Pharmacogenetic profiling and cetuximab outcome in patients with advanced colorectal cancer.

BACKGROUND: We analyzed the influence of 8 germinal polymorphisms of candidate genes potentially related to EGFR signalling (EGFR, EGF, CCND1) or antibody-directed cell cytotoxicity (FCGR2A and FCGR3A) on outcome of colorectal cancer (CRC) patients receiving cetuximab-based therapy. METHODS: Fifty-eight advanced CRC patients treated with cetuximab-irinotecan salvage therapy between 2001 and 2007 were analyzed (mean age 60; 50 PS 0-1). The following polymorphisms were analyzed on blood DNA: EGFR (CA repeats in intron 1, -216 G > T, -191C > A, R497K), EGF (A61G), CCND1 (A870G), FCGR2A (R131H), FCGR3A (F158V). Statistical analyses were conducted on the total population and on patients with wt KRas tumors. All SNPs were considered as ternary variables (wt/wt vs wt/mut vs mut/mut), with the exception of -191C > A EGFR polymorphism (AA patient merged with CA patients). RESULTS: Analysis of skin toxicity as a function of EGFR intron 1 polymorphism showed a tendency for higher toxicity in patients with a low number of CA-repeats (p = 0.058). CCND1 A870G polymorphism was significantly related to clinical response, both in the entire population and in KRas wt patients, with the G allele being associated with a lack of response. In wt KRas patients, time to progression (TTP) was significantly related to EGFR -191C > A polymorphism with a longer TTP in CC patients as compared to others, and to CCND1 A870G polymorphism with the G allele being associated with a shorter TTP; a multivariate analysis including these two polymorphisms only retained CCND1 polymorphism. Overall survival was significantly related to CCND1 polymorphism with a shorter survival in patients bearing the G allele, and to FCGR3A F158V polymorphism with a shorter survival in VV patients (in the entire population and in KRas wt patients). FCGR3A F158V and CCND1 A870G polymorphisms were significant independent predictors of overall survival. CONCLUSIONS: Present original data obtained in wt KRas patients corresponding to the current cetuximab-treated population clearly suggest that CCND1 A870G polymorphism may be used as an additional marker for predicting cetuximab efficacy, TTP and overall survival. In addition, FCGR3A F158V polymorphism was a significant independent predictor of overall survival.

PREDOMOS study, impact of a social intervention program for socially isolated elderly cancer patients: study protocol for a randomized controlled trial.

BACKGROUND: Cancer incidence and social isolation increase along with advanced age, and social isolation potentiates the relative risk of death by cancer. Once spotted, social isolation can be averted with the intervention of a multidisciplinary team. Techniques of automation and remote assistance have already demonstrated their positive impact on falls prevention and quality of life (QoL), though little is known about their impact on socially isolated elderly patients supported for cancer. The primary objective of the PREDOMOS study is to evaluate the impact of establishing a Program of Social intervention associated with techniques of Domotic and Remote assistance (PS-DR) on the improvement of QoL of elderly isolated patients, treated for locally advanced or metastatic cancer. The secondary objectives include treatment failure, tolerance, survival, and autonomy. METHODS/DESIGN: This trial is a multicenter, prospective, randomized, placebo-controlled, open-label, two-parallel group study. The setting is 10 French oncogeriatric centers. Inclusion criteria are patients aged at least 70 years with a social isolation risk and a histological diagnosis of cancer, locally advanced or metastatic disease. The groups are (1) the control group, receiving usual care; (2) the experimental group, receiving usual care associating with monthly social assistance, domotic, and remote assistance. Participants are randomized in a 1:1 allocation ratio. Evaluation times involve inclusion (randomization) and follow-up (12 months). The primary endpoint is QoL at 3 months (via European Organization for Research and Treatment of Cancer (EORTC) QLQ C30); secondary endpoints are social isolation, time to treatment failure, toxicity, dose response-intensity, survival, autonomy, and QoL at 6 months. For the sample size, 320 individuals are required to obtain 90% power to detect a 10-point difference (standard deviation 25) in QoL score between the two groups (20% loss to follow-up patients expected). DISCUSSION: The randomized controlled design is the most appropriate design to demonstrate the efficacy of a new experimental strategy (Evidence-Based Medicine Working Group classification). National and international recommendations could be updated based on the findings of this study. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02829762 . Registered on 29 June 2016.

