OBJECTIVEWe used targeted metabolomics in pregnant mothers to compare maternal metabolite associations with maternal BMI, glycemia, and insulin sensitivity.RESEARCH DESIGN AND METHODSTargeted metabolomic assays of clinical metabolites, amino acids, and acylcarnitines were performed on fasting and 1-h postglucose serum samples from European ancestry, Afro-Caribbean, Thai, and Mexican American mothers (400 from each ancestry group) who participated in the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study and underwent an oral glucose tolerance test at ∼28 weeks gestation.RESULTSK-means clustering, which identified patterns of metabolite levels across ancestry groups, demonstrated that, at both fasting and 1-h, levels of the majority of metabolites were similar across ancestry groups. Meta-analyses demonstrated association of a broad array of fasting and 1-h metabolites, including lipids and amino acids and their metabolites, with maternal BMI, glucose levels, and insulin sensitivity before and after adjustment for the different phenotypes. At fasting and 1 h, a mix of metabolites was identified that were common across phenotypes or associated with only one or two phenotypes. Partial correlation estimates, which allowed comparison of the strength of association of different metabolites with maternal phenotypes, demonstrated that metabolites most strongly associated with different phenotypes included some that were common across as well as unique to each phenotype.CONCLUSIONSMaternal BMI and glycemia have metabolic signatures that are both shared and unique to each phenotype. These signatures largely remain consistent across different ancestry groups and may contribute to the common and independent effects of these two phenotypes on adverse pregnancy outcomes.

Background We describe the genomic landscape of circulating tumour DNA (ctDNA) across pathological subtypes of metastatic breast cancer. Methods 255 clinically annotated patients with ctDNA testing by Guardant360 were stratified into HR+, HER2+, and TNBC cohorts. Frequency and heterogeneity of alterations were reported. Paired ctDNA and tissue sequencing were compared for a subset of patients. The association of ctDNA and metastatic sites of disease on imaging was also assessed. Findings 89% of patients had at least one ctDNA alteration detected. The most common single nucleotide variants (SNVs) for HR+ patients were PIK3CA, ESR1 , and TP53 . For HER2+, these were TP53, PIK3CA , and ERBB2 with ERBB2 as the most frequent copy number variant (CNV). For TNBC, the most common SNVs were TP53 and PIK3CA , and the most frequent CNVs were MYC, CCNE1 , and PIK3CA . TNBC patients had a significantly higher mutant allele frequency (MAF) of the highest variant compared to HR+ or HER2+ patients ( P <0.05). Overall, alterations in PIK3CA, ESR1 , and ERBB2 were observed in 39.6%, 16.5%, and 21.6% of patients, respectively. Agreement between blood and tissue was 79–91%. MAF and number of alterations were significantly associated with number of metastatic sites on imaging ( P <0.0001). Interpretation These data demonstrate the genetic heterogeneity of metastatic breast cancer in blood, the high prevalence of clinically actionable alterations, and the potential to utilise ctDNA as a surrogate for tumour burden on imaging. Funding Lynn Sage Cancer Research Foundation, OncoSET Precision Medicine Program, and REDCap support was funded by the National Institutes of Health UL1TR001422.

