Early taxane exposure and neurotoxicity in breast cancer patients.

INTRODUCTION: Breast cancer is the most diagnosed tumor and a leading cause of cancer death in women worldwide. Taxanes are the most used chemotherapeutic agents and are strictly connected to neurotoxicity. Taxane-induced neuropathy (TIN) significantly impacts patients' quality of life (QOL). Early identification and management of TIN could improve preventive strategies to preserve patients' QOL during and after breast cancer treatment. OBJECTIVE: This prospective, observational study aimed to evaluate the taxane-induced neuropathy (TIN) in early breast cancer patients treated with weekly paclitaxel at an earlier stage and identify any correlation between TIN and QOL. METHODS: Data from stage I-III breast cancer patients treated with taxane-based therapy between 2018 and 2022 were collected at the Medical Oncology Unit of the University Hospital of Cagliari. Peripheral neuropathy was evaluated using the NCI-CTCAE scale (National Cancer Institute, Common Terminology Criteria for Adverse Events) at every drug administration. In contrast, QOL was assessed using EORTC QLC-CIPN20 and FACT-Taxane questionnaire at baseline (T0), after 4 weeks (T1) and 12 (T2) weeks of treatment. Statistical analysis was performed to evaluate the correlation between neurotoxicity and QOL. RESULTS: Neurotoxicity incidence peaked at the third, fourth, and sixth week of treatment, with patients reporting grade 1 and 2 neurotoxicity. Simultaneously with increasing doses of paclitaxel, significant differences in QOL were observed in early treatment cycles relating to TIN presentation. Patients with higher neurotoxicity grades reported lower QOL scores. CONCLUSIONS: Despite the absence of effective treatments to prevent paclitaxel-induced neurotoxicity, symptoms are managed through dosage reduction, delay, or treatment interruption. Future research should focus on identifying neuroprotective measures to avoid an irreversible decline in the quality of life for breast cancer survivors.

Influence of antidiabetic drugs on glucose metabolism and immune response in patients with metastatic pancreatic ductal adenocarcinoma receiving gemcitabine plus nab-paclitaxel as first-line treatment.

BACKGROUND: Association between pancreatic ductal adenocarcinoma (PDAC) and type 2 diabetes mellitus (DM2) has long been evaluated. Indeed, DM2 can be both an epiphenomenon of PDAC and a risk factor. The present study aimed to investigate the correlation between overall survival (OS) and antidiabetic drugs in patients with metastatic pancreatic ductal adenocarcinoma and DM2. METHOD: Data from 232 patients were collected retrospectively from 2014 to 2021. 174 from AOU Cagliari Medical Oncology and 58 from AOU Ancona Medical Oncology. All patients received gemcitabine plus nab-paclitaxel first-line chemotherapy. We aimed to evaluate the correlation between DM2, anti-diabetic medications and overall survival. Survival distribution was assessed by Kaplan-Meier curves. RESULTS: Median age was 68±9, 127 (55%) were male. 138/232 (59%) patients were not affected by DM2, 94/232 (41%) were affected by DM2. 57 were insulin-treated and 37 were metformin-treated. DM2 treated patients showed an higher median overall survival (26 vs 12 months, p = 0,0002). Among DM2 patients insulin-treated and metformin-treated showed an mOS of 21 months and 33 months, respectively. CONCLUSIONS: Results showed a correlation between treated DM2 and higher mOS in patients with mPDAC. Limitations due to retrospective data collection must be considered. Further studies in this setting are needed.

Liquid Biopsy-Driven Cetuximab Rechallenge Strategy in Molecularly Selected Metastatic Colorectal Cancer Patients.

