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.

CDX-2 expression correlates with clinical outcomes in MSI-H metastatic colorectal cancer patients receiving immune checkpoint inhibitors.

Immune checkpoint inhibitors (ICIs) showed efficacy in metastatic colorectal cancer (mCRC) with mismatch-repair deficiency or high microsatellite instability (dMMR-MSI-H). Unfortunately, a patient's subgroup did not benefit from immunotherapy. Caudal-related homeobox transcription factor 2 (CDX-2) would seem to influence immunotherapy's sensitivity, promoting the chemokine (C-X-C motif) ligand 14 (CXCL14) expression. Therefore, we investigated CDX-2 role as a prognostic-predictive marker in patients with mCRC MSI-H. We retrospectively collected data from 14 MSI-H mCRC patients treated with ICIs between 2019 and 2021. The primary endpoint was the 12-month progression-free-survival (PFS) rate. The secondary endpoints were overall survival (OS), PFS, objective response rate (ORR), and disease control rate (DCR). The PFS rate at 12 months was 81% in CDX-2 positive patients vs 0% in CDX-2 negative patients (p = 0.0011). The median PFS was not reached (NR) in the CDX-2 positive group versus 2.07 months (95%CI 2.07-10.8) in CDX-2 negative patients (p = 0.0011). Median OS was NR in CDX-2-positive patients versus 2.17 months (95% Confidence Interval [CI] 2.17-18.7) in CDX2-negative patients (p = 0.026). All CDX-2-positive patients achieved a disease response, one of them a complete response. Among CDX-2-negative patients, one achieved stable disease, while the other progressed rapidly (ORR: 100% vs 0%, p = 0.0005; DCR: 100% vs 50%, p = 0.02). Twelve patients received 1st-line pembrolizumab (11 CDX-2 positive and 1 CDX-2 negative) not reaching median PFS, while two patients (1 CDX-2 positive and 1 CDX-2 negative) received 3rd-line pembrolizumab reaching a median PFS of 10.8 months (95% CI, 10.8-12.1; p = 0.036). Although our study reports results on a small population, the prognostic role of CDX-2 in CRC seems confirmed and could drive a promising predictive role in defining the population more sensitive to immunotherapy treatment. Modulating the CDX-2/CXCL14 axis in CDX-2-negative patients could help overcome primary resistance to immunotherapy.

Nodal Merkel Cell Carcinoma with Unknown Primary Site and No Distant Metastasis: A Single-Center Series.

Merkel cell carcinoma (MCC) is a very rare and aggressive neuroendocrine carcinoma originating from Merkel cells, typically with a skin nodule; however, it exceptionally presents with only a basin lymph node localization, with neither a cutaneous primary site nor distant metastases. From 1996 to 2020, among patients with histologically confirmed MCC managed at a neuroendocrine neoplasm-referral center, we selected those with an exclusive nodal basin, no distant metastasis, and an unknown primary site defined by cross-sectional and physical examination. A total of 55 out of 310 patients fulfilled the selection criteria. The median age was 64 years and the majority were males. Inguinal lymph-nodes were the most common anatomic site. With a median follow-up of 4.3 years, the 5-year relapse-free survival (RFS) rate was 56.6 (95% CI 42.0-68.8%) and the 5-year cancer specific survival (CSS) rate was 68.5 (95% CI 52.8-79.9%) for the whole population. The 36 patients (65.5%) undergoing lymphadenectomy (LND) + radiotherapy (RT) ± chemotherapy had a 5-year RFS rate of 87.2% (95% CI 65.5-95.7%) and a 5-year CSS rate of 90.5% (95% CI 67.0-97.5), which were better than those receiving LND alone. In a multivariable analysis, the survival benefit for LND + RT remained significant. Results from one of the largest single-center series of nMCC-UP suggest that a curative approach including RT can be effective, similar to what is observed for stage IIIB MCC. Multicentric studies with homogenous populations should be carried out in this controversial clinical entity, to minimize the risk of biases and provide robust data.

