Durable Clinical Benefit With Nivolumab Plus Ipilimumab in DNA Mismatch Repair-Deficient/Microsatellite Instability-High Metastatic Colorectal Cancer.

Purpose Nivolumab provides clinical benefit (objective response rate [ORR], 31%; 95% CI, 20.8 to 42.9; disease control rate, 69%; 12-month overall survival [OS], 73%) in previously treated patients with DNA mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC); nivolumab plus ipilimumab may improve these outcomes.

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

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. Areas covered: 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.

Trends in colorectal cancer mortality in hispanics: a SEER analysis.

Background: Colorectal cancer (CRC) mortality among Hispanics is lower than Non-Hispanic Whites (NHW). If Hispanics receive equitable care and achieve the same degree of health benefit, their trend of better survival should be maintained. This study assesses mortality trends among Hispanics overtime to compare their survival improvement with NHW.

Pharmacogenomics in colorectal cancer: current role in clinical practice and future perspectives.

The treatment scenario of colorectal cancer (CRC) has been evolving in recent years with the introduction of novel targeted agents and new therapeutic strategies for the metastatic disease. An extensive effort has been directed to the identification of predictive biomarkers to aid patients selection and guide therapeutic choices. Pharmacogenomics represents an irreplaceable tool to individualize patients treatment based on germline and tumor acquired somatic genetic variations able to predict drugs response and risk of toxicities.

The subgroups of the phase III RECOURSE trial of trifluridine/tipiracil (TAS-102) versus placebo with best supportive care in patients with metastatic colorectal cancer.

Background: In the phase III RECOURSE trial, trifluridine/tipiracil (TAS-102) extended overall survival (OS) and progression-free survival (PFS) with an acceptable toxicity profile in patients with metastatic colorectal cancer refractory or intolerant to standard therapies. The present analysis investigated the efficacy and safety of trifluridine/tipiracil in RECOURSE subgroups.

Methods: Primary and key secondary end-points were evaluated using a Cox proportional hazards model in prespecified subgroups, including geographical subregion (United States of America [USA], European Union [EU], Japan), age (<65 years, ≥65 years) and v-Ki-ras2 Kirsten rat sarcoma 2 viral oncogene homologue (KRAS) status (wild type, mutant).

Cetuximab Combined With Induction Oxaliplatin and Capecitabine, Followed by Neoadjuvant Chemoradiation for Locally Advanced Rectal Cancer: SWOG 0713.

Background: Neoadjuvant chemoradiation (NCRT) is standard treatment for locally advanced rectal cancer. Pathologic complete response (pCR) has associated with improved survival. In modern phase III trials of NCRT, pCR ranges from 10% to 20%.

Rationale for combination of therapeutic antibodies targeting tumor cells and immune checkpoint receptors: Harnessing innate and adaptive immunity through IgG1 isotype immune effector stimulation.

Immunoglobulin (Ig) G1 antibodies stimulate antibody-dependent cell-mediated cytotoxicity (ADCC). Cetuximab, an IgG1 isotype monoclonal antibody, is a standard-of-care treatment for locally advanced and recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN) and metastatic colorectal cancer (CRC). Here we review evidence regarding the clinical relevance of cetuximab-mediated ADCC and other immune functions and provide a biological rationale concerning why this property positions cetuximab as an ideal partner for immune checkpoint inhibitors (ICIs) and other emerging immunotherapies.

A Polymorphism within the Vitamin D Transporter Gene Predicts Outcome in Metastatic Colorectal Cancer Patients Treated with FOLFIRI/Bevacizumab or FOLFIRI/Cetuximab.

Vitamin D exerts its inhibitory influence on colon cancer growth by inhibiting Wnt signaling and angiogenesis. We hypothesized that SNPs in genes involved in vitamin D transport, metabolism, and signaling are associated with outcome in metastatic colorectal cancer (mCRC) patients treated with first-line FOLFIRI and bevacizumab. 522 mCRC patients enrolled in the FIRE-3 (discovery cohort) and TRIBE (validation set) trials treated with FOLFIRI/bevacizumab were included in this study.

CXCL9, CXCL10, CXCL11/CXCR3 axis for immune activation - A target for novel cancer therapy.

