Prediction of pathological response to neoadjuvant treatment in rectal cancer with a two-protein immunohistochemical score derived from stromal gene-profiling

Gonçalves-Ribeiro, Samuel; Sanz‐Pamplona, Rebeca; Vidal, Álvaro; Sanjuán, Xavier; Díaz-Maroto, Natalia Guillén; Soriano, Antonio; Guardiola, Jordi; Albert, Nerea; Martínez-Villacampa, M.; López, Ilse; Santos, Cristina; Serra-Musach, Jordi; Salazar, Ramón; Capellà, Gabriel; Villanueva, Alberto; Mollevı́, David G.

doi:10.1093/annonc/mdx293

Cited by 39 publications

(29 citation statements)

References 19 publications

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“…The number of samples for whole‐exome sequencing and expression microarray analysis was small, potentially causing bias. Laser‐capture microdissection may have missed some information associated with the response to CRT from the stromal compartment. Nonetheless, this study has demonstrated key roles for TILs, neoantigens and PD‐1/LAG3 signalling in rectal tumour regression with CRT.…”

Section: Discussionmentioning

confidence: 82%

Immunogenomic profiles associated with response to neoadjuvant chemoradiotherapy in patients with rectal cancer

Akiyoshi

Tanaka

Kiyotani

et al. 2019

British Journal of Surgery

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Background Accumulating evidence suggests that radiotherapy success has an immune‐associated component. The immunogenomic profiles associated with responses to chemoradiotherapy (CRT) were assessed in patients with locally advanced rectal cancer in this study. Methods CD8+ tumour‐infiltrating lymphocyte (TIL) and stromal lymphocyte densities were assessed by immunohistochemistry using pretreatment biopsies from patients with advanced rectal cancer who had preoperative CRT. Whole‐exome sequencing and gene expression microarray analysis were conducted to investigate the genomic properties associated with the response to CRT and CD8+ TIL density. Response to CRT was determined based on Dworak tumour regression grade (TRG); tumours with complete (TRG 4) or near‐complete (TRG 3) regression were grouped as good responders, and those with TRG 1 as non‐responders. Results Immunohistochemical examinations (275 patients) showed that pre‐CRT CD8+ TIL density was associated with better response to CRT and improved recurrence‐free survival, whereas pre‐CRT stromal CD8+ cell density was not associated with either response to CRT or recurrence‐free survival. Whole‐exome sequencing (74 patients) showed that the numbers of single‐nucleotide variations (SNVs) and neoantigens predicted from SNVs were higher in good responders than in non‐responders, and these correlated positively with CD8+ TIL density (rS = 0·315 and rS = 0·334 respectively). Gene expression microarray (90 patients) showed that CD8A expression correlated positively with the expression of programmed cell death 1 (PDCD1) (rS = 0·264) and lymphocyte‐activation gene 3 (LAG3) (rS = 0·507). Conclusion Pre‐CRT neoantigen‐specific CD8+ T cell priming may be a key event in CRT responses where immune checkpoint molecules could be useful targets to enhance tumour regression.

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Section: Discussionmentioning

confidence: 82%

Immunogenomic profiles associated with response to neoadjuvant chemoradiotherapy in patients with rectal cancer

Akiyoshi

Tanaka

Kiyotani

et al. 2019

British Journal of Surgery

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“…Gonçalves-Ribeiro et al (11) revealed that CAFs have a protective effect on CRC cells. It has also been reported that the expression of CAFs-associated fibronectin 1 and collagen 3A1 can predict the absence of response to neoadjuvant treatment in locally advanced rectal carcinoma (30). The potential mechanisms involved are as follows: i) CAFs can secrete collagen type I, which can decrease chemotherapeutic drug uptake in tumors and then induce drug resistance (31,32); ii) soluble factors secreted by CAFs can induce the activation of PI3K/AKT/survivin and JAK/STAT pathways, which may provide protection from cell death, ensure correct DNA repair and eventually induce resistance to oxaliplatin and 5-FU; and iii) chemotherapy-treated CAFs can secrete specific cytokines and chemokines, including IL-17A, which may promote cancer-initiating cell self-renewal and tumor resistance (33).…”

Section: Discussionmentioning

confidence: 95%

Response prediction to oxaliplatin plus 5‑fluorouracil chemotherapy in patients with colorectal cancer using a four‑protein immunohistochemical model

