Neoadjuvant immunotherapy leads to pathological responses in MMR-proficient and MMR-deficient early-stage colon cancers

Chalabi, Myriam; Fanchi, Lorenzo F.; Dijkstra, Krijn K.; Berg, José G. van den; Aalbers, Arend G. J.; Sikorska, Karolina; López-Yurda, Marta; Grootscholten, Cecile; Beets, Geerard L.; Snæbjörnsson, Pétur; Maas, Monique; Mertz, Marjolijn; Veninga, Vivien; Bounova, Gergana; Broeks, Annegien; Beets‐Tan, Regina G. H.; Wijkerslooth, Thomas R. de; Lent, Anja U. van; Marsman, Hendrik A.; Nuijten, Elvira; Kok, Niels F. M.; Kuiper, M.; Verbeek, Wieke H.M.; Kok, Marleen; Leerdam, Monique E. van; Schumacher, Ton N.; Voest, Emile E.; Haanen, John B.A.G.

doi:10.1038/s41591-020-0805-8

Cited by 957 publications

(791 citation statements)

References 63 publications

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“…(n = 20/20) pathological response in dMMR and a 27% (n = 4/15) pathological response in proficient MMR tumors after 4 weeks of treatment. 39 Although pathological stage is the key determinant of treatment and survival, additional predictive and prognostic markers are crucial. In this context, MSI, KRAS, 18q loss of heterozygosity, and TP53 and BRAF mutations have been studied, but most are not included in the treatment guidelines.…”

Section: Discussionmentioning

confidence: 99%

Survival outcome of adjuvant chemotherapy in deficient mismatch repair stage III colon cancer

Shaib

Zakka

Jiang

et al. 2020

Cancer

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Background The prognostic impact of DNA mismatch repair (MMR) status remains controversial in patients with stage III colon cancer who are treated with adjuvant chemotherapy (AC). The aim of this study was to evaluate the survival outcome of AC in deficient mismatch repair (dMMR)/microsatellite instable (MSI) stage III CC. Methods Patients with pathological stage III CC between 2010 and 2013 were identified from the National Cancer Database using International Classification of Diseases for Oncology (3rd Edition) morphology and topography codes 8140, 8480, and C18.0‐18.8. Patients with pathologic stage T3N2, T4N1, or T4N were considered high risk; patients with stage T3N1 were considered low risk. Univariate and multivariable analyses were conducted, and Kaplan‐Meier analysis and Cox proportional hazards models were used to identify the association between AC and overall survival (OS). Results A total of 9226 patients with pathological stage III CC were identified, of which 2384 (25.8%) were MSI‐high (MSI‐H) and met the inclusion criteria of the final analysis. MSI‐low (MSI‐L) patients (n = 6842) were excluded. There was a preponderance of women (55.0% [n = 1311]), and 76.6% (n = 1825) of patients were non‐Hispanic white. The median age was 65 years (range, 19‐90 years). The primary sites were the cecum (29.7% [n = 707]), ascending colon (26.0% [n = 620]), sigmoid colon (17.2% [n = 410]), and transverse colon (10.8% [n = 257]). The most common tumor grade was moderately differentiated (n = 50.4% [1202]), followed by poorly differentiated (34.1% [n = 813]) and well differentiated (5.1% [n = 121]). High‐risk pathologic stage III CC (T4N1, TxN2) constituted 51.0% (n = 1215) of the study population. High‐risk stage III was associated with worse OS compared with low‐risk stage III on univariate (P < .001) analysis and displayed a similar trend on multivariable analysis, without a statistically significant difference. Multiagent AC was associated with improved OS compared with no treatment on univariate (P < .001) and multivariable (P < .001) analysis. When stratified by risk status, multiagent AC was associated with improved OS compared with no treatment for high‐risk (P < .001) and low‐risk (P < .001) stage III disease. Conclusion Adjuvant chemotherapy is associated with better OS in stage III dMMR/MSI‐H CC. An enhanced benefit was shown for high‐risk stage III disease.

