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Gastric and esophageal adenocarcinomas represent a biologically heterogeneous disease. The identification, in early eighties, of human epidermal growth factor receptor 2 (HER2) overexpression, being present in 12 to 20% of the cases, marked a major milestone in the efforts of unraveling the molecular complexity of this disease. This led to the development of anti-HER2-therapies, trastuzumab being the first to demonstrate, in combination with cisplatin and 5FU/capecitabine chemotherapy, an improvement in response rate and survival in the first-line setting of patients with metastatic, HER2-positive gastroesophageal adenocarcinomas. Afterwards, during a decade, several studies have tried new strategies either to block HER2 pathway differently or to combine different anti-HER2, without efficacy. Everything changed with studies demonstrating additive effect between anti-HER2 and immune checkpoint inhibitors and leading to phase III clinical trials combining anti-HER2 and anti-PD-L1/PD1 therapies. Pembrolizumab, a PD-1 inhibitor, was recently granted by FDA an accelerated approval, in patients with HER2-positive gastro-oesophageal adenocarcinomas, in combination with trastuzumab and platinum-based chemotherapy following meaningful improvement in overall response rate over standard treatment. Progression-free and overall-survival results are still awaited to change our first-line standard treatment. Furthermore, new HER2 inhibitors have been developed, blocking HER2-mediated pathway signaling via different mechanisms from pan-HER inhibition to anti-HER2 antibody drug conjugates with promising results in pretreated patients. Trastuzumab-deruxtecan has in particular showed interesting results in pretreated patients. We present here a review of the recent data and perspectives in HER2-positive metastatic gastroesophageal adenocarcinomas.

Peritoneal carcinomatosis (pcm) in metastatic pancreatic ductal adenocarcinomas (mpdac) is frequently encountered in day-to-day practice, but rarely addressed in the literature. The objective of the present study was to describe the management and outcome of patients diagnosed with pcm. Data for all consecutive patients with mpdac treated in our centre between 1 January 2014 and 31 August 2015 were analyzed retrospectively. Computed tomography imaging was centrally reviewed by a dedicated radiologist to determine the date of pcm diagnosis. The analysis included 48 patients. Median age in the group was 61 years, and 41 patients had an Eastern Cooperative Oncology Group performance status (ecog ps) of 0&ndash, 1. All patients presented with pcm either synchronously (group 1) or metachronously (group 2). Those groups differed significantly by baseline ecog ps and neutrophil-to-lymphocyte ratio (nlr), with ecog ps being poorer and nlr being higher in group 1. In addition to pcm, the main sites of metastasis were liver (62.5%) and lungs (31.3%). First-line chemotherapy in 36 patients (75%) was folfirinox (fluorouracil&ndash, irinotecan&ndash, leucovorin&ndash, oxaliplatin). The median overall survival for the entire population was 10.81 months [95% confidence interval (ci): 7.16 months to 14.16 months], it was 13.17 months (95% ci: 5.9 months to 15.4 months) for patients treated with folfirinox. Median overall survival was 7.13 months (95% ci: 4.24 months to 10.41 months) for patients in group 1 and 14.34 months (95% ci: 9.79 months to 19.91 months) for patients in group 2, p = 0.1296. Compared with other metastatic sites, synchronous pcm seems to be a poor prognostic factor. It could be more frequently associated with a poor ecog ps and a nlr greater than 5 in this group of patients. In patients with mpdac and pcm, either synchronous or metachronous, folfirinox remains an efficient regimen.

PurposeThe objective of this study was to build and validate a radiomic signature to predict early a poor outcome using baseline and 2-month evaluation CT and to compare it to the RECIST1·1 and morphological criteria defined by changes in homogeneity and borders.MethodsThis study is an ancillary study from the PRODIGE-9 multicentre prospective study for which 491 patients with metastatic colorectal cancer (mCRC) treated by 5-fluorouracil, leucovorin and irinotecan (FOLFIRI) and bevacizumab had been analysed. In 230 patients, computed texture analysis was performed on the dominant liver lesion (DLL) at baseline and 2 months after chemotherapy. RECIST1·1 evaluation was performed at 6 months. A radiomic signature (Survival PrEdiction in patients treated by FOLFIRI and bevacizumab for mCRC using contrast-enhanced CT TextuRe Analysis (SPECTRA) Score) combining the significant predictive features was built using multivariable Cox analysis in 120 patients, then locked, and validated in 110 patients. Overall survival (OS) was estimated with the Kaplan-Meier method and compared between groups with the logrank test. An external validation was performed in another cohort of 40 patients from the PRODIGE 20 Trial.ResultsIn the training cohort, the significant predictive features for OS were: decrease in sum of the target liver lesions (STL), (adjusted hasard-ratio(aHR)=13·7, p=1·93×10–7), decrease in kurtosis (ssf=4) (aHR=1·08, p=0·001) and high baseline density of DLL, (aHR=0·98, p0·02 had a lower OS in the training cohort (pConclusionA radiomic signature (combining decrease in STL, density and computed texture analysis of the DLL) at baseline and 2-month CT was able to predict OS, and identify good responders better than RECIST1.1 criteria in patients with mCRC treated by FOLFIRI and bevacizumab as a first-line treatment. This tool should now be validated by further prospective studies.Trial registrationClinicaltrial.gov identifier of the PRODIGE 9 study: NCT00952029.Clinicaltrial.gov identifier of the PRODIGE 20 study: NCT01900717.

4007 Background: The benefit of adapted physical activity (APA) on health-related quality of life (HRQoL) in Pts with advanced pancreatic ductal adenocarcinoma (aPDAC) treated by chemotherapy (CTx) has never been prospectively assessed. Methods: Pts with aPDAC and ECOG performance status (PS) 0–2 were randomized 1:1 to receive usual care (UC) including first-line CTx at the investigator’s choice (standard arm), or UC plus a home-based 16-week APA program (APA arm). The APA program consisted of personalized aerobic and resistance exercises, with a weekly remote supervision by an APA professional trainer, and unsupervised sessions with a family member or friend (APA partner). The primary objective was the effect on HRQoL at week 16 (W16) measured by 3 dimensions of the EORTC QLQ-C30, global health status (GHS), physical functioning (PF), and fatigue (FA), with a one-sided type I error of 0.016 for each dimension. The primary HRQoL analysis was performed in Pts with available baseline and W16 scores for the 3 targeted dimensions (mITT1). Secondary analyses of HRQoL changes by the mixed model for repeated measures (MMRM) and time until definitive deterioration (TUDD) methods included Pts with baseline and ≥1 follow-up score (mITT2). Differences > 5 points in scores were considered clinically significant. Results: A total of 313 Pts (median age: 64 years; men: 55%, ECOG PS 0-1: 93%; metastatic: 77%; FOLFIRINOX: 78%, gemcitabine-based: 13%) were included from 11/2014 to 10/2020 (standard arm: n = 157, APA arm: n = 156). In the mITT1 population (n = 172), mean differences in HRQoL at W16 adjusted from baseline were -0.98 (SD 23.87; p = 0.39), -2.08 (SD 21.34; p = 0.26), and 4.16 (SD 29.18; p = 0.18) for GHS, PF, and FA, respectively. In the mITT2 population (n = 259), APA was associated with significant improvements in 5 (GHS, PF, cognitive functioning [CF], social functioning [SF], appetite loss) and 8 (GHS, CF, emotional functioning [EF], SF, insomnia, constipation, pain, financial difficulties) dimensions of HRQoL by MMRM and TUDD, respectively (Table). Secondary endpoints, including overall survival, progression-free survival, and chemotherapy toxicity will be presented. Conclusions: APA in combination with usual care improved several dimensions of HRQoL in Pts with aPDAC receiving first-line CTx. Clinical trial information: NCT02184663. [Table: see text]

