Purpose
Plasma cell-free DNA (cfDNA) analysis is increasingly used clinically for cancer genotyping, but may lead to incidental identification of germline risk alleles. We studied EGFR T790M mutations in non-small cell lung cancer (NSCLC) toward the aim of discriminating germline and cancer-derived variants within cfDNA.
Experimental Design
Patients with EGFR-mutant NSCLC, some with known germline EGFR T790M, underwent plasma genotyping. Separately, deidentified genomic data and buffy coat specimens from a clinical plasma next-generation sequencing (NGS) laboratory were reviewed and tested.
Results
In patients with germline T790M mutations, the T790M allelic fraction (AF) in cfDNA approximates 50%, higher than that of EGFR driver mutations. Review of plasma NGS results reveals three groups of variants: a low AF tumor group, a heterozygous group (~50% AF), and a homozygous group (~100% AF). As the EGFR driver mutation AF increases, the distribution of the heterozygous group changes, suggesting increased copy number variation from increased tumor content. Excluding cases with high copy number variation, mutations can be differentiated into somatic variants and incidentally identified germline variants. We then developed a bioinformatic algorithm to distinguish germline and somatic mutations; blinded validation in 21 cases confirmed a 100% positive predictive value for predicting germline T790M. Querying a database of 31,414 patients with plasma NGS, we identified 48 with germline T790M, 43 with non-squamous NSCLC (p<0.0001).
Conclusion
With appropriate bioinformatics, plasma genotyping can accurately predict the presence of incidentally detected germline risk alleles. This finding in patients indicates a need for genetic counseling and confirmatory germline testing.
The study was conducted to evaluate the prevalence of abnormal levels of several serum tumour markers in an institutionalized elderly population. Serum tumour markers assay of carcinoembryonic antigen (CEA), the carbohydrate antigens CA 19-9, CA 72-4 and CA 15-3 (Enzymun-test, Boehringer Mannheim GmbH Diagnostic), alpha-fetoprotein (AFP) and prostate specific antigen (PSA) (Abbot Diagnostic Division) were performed in 228 unselected, institutionalized elderly subjects, whose mean age (SD) was 82.4 (5. 79) range (66-99 years). Patients with acute or neoplastic diseases were excluded from the study. The serum markers were also measured in 52 healthy young adults (controls). Using the established threshold values, 92 subjects (40%) were found to have at least one elevated marker. PSA was elevated in 33%, CA 19-9 in 16%, CEA in 11. 5%, CA 15-3 in 11%, CA 72-4 in 8% and AFP in 3%. We found a significant difference in the serum levels between the two groups for CEA, CA 19-9. CA 15-3, and PSA (p < 0.0001). Healthy aged people appear to have an elevated prevalence of elevated levels of serum tumour markers. The results suggest that apart from PSA, elevated antigen levels in elderly subjects are related to the ageing process itself rather than to occult pathology.
The poly(ADP‐ribose) polymerase‐1/2 inhibitor veliparib is active against tumors deficient in homologous DNA damage repair. The pharmacokinetics and safety of veliparib extended‐release (ER) were evaluated in patients with advanced solid tumors. This phase I study assessed veliparib‐ER up to 800 mg once daily or 600 mg twice daily. Dose‐limiting toxicities (DLTs), recommended phase II dose (RP2D), and maximum tolerated dose (MTD) were assessed in cycle 1 and safety/tolerability during continuous administration (28‐day cycles). Seventy‐one patients (n = 53 ovarian, n = 17 breast, n = 1 prostate carcinoma) received veliparib; 50 had deleterious breast cancer susceptibility (BRCA) gene mutations. Single‐dose veliparib‐ER 200 mg (fasting) led to 58% lower peak concentration and similar area under the concentration‐time curve compared with veliparib immediate‐release (IR). Three patients experienced DLTs (grade 2: asthenia; grade 3: nausea/vomiting, seizure). RP2D and MTD for veliparib‐ER were 400 mg BID. The most frequent adverse events (AEs) were nausea (78.9%) and vomiting (50.7%). The most common grade 3/4 treatment‐related AEs were as follows: thrombocytopenia (7.0%), nausea, and anemia (4.2% each). Overall, 12 (27.3%) patients with ovarian and 10 (62.5%) patients with breast carcinoma had a partial response. Veliparib‐ER, versus veliparib‐IR, exhibited an improved pharmacokinetic profile and was well tolerated in patients with ovarian and BRCA‐mutated breast cancers.
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