Astrid Lièvre

Role of microsatellite instability in the management of colorectal cancers

Microsatellite instability is the consequence of a deficient mismatch repair system. It has a key role in the diagnostic strategy of Lynch syndrome, where tumours are all characterized by the presence of this phenotype. Microsatellite instability is therefore essential in the selection of colorectal cancer patients in whom a germline analysis of Mismatch Repair genes is possibly indicated. Moreover, microsatellite instability tumours are associated with a good prognosis and a resistance to fluorouracil-based adjuvant chemotherapy, which has a clinical application mainly in stage II colon cancer patients in whom adjuvant chemotherapy has a less beneficial effect than in stage III and outcome in presence of microsatellite instability is excellent. Recent data suggest that impact of microsatellite instability on benefit to fluorouracil-based adjuvant chemotherapy is dependent of the molecular mechanism involved in this genetic instability since an improved survival has been reported with adjuvant fluorouracil in microsatellite instability colorectal cancers of germline origin but not in sporadic cases. Predictive value of microsatellite instability on response to fluorouracil/oxaliplatin adjuvant chemotherapy has been less evaluated but recent studies suggest that the favorable outcome of Microsatellite instability tumours is maintained in patients receiving FOLFOX.

Second‐line chemotherapy for advanced biliary tract cancer after failure of the gemcitabine‐platinum combination: A large multicenter study by the Association des Gastro‐Entérologues Oncologues

Few data are available on second‐line chemotherapy (CT2) for advanced biliary tract cancer (ABTC). The aim of this multicenter study was to describe the CT2 regimens used, the response rates, and the outcomes of patients treated with various CT2 regimens.

Evaluating Patient-Derived Colorectal Cancer Xenografts as Preclinical Models by Comparison with Patient Clinical Data

Development of targeted therapeutics required translationally relevant preclinical models with well-characterized cancer genome alterations. Here, by studying 52 colorectal patient-derived tumor xenografts (PDX), we examined key molecular alterations of the IGF2-PI3K and ERBB-RAS pathways and response to cetuximab. PDX molecular data were compared with that published for patient colorectal tumors in The Cancer Genome Atlas. We demonstrated a significant pattern of mutual exclusivity of genomic abnormalities in the IGF2-PI3K and ERBB-RAS pathways. The genomic anomaly frequencies observed in microsatellite stable PDX reproduce those detected in nonhypermutated patient tumors. We found frequent IGF2 upregulation (16%), which was mutually exclusive with IRS2, PIK3CA, PTEN, and INPP4B alterations, supporting IGF2 as a potential drug target. In addition to maintaining the genomic and histologic diversity, correct preclinical models need to reproduce drug response observed in patients. Responses of PDXs to cetuximab recapitulate also clinical data in patients, with partial or complete response in 15% (8 of 52) of PDXs and response strictly restricted to KRAS wild-type models. The response rate reaches 53% (8 of 15) when KRAS, BRAF, and NRAS mutations are concomitantly excluded, proving a functional cross-validation of predictive biomarkers obtained retrospectively in patients. Collectively, these results show that, because of their clinical relevance, colorectal PDXs are appropriate tools to identify both new targets, like IGF2, and predictive biomarkers of response/resistance to targeted therapies.

Role of fluorine 18 fluorodeoxyglucose positron emission tomography/computed tomography in gastrointestinal cancers

Fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) has become a routine imaging modality for many malignancies and its use is currently increasing. In the present review article, we will summarize the evidence for FDG-PET/CT use in digestive cancers (excluding neuroendocrine tumours), and review the existing recommendations. While PET/CT is nowadays considered to be an important tool in the initial workup of oesophageal and anal cancers, new data are emerging regarding its use in assessing therapeutic efficacy, radiotherapy treatment planning, and detection of recurrence in case of isolated tumour marker elevation. Moreover, PET/CT may help decision making by detecting distant metastatic sites especially in potentially resectable metastatic colorectal cancer and, to a lesser extent, in localized gastric and pancreatic cancers. Finally, incidental focal colonic FDG uptakes require exploration by colonoscopy, as they are often associated with premalignant or malignant lesions.

