BRAF V600E/RAS Mutations and Lynch Syndrome in Patients With MSI-H/dMMR Metastatic Colorectal Cancer Treated With Immune Checkpoint Inhibitors.

BACKGROUND: We pooled data from 2 cohorts of immune checkpoint inhibitors-treated microsatellite instability-high/mismatch repair-deficient (MSI/dMMR) metastatic colorectal cancer patients to evaluate the prognostic value of RAS/BRAFV600E mutations and Lynch syndrome (LS). PATIENTS AND METHODS: Patients were defined as LS-linked if germline mutation was detected and as sporadic if loss of MLH1/PMS2 expression with BRAFV600E mutation and/or MLH1 promoter hypermethylation, or biallelic somatic MMR genes mutations were found. Progression-free survival (PFS) and overall survival (OS) were adjusted on prognostic modifiers selected on unadjusted analysis (P < .2) if limited number of events. RESULTS: Of 466 included patients, 305 (65.4%) and 161 (34.5%) received, respectively, anti-PD1 alone and anti-PD1+anti-CTLA4 in the total population, 111 (24.0%) were treated in first-line; 129 (28.8%) were BRAFV600E-mutated and 153 (32.8%) RAS-mutated. Median follow-up was 20.9 months. In adjusted analysis of the whole population (PFS/OS events = 186/133), no associations with PFS and OS were observed for BRAFV600E-mutated (PFS HR= 1.20, P = .372; OS HR = 1.06, P = .811) and RAS-mutated patients (PFS HR = 0.93, P = .712, OS HR = 0.75, P = .202). In adjusted analysis in the Lynch/sporadic status-assigned population (n = 242; PFS/OS events = 80/54), LS-liked patients had an improved PFS compared to sporadic cases (HR = 0.49, P = .036). The adjusted HR for OS was 0.56 with no significance (P = .143). No adjustment on BRAFV600E mutation was done due to collinearity. CONCLUSION: In this cohort, RAS/BRAFV600E mutations were not associated with survival while LS conferred an improved PFS.

Prognostic role of infracentimetric colorectal liver metastases.

BACKGROUND: The number of lesions and the size of the largest (CRLMmax) have been widely investigated as prognostic factors in patients with colorectal liver metastases (CRLM). The aim of the present study was to assess whether, in patients undergoing curative liver resection, the presence of infracentimetric lesions could affect recurrence-free survival (RFS) and overall survival (OS). METHODS: Patients who underwent a liver resection for CRLM between 2001 and 2019 were included. The size of CRLM was measured on the surgical specimen. The best cut-off of the smallest lesion (CRLMmin) associated with RFS was determined through the time-dependent ROC analysis. A multivariate Cox regression analysis was carried out. RESULTS: Overall, 227 patients were included. Median follow-up time was 50 months [IQR 26-84]. Recurrence occurred for 151 (66.5%) patients (liver recurrence in 67.5%, while exclusive extra-hepatic recurrence in 32.5%). The best cut-off for CRLMmin associated with RFS was 9 mm, with 12- and 24-month td-AUC 0.56 and 0.52 respectively. CRLMmin ≤ 9 mm was found to be an independent prognostic factor that impairs RFS at multivariate analysis (HR 1.534 (1.02-2.32), p = 0.042). In particular, CRLMmin ≤ 9 mm was correlated with impaired hepatic RFS (HR 1.860 (1.15-3.01), p = 0.011), but not extra-hepatic RFS. CONCLUSIONS: Infracentimetric metastases (≤ 9 mm) are an independent prognostic factor that impairs hepatic RFS. This result suggests the potential benefit of neoadjuvant chemotherapy (CT) also in selected patients with initially resectable lesions, in case of CRLM ≤ 9 mm on preoperative imaging.

Deficient mismatch repair/microsatellite unstable colorectal cancer: therapeutic advances and questions.

