Purpose: The multi-kinase inhibitor (mKi) regorafenib has demonstrated efficacy in chemorefractory patients with metastatic colorectal cancer (mCRC). However, lack of predictive biomarkers and concerns over significant toxicities hamper the use of regorafenib in clinical practice. Experimental Design: Serial liquid biopsies were obtained at baseline and monthly until disease progression in chemorefractory patients with mCRC treated with regorafenib in a phase II clinical trial (PROSPECT-R n = 40; NCT03010722) and in a multicentric validation cohort (n = 241). Tissue biopsies collected at baseline, after 2 months and at progression in the PROSPECT-R trial were used to establish patient-derived organoids (PDO) and for molecular analyses. MicroRNA profiling was performed on baseline bloods using the NanoString nCounter platform and results were validated by digital-droplet PCR and/or ISH in paired liquid and tissue biopsies. PDOs co-cultures and PDO-xenotransplants were generated for functional analyses. Results: Large-scale microRNA expression analysis in longitudinal matched liquid and tissue biopsies from the PROSPECT-R trial identified MIR652–3p as a biomarker of clinical benefit to regorafenib. These findings were confirmed in an independent validation cohort and in a “control” group of 100 patients treated with lonsurf. Using ex vivo co-culture assays paired with single-cell RNA-sequencing of PDO established pre- and post-treatment, we modeled regorafenib response observed in vivo and in patients, and showed that MIR652–3p controls resistance to regorafenib by impairing regorafenib-induced lethal autophagy and by orchestrating the switch from neo-angiogenesis to vessel co-option. Conclusions: Our results identify MIR652–3p as a potential biomarker and as a driver of cell and non–cell-autonomous mechanisms of resistance to regorafenib.

Background: First-line decision making is the key to the successful care of mCRC patients and RAS/BRAF status is crucial to select the best targeted agent. In hub centers, a relevant proportion of patients referred from small volume centers may not have standard tissue-based (STB) molecular results available at the time of the first visit (T0). Liquid biopsy (LB) may help circumvent these hurdles. Methods: A monoinstitutional prospective head-to-head comparison of LB versus (vs.) STB testing was performed in a real-world setting. Selection criteria included: mCRC diagnosis with unknown RAS/BRAF status at T0, tumoral tissue archived in external centers, no previous treatment with anti-EGFR. At T0, patients underwent plasma sampling for LB testing and procedure for tissue recovery. RAS/BRAF genotyping was carried out by droplet digital PCR on circulating-tumoral (ct) DNA. The primary endpoint was the comparison of time to LB (T1) vs. STB (T2) results using the Mann–Whitney U test. Secondary endpoints were the concordance between LB and STB defined as overall percent agreement and the accuracy of LB in terms of specificity, sensitivity, positive and negative predictive value. We also performed an exploratory analysis on urinary (u) ctDNA. Results: A total of 33 mCRC patients were included. Mean T1 and T2 was 7 and 22 days (d), respectively (p < 0.00001). T2 included a mean time for archival tissue recovery of 17 d. The overall percent agreement between LB and STB analysis was 83%. Compared to STB testing, LB specificity and sensitivity were 90% and 80%, respectively, with a positive predictive value of 94% and negative one of 69%. In detail, at STB and LB testing, RAS mutation was found in 45% and 42% of patients, respectively; BRAF mutation in 15%. LB results included one false positive and four false negative. False negative cases showed a significantly lower tumor burden at basal CT scan. Concordance between STB and uctDNA testing was 89%. Conclusions: Faster turnaround time, high concordance and accuracy are three key points supporting the adoption of LB in routinary mCRC care, in particular when decision on first-line therapy is urgent and tissue recovery from external centers may require a long time. Results should be interpreted with caution in LB wild-type cases with low tumor burden.