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Section: Discussionmentioning

confidence: 99%

Survival outcome of adjuvant chemotherapy in deficient mismatch repair stage III colon cancer

Shaib

Zakka

Jiang

et al. 2020

Cancer

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“…However, TMB does not capture the full evolutionary history of the tumor and several patients do not respond despite their TMB status. In addition, a recent study has shown that mismatch repair-proficient colorectal cancers can also achieve clinical response 44 . Motivated by this, we propose that immune dN/dS can be used, in addition to TMB and escape mechanisms, to stratify patients into adapted and escaped.…”

Section: Discussionmentioning

confidence: 99%

“…However, recent studies have shown that even mismatch repair proficient tumors display a pathological response 44 , emphasizing the need for quantifying the true immunogenicity of the cancer genome and their potential clinical response to immunotherapy.…”

Section: Introductionmentioning

confidence: 99%

dN/dSdynamics quantify tumour immunogenicity and predict response to immunotherapy

Zapata

Caravagna

Williams

et al. 2020

Preprint

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Immunoediting is a major force during cancer evolution that selects for clones with low immunogenicity (adaptation), or clones with mechanisms of immune evasion (escape). However, quantifying immunogenicity in the cancer genome and how the tumour-immune coevolutionary dynamics impact patient outcomes remain unexplored. Here we show that the ratio of nonsynonymous to synonymous mutations (dN/dS) in the immunopeptidome quantifies tumor immunogenicity and differentiates between adaptation and escape. We analysed 8,543 primary tumors from TCGA and validated immune dN/dS as a measure of selection associated with immune infiltration in immune-adapted tumours. In a cohort of 308 metastatic patients that received immunotherapy, pre-treatment lesions in non-responders showed increased immune selection (dN/dS<1), whereas responders did not and instead harboured a higher proportion of genetic escape mechanisms. Ultimately, these findings highlight the potential of evolutionary genomic measures to predict clinical response to immunotherapy.

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“…In recent years, immunotherapy has been a hotspot in the research of major tumor types. In the COAD eld, research on the high-level microsatellite instability(MSI-H) population has been carried out successively since 2015, from Keynote 016, Keynote 164 to Checkmate 142 and NICHE research results all indicate the extraordinary e cacy of immunotherapy [33][34][35][36]. The patients with MSI-H have a better prognosis than those with microsatellite stability(MSS).…”

Section: Discussionmentioning

confidence: 99%

Establishment of an immune-related gene pairs model to predict colon adenocarcinoma prognosis

Luo

Liu

Wang

et al. 2020

Preprint

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Background. Colon cancer is the most common type of gastrointestinal cancer and has high morbidity and mortality. Colon adenocarcinoma(COAD) is the main pathological type of colon cancer. There is a lot of evidence describing the correlation between the prognosis of COAD and the immune system. The objective of the current study was the development of a robust prognostic immune-related gene pairs (IRGPs) model for estimating overall survival of COAD. Methods. The gene expression profiles and clinical information of patients with colon adenocarcinoma come from TCGA and GEO databases and are divided into training and validation cohorts. Immune genes were selected which show significantly association with prognosis. Results. Among 1647 immune genes, a 17 IRGPs model was built which was significantly associated with OS in the training cohort. In the training and validation data set, the IRGPs model divided patients into high-risk groups and low-risk groups, and the prognosis of the high-risk group was significantly worse(P＜0.001). Univariate and multivariate Cox proportional hazard analysis confirmed the feasibility of this model. Functional analysis confirmed that multiple tumor progression and stem cell growth-related pathways in high-risk groups were up-regulated. T cells regulatory and Macrophage M0 were significantly highly expressed in the high-risk group. Conclusion. We successfully constructed an IRGPs model that can predict the prognosis of COAD, which provides new insights into the treatment strategy of COAD.

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Neoadjuvant immunotherapy leads to pathological responses in MMR-proficient and MMR-deficient early-stage colon cancers

Cited by 957 publications

References 63 publications

Survival outcome of adjuvant chemotherapy in deficient mismatch repair stage III colon cancer

Survival outcome of adjuvant chemotherapy in deficient mismatch repair stage III colon cancer

dN/dSdynamics quantify tumour immunogenicity and predict response to immunotherapy

Establishment of an immune-related gene pairs model to predict colon adenocarcinoma prognosis

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