Over the past decade there have been significant advances in the molecular
characterization of colorectal cancer (CRC) that are driving treatment decisions. Expanded
RAS testing beyond KRAS exon 2 ...was established as
crucial for identifying patients who will respond to anti-epidermal growth factor receptor
(EGFR) therapies and low-frequency mutations in RAS/tumor heterogeneity
are gaining recognition as potential mechanisms of resistance. Despite this progress, the
fact that we do not understand why left-sided but not right-sided tumors have improved
outcomes following anti-EGFR therapy highlights our superficial understanding of this
disease. Even with few new targeted agents receiving approval in CRC, the incorporation of
next-generation sequencing into clinical decision making represents an important step
forward. Biomarkers such as BRAF mutations, microsatellite instability,
and HER2 amplification represent promising molecular aberrations with
therapies in various stages of development, and highlight the importance of companion
diagnostics in supporting targeted agents. In this review, we will discuss the importance
of incorporating biomarkers into clinical decision making and regimen selection in CRC. We
will particularly focus on the recent evidence suggesting an important role for tumor
location in selecting first-line therapy, the importance of recent advances in biomarker
development and molecular subtyping, as well as recently approved agents (regorafenib and
TAS-102) and promising targeted agents that have the potential to change the standard of
care.
Background
Colorectal cancer (CRC) incidence is increasing in adults younger than 50 years. This study evaluated clinical and molecular features to identify those features unique to early‐onset CRC ...that differentiate these patients from patients 50 years old or older.
Methods
Baseline characteristics were evaluated according to the CRC onset age with 3 independent cohorts. A fourth cohort was used to describe the impact of age on the consensus molecular subtype (CMS) prevalence.
Results
This retrospective review of more than 36,000 patients with CRC showed that early‐onset patients were more likely to have microsatellite instability (P = .038), synchronous metastatic disease (P = .009), primary tumors in the distal colon or rectum (P < .0001), and fewer BRAF V600 mutations (P < .001) in comparison with patients 50 years old or older. Patients aged 18 to 29 years had fewer adenomatous polyposis coli (APC) mutations (odds ratio OR, 0.56; 95% confidence interval CI, 0.35‐0.90; P = .015) and an increased prevalence of signet ring histology (OR, 4.89; 95% CI, 3.23‐7.39; P < .0001) in comparison with other patients younger than 50 years. In patients younger than 40 years, CMS1 was the most common subtype, whereas CMS3 and CMS4 were uncommon (P = .003). CMS2 was relatively stable across age groups. Early‐onset patients with inflammatory bowel disease were more likely to have mucinous or signet ring histology (OR, 5.54; 95% CI, 2.24‐13.74; P = .0004) and less likely to have APC mutations (OR, 0.24; 95% CI, 0.07‐0.75; P = .019) in comparison with early‐onset patients without predisposing conditions.
Conclusions
Early‐onset CRC is not only distinct from traditional CRC: special consideration should be given to and further investigations should be performed for both very young patients with CRC (18‐29 years) and those with predisposing conditions. The etiology of the high rate of CMS1 in patients younger than 40 years deserves further exploration.
Early‐onset colorectal cancer (at an age <50 years) has distinct clinical and molecular features, including increased prevalences of synchronous metastatic disease, microsatellite instability, primary tumors located in the distal colon or rectum, and consensus molecular subtype 1 and fewer mutations in BRAF V600, in comparison with colorectal cancer in patients older than 50 years. Among patients with early‐onset colorectal cancer, those aged 18 to 29 years and those with predisposing conditions are distinct from the other patients younger than 50 years, and this suggests that considering all patients with colorectal cancer younger than 50 years together may not be appropriate.
Recent data suggest that the risk of young-onset colorectal cancer (yCRC), in adults less than 50 years of age, is increasing. To confirm findings and identify contemporary trends worldwide, we ...conducted a systematic review of studies examining population-level trends in yCRC epidemiology.
We searched MEDLINE (1946-2018), EMBASE (1974-2018), CINAHL (1982-2018), and Cochrane Database of Systematic Reviews (2005-2018) for studies that used an epidemiologic design, assessed trends in yCRC incidence or prevalence, and published in English. Extracted information included country, age cut-off for yCRC, and reported trends in incidence or prevalence (e.g. annual percent change APC). We pooled similarly reported trend estimates using random effects models.
Our search yielded 8695 articles and after applying our inclusion criteria, we identified 40 studies from 12 countries across five continents. One study assessed yCRC prevalence trends reporting an APCp of + 2.6 and + 1.8 among 20-39 and 40-49 year olds, respectively. 39 studies assessed trends in yCRC incidence but with substantial variability in reporting. Meta-analysis of the most commonly reported trend estimate yielded a pooled overall APCi of + 1.33 (95% CI, 0.97 to 1.68; p < 0.0001) that is largely driven by findings from North America and Australia. Also contributing to these trends is the increasing risk of rectal cancer as among 14 studies assessing cancer site, nine showed an increased risk of rectal cancer in adults less than 50 years with APCi up to + 4.03 (p < 0.001).
Our systematic review highlights increasing yCRC risk in North America and Australia driven by rising rectal cancers in younger adults over the past two decades.
Colorectal cancers are classified as right/left-sided based on whether they occur before/after the splenic flexure, with established differences in molecular subtypes and outcomes. However, it is ...unclear if this division is optimal and whether precise tumor location provides further information.
In 1,876 patients with colorectal cancer, we compared mutation prevalence and overall survival (OS) according to side and location. Consensus molecular subtype (CMS) was compared in a separate cohort of 608 patients.
