Lymphocytic response to tumour and deficient DNA mismatch repair identify subtypes of stage II/III colorectal cancer associated with patient outcomes

Williams, David S.; Mouradov, Dmitri; Jorissen, Robert N.; Newman, Marsali; Amini, Elham; Nickless, David; Teague, Julie A.; Fang, Catherine; Palmieri, Michelle; Parsons, Marie J.; Sakthianandeswaren, Anuratha; Li, Shan; Ward, Robyn L.; Hawkins, Nicholas J.; Faragher, Ian; Jones, Ian T.; Gibbs, Peter; Sieber, Oliver M.

doi:10.1136/gutjnl-2017-315664

Cited by 56 publications

(59 citation statements)

References 46 publications

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“…13 Immune reaction plays a key role in suppressing tumor development and progression, [14][15][16] and high-level infiltrates of lymphocytes in colorectal cancer have been associated with better clinical outcomes. [17][18][19][20][21][22] Four tumor subtypes can be created based on the TIME framework, [9][10][11][12] including the CD274 high /TIL present subtype (TIME 2) which generally responds to immunotherapy, the CD274 low /TIL present subtype (TIME 3) which suggests presence of other suppressor pathways in immune tolerance, the CD274 high /TIL absent subtype (TIME 4) which indicates intrinsic induction of the CD274 pathway, and the CD274 low /TIL absent subtype (TIME 1) which reflects immune "ignorance. "…”

Section: Introductionmentioning

confidence: 99%

TIME (Tumor Immunity in the MicroEnvironment) classification based on tumor CD274 (PD-L1) expression status and tumor-infiltrating lymphocytes in colorectal carcinomas

et al. 2018

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Inhibitors targeting the (programmed cell death 1, PD-1) immune checkpoint pathway have revolutionized cancer treatment strategies. The TIME (Tumor Immunity in the MicroEnvironment) classification based on tumor ( ligand 1, PD-L1) expression and tumor-infiltrating lymphocytes (TIL) has been proposed to predict response to immunotherapy. It remains to be determined clinical, pathological, and molecular features of TIME subtypes of colorectal cancer. Using 812 colon and rectal carcinoma cases from the Nurses' Health Study and Health Professionals Follow-up Study, we examined the association of tumor characteristics and survival outcomes with four TIME subtypes (TIME 1, /TIL; TIME 2, /TIL; TIME 3, /TIL; and TIME 4, /TIL). In survival analyses, Cox proportional hazards models were adjusted for potential confounders, including microsatellite instability (MSI) status, CpG island methylator phenotype (CIMP) status, LINE-1 methylation level, and ,, and mutation status. TIME subtypes 1, 2, 3 and 4 had 218 (27%), 117 (14%), 103 (13%), and 374 (46%) colorectal cancer cases, respectively. Compared with TIL-absent subtypes (TIME 1 and 4), TIL-present subtypes (TIME 2 and 3) were associated with high-level MSI, high-degree CIMP, mutation, and higher amounts of neoantigens ( < 0.001). TIME subtypes were not significantly associated with colorectal cancer-specific or overall survival. In conclusion, TIL-present TIME subtypes of colorectal cancer are associated with high levels of MSI and neoantigen load, supporting better responsiveness to cancer immunotherapy. Further studies examining tumor molecular alterations and additional factors in the tumor microenvironment may inform development of immunoprevention and immunotherapy strategies.

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Section: Introductionmentioning

confidence: 99%

TIME (Tumor Immunity in the MicroEnvironment) classification based on tumor CD274 (PD-L1) expression status and tumor-infiltrating lymphocytes in colorectal carcinomas

et al. 2018

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“…Extended use of clinical information, such as details of treatment for recurrence may improve model performance. Furthermore, incorporation of molecular prognostic indicators such as microsatellite instability, KRAS / BRAF mutation and chromosome instability, or stroma and immune markers such as the Immunoscore, has potential for refining predictions.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of the transferability of survival calculators for stage II/III colon cancer across healthcare systems

