Louis de Mestier

MEK in cancer and cancer therapy

The mitogen-activated extracellular signal-regulated kinase (MEK) pathway is one of the best-characterized kinase cascades in cancer cell biology. It is triggered by either growth factors or activating mutations of major oncogenic proteins in this pathway, the most common being Ras and Raf. Deregulation of this pathway is frequently observed and plays a central role in the carcinogenesis and maintenance of several cancers, including melanoma, pancreatic, lung, colorectal, and breast cancers. Targeting these kinases offers promise of novel therapies. MEK inhibitors (MEKi) are currently under evaluation in clinical trials and many have shown activity. In this review, we comprehensively examine the role of the MEK pathway in carcinogenesis and its therapeutic potential in cancer patients, with a focus on MEKi. We describe the clinical perspectives of MEKi in the two main models of Ras-ERK driven tumors, BRAF-mutant (addicted to the pathway) and KRAS-mutant (non-addicted). We also highlight the known mechanisms of resistance to MEKi and emerging strategies to overcome it.

High c-Met expression in stage I-II pancreatic adenocarcinoma: proposal for an immunostaining scoring method and correlation with poor prognosis.

AIMSnc-Met is an emerging biomarker in pancreatic ductal adenocarcinoma (PDAC); there is no consensus regarding the immunostaining scoring method for this marker. We aimed to assess the prognostic value of c-Met overexpression in resected PDAC, and to elaborate a robust and reproducible scoring method for c-Met immunostaining in this setting.nnnMETHODS AND RESULTSnc-Met immunostaining was graded according to the validated MetMab score, a classic visual scale combining surface and intensity (SI score), or a simplified score (high c-Met: ≥ 20% of tumour cells with strong membranous staining), in stage I-II PDAC. A computer-assisted classification method (Aperio software) was developed. Clinicopathological parameters were correlated with disease-free survival (DFS) and overall survival(OS). One hundred and forty-nine patients were analysed retrospectively in a two-step process. Thirty-seven samples (whole slides) were analysed as a pre-run test. Reproducibility values were optimal with the simplified score (kappa = 0.773); high c-Met expression (7/37) was associated with shorter DFS [hazard ratio (HR) 3.456, P = 0.0036] and OS (HR 4.257, P = 0.0004). c-Met expression was concordant on whole slides and tissue microarrays in 87.9% of samples, and quantifiable with a specific computer-assisted algorithm. In the whole cohort (n = 131), patients with c-Met(high) tumours (36/131) had significantly shorter DFS (9.3 versus 20.0 months, HR 2.165, P = 0.0005) and OS (18.2 versus 35.0 months, HR 1.832, P = 0.0098) in univariate and multivariate analysis.nnnCONCLUSIONSnSimplified c-Met expression is an independent prognostic marker in stage I-II PDAC that may help to identify patients with a high risk of tumour relapse and poor survival.

Primary tumor resection in colorectal cancer with unresectable synchronous metastases: A review

At the time of diagnosis, 25% of patients with colorectal cancer (CRC) present with synchronous metastases, which are unresectable in the majority of patients. Whether primary tumor resection (PTR) followed by chemotherapy or immediate chemotherapy without PTR is the best therapeutic option in patients with asymptomatic CRC and unresectable metastases is a major issue, although unanswered to date. The aim of this study was to review all published data on whether PTR should be performed in patients with CRC and unresectable synchronous metastases. All aspects of the management of CRC were taken into account, especially prognostic factors in patients with CRC and unresectable metastases. The impact of PTR on survival and quality of life were reviewed, in addition to the characteristics of patients that could benefit from PTR and the possible underlying mechanisms. The risks of both approaches are reported. As no randomized study has been performed to date, we finally discussed how a therapeutic strategys trial should be designed to provide answer to this issue.

Prognostic factors in patients with non resectable metastatic colorectal cancer in the era of targeted biotherapies: Relevance of Köhne's risk classification

BACKGROUNDnKöhnes prognostic classification has been previously proposed, based on performance status, alkaline phosphatase level, number of metastatic sites and white blood cells count.nnnAIMSnTo identify prognostic factors for survival and to assess the validity of Köhnes classification, in the era of targeted biotherapies, in patients treated with chemotherapy for non resectable metastatic colorectal cancer.nnnMETHODSnA total of 290 consecutive patients were retrospectively identified in all gastroenterology units of one French county, between 2004 and 2008. Univariate and multivariate analysis for overall survival were performed using pre-treatment patient characteristics.nnnRESULTSnAll data were available for prognostic categorization in 133 patients. Median survival was 22.1 months. The distribution and median survival for Köhnes prognostic groups were as following: good (n=73; 24.8 months), intermediate (n=35; 24.2 months), and poor (n=25; 7.0 months). The survival difference was significant between good and poor prognostic groups (p<0.01) and between intermediate and poor prognostic groups (p<0.01), but not between good and intermediate prognostic groups (p=0.5). The two independent prognostic factors of survival in multivariate analysis were performance status 0/1 (p<0.01) and white blood cells count<10×10(9)/L (p<0.01).nnnCONCLUSIONSnThe relevance of Köhnes classification is questioned. A simplified score could be validated by largest studies, based on white blood cells count and performance status.

