The role of tumor angiogenesis as a therapeutic target in colorectal cancer

<p><b>Introduction</b>: Angiogenesis is a complex process regulated by several pro- and anti-angiogenic factors, thus the loss of its fine equilibrium plays a key role in colorectal cancer (CRC) development and progression. Therapeutic agents targeting VEGF/VEGFR signaling, the main regulator of this process, proved to be effective across different treatment lines in metastatic CRC (mCRC) and contributed greatly to improve patients’ survival in recent years.</p> <p><b>Areas covered</b>: This review aimed to summarize the actual body of knowledge available on the VEGF pathway in CRC, including currently available anti-angiogenic drugs and treatment challenges, mechanisms of resistance, promising predictive biomarkers and future perspectives.</p> <p><b>Expert commentary</b>: Angiogenesis inhibition in subsequent lines of treatment is a valid strategy in the continuum of care of mCRC patients. In this scenario, the availability of multiple agents warrants to tailor therapy to an individualized approach. However, the validation of predictive biomarkers to aid therapeutic decisions remains an issue. Intrinsic and adaptive resistance to anti-angiogenic agents comprises distinct and intertwined processes, eventually leading to treatment failure and disease progression. The expanding knowledge on the mechanisms underlying the angiogenesis pathway, different potential treatment targets and mechanisms of tumor resistance, may lead to promising new perspectives in this field.</p

Genetic Diversity of the KIR/HLA System and Outcome of Patients with Metastatic Colorectal Cancer Treated with Chemotherapy

<div><p>Objective</p><p>To explore genes of the killer-cell immunoglobulin-like receptor (KIR) and of the HLA ligand and their relationship with the outcome of metastatic colorectal cancer (mCRC) patients treated with first-line 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI).</p><p>Methods</p><p>A total of 224 mCRC patients were screened for KIR/HLA typing. The determination of the KIR/HLA combinations was based upon the gene content and variants. Genetic associations with complete response (CR), time to progression (TTP) and overall survival (OS) were evaluated by calculating odds and hazard ratios. Multivariate modeling with prognostic covariates was also performed.</p><p>Results</p><p>For CR, the presence of KIR2DL5A, 2DS5, 2DS1, 3DS1, and KIR3DS1/HLA-Bw4-I80 was associated with increased CR rates, with median ORs ranging from 2.1 to 4.3, while the absence of KIR2DS4 and 3DL1 was associated with increased CR rates (OR 3.1). After univariate analysis, patients that underwent resective surgery of tumor, absence of KIR2DS5, and presence of KIR3DL1/HLA-Bw4-I80 showed a significant better OS (HR 1.5 to 2.8). Multivariate analysis identified as parameters independently related to OS the type of treatment (surgery; HR 2.0) and KIR3DL1/HLA-Bw4-I80 genotype (HR for T-I80 2.7 and for no functional KIR/HLA interaction 1.8). For TTP, no association with KIR/HLA genes was observed.</p><p>Conclusion</p><p>This study, for the first time, evidences that the genotyping for KIR-HLA pairs are found predictive markers associated with complete response and improves overall survival prediction of FOLFIRI treatment response in metastatic colorectal cancer. These results suggest a role of the KIR/HLA system in patient outcome, and guide new research on the immunogenetics of mCRC through mechanistic studies and clinical validation.</p></div

KIR3D and HLA-B ligands and their association with the CR rate.

<p>The NK effector functions are determined by the cumulative signal generated via the ligation of activating and inhibitory NK cell receptors with their putative HLA ligand on target cells. Activating (KIR3DS1) and inhibitory (KIR3DL1) receptors are genes of a same locus and have similar HLA-B ligand specificity with thus a possible balancing role in the NK response. The KIR3D receptor can recognize the HLA-B molecules carrying the Bw4 common epitope (Bw4-I80 and Bw4-T80 variants), but not the Bw6 motif. The figure shows a greater frequency of patients with CR in patients carrying KIR3Ds with the Bw4-I80 ligand (10%) than in patients with Bw4-T80 (0%) or Bw6/6 (4%). Among the HLA-Bw4-I80 ligand, the presence of the KIR3DS1 gene is associated with a trend towards improved CR rate (Chi square test for trend, p 0.016). + and – indicate presence or absence of the gene, respectively.</p

Association between KIR/HLA and complete response (CR) rate.

