Highlights of This Issue

Plasma-based comprehensive tumor genotyping expands access to standard-of-care precision oncology to patients previously ineligible due to barriers associated with tissue sampling. Despite this, comprehensive and clinically relevant validation studies are lacking, which leaves clinicians unable to properly vet and interpret available options. Odegaard and colleagues describe definitive analytical and clinical validation studies of a comprehensive tumor-derived cell-free DNA sequencing assay for clinical genotyping of advanced solid tumors and report experience applying this technology in the clinical care of 10,593 consecutive patients. These data establish this technology as a clinically effective and accurate tumor genotyping alternative for patients for whom tissue genotyping is infeasible.

Current platforms to explore the genomic causes of primary or acquired resistance to cancer therapies rely on the analysis of DNA from tumor samples. Toledo and colleagues applied a blood-based, tumor-free genomic strategy based on whole-exome sequencing of germline and plasma cell-free DNA from a refractory metastatic colorectal cancer patient and identified a somatic KDR/VEGFR2 mutation located at the entrance of the receptor's ATP-binding pocket domain. The authors validated their findings in vitro and in vivo to show that therapy modulating KDR/VEGFR2 somatic mutations occur in 1% to 3% of samples across tumor types.

Clinical gains that have been observed using immune checkpoint agents in a wide array of malignancies have, unfortunately, not translated to glioblastoma. Through integrative cross-platform analyses, Kesarwani and colleagues demonstrate that aberrant tryptophan metabolism represents a metabolic node in glioblastoma and serves as an immune checkpoint. Importantly, although targeting this metabolic pathway using an agent capable of crossing the blood brain barrier has no antitumor activity alone, potent sensitization is observed when combined with radiation by mitigating radiation-induced immune checkpoint reactivation. These findings offer a framework for novel combinatorial strategies that may be tested clinically in this otherwise recalcitrant tumor.

Mutations in HOXB13 highlights HOX protein regulation as a critical factor in prostate cancer initiation and progression. HOX proteins, however, depend upon their cofactors to regulate transcriptional specificity and function. Bhanvadia and colleagues show that expression of the HOX cofactors MEIS1 and MEIS2 renders prostate tumors more indolent by regulating pathways involved in cMYC signaling, cell proliferation, cell adhesion, and cell differentiation. These data suggest that MEIS-positive prostate tumors represent a less-aggressive form of prostate cancer.