Zhou

et al. 2019

Oncol Lett

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The response of cancer patients to oxaliplatin combined with 5-fluorouracil (5-FU) is difficult to predict. It has been reported that carcinoma-associated fibroblasts (CAFs) could induce AKT and ERK phosphorylation, and upregulate survivin expression in colorectal cancer (CRC) cells, which could lead to oxaliplatin plus 5-FU resistance. A total of 71 patients with advanced CRC (aCRC) treated with oxaliplatin plus 5-FU were included in the present study. These patients comprised 46 chemotherapy responders and 25 non-responders. The expression levels of α-smooth muscle actin (α-SMA), phosphorylated (p)-AKT, p-ERK and survivin were determined by immunohistochemical evaluation of paraffin-embedded samples from patients. A predictive model was established using a Probabilistic Neural Network model. The high expression of α-SMA, p-AKT and survivin in patients with aCRC were associated with oxaliplatin plus 5-FU resistance (P<0.001, P= 0.023 and P= 0.001, respectively). Furthermore, patients with stage IV CRC exhibiting high expression levels of α-SMA and survivin experienced a reduced progression-free survival time compared with patients with low expressions of α-SMA and survivin (5.5 vs. 15.0 months; 5.5 vs. 15.0 months; P=0.005 and P=0.001, respectively). Stage IV CRC and high survivin expression predicted a reduced overall survival time compared with that for patients with stage IV CRC and low survivin expression (50.0 vs. 15.0 months; P<0.001). Patients with α-SMA, p-AKT, p-ERK and survivin overexpression were more likely to present with intrinsic resistance to the oxaliplatin plus 5-FU regimen (the accuracies of modeling, validation and prediction were 83.7, 92.9 and 85.7%, respectively). In conclusion, the multifactorial predictive biomarker model of α-SMA, p-AKT, p-ERK and survivin expression for patients with aCRC to predict intrinsic resistance to oxaliplatin plus 5-FU regimens is of great efficiency and accuracy. Patients with high expression of this predictive model may be intrinsically resistant to the oxaliplatin and 5-FU regimen.

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“…In addition, other collagens also play important roles in therapy resistance. COL3A1 optimally predicted the absence of a response to neoadjuvant treatment in rectal cancer and the resistance of ovarian cancer cells to topotecan and paclitaxel [187,188]. High COLVI expression promoted anoikis resistance and affected the response of salivary gland cancer to radiotherapy and colorectal cancer to adjuvant chemotherapy [189][190][191].…”

Section: Subtype Of Mmps Associated Collagen Pathological Functions Omentioning

confidence: 99%

The role of collagen in cancer: from bench to bedside

et al. 2019

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Collagen is the major component of the tumor microenvironment and participates in cancer fibrosis. Collagen biosynthesis can be regulated by cancer cells through mutated genes, transcription factors, signaling pathways and receptors; furthermore, collagen can influence tumor cell behavior through integrins, discoidin domain receptors, tyrosine kinase receptors, and some signaling pathways. Exosomes and microRNAs are closely associated with collagen in cancer. Hypoxia, which is common in collagen-rich conditions, intensifies cancer progression, and other substances in the extracellular matrix, such as fibronectin, hyaluronic acid, laminin, and matrix metalloproteinases, interact with collagen to influence cancer cell activity. Macrophages, lymphocytes, and fibroblasts play a role with collagen in cancer immunity and progression. Microscopic changes in collagen content within cancer cells and matrix cells and in other molecules ultimately contribute to the mutual feedback loop that influences prognosis, recurrence, and resistance in cancer. Nanoparticles, nanoplatforms, and nanoenzymes exhibit the expected gratifying properties. The pathophysiological functions of collagen in diverse cancers illustrate the dual roles of collagen and provide promising therapeutic options that can be readily translated from bench to bedside. The emerging understanding of the structural properties and functions of collagen in cancer will guide the development of new strategies for anticancer therapy.

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Prediction of pathological response to neoadjuvant treatment in rectal cancer with a two-protein immunohistochemical score derived from stromal gene-profiling

Abstract: We developed a two-protein immunohistochemical classifier that performs well at predicting the non-response to neoadjuvant treatment in rectal cancer.

Cited by 39 publications

References 19 publications

Immunogenomic profiles associated with response to neoadjuvant chemoradiotherapy in patients with rectal cancer

Immunogenomic profiles associated with response to neoadjuvant chemoradiotherapy in patients with rectal cancer

Response prediction to oxaliplatin plus 5‑fluorouracil chemotherapy in patients with colorectal cancer using a four‑protein immunohistochemical model

The role of collagen in cancer: from bench to bedside

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