Consensus molecular subtypes of colorectal cancer in clinical practice: A translational approach

AbstractGene expression-based subtypes of colorectal cancer have clinical relevance, but the representativeness of primary tumors and the consensus molecular subtypes (CMS) for metastatic cancers is not well known. We investigated the metastatic heterogeneity of CMS. The best approach to subtype translation was delineated by comparisons of transcriptomic profiles from 317 primary tumors and 295 liver metastases, including multi-metastatic samples from 45 patients and 14 primary-metastasis sets. Associations were validated in an external data set (n = 618). Projection of metastases onto principal components of primary tumors showed that metastases were depleted of CMS1-immune/CMS3-metabolic signals, enriched for CMS4-mesenchymal/stromal signals, and heavily influenced by the microenvironment. The tailored CMS classifier (available in an updated version of the R package CMScaller) therefore implemented an approach to regress out the liver tissue background. The majority of classified metastases were either CMS2 or CMS4. Nonetheless, subtype switching and inter-metastatic CMS heterogeneity were frequent and increased with sampling intensity. Poor-prognostic value of CMS1/3 metastases was consistent in the context of intra-patient tumor heterogeneity.

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Consensus molecular subtypes in metastatic colorectal cancer treated with sequential versus combined fluoropyrimidine, bevacizumab and irinotecan (XELAVIRI trial)

European Journal of Cancer ◽

10.1016/j.ejca.2021.08.017 ◽

2021 ◽

Vol 157 ◽

pp. 71-80

Author(s):

Arndt Stahler ◽

Volker Heinemann ◽

Veronika Schuster ◽

Kathrin Heinrich ◽

Annika Kurreck ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Molecular Subtypes

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Liquid biopsy-driven anti-EGFR rechallenge in patients with metastatic colorectal cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.3577 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 3577-3577

Author(s):

Stefano Mariani ◽

Marco Puzzoni ◽

Nicole Liscia ◽

Valentino Impera ◽

Andrea Pretta ◽

...

Keyword(s):

Colorectal Cancer ◽

Clinical Practice ◽

Metastatic Colorectal Cancer ◽

Liquid Biopsy ◽

Selection Criteria ◽

Wild Type ◽

Braf Mutations ◽

Previous Response ◽

Clinical Variables ◽

Ct Dna

3577 Background: The rechallenge with EGFR inhibitors represents an emerging strategy for anti-EGFR pre-treated patients with RAS wild type colorectal cancer (CRC). Unfortunately definitive selection criteria for anti-EGFR rechallenge in this setting are lacking. Very recently RAS wild type status on circulating tumor DNA (ct-DNA) at the time of rechallenge along with already known clinical criteria emerged as a potential watershed for this strategy. In the present study we explored liquid biopsy-driven anti-EGFR rechallenge strategy in the clinical practice for patients with metastatic colorectal cancer. Methods: Ct-DNA from RAS and BRAF wild type metastatic CRC patients previously treated with an anti-EGFR containing therapy was analyzed for RAS/BRAF mutations with the aim to evaluate the rechallenge strategy with anti-EGFR. The ct-DNA was analyzed for RAS-BRAF mutations using pyro-sequencing (PyroMark Q24 MDx Workstation) and nucleotide sequencing (Genetic Analyzer ABI3130) assays. Real-time PCR (Idylla) and droplet digital PCR (QX200 System) were performed to confirm the RAS-BRAF mutation status. Several clinical variables including previous response to anti EGFR containing therapy, tumor sidedness and anti-EGFR free interval were evaluated in relation to outcome. Tumor response evaluation was performed according to RECIST 1.1. Differences between categorical variables were evaluated using the Fisher’s exact test. Survival probability over time was estimated by the Kaplan–Meier method. Significant differences in the probability of survival between the strata were evaluated by log-rank test. Results: Twenty patients were included in the study. All patients were tested for RAS-BRAF mutations in ct-DNA. Fourteen patients (70%) showed a RAS-BRAF WT molecular profile, six patients (30%) showed a KRAS mutation. All the patients with ct-DNA RAS-BRAF WT profile underwent rechallenge with anti-EGFR. In details 11 patients (78.6%) underwent irinotecan+ cetuximab treatment, whereas 3 patients (21.4%) underwent panitumumab monotherapy. As for the outcome results to the rechallenge strategy, the median OS was 7 months (95% CI 5.0 to 13.0), the median PFS was 3 months (95% CI 2.0 to 6.0), the ORR was 27.3% with a DCR of 54.5%. Among the clinical variables evaluated as putative predictive/prognostic factors, previous response to anti-EGFR treatment was related to a not statistically significant improved OS (12 months vs 5 months HR:0.19 p: 0.06) and to a statistically significant improved ORR (75% vs 0% p:0.03). Conclusions: The rechallenge strategy with anti-EGFR confirmed to be feasible in clinical practice. The clinical outcome resulted consistent with the literature data. In addition to the molecular selection through the analysis of ct-DNA for RAS, previous response to anti EGFR treatment is confirmed as a prospective selection criteria for this therapeutic option.