Benefits of early palliative care referral in oncology are well-validated. At the Veneto Institute of Oncology-IRCCS, a simultaneous-care outpatient clinic (SCOC) has been active since 2014, where patients with advanced cancer are evaluated by an oncologist together with a palliative care team. We prospectively assessed SCOC patients’ characteristics and SCOC outcomes through internal procedure indicators. Data were retrieved from the SCOC prospectively maintained database. There were 753 eligible patients. The median age was 68 years; primary tumor sites were gastrointestinal (75.2%), genitourinary (15.0%) and other sites (9.8%). Predominant symptoms were psychological issues (69.4%), appetite loss (67.5%) and pain (65.9%). Dyspnea was reported in 53 patients (7%) in the referral form, while it was detected in 226 patients (34.2%) during SCOC visits (p < 0.0001). Median survival of patients after the SCOC visit was 7.3 months. Survival estimates by the referring oncologist were significantly different from the actual survival. Psychological intervention was deemed necessary and undertaken in 34.6% of patients, and nutritional support was undertaken in 37.9% of patients. Activation of palliative care services was prompted for 77.7% of patients. Out of 357 patients whose place of death is known, 69.2% died at home, in hospice or residential care. With regard to indicators’ assessment, the threshold was reached for 9 out of 11 parameters (81.8%) requested by the procedure. This study confirmed the importance of close collaboration between oncologists and palliative care teams in responding properly to cancer patients’ needs. The introduction of a procedure with indicators allowed punctual assessment of a team’s performance.

PARP inhibitors are largely recognized as active drugs in BRCA-mutated breast and ovarian malignancies. In pancreatic ductal adenocarcinoma, the PARP inhibitor olaparib has recently been approved as maintenance treatment in patients with germline BRCA mutations reaching disease control after a platinum-based first line chemotherapy, proving significant benefit on progression free survival. On the other hand, little evidence is available regarding olaparib as single agent after progression with standard treatment in BRCA-mutated pancreatic ductal adenocarcinoma. A 61-year-old female patient harboring germline BRCA2 mutation was treated at our institution for a pancreatic ductal adenocarcinoma with lung and liver metastases. The patient received three previous lines of treatment with standard therapies, as follows: after the third line treatment failure, we started a further line of treatment with olaparib in off-label prescription. After the first two cycles, a CT scan documented partial response, with complete regression of lung metastases. The response was maintained after four cycles, with further response and clinical benefit. The radiologic and clinical response was maintained for 6 months. This case highlights the potential of olaparib as single agent after progression with standard treatment in BRCA-mutated pancreatic cancer.

We read the manuscript by Dr Schuurhuizen et al., questioning the validity of the global quality of life (QoL) measurements in metastatic colorectal cancer (mCRC) [1].

There is limited evidence comparing second-line therapies following gemcitabine plus nab-paclitaxel (GemNab) in metastatic pancreatic ductal adenocarcinoma (PDAC). This study aimed to compare the effectiveness and safety of 5-fluorouracil plus nanoliposomal irinotecan (5-FU + Nal-IRI) versus oxaliplatin-based regimens (FOLFOX/XELOX) in this setting. We retrospectively analyzed 445 patients with metastatic PDAC progressing after first-line GemNab, treated across 12 centers in Italy and Asia (2014-2024). Patients received either 5-FU + Nal-IRI (n = 180) or FOLFOX/XELOX (n = 265) as second-line therapy. The primary endpoint was overall survival (OS); secondary endpoints included progression-free survival (PFS), overall response rate (ORR), and safety. Exact propensity score matching was carried out to reduce baseline imbalances. In the matched cohort, median OS was 7.2 months [95% confidence interval (CI) 5.8-8.4 months] for 5-FU + Nal-IRI and 5.8 months (95% CI 4.1-6.8 months) for FOLFOX/XELOX [hazard ratio (HR) 0.74, 95% CI 0.58-0.95, P = 0.015], and median PFS was 3.0 months (95% CI 2.5-3.6 months) versus 2.5 months (95% CI 2.2-2.9 months), respectively (HR 0.75, 95% CI 0.61-0.91, P = 0.0048). ORR was similar (9% versus 10%, P = 0.79). Grade 3-4 adverse events were more frequent with 5-FU + Nal-IRI (31.1% versus 9.4%), particularly anemia (13.9% versus 1.7%) and diarrhea (5.6% versus 1.2%). FOLFOX/XELOX was associated with higher rates of any-grade thrombocytopenia and peripheral neuropathy. 5-FU + Nal-IRI showed a modest yet statistically significant survival advantage compared with FOLFOX/XELOX in patients with metastatic PDAC previously treated with GemNab, despite being associated with a higher incidence of adverse events. None the less, the selection of second-line therapy should be guided by a balanced evaluation of both efficacy and toxicity profiles.