRCA2. Functionally, CIP2A depletion was shown to inhibit the expression of its target protein c-Myc. Loss of CIP2A also inhibited anchorage-independent growth in breast cancer cells. Finally, CIP2A was shown to support MDA-MB-231 xenograft growth in nude mice. Conclusions: Our data show that CIP2A is associated with clinical aggressivity in human breast cancer and promotes the malignant growth of breast cancer cells. Thus, these results validate the role of CIP2A as a clinically relevant human oncoprotein and warrant further investigation of CIP2A as a therapeutic target in breast cancer treatment. (Clin Cancer Res 2009;15(16):5092–100)

International audience; Colorectal (CRC) and gastroesophageal (GEC) cancers unusually spread to the bone. However, bone metastases (BM) are responsible for skeletal-related events (SREs) associated with an altered quality of life. Aiming to describe the characteristics and prognostic influence of BM from gastro-intestinal cancers, we performed a retrospective analysis of prospectively collected data in patients treated in our institution (1996-2006). 189 patients (5.5 %) developed BM: 79 with GEC and 110 with CRC. 57 patients had bone-exclusive metastases. In univariate analyses, the median time to BM occurrence was correlated with the primary tumour (PT) localisation, surgery, histology and TNM staging. However, in multivariate analyses, the occurrence delay was significantly shorter only for patients with GEC (HR 2.1), N1-2 status (HR 1.9), M1 status (HR 2.4), and epidermoid carcinoma (HR 6.0). Pain was the most frequent clinical sign leading to BM diagnosis (77.2 %). SRE occurred in 55 % of patients. Median overall survivals (OSs) of patients with CRC and GEC were 9.4 months [95 % confidence interval (95 % CI) 6.4-11.1] and 3.4 months (95 % CI 2.5-9.0), respectively. In univariate analyses, OS was correlated with PT surgery and NM staging, and the number of BM. In multivariate analyses, only the PT surgery and the number of BM remained correlated with OS. Our results suggest that there may be a subset of patients associated with a quicker development of BM. Given their higher risk of SRE, they could benefit from an early screening, calling for further prospective studies encompassing patients with and without BM.

Purpose: The standard radiotherapy (RT) of breast cancer consists of 50 Gy external beam RT (EBRT) to the whole breast followed by an electron boost of 10–16 Gy to the tumor bed, but this has several cosmetic disadvantages. Intraoperative radiotherapy (IORT) could be an alternative to overcome these. Methods and Materials: We evaluated 50 women with early breast cancer operated on in a dedicated IORT facility. Median dose of 10 Gy was delivered using 9-MeV electron beams. All patients received postoperative EBRT (50 Gy in 2 Gy fractions). Late toxicity and cosmetic results were assessed independently by two physicians according to the Common Terminology Criteria for Adverse Event v3.0 grading system and the European Organization for Research and Treatment of Cancer questionnaires. Results: After a median follow-up of 9.1 years (range, 5–15 years), two local recurrences were observed within the primary tumor bed. At the time of analysis, 45 patients are alive with (n = 1) or without disease. Among the 42 disease-free remaining patients, 6 experienced Grade 2 late subcutaneous fibrosis within the boost area. Overall, the scores indicated a very good quality of life and cosmesis was good to excellent in the evaluated patients. Conclusion: Our results confirm that IORT given as a boost after breast-conserving surgery is a reliable alternative to conventional postoperative fractionated boost radiation.

This study compares the evolution in statistical design reporting for phase II cancer clinical trials published in the six following leading journals: American Journal of Clinical Oncology, Annals of Oncology, British Journal of Cancer, Cancer, European Journal of Cancer and Journal of Clinical Oncology. Only articles where tumour response was considered as the primary endpoint were selected. A total of 393 phase II trials published in 1995 (n=185) and 2000 (n=208) were reviewed. Neither sample size nor design parameters were specified in 157 (85%) and 113 (46%) papers in 1995 and 2000, respectively. 28 (15%) and 95 (46%) papers included at least some information on the statistical designs used: Gehan (4.3% and 3.3%), Fleming (2.2% and 4.3%), and Simon (2.7% and 11.0%). Ad hoc, non-referenced methods were used in 5.9% and 27.3% articles in 1995 and 2000, respectively. Although there is an increase in the mention of at least some statistical design parameters in phase II cancer clinical trials over a 5-year period in these selected cancer journals, the use of referenced methods is still short or often inadequate.