The microsatellite instability (MSI) phenotype is related to a deficiency of the DNA mismatch repair (dMMR) system and is observed in 5% of metastatic colorectal cancers (mCRCs). MSI/dMMR phenotype testing should be routine for all CRCs regardless of stage. Two complementary techniques with a high concordance (90-97%) allow us to determine the MSI/dMMR status of a tumor: immunohistochemistry and polymerase chain reaction. Since 2020 and the results of the phase III KEYNOTE 177 trial, pembrolizumab [anti-programmed cell death protein 1 (PD1)] is the new standard of care in first-line MSI/dMMR mCRC. To date, no combination of chemtotherapy ± targeted therapy with immune checkpoint inhibitors (ICIs) has been validated in the management of MSI/dMMR mCRC, and it is not known whether this combination would be beneficial. It is also unclear whether dual therapy with two ICIs is more effective than monotherapy. Several phase III trials are ongoing to answer these questions. Despite a high response rate and long-term benefit of a first line by anti-PD1, 30-50% of patients with MSI/dMMR mCRC experience an early or secondary progression. There are currently no validated predictive biomarkers of anti-PD1 ± anti-cytotoxic T lymphocyte antigen-4 resistance in patients with MSI/dMMR mCRC. In case of early progression on ICIs, the first two questions to consider are the possibility of pseudoprogression and the correct diagnosis of MSI/dMMR status. To date, there are no data on the use of adjuvant ICIs for MSI/dMMR resected colon cancers. By contrast, data are accumulating regarding the efficacy of neoadjuvant ICIs, with at least two-thirds of patients in the different trials in pathological complete response, making it possible to envisage 'Watch and wait' strategies in future.

[An update on total neoadjuvant treatment of adenocarcinoma of the rectum]. / Actualisation des données sur le traitement néoadjuvant total de l'adénocarcinome du rectum.

A major advance has been made in the management of rectal cancer, with the emergence in 2021 of total neoadjuvant treatment. The main publications from the RAPIDO and PRODIGE-23 trials reported a significant improvement in progression-free survival and the pathological complete response rate. The aim of this review is to synthesize recent data on neoadjuvant treatment of rectal cancer, to explain the long-term results of the RAPIDO and PRODIGE-23 trials, and to put them into perspective, considering current advances in de-escalation strategies. The update of the 5-year survival data from the RAPIDO trial highlights an increased risk of loco-regional relapse, with 11.7% of relapses in the experimental group and 8.1% in the control group, while the update of the PRODIGE-23 trial confirms the benefits of this treatment regimen, with a significant improvement in overall survival. In addition, the results of the OPRA and PROPSPECT trials confirm the benefit of total neoadjuvant treatment with induction chemotherapy, as well as the possibility of surgical de-escalation in the OPRA trial and radiotherapy in the PROSPECT trial. The challenge for the future is to identify patients who require total neoadjuvant treatment with the aim of curative surgery to obtain a cure without local or distant relapse, and those for whom therapeutic de-escalation can be envisaged.

Imaging-guided prognostic score-based approach to assess the benefits of combotherapy versus monotherapy with immune checkpoint inhibitors in metastatic MSI-H colorectal cancer patients.

BACKGROUND: This retrospective study determined survival responses to immune checkpoint inhibitors (ICIs), comparing mono- (mono) and combo-immunotherapy (combo) in patients with microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC) by analyzing quantitative imaging data and clinical factors. METHODS: One hundred fifty patients were included from two centers and divided into training (n = 105) and validation (n = 45) cohorts. Radiologists manually annotated chest-abdomen-pelvis computed tomography and calculated tumor burden. Progression-free survival (PFS) was assessed, and variables were selected through Recursive Feature Elimination. Cutoff values were determined using maximally selected rank statistics to binarize features, forming a risk score with hazard ratio-derived weights. RESULTS: In total, 2258 lesions were annotated with excellent reproducibility. Key variables in the training cohort included: total tumor volume (cutoff: 73 cm3), lesion count (cutoff: 20), age (cutoff: 60) and the presence of peritoneal carcinomatosis. Their respective weights were 1.13, 0.96, 0.91, and 0.38, resulting in a risk score cutoff of 1.36. Low-score patients showed similar overall survival and PFS regardless of treatment, while those with a high-score had significantly worse survivals with mono vs combo (P = 0.004 and P = 0.0001). In the validation set, low-score patients exhibited no significant difference in overall survival and PFS with mono or combo. However, patients with a high-score had worse PFS with mono (P = 0.046). CONCLUSIONS: A score based on total tumor volume, lesion count, the presence of peritoneal carcinomatosis, and age can guide MSI-H mCRC treatment decisions, allowing oncologists to identify suitable candidates for mono and combo ICI therapies.

Prognosis and chemosensitivity of non-colorectal alimentary tract cancers with microsatellite instability.