Background Medulloblastomas may occur in a predisposition context, including familial adenomatosis polyposis. Medulloblastomas related to a germline pathogenic variant of adenomatous polyposis coli (APC) remain rare and poorly described. Their similarities with sporadic WNT medulloblastomas still require description. Methods We performed a multicentric retrospective review of 12 patients treated between 1988 and 2018 for medulloblastoma with an identified or highly suspected (personal or familial history) APC germline pathogenic variant. We report personal and familial history APC gene pathogenic variants whenever available: clinical and histologic characteristics of the medulloblastoma, treatments, and long-term outcome, including second tumor and late sequelae. Results Medulloblastomas associated with APC pathogenic variants are mainly classic (11/11 patients, 1 not available), nonmetastatic (10/12 patients) medulloblastomas, with nuclear immunoreactivity for ß-catenin (9/9 tested cases). Ten of 11 assessable patients are disease free with a median follow-up of 10.7 years (range, 1–28 y). Secondary tumors included desmoid tumors in 7 patients (9 tumors), 1 thyroid carcinoma, 2 pilomatricomas, 1 osteoma, 1 vertebral hemangioma, and 1 malignant triton in the radiation field, which caused the only cancer-related death in our series. Conclusions Medulloblastomas associated with an APC pathogenic variant have an overall favorable outcome, even for metastatic tumors. Yet, long-term survival is clouded by second tumor occurrence; treatment may play some role in some of these second malignancies. Our findings raise the question of applying a de-escalation therapeutic protocol to treat patients with APC germline pathogenic variants given the excellent outcome, and reduced intensity of craniospinal irradiation may be further evaluated.

The POLD1 gene is involved in DNA proofreading to ensure accurate DNA replication. Some germline alterations in its exonuclease domain are associated with predisposition to cancers and colonic polyps. Only a few pathogenic variants have been clearly identified so far. Here we report a novel variant: c.1458GT p.(Lys486Asn) that we classified as pathogenic, detected in two putatively unrelated families. The cancer spectrum was very similar to Lynch syndrome, implying an overlapped tissue susceptibility. The common presence of colonic polyps in carriers and the MMR proficient phenotype in tumors were distinctive features suggesting POLD1 implication. Some clinical characteristics observed in the carriers of this variant differed from those reported previously, suggesting a potential genotype/phenotype correlation, and very likely in relation to the functional importance of affected residues. Our findings provide further insight into understanding the role of POLD1 in cancer-related risk.

Background Nab-paclitaxel/gemcitabine (AG) and FOLFIRINOX (FFX) are promising drugs in metastatic pancreatic cancer (MPC). This study evaluated a new first-line sequential treatment (AG followed by FFX) in MPC that might overcome resistance to primary therapy and delay tumor progression. Patients and methods Patients with histologically/cytologically confirmed MPC were included in a multicentric trial receiving AG (day 1, 8 and 15) followed by FFX (day 29 and 43). In phase Ib, three dose-levels were tested for maximum tolerated dose (MTD) and recommended phase II dose. In phase II, the main outcome was the objective response rate (ORR) and secondarily safety, progression-free survival (PFS) and overall survival (OS). Results In phase Ib, we included 33 patients (31 assessable) of median age 61.0 years (range 42-75 years) and represented by 54.8% males. Five dose-limiting toxicities were reported without any death. The main grade 3/4 toxicities were neutropenia with spontaneous resolution (35.5%/32.3%), venous thromboembolism (grade 3: 22.6%) and thrombopenia (grade 3: 29.0%), while the MTD was not reached. In phase II, we included 58 patients of median age 60 years (range 34-72 years), 50% males and with Eastern Cooperative Oncology Group stage score 0 and 1 of 37.9% and 62.1%, respectively. They received a median of 4 (1-9) cycles in 8.5 months (0.5-19.8 months). The ORR was 64.9% [95% confidence interval (CI) 51.1% to 77.1%], and neurotoxicity was remarkably low. The main grade 3-4 toxicities were venous thromboembolism, thrombopenia, neutropenia/febrile neutropenia, nausea, diarrhea, weight loss and asthenia without any death. Tumor response was complete in 3.5% and partial in 61.4%, while disease was stable in 19.3% and progressive in 15.8% of patients. The median PFS was 10.5 months (95% CI 6.0-12.5 months) and median OS was 15.1 months (95% CI 10.6-20.1 months). Conclusion Sequential AG and FFX showed acceptable toxicity as first-line treatment with no limiting neurotoxicity, while high response rate and survival justify randomized trials., Highlights • AG and FFX are promising drugs in MPC. • We hypothesize that nab-paclitaxel by targeting tumor microenvironment would increase FFX access in sequential treatment. • Phase Ib-II trial with AG followed by FFX showed acceptable toxicity with no limiting neurotoxicity. • The high response rate and promising survival justify a further randomized trial.

Background BRAF V600E mutations occurring in about 10% of metastatic colorectal cancers (mCRCs) are usually associated with a poor outcome. However, their prognostic factors are unknown. Materials and Methods We built a multicenter clinico-biological database gathering data from patients with BRAFV600E-mutant mCRC treated in one of the 16 French centers from 2006 to 2017. The primary endpoint was to identify prognostic factors using a Cox model. Results We included 287 patients (median age, 67 years [28–95]; female, 57%). Their median overall survival was 20.8 months (95% confidence interval [CI], 17.97–27.04), and median progression-free survival in the first-line setting was 4.34 months (95% CI, 3.81–5.03). Chemotherapy regimen and biological agents (antiangiogenic or anti-epidermal growth factor receptor) were not associated with overall and progression-free survival. Stage IV disease (synchronous metastases) and absence of curative-intent surgery were statistically associated with poor overall survival. Among the 194 patients with mismatch repair (MMR) status available, overall survival was significantly longer in patients with deficient MMR tumors compared with those with proficient MMR tumors (adjusted hazard ratio = 0.56; p = .009). Conclusion Despite that BRAFV600E-mutant mCRCs are associated with poor overall and progression-free-survival, patients with deficient MMR tumors and/or resectable disease experienced a longer survival. These results highlight the importance of MMR testing and resectability discussion in patients with BRAFV600E mCRC in day-to-day practice. Implications for Practice Mismatch repair (MMR) testing and resectability discussion in patients with BRAFV600E metastatic colorectal cancer (mCRC) should be performed in day-to-day practice to steer treatment decision making in patients with BRAFV600E-mutant mCRC.