Pancreatic Adenocarcinoma Therapeutic Targets Revealed by Tumor-Stroma Cross-Talk Analyses in Patient-Derived Xenografts.

Preclinical models based on patient-derived xenografts have remarkable specificity in distinguishing transformed human tumor cells from non-transformed murine stromal cells computationally. We obtained 29 pancreatic ductal adenocarcinoma (PDAC) xenografts from either resectable or non-resectable patients (surgery and endoscopic ultrasound-guided fine-needle aspirate, respectively). Extensive multiomic profiling revealed two subtypes with distinct clinical outcomes. These subtypes uncovered specific alterations in DNA methylation and transcription as well as in signaling pathways involved in tumor-stromal cross-talk. The analysis of these pathways indicates therapeutic opportunities for targeting both compartments and their interactions. In particular, we show that inhibiting NPC1L1 with Ezetimibe, a clinically available drug, might be an efficient approach for treating pancreatic cancers. These findings uncover the complex and diverse interplay between PDAC tumors and the stroma and demonstrate the pivotal role of xenografts for drug discovery and relevance to PDAC.

Monoclonal antibodies for treating gastric cancer: promises and pitfalls.

INTRODUCTION: Gastric cancer (GC) presents dismal prognosis when diagnosed at advanced stages, standard chemotherapy having shown little efficacy. Introduction of biotherapies interfering with novel targets and signaling pathways is currently an emerging strategy. AREAS COVERED: Only two monoclonal antibodies (trastuzumab and ramucirumab) have been approved, mostly in association with cytotoxics. Conversely, testing other promising biotherapies (panitumumab, cetuximab, bevacizumab, rilotumumab) have yielded conflicting results, since encouraging early clinical trials have failed to be confirmed in larger phase-III studies. Empirical and underpowered strategies when designing combinational studies, lack of comprehensive knowledge of pharmacokinetics/pharmacodynamics (PK/PD) relationships, and underestimation of the large inter-patient variability in drug exposure levels with monoclonal antibodies, could explain the failures in developing biotherapies in gastric cancer. This review covers the achievements and limits of monoclonal antibodies in gastric cancer and proposes clues to overcome current failures. EXPERT OPINION: Trastuzumab efficacy could be improved thanks to its combination with triplet chemotherapy or with another anti-HER2 agents or in continuation during second-line chemotherapy. Concerning ramucirumab, further studies are necessary to prove its interest in first line treatment of advanced GC, to use the optimal dose in each patient-given the large inter-patients variability, and to find predictive biomarkers of efficacy.

Severe hypersensitivity pneumonitis associated with everolimus therapy for neuroendocrine tumour: a case report.

BACKGROUND: Novel therapeutic agents are currently being investigated for neuroendocrine tumour treatment. CASE PRESENTATION: We report here on the case of a patient presenting with hypersensitivity pneumonitis while being treated with everolimus, a mammalian target of rapamycin (mTOR) inhibitor. CONCLUSION: Side effects of everolimus should be familiar to clinicians, including nonspecialists, and be monitored carefully to allow for prompt management.

Rapid deaminator status is associated with poor clinical outcome in pancreatic cancer patients treated with a gemcitabine-based regimen.

BACKGROUND: Gemcitabine is a mainstay in the treatment of biliary and pancreatic cancers, with limited efficacy in most settings. The gemcitabine elimination pattern is primarily driven by deamination in the liver by CDA. CDA is affected by genetic polymorphisms, leading to marked variations in activity and, subsequently, to erratic drug plasma exposures in patients administered with standard dosage. CDA deficiency has been a rising concern with gemcitabine since several studies have proven that poor metabolizer patients experience life-threatening toxicities upon drug intake. In theory, ultrarapid metabolizer (UM) patients should be conversely at risk of treatment failure, although thus far few studies have addressed this issue in digestive oncology. PATIENTS & METHODS: A pilot study was conducted on 40 pancreatic cancer patients, all treated with gemcitabine-based therapy. CDA status was primarily established on a phenotypic basis determined by measurement of residual CDA enzymatic activity in serum. Additionally, a search for c208G>A and c79A>C polymorphisms was carried out. RESULTS: No patients carrying c208G>A polymorphisms were found, and only heterozygous c79A>C patients were observed. Eight out of the 40 patients (i.e., 20%) were identified as UM, with CDA activities over 6 U/mg. CDA activity was significantly different between progressive disease patients and patients with controlled disease (8.4 vs 3 U/mg; p < 0.001). Conversely, fewer gemcitabine-related severe toxicities were observed in UM patients. CONCLUSION: This pilot study strongly suggests that UM patients are nearly five-times more likely to have progressive disease than patients with normal or low CDA activities, and that beside molecular events at the tumor level, upstream deregulations affecting drug disposition should be taken into account.