Purpose: Circulating tumor DNA (ctDNA) is a promising tool for noninvasive longitudinal monitoring of genomic alterations. We analyzed serial ctDNA to characterize genomic evolution in progressive metastatic breast cancer.Experimental Design: This was a retrospective cohort between 2015 and 2019 obtained under an Institutional Review Boardapproved protocol at Northwestern University (Chicago, IL). ctDNA samples were analyzed with Guardant360 nextgeneration sequencing (NGS) assay. A total of 86 patients had at least two serial ctDNA collections with the second drawn at first post-NGS progression (PN1) by imaging and clinical assessment. A total of 27 participants had ctDNA drawn at second post-NGS clinical progression (PN2). We analyzed alterations, mutant allele frequency (MAF), number of alterations (NOA), and sites of disease on imaging in close proximity to ctDNA evaluation. Matched pairs' variations in MAF, NOA, and alterations at progression were tested through Wilcoxon test. We identified an independent control cohort at Massachusetts General Hospital (Boston, MA) of 63 patients with serial ctDNA sampling and no evidence of progression.Results: We identified 44 hormone receptor-positive, 20 HER2 þ , and 22 triple-negative breast cancer cases. The significant alterations observed between baseline and PN1 were TP53 (P < 0.0075), PIK3CA (P < 0.0126), AR (P < 0.0126), FGFR1 (P < 0.0455), and ESR1 (P < 0.0143). Paired analyses revealed increased MAF and NOA from baseline to PN1 (P ¼ 0.0026, and P < 0.0001, respectively). When compared with controls without progression, patients with ctDNA collection at times of progression were associated with increased MAF and NOA (P ¼ 0.0042 and P < 0.0001, respectively).Conclusions: Serial ctDNA testing identified resistance alterations and increased NOA and MAF were associated with disease progression. Prospective longitudinal ctDNA evaluation could potentially monitor tumor genomic evolution.

Introduction: Roughly one third of new non-small cell lung cancer (NSCLC) is diagnosed at early stages. While lobectomy can improve mortality in this group, about 30-55% of patients will experience disease recurrence. Increased investigation into the factors affecting recurrence, particularly tumor molecular genetics such as EGFR mutations, is needed. Materials and Methods: We conducted a single-center retrospective study of 282 patients with early or locally advanced lung adenocarcinoma, with or without EGFR mutations, who underwent definitive therapy. We then assessed recurrence, stage at recurrence, time to recurrence and progression-free survival (PFS). Results: We identified 142 patients with EGFR-mutated and 140 EGFR-wildtype lung adenocarcinoma. Overall progression between groups was equivalent at ~40% at 5 years; no difference in PFS was observed at any time-point. However, among those who recurred, EGFR-mutated lung cancer had increased rates of metastatic recurrence compared to EGFR-wildtype disease (97% vs 68%, p = 0.007). Conclusions: EGFR-mutated disease may be associated with a higher risk of metastatic recurrence. Molecular testing may be a promising tool for risk stratification and surveillance following definitive management for early stage disease. Future prospective, multi-center cohort studies are needed to confirm these findings and improve our understanding of how EGFR mutation contributes to prognosis and clinical outcomes.

There have been numerous controversies surrounding cosmetic products and increased cancer risk. Such controversies include associations between parabens and breast cancer, hair dyes and hematologic malignancies, and talc powders and ovarian cancer. Despite the prominent media coverage and numerous scientific investigations, the majority of these associations currently lack conclusive evidence. In 2016, the US Food and Drug Administration (FDA) made publically available all adverse event reports in Center for Food Safety and Applied Nutrition’s Adverse Event Reporting System (CAERS), which includes complaints related to cosmetic products. We mined CAERS for cancer-related reports attributed to cosmetics. Between 2004 and 2017, cancer-related reports caused by cosmetics represented 41% of all adverse events related to cosmetics. This yielded 4427 individual reports of cancer related to a cosmetic product. Of these reports, the FDA redacted the specific product names in 95% of cancer-related reports under the Freedom of Information Act exemptions, most likely due to ongoing legal proceedings. For redacted reports, ovarian cancer reports dominated (n = 3992, 90%), followed by mesothelioma (n = 92, 2%) and malignant neoplasm unspecified (n = 46, 1%). For nonredacted reports, or those reports whose product names were not withheld (n = 218), 70% were related to ovarian cancer attributed to talc powders, followed by skin cancer (11%) and breast cancer (5%) attributed to topical moisturizers. Currently, CAERS is of limited utility, with the available data having been subjected to significant reporter bias and a lack of supportive information such as demographic data, medical history, or concomitant product use. Although the system has promise for safeguarding public health, the future utility of the database requires broader reporting participation and more complete reporting, paired with parallel investments in regulatory science and improved molecular methods.