Clinical Effects of Adjuvant Active Specific Immunotherapy Differ between Patients with Microsatellite-Stable and Microsatellite-Instable Colon Cancer

Weger, Vincent A. de; Turksma, Annelies W.; Voorham, Quirinus J.M.; Euler, Zelda; Bril, Herman; Eertwegh, Alfons J. van den; Bloemena, Elisabeth; Pinedo, H.M.; Vermorken, Jan B.; Tinteren, Harm van; Meijer, Gerrit A.; Hooijberg, Erik

doi:10.1158/1078-0432.ccr-11-1716

Cited by 63 publications

(52 citation statements)

References 31 publications

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“…The DSS and RFI data on the 106 patients in the current study are presented in Fig. 2 and are at large in agreement with the data published by us previously on the larger group of 196 patients (28).…”

Section: Patient Characteristics Infiltrating T Cell Numberssupporting

confidence: 92%

“…Of these 106 tumor samples, 99 were available for CD3 staining and 104 for CD8 staining. (28). The distribution of patient characteristics between the various subgroups was similar to that in the original study reported by Vermorken and colleagues (27).…”

Section: Patient Characteristics Infiltrating T Cell Numberssupporting

confidence: 82%

“…In the present study, we focused on the parameters tumor stage, microsatellite status of the tumor, T-cell infiltration, and (adjuvant ASI) treatment and their respective bearing on clinical outcome measured as DSS and RFI over a follow-up period of 15 years. To assess comparability of the selected study cohort to our previous study (28), Kaplan-Meier curves were used to depict survival in groups defined by microsatellite status (MSI vs. MSS), stage (II or III), and treatment (ASI vs. control). The DSS and RFI data on the 106 patients in the current study are presented in Fig.…”

Section: Patient Characteristics Infiltrating T Cell Numbersmentioning

confidence: 99%

“…The group of patients with MSI tumors had an increased survival rate independent of ASI therapy. Patients with stage II MSS tumors showed a significantly increased recurrence-free survival when they received ASI (28).…”

Section: Introductionmentioning

confidence: 98%

“…The recurrence-free interval (RFI) for patients with stage II tumors was significantly extended for patients treated with surgery plus ASI compared with surgery alone but not for stage III patients (27). In a retrospective follow-up study, tumor samples from these patients were analyzed for their microsatellite status; 17% of the samples were MSI and 83% were MSS tumors (28). The group of patients with MSI tumors had an increased survival rate independent of ASI therapy.…”

Section: Introductionmentioning

confidence: 99%

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Extent and Location of Tumor-Infiltrating Lymphocytes in Microsatellite-Stable Colon Cancer Predict Outcome to Adjuvant Active Specific Immunotherapy

Turksma

Coupé

Shamier

et al. 2016

Clinical Cancer Research

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Purpose: To determine the prognostic and predictive value of tumor-infiltrating lymphocytes (TIL) in colon cancer in a cohort of patients who previously took part in a trial on adjuvant active specific immunotherapy (ASI).Experimental Design: We determined the number and location of CD3 and CD8 positive T cells in archival tumor samples of 106 colon cancers. We correlated stromal and epithelial TIL numbers with tumor stage and treatment and determined the effects on disease-specific survival (DSS) and recurrence-free interval (RFI).Results: On the basis of the data presented, we concluded that (i) high numbers of stromal CD3 T cells have positive prognostic value measured as DSS for patients with stage II microsatellitestable tumors and (ii) high numbers of epithelial CD8-positive T cells have positive prognostic value measured as RFI for the group of patients with stage II microsatellite-stable tumors as well as for the whole group (so stage II plus stage III together). Furthermore, we concluded that high numbers of pre-existing stromal CD3-positive T cells are of positive predictive value in adjuvant ASI treatment measured as DSS as well as RFI.Conclusions: ASI therapy may contribute to an improved DSS and RFI in patients with microsatellite-stable colon tumors harboring high numbers of pre-existing stromal CD3 þ TIL.Validation in future clinical trials is awaited. Clin Cancer Res; 22(2); 346-56. Ó2015 AACR.