Introduction Adenocarcinoma of the pancreas remains one of the most difficult malignancies to treat. Its incidence has steadily increased over the past four decades, and its prognosis is still dismal. Aim To assess tumor control and the palliative benefit of 5-fluorouracil (5-FU), cisplatin (CDDP), and radiotherapy in patients with advanced pancreatic cancer. Methodology Systemic chemotherapy consisted of 5-FU (600 mg/m2), given as a 22-hour infusion on days 1 to 5, and CDDP (100 mg/m2), given as a 90-minute infusion on day 2. Treatment courses were repeated identically on day 21. Radiotherapy was delivered using megavolt irradiation of 25-MV photons with a two- or four-field isocentric technique. Results Twenty-seven patients were treated with this radiochemotherapy (RCT). Twenty-one patients (78%) completed initial treatment. The median dose of radiation therapy delivered was 42.5 Gy. At the time of evaluation (1 month after the end of the RCT), no grade 4 (WHO) toxicity was observed; 12 patients had improved or stable body weight; pain was improved for 20 patients, with 11 experiencing no pain; and analgesic consumption decreased for 18 patients, of whom 11 stopped intake. The clinical benefit response was 7/27 (26%). Median survival and time to progression were, respectively, 9 and 4.4 months. Conclusion This RCT regimen had a good impact on clinical benefit in locally advanced pancreatic carcinoma, without severe side effects.

e17502Background: Neuroendocrine cervical carcinoma (NECC) is a very aggressive and rare disease. To date, only 2 prospective studies with scarce patient numbers have been reported in the literatur...

11055 Background: The optimal management of malignant phyllod tumors (MPT) is poorly documented. Objective:To study the characteristics and outcome of MPT patients (pts). Methods: Retrospective study from the nation-wide French sarcoma network (NetSarc) from 2000 to 2016. Inclusion criteria was central pathological review of MPT. End-points were local recurrence-free survival (LRFS), metastasis-free survival (MFS), and overall survival (OS). Results: 212 pts, from 13 centers, were included. Median age was 52.8 years (range: 16.8 - 90.5). All localized MPT pts (96.7%) underwent surgery with 41.4% of mastectomy. The median size was 5.8 cm (range: 1.5 - 30). R1/R2 resection was achieved in 40.1% pts (26.9% 1-2 mm margin, 12.2% 3-7 mm, 20.3% ≥8 mm), with 44.8% of second surgery (SS) for a final mastectomy rate of 72.6%. Presurgical biopsy was performed in 86.3% and associated with R0 resection ( p=0.044) and better LRFS ( p=0.012). Median follow-up was 4.1 years (range 0-14.8) and revealed 34 (16.6%), 48 (22.9%), 44 (20.8%) events for LRFS, MFS and OS, respectively. The 2-year OS rate was 89%. Prognostic factors found in multivariate analysis are presented in Table 1. Wider margins (≥8mm) were not associated with better outcomes. Adjuvant radiotherapy and chemotherapy were performed in 43.6% and 13.3% respectively and associated with longer LRFS, not significant in multivariate analysis. Conclusions: Mastectomy is associated with better local control, but not with MFS and OS. Age, tumor necrosis and metastatic disease are associated with poor prognosis in MPT pts. Our study suggests that margins of 3 mm are necessary and sufficient for the surgical management of MPT and emphasizes the importance of SS to obtain clear margins. [Table: see text]

e15048 Background: Efficacy results of Folfox or Folfiri chemotherapies (CT) are not different as 1st line in mCRC patients, alone or with targeted therapies. No data reported on progression-free survival (PFS) of 1st line Folfiri after Folfox-based adjuvant CT and of 2nd line Folfiri-based CT after a Folfox-based 1st line. The objective was to evaluate the efficacy of a Folfiri-based CT after adjuvant or 1stline Folfox-based treatment. Methods: 210 of 568 pts from a mCRC database were retrospectively selected and divided in 2 cohorts: pts who received adjuvant Folfox then Folfiri as 1st line treatment (n = 76, AdjF) and those treated with Folfox as 1st line treatment then Folfiri 2nd line (n = 134, FFox). PFS1 was the time from beginning of Folfox to 1st progression and PFS2 the time from the Irinotecan-based CT to 2ndprogression. Results: Median age was 62 (22-80). 49.3% pts had synchronous liver (72%) metastases. Primary tumour was right and left colon in 22% and 70% patients. Primary tumour was resected in 91% pts (98.7% and 86.6% in the AdjF and FFox groups, p= 0.003). KRASand BRAF-mutated status were found in 21.8% and 4.7% pts. In the AdjF group, pts received Folfiri as 1st line combined with Bevacizumab (Beva) or anti-EGFR therapy (Cetuximab or Panitumumab) in 70% and 13% cases. In the FFox group, 1st line Folfox-based CT was associated with Beva and anti-EGFRs in 7 and 6% pts, and 2ndline Folfiri-based CT with Beva or Aflibercept in 51 and 4% pts, and with anti-EGFRs in 7.5%. Median duration of a therapeutic line was 5 months (0-29.8). Grade 3-4 toxicities were for the AdjF and FFox groups respectively, diarrhea 13/15%, neutropenia (febrile) 16(7)/37%(1%) and neuropathy 24/18%. Response rates were 55.3% and 68.7% in the AdjF and FFox groups. Median PFS1 were 14 (95%CI:10-16) and 10 (95%CI:8-11) months in the AdjF and FFox groups, and PFS2 10 (95%CI:8-11) and 7 (95%CI:6-9) months, respectively. Median overall survival was 43 (95%CI:39-50) and 33 months (95%CI:26-36) respectively. Conclusions: Results in terms of survival are in favor of the AdjFFox group. It would be interesting to identify a subgroup of pts rapidly progressing after adjuvant Folfox, who might show the same profile than pts in the FFox group.