Jorissen

Croxford

Jones

et al. 2019

Intl Journal of Cancer

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Adjuvant! Online Inc (A!O), the Memorial Sloan Kettering Cancer Center (MSKCC), MD Anderson (MDA) and Mayo Clinic (MC) provide calculators to predict survival probabilities for patients with resected early‐stage colon cancer, trained on data from United States (US) patient cohorts or patients enrolled in international clinical trials. Limited data exist on the transferability of calculators across healthcare systems. Calculator transferability to Australian community practice was evaluated for 1,401 stage II/III patients. Calibration and discrimination were assessed for overall (OS), cancer‐specific (CSS) or recurrence‐free survival (RFS). The US patient cohort‐based calculators, A!O, MSKCC and MDA, significantly overestimated risks of recurrence and death in Australian patients, with 5‐year OS, CSS and RFS prediction differences of −6.5% to −9.9%, −9.1% to −14.4% and − 3.8% to −6.8%, respectively (p < 0.001). Significant heterogeneity in calibration was observed for subgroups by tumor stage and treatment, age, gender, tumor location, ECOG and ASA score. Calibration appeared acceptable for the clinical trial patient‐based MC calculator, but restricted tool applicability (stage III patients, ≥12 examined lymph nodes, receiving adjuvant treatment) limited the sample size. Compared to AJCC 7th edition tumor staging, calculators showed improved discrimination for OS, but no improvement for CSS and RFS. In conclusion, deficiencies in calibration limited transferability of US patient cohort‐based survival calculators for early‐stage colon cancer to the setting of Australian community practice. Our results demonstrate the utility for multi‐feature survival calculators to improve OS predictions but highlight the importance for performance assessment of tools prior to implementation in an external health care setting.

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“…TIL were scored blindly and independently by two observers (Xiaoli Jia and Bin Li). Density of TIL for these tumors as scored using H&E stained tissue sections has been reported previously [8,12]. Tumors were classi ed into TIL-low (< 2 TILs per hpf) and TIL-high (≥ 2 TILs per hpf) cases.…”

Section: Evaluation Of Tilmentioning

confidence: 99%

Clinicopathological characteristics, molecular alterations and prognosis of mucinous histology in colorectal adenocarcinoma patients

Jia

Yan

2020

Preprint

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Background Mucinous adenocarcinoma (MAC) is conventionally diagnosed by WHO definition when the extracellular mucin is more than 50% of the tumour area. The study is aimed at analyzing the clinicopathological characteristics, mutation spectrum, and prognosis of the colorectal adenocarcinoma (CRC) with any mucinous proportion or feature. Methods Clinical and pathological information for 50 patients were reviewed and recorded. Mutation analyses for exon 2–4 of KRAS gene and exon 15 of BRAF gene were performed by Sanger sequencing. Expression of DNA mismatch repairs (MMRs) and P53 proteins was evaluated by immunohistochemistry (IHC). Density of tumour infiltrating lymphocyte (TIL) status was scored. We also evaluated the percentage of glands producing mucin and the morphology of the different tumor cells types in mucin pools. We retrospectively analyzed prognosis of 43 patients with Stage II-III MAC. The primary outcome was progression-free survival (PFS). Results The overall frequencies of KRAS and BRAF mutations were 37.9% and 4.4%, respectively. Patients with MAC exhibiting high levels of mucin were related to the increase of tumor diameter (P = 0.038), but were not associated with any of the other clinicopathological parameters. The proportion or variable morphology of mucinous component did not stratify PFS in Stage II-III tumours. It is interesting to note that male patients had lower TIL compared with female patients (P = 0.018). TIL-low tumors were also correlated with advanced stage (P = 0.041). TIL status was a strong independent predictor of PFS in stage II-III mucinous component tumours (p < 0.001). All four IV stage patients were also classified into TIL-low case. No parameters were independently associated with outcome after adjusting for tumour stage in multivariate analysis. Conclusions TIL status could more accurately determine the biology of the MAC feature for appropriate management, irrespective of quantity or morphology of mucinous component.

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Lymphocytic response to tumour and deficient DNA mismatch repair identify subtypes of stage II/III colorectal cancer associated with patient outcomes

Cited by 56 publications

References 46 publications

TIME (Tumor Immunity in the MicroEnvironment) classification based on tumor CD274 (PD-L1) expression status and tumor-infiltrating lymphocytes in colorectal carcinomas

TIME (Tumor Immunity in the MicroEnvironment) classification based on tumor CD274 (PD-L1) expression status and tumor-infiltrating lymphocytes in colorectal carcinomas

Evaluation of the transferability of survival calculators for stage II/III colon cancer across healthcare systems

Clinicopathological characteristics, molecular alterations and prognosis of mucinous histology in colorectal adenocarcinoma patients

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