Abstract
Immune checkpoint inhibition (CPI) for metastatic colorectal cancer (mCRC) with deficient mismatch repair (dMMR) demonstrates high clinical activity that appears durable, but the impact of ...CPI on pathological tumor response is unknown. In this retrospective analysis, our objective was to assess pathological response and clinical outcomes in dMMR mCRC patients treated with CPI prior to surgical resection of primary and/or metastatic tumor. Among 121 advanced dMMR mCRC patients treated with CPI at 2 institutions between November 2016 and December 2018, 14 underwent surgery. Pathologic complete response was noted in the resected specimens of 13 patients despite the presence of residual tumor on preoperative imaging in 12 of those patients. With median follow-up of 9 months, no patients have had disease relapse or progression. For this small retrospective study, the data suggest that residual radiographic tumor may not require systematic resection following response to anti-PD1–based therapy. However, larger prospective studies are warranted.
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.
Human papillomavirus (HPV) is found in 90% of squamous cell carcinomas of the anal canal (SCCA). We investigated the clinical validity of HPV circulating tumor DNA (ctDNA) detection in patients ...enrolled in the Epitopes-HPV02 trial that demonstrated the efficacy of docetaxel, cisplatin, and 5-FU as first-line chemotherapy in advanced SCCA.
According to the protocol, serum samples were collected before chemotherapy and on completion of chemotherapy. HPV16 ctDNA was quantified by droplet digital PCR (ddPCR) and correlated with prospectively registered patient characteristics and outcomes. A landmark was set at the time of chemotherapy completion for postchemotherapy progression-free survival (PFS) analyses.
Among 57 patients with HPV16-related advanced SCCA, HPV ctDNA was detected in 91.1% (95% confidence interval, 81.1-96.2) of baseline samples. Baseline HPV ctDNA levels were not associated with any patient characteristics; baseline ctDNA level below the cutoff obtained by AUC (area under the curve) was associated with a longer PFS (HR = 2.1;
= 0.04). Among the 36 patients who completed 5 months of chemotherapy, residual HPV ctDNA was detected after chemotherapy in 38.9% of patients. Residual HPV ctDNA detected at chemotherapy completion was associated with shorter postchemotherapy PFS (median PFS 3.4 months vs. not reached; HR = 5.5;
< 0.001) and a reduction of 1-year overall survival rate (OR = 7.0;
= 0.02).
This prospective study in advanced SCCA demonstrated a significant prognostic impact of HPV ctDNA level before first-line chemotherapy and HPV ctDNA negativity after chemotherapy completion. With a limited cost and short turnaround, this assay is a promising tool to optimize the therapeutic management of SCCA.
.
Pancreatic ductal adenocarcinoma (PDAC) is expected to become the second leading cause of cancer death by 2030. Current therapeutic options are limited, warranting an urgent need to explore ...innovative treatment strategies. Due to specific microenvironment constraints including an extensive desmoplastic stroma reaction, PDAC faces major metabolic challenges, principally hypoxia and nutrient deprivation. Their connection with oncogenic alterations such as KRAS mutations has brought metabolic reprogramming to the forefront of PDAC therapeutic research. The Warburg effect, glutamine addiction, and autophagy stand as the most important adaptive metabolic mechanisms of cancer cells themselves, however metabolic reprogramming is also an important feature of the tumor microenvironment, having a major impact on epigenetic reprogramming and tumor cell interactions with its complex stroma. We present a comprehensive overview of the main metabolic adaptations contributing to PDAC development and progression. A review of current and future therapies targeting this range of metabolic pathways is provided.
Immune checkpoint inhibitors (ICI) have reshaped therapeutic strategies for cancer patients. The development of ICI for early stage colorectal cancer is accompanied by specific challenges: (i) the ...selection of patients who are likely to benefit from these treatments, i.e., patients with tumors harboring predictive factors of efficacy of ICI, such as microsatellite instability and/or mismatch repair deficiency (MSI/dMMR), or other potential parameters (increased T cell infiltration using Immunoscore® or others, high tumor mutational burden, POLE mutation), (ii) the selection of patients at risk of disease recurrence (poor prognostic features), and (iii) the choice of an accurate clinical trial methodological framework. In this review, we will discuss the ins and outs of clinical research of ICI for early stage MSI/dMMR CC patients in adjuvant and neoadjuvant settings. We will then summarize data that might support the development of ICI in localized colorectal cancer beyond MSI/dMMR.
