Background: Worldwide, colorectal cancer (CRC) has the second highest mortality rate of all malignancies. Sequencing efforts on primary CRC (pCRC) have led to extensive knowledge about its genomic landscape. Because the molecular characteristics change over time and under treatment pressure, tumor characteristics of metastases can differ from those of the primary tumor. Therefore, better insight into the genomic alterations of metastatic CRC (mCRC) is key to improve treatment strategies.Methods: We investigated whole genome sequencing (WGS) data of metastases of 429 CRC patients participating in the CPCT-02 study (NCT01855477). Based on prior treatment data, patients were divided into a group who did and a group who did not receive systemic treatment prior to the moment the biopsy was taken. Our sequencing data was compared to publicly available data from pCRC. In addition, observed molecular patterns were associated with pretreatment regimens and clinical outcome. The potential value of WGS analysis for current clinical practice was explored.Results: Compared to pCRC we found that TP53, ZFP36L2, KRAS, and APC were more frequently mutated in mCRC whereas PIK3CA mutations were less frequent. Clear shifts in the relative contributions of mutational signatures were observed in mCRC compared to pCRC. We identified a subgroup of both pretreated and untreated mCRC samples characterized by signatures rarely found in pCRC (SBS9/39/41). Effects of prior treatment were observed in pretreated patients versus untreated patients on the total number of aberrations, mutational signatures, and CNVs. Based on their molecular landscape, 55% of the patients could qualify for on-or off-label FDAapproved targeted treatments. In addition to KRAS/NRAS and BRAF, mutations in FBXW7 were associated with poor response to EGFR-targeted treatments.Conclusions: Differences in driver genes and mutational signatures were observed between mCRC and pCRC, and genomic effects of prior treatment were observed in pretreated mCRC patients versus untreated patients. In conclusion, this study provides an unprecedentedly comprehensive insight into the molecular landscape of mCRC and identifies clinically useful genomic features for future patient management.Clinical trial identification: NCT01855477.
using immunohistochemistry for p53 (p53 wild-type "p53wt" or p53 aberrant "p53abn" expression) and mismatch repair (MMR) proteins (MLH1, PMS2, MSH2, and MSH6), considering MMR deficiency (MMRd) when a loss of MMR nuclear staining for at least one protein was identified. Identification of POLE mutations (POLE-EDM) was made by sequencing exons 9e14. Only pathogenic variants described in COSMIC database were considered for further analysis. Clinicopathological variables and survival ([RFS, relapse free survival; OS, overall survival]) correlations were assessed by the Kaplan Meier method and log rank.Results: A cohort of 54 patients fulfilled clinical and pathological criteria. Distribution by histological subtype was: endometrioid (46.3%), serous (33.3%), undifferentiated (11.1%), mixed (5.6%), and clear cell (3.7%). Molecular profile was fully evaluable in 49 samples: MMRd (26.5%), POLE-EDM (12.2%), p53wt (22.5%), p53abn (38.8%). Regardless of molecular subtype, 5 year relapse rate was: POLE 0%, MMRd 31.6%, p53wt 35.7%, p53abn 48.9% (p¼0.23), and 5 year OS rate was: POLE-EDM 100%, MMRd 76.2%, p53wt 48% and p53abn 38.5% (p¼0.18). Considering only endometrioid subtype, there was a statistically significant correlation of the molecular classification with 5 year OS (p¼0.02).Conclusions: To our knowledge, this is the first series that has evaluated the molecular classification focused on early-stage HG-EC, including all histologies. Patients with POLE-EDM have an excellent prognosis, with no relapses in this subgroup, whereas patients with p53abn have the worst prognosis. The application of molecular classification in daily practice could be useful in a better design of adjuvant therapy.Legal entity responsible for the study: The authors.
Results: 375 samples were profiled for HRD status and were divided into four tiers based on the weight of HRD-related mutation pattern. Cox model showed significant survival difference (p-value ¼ 0.001) proportional to the weight of HRD mutation pattern with higher weight being the longest survival and vice versa. 223 and 152 samples were categorized as HRD and non-HRD based on optimized threshold and survival difference remains significant (p-value ¼ 0.0017). Similar survival difference was observed (p-value¼0.0013) suggesting the validity of the method on targeted sequencing. Out of 124, 49 and 19 breast, ovarian and prostate cancer samples, 13, 11 and 4 of them were labeled as HRD positive based on known HRD causing variants. All but one HRD positive samples were consistently classified by our method.Conclusions: Our results showed that NMF method is able to faithfully detect HRD samples. The method can be applied to WES as well as targeted sequencing and achieve equally significant survival difference between samples with different HR status. Upon detecting HRD, this method can identify additional HRD patients and therefore make better patient stratification.
Background: PROs enable direct measurement of the experiences of pts with cancer related to an intervention. Regulators increasingly use PROs to inform the risks and benefits of new drug candidates, focusing on 3 core concepts: physical functioning (PF), disease-related symptoms (DRS), and symptomatic adverse events (AEs). Dostarlimab is an investigational antieprogrammed death-1 monoclonal antibody that has shown activity in pts with advanced dMMR EC (objective response rate, 42%; disease control rate, 58%) and an acceptable safety profile. Here, we report on PROs in pts treated with dostarlimab in the single-arm GARNET trial.Methods: Pts with recurrent or advanced dMMR/MSI-H EC that progressed on a platinum regimen received 500 mg Q3W*4 of dostarlimab, then 1000 mg Q6W until disease progression or discontinuation (DC). PRO assessment, an exploratory endpoint, was measured using the EORTC-QLQ-C30. PROs were collected at baseline (BL), each dose cycle, and after DC. For PF and DRS (pain and fatigue), we conducted multi-item descriptive analyses, including change from BL. For symptomatic AEs and tolerability (nausea, vomiting, constipation, diarrhea, tiredness/fatigue), we conducted item-level analyses to understand response distribution and change in response categories from BL: improved, stable, and 1-, 2-, or 3-category worsening.Results: PRO data were available for 66/104 pts who received 1 dose of dostarlimab. Questionnaire compliance was consistent across domains, ranging from 100% at BL to 45% at cycle 7. Pain, fatigue, and PF were maintained above BL starting at cycles 1, 3, and 4, respectively. Symptomatic AEs were experienced by a minority of pts, with <25% and <6% of pts having 1-or 2-category worsening, respectively. Improved scores were reported by 6% to 37% of pts.Conclusions: PROs from the GARNET trial showed that dostarlimab was generally well tolerated and disease-related symptoms were improved or maintained while on treatment. These data, along with the efficacy and safety profile of dostarlimab, support use of dostarlimab in pts with dMMR/MSI-H advanced EC.Clinical trial identification: NCT02715284.
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