Multiple Acquired Mutations Captured by Liquid Biopsy in the EGFR Addicted Metastatic Colorectal Cancer.

Clinical Practice Points • Metastatic colorectal cancer is one of the most common causes of cancer death worldwide. • Primary and acquired resistance mechanisms to anti-EGFR treatment are a challenging topic with several clinical implications. • Primary resistance is defined by the presence of activating mutations in BRAF and RAS genes before treatment initiation, while acquired resistance refers to the selection of pre-existing mutant clones or de novo acquisition of mutations under the pressure of anti EGFR treatment. • Testing mutations in RAS and BRAF genes as predictive biomarkers is mandatory. • Liquid biopsy has acquired growing importance and showed to be reliable when compared to tissue NGS. • Liquid biopsy offers a full overview of the genetic landscape of the disease, overcoming spatial and temporal heterogeneity, when compared to tissue biopsy. • Liquid biopsy can be used to capture the changes in biology of cancer cells under the selective pressure of targeted agents over time. • Using complementary techniques allows to increase the diagnostic power and the biological significance of the results

Small Bowel Metastasis in a Stage IV Melanoma Patient: A Report of Multimodal Approach

Among all skin cancers melanoma is the most aggressive and the first responsible of death because of its metastatic power. Small bowel melanoma metastases are a rare condition, probably underestimated if we consider the high incidence in autoptic findings. Usually, it comes as a single or multiple protruding lesions with polypoid aspects that is able to cause intussusception, blood loss anemia, and palpable mass and abdominal pain. We present a case of a 58-year-old male, diagnosed in July 2018 for melanoma that in 2021 showed sudden anemia. Video Capsule Endoscopy demonstrated an ulcerated lesion in the proximal ileum. Several approaches are available for the treatment of this lesion, but specific indications for surgery have not yet been defined. We adopted a watchful waiting approach to not let the patient undergo an excessive surgical stress, considering the risk of tumor progression. Surgery was performed after multidisciplinary revision of the case

Real-world clinical outcome and safety of adjuvant therapy in stage III melanoma patients: Data from two Academic Italian Institutions

: Adjuvant immunotherapy (IO) and targeted therapy (TT) have improved relapse-free survival (RFS) in patients with stage III melanoma, although about 25% of them relapse within a year. However, real-world data on treatment efficacy and safety as well as management of treatment recurrences are still limited. We retrospectively analyzed 113 patients with stage III melanoma who received at least one cycle of anti-PD-1 (nivolumab or pembrolizumab) or dabrafenib + trametinib as adjuvant therapy. Most of patients included into the analyses harbor BRAV600E mutation (66.4%) and had a stage IIIC melanoma (63.7%). Immunotherapy was administered in 48.7% of patients, whereas targeted therapy in 51.3% At data cut-off, median RFS was not reached with 12- and 24-months RFS of 81% and 64%, respectively. No new adverse events were registered. Thirty patients (26.5%) relapsed, mainly at distant sites. Patient treated with IO recurred mostly during adjuvant treatment (ON-treatment) while patients treated with TT relapsed at the end of treatment (OFF-treatment). At relapse, surgery, radiotherapy and systemic therapy were used alone or in combination. Among patients who started a first-line therapy, an excellent response switching to a different treatment was observed. Real-world outcomes and safety of adjuvant treatment for resected stage III melanoma appear comparable to clinical trials data. Moreover, management of recurrences depends on type of relapse (loco-regional vs distant) and timing (during vs OFF treatment). Furthermore, patients who relapse after adjuvant TT respond well to subsequent anti-PD1 based therapy

Mixed Neuroendocrine Non-Neuroendocrine Neoplasms of the Gastrointestinal Tract: A Case Series