Chemokines are proteins which induce chemotaxis, promote differentiation of immune cells, and cause tissue extravasation. Given these properties, their role in anti-tumor immune response in the cancer environment is of great interest. Although immunotherapy has shown clinical benefit for some cancer patients, other patients do not respond.

Molecular Landscape and Treatment Options for Patients with Metastatic Colorectal Cancer.

Over the last 20 years, median survival for patients with metastatic colorectal cancer (CRC) has remarkably improved from about 12 to over 30 months, mainly because of the development of new agents and patient selection using predictive biomarkers. However, the identification of the most effective treatment for an individual patient is still a challenge. Molecular profiling of CRC has made great progress, but it is limited by tumor heterogeneity and absence of driver mutation.

Colorectal cancer in 2017: Practice-changing updates in the adjuvant and metastatic setting.

2017 has been full of new discoveries that will influence the treatment of colorectal cancer. In the adjuvant setting, 3 months of chemotherapy might now be considered a new standard of care. Various other new treatments and promising biomarkers have also become available that will improve survival outcomes and the quality of life of many patients with metastatic disease.

Determination of an optimal response cut-off able to predict progression-free survival in patients with well-differentiated advanced pancreatic neuroendocrine tumours treated with sunitinib: an alternative to the current RECIST-defined response.

Background: Sunitinib prolongs progression-free survival (PFS) in patients with advanced pancreatic neuroendocrine tumours (pNET). Response Evaluation Criteria in Solid Tumors (RECIST)-defined partial responses (PR; classically defined as ⩾30% size decrease from baseline) are infrequent.

Methods: Individual data of pNET patients from the phase II [NCT00056693] and pivotal phase III [NCT00428597] trials of sunitinib were analysed in this investigator-initiated, post hoc study.

Comparative molecular analyses of left-sided colon, right-sided colon, and rectal cancers.

Tumor sidedness has emerged as an important prognostic and predictive factor in the treatment of colorectal cancer. Recent studies demonstrate that patients with advanced right-sided colon cancers have a worse prognosis than those with left-sided colon or rectal cancers, and these patient subgroups respond differently to biological therapies. Historically, management of patients with metastatic colon and rectal cancers has been similar, and colon and rectal cancer patients have been grouped together in large clinical trials.

Randomized study of etirinotecan pegol versus irinotecan as second-line treatment for metastatic colorectal cancer.

Purpose: Etirinotecan pegol (EP) is a long-acting topoisomerase-I inhibitor designed to provide sustained exposure to SN-38 (active metabolite of irinotecan). This phase II study compared EP versus irinotecan as second-line treatment for KRAS-mutant, irinotecan-naïve, metastatic colorectal cancer (mCRC).

Methods: Patients were randomized to EP 145 mg/m or irinotecan 350 mg/m Q21d until disease progression/unacceptable toxicity.

Colorectal cancer: epigenetic alterations and their clinical implications.

Colorectal cancer (CRC) is a heterogeneous disease with distinct molecular and clinical features, which reflects the wide range of prognostic outcomes and treatment responses observed among CRC patients worldwide. Our understanding of the CRC epigenome has been largely developed over the last decade and it is now believed that among thousands of epigenetic alterations present in each tumor, a small subgroup of these may be considered as a CRC driver event. DNA methylation profiles have been the most widely studied in CRC, which includes a subset of patients with distinct molecular and clinical features now categorized as CpG island methylator phenotype (CIMP).

Understanding the role of primary tumour localisation in colorectal cancer treatment and outcomes.

Metastatic colorectal carcinoma (mCRC) is a heterogeneous disease with differing outcomes and clinical responses and poor prognosis. CRCs can be characterised by their primary tumour location within the colon. The left-sided colon, derived from the hindgut, includes the distal third of the transverse colon, splenic flexure, descending colon, sigmoid colon and rectum.

Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study.

Background: Metastatic DNA mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) colorectal cancer has a poor prognosis after treatment with conventional chemotherapy and exhibits high levels of tumour neoantigens, tumour-infiltrating lymphocytes, and checkpoint regulators. All of these features are associated with the response to PD-1 blockade in other tumour types. Therefore, we aimed to study nivolumab, a PD-1 immune checkpoint inhibitor, in patients with dMMR/MSI-H metastatic colorectal cancer.