Background: Rechallenge with EGFR inhibitors represents a promising strategy for patients with RAS wild type (WT) colorectal cancer (CRC) but definitive selection criteria are lacking. Recently, the RAS WT status on circulating tumor DNA (ct-DNA) emerged as a potential watershed for this strategy. Our study explored the liquid biopsy-driven cetuximab rechallenge in a RAS and BRAF WT selected population. Methods: CRC patients with RAS and BRAF WT both on tumor tissue and on ct-DNA at baseline receiving rechallenge with cetuximab were eligible for our analysis. Ct-DNA was analyzed for RAS-BRAF mutations with pyro-sequencing and nucleotide sequencing assays. Real-time PCR and droplet digital PCR were performed to confirm the RAS-BRAF mutational status. Results: A total of 26 patients were included in our analysis. In the global population, RR was 25.0%, median overall survival (mOS) was 5.0 months, and median progression-free survival (mPFS) was 3.5 months. Previous response to anti-EGFR was associated with improved mPFS (5.0 vs. 2.0 months, HR: 0.26, p = 0.048); anti-EGFR free interval > 14 months and anti-EGFR free interval > 16 months were associated with improved mPFS (respectively 7.0 vs. 3.0 months, HR: 0.27, p = 0.013 and not reached vs. 3.0 months, HR: 0.20, p = 0.002) and with improved mOS (respectively 13.0 vs. 5.0 months, HR: 0.27, p = 0.013 and 13.0 vs. 5.0 months, HR: 0.20, p = 0.002). Previous lines >2 were correlated with improved mPFS (4.0 vs. 1.0 month, HR: 0.05, p = 0.041) and with improved mOS (7.0 vs. 1.0 month, HR: 0.045, p = 0.034). In a multiple logistic regression model, only the anti-EGFR free interval was confirmed to be a significant predictor for mOS and mPFS. Conclusions: Liquid biopsy-driven cetuximab rechallenge was confirmed to be effective. The clinical outcome was consistent with available results from phase II studies. In addition to the molecular selection through the analysis of ct-DNA for RAS, the long anti-EGFR free interval is confirmed as a prospective selection criterion for this therapeutic option.

Molecular-driven treatment for biliary tract cancer: the promising turning point.

INTRODUCTION: In the past, targeted therapies have not shown positive results as they have been used without adequate molecular selection of patients with biliary tract cancer (BTC). This has led to an expansion of research on characteristics and molecular selection to identify new effective strategies in this setting. Improved knowledge of the molecular biology of these neoplasms has highlighted their extraordinary heterogeneity and has made it possible to identify targetable gene alterations, including fibroblast growth factor receptor (FGFR) 2 gene fusions, and isocitrate dehydrogenase (IDH) mutations. The FDA recently approved ivosidenib and pemigatinib for the treatment of BTCs. AREAS COVERED: We review data in the literature regarding targeted therapies for the treatment of BTCs, as well as on the prospects deriving from the extraordinary molecular heterogeneity of these neoplasms. EXPERT OPINION: At present, it is essential to evaluate the expression of the genetic alterations expressed by these neoplasms to offer patients an increasingly personalized therapeutic approach. Studies are needed to better define the limits and potentials of targeted therapies and their role in the therapeutic algorithm to improve the poor prognosis of these patients.

Uncovering key targets of success for immunotherapy in pancreatic cancer.

INTRODUCTION: Despite available treatment options, pancreatic ductal adenocarcinoma (PDAC) is frequently lethal. Recent immunotherapy strategies have failed to yield any notable impact. Therefore, research is focussed on unearthing new drug targets and therapeutic strategies to tackle this malignancy and attain more positive outcomes for patients. AREAS COVERED: In this perspective article, we evaluate the main resistance mechanisms to immune checkpoint inhibitors (ICIs) and the approaches to circumvent them. We also offer an assessment of concluded and ongoing trials of PDAC immunotherapy. Literature research was performed on Pubmed accessible through keywords such as: 'pancreatic ductal adenocarcinoma,' 'immunotherapy,' 'immunotherapy resistance,' 'immune escape,' 'biomarkers.' Papers published between 2000 and 2021 were selected. EXPERT OPINION: The tumor microenvironment is a critical variable of treatment resistance because of its role as a physical barrier and inhibitory immune signaling. Promising therapeutic strategies appear to be a combination of immunotherapeutics with other targeted treatments. Going forward, predictive biomarkers are required to improve patient selection. Biomarker-driven trials could enhance approaches for assessing the role of immunotherapy in PDAC.