Is palliative laparoscopic hyperthermic intraperitoneal chemotherapy effective in patients with malignant hemorrhagic ascites

Malignant hemorrhagic ascites may complicate the terminal evolution of digestive cancers with peritoneal carcinomatosis. It has a bad influence on prognosis and may severely impair patients’ quality of life. Palliative laparoscopic hyperthermic intraperitoneal chemotherapy (HIPEC) has been proposed to treat debilitating malignant ascites. Two cases of peritoneal carcinomatosis causing hemorrhagic ascites and severe anemia that needed iterative blood transfusions are reported. These patients were treated by laparoscopic HIPEC (mitomycin C and cisplatin with an inflow temperature of 43°C), resulting in cessation of peritoneal bleeding. No postoperative complication or relapse of ascites occurred during the following months. No more blood transfusion was needed. Laparoscopic HIPEC might be an effective and safe therapeutic option to consider in patients with malignant hemorrhagic ascites.

Prolonged Survival in a Patient with Neuroendocrine Tumor of the Cecum and Diffuse Peritoneal Carcinomatosis

Peritoneal carcinomatosis is a well-known factor of poor prognosis in patients with digestive adenocarcinomas. Peritoneal dissemination may also occur in midgut well-differentiated neuroendocrine tumors, but its influence on survival is ill-defined. We report here the history of a 64-year-old woman who had a neuroendocrine tumor of the cecum with multiple synchronous metastases in the liver and diffuse peritoneal carcinomatosis. She underwent surgical resection of the primary tumor and cytoreduction of liver metastases, and received subsequently chemotherapy and somatostatin analogs. In spite of the widespread extension of the disease, she survived for 13 years and died from a carcinoid heart disease. We discuss the natural history and prognostic factors in patients with midgut well-differentiated neuroendocrine tumors, with a focus on the impact of the peritoneal carcinomatosis.

Unravelling the pharmacologic opportunities and future directions for targeted therapies in gastro-intestinal cancers part 2: Neuroendocrine tumours, hepatocellular carcinoma, and gastro-intestinal stromal tumours.

Until the 1990s, cytotoxic chemotherapy has been the cornerstone of medical therapy for gastrointestinal (GI) cancers. Better understanding of the cancer cell molecular biology has led to the therapeutic revolution of targeted therapies, i.e. monoclonal antibodies or small molecule inhibitors directed against proteins that are specifically overexpressed or mutated in cancer cells. These agents, being more specific to cancer cells, were expected to be less toxic than conventional cytotoxic agents. However, their effects have sometimes been disappointing, due to intrinsic or acquired resistance mechanisms, or to an activity restricted to some tumour settings, illustrating the importance of patient selection and early identification of predictive biomarkers of response to these therapies. Targeted agents have provided clinical benefit in many GI cancer types. Particularly, some GI tumours are considered chemoresistant and targeted therapies have offered a new therapeutic base for their management. Hence, somatostatin receptor-directed strategies, sorafenib, and imatinib have revolutioned the management of neuroendocrine tumours (NET), hepatocellular carcinoma (HCC), and gastrointestinal stromal tumours (GIST), respectively, and are now used as first-line treatment in many patients affected by these tumours. However, these agents face problems of resistances and identification of predictive biomarkers from imaging and/or biology. We propose a comprehensive two-part review providing a panoramic approach of the successes and failures of targeted agents in GI cancers to unravel the pharmacologic opportunities and future directions for these agents in GI oncology. In this second part, we will focus on NET, HCC, and GIST, whose treatment relies primarily on targeted therapies.