Tandem repeat variation near the HIC1 (hypermethylated in cancer 1) promoter predicts outcome of oxaliplatin-based chemotherapy in patients with metastatic colorectal cancer.

Background: The hypermethylated in cancer 1/sirtuin 1 (HIC1/SIRT1) axis plays an important role in regulating the nucleotide excision repair pathway, which is the main oxaliplatin-induced damage-repair system. On the basis of prior evidence that the variable number of tandem repeat (VNTR) sequence located near the promoter lesion of HIC1 is associated with HIC1 gene expression, the authors tested the hypothesis that this VNTR is associated with clinical outcome in patients with metastatic colorectal cancer who receive oxaliplatin-based chemotherapy.

Methods: Four independent cohorts were tested.

Biomarker-driven and molecular targeted therapies for colorectal cancers.

Improved clinical selection and identification of new molecules and innovative strategies have widened treatment options and increased overall survival in metastatic colorectal cancer patients in recent years. Biomarker-driven therapies represent an emerging issue in this field and new targeted treatments are under investigation and probably will be soon adopted into daily clinical practice. In the present review, the role RAS, BRAF mutations, Her2 amplification, microsatellite instability, and CpG island methylator phenotype are discussed according to their possible roles as prognostic, predictive markers, as well as possible biomarker-driven treatment options.

DNA mismatch repair deficiency and hereditary syndromes in Latino patients with colorectal cancer.

Background: The landscape of hereditary syndromes and clinicopathologic characteristics among US Latino/Hispanic individuals with colorectal cancer (CRC) remains poorly understood.

Methods: A total of 265 patients with CRC who were enrolled in the Hispanic Colorectal Cancer Study were included in the current study. Information regarding CRC risk factors was elicited through interviews, and treatment and survival data were abstracted from clinical charts.

Effect of First-Line Chemotherapy Combined With Cetuximab or Bevacizumab on Overall Survival in Patients With KRAS Wild-Type Advanced or Metastatic Colorectal Cancer: A Randomized Clinical Trial.

Importance: Combining biologic monoclonal antibodies with chemotherapeutic cytotoxic drugs provides clinical benefit to patients with advanced or metastatic colorectal cancer, but the optimal choice of the initial biologic therapy in previously untreated patients is unknown.

Objective: To determine if the addition of cetuximab vs bevacizumab to the combination of leucovorin, fluorouracil, and oxaliplatin (mFOLFOX6) regimen or the combination of leucovorin, fluorouracil, and irinotecan (FOLFIRI) regimen is superior as first-line therapy in advanced or metastatic KRAS wild-type (wt) colorectal cancer.

Design, Setting, And Participants: Patients (≥18 years) enrolled at community and academic centers throughout the National Clinical Trials Network in the United States and Canada (November 2005-March 2012) with previously untreated advanced or metastatic colorectal cancer whose tumors were KRAS wt chose to take either the mFOLFOX6 regimen or the FOLFIRI regimen as chemotherapy and were randomized to receive either cetuximab (n = 578) or bevacizumab (n = 559).

Predictive value of TLR7 polymorphism for cetuximab-based chemotherapy in patients with metastatic colorectal cancer.

The TLR7 and TLR9 signalings are implicated in the regulation of the immune system through type-I interferon induction. Preclinical studies have demonstrated the immunomodulatory and antitumor effects of TLR7 and TLR9 agonists in combination with cetuximab. We tested the hypothesis that genetic variations in TLR7 and TLR9 and their downstream molecules IRF5 and IRF7 were associated with outcomes in metastatic colorectal cancer (mCRC) patients receiving cetuximab-based chemotherapy.

What We Know About Stage II and III Colon Cancer: It's Still Not Enough.

The introduction of oxaliplatin as adjuvant treatment for stage III colon cancer in 2004 has been the last practice changing progress in adjuvant treatment for patients with early colon cancer. Since then, many prognostic and predictive biomarkers have been studied, but only DNA mismatch repair status has been validated as having an important prognostic value. Accordingly, TNM and clinical-pathological patterns, such as pT4 lesions and lymph node sampling <12 nodes, are the main factors that guide physicians' choice regarding adjuvant treatment.