ctDNA Predicts Overall Survival in Patients With NSCLC Treated With PD-L1 Blockade or With Chemotherapy.

PURPOSE: Identification of predictors for overall survival (OS) allows timely detection of clinical efficacy signals and therefore facilitates treatment decisions. We assessed the association between circulating tumor DNA (ctDNA) metrics and the primary end point of OS in a subset of previously treated patients with locally advanced or metastatic non-small-cell lung cancer, who underwent atezolizumab or docetaxel treatment in the open-label randomized phase III OAK trial. MATERIALS AND METHODS: Plasma from 94 patients at baseline and at subsequent cycles of therapy every 3 weeks was analyzed retrospectively for ctDNA. ctDNA was measured by allele frequency and mutant molecules per milliliter (MMPM). Concordance between various per-sample metrics and clinical outcome were assessed using C index. RESULTS: Of all the ctDNA metrics tested, the association of median MMPM at 6 weeks with OS in patients treated with atezolizumab or docetaxel had a C index > 0.7. The OS hazard ratios relative to high ctDNA above median MMPM within each arm were 0.28 (95% CI, 0.11 to 0.75) for atezolizumab and 0.19 (95% CI, 0.08 to 0.48) for docetaxel. For patients who had ctDNA median MMPM levels of < 4.79, the median survival time was more than 17 months in docetaxel-treated patients and the median survival time was not reached in the atezolizumab-treated patients. CONCLUSION: ctDNA MMPM levels measured at 6 weeks post-treatment are associated with OS in advanced non-small-cell lung cancer. Our results suggest that ctDNA has the potential for a noninvasive early liquid biopsy predictor for OS that warrants further studies to demonstrate its utility in clinical development.

Clonal Hematopoiesis in Late-Stage Non-Small-Cell Lung Cancer and Its Impact on Targeted Panel Next-Generation Sequencing.

PURPOSE: Somatic mutations derived from the expansion of clonal populations of blood cells (clonal hematopoiesis of indeterminate potential, or CHIP) may be detected in sequencing of cell-free DNA (cfDNA) samples. We evaluated the potential implications of CHIP in targeted sequencing of plasma samples using matched peripheral blood mononuclear cells (PBMCs) from patients with lung cancer to identify potential CHIP-associated mutations. MATERIALS AND METHODS: A total of 332 plasma and corresponding PBMC samples were collected predose, cycle 1 day 1 (C1D1), from the randomized, phase III study (OAK) comparing atezolizumab versus docetaxel in previously treated patients with non-small-cell lung cancer (NSCLC). The samples were analyzed with the AVENIO ctDNA Surveillance Kit (for research use only; not for use in diagnostic procedures), a 198-kb next-generation sequencing panel targeting cancer-related genes. CHIP variants were assessed by analyzing both plasma and PBMC sequencing data. RESULTS: A range of zero to eight CHIP variants (median = one) was detected per cfDNA sample. Most of these variants were not in the Database of Single Nucleotide Polymorphisms (dbSNP). The number of CHIP variants was positively associated with age, and TP53 was the most frequently mutated gene. Furthermore, the allele frequency was less variable over time for CHIP variants than for tumor-derived variants. CONCLUSION: CHIP-derived mutations are present in late-stage NSCLC. However, not all plasma samples had CHIP mutations detected with targeted panel sequencing. Paired PBMC sequencing analysis may be needed to remove CHIP variants for comprehensive genomic profiling using plasma samples to identify true somatic mutations.

Concordance of Genomic Alterations by Next-Generation Sequencing in Tumor Tissue versus Cell-Free DNA in Stage I-IV Non-Small Cell Lung Cancer.

Molecular biomarkers hold promise for personalization of cancer treatment. However, a typical tumor biopsy may be difficult to acquire and may not capture genetic variations within or across tumors. Given these limitations, tumor genotyping using next-generation sequencing of plasma-derived circulating tumor (ct)-DNA has the potential to transform non-small cell lung cancer (NSCLC) management. Importantly, mutations detected in biopsied tissue must also be detected in plasma-derived ctDNA at different disease stages. Using the AVENIO ctDNA Surveillance kit (research use only), mutations in ctDNA from NSCLC subjects were compared with those identified in matched tumor tissue samples, retrospectively. Plasma and tissue samples were collected from 141 treatment-naïve NSCLC subjects (stage I, n = 48; stage II, n = 37; stage III, n = 33; stage IV, n = 23). In plasma samples, the median numbers of variants per subject were 4, 6, 8, and 9 in those with stage I, II, III, and IV disease, respectively. The corresponding values in tissue samples were 5, 5, 6, and 4. The overall tissue-plasma concordance of stage II through IV was 62.2% by AVENIO software call. On multivariate analysis, concordance was positively and significantly associated with tumor size and cancer stage. Next-generation sequencing-based analyses with the AVENIO ctDNA Surveillance kit could be an alternative approach to detecting genetic variations in plasma-derived ctDNA isolated from NSCLC subjects.

Atypical antipsychotic drugs and pregnancy outcome: a prospective, cohort study.

Women of childbearing age are often affected with psychotic disorders, requiring the use of antipsychotic medication during pregnancy. In the present study, we prospectively followed the pregnancies of 561 women exposed to second-generation antipsychotic agents (SGAs; study cohort) and compared these to 284 pregnant women exposed to first-generation antipsychotic agents (FGAs; comparison cohort I) and to 1122 pregnant women using drugs known as not harmful to the unborn (comparison cohort II). Subjects were enrolled through the Institute's consultation service. Major malformation rates of SGA exposed were higher compared to comparison cohort II (adjusted odds ratio, 2.17; 95% confidence interval, 1.20-3.91), possibly reflecting a detection bias concerning atrial and ventricular septal defects. Postnatal disorders occurred significantly more often in infants prenatally exposed to SGAs (15.6%) and FGAs (21.6%) compared to 4.2% of comparison cohort II. Cumulative incidences of elective terminations of pregnancy were significantly higher in both the study cohort (17%) and comparison cohort I (21%) compared to comparison cohort II (3%), whereas the rates of spontaneous abortions did not differ. The numbers of stillbirths and neonatal deaths were within the reference range. Preterm birth and low birth weight were more common in infants exposed to FGAs. To conclude, our findings did not reveal a major teratogenic risk for SGAs, making the better studied drugs of this group a treatment option during pregnancy. Because neonates exposed to SGAs or FGAs in the last gestational week are at higher risk of postnatal disorders, delivery should be planned in clinics with neonatal intensive care units.