Background Metastatic pancreatic ductal adenocarcinoma (mPDAC) is an aggressive malignancy with a median overall survival (OS) of between 8 and 11 months. However, a significant number of patients experience a longer survival, more than 18 months. The aim of this study was to describe the “long-term survivor” population and to evaluate clinical and pathological factors that might affect survival. Materials and Methods All patients with mPDAC diagnosed in the Centre Leon Bérard (Lyon, France) between January 2010 and June 2015 and who survived more than 18 months were identified. They were compared with a control cohort matched on age, sex, performance status, stage at diagnosis, primary tumor localization, treatment, and liver metastasis. Their clinical features, treatment modalities, and outcomes were analyzed. Results A total of 94 patients were included, 47 in each cohort. Both cohorts had identical characteristics as follows: women (51%), performance status ≤1 (95.7%), median age at diagnosis (60 years), and metastasis at diagnosis (83%). Median OS was 26.87 months (95% confidence interval [CI] 23–31.08) in the long-term survivor group (LS group) and 9.79 months (95% CI 5.75–11.86) in the control group (C group). Potential factors of long-term survival were explored with a logistic model (LS group vs. C group). Three factors were identified as significant prognostic factors in the univariate analysis: lymphopenia (odds ratio [OR] ref: yes = 0.26), neutrophil-to-lymphocyte ratio (NLR; OR ref >5 = 0.31), and peritoneal carcinomatosis (OR ref: yes = 0.40). NLR was the only remaining factor in our backward selection procedure. Conclusion A significant subset of patients with mPDAC can achieve long-term survival (≥18 months) in 2018. We identified low NLR as a significant prognostic factor associated with long-term survival in mPDAC. Implications for Practice Metastatic pancreatic ductal adenocarcinoma (mPDAC) is one of the most lethal types of cancer. A subset of patients with mPDAC can achieve long-term survival (≥18 months) with a modern chemotherapy regimen, such as FOLFIRINOX or gemcitabine/nab-paclitaxel. We identified low neutrophil-to-lymphocyte ratio (NLR) as a significant prognostic factor associated with long-term survival in mPDAC. Prognostic factors such as NLR might allow accurate selection of patients with mPDAC in order to consider individual therapeutic approaches. NLR should be used as a stratification factor in clinical trials.

Primary malignant melanoma of the esophagus is rare, accounting for less than 0.1–0.2% of all esophageal malignancies. It is associated with a poor outcome due to late detection and high metastatic potential. Here, we report a case of esophageal cancer, which was initially diagnosed as an adenocarcinoma and finally was confirmed as a primary malignant melanoma. This 75-year-old Caucasian male had a history of dysphagia and recent lingering abdominal pain. First biopsy showed a poorly-differentiated adenocarcinoma. He was then treated with neoadjuvant radiochemotherapy. Biopsies were repeated because of an incomplete tumor response, evaluated by endoscopic and imaging studies. The final diagnosis was a malignant melanoma. The patient has been treated with immune-checkpoint inhibitor, nivolumab, an anti-PD1 antibody.

IF 7.191 (2017); International audience; BACKGROUND:Previous studies showed that high and low body mass index (BMI) was associated with worse prognosis in early-stage colorectal cancer (CRC), and low BMI was associated with worse prognosis in metastatic CRC (mCRC). We aimed to assess efficacy outcomes according to BMI.PATIENTS AND METHODS:A pooled analysis of individual data from 2085 patients enrolled in eight FFCD first-line mCRC trials from 1991 to 2013 was performed. Comparisons were made according to the BMI cut-off: Obese (BMI ≥30), overweight patients (BMI ≥ 25), normal BMI patients (BMI: 18.5-24) and thin patients (BMI

Medulloblastoma may occur in a context of APC germline mutation and familial adenomatous polyposis. We aimed to describe clinical features of patients with medulloblastoma occurring in this context. We performed a multicentric retrospective review of French and Belgian patients treated for medulloblastoma with identified or highly suspected (personal or familial history) APC germline mutation. Genetic status, clinical and histological characteristics, treatments and outcome were reported. Eleven patients with known or suspected APC germline mutation, mostly on exon 15 (N=6/9 available data), were diagnosed with medulloblastoma at a median age of 10.6 years [6-32]. Medulloblastomas were mainly non-metastatic (N=9/11), classic (N=9/9 available data, central review ongoing), with no significant residual tumor after surgery (N=9/11). All patients underwent radiotherapy (median craniospinal dose: 35 Gy), combined with chemotherapy for 10 patients. No relapse was noticed (median follow-up: 11 years). Secondary tumors (N=8) occurred in 7 patients, including 1 lethal malignant Triton tumor in the irradiation field, 1 thyroid carcinoma, and 6 desmoid tumors (5 abdominal tumors, 1 occipital tumor in the irradiation field). Pre-symptomatic polyposis was diagnosed for 9 patients at a median age of 15.5 years, prior to medulloblastoma for 2 of them. Medulloblastomas associated with APC germline mutation have favorable clinical outcome, even for metastatic tumors, with no relapse in this small series of patients, in line with WNT-medulloblastomas’ profile. Yet, long-term survival is clouded by second tumor occurrence, with potential radiation-induced tumors. These findings raise the question of applying de-escalation therapeutic protocol for these patients with reduced intensity craniospinal irradiation.

Purpose Conflicting results are reported for maintenance treatment with bevacizumab during chemotherapy-free intervals (CFI) in metastatic colorectal cancer after induction chemotherapy. Patients and Methods In this open-label, phase III, randomized controlled trial, we compared the tumor control duration (TCD) observed with bevacizumab maintenance and with no treatment (observation) during CFI subsequent to induction chemotherapy with 12 cycles of fluorouracil, leucovorin, and irinotecan plus bevacizumab. After disease progression, the induction regimen was repeated for eight cycles, followed by a new CFI. Results From March 2010 to July 2013, 491 patients were randomly assigned. Disease progression or death occurred during induction chemotherapy in 85 patients (17%); 261 patients (53%) had at least one reinduction, 107 (22%) had two reinductions, and 56 (11%) had three or more reinductions. The median TCD was 15 months in both groups; the median progression-free survival (PFS) from randomization was 9.2 and 8.9 months in the maintenance group and observation groups, respectively. The TCD observed in both groups was higher compared with the TCD hypotheses of the trial. The median overall survival (OS) was 21.7 and 22.0 months in the maintenance and observation groups, respectively. In the per-protocol population, defined as patients with at least one reinduction after the first progression, the median duration of the first CFI was 4.3 months in both arms; the median TCD was 17.8 and 23.3 months ( P = .339), the median PFS was 9.9 and 9.5 months, and the median OS was 27.6 and 28.5 months in the maintenance and observation groups, respectively. Multivariable analysis revealed that female gender, WHO performance status ≥ 2, and unresected primary tumors were associated with a shorter TCD. Conclusion Bevacizumab maintenance monotherapy did not improve TCD, CFI duration, PFS, or OS.

