Devalingam Mahalingam

Genomic Landscape of Advanced Solid Tumors in Circulating Tumor DNA and Correlation With Tissue Sequencing: A Single Institution's Experience

PURPOSECirculating tumor DNA (ctDNA) has emerged as a promising noninvasive biomarker for baseline characterization and longitudinal monitoring of a tumor throughout disease management. The aim of this study was to evaluate the utility of ctDNA across a wide spectrum of tumor types.METHODSWe retrospectively identified 1,763 patients with advanced cancers who had next-generation sequencing of ctDNA or tumor tissue completed by a designated commercial assay at Northwestern University.RESULTSctDNA identified at least one gene alteration in 90% of patients. The number of detected alterations (NDA) and mutant allele frequency (MAF) of the most frequently mutated genes varied significantly across tumor types, with the highest MAF observed in gastric, colorectal, and breast cancers and the highest NDA observed in colorectal, lung squamous, and ovarian/endometrial cancers. TP53 was the most mutated gene in all tumor types. PIK3CA, ERBB2, BRCA1, and FGFR1 alterations were associated with breast cancer, and ESR1 mutations were exclusively detected in this tumor type. Colorectal cancer was characterized by alterations in KRAS and APC mutations, whereas KRAS, EGFR, PIK3CA, and BRAF mutations were common in lung adenocarcinoma. Concordance between blood and tissue sequencing was notably observed for truncal gene alterations (eg, APC and KRAS), whereas low concordance was often observed in genes associated with treatment resistance mechanisms (eg, RB1 and NF1). Tumor mutational burden (TMB) varied significantly across tumor types, and patients with high MAF or NDA had a significantly higher TMB score with one of the investigated platforms.CONCLUSIONThe study provided new insights into the ctDNA mutational landscape across solid tumors, suggesting new hypotheses-generating data and caveats for future histotype-agnostic workflows integrated with tissue-based biomarkers such as TMB.

A trial of radiolabeled antibody yttrium‐90–FF‐21101 for the treatment of advanced ovarian and other cancers

AbstractBackgroundYttrium‐90 FF‐21101 (90Y–FF‐21101) is a radiopharmaceutical that targets P‐cadherin as a therapy against solid tumors. A previously reported, first‐in‐human study determined that a dose of 25 mCi/m2 was safe, and a patient with clear cell carcinoma of the ovary achieved a complete response. In this article, the authors report the results of 90Y–FF‐21101 treatment in an ovarian carcinoma expansion cohort and in patients with selected solid tumors who had known high P‐cadherin expression.MethodsThe trial was conducted as an open‐label study in patients with advanced/metastatic disease. Radiologic response and safety were evaluated in patients who received 25 mCi/m2 intravenously once every three cycles of 28 days until they developed progressive disease. Evaluation of the ovarian cohort was conducted in a Simon two‐stage manner to determine further enrollment.ResultsFifty‐seven patients (20 with ovarian carcinoma) were enrolled and treated. Patients who had ovarian and solid tumors had received a median of five and three prior therapies, respectively. No complete or partial responses were observed, so the trial was ended. The median progression‐free survival was 118 days for the ovarian cohort and 55 days for the solid‐tumor cohort. The most common treatment‐related adverse events were thrombocytopenia (40%) and neutropenia (54%). One patient each developed fatal veno‐occlusive disease and intracranial hemorrhage. Patients with higher P‐cadherin levels remained on the study longer.Conclusions90Y–FF‐21101 did not meet the predefined efficacy criteria, and adverse events were consistent with 90Y agents. These data may assist in the development of other P‐cadherin–directed therapies (ClinicalTrials.gov identifier NCT02454010).