Abstract
Matched-targeted and immune checkpoint therapies have improved survival in cancer patients, but tumor heterogeneity contributes to drug resistance. Our study categorized gene mutations from next generation sequencing (NGS) into three core processes. This annotation helps decipher complex biologic interactions to guide therapy. We collected NGS data on 145 patients who have failed standard therapy (2016 to 2018). One hundred and forty two patients had data for tissue (Caris MI/X) and plasma cell-free circulating tumor DNA (Guardant360) platforms. The mutated genes were categorized into cell fate (CF), cell survival (CS), and genome maintenance (GM). Comparative analysis was performed for concordance and discordance, unclassified mutations, trends in TP53 alterations, and PD-L1 expression. Two gene mutation maps were generated to compare each NGS platform. Mutated genes predominantly matched to CS with concordance between Guardant360 (64.4%) and Caris (51.5%). TP53 alterations comprised a significant proportion of the mutation pool in Caris and Guardant360, 14.7% and 13.1%, respectively. Twenty-six potentially actionable gene alterations were detected from matching ctDNA to Caris unclassified alterations. The CS core cellular process was the most prevalent in our study population. Clinical trials are warranted to investigate biomarkers for the three core cellular processes in advanced cancer patients to define the next best therapies.
Highlights
Precision oncology strives to develop new targeted and immune therapies to improve overall survival (OS) [1]
Head and neck squamous cell carcinoma (HNSCC) and pancreatic adenocarcinoma contain the largest number of positive IHC stains (5 and 4, respectively), head and neck squamous cell carcinoma (HNSCC) (55.5%), TCC (50%), GIST (50%), and neuroendocrine tumors (NET) (50%) represent the greatest proportion of positive PD-L1 stains per cancer subtype
The utility of treating patients based on the three core cellular processes (CS, genome maintenance (GM), and cell fate (CF))
Summary
Precision oncology strives to develop new targeted and immune therapies to improve overall survival (OS) [1]. Molecular profile-based clinical trials, including IMPACT [2] and WINTHER [3], have demonstrated a clear positive impact of matched-targeted therapies (MTT) against patient-specific gene alterations over chemotherapy. Small molecule inhibitors in various stages of development are designed to block key oncogenic signaling pathways. BRAF and ALK inhibitors are Cancers 2020, 12, 701; doi:10.3390/cancers12030701 www.mdpi.com/journal/cancers. Cancers 2020, 12, 701 examples that have demonstrated increased OS in melanoma and non-small cell lung cancer (NSCLC), respectively [4,5]. Studies have shown that tumor molecular profiles are multilayered and interactive. TP53 mutations remain a clinical challenge and are associated with poor outcomes across many cancer subtypes [6,7,8]
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