// Xiaojun Jiang 1 , Daniel Pissaloux 1 , Christelle De La Fouchardiere 2 , Francoise Desseigne 2 , Qing Wang 1 , Valery Attignon 1 , Marie-Eve Fondrevelle 5 , Arnaud De La Fouchardiere 5 , Maurice Perol 2 , Philippe Cassier 2 , Christelle Seigne 3 , David Perol 3 , Isabelle Ray-Coquard 2 , Pierre Meeus 4 , Jerome Fayette 2 , Aude Flechon 2 , Axel Le Cesne 7 , Nicolas Penel 6 , Olivier Tredan 2 , Jean-Yves Blay 1, 2 1 Department of Translational Research, Centre Leon Berard, 69008 Lyon France 2 Department of Medical Oncology, Centre Leon Berard, 69008 Lyon France 3 Department of Clinical Research, Centre Leon Berard, 69008 Lyon France 4 Department of Surgery, Centre Leon Berard, 69008 Lyon France 5 Department of Pathobiology, Centre Leon Berard, 69008 Lyon France 6 Department of Medical Oncology, Centre Oscar Lambret, 59020 Lille France 7 Department of Medical Oncology, Gustave Roussy, 94805, Villejuif France Correspondence to: Xiaojun Jiang, e-mail: xiaojun.jiang@lyon.unicancer.fr Jean-Yves Blay, e-mail: jean-yves.blay@lyon.unicancer.fr Keywords: multi-kinase inhibitor, biomarker, regorafenib, chromosomal instability Received: May 06, 2015 Accepted: July 09, 2015 Published: July 21, 2015 ABSTRACT Validated predictive biomarkers for multi-tyrosine kinase inhibitors (MTKI) efficacy are lacking. We hypothesized that interindividual response variability is partially dependent on somatic DNA copy number alterations (SCNAs), particularly those of genes encoding the protein tyrosines targeted by MTKI (called target genes). Genomic alterations were investigated in MTKI responsive and non responsive patients with different histological subtypes included in the ProfiLER protocol (NCT 01774409). From March 2013 to August 2014, 58 patients with advanced cancer treated with one of 7 MTKIs were included in the ProfiLER trial and split into one discovery cohort ( n = 13), and 2 validation cohorts ( n = 12 and 33). An analysis of the copy number alterations of kinase-coding genes for each of 7 MTKIs was conducted. A prediction algorithm (SUMSCAN) based on the presence of specific gene gains (Tumor Target Charge, TTC) and losses (Tumor Target Losses, TTL) was conceived and validated in 2 independent validation cohorts. MTKI sensitive tumors present a characteristic SCNA profile including a global gain profile, and specific gains for target genes while MTKI resistant tumors present the opposite. SUMSCAN favorable patients achieved longer progression-free and overall survival. This work shows that the copy number sum of kinase-coding genes enables the prediction of response of cancer patients to MTKI, opening a novel paradigm for the treatment selection of these patients.

Objectives: Carbohydrate antigen 19-9 (CA19-9) is a sensitive and specific serum marker in pancreatic cancer. Our retrospective analysis aims to evaluate CA19-9 decrease in patients with metastatic pancreatic cancer treated in ACCORD11/PRODIGE4 (FOLFIRINOX vs. gemcitabine). Methods: A total of 342 patients were treated. CA19-9 was measured at 8 weeks (±2) in 160 patients from a total of 282 with abnormal CA19-9 values at baseline (gemcitabine arm, n = 75; FOLFIRINOX arm, n = 85). In the present study, 8-week CA19-9 decrease or greater CA19-9 decrease according to the 20 and 90% thresholds were analyzed. Progression-free survival (PFS) and overall survival (OS) were estimated in each subgroup. Results: In the FOLFIRINOX arm, patients with an 8-week CA19-9 decrease or greater CA19-9 decrease ≥20% showed improved median OS, PFS, and objective response rate. In the overall study population, median OS and PFS were significantly improved in patients with an 8-week CA19-9 decrease ≥20% (vs. p = 0.006). Conclusion: An 8-week CA19-9 decrease ≥20% is a prognostic factor for OS and PFS. The 8-week CA19-9 decrease (20% threshold) is predictive of PFS. It could help to evaluate the efficacy of FOLFIRINOX and gemcitabine regimens.

Objective:Since the description by Yaskin in 1931, it has been observed that pancreatic cancer and depression are two clinical entities that share a high affinity. This observation relies on the higher incidence of depressive syndromes associated with pancreatic cancer than in any other type of digestive tumor, and on the possible occurrence of depressive symptoms several months before the diagnosis of cancer. We present here a series of cases whose screening returned positive for depression-related diagnoses in the months prior to revelation of the cancer.Method:We employed a structured psychiatric interview based on DSM–IV criteria (SCID–I). The diagnoses considered were major depressive episode, minor depressive episode, and subsyndromal depression. All subjects were free of psychiatric history.Results:Some 15 patients were initially included: 10 presented compatible criteria for a past depressive episode, 2 presented a major depressive episode, 4 met the diagnosis of minor depression, and 4 evidenced subsyndromal depression over the one-year period prior to cancer diagnosis.Significance of results:This series of cases is consistent with previous work on the subject that suggested an increased vulnerability to depressive events in the premorbid phase of pancreatic cancer. If the possibility of depressive syndromes constituting the early stages of neoplastic disease is a common idea, it is still impossible to determine the natural history of these two disorders and therefore their causal linkage.

IMPACT: 5.922; International audience; BACKGROUND: This trial evaluated the feasibility and efficacy of combined sorafenib and irinotecan (NEXIRI) as second- or later-line treatment of patients with KRAS-mutated metastatic colorectal cancer (mCRC), who had progressed after irinotecan-based chemotherapy. METHODS: In Phase I, in a 3+3 dose escalation schedule, patients received irinotecan (125, 150 or 180 mg m(-2) every 2 weeks), in combination with 400 mg sorafenib b.d. The primary end point was the maximum-tolerated dose of irinotecan. In Phase II, the primary end point was disease control rate (DCR). Secondary end points were progression-free survival (PFS), overall survival (OS) and toxicity. RESULTS: Phase I included 10 patients (median age 63 (49-73)); no dose-limiting toxicity was seen. In Phase II, 54 patients (median age 60 (43-80) years) received irinotecan 180 mg m(-)(2) every 2 weeks with sorafenib 400 mg b.d. Nine patients (17%) remained on full-dose sorafenib. The DCR was 64.9% (95% CI, 51-77). Median PFS and OS were 3.7 (95% CI, 3.2-4.7) and 8.0 (95% CI, 4.8-9.7) months, respectively. Toxicities included Grade 3 diarrhoea (37%), neutropenia (18%), hand-foot syndrome (13%) and Grade 4 neutropenia (17%). CONCLUSION: The NEXIRI regimen showed promising activity as second- or later-line treatment in this heavily pretreated mCRC population (ClinicalTrials.gov NCT00989469).