<p>CR: complete response; PR: partial response; SD: stable disease; PD: progressive disease. + and − refer to presence and absence of a gene (respectively).</p

Presence of KIR3DS1/HLA-Bw4-I80 genotype associated with CR, improves the survival of patients stratified on combination of genes and surgical treatment.

<p>OS Kaplan-Meier survival curves (truncated at 80months) of patients stratified on patients with the identified better (A factors) and worse (B factors) prognostic combination of genes and surgical treatment.</p

Kaplan-Meier survival curves (truncated at 80months) A) Kaplan-Meier plots of OS stratified by radical surgery Yes and No refer to presence or absence of radical surgery, respectively.

<p><b>B) Kaplan-Meier plots of the association between KIR2DS5 and OS.</b> OS curves of patients with KIR2DS5 (solid black line), or without the gene (−, red dashed line). The implication of this result could not be further investigated as the ligand of KIR2DS5 has not been identified yet. <b>C) Kaplan-Meier plots of the association between KIR3DL1/HLA-B and OS.</b> OS curves of patients with KIR3DL1/HLA-Bw4-I80 (solid black line), KIR3DL1/HLA-Bw4-T80 (dashed red line), or without either one (−/−, green dashed line). <b>D) Kaplan-Meier plots of the association between a combination of surgery, KIR2DS5 and KIR3DL1/HLA and OS.</b> Yes and No refer to presence or absence of radical surgery, respectively. − refers to the absence of the gene. Kaplan-Meier method, and log-rank were used to test the differences between subgroups. 0.95 LCL and 0.95 UCL; lower and upper 95th percentile, respectively; CI (95%); 95% confidence interval.</p

Association between the number of activating KIR (aKIR) genes and complete response (CR) rate.

<p>The KIR gene analysis shows a trend (chi squared test for trend, p<0.001) between an increasing number of aKIR genes (KIR2DS3 and KIR2DS5; ligand unknown) or aKIR/HLA-ligand (KIR2DS1/HLA-C2, KIR2DS2/HLA-C1, KIR2DS4full/HLA-Cw*04, KIR3DS1/HLA-Bw4) and the rate of CR.</p

Characteristics of the mCRC patients treated with FOLFIRI.

<p><b>$ Radical surgery:</b> Surgical resection of locally recurrent cancer.</p

Image_3_Case report: Complete pathologic response with first-line immunotherapy combination in a young adult with massive liver dissemination of mismatch repair–deficient metastatic colorectal cancer: Immunological and molecular profiling.jpeg

The current level of evidence for immunotherapy in previously untreated microsatellite unstable metastatic colorectal cancer is based on recent pieces of evidence of few studies that demonstrated durable response and clinical benefit, in terms of objective response rate, disease control rate, and progression-free survival in this subgroup of patients. On the basis of combinatorial immunotherapy with nivolumab plus ipilimumab, we report the exceptional case of a complete pathological response in a 21-year-old woman presenting a clinically aggressive stage IV colorectal cancer with massive nodal and liver involvement. Extensive molecular analyses based on whole genome next-generation DNA sequencing, RNA sequencing, fluorescent multiplex immunohistochemistry, and flow cytometry provided a detailed description of tumoral and immunological characteristics of this noteworthy clinical case.</p

Image_4_Case report: Complete pathologic response with first-line immunotherapy combination in a young adult with massive liver dissemination of mismatch repair–deficient metastatic colorectal cancer: Immunological and molecular profiling.jpeg

The current level of evidence for immunotherapy in previously untreated microsatellite unstable metastatic colorectal cancer is based on recent pieces of evidence of few studies that demonstrated durable response and clinical benefit, in terms of objective response rate, disease control rate, and progression-free survival in this subgroup of patients. On the basis of combinatorial immunotherapy with nivolumab plus ipilimumab, we report the exceptional case of a complete pathological response in a 21-year-old woman presenting a clinically aggressive stage IV colorectal cancer with massive nodal and liver involvement. Extensive molecular analyses based on whole genome next-generation DNA sequencing, RNA sequencing, fluorescent multiplex immunohistochemistry, and flow cytometry provided a detailed description of tumoral and immunological characteristics of this noteworthy clinical case.</p