Should platinum-based chemotherapy be preferred for germline BReast CAncer genes (BRCA) 1 and 2-mutated pancreatic ductal adenocarcinoma (PDAC) patients? A systematic review and meta-analysis.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers worldwide. Recent studies have shown that 4-20% of patients with PDAC have a germline BReast CAncer (gBRCA) genes 1 and 2 mutation (m). Because homologous recombination is impaired in patients with gBRCAm, some reports suggested that these tumors may be more sensitive to platinum compounds. Therefore, this systematic review and meta-analysis focused on benefit of patients with gBRCAm receiving a platinum-based chemotherapy (PtCh) compared with those treated with a non-platinum-based chemotherapy (NPtCh). MATERIAL AND METHODS: The following electronic databases were searched from inception to May 12, 2018: PubMed (MEDLINE), EMBASE, and Cochrane Library. Abstracts from conferences were also reviewed for inclusion. Cohort, case-control and randomized studies of patients with PDAC and gBRCAm were eligible for inclusion if they provided data to compare patients receiving PtCh vs NPtCh. The primary endpoint was overall survival (OS) in the PtCh group vs the NPtCh group in patients with clinical stage III (locally advanced) or IV (metastatic) (CS III-IV) PDAC. RESULTS: Of 112 studies identified, 6 were included (total of 108 patients); of these, 4 provided sufficient data for meta-analysis. Half of the patients were males, with a mean age ranging from 58 to 63 years. The OS in the 85 patients with CS III-IV PDAC was higher in the PtCh group (23.7 vs 12.2 months; mean difference of 10.21 months, 95% confidence interval [CI] 5.05-15.37; P < 0.001; very low quality of evidence). PtCh was associated with a lower mortality (62.3 vs 87.5%; relative risk of 0.80, 95%CI 0.66-0.97; P = 0.021; very low quality of evidence). CONCLUSION: Our study confirmed the hypothesis that patients with CS III-IV gBRCAm preferably benefit from a PtCh compared with NPtCh. However the very low quality of evidence should induce to be careful about the risk of potential biases. The generated hypothesis should be prospectively investigated in homogenous clinical settings.

Outcome of EGFR-mutated adenocarcinoma NSCLC patients with changed phenotype to squamous cell carcinoma after tyrosine kinase inhibitors: A pooled analysis with an additional case.

The onset of a new histology is a resistant mechanism to tyrosine kinase inhibitors (TKI) in lung adenocarcinoma (ADK), but this phenomenon has not yet been fully clarified. We present a pooled analysis of the outcomes of EGFR-mutated ADK patients with changed phenotype to squamous cell carcinoma (SqCC) following TKI, along with the description of an additional case. A 67-year-old woman with EGFR-mutated NSCLC received gefitinib and subsequently osimertinib, due to the presence of T790 M at progression. The re-biopsy after third-generation TKI revealed SqCC histology along with the basal EGFR mutation, while T790 M disappeared. The patient rapidly progressed and died despite two chemotherapy cycles. Since this first description of SqCC transformation appearing after treatment with the third-generation TKI osimertinib, other 16 patients, with EGFR-mutated ADK developing a transformation to SqCC histology after treatment with TKIs, were up to now published. From our pooled analysis emerged that most patients were female (82%), 41% were former smokers and no current smokers were identified. Median time to SqCC onset was 11.5 months. In all cases, basal EGFR mutation was maintained, and 11 patients (65%) developed an acquired mutation on exon 20. Interestingly also 790 M mutation appeared in 8 patients (47%). The median survival after SqCC diagnosis was 3.5 months regardless the treatments received. Therefore, EGFR-mutated lung ADK destined to develop a squamous phenotype were often smokers and maintained the baseline genomic alterations. The prognosis after SqCC diagnosis was extremely poor and current treatments largely inefficacious.

Systemic therapies in patients with advanced well-differentiated pancreatic neuroendocrine tumors (PanNETs): When cytoreduction is the aim. A critical review with meta-analysis.

INTRODUCTION: Cytoreduction is sometimes an important aim of systemic anti-tumor therapies in well-differentiated pancreatic neuroendocrine tumors (PanNETs). As there is not a gold standard treatment for these tumors in this field, we conducted a literature review in order to identify objective criteria for treatment choice. MATERIALS AND METHODS: We critically reviewed and performed a meta-analysis of all published clinical studies of systemic therapies in patients with well-differentiated unresectable PanNETs, selecting only those articles which reported tumor shrinkage (TS) with a waterfall plot (WP). Tumor downsizing of ≥10% was considered as objective response. RESULTS: We selected 17 out of 2758 studies, comprising 1118 patients with tumor response reported as WP. Proliferation index, tumor burden and anti-tumor therapies were heterogeneous. Chemotherapy alone (mainly, capecitabine/temozolomide) or in combination showed the best results, with ≥10% TS ranging from 65% to 93%. Peptide receptor radionuclide therapy combined with chemotherapy (Chemo-PRRT) and sunitinib appeared promising by inducing objective response in a significant proportion of patients (93% and 60%, respectively). Time to tumor response was reported in only two trials. No clear clinical and/or biological predictive factors emerged. CONCLUSION: Based on response criteria used in our retrospective analysis, systemic chemotherapy alone or in combination appeared to have the main cytoreductive impact. However no conclusions regarding either a specific regimen or combination can be drawn. Furthermore, tumor population selection and/or choice of regimen may have a significant influence. Further analysis should be also conducted to identify potential predictive biomarkers of responses, in order to design future prospective interventional clinical trials enrolling more homogenous populations of advanced well-differentiated PanNETs.