Angiogenesis Inhibitors and Immunomodulation in Renal Cell Cancers: The Past, Present, and Future.

Angiogenesis inhibitors have been adopted into the standard armamentarium of therapies for advanced-stage renal cell carcinomas (RCC), but more recently, combination regimens with immune checkpoint inhibitors have demonstrated better outcomes. Despite this, the majority of affected patients still eventually experience progressive disease due to therapeutic resistance mechanisms, and there remains a need to develop novel therapeutic strategies. This article will review the synergistic mechanisms behind angiogenesis and immunomodulation in the tumor microenvironment and discuss the pre-clinical and clinical evidence for both clear-cell and non-clear-cell RCC, exploring opportunities for future growth in this exciting area of drug development.

Clinical and molecular profile of young adults with early-onset colorectal cancer: Experience from four Australian tertiary centers.

BACKGROUND: Patients with early-onset colorectal cancer (EO-CRC) have unique characteristics. Contemporary data on the pathological and molecular features, and survival of EO-CRC are limited in the Australian context. AIM: To determine the demographic, histopathological and molecular characteristics of adults with EO-CRC, and their survival. METHODS: We conducted a retrospective study of adults aged 18-49 years with EO-CRC who were referred to the Illawarra Shoalhaven Local Health District, South Eastern Sydney Local Health District and Royal North Shore Hospital in New South Wales, Australia, between 2014 and 2018. RESULTS: Of 257 patients included, 94 (37%) patients presented with de novo metastatic CRC, 80% patients had near-average risk family history and 89% had a symptomatic presentation. In 159 patients with nonmetastatic disease at diagnosis, stage III disease (OR 3.88 [95% CI: 1.13-13.3]; p = .03) and the presence of perineural invasion (PNI) (OR 6.63 [95% CI: 2.21-19.84]; p = .001) were risk factors associated with the development of metastatic disease. Among 94 patients with de novo metastatic disease, 43 (43%) and 12 (14%) patients harbored a KRAS or BRAF V600E mutation, respectively. The median overall survival was 29.6 months (95% CI: 20.4-38.7). BRAF mutation was associated with inferior survival (HR 3.00 [95% CI: 1.30-6.94]; p = .01). CONCLUSION: The prevalence of KRAS and BRAF mutations in our cohort is similar to the overseas experience. Stage III disease at diagnosis, presence of PNI and BRAF mutation are adverse prognostic indicators. A better understanding of the molecular landscape is needed for this patient cohort, so as to better tailor prevention strategies, screening and treatment pathways.

Efficacy of immune checkpoint inhibitors in older adults with advanced stage cancers: A meta-analysis.

OBJECTIVES: There is uncertainty whether older patients derive a similar benefit from immune checkpoint inhibitors (ICI) as younger patients. We performed a meta-analysis of ICI trials in advanced cancers to better estimate treatment benefit in the older population. MATERIALS AND METHODS: We performed an electronic search for randomized trials of ICI, either as monotherapy or in combination with other agents. Hazard ratios (HR) for subgroups defined by different age cut-offs were extracted. Pooled overall survival (OS) treatment estimates were calculated using the inverse variance weighted method. RESULTS: In nineteen trials comparing ICI monotherapy versus non-ICI treatment, there was no significant treatment-age interaction (age ≥ 65 years: N = 6064, HR 0.73; age < 65 years: N = 7250, HR 0.79; P-interaction = 0.27). Findings were similar at older age cut-offs of 70 years (age ≥ 70 years: N = 433, HR = 0.93; age < 70 years: N = 169, HR = 0.95; P-interaction = 0.91) and 75 years (age ≥ 75 years: N = 139, HR = 0.75; age < 75 years: N = 1133, HR = 0.61; P-interaction = 0.72) respectively, and for trials of ICI combination therapy. CONCLUSION: ICI therapy improves OS in both younger and older patients with advanced cancers, and the magnitude of improvement does not depend on age. Patient selection for ICI therapy should be done based on performance status and adequate organ function independently of age.