Pancreatic neuroendocrine tumors in von Hippel–Lindau disease

Dear Editor, TY Park et al. recently reported a retrospective series of 55 patients with von Hippel–Lindau (VHL) disease and pancreatic involvement [1]. Since VHL disease is a rare genetic condition, this fairly large series might be of valuable information. However, we are quite surprised by the patient selection. Particularly, we do not know the reason why so many patients were excluded from the “VHL population”: the gold standard is genetic testing and only half of the patients had molecular confirmation of the diagnosis. Pancreatic involvement is frequent in VHL disease, including pancreatic cysts, serous cystadenomas and pancreatic neuroendocrine tumors (PNETs) [2]. Among them, PNETs are the major (if not exclusive) concern, because of the significant risk of metastatic course, thus warranting surgical resection or rigorous observation. Hence, it is of major importance to firmly assess the diagnosis of PNETs. Notably, the diagnosis criteria used by Park et al. (i.e. hypervascular mass strongly enhancing on computed tomography scan during arterial phase) is surprising and not validated [1]. Particularly, such criteria may not allow for accurate differentiation between PNET and metastasis from renal cell carcinoma or, more frequently, a pseudo-solid form of microcystic serous adenoma [3]. In a series, the latter accounted for the final pathological diagnosis of 15% of pancreatic surgical resections performed for presumed PNET [4]. Hence, diagnosis inaccuracy could explain the unusual rate (32.7%, twofold higher than that in the literature) of patients with PNET in the study by Park et al. [1]. Obtaining positive somatostatin-receptor scintigraphy and/or pathological confirmation is the optimal way to assess a firm diagnosis of PNET [5]. Management of VHL-related PNET is challenging, not only due to their frequent multiplicity but also due to simultaneous other life-threatening organs involvement (renal cancer, hemangioblastoma, and pheochromocytoma). Efforts have been made over the past decades to define the PNET patients requiring surgery, as reported by Libutti et al. [6], with the aim of a parenchyma-sparing strategy. In addition, we have recently reported that removing only the deemed

Pancreas Cancer-Associated Polymyositis of the Legs Regressing After Cephalic Duodenopancreatectomy: Case Report and Review of the Literature

CONTEXTnInflammatory myopathy, such as polymyositis, has been widely reported as paraneoplastic syndrome associated with various malignancies. However, its association with pancreas adenocarcinoma is very uncommon.nnnCASE REPORTnA case of a patient with paraneoplastic polymyositis of both legs associated with pancreatic adenocarcinoma is reported here. The diagnosis of polymyositis was highlighted by MRI and confirmed by histopathological examination. The surgical resection of the primary tumor led to the complete resolution of polymyositis with no further recurrence despite later metastases.nnnCONCLUSIONnThe association between pancreatic cancer and paraneoplastic polymyositis is very uncommon and has to be recognized by clinicians.

Abstract 3824: c-MET as a prognostic biomarker and therapeutic target in patients with poor prognostic pancreatic adenocarcinoma following surgical resection

Context: Pancreatic ductal adenocarcinoma (PDAC) displays a prominent desmoplastic stromal reaction, leading to tumor hypoxia and driving a selective pressure towards cancer cells with aggressive phenotype. Activation of the HGF/c-MET pathway is involved in tumor-stroma interactions and promotes PDAC cells proliferation, invasion, EMT, and stem cellness. As a background for identifying tumors that could benefit from MET inhibitors, we set a study looking at c-MET expression in PDAC and its association with clinical/pathological features, hypoxia, and survival. Patients and methods: Patients who underwent curative surgical resection for PDAC and received no adjuvant chemotherapy (“pure” prognostic value) were selected for this study. c-MET expression was assessed using immunochemistry and graded on a scale (combining the intensity of staining and the % of stained cells) from 0 to 4, along with the microenvironment characteristics as defined by HIF-1α and CA9 immunostaining (hypoxia), CD31 expression (microvascular density [MVD]), and stroma abundance. Clinical, pathological, and molecular biomarkers have been correlated with disease-free (DFS) and overall (OS) survivals. Results: thirty-seven patients have been analyzed in this study. Twenty-seven percent of tumors (10/37) were c-MET high (score ≥ 3). High c-MET expression was associated with moderate/poor differentiation (p = 0.017), presence of isolated tumor cells in the stroma (p = 0.023), and low stroma abundance (r = -0.445, p = 0.0074), but not with hypoxia-related markers (HIF-1α, CA9, or MVD). High c-MET expression was associated with shorter DFS (median: 7.7 vs 33.0 months, HR = 2.207, p=0.025) and OS (median: 12.1 vs 38.9 months, HR = 2.207, p=0.0099) than low c-MET expression in PDAC. High c-MET expression combined with tumor size > 20 mm and lymph node ratio (defined as the ratio of lymph nodes with tumor metastasis to the total lymph nodes dissected) > 0.20 predicted risk of early local or distant recurrence (RFS Conclusion: c-MET appears to be a strong prognostic marker in resected PDAC that may help to identify patients at high risk of early recurrence. c-MET was not correlated with hypoxia in this study, but was associated with aggressive tumor features (poor differentiation, isolated tumor cells in the stroma, low stroma abundance). PDAC overexpressing c-MET may represent a subgroup candidate for intensified adjuvant treatment or clinical trials with MET inhibitors. Citation Format: Cindy NEUZILLET, Jerome CROS, Annemilai TIJERAS-RABALLAND, Julien MOROCH, Louis DE MESTIER, Pierre BEDOSSA, Valerie PARADIS, Alain SAUVANET, Jean-Baptiste BACHET, Armand DE GRAMONT, Esteban CVITKOVIC, Eric RAYMOND, Pascal HAMMEL, Anne COUVELARD. c-MET as a prognostic biomarker and therapeutic target in patients with poor prognostic pancreatic adenocarcinoma following surgical resection. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3824. doi:10.1158/1538-7445.AM2014-3824