Publications by authors named "Carole Vitellius"

6 Publications

  • Page 1 of 1

Maintenance therapies in metastatic pancreatic cancer: present and future with a focus on PARP inhibitors.

Ther Adv Med Oncol 2020 9;12:1758835920937949. Epub 2020 Jul 9.

GI Oncology, Medical Oncology Department, Institut Curie Saint-Cloud, Versailles Saint-Quentin University, Saint-Cloud, France.

Metastatic pancreatic ductal adenocarcinomas (PDACs) are now more effectively controlled using chemotherapy combinations such as FOLFIRINOX and gemcitabine plus nab-paclitaxel (NabP) regimens with a subset of patients who achieve a sustained tumor stabilization or response. The next challenge is to design maintenance therapies that result in continued tumor control with minimal toxicity. Quality of life should always be a priority in these patients with prolonged survival. Gradually tapering off the intensity of chemotherapy by suppressing drug(s) in the combination is one option. Thus, maintenance with 5-fluorouracil or gemcitabine as single agents after FOLFIRINOX or gemcitabine-NabP induction, respectively, seems to be a promising approach to minimize neurotoxicity while maintaining efficacy. Another option is to introduce maintenance drug(s) with different anti-tumoral actions. The recent example of olaparib in patients with BRCA mutated PDAC provides a promising proof-of-concept of a switch maintenance strategy in this setting.
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July 2020

Impact of Driver Mutations on the Evolution of Isolated Metachronous Lung Metastasis of Pancreatic Ductal adenocarcinoma.

Mol Diagn Ther 2020 08;24(4):443-449

Department of Gastroenterology and Digestive Oncology, CHU Angers, 4 rue Larrey, 49933, Angers Cedex 9, France.

Background: The incidence of pancreatic ductal adenocarcinoma (PDAC) is increasing sharply. The survival of patients with metastases is usually about a year. However, the occurrence of isolated lung metastases after resection of the primary tumor, although rare, seems to indicate a better prognosis, with an average survival ranging from 40 to 80 months. KRAS, TP53, CDK2NA, and SMAD4 are the most common driver genes in pancreatic adenocarcinoma.

Objective: Our objectives were to determine whether a link exists between survival and mutations of driver genes in patients with isolated pulmonary metastases.

Methods: All patients who underwent curative surgery in our institution between 2010 and 2018 were included in the study. From these, we identified patients for whom recurrence was only pulmonary and those with metastases at other sites. KRAS, TP53, CDK2NA, and SMAD4 were analyzed on the primary tumor of patients with pulmonary metastases.

Results: Among 233 patients diagnosed with PDAC in our institution over 8 years, 41 (17.5%) underwent curative surgery. Of these, seven (3%) developed isolated pulmonary metastases, 32 developed other metastases, and two did not recur. Median survival was 59 months for patients with isolated lung metastases and 25.3 months for patients with metastases at other sites. An absence of mutations of two driver genes in primary tumors (CDK2NA and SMAD4) was observed in patients with isolated pulmonary metastases.

Conclusions: The absence of mutations in the CDK2NA and SMAD4 tumor-suppressor genes in patients with isolated pulmonary metastases contrasts with the commonly observed high rates of driver gene mutations and suggests a link with overall survival.
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August 2020

Withholding the Introduction of Anti-Epidermal Growth Factor Receptor: Impact on Outcomes in RAS Wild-Type Metastatic Colorectal Tumors: A Multicenter AGEO Study (the WAIT or ACT Study).

Oncologist 2020 02 2;25(2):e266-e275. Epub 2019 Oct 2.

Department of Gastroenterology, Cochin Hospital, Paris, France.

Background: Patients with RAS wild-type (WT) nonresectable metastatic colorectal cancer (mCRC) may receive either bevacizumab or an anti-epidermal growth factor receptor (EGFR) combined with first-line, 5-fluorouracil-based chemotherapy. Without the RAS status information, the oncologist can either start chemotherapy with bevacizumab or wait for the introduction of the anti-EGFR. Our objective was to compare both strategies in a routine practice setting.

