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IDH1-mutated intrahepatic cholangiocarcinomas (IDH1m iCCAs) could be treated with anti-IDH1 drugs, although the high heterogeneity in this class of tumours could limit treatment efficacy.We selected 125 IDH1m iCCAs that were treated as resectable, locally advanced, or metastatic and were screened by the NGS-based FoundationOne gene panel. We conducted a mutation-based clustering of tumours and survival analysis.Three main clusters were identified. The most altered pathways in cluster 1 were cell cycle and apoptosis, RTK/RAS, PI3K, and chromatin modification. Of note, CDKN2A/2B were mutated in 41/44 patients of this cluster. In cluster 2, the most affected pathways were as follows: Chromatin modification, DNA damage control, PI3K, and RTK/RAS. In this cluster, the most frequently mutated genes were ARID1A and PBRM1. The most altered pathways in cluster 3 were as follows: Cell cycle and apoptosis, DNA damage control, TP53, and chromatin modification. Importantly, TP53 was mutated only in cluster 3 patients. In the cohort of patients treated with surgery, cluster 2 showed statistically significant better disease-free survival (DFS) and overall survival (OS) compared with patients in cluster 3 and cluster 1 (p = 0.0014 and p = 0.0003, respectively). In the advanced setting, cluster 2 experienced a statistically significant better PFS (p = 0.0012), a tendency toward a better OS from first-line treatment, and a better OS from first-line progression compared with patients in cluster 1 and cluster 3 (p = 0.0017). We proposed an easy-to-use algorithm able to stratify patients in the three clusters on the basis of the genomic profile.We highlighted three different mutation-based clusters with prognostic significance in a cohort of IDH1m iCCAs.

Biliary tract cancers are rare malignancies with a poor prognosis and scarce therapeutic strategies. The significance of BRCAness in this setting is already unknown.Tissue specimens of BTC patients treated with platinum-based chemotherapy have been analyzed through the FOUNDATIONPne assay.72/150 (48%) BRCAness mutated and 78/150 (52.0%) wild type (WT) patients were included. The most commonly mutated genes in the BRCAness mutated group were: ARID1A (N = 32, 44%), CDKN2A (N = 23, 32%), KRAS/NRAS (N = 16, 22%), CDKN2B (N = 13, 18%), BRCA2 (N = 13, 18%), PBRM1 (N = 12, 17%), ATM (N = 11, 15%), FGFR2 (N = 10, 14%), TP53 (N = 8, 11%), IRS2 (N = 7, 10%), CREBBP (N = 7, 10%) (table 3, figure 1). At the univariate analysis BRCAness mutation was associated with longer median Progression Free Survival (mPFS) (HR 0.68; 95% CI 0.49-0.95; p = 0.0254); it was not associated with longer mOS but a trend toward a benefit in survival was found (HR 0.77; 95% CI 0.50-1.19; p = 0.2388). Patients with BRCAness mutation showed a higher percentage of disease control rate (77.8 vs 67.9; p = 0.04) compared to patients WT. Multivariate analysis confirmed BRCAness mutation (HR 0.66; 95% CI: 0.45-0.98; p = 0.0422) as independent favorable prognostic factors for PFS and a positive trend was found for OS (HR 0.84; 95% CI: 0.53-1.33; p = 0.3652).BRCAness BTC patients showed a better PFS compared BRCAnessWT patients after exposure to platinum-based chemotherapy. Moreover, the OS curves' trend showed in our analysis suggests that BRCAness mutated patients could benefit from a maintenance therapy with PARPi.

Background: Gemcitabine plus nab-paclitaxel (Gem-Nab) represents a standard first-line treatment for metastatic pancreatic cancer (mPC), but few data are available for elderly patients. We aimed to add evidence about safety and efficacy of Gem-Nab in this population. Methods: We collected data of 156 patients with mPC aged ≥65 years receiving Gem-Nab. Patients were stratified according to age: 0.05). The starting dose of Gem-Nab did not affect PFS and OS (p > 0.05). Conclusion: Gem-Nab is active and effective in older patients with mPC, with the results in line with the general mPC population enrolled in clinical trials. Mild dose modifications for elderly patients might be considered to improve safety without impairing efficacy.

Background Neoadjuvant chemoradiotherapy (CRT) in locally advanced rectal cancer (LARC) does not achieve effective control of distant metastases. Induction chemotherapy is a promising strategy, and bevacizumab (BV) could improve the results of CRT. 5-Fluorouracil, oxaliplatin and irinotecan (FOLFOXIRI) plus BV is a treatment option in metastatic colorectal cancer. We evaluate feasibility and efficacy of neoadjuvant treatment comprising induction FOLFOXIRI plus BV followed by CRT with fluoropyrimidines plus BV. Methods In this phase II single-arm trial, patients node-positive or clinical T4 or high-risk T3 LARC underwent 6 cycles of induction FOLFOXIRI plus BV, followed by CRT (50.4 Gy plus concomitant capecitabine) and BV (5 mg/kg on days 1, 15 and 28). Surgery was planned 8 weeks after completion of CRT. Primary end-point was 2-year disease-free survival (DFS). Results We enrolled 49 patients: All but one (withdrewing consent after enrolment) were included in the per-protocol analyses. The study met its primary end-point: 36 patients were free of recurrence at 2 years (2-y DFS: 80.45%, 95% confidence interval [CI]: 78.79–82.10). Forty-four patients underwent surgery; pathologic complete response rate was 36.4%. Forty-six patients completed induction: neutropenia (41.6%) and diarrhoea (12.5%) were main G3/4 toxicities. Forty-five patients received CRT, but the protocol was amended and the capecitabine schedule during CRT was slightly modified after 13 patients due to the incidence of G3 hand-foot syndrome and proctitis (23.1%). After amendment, no severe events during CRT were reported. Conclusions FOLFOXIRI plus BV followed by CRT plus BV is feasible and active. Results in terms of DFS suggest that this strategy may improve distant disease control in LARC.