Search

Background: There is mounting evidence that microscopically positive (R1) margins in patients with colorectal cancer (CRC) may represent a surrogate for aggressive cancer biology rather than technical failure during surgery. However, whether detectable biological differences exist between CRC with R0 and R1 margins is unknown. We sought to investigate whether mismatch repair (MMR) status differs between Stage III CRC with R0 or R1 margins. Methods: Patients treated for Stage III CRC from January 1, 2016 to December 31, 2019 were identified by using the Danish Colorectal Cancer Group database. Patients were stratified according to MMR status (proficient [pMMR] vs. deficient [dMMR]) and margin status. Outcomes of interest included the R1 rate according to MMR and overall survival. Results: A total of 3636 patients were included, of whom 473 (13.0%) had dMMR colorectal cancers. Patients with dMMR cancers were more likely to be elderly, female, and have right-sided cancers. R1 margins were significantly more common in patients with dMMR cancers (20.5% vs. 15.2%, p < 0.001), with the greatest difference seen in the rate of R1 margins related to the primary tumour (8.9% vs. 4.7%) rather than to lymph node metastases (11.6% vs. 10.5%). This association was seen in both right- and left-sided cancers. On multivariable analyses, R1 margins, but not MMR status, were associated with poorer survival, alongside age, pN stage, perineural invasion, and extramural venous invasion. Conclusions: In patients with Stage III CRC, dMMR status is associated with increased risks of R1 margins following potentially curative surgery, supporting the use of neoadjuvant immunotherapy in this patient group. [ABSTRACT FROM AUTHOR]

Part 1 of the RUBY trial (NCT03981796) evaluated dostarlimab plus carboplatin–paclitaxel compared with placebo plus carboplatin–paclitaxel in patients with primary advanced or recurrent endometrial cancer (EC). At the first interim analysis, the trial met one of its dual primary endpoints with statistically significant progression-free survival benefits in the mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) and overall populations. Overall survival (OS) results are reported from the second interim analysis. RUBY is a phase III, global, double-blind, randomized, placebo-controlled trial. Part 1 of RUBY enrolled eligible patients with primary advanced stage III or IV or first recurrent EC who were randomly assigned (1 : 1) to receive either dostarlimab (500 mg) or placebo, plus carboplatin–paclitaxel every 3 weeks for 6 cycles followed by dostarlimab (1000 mg) or placebo every 6 weeks for up to 3 years. OS was a dual primary endpoint. A total of 494 patients were randomized (245 in the dostarlimab arm; 249 in the placebo arm). In the overall population, with 51% maturity, RUBY met the dual primary endpoint for OS at this second interim analysis, with a statistically significant reduction in the risk of death [hazard ratio (HR) = 0.69, 95% confidence interval (CI) 0.54 - 0.89, P = 0.0020] in patients treated with dostarlimab plus carboplatin–paclitaxel versus carboplatin–paclitaxel alone. The risk of death was lower in the dMMR/MSI-H population (HR = 0.32, 95% CI 0.17 - 0.63, nominal P = 0.0002) and a trend in favor of dostarlimab was seen in the mismatch repair-proficient/microsatellite stable population (HR = 0.79, 95% CI 0.60 - 1.04, nominal P = 0.0493). The safety profile for dostarlimab plus carboplatin–paclitaxel was consistent with the first interim analysis. Dostarlimab in combination with carboplatin–paclitaxel demonstrated a statistically significant and clinically meaningful OS benefit in the overall population of patients with primary advanced or recurrent EC while demonstrating an acceptable safety profile. • RUBY compared dostarlimab + chemotherapy to chemotherapy alone in patients with primary advanced/recurrent EC. • RUBY showed statistically significant and clinically relevant improvements in OS with dostarlimab + chemotherapy. • These are clinically important results for patients with primary advanced/recurrent EC. • This represents a new standard of care for primary advanced/recurrent EC. [ABSTRACT FROM AUTHOR]

