Publications by authors named "Françoise Desseigne"

34 Publications

Medulloblastomas associated with an APC germline pathogenic variant share the good prognosis of CTNNB1-mutated medulloblastomas.

Neuro Oncol 2020 01;22(1):128-138

Curie Institute, SIREDO Cancer Center (Care, Innovation and Research in Pediatric, Adolescents, and Young Adults Oncology), Paris, France.

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.
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http://dx.doi.org/10.1093/neuonc/noz154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6954432PMC
January 2020

Long-Term Survivors in Metastatic Pancreatic Ductal Adenocarcinoma: A Retrospective and Matched Pair Analysis.

Oncologist 2019 12 4;24(12):1543-1548. Epub 2019 Jun 4.

Department of Medical Oncology, Centre Leon Bérard, Lyon, France.

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] = 0.26), neutrophil-to-lymphocyte ratio (NLR; OR = 0.31), and peritoneal carcinomatosis (OR = 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.
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http://dx.doi.org/10.1634/theoncologist.2018-0786DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6975934PMC
December 2019

Characteristics of Mutant, Deficient Mismatch Repair/Proficient Mismatch Repair, Metastatic Colorectal Cancer: A Multicenter Series of 287 Patients.

Oncologist 2019 12 31;24(12):e1331-e1340. Epub 2019 May 31.

Department of Gastroenterology, Poitiers University Hospital, Poitiers, France.

Background: 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 -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; = .009).

Conclusion: Despite that -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 mCRC in day-to-day practice.

Implications For Practice: Mismatch repair (MMR) testing and resectability discussion in patients with metastatic colorectal cancer (mCRC) should be performed in day-to-day practice to steer treatment decision making in patients with -mutant mCRC.
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http://dx.doi.org/10.1634/theoncologist.2018-0914DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6975964PMC
December 2019

Early evaluation using a radiomic signature of unresectable hepatic metastases to predict outcome in patients with colorectal cancer treated with FOLFIRI and bevacizumab.

Gut 2020 03 17;69(3):531-539. Epub 2019 May 17.

Radiology, Hopital Maison Blanche, Reims, Champagne-Ardenne, France.

Purpose: The 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.

Methods: This 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.

Results: In 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), decrease in kurtosis (ssf=4) (aHR=1·08, p=0·001) and high baseline density of DLL, (aHR=0·98, p<0·001). Patients with a SPECTRA Score >0·02 had a lower OS in the training cohort (p<0·0001), in the validation cohort (p<0·0008) and in the external validation cohort (p=0·0027). SPECTRA Score at 2 months had the same prognostic value as RECIST at 6 months, while non-response according to RECIST1·1 at 2 months was not associated with a lower OS in the validation cohort (p=0·238). Morphological response was not associated with OS (p=0·41).

Conclusion: A 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 Registration: Clinicaltrial.gov identifier of the PRODIGE 9 study: NCT00952029.Clinicaltrial.gov identifier of the PRODIGE 20 study: NCT01900717.
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http://dx.doi.org/10.1136/gutjnl-2018-316407DOI Listing
March 2020

Primary malignant melanoma of the esophagus, treated with immunotherapy: a case report.

Immunotherapy 2018 08;10(10):831-835

Department of Medical Oncology, Centre Leon Berard, Claude Bernard University, Lyon, France.

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.
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http://dx.doi.org/10.2217/imt-2018-0011DOI Listing
August 2018

Efficacy of Sym004 in Patients With Metastatic Colorectal Cancer With Acquired Resistance to Anti-EGFR Therapy and Molecularly Selected by Circulating Tumor DNA Analyses: A Phase 2 Randomized Clinical Trial.

JAMA Oncol 2018 Apr 12;4(4):e175245. Epub 2018 Apr 12.

Symphogen A/S, Ballerup, Denmark.