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Analysis of Clinical and Economic Implications of Esmo 2014 Clinical Practice Guidelines for Metastatic Colorectal Cancer Treatment

Value in Health ◽

10.1016/j.jval.2015.09.1111 ◽

2015 ◽

Vol 18 (7) ◽

pp. A446

Author(s):

J Suarez

Keyword(s):

Colorectal Cancer ◽

Clinical Practice ◽

Cancer Treatment ◽

Metastatic Colorectal Cancer ◽

Clinical Practice Guidelines ◽

Practice Guidelines ◽

Economic Implications ◽

Colorectal Cancer Treatment

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Using cancer risk algorithms to improve risk estimates and referral decisions

Communications Medicine ◽

10.1038/s43856-021-00069-1 ◽

2022 ◽

Vol 2 (1) ◽

Author(s):

Olga Kostopoulou ◽

Kavleen Arora ◽

Bence Pálfi

Keyword(s):

Colorectal Cancer ◽

Clinical Practice ◽

Cancer Risk ◽

General Practitioners ◽

Learning Tools ◽

Cancer Symptoms ◽

Referral Decisions ◽

Risk Estimates ◽

Discernible Effect ◽

Over Time

Abstract Background Cancer risk algorithms were introduced to clinical practice in the last decade, but they remain underused. We investigated whether General Practitioners (GPs) change their referral decisions in response to an unnamed algorithm, if decisions improve, and if changing decisions depends on having information about the algorithm and on whether GPs overestimated or underestimated risk. Methods 157 UK GPs were presented with 20 vignettes describing patients with possible colorectal cancer symptoms. GPs gave their risk estimates and inclination to refer. They then saw the risk score of an unnamed algorithm and could update their responses. Half of the sample was given information about the algorithm’s derivation, validation, and accuracy. At the end, we measured their algorithm disposition. We analysed the data using multilevel regressions with random intercepts by GP and vignette. Results We find that, after receiving the algorithm’s estimate, GPs’ inclination to refer changes 26% of the time and their decisions switch entirely 3% of the time. Decisions become more consistent with the NICE 3% referral threshold (OR 1.45 [1.27, 1.65], p < .001). The algorithm’s impact is greatest when GPs have underestimated risk. Information about the algorithm does not have a discernible effect on decisions but it results in a more positive GP disposition towards the algorithm. GPs’ risk estimates become better calibrated over time, i.e., move closer to the algorithm. Conclusions Cancer risk algorithms have the potential to improve cancer referral decisions. Their use as learning tools to improve risk estimates is promising and should be further investigated.

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Biomarker testing and mutation prevalence in metastatic colorectal cancer patients in five European countries using a large oncology database

Future Oncology ◽

10.2217/fon-2020-0975 ◽

2021 ◽

Author(s):

George Kafatos ◽

Victoria Banks ◽

Peter Burdon ◽

David Neasham ◽

Caroline Anger ◽

...

Keyword(s):

Colorectal Cancer ◽

Clinical Practice ◽

Metastatic Colorectal Cancer ◽

Cancer Patients ◽

Braf Mutation ◽

European Countries ◽

High Prevalence ◽

Biomarker Testing ◽

Colorectal Cancer Patients ◽

Over Time

Background: The literature on biomarker testing for metastatic colorectal cancer (mCRC) in Europe is scarce. This study aimed to estimate the percentage of mCRC patients from five European countries tested for biomarkers over time. Materials & methods: An oncology database was retrospectively analyzed; evaluated biomarkers were RAS, BRAF and microsatellite instability (MSI). The patients were drug treated during 2018 and tested for relevant biomarkers in 2013–2018. Results: RAS testing was conducted in >90% of mCRC patients from 2014 onwards. BRAF testing increased from 31% of mCRC patients in 2013 to 67% in 2018. MSI testing increased from 10 to 41%. There was no notable trend over time for RAS and BRAF mutation or MSI-high prevalence. Conclusion: Biomarker testing among patients diagnosed with mCRC was increased over time. This study demonstrates the quick uptake of biomarker testing in clinical practice. These findings are significant as biomarker-based drugs are becoming more common.

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