Case report: Complete pathologic response with first-line immunotherapy combination in a young adult with massive liver dissemination of mismatch repair–deficient metastatic colorectal cancer: Immunological and molecular profiling

The current level of evidence for immunotherapy in previously untreated microsatellite unstable metastatic colorectal cancer is based on recent pieces of evidence of few studies that demonstrated durable response and clinical benefit, in terms of objective response rate, disease control rate, and progression-free survival in this subgroup of patients. On the basis of combinatorial immunotherapy with nivolumab plus ipilimumab, we report the exceptional case of a complete pathological response in a 21-year-old woman presenting a clinically aggressive stage IV colorectal cancer with massive nodal and liver involvement. Extensive molecular analyses based on whole genome next-generation DNA sequencing, RNA sequencing, fluorescent multiplex immunohistochemistry, and flow cytometry provided a detailed description of tumoral and immunological characteristics of this noteworthy clinical case

Locoregional Therapies and Remodeling of Tumor Microenvironment in Pancreatic Cancer

Despite the advances made in treatment, the prognosis of pancreatic ductal adenocarcinoma (PDAC) remains dismal, even in the locoregional and locally advanced stages, with high relapse rates after surgery. PDAC exhibits a chemoresistant and immunosuppressive phenotype, and the tumor microenvironment (TME) surrounding cancer cells actively participates in creating a stromal barrier to chemotherapy and an immunosuppressive environment. Recently, there has been an increasing use of interventional radiology techniques for the treatment of PDAC, although they do not represent a standard of care and are not included in clinical guidelines. Local approaches such as radiation therapy, hyperthermia, microwave or radiofrequency ablation, irreversible electroporation and high-intensity focused ultrasound exert their action on the tumor tissue, altering the composition and structure of TME and potentially enhancing the action of chemotherapy. Moreover, their action can increase antigen release and presentation with T-cell activation and reduction tumor-induced immune suppression. This review summarizes the current evidence on locoregional therapies in PDAC and their effect on remodeling TME to make it more susceptible to the action of antitumor agents

ctDNA as promising tool for the assessment of minimal residual disease (MRD) and the need of an adjuvant treatment in gastroesophageal adenocarcinoma

Gastroesophageal adenocarcinoma is a challenging disease due to its poor prognosis and the presence of few therapeutic options. For these reasons, it is mandatory to identify the subgroup of patients who are at high risk for relapse after curative-intention surgery. In the last years, liquid biopsy has aroused great interest in cancer treatment for its feasibility and the possibility to capture tumor heterogeneity in a real-time way. In postoperative setting, the interest is directed to the identification of Minimal Residual Disease (MRD), defined as isolated or small cluster of cancer cells that residues after curative-intention surgery, and are undetectable by conventional radiological and clinical exams. This review wants to summarize current evidence on the use of liquid biopsy in gastroesophageal cancer, focusing on the detection of ctDNA in the postoperative setting and its potential role as a guide for treatment decision

Patients with early-onset metastatic colorectal cancer as an emerging distinctive clinical and molecular phenomenon