Importance: Acquired resistance to anti-EGFR therapy (epidermal growth factor receptor) is frequently due to RAS and EGFR extracellular 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-type KRAS exon 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 targeted EGFR ECD-mutated cancer cells, and a decrease in EGFR ECD ctDNA occurred in Sym004-treated patients. However, this did not translate into clinical benefit in patients with EGFR ECD mutations, likely owing to co-occurring resistance mechanisms. A subgroup of patients was defined by ctDNA (RAS/BRAF/EGFR ECD-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.
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http://dx.doi.org/10.1001/jamaoncol.2017.5245DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5885274PMC
April 2018

Bevacizumab Maintenance Versus No Maintenance During Chemotherapy-Free Intervals in Metastatic Colorectal Cancer: A Randomized Phase III Trial (PRODIGE 9).

J Clin Oncol 2018 03 18;36(7):674-681. Epub 2018 Jan 18.

Thomas Aparicio, Centre Hospitalier Universitaire (CHU) Saint Louis, Assistance Public Hôpitaux de Paris (APHP), and Université Paris 7, Sorbonne Paris Cité; Julien Taieb, Hôpital Européen Georges Pompidou, Paris; Francois Ghiringhelli, Centre Georges-François Leclerc; Karine Le Malicot, Fédération Francophone de Cancérologie Digestive; Come Lepage, CHU Le Bocage, Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche (UMR) 1231, Dijon; Valérie Boige, Institut Gustave Roussy, Villejuif; Olivier Bouché, CHU Robert Debré, Reims; Jean-Marc Phelip, CHU Saint Etienne-Hôpital Nord, Saint Priest en Jarez; Eric François, Centre Antoine Lacassagne, Nice; Christian Borel, Paul Strauss Center, Strasbourg; Roger Faroux, Centre Hospitalier (CH) La Roche sur Yon, La Roche sur Yon; Laetitia Dahan, CHU La Timone, Aix-Marseille-University, Marseille; Stéphane Jacquot, Centre de Cancérologie du Grand Montpellier, Montpellier; Dominique Genet, Accompagnement de la Recherche Clinique Hospitalière (ARCH)/Polyclinique, Limoges; Faiza Khemissa, CH Saint Jean, Perpignan; Etienne Suc, Clinique Saint Jean du Languedoc, Toulouse; Françoise Desseigne, Centre Léon Bérard, Lyon; Patrick Texereau, CH Layne, Mont-De-Marsan; and Jaafar Bennouna, Institut de Cancérologie de l'Ouest, Saint Herblay, France.

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.
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http://dx.doi.org/10.1200/JCO.2017.75.2931DOI Listing
March 2018

Retrospective Analysis of CA19-9 Decrease in Patients with Metastatic Pancreatic Carcinoma Treated with FOLFIRINOX or Gemcitabine in a Randomized Phase III Study (ACCORD11/PRODIGE4).

Oncology 2017 6;93(6):367-376. Epub 2017 Oct 6.

Department of Medical Oncology, Institut de Cancérologie de l'Ouest, St. Herblain, France.

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. <20%). The 8-week CA19-9 decrease was predictive of PFS (interaction test significant according to treatment arm; 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.
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http://dx.doi.org/10.1159/000477850DOI Listing
March 2018

Use of gemcitabine as a second-line treatment following chemotherapy with folfirinox for metastatic pancreatic adenocarcinoma.

Oncol Lett 2017 Jun 20;13(6):4917-4924. Epub 2017 Apr 20.

Department of Medical Oncology, Centre Léon Bérard, 69008 Lyon, France.

There is a lack of prospective data about second-line treatments for metastatic pancreatic ductal adenocarcinoma patients. This is partially due to recent changes in first-line chemotherapy treatments. Despite this dearth of information, 50.0% of the patients who experience failure with first-line folinic acid, 5-fluorouracil, irinotecan and oxaliplatin (folfirinox) treatment are eligible for additional chemotherapy. In this setting, gemcitabine is widely used without any standard recommendations available. The present study evaluated 42 patients who received gemcitabine subsequent to a first-line treatment of folfirinox between January 2008 and December 2012 at the Centre Léon Bérard (Lyon, France). Clinical data, biological data and tumor characteristics were retrospectively analyzed to identify prognostic factors for successful treatment with gemcitabine. In total, 11 patients (26.2%) experienced control of their cancer with gemcitabine treatment. However, there was no predictive marker for their response to the drug. The median overall survival was 3.6 months from gemcitabine initiation [95% confidence interval (CI), 2.1-5.1]. The median length of gemcitabine treatment was 1.5 months (95% CI, 0.3-13.3). Among the 11 patients who were successfully treated with gemcitabine, 6 were resistant to first-line folfirinox treatment. Patients who were non responsive to folfirinox had a higher probability of success with gemcitabine compared with patients that responded to folfirinox (54.5 vs. 21.4%, respectively; P=0.061). The present study did not identify any clinical or biological marker with a predictive value for successful gemcitabine treatment. Furthermore, successful gemcitabine treatment was not correlated with patients' response to first-line folfirinox treatment. This suggests an absence of cross-resistance in the chemotherapy protocols and provides evidence for effective cancer treatment with the second-line gemcitabine therapy.
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http://dx.doi.org/10.3892/ol.2017.6061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5453056PMC
June 2017