Introduction:KRAS, BRAF, and DNA mismatch repair (MMR) mutations aid clinical decision-making for colorectal cancer (CRC) patients. To ensure accurate predictions, the prognostic utilities of these biomarkers and their combinations must be individualized for patients with various TNM stages. Methods: Here, we retrospectively analyzed the clinicopathological features of 904 Korean CRC patients who underwent CRC surgery in three teaching hospitals from 2011 to 2013; we also assessed the prognostic utilities of KRAS, BRAF, and MMR mutations in these patients. Results: The overall frequencies of KRAS and BRAF mutations were 35.8% and 3.2%, respectively. Sixty-nine patients (7.6%) lacking expression of ≥1 MMR protein were considered MMR protein deficient (MMR-D); the remaining patients were considered MMR protein intact. KRAS mutations constituted an independent risk factor for shorter overall survival (OS) in TNM stage I–IV and stage III patients. BRAF mutations were associated with shorter OS in TNM stage I–IV patients. MMR-D status was strongly positive prognostic in TNM stage I–II patients. Discussion/Conclusion: To our knowledge, this is the first multicenter study to explore the prognostic utilities of KRAS, BRAF, and MMR statuses in Korean CRC patients. Various combinations of KRAS, BRAF, and DNA MMR mutations serve as genetic signatures that affect tumor behavior; they are prognostic in CRC patients. [ABSTRACT FROM AUTHOR]

Background: Stage II colon cancer (CC) exhibits considerable prognostic heterogeneous. Our objective was to assess survival but also the prognosis impact of microsatellite instability (MSI) in patients with stage IIC (T4bN0M0) CC., Patients and Methods: We conducted a retrospective observational study including all patients who had primary stage IIC CC resection between 2010 and 2020 in 2 expert centers. The primary endpoint was overall survival (OS) and disease-free survival (DFS) and time-to-relapse (TTR) were secondary endpoints., Results: Sixty-six patients, median age of 74 years [30-95], were included, with 37.9% presenting MSI (n = 25). Organ invasion involved the last ileal loop (n = 17), another colonic segment (n = 15), omentum (n = 13), visceral peritoneum (n = 13), and the bladder (n = 4). Surgical quality criteria showed complete monobloc resection in all patients and 93.9% R0 resection. After a median follow-up of 5 years [3.5-6.6], the entire population showed a 5-year OS of 65.2% [53.0-80.3] and 5-year DFS of 53.5% [41.1-69.6], with 18.9% [6.8-29.4] experiencing relapses at 5 years. The MSI phenotype correlated with improved 5-year OS (75.5% [56.5-100] vs. 59.5% [44.9-79.0], HR 0.41 [0.17-0.99]; P = .04), but DFS and TTR did not differ. Adjuvant chemotherapy was administered to 34.9% of patients. Univariate analysis identified age > 65 years, MSI status, and the number of nodes as factors associated with OS., Conclusion: These data underline, in relation to a low rate of relapse, the lack of consensus regarding the appropriate indication for adjuvant chemotherapy in this high-risk stage II population., Competing Interests: Disclosure The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: TS received personal fees from Merck Serono. OD received personal fees from Bristol-Myers-Squibb, Merck & Co Inc, Merck-Serono, Sanofi, and Servier. RC received personal fees from Bristol-Myers Squibb, Exeliom Biosciences, and Enterome. TA reported attending advisory board meetings and/or receiving consulting fees from Abbvie, Aptitude Health, Bristol Myers Squibb, Gritstone Oncology, Gilead, GlaxoSmithKline, Merck & Co Inc, Nordic Oncology, Seagen, Servier, and Takeda; honoraria for lectures, presentations, or speakers bureaus from Bristol Myers Squibb, GlaxoSmithKline, Merck & Co Inc, Merck Serono, Roche, Sanofi, Seagen, Servier, and Takeda; support for meetings from Merck & Co Inc and and a DMC member role for Inspirna. All other authors have no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: The predictive role of mismatch repair (MMR) status for survival outcomes and sensitivity in neoadjuvant chemoradiotherapy settings for patients with locally advanced rectal cancer (LARC) has been inconclusive. Methods: A retrospective cohort of patients with LARC treated with neoadjuvant chemoradiotherapy (nCRT) was recruited. After adjusting for baseline characteristics, we used propensity score matching to reduce the effect of potential confounding factors on MMR status. The primary analysis was based on overall survival as the more important endpoint. Results: This study included 269 patients. Patients with defective MMR (dMMR) were younger (58.5% vs. 60.0%, p=0.0274) and had lower body mass indices (p=0.0091), higher differentiation grades (p=0.0889), and more advanced rectal cancers (clinical T4 or T4b, p=0.0851; M1, p=0.0055) than those with proficient MMR (pMMR). However, propensity score-matched patients with dMMR (p=0.0013) exhibited superior overall survival, even in the M1 subgroup. More importantly, patients with proficient MMR who undergo early pathological downstaging, especially lymph node pathological downstaging, can achieve a prognosis similar to that of patients with dMMR. Conclusion: The clinical significance of this retrospective study mainly includes two points: (1) Data from our study confirmed that LARC patients with dMMR status had better overall survival rates after nCRT, even in the M1 subgroup. (2) Similar survival outcomes were observed in older and female patients with early lymph node pathological downstaging, regardless of dMMR or pMMR. [ABSTRACT FROM AUTHOR]