Materials And Methods: This multicenter, retrospective, propensity score-weighted study included patients with a RAS WT nonresectable mCRC, treated between 2013 and 2016 by a 5-FU-based chemotherapy, with either delayed anti-EGFR or immediate anti-vascular endothelial growth factor (VEGF). Primary criterion was overall survival (OS). Secondary criteria were progression-free survival (PFS) and objective response rate (ORR).

Results: A total of 262 patients (129 in the anti-VEGF group and 133 in the anti-EGFR group) were included. Patients receiving an anti-VEGF were more often men (68% vs. 56%), with more metastatic sites (>2 sites: 15% vs. 9%). The median delay to obtain the RAS status was 19 days (interquartile range: 13-26). Median OS was not significantly different in the two groups (29 vs. 30.5 months, p = .299), even after weighting on the propensity score (hazard ratio [HR] = 0.86, 95% confidence interval [CI], 0.69-1.08, p = .2024). The delayed introduction of anti-EGFR was associated with better median PFS (13.8 vs. 11.0 months, p = .0244), even after weighting on the propensity score (HR = 0.74, 95% CI, 0.61-0.90, p = .0024). ORR was significantly higher in the anti-EGFR group (66.7% vs. 45.6%, p = .0007).

Conclusion: Delayed introduction of anti-EGFR had no deleterious effect on OS, PFS, and ORR, compared with doublet chemotherapy with anti-VEGF.

Implications For Practice: For RAS/RAF wild-type metastatic colorectal cancer, patients may receive 5-fluorouracil-based chemotherapy plus either bevacizumab or an anti-epidermal growth factor receptor (EGFR). In daily practice, the time to obtain the RAS status might be long enough to consider two options: to start the chemotherapy with bevacizumab, or to start without a targeted therapy and to add the anti-EGFR at reception of the RAS status. This study found no deleterious effect of the delayed introduction of an anti-EGFR on survival, compared with the introduction of an anti-vascular endothelial growth factor from cycle 1. It is possible to wait one or two cycles to introduce the anti-EGFR while waiting for RAS status.
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February 2020

Contribution of the OC Sensor immunoassay in comparison to the Hemoccult II guaiac-test in organized colorectal cancer screening.

Eur J Epidemiol 2019 Feb 8;34(2):163-172. Epub 2018 Dec 8.

Service d'Hépato-gastro-entérologie, CHU Angers, 4, rue Larrey, 49933, Angers Cedex 09, France.

Colorectal cancer (CRC) is a major cause of cancer-related death of worldwide with high incidence and mortality rate, accessible to a screening program in France, first with guaiac- based fecal occult blood test (g-FOBT) then with fecal immunochemical tests (FIT), since 2015, because of better accuracy. The aim of our study was to compare the characteristics of screen-detected lesions in two successive CRC screening campaigns, using two different tests (Hemoccult II and OC Sensor) in the department of Maine-et-Loire, and to precise the performance of these tests [participation rate, detection rates (DR), positive predictive value (PPV)]. Participants, invited by CAP SANTE 49, with polyps or cancer at the colonoscopy after a positive screening test between 01/01/2013 and 31/12/2016 were included. A guaiac-based fecal occult blood test (g-FOBT) was used from January 2013 to December 2014 and a FIT was used from June 2015 to December 2016). 2575 participants, 642 in g-FOBT group and 1933 in FIT group had lesions. Participation rate was not different between tests (p = 0.104), whereas DR and PPV were statistically higher in FIT for all lesions (2.61, 95% CI [2.50-2.70] vs 0.93, 95% CI [0.90-1.00], p < 0.0001 and 64.84, 95% CI [63.10-66.60], 50.00, 95% CI [47.30-52.70], p < 0.0001 respectively). FIT detects more precancerous lesions (adenomas, p < 0.001, and advanced adenomas, p < 0.001) than g-FOBT but g-FOBT detects more serrated polyps (p = 0.025). AAs were more in right colon in FIT than g-FOBT (p = 0.035). No different participation rate was detected between FIT and g-FOBT but DR and PPV of all lesions was higher with FIT.
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February 2019

The combination of everolimus and zoledronic acid increase the efficacy of gemcitabine in a mouse model of pancreatic adenocarcinoma.