Mutation prevalence differed by side and location for
, and
Within left- and right-sided tumors, there remained substantial variations in mutation rates. For example, within right-sided tumors,
mutations decreased from 70% for cecal, to 43% for hepatic flexure location (
= 0.0001), while
V600 mutations increased from 10% to 22% between the same locations (
< 0.0001). Within left-sided tumors, the sigmoid and rectal region had more
mutations (
= 0.027), less
(
= 0.0009),
(
= 0.0033), or
mutations (
< 0.0001), and less MSI (
< 0.0001) than other left-sided locations. Despite this, a left/right division preceding the transverse colon maximized prognostic differences by side and transverse colon tumors had K-modes mutation clustering that appeared more left than right sided. CMS profiles showed a decline in CMS1 and CMS3 and rise in CMS2 prevalence moving distally.
Current right/left classifications may not fully recapitulate regional variations in tumor biology. Specifically, the sigmoid-rectal region appears unique and the transverse colon is distinct from other right-sided locations.
.
Research suggests that colorectal cancer (CRC) is associated with mental health disorders, primarily anxiety and depression. To synthesize this evidence, we conducted a systematic review and ...meta-analysis of studies evaluating the onset of anxiety and depression among patients with CRC. We searched EMBASE and Medline from inception to June 2022. We included original, peer-reviewed studies that: used an epidemiologic design; included patients with CRC and a comparator group of individuals without cancer; and evaluated anxiety and depression as outcomes. We used random effects models to obtain pooled measures of associations. Quality assessment was completed using the Newcastle-Ottawa scale. Of 7326 articles identified, 8 were eligible; of which 6 assessed anxiety and depression and 2 assessed depression only. Meta-analyses showed a non-significant association between CRC and anxiety (pooled HR 1.67; 95% CI 0.88 to 3.17) and a significant association between CRC and depression (pooled HR 1.78; 95% CI 1.23 to 2.57). Predictors of anxiety and depression among patients with CRC included clinical characteristics (e.g., comorbidities, cancer stage, cancer site), cancer treatment (e.g., radiotherapy, chemotherapy, colostomy), and sociodemographic characteristics (e.g., age, sex). The impacts of anxiety and depression in patients with CRC included increased mortality and decreased quality of life. Altogether, our systematic review and meta-analysis quantified the risks and impacts of CRC on anxiety and depression, particularly an increased risk of depression after CRC diagnosis. Findings provide support for oncologic care that encompasses mental health supports for patients with CRC.
Immunotherapy-based monotherapy treatment in metastatic pancreatic ductal adenocarcinoma (mPDAC) has shown limited benefit outside of the mismatch repair deficiency setting, while safety and efficacy ...of combining dual-checkpoint inhibitor immunotherapy with chemotherapy remains uncertain. Here, we present results from the CCTG PA.7 study (NCT02879318), a randomized phase II trial comparing gemcitabine and nab-paclitaxel with and without immune checkpoint inhibitors durvalumab and tremelimumab in 180 patients with mPDAC. The primary endpoint was overall survival. Secondary endpoints included progression-free survival and objective response rate. Results of the trial were negative as combination immunotherapy did not improve survival among the unselected patient population (p = 0.72) and toxicity was limited to elevation of lymphocytes in the combination immunotherapy group (p = 0.02). Exploratory baseline circulating tumor DNA (ctDNA) sequencing revealed increased survival for patients with KRAS wildtype tumors in both the combination immunotherapy (p = 0.001) and chemotherapy (p = 0.004) groups. These data support the utility of ctDNA analysis in PDAC and the prognostic value of ctDNA-based KRAS mutation status.
Platelets serve as “first responders” during normal wounding and homeostasis. Arising from bone marrow stem cell lineage megakaryocytes, anucleate platelets can influence inflammation and immune ...regulation. Biophysically, platelets are optimized due to size and discoid morphology to distribute near vessel walls, monitor vascular integrity, and initiate quick responses to vascular lesions. Adhesion receptors linked to a highly reactive filopodia-generating cytoskeleton maximizes their vascular surface contact allowing rapid response capabilities. Functionally, platelets normally initiate rapid clotting, vasoconstriction, inflammation, and wound biology that leads to sterilization, tissue repair, and resolution. Platelets also are among the first to sense, phagocytize, decorate, or react to pathogens in the circulation. These platelet first responder properties are commandeered during chronic inflammation, cancer progression, and metastasis. Leaky or inflammatory reaction blood vessel genesis during carcinogenesis provides opportunities for platelet invasion into tumors. Cancer is thought of as a non-healing or chronic wound that can be actively aided by platelet mitogenic properties to stimulate tumor growth. This growth ultimately outstrips circulatory support leads to angiogenesis and intravasation of tumor cells into the blood stream. Circulating tumor cells reengage additional platelets, which facilitates tumor cell adhesion, arrest and extravasation, and metastasis. This process, along with the hypercoagulable states associated with malignancy, is amplified by IL6 production in tumors that stimulate liver thrombopoietin production and elevates circulating platelet numbers by thrombopoiesis in the bone marrow. These complex interactions and the “first responder” role of platelets during diverse physiologic stresses provide a useful therapeutic target that deserves further exploration.
Although dual HER2 inhibition has shown promising clinical activity in patients with RAS wild-type HER2-positive metastatic colorectal cancer, predictive biomarkers of response/resistance are less ...well characterized. Activating HER2/RTK/MAPK genomic alterations appears to blunt the clinical benefit of dual anti-HER2 therapy and may hold a potential albeit partial role in patient selection. See related article by Randon et al., p. 436.
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