Metastasis continues to be the primary cause of all cancer-related deaths despite the recent advancements in cancer treatments. To evaluate the role of mutations in overall survival (OS) and treatment outcomes, we analyzed 957 metastatic patients with seven major cancer types who had available molecular testing results with a FoundationOne CDx^® panel. The most prevalent genes with somatic mutations were TP53, KRAS, APC, and LRP1B. In this analysis, these genes had mutation frequencies higher than in publicly available datasets. We identified that the somatic mutations were seven mutually exclusive gene pairs and an additional fifty-two co-occurring gene pairs. Mutations in the mutually exclusive gene pair APC and CDKN2A showed an opposite effect on the overall survival. However, patients with CDKN2A mutations showed significantly shorter OS (HR: 1.72, 95% CI: 1.34–2.21, p < 0.001) after adjusting for cancer type, age at diagnosis, and sex. Five-year post metastatic diagnosis survival analysis showed a significant improvement in OS (median survival 28 and 43 months in pre-2015 and post-2015 metastatic diagnosis, respectively, p = 0.00021) based on the year of metastatic diagnosis. Although the use of targeted therapies after metastatic diagnosis prolonged OS, the benefit was not statistically significant. However, longer five-year progression-free survival (PFS) was significantly associated with targeted therapy use (median 10.9 months (CI: 9.7–11.9 months) compared to 9.1 months (CI: 8.1–10.1 months) for non-targeted therapy, respectively, p = 0.0029). Our results provide a clinically relevant overview of the complex molecular landscape and survival mechanisms in metastatic solid cancers.

Immune-related adverse events (IRAEs) are a common yet problematic phenomenon in patients who are treated with immune checkpoint inhibitors (ICIs). Current research efforts have explored the exact pathophysiology of IRAEs in the clinical setting. However, a rare subset of IRAEs that is less highlighted and may cause detrimental effects are hematological IRAEs (heme-IRAEs). Of note, immune-induced eosinophilia itself is a heme-IRAE that is worthy of further investigation. In this report, we present two cases of advanced staged non-small cell lung cancer (NSCLC) treated with single-agent pembrolizumab, and who subsequently sustained markedly elevated eosinophil counts (EEC) on laboratory findings. The two patients were Caucasian and both were diagnosed with NSCLC, although with differing histologies: a 76-year-old male with adenocarcinoma and a 66-year-old female with squamous cell carcinoma. Programmed death-ligand 1 (PD-L1) expression was detected via immunohistochemistry (IHC) and molecular tumor profiling did not show any actionable oncogenic mutations. Both patients were treatment-naïve and received pembrolizumab as first-line systemic therapy. The male patient, a former heavy smoker, underwent 18 months of pembrolizumab treatment before high eosinophil counts and was diagnosed with immunotherapy-related apoptotic colopathy after colonoscopy. Following pembrolizumab discontinuation, he remains under surveillance with good disease control and does not show any ongoing symptoms. The female patient, a never-smoker, underwent 15 cycles of pembrolizumab before the discontinuation of the treatment after consistently high levels of eosinophil counts. Both patients were treated with systemic corticosteroids after the discontinuation of immunotherapy, and their eosinophil levels returned to normal values. However, the female patient declined any further therapy and expired 24 months after the discontinuation of immunotherapy. Immune-induced eosinophilia is a rare event and reported in only 2.9% of NSCLC cases. Outcomes in the two patients differed, indicating that further research related to eosinophilia and its causes in the context of varying histologies and clinical profiles of patients is warranted.

Non-small cell lung cancer is a devastating disease and with the advent of targeted therapies and molecular testing, the decision-making process has become complex. While established guidelines and pathways offer some guidance, they are difficult to utilize in a busy community practice and are not always implemented in the community. The rationale of the study was to identify a cohort of patients with lung adenocarcinoma at a City of Hope community site (n = 11) and utilize their case studies to develop a decision-making framework utilizing fast-and-frugal tree (FFT) heuristics. Most patients had stage IV (N = 9, 81.8%) disease at the time of the first consultation. The most common symptoms at initial presentation were cough (N = 5, 45.5%), shortness of breath (N = 3, 27.2%), and weight loss (N = 3, 27.2%). The Eastern Cooperative Oncology Group (ECOG) performance status ranged from 0-1 in all patients in this study. Distribution of molecular drivers among the patients were as follows: EGFR (N = 5, 45.5%), KRAS (N = 2, 18.2%), ALK (N = 2, 18.2%), MET (N = 2, 18.2%), and RET (N = 1, 9.1%). Seven initial FFTs were developed for the various case scenarios, but ultimately the decisions were condensed into one FFT, a molecular stage IV FFT, that arrived at accurate decisions without sacrificing initial information. While these FFT decision trees may seem arbitrary to an experienced oncologist at an academic site, the simplicity of their utility is essential for community practice where patients often do not get molecular testing and are not assigned proper therapy.

Lung cancer patients undergoing systemic treatment with immune checkpoint inhibitors (ICIs) can lead to severe immune-related adverse events (irAEs) that may warrant immediate hospitalization. Patients with thoracic malignancies hospitalized at City of Hope while undergoing treatment with ICIs were identified. Pathology and available next-generation sequencing (NGS) data, including the programmed death-ligand 1 (PD-L1) status and clinical information, including hospitalizations, invasive procedures, and the occurrence of irAEs, were collected. Unpaired T-tests, Chi-square/Fisher’s exact test, and logistic regression were used to analyze our cohort. The overall survival (OS) was calculated and compared using univariate and multivariate COX models. Ninety patients with stage IV lung cancer were admitted after ICI treatment. Of those patients, 28 (31.1%) had documented irAEs. Genomic analyses showed an enrichment of LRP1B mutations (n = 5/6 vs. n = 7/26, 83.3% vs. 26.9%; odds ratio (OR) (95% confidence interval (CI): 13.5 (1.7–166.1); p < 0.05) and MLL3 mutations (n = 4/6, 66.7% vs. n = 5/26, 19.2%; OR (95% CI): 8.4 (1.3–49.3), p < 0.05) in patients with irAE occurrences. Patients with somatic genomic alterations (GAs) in MET (median OS of 2.7 vs. 7.2 months; HR (95% CI): 3.1 (0.57–17.1); p < 0.05) or FANCA (median OS of 3.0 vs. 12.4 months; HR (95% CI): 3.1 (0.70–13.8); p < 0.05) demonstrated a significantly shorter OS. Patients with irAEs showed a trend toward improved OS (median OS 16.4 vs. 6.8 months, p = 0.19) compared to hospitalized patients without documented irAEs. Lung cancer patients who required treatment discontinuance or interruption due to irAEs (n = 19) had significantly longer OS (median OS 18.5 vs. 6.2 months; HR (95% CI): 0.47 (0.28–0.79); p < 0.05). Our results showed a significant survival benefit in lung cancer patients hospitalized due to irAEs that necessitated a treatment interruption. Patients with positive somatic GAs in MET and FANCA were associated with significantly worse OS compared to patients with negative GAs.