Background Pancreatic carcinoma is one of the leading causes of cancer-related mortality. At the time of diagnosis, 30% of patients present with a locally advanced pancreatic carcinoma (LAPC). As circulating tumor cells (CTCs) count may be a surrogate of the cancer metastatic abilities, CTC detection rates and prognostic value were studied in a prospective cohort of LAPC patients. Patients and methods An LAP07 international multicenter randomized study assesses in patients whose LAPC is controlled after 4 months of chemotherapy whether chemoradiotherapy could increase survival versus continuation of chemotherapy. A subgroup of patients included in the LAP07 trial was screened for CTCs (CellSearch®) before the start of the chemotherapy and after 2 months of treatment. Patient characteristics and survival were obtained prospectively and were correlated with CTC detection. Results Seventy-nine patients were included. One or more CTCs/7.5 ml were detected in 5% of patients before treatment and in 9% of patients after 2 months of treatment (overall detection rate: 11% of patients). CTC positivity was associated with poor tumor differentiation (P = 0.04), and with shorter overall survival (OS) in multivariable analysis (RR = 2.5, P = 0.01), together with anemia. Conclusions The evaluation of micrometastatic disease using CTC detection appears as a promising prognostic tool in LAPC patients.

Necrotizing Infundibular Crystalline Folliculitis (NICF) is rare entity of unknown pathogenesis presenting as follicular crystalline papules arising in seborrheic areas. We report 2 cases of NICF in patients under targeted therapy for metastatic adenocarcinoma. In one case, the lesions reappeared cyclically every 3 weeks after each injection and in the other case, lesions persisted until disruption of the continuous oral therapy. Punch-biopsies demonstrated folliculitis with a plugging crystalline material associated with either bacteria or yeast. These are the first descriptions of drug-induced NICF.

International audience; To determine if the at-risk single-nucleotide polymorphism (SNP) alleles for colorectal cancer (CRC) could contribute to clinical situations suggestive of an increased genetic risk for CRC, we performed a prospective national case-control study based on highly selected patients (CRC in two first-degree relatives, one before 61 years of age; or CRC diagnosed before 51 years of age; or multiple primary CRCs, the first before 61 years of age; exclusion of Lynch syndrome and polyposes) and controls without personal or familial history of CRC. SNPs were genotyped using SNaPshot, and statistical analyses were performed using Pearson's chi(2) test, Cochran-Armitage test of trend and logistic regression. We included 1029 patients and 350 controls. We confirmed the association of CRC risk with four SNPs, with odds ratio (OR) higher than previously reported: rs16892766 on 8q23.3 (OR: 1.88, 95% confidence interval (CI): 1.30-2.72; P=0.0007); rs4779584 on 15q13.3 (OR: 1.42, CI: 1.11-1.83; P=0.0061) and rs4939827 and rs58920878/Novel 1 on 18q21.1 (OR: 1.49, CI: 1.13-1.98; P=0.007 and OR: 1.49, CI: 1.14-1.95; P=0.0035). We found a significant (P

Background We sought to assess the benefit-risk balance of FOLFIRINOX versus gemcitabine in patients with metastatic pancreatic adenocarcinoma. Methods We used generalized pairwise comparisons. This statistical method permits the simultaneous analysis of several prioritized outcome measures. The first priority outcome was survival time (OS). Differences in OS that exceeded two months were considered clinically relevant. The second priority outcome was toxicity. The overall treatment effect was quantified using the net chance of a better outcome, which can be interpreted as the net probability for a random patient treated in the FOLFIRINOX group to have a better overall outcome than a random patient in the gemcitabine group. Results In this trial 342 patients received either FOLFIRINOX or gemcitabine. The net chance of a better outcome favored strongly and significantly the FOLFIRINOX group (24.7; P

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.

4109Background: Folfirinox (FFX) and Nab-paclitaxel/Gemcitabine (AG) showed significant efficacy improvement compared to Gemcitabine alone in metastatic pancreatic cancer (mPC). Alternating AG and ...

Importance Acquired resistance to anti-EGFR therapy (epidermal growth factor receptor) is frequently due toRASandEGFRextracellular domain (ECD) mutations in metastatic colorectal cancer (mCRC). Some anti-EGFR–refractory patients retain tumor EGFR dependency potentially targetable by agents such as Sym004, which is a mixture of 2 nonoverlapping monoclonal antibodies targeting EGFR. Objective To determine if continuous blockade of EGFR by Sym004 has survival benefit. Design, Setting, and Participants Multicenter, phase 2, randomized, clinical trial comparing 2 regimens of Sym004 with investigator’s choice from March 6, 2014, through October 15, 2015. Circulating tumor DNA (ctDNA) was analyzed for biomarker and tracking clonal dynamics during treatment. Participants had wild-typeKRASexon 2 mCRC refractory to standard chemotherapy and acquired resistance to anti-EGFR monoclonal antibodies. Interventions Participants were randomly assigned in a 1:1:1 ratio to Sym004, 12 mg/kg/wk (arm A), Sym004, 9 mg/kg loading dose followed by 6 mg/kg/wk (arm B), or investigator’s choice of treatment (arm C). Main Outcomes and Measures Overall survival (OS). Secondary end points included preplanned exploratory biomarker analysis in ctDNA. Results A total of 254 patients were randomized (intent-to-treat [ITT] population) (median age, 63 [range, 34-91] years; 63% male; n = 160). Median OS in the ITT population was 7.9 months (95% CI, 6.5-9.9 months), 10.3 months (95% CI, 9.0-12.9 months), and 9.6 months (95% CI, 8.3-12.2 months) for arms A, B, and C, respectively (hazard ratio [HR], 1.31; 95% CI, 0.92-1.87 for A vs C; and HR, 0.97; 95% CI, 0.68-1.40 for B vs C). The ctDNA revealed high intrapatient genomic heterogeneity following anti-EGFR therapy. Sym004 effectively targetedEGFRECD-mutated cancer cells, and a decrease inEGFRECD ctDNA occurred in Sym004-treated patients. However, this did not translate into clinical benefit in patients withEGFRECD mutations, likely owing to co-occurring resistance mechanisms. A subgroup of patients was defined by ctDNA (RAS/BRAF/EGFRECD-mutation negative) associated with improved OS in Sym004-treated patients in arm B compared with arm C (median OS, 12.8 and 7.3 months, respectively). Conclusions and Relevance Sym004 did not improve OS in an unselected population of patients with mCRC and acquired anti-EGFR resistance. A prospective clinical validation of Sym004 efficacy in a ctDNA molecularly defined subgroup of patients with refractory mCRC is warranted. Trial Registration clinicaltrialsregister.eu Identifier:2013-003829-29

To assess the rate of R(0) resection of liver metastases achieved after chemotherapy with FOLFIRINOX.Patients with histologically proven primary colorectal cancer and bidimensionally measurable liver metastasis, not fully resectable based on technical inability to achieve R(0) resection, but potentially resectable after tumor reduction, were given FOLFIRINOX: oxaliplatin 85 mg/m(2), irinotecan 180 mg/m(2), leucovorin 400 mg/m(2), bolus fluorouracil 400 mg/m(2) and fluorouracil 46-h continuous IV infusion 2,400 mg/m(2), every 2 weeks for a maximum of 12 cycles.Thirty-four patients were enrolled. Response rate before surgery was 70.6% (95%CI: 52.5-84.9). Twenty-eight patients (82.4%) underwent hepatic resection and nine achieved R(0) resection [26.5% (95% CI: 12.9-44.4%)]. The rate of clinical complete remission after surgery was 79.4%. Two-year overall survival was 83%. The most frequent grade 3 or 4 toxicities were neutropenia (64.8%), diarrhea (29.4%), fatigue (23.5%), abdominal cramps (14.7%), neuropathy and nausea (11.8% each), and AST/ALT elevation (14.7/11.8%). Only one patient experienced febrile neutropenia, four patients withdrew due to toxicity and no toxic death was observed.FOLFIRINOX, with an acceptable toxicity profile, shows a high response rate in liver metastases from colorectal cancer. The rate of hepatic resection in patients initially not resectable, is attractive and warrants further assessment of this regimen in randomized studies compared to standard regimens.