Background: Despite a reduction of both incidence and mortality from CRC in the elderly population, several studies published in the last decade have shown an increase in the incidence of early-onset CRC (EO-CRC), conventionally defined as cancer that occurs in adults between the ages of 18 and 49. Clinical and prognostic data on this setting are limited and conflicting. The aim of our study was to evaluate the clinical, prognostic, and molecular profiles of metastatic EO-CRC patients (age at diagnosis # 50) in order to identify potentially relevant differences compared to a control group late-onset CRC (LO-CRC). Methods: We retrospectively collected data from 1272 metastatic colorectal cancers from 5 different Italian Institutions: 693 (54.5%) EO-CRC and 579 (45.5%) LO-CRC as control group. All patients had one or more metastatic sites, molecular profiling available (including RAS, BRAF, and MSI status), and underwent at least one line of treatment for metastatic disease. The main objective of the study was to the evaluate clinical outcome for the global population of EO-CRC patients in different clinical and molecular subgroups according to RAS and BRAF status and in comparison to patients included in the control group. Results: In the EO-CRC group median age was 42.8 (20.0-50.9) and 66.7 (51.0-86.2) in the control group. M/F ratios were 1:1 and 2:1, respectively. In the overall population, mOS was 34,7 in EO-CRC pts vs 43,0 months (mo) (p , 0,0001) in the control group. In the RAS/BRAF mutated subgroup mOS in EO-CRC pts was 30,3 vs 34,0 mo in the control group (p = 0,0156). In RAS/BRAF wild-type subgroup mOS in EO-CRC pts was 43,0 vs 50,0mo(p = 0,0290). Finally, in the BRAF V600E mutated subgroup EO-CRC pts showed a 16mo mOS vs 26mo (p = 0,04). In the overall population, mPFS was 11,0 in EO-CRC pts vs 14,0 mo (p, 0,0001) in the control group. Furthermore, the overall response rate (ORR) was 63% in EO-CRC and 67% in LO-CRC. Conclusions: Findings from a large population of EO-CRC patients indicate a general worse prognosis for patients with early-onset colorectal cancer compared to late-onset patients. Interestingly this seems to occur regardless of the molecular status. These observations might have a considerable impact on clinical practice and research. Subsequent investigations will be needed to further understand the specific clinical and molecular characteristics of this growing group of patients to better define the more appropriate treatment strateg

Negative hyperselection of elderly patients with RAS and BRAF wild-type metastatic colorectal cancer receiving initial panitumumab plus FOLFOX or 5-FU/LV

Background: Upfront anti-EGFR therapy represents the standard of care for patients with left-sided, MSS/pMMR, RAS and BRAF wild-type mCRC. Molecular 'hyperselection' may optimize EGFR inhibition by detecting additional resistance alterations.Materials and methods: We used comprehensive genomic profiling on archival samples of elderly patients enrolled in the PANDA trial to detect: HER2 amplification/mutations; MET amplification; NTRK/ROS1/ALK/RET rearrangements; PIK3CA exon 20 mutations; PTEN alterations; AKT1 mutations; MAP2K1 mutations. We defined 'Gene Altered' (GA) patients whose tumour harboured at least one alteration, and 'Hyperselected' (HS) those without. Survival and tumour response outcomes were correlated to hyperselection status alone or combined with primary tumour sidedness or treatment arm.Results: Genomic alterations were detected in 41/147 patients (27.9%). PFS, OS and ORR were inferior in GA versus HS (median PFS: 7.6 versus 12.8 months, HR = 2.08, 95% CI: 1.43-3.03, p < 0.001; median OS: 20.0 versus 29.5 months, HR = 1.82, 95% CI:1.23-2.69, p = 0.002; ORR: 51% versus 71%; OR = 0.43, 95% CI: 0.21-0.91, p = 0.02). In the multivariable models, the impact of hyperselection on PFS and OS was confirmed. Lower ORR was observed with 5-FU/LV/panitumumab in GA (40% versus 62%), but not in HS (70% versus 72%). GA was associated with worse survival and response regardless of primary tumour sidedness, whereas in the HS subgroup, right-and left sided tumours had similar outcomes.Conclusions: Molecular hyperselection and comprehensive genomic profiling have a potential usefulness in elderly patients with RAS/BRAF wild-type, pMMR/MSS mCRC, eligible for upfront EGFR inhibition

Image_6_Case report: Complete pathologic response with first-line immunotherapy combination in a young adult with massive liver dissemination of mismatch repair–deficient metastatic colorectal cancer: Immunological and molecular profiling.jpeg

The current level of evidence for immunotherapy in previously untreated microsatellite unstable metastatic colorectal cancer is based on recent pieces of evidence of few studies that demonstrated durable response and clinical benefit, in terms of objective response rate, disease control rate, and progression-free survival in this subgroup of patients. On the basis of combinatorial immunotherapy with nivolumab plus ipilimumab, we report the exceptional case of a complete pathological response in a 21-year-old woman presenting a clinically aggressive stage IV colorectal cancer with massive nodal and liver involvement. Extensive molecular analyses based on whole genome next-generation DNA sequencing, RNA sequencing, fluorescent multiplex immunohistochemistry, and flow cytometry provided a detailed description of tumoral and immunological characteristics of this noteworthy clinical case.</p

