The incidence of early-onset colorectal cnacer-ie, colorectal cancer diagnosed in patients under the age of 50 years- has been increasing around the world. This Series paper provides a comprehensive ...review on the topic of early-onset colorectal cancer, including examining the epidemiology of early-onset colorectal cancer around the world, clinical and pathological features, genetic and epigenetic landscapes, and emerging data on the clinical risk factors associated with this malignancy. Evidence-based approaches to prevention and early detection are also presented.
Christopher Lieu, co-director of gastrointestinal medical oncology and the associate director for clinical research at the University of Colorado Cancer Center (CO, USA) discusses the importance of ...biomarker testing in metastatic colorectal cancer to inform personalized patient care.
The incidence rates of colorectal cancers are increasing in young adults. The objective of this study was to investigate genomic differences between tumor samples collected from younger and older ...patients with colorectal cancer.
DNA was extracted from 18,218 clinical specimens, followed by hybridization capture of 3,769 exons from 403 cancer-related genes and 47 introns of 19 genes commonly rearranged in cancer. Genomic alterations (GA) were determined, and association with patient age and microsatellite stable/microsatellite instability high (MSS/MSI-H) status established.
Overall genomic alteration rates in the younger (<40) and older (≥50) cohorts were similar in the majority of the genes analyzed. Gene alteration rates in the microsatellite stable (MSS) younger and older cohorts were largely similar, with several notable differences. In particular,
(FDR < 0.01) and
(FDR = 0.01) alterations were more common in younger patients with colorectal cancer, and
(FDR < 0.01),
(FDR < 0.01),
(FDR < 0.01), and
(FDR < 0.01) were more commonly altered in older patients with colorectal cancer. In the MSI-H cohort, the majority of genes showed similar rate of alterations in all age groups, but with significant differences seen in
(FDR < 0.01),
(FDR < 0.01), and KRAS (FDR < 0.01).
Tumors from younger and older patients with colorectal cancer demonstrated similar overall rates of genomic alteration. However, differences were noted in several genes relevant to biology and response to therapy. Further study will need to be conducted to determine whether the differences in gene alteration rates can be leveraged to provide personalized therapies for young patients with early-onset sporadic colorectal cancer.
An increasing number of studies are describing potential uses of circulating tumour DNA (ctDNA) in the care of patients with colorectal cancer. Owing to this rapidly developing area of research, the ...Colon and Rectal-Anal Task Forces of the United States National Cancer Institute convened a panel of multidisciplinary experts to summarize current data on the utility of ctDNA in the management of colorectal cancer and to provide guidance in promoting the efficient development and integration of this technology into clinical care. The panel focused on four key areas in which ctDNA has the potential to change clinical practice, including the detection of minimal residual disease, the management of patients with rectal cancer, monitoring responses to therapy, and tracking clonal dynamics in response to targeted therapies and other systemic treatments. The panel also provides general guidelines with relevance for ctDNA-related research efforts, irrespective of indication.
Fibroblast growth factor (FGF) signaling regulates cell proliferation, differentiation, survival, angiogenesis, and wound healing. Compelling evidence for deregulated FGF signaling in tumorigenesis ...continues to emerge, and a growing body of research suggests that FGF may also play an integral role in the resistance to anti-VEGF therapy. Although agents targeting FGF signaling are early in development, the potential to target both the VEGF and FGF pathways may translate into improvements in the clinical care of cancer patients.
Sporadic colorectal cancer has traditionally been viewed as a malignancy of older individuals. However, as the global prevalence of the disease diagnosed in younger individuals (<50 years) is ...expected to increase within the next decade, greater recognition is now being given to early-onset colorectal cancer. The cause of the predicted rise in prevalence is largely unknown and probably multifactorial. In this Series paper, we discuss the potential underlying causes of early-onset colorectal cancer, the role of energy balance, biological and genomic mechanisms (including microbiome aspects), and the treatment of early-onset colorectal cancer. We have specifically considered the psychosocial challenges of being diagnosed with colorectal cancer at younger age and the potential financial toxicity that might ensue. This Series paper brings a comprehensive review based on the existing data in the hopes of optimising the overall outcomes for patients with early-onset colorectal cancer.
Circulating angiogenic factors are altered in patients with mCRC receiving bevacizumab. Evaluation of alterations in levels of VEGF ligands may provide insights into possible resistance mechanisms.
...PlGF, VEGF-A, VEGF-C, and VEGF-D were measured from two cohorts of patients. Sequential plasma samples were obtained from a discovery cohort of 42 patients treated with chemotherapy and bevacizumab. A validation cohort included plasma samples from a cross-sectional of 403 patients prior to chemotherapy, or after progression on a regimen with or without bevacizumab.
In the discovery cohort, VEGF-C was increased prior to progression and at progression (+49% and +95%, respectively, p<0.01), consistent with previously reported elevations in PlGF. Levels of VEGF-D were increased (+23%) at progression (p=0.05). In the validation cohort, samples obtained from patients after progression on a regimen with bevacizumab had higher levels of PlGF and VEGF-D (+43% and +6%, p=0.02, p=0.01, respectively) compared to untreated patients, but failed to validate the increase in VEGF-C seen in the first cohort. Patients who progressed on chemotherapy with bevacizumab had significantly elevated levels of PlGF (+88%) but not VEGF-C and VEGF-D compared to patients treated with chemotherapy alone. Elevations of PlGF and VEGF-D appeared transient and returned to baseline with a half-life of 6 weeks.
Increases in PlGF and VEGF-D were observed after progression on chemotherapy with bevacizumab. These changes appear to be reversible after discontinuing therapy. These ligands are associated with resistance to bevacizumab-containing chemotherapy in mCRC, but causation remains to be established.
The WNT signaling cascade is integral in numerous biological processes including embryonic development, cell cycle regulation, inflammation, and cancer. Hyperactivation of WNT signaling secondary to ...alterations to varying nodes of the pathway have been identified in multiple tumor types. These alterations converge into increased tumorigenicity, sustained proliferation, and enhanced metastatic potential. This review seeks to evaluate the evidence supporting the WNT pathway in cancer, the therapeutic strategies in modulating this pathway, and potential challenges in drug development.
Implications for Practice:
The WNT signaling cascade is integral in numerous biological processes, including cell cycle regulation and cancer. Alterations in WNT signaling have been identified in numerous tumor types, and in recent years, numerous WNT pathway modulators have been tested in preclinical studies. These agents are now being investigated in the clinical arena, and this review describes the WNT pathway and therapeutics currently in development.
The WNT signaling cascade is integral in numerous biological processes, including cell cycle regulation and cancer. Alterations in WNT signaling have been identified in numerous tumor types, and in recent years, numerous WNT pathway modulators have been tested in preclinical studies. These agents are now being investigated in the clinical arena, and this review describes the WNT pathway and therapeutics currently in development.
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