Objective: Endometrial cancer is the most common gynecologic malignancy worldwide, and lymph node metastasis is a major prognostic factor for patients with this cancer. Mismatch repair (MMR) deficiency is known to play a critical role in the development of endometrial cancer, but its association with lymph node metastasis and recurrence remains unclear. In this study, we aimed to investigate the correlation between MMR status and lymph node metastasis/recurrence rate in endometrial cancer. Methods: We retrospectively analyzed 59 patients with endometrial cancer who underwent surgery and received MMR testing at out institution between 2010 and 2022. Immunohistochemistry was performed to assess the expression of MMR, including MLH1, PMS2, MSH2, and MSH6. Results: Of these patients, 14 (23.7%) had MMR deficiency. The MMR deficient group had a higher proportion of early stage (stage I and II) compared to the MMR proficient group (78.6% vs. 64.4%). However, lymph node metastasis was more common in the MMR deficient group (21.4%) compared to the MMR proficient group (13.3%) (p=0.038). Furthermore, the recurrence rate was higher in the MMR deficient group (21.4% vs. 15.6%). Conclusion: Therefore, MMR status may serve as a useful biomarker to predict the risk of lymph node metastasis and recurrence in patients with endometrial cancer. Based on our findings, knowing the MMR status before surgery may help in determining an appropriate surgical plan, which could potentially improve the prognosis and quality of life of the patients. Further studies with larger sample sizes are needed to validate our findings. [ABSTRACT FROM AUTHOR]

Abstract Background HER2 is a well-established therapeutic target in breast and gastric cancers, while the role of HER2 in colorectal cancer is unclear, and no studies have explored the impact of HER2 on the outcome of stage II colorectal cancer patients treated with 5-fluorouracial based adjuvant chemotherapy. Methods We analyzed HER2 mRNA expression of 206 patients in GSE39582 dataset and explored the impact of HER2 expression on benefit from adjuvant chemotherapy for stage II colon cancer patients. We further validated the finding by retrospectively analyzing HER2 detection of immunohistochemistry in a cohort of 282 patients in Fudan University Shanghai Cancer Center (FUSCC). Results In GSE39582 dataset, chemo-treated HER2-high patients had a better overall survival (OS) and relapse-free survival (RFS) versus chemo-naïve HER2-high patients (5-year OS: 100% vs 69.5%, 5-year RFS: 100% and vs 64%, P = 0.027 and 0.025, respectively). On the contrary, chemo-treated HER2-low patients had a worse RFS compared with chemo-naïve HER2-low patients (5-year RFS: 65.6% vs 82.1%, P = 0.022). In FUSCC cohort, chemo-treated HER2-positive patients exhibited better OS vs chemo-naïve HER2-positive patients (5-year OS: 100% vs 73.8%, P < 0.001), and showed marginal evidence of a lower probability of recurrence (5-year RFS: 74.4% vs 58.7%, P = 0.072). After stratifying by mismatch repair (MMR) status, the results only kept consistency in patients with pMMR status. Conclusions HER2-positve patients with stage II colorectal cancer can benefit from 5-fluorouracial based adjuvant chemotherapy, especially for patients with pMMR status. [ABSTRACT FROM AUTHOR]

Background: Antibodies against programmed death 1 (PD-1) and its ligand programmed death ligand 1 (PD-L1) have recently demonstrated promising results in gastric cancer (GC). PD-L1 expression, the presence of tumor-infiltrating lymphocytes (TILs), and mismatch repair (MMR) deficiency have been proposed as predictive biomarkers for anti-PD-1/PD-L1 antibodies. The aim of this study was to investigate the clinical relevance of PD-L1 expression with TIL, MMR, and Epstein-Barr virus (EBV) status in GC. Methods: We performed a tissue microarray analysis in 487 advanced GC patients who underwent gastrectomy. PD-L1 expression on tumor cells (TCs) and tumor-infiltrating immune cells (TIICs), the densities of TILs, and MMR status were evaluated by immunohistochemistry. EBV was detected by in situ hybridization. Results: PD-L1 expression on TCs and TIICs, MMR deficiency, and EBV positivity were identified in 22.8, 61.4, 5.1, and 5.1 % cases respectively. PD-L1 expression was more frequently observed in the elderly (TCs P = 0.002), in males (TCs P = 0.029; TIICs P = 0.043), in patients with poorly differentiated adenocarcinoma with solid-type histological features (TCs P < 0.001; TIICs P < 0.001), in patients with MMR deficiency (TCs P < 0.001; TIICs P < 0.001), and in patients with EBV positivity (TCs P = 0.001; TIICs P = 0.050). Strong association was observed between PD-L1 expression and high densities of CD3-positive, CD8-positive, or forkhead box P3 positive TILs (TCs P < 0.001; TIICs P < 0.001). Neither PD-L1 expression on TCs nor that on TIICs was an independent prognostic factor in multivariate analysis. Conclusions: In GC, PD-L1 expression was associated with distinct clinicopathological features, including high densities of TILs, MMR deficiency, and EBV positivity, but was not a prognostic factor. [ABSTRACT FROM AUTHOR]