Image_3_Case report: Complete pathologic response with first-line immunotherapy combination in a young adult with massive liver dissemination of mismatch repair–deficient metastatic colorectal cancer: Immunological and molecular profiling.jpeg

The current level of evidence for immunotherapy in previously untreated microsatellite unstable metastatic colorectal cancer is based on recent pieces of evidence of few studies that demonstrated durable response and clinical benefit, in terms of objective response rate, disease control rate, and progression-free survival in this subgroup of patients. On the basis of combinatorial immunotherapy with nivolumab plus ipilimumab, we report the exceptional case of a complete pathological response in a 21-year-old woman presenting a clinically aggressive stage IV colorectal cancer with massive nodal and liver involvement. Extensive molecular analyses based on whole genome next-generation DNA sequencing, RNA sequencing, fluorescent multiplex immunohistochemistry, and flow cytometry provided a detailed description of tumoral and immunological characteristics of this noteworthy clinical case.</p

Image_4_Case report: Complete pathologic response with first-line immunotherapy combination in a young adult with massive liver dissemination of mismatch repair–deficient metastatic colorectal cancer: Immunological and molecular profiling.jpeg

The current level of evidence for immunotherapy in previously untreated microsatellite unstable metastatic colorectal cancer is based on recent pieces of evidence of few studies that demonstrated durable response and clinical benefit, in terms of objective response rate, disease control rate, and progression-free survival in this subgroup of patients. On the basis of combinatorial immunotherapy with nivolumab plus ipilimumab, we report the exceptional case of a complete pathological response in a 21-year-old woman presenting a clinically aggressive stage IV colorectal cancer with massive nodal and liver involvement. Extensive molecular analyses based on whole genome next-generation DNA sequencing, RNA sequencing, fluorescent multiplex immunohistochemistry, and flow cytometry provided a detailed description of tumoral and immunological characteristics of this noteworthy clinical case.</p

Image_2_Case report: Complete pathologic response with first-line immunotherapy combination in a young adult with massive liver dissemination of mismatch repair–deficient metastatic colorectal cancer: Immunological and molecular profiling.jpeg

The current level of evidence for immunotherapy in previously untreated microsatellite unstable metastatic colorectal cancer is based on recent pieces of evidence of few studies that demonstrated durable response and clinical benefit, in terms of objective response rate, disease control rate, and progression-free survival in this subgroup of patients. On the basis of combinatorial immunotherapy with nivolumab plus ipilimumab, we report the exceptional case of a complete pathological response in a 21-year-old woman presenting a clinically aggressive stage IV colorectal cancer with massive nodal and liver involvement. Extensive molecular analyses based on whole genome next-generation DNA sequencing, RNA sequencing, fluorescent multiplex immunohistochemistry, and flow cytometry provided a detailed description of tumoral and immunological characteristics of this noteworthy clinical case.</p

Image_5_Case report: Complete pathologic response with first-line immunotherapy combination in a young adult with massive liver dissemination of mismatch repair–deficient metastatic colorectal cancer: Immunological and molecular profiling.jpeg

The current level of evidence for immunotherapy in previously untreated microsatellite unstable metastatic colorectal cancer is based on recent pieces of evidence of few studies that demonstrated durable response and clinical benefit, in terms of objective response rate, disease control rate, and progression-free survival in this subgroup of patients. On the basis of combinatorial immunotherapy with nivolumab plus ipilimumab, we report the exceptional case of a complete pathological response in a 21-year-old woman presenting a clinically aggressive stage IV colorectal cancer with massive nodal and liver involvement. Extensive molecular analyses based on whole genome next-generation DNA sequencing, RNA sequencing, fluorescent multiplex immunohistochemistry, and flow cytometry provided a detailed description of tumoral and immunological characteristics of this noteworthy clinical case.</p