Necrotizing Infundibular Crystalline Folliculitis (NICF) Induced by Anti-Tumoral Therapies: Report of 2 Cases.

Am J Dermatopathol 2017 Oct;39(10):764-766

*Service de dermatologie, Hôpital Edouard Herriot, Lyon, France; †Service de pathologie, Hôpital Edouard Herriot, Lyon, France; ‡Département d'oncologie médicale, Centre Léon Bérard, Lyon, France; and §Département de Biopathologie, Centre Léon Bérard, Lyon, France.

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.
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http://dx.doi.org/10.1097/DAD.0000000000000743DOI Listing
October 2017

An assessment of the benefit-risk balance of FOLFIRINOX in metastatic pancreatic adenocarcinoma.

Oncotarget 2016 Dec;7(50):82953-82960

International Drug Development Institute (IDDI), San Francisco, CA 94109, USA.

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<.001), suggesting a favorable benefit-risk balance of FOLFIRINOX versus gemcitabine. The positive benefit-risk balance of FOLFIRINOX was observed throughout all sensitivity analyses.

Conclusions: Generalized pairwise comparisons are useful to perform a quantitative assessment of the benefit-risk balance of new treatments. It provides a clinically intuitive way of comparing patients with respect to all important efficacy and toxicity outcomes. Overall the benefit-risk balance of FOLFIRINOX was strongly positive.
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http://dx.doi.org/10.18632/oncotarget.12761DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5347744PMC
December 2016

Radiochemotherapy Versus Surgery in Nonmetastatic Anorectal Neuroendocrine Carcinoma: A Multicenter Study by the Association des Gastro-Entérologues Oncologues.

Medicine (Baltimore) 2015 Oct;94(42):e1864

From the Department of Gastroenterology and Digestive Oncology, Cochin Teaching Hospital, Paris Descartes University, Paris, France (BB, RC); Department of Digestive Oncology, Georges Pompidou European Hospital, Paris Descartes University, Paris, France (CL, PR); Department of Gastroenterology, Edouard Herriot Hospital, Lyon, France (TW); Department of Gastroenterology, Tours Teaching Hospital, Tours Cedex 9, France (TL); Department of Medical Oncology, Claudius Regaud Institute, Toulouse, France (RG); Department of Gastroenterology, Rennes Teaching Hospital, Rennes, France (SM); Department of Gastroenterology, Poitiers Teaching Hospital, Poitiers, France (DT); Department of Medical Oncology, Leon Berard Hospital, Lyon, France (FD); Department of Gastroenterology, Saint Louis Hospital, Paris, France (NL); Department of Digestive Oncology, Saint Antoine Hospital, Paris, France (PA); Department of Medical Oncology, Oscar Lambret Hospital, Lille, France (FEH); and Department of Pathology, Cochin Teaching Hospital, Paris Descartes University, Paris, France (BT).

