On the pharmacogenetics of non-small cell lung cancer treatment

Abstract: Introduction. Despite many clinical efforts, non-small-cell lung cancer (NSCLC) has a dismal 5-year survival rate of 16%, and high incidence of recurrence. The success of biologically targeted agents, as well as the activity of well-established chemotherapeutic regimens, has been limited by inherited/acquired resistance, and biomarkers to adapt the prescription of anticancer drugs to patients' features are urgently warranted. Areas covered. In oncology, pharmacogenetics should provide the way to select patients who may benefit from a specific therapy that best match the individual and tumor genetic profile, thus allowing maximum activity and minimal toxicity. The present review summarizes the main findings on NSCLC pharmacogenetics, critically reappraising the most important studies on polymorphisms correlated with outcome of pemetrexed and EGFR-inhibitors, and provides perspective on clinical application of genomic tests for treatment decision-making. Expert Opinion. A major challenge in NSCLC is the identification of subgroups of diseases/patients that will truly benefit from specific treatments. Ideally, convenient and minimally invasive tests to decipher biomarkers of chemosensitivity/resistance and toxicity should be developed alongside novel anticancer treatments. Integration with the latest generation of whole-genome analyses and liquid biopsies as well as prospective validation in large cohorts of patients will overcome the limitations of the traditional pharmacogenetic approaches

Neuropsychiatric adverse drug reactions with oral tyrosine kinase inhibitors in metastatic colorectal cancer: an analysis from the FDA Adverse Event Reporting System

IntroductionNew oral tyrosine kinase inhibitors (TKIs) are approved for metastatic colorectal cancer (mCRC). The aim of this study was to assess the neuropsychiatric adverse drug reactions (ADRs) of these drugs reported in the FDA Adverse Event Reporting System (FAERS) database.MethodsAll reports with regorafenib (REG) and encorafenib (ENC) as the primary suspect, and reported in the FAERS between 2012 and 2022, were collected. A descriptive and disproportionality analyses were conducted.ResultsOut of 4,984 cases, 1,357 (30.2%) reported at least one neuropsychiatric ADR. New potential signals for REG included neuropathy peripheral (n = 265; reporting odds ratio, ROR = 19.48, 95% confidence interval, CI 95% = 17.52-22.47; information component, IC = 2.89, IC025-IC075 = 2.77-3.02), hyperesthesia (n = 18; ROR = 12.56, CI 95% = 7.90-19.96; IC = 2.25, IC025-IC075 = 1.79-2.72), taste disorder (n = 41; ROR = 9.91, CI 95% = 7.29-13.49; IC = 2.18, IC025-IC075 = 1.88-2.49), poor quality sleep (n = 18; ROR = 6.56, CI 95% = 4.13-10.42; IC = 1.74, IC025-IC075 = 1.27-2.20), altered state of consciousness (n = 15; ROR = 5.50, CI 95% = 3.31-9.14; IC = 1.57, IC025-IC075 = 1.06-2.07), depressed mood (n = 13; ROR = 1.85, CI 95% = 1.07-3.19; IC = 0.58, IC025-IC075 = 0.04-1.13) and insomnia (n = 63; ROR = 1.48, CI 95% = 1.15-1.89; IC = 0.38, IC025-IC075 = 0.13-0.63). For ENC comprised depressed mood (n = 4; ROR = 5.75, CI 95% = 2.15-15.39; IC = 1.74, IC025-IC075 = 0.76-2.73) and cognitive disorders (n = 3; ROR = 4.71, CI 95% = 1.51-14.66; IC = 1.54, IC025-IC075 = 0.41-2.68).DiscussionThis study identified new unknown potential neuropsychiatric ADRs. Further investigations are required to better define the neurotoxicity of TKIs in mCRC patients

Molecular Bases for Combinatorial Treatment Strategies in Patients with KRAS Mutant Lung Adenocarcinoma and Squamous Cell Lung Carcinoma

Innovative therapeutic agents have significantly improved outcomes, with an acceptable safety profile, in a substantial proportion of non-small cell lung cancer (NSCLC) patients in whom the malignant phenotype of the disease is determined by oncogenic molecular alterations. However, the benefit seen with these treatment models has not translated well to NSCLCs with KRAS mutations or squamous cell histology. Although efforts have been made to develop precision medicine approaches, KRAS mutant NSCLC and lung squamous cell carcinoma (LSCC) continue to display resistance to therapy. Recently, based on the results of the Phase III SQUIRE trial, the EGFR monoclonal antibody necitumumab received FDA authorization in combination with cisplatin and gemcitabine for first line treatment of patients with metastatic LSCC. Among the molecular compounds tested in KRAS mutant NSCLC patients, the MEK inhibitor, selumentinib, combined with docetaxel in second line setting, determined a progression-free survival improvement, but no overall survival advantage. Better understanding is needed in regard to signaling pathways which cooperate to induce oncogene transformation in LSCC and KRAS mutant NSCLC and could determine intrinsic or acquired resistance to necitumumab and selumetinib. Greater understanding of such pathways will provide a molecular base upon which to improve the scant clinical benefit with these compounds