•Adjuvant chemotherapy in stage II CC patients is guided by clinicopathologic findings.•Novel biomarkers to lead to more accurate treatment decisions are an unmet clinical need.•Clinical implications ...of prognostic biomarkers that need to be evaluated are reviewed.•Immunoscore, ctDNA, and AI are the most promising markers, however these still require further validation.
Colon cancer (CC) has the highest incidence rate among gastrointestinal cancers and ranks the third in mortality among all cancers, which contributes to the current CC burden and constitutes a major public health issue. While therapeutic strategies for stage I, III, and IV CC are standardized, those for stage II CC remain debatable. The choice of adjuvant chemotherapy for patients with stage II CC depends on stage (pT4) and grade (high) of the disease, the presence of venous, perinervous, and/or lymphatic emboli, or the need of suboptimal surgery (tumor with initial occlusion or perforation needing emergency surgeries, <12 lymph nodes harvested). Several prognostic factors that have been validated in retrospective studies can potentially define a population of CC patients at low and high-risk for reccurence. The role of biomarkers is becoming increasingly important for the future personalized treatment options. We conducted a systematic overview of potential prognostic biomarkers with possible clinical implications in stage II CC.
Over the past years, colorectal cancer (CRC) was subtyped according to its molecular and genetic characteristics, allowing the development of therapeutic strategies, based on predictive biomarkers. ...Biomarkers such as microsatellite instability (MSI), RAS and BRAF mutations, HER2 amplification or NTRK fusions represent major tools for personalized therapeutic strategies. Moreover, the routine implementation of molecular predictive tests provides new perspectives and challenges for the therapeutic management of CRC patients, such as liquid biopsies and the reintroduction of anti-EGFR monoclonal antibodies. In this review, we summarize the current landscape of targeted therapies for metastatic CRC patients, with a focus on new developments for EGFR blockade and emerging biomarkers (MSI, HER2, NTRK).
Microsatellite instability (MSI) is a tumor phenotype related to a deficient DNA mismatch repair system (dMMR). This phenotype, observed in 5% of metastatic mCRC but 10-18% of localized CRC, is ...associated with high tumor mutational burden with highly immunogenic neoantigens. It has emerged as a major predictive biomarker for the efficacy of ICIs. In this review, we will present a comprehensive overview of the literature concerning the efficacy of ICIs in MSI/dMMR mCRC, with a focus on new developments in first-line metastatic setting. Then, we will present current and future challenges of immuno-oncology for patients with MSI/dMMR metastatic CRC.
Opinion statement
The
BRAF
activating mutation, harbored by approximately 10% of colorectal cancers (CRC), confers dramatic prognosis to advanced diseases. In early-stage setting, the identification ...of the
BRAF
mutation does not impact the therapeutic decision. Yet, the
BRAF
mutation could be considered as a stratification factor in adjuvant trials, because of its prognostic impact after relapse. Moreover, both
BRAF
mutation and mismatch repair (MMR) statuses should be determined in all CRC to help identify sporadic tumors versus Lynch syndrome-related tumors. Indeed, in patients with MMR-deficient (dMMR) tumors and MLH1 loss of expression, the
BRAF
V600E mutation indicates a sporadic origin. In advanced
BRAF
-mutated CRC, the standard of care remains fluoropyrimidine-based cytotoxic regimen in combination with bevacizumab. Although a recent meta-analysis showed that there was insufficient data to justify the exclusion of anti-EGFR monoclonal antibodies, antiangiogenic agents should be preferred in the first-line setting. Despite the lack of a randomized phase 3 study dedicated to
BRAF
-mutated CRC, chemotherapy intensification combining a quadruple association of 5-fluorouracil, oxaliplatin, irinotecan (FOLFOXIRI), and bevacizumab seems like a valid option. Although first results with BRAF inhibitors as single agents in
BRAF
-mutated CRC were disappointing, their association with therapies targeting the MAPK pathway seems to overcome the primary resistance to BRAF inhibition. In the field of sporadic CRC, the
BRAF
mutation is strongly associated with MMR deficiency. Considering breakthrough results of immune checkpoint inhibitors in dMMR repair tumors, determination of the MMR status appears to be mandatory. Given the dramatic prognosis conferred by the
BRAF
mutation, patients with
BRAF
-mutated advanced CRC need to be systematically identified and proposed for clinical trial enrolment in order to benefit from innovative therapies.
PDF