Oncotarget 2018 Jun 15;9(46):28069-28082. Epub 2018 Jun 15.

Department of Gastroenterology, University Hospital Centre, Angers, France.

Background: Gemcitabine is a standard treatment for pancreatic adenocarcinoma. Many mechanisms are involved in gemcitabine resistance, such as reduced expression of the human equilibrative nucleoside transporter 1 (hENT1) membrane transporter, deoxycytidine kinase deficiency, and changes in the signal transmission of mitogen-activity protein kinase (MAPK) and the phosphoinositide 3-kinase (PI3K) pathways.

Aim: To evaluate the anti-tumor efficiency of blocking signaling pathways using combined action of gemcitabine, everolimus and zoledronic acid versus gemcitabine alone in a mouse subcutaneous xenograft.

Methods: Implantations of two human pancreatic adenocarcinoma cells lines (PANC1, K-ras mutated and gemcitabine-resistant; and BxPc3, wild-type K-ras and gemcitabine-sensitive) were performed on male athymic nude mice. The mice received different treatments: gemcitabine, gemcitabine plus everolimus, everolimus, gemcitabine plus zoledronic acid, everolimus plus zoledronic acid, or gemcitabine plus everolimus and zoledronic acid, for 28 days. We measured the tumor volume and researched the expression of the biomarkers involved in the signaling pathways or in gemcitabine resistance.

Results: In wild-type K-ras tumors, the combinations of gemcitabine plus everolimus; zoledronic acid plus everolimus; and gemcitabine plus zoledronic acid and everolimus slowed tumor growth, probably due to caspase-3 overexpression and reduced Annexin II expression. In mutated K-ras tumors, gemcitabine plus everolimus and zoledronic acid, and the combination of zoledronic acid and everolimus, decreased tumor volume as compared to gemcitabine alone, inhibiting the ERK feedback loop induced by everolimus.

Conclusion: The combination of zoledronic acid and everolimus has an antitumor effect and could increase gemcitabine efficacy.
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June 2018

Relationship Between the Expression of O-Methylguanine-DNA Methyltransferase (MGMT) and p53, and the Clinical Response in Metastatic Pancreatic Adenocarcinoma Treated with FOLFIRINOX.

Clin Drug Investig 2017 Jul;37(7):669-677

Department of Gastroenterology, University Hospital Centre, Angers, France.

Background: To date, no predictive biomarker for the efficacy of FOLFIRINOX in metastatic pancreatic adenocarcinoma has been demonstrated. Deficiency in O-methylguanine-DNA methyltransferase (MGMT) has been associated with a therapeutic response in endocrine tumors of the pancreas and the lack of expression of protein 53 (p53) could interfere with the action of MGMT.

Objective: The aim of our study was to assess the prevalence of MGMT and p53 in patients with metastatic pancreatic adenocarcinoma treated with FOLFIRINOX as a first-line treatment and to investigate their association with therapeutic response and survival.

Patients And Methods: The immunohistochemical expression of MGMT was recorded as present or absent and the expression of p53 was semi-quantitatively scored in 30 patients with metastatic pancreatic adenocarcinoma, at Angers Hospital in France between September 2011 and June 2015. Clinical and radiologic data were collected retrospectively.

Results: The presence or absence of MGMT expression entailed no significant differences in response rate. Median values of progression-free survival (PFS) and overall survival (OS) were lower in patients with MGMT expression, but sample size is too small to conclude that there is a statistically significant difference. No significant relationship for response rate and PFS was observed in relation with p53 expression. By contrast, patients with a strong tumor expression of p53 had a significantly lower OS compared to patients with no or weak expression of the protein (p = 0.027). There was a positive correlation between the expression of p53 and MGMT (p = 0.08).

Conclusions: These preliminary findings suggest that for patients treated with FOLFIRINOX as a first-line treatment for metastatic pancreatic adenocarcinoma, the immunohistochemical evaluation of MGMT could not predict the clinical outcome; however, the survival was not significant probably because of the under-powered study (due to small sample size). A strong tumor expression of p53 is associated with a poor prognosis of OS.
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July 2017