The KRAS mutation detection within the initial management of patients with metastatic colorectal cancer: a status report in France in 2011.

BACKGROUNDnThe detection of KRAS mutations is mandatory to initiate an anti-epidermal growth factor receptor (EGFR) antibody in the treatment of metastatic colorectal carcinoma (mCRC).nnnPATIENTS AND METHODSnThis observational retrospective study was performed in 160 French centres during a 2-week period in 2011. Its main objective was to evaluate the rate of KRAS testing in patients with mCRC having initiated their first-line therapy. Secondary objectives included time of process, techniques used and reasons for non-prescription.nnnRESULTSnFive hundred and thirty eight mCRC patients (67.1 ± 11.3 years, synchronous metastases: 69.9%) were enrolled in the study. KRAS testing was prescribed in 81.1% of patients, in a median of 15 days after the diagnosis of metastases, and of 15 days prior to the initiation of the first-line metastatic chemotherapy. KRAS status was available for 87% of patients, after 23.6 ± 28.2 days, but after the choice of the first-line therapy in 56.6% of patients. Heterogeneity of reception time was noteworthy within regions (8.3 ± 7 days to 38.8 ± 101 days). KRAS testing was not prescribed mainly due to the planned non-prescription of an anti-EGFR antibody.nnnCONCLUSIONnThis study confirmed that KRAS testing is definitely part of the management of most of mCRC patients, despite discrepancies observed in the rate of prescription and the time of results.

Intérêt clinique des mutations de BRAF dans le cancer colorectal

BRAF mutations, present in 5 to 10% of colorectal cancers, have a proved oncogenic effect which is linked to their implication in the RAS/MAPK intracellular signalling pathway and they occurred at early stage of colorectal carcinogenesis. Many studies have therefore assessed their clinical significance as diagnostic and prognostic marker in colorectal cancers. More recently, their location downstream to EGFR and KRAS in the RAS/MAPK pathway have led to their evaluation as predictive marker of resistance to anti-EGFR monoclonal antibodies. This article aims to review the role of BRAF mutations in the diagnostic strategy of Lynch syndrome, their prognostic value in colorectal cancers and their potential value as predictive marker of resistance to anti-EGFR antibodies.

Second- and third-line chemotherapy in patients with metastatic pancreatic adenocarcinoma: Feasibility and potential benefits in a retrospective series of 117 patients

BACKGROUNDnChemotherapy is effective in metastatic pancreatic adenocarcinoma (PAC), but the benefits of second- and third-line chemotherapy remain unclear.nnnMETHODSnWe studied all patients followed consecutively for metastatic PAC, and registered at our institution between 1997 and 2006. We retrospectively analyzed the following data in terms of chemotherapy: tumor response; time to tumor progression (TTP) for each line; and overall survival (OS). Efficacy of second-line regimens was assessed using the growth modulation index (GMI).nnnRESULTSnOut of 117 patients, 99 (85%) received at least one line of chemotherapy, 53 (45%) received two lines and 24 (21%) had three or more lines. Median OS was 6.7 months for all 117 patients, 1.8 months for 18 patients who never received chemotherapy, 4.6 months for 46 patients who received one-line chemotherapy and 11.5 months for 53 patients who received at least two lines. Median OS from the beginning of the second-line was 4.7 months. The GMI demonstrated beneficial effects of second-line treatment on disease progression, with a GMI greater than 1.33 in 57% (30/53) of patients.nnnCONCLUSIONnMore than half the patients with metastatic PAC progression while receiving one-line chemotherapy achieved better disease control on receiving two lines of treatment.

