Abstract:
First study:
Keratinocyte cancer (KC) is the most prevalent malignancy in Caucasians, with incidence having continued to rise over the past 40 years. Australia has the highest reported incidence of KC, with the most extreme incidence rates recorded in North Queensland. This study aims to investigate and elucidate the environmental and host risk factors responsible for keratinocyte cancer development in the high-risk population of Australia.
In this case-control study, cases were immune-competent adults from Townsville, Australia, who had a new basal cell carcinoma or squamous cell carcinoma histologically confirmed during 2004-2009. Cases were age-matched (±5years) to immune-competent, community-based controls from Townsville with no prior history of keratinocyte cancer
This study included 112 squamous cell carcinoma (SCC), 95 basal cell carcinoma (BCC), and 122 controls. Compared to the controls, both BCC and SCC were significantly less educated; they were more likely to have light eyes and light color hair, more freckling on the face, a higher amount of solar lentigines, and a greater tendency to burn from sunlight exposure. In the multivariate analysis, we found a significant association between SCC and lower academic qualification (OR=2.35 p=0.10), freckling (OR=1.04 p<0.01), solar lentigines (OR=1.02 p=0.01), the propensity to sunburn (OR=2.75 p=0.01) and a high number of accumulated hours of sunlight exposure (OR=2.43 p=0.04). Additionally, we found a significant association between BCC and less propensity to sunburn (OR=2.68 p=0.01), freckling (OR=1.05 p<0.01), and a high or medium number of accumulated hours of sunlight exposure (high: OR=2.36 p=0.04; medium: OR=2.33 p=0.03). No significant differences were found with respect to gender, history of internal cancers, smoking, alcohol consumption, diet, or use of sun protection (wearing a hat, long-sleeved shirt, and sunscreen).
This study provides evidence that a sun-sensitive phenotype and prolonged sun exposure contribute to the risk of developing KC. Notably, the frequency of sun-protective practices did not appear to reduce the risk of KC.
Second study
The prognosis for patients with advanced melanoma has improved significantly with the introduction of monoclonal antibodies targeting immune regulatory checkpoint receptors, such as anti-programmed cell death 1 (PD-1) and anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) (101, 102), improving overall survival (OS) and reducing the risk of recurrence (101, 103, 113, 184, 185).
Therapy with immune checkpoint inhibitors (ICIs) is often associated with immune-related adverse events (irAEs) (113, 116, 186). They have been described with varying degrees of severity in different organ systems, ranging from mild inflammation to life-threatening organ damage (122). Recently published data has shown an association between irAEs and improved outcomes of patients treated with immune checkpoints inhibitor (101, 107, 113, 119, 122, 127). Given the immune mechanism of action of ICI, it is reasonable to associate the development of autoimmune events with improved outcome, as activation of the immune system could lead to both tumor response and autoimmunity (127). Reports of patients developing irAEs during treatment with ICIs have been contradictory regarding the impact of toxicity on survival outcomes, and a clear association between these two variables has not been found yet. In addition, it remains uncertain whether these observations can be explained by the role of irAEs as an indicator of drug activity (113). Finally, little is known regarding the impact of other variables on the association between irAEs and outcomes (113).
The primary aim of this cohort study was to assess the association between irAEs and disease control rate in patients with stage IV melanoma receiving first-line PD-1- based immunotherapy. Patients with complete response, partial response, and stable disease as the best overall response (BOR) according to RECIST 1.1 were included in the disease control group. Patients with progressive disease as the BOR were included in the primary resistance group. Secondary endpoints were PFS and OS.
Among 319 patients, 53% experienced at least one irAE. Patients who experienced irAEs had a higher percentage of disease control in comparison to those who did not, independently of the CTCAE grade (69.8% vs. 49.3%). In multivariate analysis, development of grade 3 and 4 irAEs was significantly associated with a protective effect for the outcome primary resistance (OR: 0.40 95% CI 0.23-0.70, p=0.001). The presence of any grade irAEs was significantly associated with increased OS (irAEs grade 1-2 HRadj: 0.61 95% CI: 0.4-0.93, p=0.02, irAEs grade 3-4 HRadj: 0.55 95% CI 0.31-0.99, p=0.04), but not with PFS (irAEs grade 1-2 HRadj: 1.21 95% CI: 0.91-1.79, p=0.16, irAEs grade 3-4 HRadj: 1.14 95% CI 0.83-2.02, p=0.24).
Conclusion: The occurrence of irAEs with laboratory expression is associated with a favorable response and OS, suggesting that irAEs may be a predictive factor in this setting.