Targetting esophageal and gastric cancers with monoclonal antibodies.

Target therapies and notably monoclonal antibodies are currently being considered for esophageal, gastric, and gastroesophageal junction cancers. EGFR was found to be overexpressed in 60-86% of gastric or gastroesophageal tumors and in 50-70% of esophageal cancers. Cetuximab was shown to be a radiosensitizing agent in the treatment of ENT neoplasia. These results led to several phase II encouraging therapeutic trials evaluating the combination of cetuximab with radiochemotherapy in locally advanced esophageal cancers. Numerous encouraging phase II trials evaluating cetuximab combined with chemotherapy in patients with gastric adenocarcinoma or gastroesophageal junction cancer were reported. These promising results are still to be confirmed by the ongoing phase III trials. Several studies reported HER2 overexpression in gastric cancer (7-34%), which appeared to be associated with poorer prognosis. Trastuzumab is a monoclonal antibody directed against the extracellular HER2 domain. The international phase III trial known as ToGA (Trastuzumab for Gastric Cancer) aimed to determine the clinical efficacy and acceptable toxicity profile of trastuzumab in combination with first-line chemotherapy in HER2-overexpressing gastric or gastroesophageal cancer. Angiogenesis is an essential step in the initial phase of tumorigenesis, and it is normally absent from healthy tissues except for particular physiological situations, such as wound healing. VEGF-A plays a role in endothelial growth and angiogenesis. Bevacizumab, a humanized monoclonal anti-VEGF-A antibody, is currently being studied for gastric cancer. The phase III AVAGAST study, evaluating bevacizumab in association with chemotherapy in advanced gastric adenocarcinoma, did not achieve its primary aim of improved OS in bevacizumab-treated patients.

Cetuximab after bevacizumab in metastatic colorectal cancer: is it the best sequence?

BACKGROUND: Chemotherapy combinations and addition of cetuximab or bevacizumab to chemotherapy have been shown to improve overall survival of metastatic colorectal cancer (CRC) patients. However, the efficacy of cetuximab when administered after bevacizumab failure is still unknown. METHODS: Fifty-eight consecutive patients diagnosed with advanced colorectal cancer between treated with cetuximab following irinotecan failure were included in our analysis. A multivariate Cox model analysis was performed to estimate the effect of previous bevacizumab regimen on survival. RESULTS: Thirteen (22.4%) were pre-treated with anti-VEGF agents. None of them responded to cetuximab, and this subgroup presented a significantly decreased disease-specific survival as compared to treatment-naïve patients (9.1 months vs. 4.9 months; p=0.026). This difference remained statistically significant in a multivariate Cox model after adjusting for age, sex, performance status (PS), and K-RAS status (RR=2.2; 95% CI: 1.1-4.5, p=0.03). CONCLUSION: These study results suggest that a previous anti-VEGF therapy decrease cetuximab efficiency.

Efficacy of hepatitis B virus (HBV) vaccination in treating lamivudine-resistant HBV reactivation following hepatitis B surface antigen seroconversion.

BACKGROUND: HBsAg vaccination might help to control HBV replication following nucleos(t)ide analog therapy. We tested HBsAg vaccine in a patient who developed lamivudine resistance. PATIENT AND RESULTS: An HBeAg negative HBV chronically-infected patient developed HBsAg seroconversion after 3 years of treatment by lamivudine. However, the control of HBV replication was transient and HBV DNA could be detected in the serum one year after lamivudine was stopped. Concurrently, the anti-HBs antibodies (HBsAb) titre had decreased from more than 100 IU/L to 23 IU/L. Due to the presence of rtM204V resistance mutation, lamivudine was not reintroduced and the patient was treated by HBsAg vaccination. After three injections, HBV DNA was no more detectable and the HBsAb titre reached more than 200 IU/L. CONCLUSION: This observation suggests that a regular follow up of patients presenting HBsAg seroconversion following lamivudine therapy is necessary. In these patients, a low titre of HBsAb may not prevent from lamivudine-resistant HBV reactivation. Evaluation of HBsAg vaccination to maintain HBsAb at a high titre in these patients deserves further studies.