Background: Cell-free DNA (cfDNA) is known to provide potential biomarkers for predicting clinical outcome, but its value in pancreatic ductal adenocarcinoma (PDAC) has not been fully evaluated. The aim of this study was to evaluate the clinical applicability of quantitative analysis of multiplex KRAS mutations in cell-free DNA from patients with PDAC. Methods: A total of 106 patients with PDAC were enrolled in this prospective study. The concentration and fraction of KRAS mutations were determined through multiplex detection of KRAS mutations in plasma samples by use of a droplet digital PCR kit (Bio-Rad). Results: KRAS mutations were detected in 96.1% of tissue samples. Eighty patients (80.5%) harbored KRAS mutations in cfDNA, with a median KRAS mutation concentration of 0.165 copies/μ L and a median fractional abundance of 0.415%. Multivariable analyses demonstrated that the KRAS mutation concentration [hazard ratio (HR), 2.08; 95% CI, 1.20–3.63] and KRAS fraction (HR, 1.73; 95% CI, 1.02–2.95) were significant factors for progression-free survival. KRAS mutation concentration (HR, 1.97; 95% CI, 1.05–3.67) also had prognostic implications for overall survival. Subgroup analyses showed that KRAS mutation concentration and fractional abundance significantly affected progression-free survival in resectable PDAC (P = 0.016). Moreover, when combined with the cancer biomarker CA19-9, the KRAS mutation concentration in cfDNA showed additive benefits for the prediction of overall survival. Conclusions: This study demonstrates that multiplex detection of KRAS mutations in plasma cfDNA is clinically relevant, providing a potential candidate biomarker for prognosis of PDAC.

Elucidating the molecular mechanisms by which tumors become resistant to Herceptin is critical for the treatment of Her2-overexpressed metastatic breast cancer.

Tumor-derived IL-18 induces PD-1 expression on immunosuppressive NK cells in triple-negative breast cancer Tumor-derived IL-18 induces PD-1 expression on immunosuppressive NK cells in triple-negative breast cancer

Known risk variants explain only a small proportion of breast cancer heritability, particularly in Asian women. To search for additional genetic susceptibility loci for breast cancer, here we perform a meta-analysis of data from genome-wide association studies (GWAS) conducted in Asians (24,206 cases and 24,775 controls) and European descendants (122,977 cases and 105,974 controls). We identified 31 potential novel loci with the lead variant showing an association with breast cancer risk at P < 5 × 10⁻⁸. The associations for 10 of these loci were replicated in an independent sample of 16,787 cases and 16,680 controls of Asian women (P < 0.05). In addition, we replicated the associations for 78 of the 166 known risk variants at P < 0.05 in Asians. These findings improve our understanding of breast cancer genetics and etiology and extend previous findings from studies of European descendants to Asian women.

Although sorafenib is the global standard first-line systemic treatment for unresectable hepatocellular carcinoma (HCC), it does not have reliable predictive or prognostic biomarkers. Circulating cell-free DNA (cfDNA) has shown promise as a biomarker for various cancers. We investigated the use of cfDNA to predict clinical outcomes in HCC patients treated with sorafenib. This prospective biomarker study analyzed plasma cfDNA from 151 HCC patients who received first-line sorafenib and 14 healthy controls. The concentration and VEGFA-to-EIF2C1 ratios (the VEGFA ratio) of cfDNA were measured. Low depth whole-genome sequencing of cfDNA was used to identify genome-wide copy number alteration (CNA), and the I-score was developed to express genomic instability. The I-score was defined as the sum of absolute Z-scores of sequenced reads on each chromosome. The primary aim of this study was to develop cfDNA biomarkers predicting treatment outcomes of sorafenib, and the primary study outcome was the association between biomarkers with treatment efficacy including disease control rate (DCR), time to progression (TTP) and overall survival (OS) in these patients. The cfDNA concentrations were significantly higher in HCC patients than in healthy controls (0.71 vs. 0.34 ng/μL; P < 0.0001). Patients who did not achieve disease control with sorafenib had significantly higher cfDNA levels (0.82 vs. 0.63 ng/μL; P = 0.006) and I-scores (3405 vs. 1024; P = 0.0017) than those achieving disease control. The cfDNA-high group had significantly worse TTP (2.2 vs. 4.1 months; HR = 1.71; P = 0.002) and OS (4.1 vs. 14.8 months; HR = 3.50; P < 0.0001) than the cfDNA-low group. The I-score-high group had poorer TTP (2.2 vs. 4.1 months; HR = 2.09; P < 0.0001) and OS (4.6 vs. 14.8 months; HR = 3.35; P < 0.0001). In the multivariable analyses, the cfDNA remained an independent prognostic factor for OS (P < 0.0001), and the I-score for both TTP (P = 0.011) and OS (P = 0.010). The VEGFA ratio was not significantly associated with treatment outcomes. Pretreatment cfDNA concentration and genome-wide CNA in cfDNA are potential biomarkers predicting outcomes in advanced HCC patients receiving first-line sorafenib.

Jee-Soo Lee, M.D., Eun Hye Cho, M.D., Boram Kim, M.D., Jinyoung Hong, M.D., Young-gon Kim, M.D., Yoonjung Kim, M.D., Ja-Hyun Jang, M.D., Seung-Tae Lee, M.D., Sun-Young Kong, M.D., Woochang Lee, M.D., Saeam Shin, M.D., and Eun Young Song, M.D., on behalf of the Clinical Practice Guidelines Committee of the Korean Society for Laboratory Medicine. Ann Lab Med 2024;44:195-209. https://doi.org/10.3343/alm.2023.0389