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Section: Patient Characteristics Infiltrating T Cell Numberssupporting

confidence: 92%

Section: Patient Characteristics Infiltrating T Cell Numberssupporting

confidence: 82%

Section: Patient Characteristics Infiltrating T Cell Numbersmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

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Extent and Location of Tumor-Infiltrating Lymphocytes in Microsatellite-Stable Colon Cancer Predict Outcome to Adjuvant Active Specific Immunotherapy

Turksma

Coupé

Shamier

et al. 2016

Clinical Cancer Research

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Cancer Vaccines

Smith

Dalgleish

2017

Encyclopedia of Life Sciences

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Cancer vaccines have been studied for approximately 40 years. During this time, a growing number of cancer antigen and vaccine platforms have been developed and a large number of clinical trials have been performed. These trials have regularly demonstrated an ability to activate antitumour immune responses and instances of clinical efficacy in responding patients. However, very few vaccines have achieved clinical end points in phase III trials and only one vaccine has been licenced by the FDA. With some notable exceptions, the disappointing performance of therapeutic cancer vaccines is due to a number of factors. However, recent developments in vaccination, combination immunotherapy and recent research detailing the immune suppression mediated by the tumour microenvironment offer new opportunities to realise the promise of therapeutic cancer vaccination. Key Concepts Cancer vaccines induce antitumour immune responses. Cancer vaccines have yet to realise their potential in cancer immunotherapy. The tumour microenvironment inhibits immune responses induced by cancer vaccines. Combination therapy has the potential to improve the efficacy of cancer vaccination. Cancer vaccines.

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Prognostic value of BRAF and KRAS mutation status in stage II and III microsatellite instable colon cancers

Cuba

Snæbjörnsson

Heideman

et al. 2015

Intl Journal of Cancer

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Microsatellite instability (MSI) has been associated with favourable survival in early stage colorectal cancer (CRC) compared to microsatellite stable (MSS) CRC. The BRAF V600E mutation has been associated with worse survival in MSS CRC. This mutation occurs in 40% of MSI CRC and it is unclear whether it confers worse survival in this setting. The prognostic value of KRAS mutations in both MSS and MSI CRC remains unclear. We examined the effect of BRAF and KRAS mutations on survival in stage II and III MSI colon cancer patients. BRAF exon 15 and KRAS exon 2-3 mutation status was assessed in 143 stage II (n 5 85) and III (n 5 58) MSI colon cancers by high resolution melting analysis and sequencing. The relation between mutation status and cancer-specific (CSS) and overall survival (OS) was analyzed using Kaplan-Meier and Cox regression analysis. BRAF V600E mutations were observed in 51% (n 5 73) and KRAS mutations in 16% of cases (n 5 23). Patients with double wild-type cancers (dWT; i.e., BRAF and KRAS wild-type) had a highly favourable survival with 5-year CSS of 93% (95% CI 84-100%), while patients with cancers harbouring mutations in either BRAF or KRAS, had 5-year CSS of 76% (95% CI 67-85%). In the subgroup of stage II patients with dWT cancers no cancer-specific deaths were observed. On multivariate analysis, mutation in either BRAF or KRAS vs. dWT remained significantly prognostic. Mutations in BRAF as well as KRAS should be analyzed when considering these genes as prognostic markers in MSI colon cancers.Colorectal cancer (CRC) is both clinically and biologically a heterogeneous disease. Microsatellite instability (MSI) occurs in 15% of CRC and results from a genetic or epigenetic defect in DNA mismatch repair (MMR), occurring sporadically (12%) or due to Lynch syndrome (3%). These cancers are more frequently right sided and often show poor differentiation, increased mucin formation and lymphocytic infiltration. 1 The crucial RAS-RAF-MEK-ERK signal transduction pathway is affected in both MSS and MSI CRC, and can be

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Clinical Effects of Adjuvant Active Specific Immunotherapy Differ between Patients with Microsatellite-Stable and Microsatellite-Instable Colon Cancer

Cited by 63 publications

References 31 publications

Extent and Location of Tumor-Infiltrating Lymphocytes in Microsatellite-Stable Colon Cancer Predict Outcome to Adjuvant Active Specific Immunotherapy

Extent and Location of Tumor-Infiltrating Lymphocytes in Microsatellite-Stable Colon Cancer Predict Outcome to Adjuvant Active Specific Immunotherapy

Cancer Vaccines

Prognostic value of BRAF and KRAS mutation status in stage II and III microsatellite instable colon cancers

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