Mixed neuroendocrine non-neuroendocrine neoplasms (MiNENs) refer to heterogenous rare neoplasms constituted of at least a neuroendocrine population-either well-differentiated, or more frequently poorly differentiated-and a non-neuroendocrine population, both accounting for at least 30% of the whole tumor mass. Several studies recently focused on the key genetic and epigenetic changes underlying MiNENs to better understand how they develop, and explore biological similarities among the two components and their pure counterparts. However, their molecular landscape still remains poorly understood. NGS may represent a useful tool to study this orphan disease by detecting the main genetic alterations and possible therapeutic targets. NGS analysis on tissue and/or blood samples through the Foundation One (F1) platform was performed on consecutive samples collected from four patients diagnosed with MiNENs of the gastroenteric tract. Several genetic alterations were shared among samples from the same patients, thus suggesting a common origin between them, although morphology sometimes changed at histopathological evaluation. Common molecular alterations among samples from different patients that had not been previously described to our knowledge were also detected. Finally, it is of the utmost importance to clarify if the maintenance of the 30% cut-off is still essential in defining MiNENs and really manages to include all of the mixed neoplasms

Clinical Utility of Liquid Biopsy to Detect BRAF and NRAS Mutations in Stage III/IV Melanoma Patients by Using Real-Time PCR

Liquid biopsy is a potentially useful tool for melanoma patients, also for detecting BRAS/NRAS mutations, even if the tissue analysis remains the current standard

Real-World Activity and Safety of Trifluridine-Tipiracil Plus Bevacizumab Therapy in Patients with Refractory Metastatic Colorectal Cancer

Background The combination of trifluridine-tipiracil and bevacizumab was compared with trifluridine-tipiracil monotherapy in a randomized, open-label, phase II trial, resulting in a statistically significant and clinically relevant improvement in progression-free survival (PFS), with tolerable toxicity in patients with refractory metastatic colorectal cancer (mCRC); however, evidence supporting the role of this combination in a real-world setting is limited. Objective The aim of our work was to provide further evidence on the activity and safety of this combination in a real-world series of Western mCRC patients refractory or intolerant to previous therapies. Patient and Methods We conducted a retrospective, observational study of patients with mCRC refractory or intolerant to standard therapies. Patients were treated with trifluridine-tipiracil and bevacizumab. Previous therapy with fluoropyrimidines, irinotecan, oxaliplatin, bevacizumab, aflibercept, regorafenib, and cetuximab or panitumumab (only RAS wild-type) was allowed, as was previous participation in clinical trials. Clinicopathological characteristics, overall response rate (ORR), disease control rate (DCR), overall survival (OS), PFS, and safety data were retrospectively collected and analyzed. Results We recorded 31 patients treated between 1 December 2017 and 30 June 2022. Median age was 69 years (range 38-82 years), 39% were male, 100% had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-1, tumor location was left-sided in 77% of cases, 54% had synchronous presentation, 35% were RAS mutant, 3% were BRAF mutant, and 71% underwent primary tumor resection; 64% of patients had liver metastases, 55% had lung metastases, and 23% had peritoneal carcinomatosis. The median number of previous treatment lines was 2 (range 0-5), and 84% of patients received at least one previous anti-angiogenic agent. The ORR and DCR were 3% and 71%, respectively. With a median follow-up of 8 months (range 2-39), median PFS was 6 months (95% confidence interval [CI] 3.1-8.9 months) and median OS was 14 months (95% CI 10.1-17.8 months). Adverse events of any grade were reported in 58% of patients. The most common grade 3-4 toxicities were neutropenia (19%) and anemia (6%); 35% of patients required either dose delays or dose reductions due to toxicity. Granulocyte colony-stimulating factor (G-CSF) prophylaxis was administered either on first or subsequent cycles of treatment in 35% of patients. No treatment-related deaths occurred. Sixty percent of the patients who discontinued treatment eventually received one or more lines of subsequent therapy. Conclusions Our series provides further evidence on the activity and safety of the combination of trifluridine-tipiracil and bevacizumab in a real-world series of Western refractory mCRC patients