Prognostic impact of tumour burden assessed by metabolic tumour volume on FDG PET/CT in anal canal cancer

PurposeThe aim of this study was to confirm the prognostic value of metabolic tumour volume (MTV) at the primary site on initial work-up FDG PET/CT in patients with squamous cell carcinoma (SCC) of the anal canal.MethodsPatients with a recent diagnosis of SCC of the anal canal without metastases undergoing PET/CT for initial work-up and treated with (chemo)radiotherapy were retrospectively reviewed. Computer-aided MTV and SUVmax were determined. Survival rates were estimated using the Kaplan-Meier method. Cox regression analysis was used to evaluate prognostic variables of progression-free survival and overall survival (OS).ResultsThe study group comprised 75 patients who had an initial work-up PET/CT. Five patients (6.7xa0%) had stage I disease, 22 (29.3xa0%) stage II disease, 20 (26.7xa0%) stage IIIA disease, and 28 (37.3xa0%) stage IIIB disease. Median follow-up was 51xa0months (range 10xa0–xa0117xa0months). Global 4-year OS was 82.7xa0%, ranging from 100xa0% in patients with stage I disease to 75xa0% in patients with stage IIIB disease. MTV at the primary site was significantly and independently correlated with OS (pu2009<u20090.05), as patients with MTV less than 7xa0cm3 had a better prognosis. SUVmax was not correlated with survival parameters. Metabolic involvement of the inguinal lymph nodes was also correlated with a poor outcome in the univariate analysis (pu2009<u20090.05).ConclusionMTV at the primary site is a prognostic biomarker in anal canal cancer. Hypermetabolic inguinal lymph nodes also appear to be correlated with survival.

Management of patients over 80 years of age treated with resection for localised colon cancer: Results from a French referral centre

BACKGROUNDnFew data are available on management of very elderly colon cancer patients, especially concerning the parameters of therapeutic decisions and the role of geriatricians.nnnMETHODSnWe retrospectively reviewed the charts of patients over 80 years of age who underwent surgery for a localised colon cancer in a French academic hospital.nnnRESULTSnA total of 176 patients underwent surgery (postoperative morbidity and mortality rates: 25% and 6.7%). Adjuvant chemotherapy was discussed at a multidisciplinary team meeting for 91% of stage III patients, but only 13.5% of them were treated. Twenty-five patients relapsed: 19 were discussed at the multidisciplinary meeting and 16 were treated (5 had a metastasectomy). Despite their increase with time, geriatric assessments were infrequent, 17% (33% after 2006), and had no impact on postoperative morbi-mortality. Median overall survival and recurrence-free survival were 65.3 months and 65.1 months, respectively. Age, emergency surgery, and Charlson comorbidity index were independent prognostic factors.nnnCONCLUSIONnSelected elderly colon cancer patients have significant access to surgery. However, postoperative morbi-mortality rates remain high and adjuvant chemotherapy rarely prescribed. Perioperative geriatric assessment, especially before surgery, should be routinely proposed to these patients to evaluate its impact on postoperative morbi-mortality and prescription of adjuvant treatment.

Chemotherapy versus self-expanding metal stent as primary treatment of severe dysphagia from unresectable oesophageal or gastro-oesophageal junction cancer.

OBJECTIVEnTo compare chemotherapy first (group 1) versus self-expanding metal stent first (group 2) for the management of malignant dysphagia in unresectable oesophageal or gastro-oesophageal junction cancer.nnnMETHODSnPatients from two university hospitals with severe malignant dysphagia (dysphagia score ≥ 2) uneligible for surgery or radiochemotherapy were evaluated retrospectively.nnnRESULTSnForty-two patients were included in group 1, and 29 in group 2. After 4 weeks, dysphagia scores improved by at least 1 point in 67% of patients in group 1 versus 93% in group 2 (p=0.01); 48% of patients in group 1 were able to eat solid food versus 68% in group 2 (p=0.054). In group 1, a self-expanding metal stent was secondarily placed in 18 patients (42.9%), whereas in group 2 dysphagia required a second self-expanding metal stent placement in 33.3% of patients.nnnCONCLUSIONnChemotherapy as the first treatment may be a valid option, avoiding self-expanding metal stent insertion in half of the patients.