Introduction: Though the tumour-node-metastasis staging classification is the standard approach to risk stratification in patients with colorectal cancer, several other important variables including the presence of extramural venous invasion (EMVI), the tumour mismatch repair status, as well as surgical technique and its influence on lymph node yield all have an impact on long-term survival. This study aims to review both the impact of the type of operation on lymph node yield: complete mesocolic excision (CME) versus right hemicolectomy, and the impact of EMVI and microsatellite instability in predicting overall survival in patients undergoing a right hemicolectomy for colon cancer., Methods: Data of all patients who underwent an elective or emergency right hemicolectomy with curative intent for colon cancer between January 2013 and June 2022 (inclusive) was collected for this single-centre retrospective study. Kaplan-Meier survival curves were calculated using the Statistical Package for the Social Sciences (SPSS version 28, IBM Corp., Armonk, NY) software, and the log-rank (Mantel-Cox) test was used to compare survival distribution between different groups., Results: A total of 421 patients underwent a right hemicolectomy for colon cancer with curative intent during the study period. EMVI was present in 173 (41%) tumours. Survival analysis showed significantly reduced cancer-related survival in patients with EMVI-positive tumours (p < 0.001), with five-year survival rates of 70% in EMVI-positive groups versus 96% in EMVI-negative groups. Subgroup analysis showed a significant difference in survival between node-positive and node-negative tumours in cancers found to have EMVI (p < 0.001). Mean lymph node yield was significantly higher in the CME group versus the standard right hemicolectomy group (p < 0.001). We found no significant difference in survival between patients with microsatellite instability-high (MSI-H) tumours and microsatellite stable (MSS) tumours (p = 0.432)., Conclusion: Consideration of tumour biology and adopting the optimum surgical technique are factors that may influence long-term survival in patients with colorectal cancer. Extramural venous invasion is an important prognostic indicator of adverse outcomes in patients with right-sided colon cancer. Our study demonstrates a reduction in survival in patients with EMVI-positive tumours when undertaking subgroup analysis by the presence or absence of nodal disease. Further research needs to be undertaken to compare the relative efficacy of neoadjuvant versus adjuvant chemotherapy in right-sided cancers known to be EMVI-positive as some patients will fail to have adjuvant chemotherapy due to postoperative complications, thereby delaying recovery and missing the optimum window for treatment., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Conroy et al.)

The prognostic relevance of innate immune cells infiltrating colorectal carcinoma lesions is highly debated. By evaluating the expression of myeloperoxidase (MPO) as a marker of neutrophil granulocytes in a large cohort of colorectal carcinoma specimens, we have observed that robust tumor-infiltration by MPO+ cells correlates with improved patient survival independently of other histopathological parameters, including disease stage. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICIs) have drastically changed the clinical care of cancer. Although cancer immunotherapy has shown promise in various types of malignancies, thus far, the proportion of patients who can benefit from ICIs is relatively small. Immune-related adverse events and high cost are unavoidable problems. Therefore, biomarkers defining patients that are most likely to benefit from ICIs are urgently needed. The expression of programmed cell death-ligand 1 (PD-L1) is a logical biomarker for the prediction of response to anti-PD1/PD-L1 immunotherapies. However, its usefulness is currently debatable because of its varied definition, threshold, and spatial/temporal heterogeneity. Recently, it was reported that the tumor mutational burden, expression of neoantigens, mismatch repair status, and specific gene mutations may be markers for the success of treatment with ICIs. Moreover, it was suggested that the fecal microbiota prior to immunotherapy may play an important role in predicting the efficacy of ICIs. In this review, we focused on these potential biomarkers for cancer immunotherapy reported in recent clinical articles. Further studies are warranted to develop a predictive model using these biomarkers, with the aim of practicing precision medicine in cancer immunotherapy. [ABSTRACT FROM AUTHOR]