Neuroendocrine carcinomas (NEC) of the anus or the rectum are a rare disease, accounting for less than 1% of all digestive malignancies. Most are metastatic at diagnosis and treated with a platinum-based chemotherapy. No guidelines for localized tumors exist. The purpose of this study was to describe the characteristics of anorectal localized NEC, their management and their outcomes.We retrospectively reviewed patients from 11 French centers with anorectal localized NEC. We compared 2 therapeutic managements: surgery (group A) versus chemotherapy with or without radiation (group B). Progression-free survival (PFS) and overall survival (OS) were estimated with the Kaplan-Meier method.A total of 24 patients were identified with a median follow-up of 25 months (3-60 months). Median age was 63 years old and 17 had a rectal tumor (71%). Mean Ki-67 was 72% (range: 20-100), and 75% of the tumors had a high proliferative index (Ki-67 > 50%). Global PFS and OS were 13.1 and 44.1 months, respectively. Thirty-seven percent of patients were in group A and 63% in group B. There was no difference between group A and group B, whether in terms of PFS (13.0 months vs. 13.2 months, P = 0.75) or OS (49.1 months vs. 39.2 months, P = 0.42).In patients with anorectal localized NEC, chemotherapy with or without radiation obtained a similar outcome as surgery and this conservative approach could be deemed a reasonable option.
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http://dx.doi.org/10.1097/MD.0000000000001864DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4620767PMC
October 2015

The sum of gains and losses of genes encoding the protein tyrosine kinase targets predicts response to multi-kinase inhibitor treatment: Characterization, validation, and prognostic value.

Oncotarget 2015 Sep;6(28):26388-99

Department of Translational Research, Centre Leon Berard, 69008 Lyon France.

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.
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http://dx.doi.org/10.18632/oncotarget.4557DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4694909PMC
September 2015

Clinical relevance of 8q23, 15q13 and 18q21 SNP genotyping to evaluate colorectal cancer risk.

Eur J Hum Genet 2016 Jan 15;24(1):99-105. Epub 2015 Apr 15.

Department of Genetics, University Hospital, Angers, France.

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 χ(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<0.0001) cumulative effect of the at-risk alleles or genotypes with OR at 1.62 (CI: 1.10-2.37), 2.09 (CI: 1.43-3.07), 2.87 (CI: 1.76-4.70) and 3.88 (CI: 1.72-8.76) for 1, 2, 3 and at least 4 at-risk alleles, respectively, and OR at 1.71 (CI: 1.18-2.46), 2.29 (CI: 1.55-3.38) and 6.21 (CI: 2.67-14.42) for 1, 2 and 3 at-risk genotypes, respectively. Combination of SNPs may therefore explain a fraction of clinical situations suggestive of an increased risk for CRC.
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http://dx.doi.org/10.1038/ejhg.2015.72DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4795220PMC
January 2016

Somatic MMR gene mutations as a cause for MSI-H sebaceous neoplasms in Muir-Torre syndrome-like patients.

Hum Mutat 2015 Mar;36(3):292-5

Edouard Herriot hospital, Central Service of Pathology, Tumor Biology Laboratory, Lyon, France.

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.
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http://dx.doi.org/10.1002/humu.22740DOI Listing
March 2015

Prodromal depression in pancreatic cancer: retrospective evaluation on ten patients.

Palliat Support Care 2015 Jun 24;13(3):801-7. Epub 2014 Jun 24.

Department of Supportive Care,Centre Léon Bérard,Lyon,France.

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.
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http://dx.doi.org/10.1017/S1478951514000728DOI Listing
June 2015

A randomized phase II trial of three intensified chemotherapy regimens in first-line treatment of colorectal cancer patients with initially unresectable or not optimally resectable liver metastases. The METHEP trial.

Ann Surg Oncol 2013 Dec 17;20(13):4289-97. Epub 2013 Aug 17.

Institut du Cancer de Montpellier-Val d'Aurelle, Montpellier Cedex 05, France,

Purpose: This study was designed to evaluate neoadjuvant intensified chemotherapy in potentially resectable or unresectable liver metastases (LM) from colorectal cancer (CRC).

Methods: 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).

Results: 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.

Conclusions: FOLFIRINOX showed promising activity in CRC patients with LM compared with standard or intensified bi-chemotherapy regimens.
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http://dx.doi.org/10.1245/s10434-013-3217-xDOI Listing
December 2013

Impact of KRAS, BRAF and PI3KCA mutations in rectal carcinomas treated with neoadjuvant radiochemotherapy and surgery.

BMC Cancer 2013 Apr 23;13:200. Epub 2013 Apr 23.

Department of Medical Oncology, Centre Léon Bérard, 28 rue Laennec, Lyon 69008, France.

