Background: Identifying the projected incidence of hepatobiliary cancers and recognizing patient cohorts at increased risk can help develop targeted interventions and resource allocation. The expected incidence of subtypes of hepatobiliary cancers in different age groups, races, and genders remains unknown. Methods: Historical epidemiological data from the Surveillance, Epidemiology, and End Results (SEER) database was used to project future incidence of hepatobiliary malignancies in the United States and identify trends by age, race, and gender. Patients ≥18 years of age diagnosed with a hepatobiliary malignancy between 2001 and 2017 were included. US Census Bureau 2017 National Population projects provided the projected population from 2017 to 2029. Age–Period–Cohort forecasting model was used to estimate future births cohort-specific incidence. All analyses were completed using R Statistical Software. Results: We included 110381 historical patients diagnosed with a hepatobiliary malignancy between 2001 and 2017 with the following subtypes: hepatocellular cancer (HCC) (68%), intrahepatic cholangiocarcinoma (iCCA) (11.5%), gallbladder cancer (GC) (8%), extrahepatic cholangiocarcinoma (eCCA) (7.6%), and ampullary cancer (AC) (4%). Our models predict the incidence of HCC to double (2001 to 2029) from 4.5 to 9.03 per 100,000, with the most significant increase anticipated in patients 70–79 years of age. In contrast, incidence is expected to continue to decline among the Asian population. Incidence of iCCA is projected to increase, especially in the white population, with rates in 2029 double those in 2001 (2.13 vs. 0.88 per 100,000, respectively; p < 0.001). The incidence of GC among the black population is expected to increase. The incidence of eCCA is expected to significantly increase, especially among the Hispanic population, while that of AC will remain stable. Discussion: The overall incidence of hepatobiliary malignancies is expected to increase in the coming years, with certain groups at increased risk. These findings may help with resource allocation when considering screening, treatment, and research in the coming years.

Background: Rates of early-onset colorectal cancer (eoCRC), defined as disease diagnosed at <50 years of age, are increasing. The incidence and spectrum of somatic and pathogenic germline variants (PGV) in this population are not well understood. Methods: This cross-sectional study leveraged Tempus’ clinicogenomic database, including de-identified records of patients diagnosed with CRC between 2000–2022, to analyze and compare eoCRC and average-onset colorectal cancer (aoCRC, disease diagnosed ≥50 years of age) patients. The frequency and spectrum of somatic mutations and PGVs in patients with eoCRC and aoCRC were evaluated and compared. Results: Among 11,006 participants in this study, 57% were male, 76% were white, and 80% had stage 4 disease. Within the total cohort, 2379 had eoCRC and 8627 had aoCRC. Among patients with eoCRC, 4.2% had a tumor with high microsatellite instability and/or deficient mismatch repair (MSI-H/dMMR) and 6.8% with aoCRC had an MSI-H/dMMR tumor (p < 0.001). The most frequent somatic mutations involved TP53, APC, and KRAS, with the most significant difference in BRAF, which was more frequently mutated in aoCRC (9.8% vs. 4.7%, p < 0.0001). In total, 1413 (59.4%) eoCRC and 4898 (56.8%) aoCRC patients had matched normal specimen (blood or saliva) sequencing and a PGV was identified in 6.9% of eoCRC and 5.0% of aoCRC patients. Conclusions: Somatic and germline mutation profiles were similar for eoCRC and aoCRC patients and may not adequately explain differences in tumor behavior and age of disease onset.

(1) Background: Cabozantinib, a multikinase inhibitor, is approved by the Food and Drug Administration (FDA) for the treatment of advanced hepatocellular carcinoma (HCC) following progression on sorafenib. Recently, atezolizumab plus bevacizumab has been approved in the first line setting for advanced HCC and has become the new standard of care. Whether cabozantinib improves outcomes following progression on immunotherapy remains unknown. We describe the clinical outcomes following treatment with immunotherapy in patients with advanced HCC who received cabozantinib. (2) Methods: We conducted a multicentric, retrospective analysis of patients with advanced HCC diagnosed between 2010–2021 at Mayo Clinic in Minnesota, Arizona, and Florida who received cabozantinib. Median overall survival and progression free survival analyses were performed using the Kaplan–Meier method. Adverse events were determined using Common Terminology Criteria for Adverse Events (CTCAE). (3). Results: We identified 26 patients with advanced HCC who received cabozantinib following progression on immunotherapy. Median progression free survival on cabozantinib therapy was 2.1 months (95% CI: 1.3–3.9) and median overall survival from time of cabozantinib initiation was 7.7 months (95% CI: 5.3–14.9). (4) Conclusion: The optimal sequencing of therapy for patients with advanced HCC following progression on immunotherapy remains unknown. Our study demonstrates that patients may benefit from treatment with cabozantinib following progression on immunotherapy.

Primary tumor resection and liver transplantation are the only curative treatment options for the management of cholangiocarcinoma (CCA). However, for patients with advanced or metastatic disease, palliative systemic therapy remains the only treatment option. The development of targeted therapeutics has begun to shift the treatment paradigm in CCA. Targets of interest in CCA include mutated isocitrate dehydrogenase-1 (mIDH-1), human epidermal growth factor receptor 2 (HER2) overexpression/amplification, and fibroblast growth factor receptor 2 (FGFR2) fusion, in addition to less frequently observed targets such as BRAF V600E, deficient mismatch repair/high microsatellite instability (dMMR/MSI-H), and high tumor mutation burden (TMB-H). These targets are observed in varying frequency among patients with intrahepatic CCA and extrahepatic CCA. Multiple novel therapies have been developed to exploit each of these targets, with some having received United States Food and Drug Administration approval for use in the second-line setting. In the current review, we discuss targets of interest in CCA and summarize current evidence evaluating available therapies directed at these targets.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide. Most patients with HCC have advanced disease at initial diagnosis, and sorafenib has been the only systemic treatment option for more than a decade in patients with advanced, unresectable HCC. However, there has been a dramatic change in the treatment algorithm in the last several years, given new drug approvals in the field. Most importantly, the combination of atezolizumab and bevacizumab has demonstrated clinically meaningful benefits in terms of response rate, progression-free survival, and overall survival compared to sorafenib in the first-line setting. Recently a phase III trial showed that the combination of durvalumab with a single dose of tremelimumab improved overall survival compared to sorafenib, while durvalumab monotherapy was found to be noninferior to sorafenib, making it an attractive alternative single agent in selected patient populations. As immunotherapy makes its way into the therapeutic landscape of HCC, other novel targeted therapies, such as lenvatinib, cabozantinib, ramucirumab, and regorafenib, have also been approved by regulatory authorities for treatment of advanced, unresectable HCC. This review article focuses on the first-line systemic treatment options for HCC while addressing some of the most important questions aimed at optimization of HCC treatment.