Rare histotypes of epithelial biliary tract tumors: A literature review

Adenocarcinoma represents the most frequent biliary tract cancer. However, other rare histotypes can be found in the biliary tract, such as cholangiolocellular carcinoma, cholangiocarcinoma with ductal plate malformation pattern, adenosquamous carcinoma, mucinous carcinoma, signet ring cell carcinoma, clear cell carcinoma, mucoepidermoid carcinoma, lymphoepithelioma-like carcinoma, and sarcomatous cholangiocarcinoma. These cancer types account for less than 10 % of all the already rare biliary tract tumors. Yet, they represent a relevant issue in everyday clinical practice, given the lack of therapeutic recommendations and the overall scarcity of data, mainly deriving from isolated small center-specific cohorts of patients.The shifts of such histotypes from the most common ones reflect genetic and molecular differences, determine changes in clinical aggressiveness, and suggest a possible variability in sensitivity to the standard treatments of biliary adenocarcinomas. The consistency and degree of these variables are still to be solidly demonstrated and investigated. Therefore, this paper aims to review the current literature concerning very infrequent and rare epithelial biliary tract cancers, focusing our attention on the clinical, molecular, and immunohistochemical features of these tumors

Prevalence of Use and Cost of Biological Drugs for Cancer Treatment: A 5-Year Picture from Southern Italy

Background and Objectives: Considering the clinical and economic burden of biological drugs in cancer treatment, it is necessary to explore how these drugs are used in routine care in Italy and how they affect the sustainability of the National Health Services. This study aimed to investigate the prevalence of use and costs of biological drugs for cancer treatment in a general population of Southern Italy in the years 2010–2014. Methods: This was a retrospective, observational study using data from the healthcare administrative databases of Messina Province for the years 2010–2014. In this study, users of biological drugs for cancer treatment were characterized and the prevalence of use and costs were calculated over time. The potential impact of biosimilars on the expenditure was also estimated. Results: Of a population of 653,810 residents in the Messina area during the study years, 2491 (0.4%) patients received at least one study drug. The most frequently used were monoclonal antibodies (mAbs) (n = 1607; 64.5%) and tyrosine kinase inhibitors (TKIs) (n = 609; 24.4%). mAbs were mainly used by females (60.3%) for metastasis due to an unspecified primary tumor, lymphomas, or breast cancer (24.2, 16.7, and 13.7%, respectively). Most users of small molecules were males (56.3%) being treated for multiple myeloma, metastasis due to unspecified primary tumor, leukemia, and lung cancer (13.1, 12.6, 9.5, and 8.9%, respectively). During the study years, the prevalence of use doubled from 0.9 to 1.8 per 1000 inhabitants; likewise, the related expenditure grew from €6.6 to €13.6 million. Based on our forecasts, this expenditure will grow to €25 million in 2020. Assuming a 50% biosimilar uptake (trastuzumab and rituximab), a potential yearly saving of almost €1 million may be achieved. Conclusions: In recent years, the use and costs of biological drugs in cancer patients have increased dramatically in a large population from Southern Italy. This trend may be counterbalanced by adopting biosimilars once they are available. Claims databases represent a valid tool to monitor the uptake of newly marketed biological drugs and biosimilars

Author Correction to: Prevalence of Use and Cost of Biological Drugs for Cancer Treatment: A 5-Year Picture from Southern Italy

Unfortunately, many errors were identified in the published article. The original article was corrected

BIM and mTOR expression levels predict outcome to erlotinib in EGFR-mutant non-small-cell lung cancer

Altres ajuts: Fellowship Award of the International Association for the Study of Lung Cancer i grant of the Italian Association for Cancer Research (AIRC My First AIRC Grant n° 14282).Abstract.BIM is a proapoptotic protein that initiates apoptosis triggered by EGFR tyrosine kinase inhibitors (TKI). mTOR negatively regulates apoptosis and may influence response to EGFR TKI. We examined mRNA expression of BIM and MTOR in 57 patients with EGFR-mutant NSCLC from the EURTAC trial. Risk of mortality and disease progression was lower in patients with high BIM compared with low/intermediate BIM mRNA levels. Analysis of MTOR further divided patients with high BIM expression into two groups, with those having both high BIM and MTOR experiencing shorter overall and progression-free survival to erlotinib. Validation of our results was performed in an independent cohort of 19 patients with EGFR-mutant NSCLC treated with EGFR TKIs. In EGFR-mutant lung adenocarcinoma cell lines with high BIM expression, concomitant high mTOR expression increased IC50 of gefitinib for cell proliferation. We next sought to analyse the signalling pattern in cell lines with strong activation of mTOR and its substrate P-S6. We showed that mTOR and phosphodiesterase 4D (PDE4D) strongly correlate in resistant EGFR-mutant cancer cell lines. These data suggest that the combination of EGFR TKI with mTOR or PDE4 inhibitors could be adequate therapy for EGFR-mutant NSCLC patients with high pretreatment levels of BIM and mTOR