Irinotecan at 180 mg/m² combined with an infusional 5-fluorouracil/leucovorin (5-FU/LV) regimen (FOLFIRI) is a standard first line therapy for metastatic colorectal cancer (mCRC). This phase II study aimed to assess whether increasing the irinotecan dose in the first line FOLFIRI regimen would benefit mCRC patients. Patients received FOLFIRI every 2 weeks for up to six cycles, comprising a 5-FU/LV regimen combined with irinotecan at 180 mg/m² (cycle 1), increasing to 220 mg/m² (cycle 2) and 260 mg/m² (cycle 3 and subsequent cycles) dependent on toxicity. Efficacy and safety were determined in the intention to treat (ITT) population and in patients able to receive irinotecan at 260 mg/m² for at least four cycles [high-dose (HD) population]. Fifty-four eligible patients were included. Among them, 44 (81.5%) formed the HD population. The ITT objective response rate was 48% (90%CI: 36–60) with 25/26 of the responses in the HD population. The disease control rate was 76% (90%CI: 65–85) and median overall survival was 20.4 months (90%CI: 6.4–27.1). The main grade 3/4 toxicities (ITT/HD populations) were neutropenia (61%/59%), and diarrhoea (18%/11%), respectively. This study confirms the feasibility of increasing the standard dose of the irinotecan component of FOLFIRI to 260 mg/m², for more than 80% of patients but does not support a clear advantage of this strategy on unselected mCRC patients.

95 Background: Perioperative chemotherapy is a standard treatment. The combination of Docetaxel- cddp-5FU(DCF) is a treatment in metastatic gastric cancer with high response rate. Preoperative RTCT is expected to increase the rate of curative resections and complete histological response. We investigate the efficacy of an optimal chemotherapy with DCF + lenograstim then preoperative RTCT with oxaliplatin - 5FU in gastric adk. Methods: Between 2009 and 2014, 33 patients with gastric adenocarcinoma(adk) were included. Inclusion criteria adk of stomach, cardia, Siewert II, III, according to staging classification T2bT3T4anyNM0 optional laparoscopy. Treatment consisted of 2 cycles docetaxel 75 mg/m2 I.V. day 1, cddp 75 mg/ m2 I.V. day 1, 5-FU 750 mg/m2 continuous infusion for 120 h, every 3 weeks and lenograstim followed by RTCT delivered in 25 daily fractions of 1.8 Gy in 5 weeks with 5Fu 250mg/m2 continuous infusion per day on days 1 to 35 and oxaliplatin 85mg/m2 day 1-14-28. Surgery was performed 4-6 weeks after RTCT. The primary endpoints were pathological response rate and secondary PFS, overall survival, morbidity and post operative mortality, toxicity. Results: 33 patients were included, 1patient progressive disease(PD) after 2 cycles of DCF, 32 patients received RTCT and 2 patients PD after RTCT, 1 patient refused surgery. 29 patients were operated and 3 non resected (peritoneal metastasis). 26 patients underwent surgery after RTCT (total gastrectomy n = 12, total gastrectomy and diaphragm surgery n = 1 lewis santy n = 11, subtotal gastrectomy n = 1, Enlarged gastrectomy transverse colectomy and partial pancreatic n = 1 D1 (n = 5) and D2 (n = 21) R0 resection rate was n = 26/26. Postoperative morbidity (n = 12) and mortality (n = 2), histology mean nods examined and involved respectively 16 and 2,5. pT0pN0 23% pT1pN0 19% pTpN2N3 20% others 38%. < 10% residual tumor 27% histologic complete response 23%. Conclusions: Promising results from trials involving preoperative chemoradiation followed by surgery in gastric cancer need to be further evaluated in a Phase III and compared with perioperative CT. Clinical trial information: NCT01565109.

Sebaceous neoplasms are a major clinical feature of Muir-Torre syndrome (MTS) associated with visceral malignancies, especially colorectal and endometrial tumors. The diagnosis of MTS relies largely on the microsatellite instability (MSI) phenotype in tumors, suggesting germline mutations in DNA mismatch repair (MMR) genes responsible for the inherited disease. We hypothesized that in some MSI-H sebaceous tumors, acquired rather than inherited mutations in MMR genes could be involved. Using next-generation sequencing, we screened MMR gene mutations in 18 MSI-H sebaceous tumors. We found mutations in 17 samples (94%). Indeed, 12/17 (71%) were shown to carry acquired somatic mutations and among 12 samples, seven were shown to be associated with additional somatic alterations like loss of heterozygosity or multiple mutations, suggesting somatic second hits. Our findings strongly suggest that somatic MMR deficiency is responsible for a proportion of MSI-H sebaceous tumors.

e14614^ Background: No predictive biomarker of tumor response or resistance to Bev has been identified in mCA. VE-C is an endothelium-specific adhesion molecule of vital importance for endothelium ...

PURPOSE: To evaluate the objective tumor response rates and toxicities of leucovorin (LV) plus fluorouracil (5-FU) cancer regimen combined with oxaliplatin (85 mg/m2) every 2 weeks on metastatic colorectal cancer patients with documented proof of progression while on bimonthly LV and 5-FU alone. PATIENTS AND METHODS: One hundred patients were enrolled onto this study and 97 received the study drugs between October 1995 and December 1996. Eighty-nine patients were eligible for per-protocol efficacy analysis with documented proof of progression on one of the following two treatments: LV 500 mg/m2 and continuous 5-FU infusion 1.5 to 2 g/m2/22 hours, days 1 through 2 every 2 weeks (FOLFUHD); or LV 200 mg/m2, bolus 5-FU 400 mg/m2, and continuous 5-FU infusion 600 mg/m2/22 hours, days 1 through 2 every 2 weeks (LV5FU2). In our study, 40 patients received FOLFUHD + 85 mg/m2 of oxaliplatin day 1 (FOLFOX3) and 57 patients received LV5FU2 + 85 mg/m2 of oxaliplatin day 1 (FOLFOX4). RESULTS: Of the 97 patients treated, 20 partial responses were observed (FOLFOX3/4: response rate, 20.6%; 95% confidence interval, 13% to 31.1%; FOLFOX3: response rate,18.4%; FOLFOX4: response rate, 23.5%). For patients treated with FOLFOX3/4, the median response duration for was 7.5 months, and the major toxicities were peripheral neuropathy and neutropenia. The incidence of grade 3 (National Cancer Institute common toxicity criteria) peripheral neuropathy was 20.6%; whereas the overall incidence of grade 3 to 4 neutropenia was 27.8%, 15%, and 36.9% for FOLFOX3/4, FOLFOX3, and FOLFOX4, respectively (P = .02). From the start of treatment, median progression-free survival was 4.7, 4.6, and 5.1 months for FOLFOX3/4, FOLFOX3, FOLFOX4, respectively, and median overall survival was 10.8, 10.6, and 11.1 months, respectively. CONCLUSION: This phase II study of oxaliplatin at 85 mg/m2 in combination with bimonthly LV plus 5-FU in patients with colorectal cancer resistant to LV plus 5-FU alone confirms the enhanced antitumor activity of oxaliplatin in combination with 5-FU.

