Prevalence, Dynamics, and Prognostic Role of Clonal Hematopoiesis of Indeterminate Potential in Patients With Breast Cancer.

PURPOSE: Clonal hematopoiesis of indeterminate potential (CHIP) is frequent in patients with solid tumors. Prospective data about CHIP prevalence at breast cancer diagnosis and its dynamic evolution under treatment selective pressure are limited. PATIENTS AND METHODS: We performed targeted error-corrected sequencing on 614 samples from 380 patients with breast cancer. We investigated the dynamics of CHIP on prospectively collected paired samples from patients with early breast cancer (eBC) receiving chemotherapy (CT) or endocrine therapy (ET). We assessed the correlation of CHIP with survival in patients with metastatic triple-negative breast cancer (mTNBC). We estimated the risk of progression to treatment-related myeloid neoplasms (t-MN) according to the clonal hematopoiesis risk score (CHRS). In exploratory analyses, we considered clonal hematopoiesis (CH) with variant allele fraction (VAF) ≥0.005. RESULTS: CHIP was identified in 15% of patients before treatment. Few CHIP emerged after treatment, and the risk of developing new mutations was similar for patients receiving CT versus ET (odds ratio [OR], 1.16; P = .820). However, CT increased the risk of developing new CH with VAF ≥0.005 (OR, 3.45; P = .002). Five TP53-mutant CH with VAF ≥0.005 emerged among patients receiving CT. Most patients had low risk of t-MN according to the CHRS score. CHIP did not correlate with survival in mTNBC. CONCLUSION: CHIP is frequent in patients with breast cancer. In this study, CT did not lead to emergence of new CHIP, and most patients had low risk of developing t-MN. This finding is reassuring, given long life expectancy of patients with eBC and the association of CHIP with morbidity and mortality. However, TP53-mutant CH with VAF ≥0.005 emerged with CT, which carries high risk of t-MN. Evolution of these small clones and their clinical significance warrant further investigation.

The Nutritional Quality and Structural Analysis of Black Soldier Fly Larvae Flour before and after Defatting.

This study aimed to assess the nutritional information and structural overview of the BSFL (black soldier fly larva) flours (full fat and defatted). The BSFL flours were obtained by freeze-drying the larvae and the removal of fat using hexane and isopropanol ratio of 3:2 (v/v), these solvents were used due to their defatting efficiency and because they are less toxic. Nutritional and structural analyses were conducted using standard methods. The full-fat and defatted flours had high protein content (45.82% and 56.11% respectively). Defatting significantly (p < 0.05) increases the protein content by approximately 10%, while the fat content decreased from 25.78% in full-fat larvae to 4.8% in defatted larvae. The compositional data were qualitatively confirmed with Universal Attenuated Total Reflectance Fourier Transform Infrared spectroscopy (UATR-FTIR) mainly in the amide I and II regions. Thermal gravimetry (TG) and differential scanning calorimeter (DSC) analysis, showed the conformational physical changes induced due to removal of fat which affected protein denaturation. DSC analysis displayed curves of both endothermic and exothermic reactions. During the first heating program, both samples had wide endothermic heating peaks ranging from 42 to 112 °C, which may be attributed to the water content in the samples evaporating. The first stage of the decomposition process was important, with loss of free and loosely bound water up to 150 °C, according to TGA curves. Protein and carbohydrates volatilized during the second stage of decomposition. The third level may be linked to polypeptide decomposition. FTIR revealed that the defatting process induced structural modifications on the amide I (1650 cm-1) and amide II (1540 cm-1) regions. Defatting has a significant effect on the functional groups and nutritional value of the BSFL. Defatted as well as full-fat flour both show good nutritional and structural characteristics for use in many food applications, however the improved proximate composition of the defatted BSFL can be applied to food products using BSFL flour as an alternative ingredient.

Identifying ERBB2 Activating Mutations in HER2-Negative Breast Cancer: Clinical Impact of Institute-Wide Genomic Testing and Enrollment in Matched Therapy Trials.

PURPOSE: The yield of comprehensive genomic profiling in recruiting patients to molecular-based trials designed for small subgroups has not been fully evaluated. We evaluated the likelihood of enrollment in a clinical trial that required the identification of a specific genomic change based on our institute-wide genomic tumor profiling. PATIENTS AND METHODS: Using genomic profiling from archived tissue samples derived from patients with metastatic breast cancer treated between 2011 and 2017, we assessed the impact of systematic genomic characterization on enrollment in an ongoing phase II trial (ClinicalTrials.gov identifier: NCT01670877). Our primary aim was to describe the proportion of patients with a qualifying ERBB2 mutation identified by our institutional genomic panel (OncoMap or OncoPanel) who enrolled in the trial. Secondary objectives included median time from testing result to trial registration, description of the spectrum of ERBB2 mutations, and survival. Associations were calculated using Fisher's exact test. RESULTS: We identified a total of 1,045 patients with metastatic breast cancer without ERBB2 amplification who had available genomic testing results. Of these, 42 patients were found to have ERBB2 mutation and 19 patients (1.8%) were eligible for the trial on the basis of the presence of an activating mutation, 18 of which were identified by OncoPanel testing. Fifty-eight percent of potentially eligible patients were approached, and 33.3% of eligible patients enrolled in the trial guided exclusively by OncoPanel testing. CONCLUSION: More than one half of eligible patients were approached for trial participation and, significantly, one third of those were enrolled in NCT01670877. Our data illustrate the ability to enroll patients in trials of rare subsets in routine clinical practice and highlight the need for these broadly based approaches to effectively support the success of these studies.

Scalable whole-exome sequencing of cell-free DNA reveals high concordance with metastatic tumors.

Whole-exome sequencing of cell-free DNA (cfDNA) could enable comprehensive profiling of tumors from blood but the genome-wide concordance between cfDNA and tumor biopsies is uncertain. Here we report ichorCNA, software that quantifies tumor content in cfDNA from 0.1× coverage whole-genome sequencing data without prior knowledge of tumor mutations. We apply ichorCNA to 1439 blood samples from 520 patients with metastatic prostate or breast cancers. In the earliest tested sample for each patient, 34% of patients have ≥10% tumor-derived cfDNA, sufficient for standard coverage whole-exome sequencing. Using whole-exome sequencing, we validate the concordance of clonal somatic mutations (88%), copy number alterations (80%), mutational signatures, and neoantigens between cfDNA and matched tumor biopsies from 41 patients with ≥10% cfDNA tumor content. In summary, we provide methods to identify patients eligible for comprehensive cfDNA profiling, revealing its applicability to many patients, and demonstrate high concordance of cfDNA and metastatic tumor whole-exome sequencing.