307 Background: Frequent overexpression and correlation with stage and survival has been reported with the EGF-R pathway in ATCC. Methods: 93 patients (pts) with locally advanced or metastatic bladder or upper urinary tract (UUT) transitional cell carcinoma were planned with a 1:2 randomisation ratio. Patients with K-Ras or H-Ras mutations were excluded. dd-MVAC included M 30 mg/m2d1, V 3 mg/m2d2, D 30 mg/m2d2 and cisplatin 70 mg/m2d2 (d1 = d14) with G-CSF support. PANI 6 mg/kg was given on d2. The number of pts was determined from the 9-month median progression-free survival (PFS) rate reported with dd-MVAC. Using a one stage Fleming design, the dd-MVAC+PANI combination will be considered to be active if at least 37 patients among 70 do not show tumor progression at 9 months (p0 = 0.50, p1 = 0.70, alpha = 0.08 and beta = 0.03). As basal-like subtype might be related to Anti-EGFR treatment response, the phenotype was determined using a Keratin 5/6 and GATA3 double immunostaining (8 basal like among 58 cases tested). Results: From September 2010 to November 2015, 96 patients (bladder 68, UUT 21, both 8) received dd-MVAC (33) or dd-MVAC+PANI (63). No significant difference was observed among baseline characteristics and prognostic factors. The median number of cycles was 6 (1-6) in both arms. At least one grade > 2 toxicity was observed in 79% and 76% of patients in the dd-MVAC and PANI arms, respectively. More dermatological adverse events were observed in the PANI arm. Objective responses were reported in 23 (70%) pts in the dd-MVAC arm and 30 pts (48%) in the PANI arm. With a median follow-up of 27 months, PFS was 6.8 months and 5.7 months in the dd-MVAC and PANI arms respectively; OS was 20.2 months and 12.5 months in the dd-MVAC and PANI arms, respectively. No association was observed between PFS and basal-like feature for patients treated by MVAC+PANI. Molecular subtyping is in progress to confirm this observation at mRNA level. Conclusions: When combined with dd-MVAC, PANI does not seem to improve efficacy in pts with ATCC. Clinical trial information: NCT02818725.

BACKGROUND Obesity is causally related with tumor development, and thus, many cancer patients are overweight or obese at diagnosis. Whether these patients need regular nutritional assessment is not known. In the present study, we evaluated the utility of Mini Nutritional Assessment (MNA), a nutritional screening/assessment questionnaire, in overweight or obese patients with metastatic tumors. PATIENTS AND METHODS Overweight or obese patients referred for initiation of systemic therapy in three cancer centers were eligible. Basic demographics and clinical data were recorded. MNA was completed at baseline and patients were divided into three groups: A (well nourished), B (at risk), and C (malnourished). Survival data were subsequently collected. The prevalence of malnutrition and prognostic significance were evaluated. RESULTS In total, 1469 patients with metastatic primaries were identified. Of them, 594 (41.9%) were overweight or obese and included in the analysis. According to MNA, almost 50% were at risk and around 12% were already malnourished at presentation. A significant difference in overall survival was found between groups [group A 17.8 (15.5-20.1) months, group B 8.2 (7.3-9.3) months, and group C 6.4 (3.2-9.6) months, P < 0.001]. Moreover, MNA was the only independent predictor of survival. CONCLUSIONS Our findings support that a significant percentage of overweight or obese cancer patients may be at nutritional risk and this is moreover related with adverse prognosis. An MNA score could be used for the identification of this risk.