Hereditary non-polyposis colon cancer (HNPCC) is a common hereditary disease characterized by a predisposition to an early onset of colorectal cancer. The majority of the HNPCC families carry germline mutations of either hMSH2 or hMLH1 genes, whereas germline mutations of hPMS1 and hPMS2 genes have rarely been observed. Almost all of the germline mutations reported so far concern typical HNPCC families. However, there are families that display aggregations of colon cancer even though they do not fulfil all HNPCC criteria (incomplete HNPCC families) as well as sporadic cases of early onset colon cancers that could be related to germline mutations of these genes. Therefore, we screened germline mutations of hMSH2 and hMLH1 genes in 3 groups of patients from France and Turkey: typical HNPCC (n = 3), incomplete HNPCC (n = 9) and young patients without apparent familial history (n = 7). By in vitro synthesis of protein assay, heteroduplex analysis and direct genomic sequencing, we identified 1 family with hMSH2 mutation and 5 families with hMLH1 mutations. Two of the 3 HNPCC families (66%) displayed hMLH1 germline mutations. Interestingly, 4 of 9 families with incomplete HNPCC (44%) also displayed mutations of hMSH2 or hMLH1 genes. In contrast, no germline mutation of these genes was found in 7 young patients. Our results show that germline mutations of hMSH2 and hMLH1 genes contribute to a significant fraction of familial predisposition to colon cancer cases that do not fulfil all diagnostic criteria of HNPCC. Int. J. Cancer 73:831–836, 1997. © 1997 Wiley-Liss, Inc.

Purpose To compare the quality of life (QoL) of patients receiving oxaliplatin, irinotecan, fluorouracil, and leucovorin (FOLFIRINOX) or gemcitabine as first-line chemotherapy and to assess whether pretreatment QoL predicts survival in patients with metastatic pancreatic cancer. Patients and Methods Three hundred forty-two patients with performance status 0 or 1 were randomly assigned to receive FOLFIRINOX (oxaliplatin, 85 mg/m2; irinotecan, 180 mg/m2; leucovorin, 400 mg/m2; and fluorouracil, 400 mg/m2 bolus followed by 2,400 mg/m2 46-hour continuous infusion, once every 2 weeks) or gemcitabine 1,000 mg/m2 weekly for 7 of 8 weeks and then weekly for 3 of 4 weeks. QoL was assessed using European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire C30 every 2 weeks. Results Improvement in global health status (GHS; P < .001) was observed in the FOLFIRINOX arm and improvement in emotional functioning (P < .001) was observed in both arms, along with a decrease in pain, insomnia, anorexia, and constipation in both arms. A significant increase in diarrhea was observed in the FOLFIRINOX arm during the first 2 months of chemotherapy. Time until definitive deterioration ≥ 20 points was significantly longer for FOLFIRINOX compared with gemcitabine for GHS, physical, role, cognitive, and social functioning, and six symptom domains (fatigue, nausea/vomiting, pain, dyspnea, anorexia, and constipation). Physical functioning, constipation, and dyspnea were independent significant prognostic factors for survival with treatment arm, age older than 65 years, and low serum albumin. Conclusion FOLFIRINOX significantly reduces QoL impairment compared with gemcitabine in patients with metastatic pancreatic cancer. Furthermore, baseline QoL scores improved estimation of survival probability when added to baseline clinical and demographic variables.

e15688Background: FOLFIRINOX (FFX) and nab-paclitaxel/gemcitabine (AG) showed significant improvement in efficacy compared to gemcitabine alone in metastatic pancreatic cancer (mPC). Alternating AG...

3531Background: Conflicting results are reported for maintenance treatment with bevacizumab (bev) during chemotherapy free intervals (CFI) in metastatic colorectal cancer (mCRC). Methods: The objec...

e15070Background: BRAF V600E mutations are rare in metastatic colorectal cancers (mCRC). Recent results showed that BRAF mutant tumors usually have a poor prognosis, resist to anti-EGFR treatment a...

This study was designed to evaluate neoadjuvant intensified chemotherapy in potentially resectable or unresectable liver metastases (LM) from colorectal cancer (CRC).Criteria for potentially resectable LM were complex hepatectomy and/or risky procedure, close contact with major vascular structures, and for unresectable LM, a future liver remnant predicted to be less than 25-30 % of total liver volume. Between October 2004 and August 2007, 125 patients were randomized to either standard (FOLFIRI/FOLFOX4) or intensified chemotherapy (FOLFIRI-HD/FOLFOX7/FOLFIRINOX). Primary endpoint was objective response rate (ORR) after 4 cycles of chemotherapy. Secondary endpoints included safety, R0 surgical resection, best ORR, progression-free survival (PFS), and overall survival (OS).A total of 122 patients were treated; 45 % of patients had less than 30 % of remaining liver tissue, 20 % had major vascular contact, and 35 % were potentially resectable. Grade 3/4 toxicities were neutropenia (24, 19, 10, 23 %) diarrhoea (0, 6, 3, 23 %), mucositis (0, 3, 0, 7 %), vomiting (7, 9, 0, 3 %), and neurotoxicity (0, 0, 10, 3 %) in arms (FOLFIRI + FOLFOX4)/FOLFIRI-HD/FOLFOX7/FOLFIRINOX, respectively. ORR was 33, 47, 43, and 57 % after the first 4 cycles in arms (FOLFIRI + FOLFOX4)/FOLFIRI-HD/FOLFOX7/FOLFIRINOX, respectively. FOLFIRINOX offered the best conversion rate to resectability (67 %). Disease-free status after chemotherapy and surgery (R0, R1, Rx) was achieved in 54 of 64 operated patients. Median PFS was 9.2 months in control arms versus 11.9 months in experimental arms (hazards ratio [HR] = 0.76, p = 0.115), and the median OS was 17.7 versus 33.4 months (HR = 0.73, p = 0.297), respectively.FOLFIRINOX showed promising activity in CRC patients with LM compared with standard or intensified bi-chemotherapy regimens.

