An exploration of immunohistochemistry-based prognostic markers in patients undergoing curative resections for colon cancer

Abstract

Background The immune system recognizes and destroys cancer cells. However, cancer cells develop mechanisms to avoid detection by expressing cell surface proteins. Specific tumour cell surface proteins (e.g. HLA-G, PD-L1, CDX2) either alone or in combination with the relative presence of immune cells (CD3 and CD8 positive T-cells) in the tumour tissue may describe the cancer cells’ ability to escape eradication by the immune system. The aim was to investigate the prognostic value of immunohistochemical markers in patients with colon cancer. Methods We conducted a retrospective study including patients diagnosed with pT3 and pT4 colon cancers. Immunohistochemical staining with HLA-G, PD-L1, CDX2, CD3, and CD8 was performed on tissue samples with representation of the invasive margin. PD-L1 expression in tumour cells and immune cells was reported conjointly. The expression of CD3 and CD8 was reported as a merged score based on the expression of both markers in the invasive margin and the tumour centre. Subsequently, a combined marker score was established based on all of the markers. Each marker added one point to the score when unfavourable immunohistochemical features was present, and the score was categorized as low, intermediate or high depending on the number of unfavourable stains. Hazard ratios for recurrence, disease-free survival and mortality were calculated. Results We included 188 patients undergoing colon cancer resections in 2011–2012. The median follow-up was 41.7 months, during which 41 (21.8%) patients had recurrence and 74 (39.4%) died. In multivariable regression analysis positive HLA-G expression (HR = 3.37, 95%CI [1.64–6.93]) was associated with higher recurrence rates, while a preserved CDX2 expression (HR = 0.23, 95%CI [0.06–0.85]) was associated with a lower risk of recurrence. An intermediate or high combined marker score was associated with increased recurrence rates (HR = 20.53, 95%CI [2.68–157.32] and HR = 7.56, 95%CI [1.06–54.16], respectively). Neither high expression of PD-L1 nor high CD3-CD8 score was significantly associated with recurrence rates. Patients with a high CD3-CD8 score had a significantly longer DFS and OS. Conclusions In tumour cells, expression of HLA-G and loss of CDX2 expression were associated with cancer recurrence. In addition, a combination of certain tumour tissue biomarkers was associated with colorectal cancer recurrence.

Prognostic value of human leukocyte antigen G expression in solid tumors: a systematic review and meta-analysis

“…Of 2821 studies identified in the initial search, after removal duplications, 2128 studies were screened by title and abstract, with 207 reports were assessed for eligibility, including full text. Finally, a total of 25 studies ( 10 , 18 – 40 ) met the inclusion criteria (see Figure 1 for study selection schema). Of these studies, 25 studies comprising data from 4871 patients reported OS outcomes and among them, only 5 studies (961 patients) reported DFS data in addition to OS.…”

“…For meta-analysis, statistical significance was defined as P <0.05. For meta-regression, in light of the small number of studies resulting in low statistical power, significance was defined quantitatively using thresholds defined by Burnand et al (17) (quantitative significance defined as ß coefficient >0.28). Publication bias was explored by visual inspection of the funnel plots.…”

Machine-Learning Identifies a Strategy for Differentiation Therapy in Solid Tumors

“…Numerous groups have since reproduced the prognostic claims [11][12][13][14][15][16][17][18][19][20][21][22][23][24] . Thirty-two independent studies, involving >13,000 unique subjects, most that used IHC and one that used IHC in combination with quantitative mass spectrometry 25 , have determined that CDX2-neg CRCs are associated with lower overall survival (OS) and DFS independent of ethnicity, DNA mismatch repair (MMR) status or stage 7,20,24,26 [Figure 1- Step 1].…”