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Colorectal cancer (CRC) is the third leading cancer diagnosed globally and an important cause of cancer-related mortality. Of interest, while we have witnessed a declining incidence trend over the past few decades in the older population, incidence rates for adolescents and young adults have been increasing steadily. Several factors may well explain this apparent epidemic in the young, namely a lack of routine screening and emerging lifestyle issues such as obesity, lack of exercise, and dietary factors. It is known that both environmental and genetic factors can increase the likelihood of developing CRC. Although inherited susceptibility is associated with the most striking increases in risk, and must always be considered in a young patient with CRC, the majority of CRCs are in fact sporadic rather than familial. Early-onset CRC is a truly heterogeneous disease, with mounting evidence to suggest that this patient population has a distinctive molecular profile, very different to late-onset CRC cases. Currently, both younger and older patients with CRC are treated in essentially the same manner, but with a better understanding of the molecular mechanisms underlying CRC in the young, we will have the opportunity to specifically tailor screening and clinical management strategies in this unique patient population in an effort to improve outcomes. The aim of this review is to outline our current knowledge of the distinguishing features of early-onset CRC, the ongoing research efforts, and the evolving evidence in this field.

Background The causative factors for the recent increase in early-onset colorectal cancer (EO-CRC) incidence are unknown. We sought to determine if early-onset disease is clinically or genomically distinct from average-onset colorectal cancer (AO-CRC). Methods Clinical, histopathologic, and genomic characteristics of EO-CRC patients (2014-2019), divided into age 35 years and younger and 36-49 years at diagnosis, were compared with AO-CRC (50 years and older). Patients with mismatch repair deficient tumors, CRC-related hereditary syndromes, and inflammatory bowel disease were excluded from all but the germline analysis. All statistical tests were 2-sided. Results In total, 759 patients with EO-CRC (35 years, n = 151; 36-49 years, n = 608) and AO-CRC (n = 687) were included. Left-sided tumors (35 years and younger = 80.8%; 36-49 years = 83.7%; AO = 63.9%; P < .001 for both comparisons), rectal bleeding (35 years and younger = 41.1%; 36-49 years = 41.0%; AO = 25.9%; P = .001 and P < .001, respectively), and abdominal pain (35 years and younger = 37.1%; 36-49 years = 34.0%; AO = 26.8%; P = .01 and P = .005, respectively) were more common in EO-CRC. Among microsatellite stable tumors, we found no differences in histopathologic tumor characteristics. Initially, differences in TP53 and Receptor Tyrosine Kinase signaling pathway (RTK-RAS)alterations were noted by age. However, on multivariate analysis including somatic gene analysis and tumor sidedness, no statistically significant differences at the gene or pathway level were demonstrated. Among advanced microsatellite stable CRCs, chemotherapy response and survival were equivalent by age cohorts. Pathogenic germline variants were identified in 23.3% of patients 35 years and younger vs 14.1% of AO-CRC (P = .01). Conclusions EO-CRCs are more commonly left-sided and present with rectal bleeding and abdominal pain but are otherwise clinically and genomically indistinguishable from AO-CRCs. Aggressive treatment regimens based solely on the age at CRC diagnosis are not warranted.

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Hepatocellular carcinoma is a common malignancy worldwide, rapidly rising in incidence. While there have been some developments in advancing therapeutic options in this disease, these have admittedly been modest to date, and as a result, this is a patient population with an inherently poor prognosis. Currently, sorafenib remains the only established systemic therapy proven to increase the overall survival of patients with advanced disease. The approval of sorafenib in 2007 ushered in the era of targeted therapies. Several phase 2 and 3 clinical trials have failed however to improve on sorafenib in the first-line setting, and no single agent has been demonstrated to impact outcomes after sorafenib failure. Having reached somewhat of an impasse in terms of drug development in hepatocellular carcinoma, enthusiasm in the field has moved toward innovative approaches such as molecular characterization and immunotherapy in an attempt to impact survival. This review highlights the current endeavors in terms of experimental research for patients with advanced hepatocellular carcinoma.

Hepatocellular carcinoma (HCC), the fifth most common cancer globally and third leading cause of cancer-related mortality is a heterogeneous disease with a highly variable clinical course. The inherent biological diversity of hepatic carcinomas may hinder therapeutic decision making and prognostication for patients. One distinct, albeit rare, subtype of primary hepatic carcinoma is combined intrahepatic cholangiocarcinoma and hepatocellular carcinoma (cHCC-ICC), which carries an overall worse prognosis than either HCC or intrahepatic cholangiocarcinoma (ICC) alone. cHCC-ICC is a primary hepatic neoplasm containing unequivocal elements of both HCC and ICC. This review will focus on understanding further the histopathology of this unique tumor type, current treatment approaches and prognoses for this rare patient population.

In this manuscript, we demonstrate that hepatic arterial infusion chemotherapy (HAIC) may provide comparable survival to resection for patients with liver-limited intrahepatic cholangiocarcinoma (IHC) and lymph node metastases (LNM). HAIC is an attractive form of liver-directed therapy and can be offered with lower morbidity and mortality risk than liver resection, while also providing adequate disease control for traditionally unresectable patients.Moreover, this manuscript bridges the translational connection between genomics and clinical care by analyzing the next generation sequencing (NGS) data for this cohort of patients, treated with both modalities. Patients with N1 disease and high-risk alterations, which included mutations in KRAS and TP53, and deletions in CDKN2A and CDKN2B, had significantly worse prognosis, regardless of treatment. Conversely, mutations in IDH1 and IDH2 as well as FGFR2 fusion events, had no association with survival. Our results support the routine use of NGS in all patients with IHC, which may provide valuable insights into which patients are unlikely to derive benefit from any form of liver-directed therapy Research.

Purpose: Immune checkpoint inhibition (ICI) alone is not active in mismatch repair–proficient (MMR-P) metastatic colorectal cancer (mCRC), nor does radiotherapy alone result in objective systemic benefit. However, combined radiotherapy plus ICI can induce systemic antitumor immunity in preclinical and clinical models. Patients and Methods: In this single-center, phase II study, patients with chemotherapy-refractory MMR-P mCRC received durvalumab 1,500 mg plus tremelimumab 75 mg every 4 weeks plus radiotherapy. The primary endpoint was objective response rate (ORR) in nonirradiated lesions. Treatment and efficacy were correlated with peripheral immune cell profiles. Results: We enrolled 24 patients, and report outcomes after a median follow-up of 21.8 (range: 15.9–26.3) months. The ORR was 8.3% (2 patients) [95% confidence interval (CI), 1.0–27.0]. The median progression-free survival was 1.8 (95% CI, 1.7–1.9) months, median overall survival was 11.4 (95% CI, 10.1–17.4) months. Twenty five percent of patients (n = 6) had treatment-related grade 3–4 adverse events. We observed increased circulating CD8+ T lymphocyte activation, differentiation, and proliferation in patients with objective response. Conclusions: This combination of radiotherapy plus ICI study did not meet the prespecified endpoint criteria to be considered worthwhile for further study. However, rare instances of systemic immune augmentation and regression in nonirradiated lesions were observed (an abscopal response). Combination durvalumab and tremelimumab plus radiotherapy is feasible in MMR-P mCRC with a manageable safety profile. Further studies of novel immunotherapy combinations, and identification of biomarkers predictive of abscopal response are warranted.