Parikh, Kaushal

Abstract Purpose: Circulating tumor fraction estimate (ctFE) is a machine learning–derived composite metric of circulating tumor DNA (ctDNA) burden. We hypothesized that pre-treatment and early on-treatment ctFE could robustly risk-stratify patients with locally advanced (LA) and oligometastatic non–small cell lung cancer (NSCLC) treated with radiotherapy (RT). Experimental Design: In a prospective phase II clinical trial (NCT03916419), 26 patients with unresectable stage IIB to IIIC NSCLC received magnetic resonance (MR)-guided hypofractionated chemoradiotherapy (chemoRT) followed by immunotherapy. Plasma ctDNA was profiled at baseline and mid-treatment (days 10–14) to derive ctFE and maximum variant allele frequency (Max VAF). A burden-based ctFE threshold derived from baseline samples was applied unchanged to mid-treatment samples and validated in two external cohorts: LA NSCLC treated with chemoRT (LA-RW; n = 94) and oligometastatic NSCLC treated with RT (OM-RW; n = 309). Results: Pre- and mid-treatment ctFE burden strongly stratified overall survival (OS) and progression-free survival (PFS), outperforming Max VAF and ctFE detectability. The baseline ctFE was prognostic for OS (HR 5.93, P = 0.005) and PFS (HR 11.08, P < 0.001) and remained significant at mid-treatment (OS: HR 7.08; PFS: HR 12.06; both P < 0.001). Early ctFE dynamics defined three molecular response groups with OS separation (median OS 60.8 vs. 13.0 vs. 2.9 months; P < 0.001). ctFE remained associated with survival in both validation cohorts. Conclusions: Early ctFE derived from a clinically available, tumor-naïve ctDNA assay enables noninvasive risk stratification in LA and oligometastatic NSCLC treated with RT, supporting its use as a practical biomarker for precision treatment adaptation.

Abstract Viral infections are estimated to contribute to 12% to 20% of all cancers worldwide, with virus-driven malignancies disproportionately affecting low- and middle-income countries, whereas metabolic and nonviral factors predominate in high-income regions. Key oncogenic viruses that cause solid tumors include high-risk human papillomaviruses, Epstein–Barr virus, hepatitis B virus, hepatitis C virus, Kaposi sarcoma–associated herpesvirus, and Merkel cell polyomavirus. Immune checkpoint inhibitors (ICI) have revolutionized cancer therapy by boosting immune responses against tumors. Although viral infection–associated tumors often exhibit “hot” immune profiles, clinical outcomes with ICIs remain inconsistent. Some studies report improved survival in virus-associated cancers, whereas others indicate no clear benefit, which might reflect high variability in tumor microenvironments and immune responses. In this review, we aim to explore the direct and indirect contribution of different viruses to carcinogenesis in solid tumors, with a particular focus on immunotherapy effectiveness based on infection status.

Targeted therapies have changed the treatment landscape of non-small-cell lung cancer and led to improved patient survival across all stages of lung cancer. Newer advances in common and novel oncogenic drivers continue to occur at vigorous speed, making it challenging to stay up to date with the rapidly evolving field. In this article, we review the emerging perspectives in the treatment of actionable targets in lung cancer. We focus on the development of newer KRAS-directed therapies, particularly on non-G12C mutations, pan-RAS inhibitors, and RAS-GTP inhibitors. We also describe the current standard of care for EGFR- and ALK-altered NSCLC and dive into the novel treatments expected to be in the clinic soon. A similar approach is taken toward MET, HER2, RET, ROS1, and FGFR alterations as emerging targets in non-small-cell lung cancer. Finally, we conclude this review with the current body of evidence for targeting TROP-2 as a novel target, potentially of importance in post-targeted therapy scenarios.