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.
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http://dx.doi.org/10.1186/1471-2407-13-200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3640970PMC
April 2013

Impact of FOLFIRINOX compared with gemcitabine on quality of life in patients with metastatic pancreatic cancer: results from the PRODIGE 4/ACCORD 11 randomized trial.

J Clin Oncol 2013 Jan 3;31(1):23-9. Epub 2012 Dec 3.

Centre Léon Bérard, Lyon, France.

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/m(2); irinotecan, 180 mg/m(2); leucovorin, 400 mg/m(2); and fluorouracil, 400 mg/m(2) bolus followed by 2,400 mg/m(2) 46-hour continuous infusion, once every 2 weeks) or gemcitabine 1,000 mg/m(2) 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.
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http://dx.doi.org/10.1200/JCO.2012.44.4869DOI Listing
January 2013

Cetuximab plus FOLFIRINOX (ERBIRINOX) as first-line treatment for unresectable metastatic colorectal cancer: a phase II trial.

Oncologist 2011 20;16(11):1557-64. Epub 2011 Oct 20.

CAC Val d'Aurelle, Montpellier, France.

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.
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http://dx.doi.org/10.1634/theoncologist.2011-0141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3233290PMC
June 2012

Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome.

JAMA 2011 Jun;305(22):2304-10

Université Lyon 1, Centre National de la Recherche Scientifique UMR5558, Villeurbanne, Centre Léon Bérard, Lyon, Cedex 08, France.

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.
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http://dx.doi.org/10.1001/jama.2011.743DOI Listing
June 2011

FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer.

N Engl J Med 2011 May;364(19):1817-25

Nancy University and Department of Medical Oncology, Centre Alexis Vautrin, Nancy, France.

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<0.001). Median progression-free survival was 6.4 months in the FOLFIRINOX group and 3.3 months in the gemcitabine group (hazard ratio for disease progression, 0.47; 95% CI, 0.37 to 0.59; P<0.001). The objective response rate was 31.6% in the FOLFIRINOX group versus 9.4% in the gemcitabine group (P<0.001). More adverse events were noted in the FOLFIRINOX group; 5.4% of patients in this group had febrile neutropenia. At 6 months, 31% of the patients in the FOLFIRINOX group had a definitive degradation of the quality of life versus 66% in the gemcitabine group (hazard ratio, 0.47; 95% CI, 0.30 to 0.70; P<0.001).

Conclusions: As compared with gemcitabine, FOLFIRINOX was associated with a survival advantage and had increased toxicity. FOLFIRINOX is an option for the treatment of patients with metastatic pancreatic cancer and good performance status. (Funded by the French government and others; ClinicalTrials.gov number, NCT00112658.).
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http://dx.doi.org/10.1056/NEJMoa1011923DOI Listing
May 2011

Intensity-dependent constitutional MLH1 promoter methylation leads to early onset of colorectal cancer by affecting both alleles.

Genes Chromosomes Cancer 2011 Mar 9;50(3):178-85. Epub 2010 Dec 9.

Centre Léon Bérard, Laboratoire de Recherche Translationnelle, Lyon, France.

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.
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http://dx.doi.org/10.1002/gcc.20842DOI Listing
March 2011

Irinotecan associated with cetuximab given every 2 weeks versus cetuximab weekly in metastatic colorectal cancer.

J Cancer Res Ther 2009 Oct-Dec;5(4):272-6

Department of Medical Oncology, Centre Leon Berard, Lyon, France.

Aim: The aim of the present study was to compare the efficacy and safety of weekly versus an every 2-week administration of cetuximab in association with irinotecan in patients with metastatic colorectal cancer (MCRC).

Methods: We reviewed the clinical records of 50 patients with MCRC who began treatment with cetuximab from February 2004 to January 2007. Two different treatment schedules were used. In the first group (N = 32), cetuximab was given at an initial dose of 400 mg/m2, followed by weekly infusions of 250 mg/m2. In the second group (N = 18), cetuximab was administered every 2 weeks at a dose of 500 mg/m2. The two groups were compared for tumor response, time to progression (TTP), overall survival (OS), and toxicity.

