Leveraging Cancer Phenotypic Plasticity for Novel Treatment Strategies.

Cancer cells, like all other organisms, are adept at switching their phenotype to adjust to the changes in their environment. Thus, phenotypic plasticity is a quantitative trait that confers a fitness advantage to the cancer cell by altering its phenotype to suit environmental circumstances. Until recently, new traits, especially in cancer, were thought to arise due to genetic factors; however, it is now amply evident that such traits could also emerge non-genetically due to phenotypic plasticity. Furthermore, phenotypic plasticity of cancer cells contributes to phenotypic heterogeneity in the population, which is a major impediment in treating the disease. Finally, plasticity also impacts the group behavior of cancer cells, since competition and cooperation among multiple clonal groups within the population and the interactions they have with the tumor microenvironment also contribute to the evolution of drug resistance. Thus, understanding the mechanisms that cancer cells exploit to tailor their phenotypes at a systems level can aid the development of novel cancer therapeutics and treatment strategies. Here, we present our perspective on a team medicine-based approach to gain a deeper understanding of the phenomenon to develop new therapeutic strategies.

Neoadjuvant-modified FOLFIRINOX vs nab-paclitaxel plus gemcitabine for borderline resectable or locally advanced pancreatic cancer patients who achieved surgical resection.

We conducted an institutional study to compare the clinical and pathological efficacy between the neoadjuvant therapy (NAT)-modified FOLFIRINOX (mFOLF) vs nanoparticle albumin-bound paclitaxel plus gemcitabine (nab-P/G) for borderline resectable pancreatic cancer (BRPC) and locally advanced pancreatic cancer (LAPC) patients who completed resection. The study retrospectively enrolled patients with pathologically confirmed BRPC or LAPC from 2010 to 2018 at our institution. The survival rates were determined by the Kaplan-Meier method and log-rank test was used to test differences. Cox's proportional hazard model was used to assess survival with respect to covariates. Seventy-two patients who completed at least two cycles of neoadjuvant chemotherapy and surgical resection were included, with 52 (72.2%) patients receiving mFOLF and 20 (27.8%) receiving nab-P/G. Patients treated with mFOLF had statistically higher rates of RECIST 1.1 partial or complete response (16/52 vs 1/20, P = .028). Additionally, mFOLF patients had greater pathological tumor size reduction, fewer positive lymph nodes, and higher treatment response grade compared to the nab-P/G patients (all P < .05). The median overall survival was 33.3 months vs 27.1 months (P = .105), and distant metastasis-free survival (DMFS) was 21.3 months vs 14.6 months (P = .042) in the mFOLF vs nab-P/G groups, respectively. On multivariate analysis, mFOLF (hazard ratio, 0.428; 95% confidence interval [CI], 0.186-0.987) and abnormal postoperative CA 19-9 (hazard ratio, 2.47; 95% CI, 1.06-5.76) were associated with DMFS. Among patients with BRPC and LAPC who complete surgical resection, neoadjuvant mFOLF was associated with improved pathological and clinical outcomes compared with nab-P/G.

Epidermal growth factor receptor (EGFR)-targeted therapies in esophagogastric cancer.

Esophageal and gastric cancer incidence has been increasing worldwide. Most cases are diagnosed in advanced stages, and current therapy has not been able to improve the modest survival rates after diagnosis. Epidermal growth factor receptor expression has been found to correlate with poor prognosis and aggressive disease in esophagogastric cancers. Targeting these receptors through monoclonal antibody or downstream inhibition of tyrosine kinase has produced some encouraging results. The Trastuzumab for Gastric Cancer (ToGA) trial demonstrated that trastuzumab, a monoclonal antibody directed against the Her-2 receptor improves survival in Her-2 positive advanced gastric and gastro-esophageal cancers. Encouraging results have been reported in the ongoing clinical trials of EGFR-directed therapies in combination with concurrent chemoradiation for the locally advanced esophagogastric cancers. Identification of pertinent biomarkers of efficacy will likely lead to further optimization of EGFR-directed treatment. In the current article, we will be discussing the mechanisms of action, completed phase II/III trials and future of epidermal growth factor targeted-therapy in gastric and esophageal cancers.