BACKGROUND: Data on outcomes of microsatellite instable and/or mismatch repair deficient (dMMR/MSI) digestive non-colorectal tumors are limited. AIMS: To evaluate overall survival (OS) of patients with dMMR/MSI digestive non-colorectal tumor. METHODS: All consecutive patients with a dMMR/MSI digestive non-colorectal tumor were included in this French retrospective multicenter study. RESULTS: One hundred and sixteen patients were included with a mean age of 63.6 years and 32.6% with a Lynch syndrome. Most tumors were oesophago-gastric (54.3%) or small bowel (32.8%) adenocarcinomas and at a localized stage at diagnosis (86.7%). In patients with localized tumors and R0 resection, median OS was 134.0 ± 64.2 months. Median disease-free survival (DFS) was 100.3 ± 65.7 months. Considering oesophago-gastric tumors, median DFS was improved when chemotherapy was added to surgery (not reached versus 22.8 ± 10.0 months, p = 0.03). In patients with advanced tumors treated by chemotherapy, median OS was 14.2 ± 1.9 months and median progression-free survival was 7.4 ± 1.6 months. CONCLUSION: dMMR/MSI digestive non-colorectal tumors are mostly diagnosed at a non-metastatic stage with a good prognosis. Advanced dMMR/MSI digestive non-colorectal tumors have a poor prognosis with standard chemotherapy.

Mutations de l'ADN dans les cholangiocarcinomes : cibler IDH1 et autres mutations.

DNA mutations in cholangiocarcinoma: targeting IDH1 and other mutations Biliary tract cancers (BTC) are rare cancers with a poor prognosis, particularly at the metastatic stage, with a 5-year survival rate not exceeding 7%. Two lines of chemotherapy are currently recommended in France, with cisplatin-gemcitabine and 5 FU-oxaliplatin as first and second-line treatment respectively, allowing a median survival of approximately one year. However, many studies have shown that BTC, and more particularly intrahepatic cholangiocarcinoma, have a high somatic alteration rate (mutations, fusions, or amplifications). Some of these alterations are potential therapeutic targets. To date, only ivosidenib and pemigatinib, targeting IDH1 mutations and FGFR2 fusions respectively, are approved in France for pre-treated patients with these molecular alterations. Many other potentially targetable alterations are found in BTC, including mutations in genes involved in DNA repair, BRAF, HER2 and the recently exploited KRASG12C mutation. This review will focus on targetable mutations in BTC and develop the main molecules that can be used in BTC with these actionable alterations, offering new therapeutic perspectives for these patients, with the ultimate goal of improving their prognosis.

Immunotherapy and Hepatocellular Cancer: Where Are We Now?

Immunotherapy has demonstrated its effectiveness in many cancers. In hepatocellular carcinoma (HCC), promising results shown in the first phase II studies evaluating anti-PD-1 or anti-PD-L1 monotherapies resulted in their approval in the United States. Approval was not obtained in Europe; subsequent randomized studies in first- or second-line treatment did not confirm these initial results. However, first data with immunotherapy plus antiangiogenic treatments or dual immunotherapy combinations were positive. In this context, the combination of bevacizumab and atezolizumab took the lead. The IMbrave150 trial revealed an improved objective response rate (ORR), progression-free survival, and overall survival with this combination versus the previous standard, sorafenib. Subsequent results of dual immunotherapy with the anti-CTLA-4 and anti-PD-1 monotherapies tremelimumab and durvalumab (also superior to sorafenib monotherapy) confirmed the value of using a combination in first-line treatment. These significant therapeutic advances, and the increase in ORR, raise two main questions. Whereas response was very limited with previous treatments, the ORR reported with these new combinations are between 20% and 30%. This raises the question of whether immunotherapy (ICI single agent, combination of ICI with antiangiogenic agent or other antitumoral treatment) can be used in patients beyond those in BCLC group C, the traditional candidate group for systemic therapy. We have thus seen an increasing number of patients previously treated with trans-arterial chemoembolization (BCLC group B) receiving these new treatments, and we develop the results of several studies combining loco-regional therapies and immunotherapy-based systemic treatments. The other major question is that of how and when to use these medical treatments as "adjuvants" to interventional radiology or surgery; the results of several works are discussed for this purpose. In this review, we cover all of these points in a fairly comprehensive manner.