Results: All patients had received irinotecan and 5-fluorouracil; a majority had previously received oxaliplatin. Disease control (partial response + stable disease) was achieved in 56.3% of patients receiving weekly cetuximab versus 77.8% in the other group (P = 0.21). The median follow-up for all patients was 34.2 months. TTP (Group 1: 28% vs. Group 2: 18%, P = 0.9356) and OS (Group 1: 75% vs. Group 2: 72%, P = 0.6748) rates at 7 months were similar in the two groups. Skin toxicity was the most relevant adverse event: 78.1% of the patients had acne-like rash in the first group and 61% in the second group. However, only one patient in each group had a grade 3 toxic reaction.

Conclusion: There is no major difference of efficacy and safety between cetuximab given every 2 weeks and a weekly dosing regimen, in association with irinotecan.
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http://dx.doi.org/10.4103/0973-1482.59907DOI Listing
May 2010

Phase I study of daily irinotecan as a radiation sensitizer for locally advanced pancreatic cancer.

Int J Radiat Oncol Biol Phys 2010 Jun 29;77(2):409-13. Epub 2010 Jan 29.

Department of Medical Oncology, University of Lyon-Centre Léon Bérard, Lyon, France.

Purpose: The study aimed to determine the maximum tolerated dose of daily irinotecan given with concomitant radiotherapy in patients with locally advanced adenocarcinoma of the pancreas.

Methods And Materials: Between September 2000 and March 2008, 36 patients with histologically proven unresectable pancreas adenocarcinoma were studied prospectively. Irinotecan was administered daily, 1 to 2 h before irradiation. Doses were started at 6 mg/m(2) per day and then escalated by increments of 2 mg/m(2) every 3 patients. Radiotherapy was administered in 2-Gy fractions, 5 fractions per week, up to a total dose of 50 Gy to the tumor volume. Inoperability was confirmed by a surgeon involved in a multidisciplinary team. All images and responses were centrally reviewed by radiologists.

Results: Thirty-six patients were enrolled over a period of 8 years through eight dose levels (6 mg/m(2) to 20 mg/m(2) per day). The maximum tolerated dose was determined to be 18 mg/m(2) per day. The dose-limiting toxicities were nausea/vomiting, diarrhea, anorexia, dehydration, and hypokalemia. The median survival time was 12.6 months with a median follow-up of 53.8 months. The median progression-free survival time was 6.5 months, and 4 patients (11.4%) with very good responses could undergo surgery.

Conclusions: The maximum tolerated dose of irinotecan is 18 mg/m(2) per day for 5 weeks. Dose-limiting toxicities are mainly gastrointestinal. Even though efficacy was not the aim of this study, the results are very promising, with a median survival time of 12.6 months.
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http://dx.doi.org/10.1016/j.ijrobp.2009.05.008DOI Listing
June 2010

Endobronchial metastases from colorectal adenocarcinomas: clinical and endoscopic characteristics and patient prognosis.

Oncology 2007 2;73(5-6):395-400. Epub 2008 Jun 2.

Oncology Department, Centre Léon Bérard, Lyon, France.

Background: Endobronchial metastases (EBM) secondary to extrapulmonary solid malignant tumours are rare but may occur. The most common extrathoracic malignancies associated with EBM are breast, renal and colorectal carcinomas. This study aimed to evaluate the clinical and bronchoscopic aspects of EBM from colorectal carcinomas and the prognosis of the patients.

Methods: EBM were diagnosed in 7 patients with colorectal carcinomas between 2004 and 2005. All patients underwent colorectal resection at the time of primary tumour diagnosis. Bronchial involvement was proved by bronchoscopy, and the metastatic nature of the lesions was confirmed histopathologically in all patients. EBM patients were compared with a control group of 7 patients with pulmonary metastases from colorectal cancer.

Results: Median age at time of colorectal carcinoma was 55 years in EBM patients and 57 years in controls. Distressing airway symptoms caused by EBM were relieved by use of newer intrabronchial therapies: radiotherapy, brachytherapy and cryotherapy. One patient underwent metastasis resection. The median survival after diagnosis of EBM was 18.9 months. All patients had pulmonary metastases. The median survival after diagnosis of pulmonary metastasis from colorectal carcinoma was 55.7 months in EBM patients and 12.7 months in controls (p < 0.005).