Background Conventional treatment for locally advanced rectal cancer usually combines neoadjuvant radiochemotherapy and surgery. Until recently, there have been limited predictive factors (clinical or biological) for rectal tumor response to conventional treatment. KRAS, BRAF and PIK3CA mutations are commonly found in colon cancers. In this study, we aimed to determine the mutation frequencies of KRAS, BRAF and PIK3CA and to establish whether such mutations may be used as prognostic and/or predictive factors in rectal cancer patients. Methods We retrospectively reviewed the clinical and biological data of 98 consecutive operated patients between May 2006 and September 2009. We focused in patients who received surgery in our center after radiochemotherapy and in which tumor samples were available. Results In the 98 patients with a rectal cancer, the median follow-up time was 28.3 months (4–74). Eight out of ninety-eight patients experienced a local recurrence (8%) and 17/98 developed distant metastasis (17%). KRAS, BRAF and PIK3CA were identified respectively in 23 (23.5%), 2 (2%) and 4 (4%) patients. As described in previous studies, mutations in KRAS and BRAF were mutually exclusive. No patient with local recurrence exhibited KRAS or PIK3CA mutation and one harbored BRAF mutation (12.5%). Of the seventeen patients with distant metastasis (17%), 5 were presenting KRAS mutation (29%), one BRAF (5%) and one PIK3CA mutation (5%). No relationship was seen between PIK3CA, KRAS or BRAF mutation and local or distant recurrences. Conclusion The frequencies of KRAS, BRAF and PIK3CA mutations in our study were lower than the average frequencies reported in colorectal cancers and no significant correlation was found between local/distant recurrences and KRAS, BRAF or PIK3CA mutations. Future studies with greater number of patients, longer follow-up time and greater power to predict associations are necessary to fully understand this relationship.

International audience; CONTEXT: Providing accurate estimates of cancer risks is a major challenge in the clinical management of Lynch syndrome. OBJECTIVE: To estimate the age-specific cumulative risks of developing various tumors using a large series of families with mutations of the MLH1, MSH2, and MSH6 genes. DESIGN, SETTING, AND PARTICIPANTS: Families with Lynch syndrome enrolled between January 1, 2006, and December 31, 2009, from 40 French cancer genetics clinics participating in the ERISCAM (Estimation des Risques de Cancer chez les porteurs de mutation des gènes MMR) study; 537 families with segregating mutated genes (248 with MLH1; 256 with MSH2; and 33 with MSH6) were analyzed. MAIN OUTCOME MEASURE: Age-specific cumulative cancer risks estimated using the genotype restricted likelihood (GRL) method accounting for ascertainment bias. RESULTS: Significant differences in estimated cumulative cancer risk were found between the 3 mutated genes (P = .01). The estimated cumulative risks of colorectal cancer by age 70 years were 41% (95% confidence intervals [CI], 25%-70%) for MLH1 mutation carriers, 48% (95% CI, 30%-77%) for MSH2, and 12% (95% CI, 8%-22%) for MSH6. For endometrial cancer, corresponding risks were 54% (95% CI, 20%-80%), 21% (95% CI, 8%-77%), and 16% (95% CI, 8%-32%). For ovarian cancer, they were 20% (95% CI, 1%-65%), 24% (95% CI, 3%-52%), and 1% (95% CI, 0%-3%). The estimated cumulative risks by age 40 years did not exceed 2% (95% CI, 0%-7%) for endometrial cancer nor 1% (95% CI, 0%-3%) for ovarian cancer, irrespective of the gene. The estimated lifetime risks for other tumor types did not exceed 3% with any of the gene mutations. CONCLUSIONS: MSH6 mutations are associated with markedly lower cancer risks than MLH1 or MSH2 mutations. Lifetime ovarian and endometrial cancer risks associated with MLH1 or MSH2 mutations were high but do not increase appreciably until after the age of 40 years.

BACKGROUND Data are lacking on the efficacy and safety of a combination chemotherapy regimen consisting of oxaliplatin, irinotecan, fluorouracil, and leucovorin (FOLFIRINOX) as compared with gemcitabine as first-line therapy in patients with metastatic pancreatic cancer. METHODS We randomly assigned 342 patients with an Eastern Cooperative Oncology Group performance status score of 0 or 1 (on a scale of 0 to 5, with higher scores indicating a greater severity of illness) to receive FOLFIRINOX (oxaliplatin, 85 mg per square meter of body-surface area; irinotecan, 180 mg per square meter; leucovorin, 400 mg per square meter; and fluorouracil, 400 mg per square meter given as a bolus followed by 2400 mg per square meter given as a 46-hour continuous infusion, every 2 weeks) or gemcitabine at a dose of 1000 mg per square meter weekly for 7 of 8 weeks and then weekly for 3 of 4 weeks. Six months of chemotherapy were recommended in both groups in patients who had a response. The primary end point was overall survival. RESULTS The median overall survival was 11.1 months in the FOLFIRINOX group as compared with 6.8 months in the gemcitabine group (hazard ratio for death, 0.57; 95% confidence interval [CI], 0.45 to 0.73; P

International audience; Constitutional epimutation is one of the causes for MLH1 gene inactivation associated with hereditary non-polyposis colon cancer (HNPCC) syndrome. Here we investigate MLH1 promoter hypermethylation in 110 sporadic early-onset colorectal cancer patients. Variable levels of hypermethylation were detected in 55 patients (50%). Importantly a reduced MLH1 gene expression was found in patients with high-level methylation, with the association of microsatellite instability (MSI) in their tumor cells. Such high-level methylation accounts for 7.4% of all patients included in this study. Furthermore, we found that in one case constitutional methylation affected both alleles, indicating a post-zygotic methylation dysregulation. Our findings suggest that constitutional epimutation is a mechanism underlying early-onset colorectal cancer, although it is involved in only a small proportion of patients, who require appropriate surveillance. Our findings provide further insight into the role of aberrant constitutional methylation in colon carcinogenesis and raise the question of whether prevalent low-level methylation constitutes a potential risk factor for cancer development.

La majorite des tumeurs colorectales et anales sont respectivement des adenocarcinomes et des cancers epidermoides. D’autres types histologiques tres rares peuvent s’observer. Ils sont souvent a l’origine de difficultes diagnostiques. Il s’agit des melanomes, des tumeurs carcinoides, des tumeurs neuroendocrines indifferenciees, des cancers epidermoides du colon et du rectum, des sarcomes et des lymphomes. Il faut ajouter des tumeurs specifiques de l’anus, tels que la maladie de Paget, le carcinome a cellules basales et la maladie de Bowen. Cette liste n’est toutefois pas exhaustive. Dans ce chapitre, nous decrivons les tumeurs rares du colon, du rectum et de l’anus en renvoyant le lecteur, pour certaines d’entre elles, aux chapitres specifiques de cet ouvrage (lymphome, melanome…). Pour les tumeurs non precedemment analysees, nous decrivons leur diagnostic, l’evaluation de leur stade de developpement et leur prise en charge. Du fait de la rarete, cette prise en charge reste toutefois souvent controversee.