Discussion: EBM are generally underdiagnosed in patients with colorectal carcinoma. Bronchoscopy is not part of the standard evaluation of these patients. Physicians must be more attentive to pulmonary symptoms, even when patients' pulmonary metastases are known. Various management options are available for localized endobronchial tumours.

Conclusion: On average, EBM are diagnosed about 5 years after the diagnosis of the primary tumour, which is a relatively long lead time. Although this metastatic location usually implies a very negative prognosis regarding life expectancy, it did not seem to significantly reduce survival in our patients. Local treatments allow substantial improvement of pulmonary symptoms.
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http://dx.doi.org/10.1159/000136794DOI Listing
August 2008

[Cardiac metastases and colorectal cancer: a case study].

Gastroenterol Clin Biol 2007 Jun-Jul;31(6-7):621-3

Département de Cancérologie Médicale, Centre Léon Bérard, 28 rue Laennec, 69008 Lyon.

We report the case of a patient with asymptomatic and fortuitously detected right ventricular colorectal cancer metastasis. These metastatic lesions are uncommon and after a description of the index case we provide a review of the most recently published cases.
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http://dx.doi.org/10.1016/s0399-8320(07)89443-7DOI Listing
December 2007

Novel biallelic mutations in MSH6 and PMS2 genes: gene conversion as a likely cause of PMS2 gene inactivation.

Hum Mutat 2007 Nov;28(11):1084-90

Centre Léon Bérard, Unité d'Oncologie Moléculaire, Lyon, France.

Since the first report by our group in 1999, more than 20 unrelated biallelic mutations in DNA mismatch repair genes (MMR) have been identified. In the present report, we describe two novel cases: one carrying compound heterozygous mutations in the MSH6 gene; and the other, compound heterozygous mutations in the PMS2 gene. Interestingly, the inactivation of one PMS2 allele was likely caused by gene conversion. Although gene conversion has been suggested to be a mutation mechanism underlying PMS2 inactivation, this is the first report of its involvement in a pathogenic mutation. The clinical features of biallelic mutation carriers were similar to other previously described patients, with the presence of café-au-lait spots (CALS), early onset of brain tumors, and colorectal neoplasia. Our data provide further evidence of the existence, although rare, of a distinct recessively inherited syndrome on the basis of MMR constitutional inactivation. The identification of this syndrome should be useful for genetic counseling, especially in families with atypical hereditary nonpolyposis colon cancer (HNPCC) associated with childhood cancers, and for the clinical surveillance of these mutation carriers.
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http://dx.doi.org/10.1002/humu.20569DOI Listing
November 2007

Estimating cancer risk in HNPCC by the GRL method.

Eur J Hum Genet 2007 Aug 2;15(8):831-6. Epub 2007 May 2.

INSERM, U535, Villejuif, France.

Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant syndrome caused by germline mutations of the mismatch repair (MMR) genes. Only a few studies have taken into account the selection of families tested for these mutations in estimating colorectal cancer (CRC) risk in carriers. They found much lower estimates of CRC risks than previous ones, but these estimates lacked precision despite the large number of families. The aim of this study was to evaluate the efficiency of the 'genotype restricted likelihood' (GRL) method that provides unbiased estimates of risks whatever the ascertainment process of families, and to estimate CRC and endometrial cancer risk for carriers of the MMR genes. Efficiency of the GRL method was evaluated using simulations. Risks were estimated from a sample of 36 families diagnosed with HNPCC and carrying a mutation of MSH2 or MLH1, ascertained through a cancer family clinic in Lyon (France). The efficiency of the GRL method was found to be strongly dependent on the proportion of family members tested. By age 70 years, CRC risk was estimated at 47% (95% confidence interval: 12-98%) for men and 33% (95% confidence interval: 24-54%) for women. The endometrial cancer risk was only 14% (confidence interval: 6-20%). As methods allowing for the selection of families lack efficiency, large-scale family studies should be undertaken and data should be pooled to provide reliable and precise estimates of risks for an optimal familial management.
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http://dx.doi.org/10.1038/sj.ejhg.5201843DOI Listing
August 2007