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Background: Clinical and genomic data from patients with early-stage breast cancer suggest more aggressive disease in premenopausal women. However, the association between age, disease course, and molecular profile from liquid biopsy in metastatic breast cancer (MBC) is not well characterized., Methods: Patients were classified as premenopausal (< 45 years), perimenopausal (45-55 years), or postmenopausal (> 55 years). Cohort 1 consisted of patients with MBC who consented for prospective serial evaluation of circulating tumor cells (CTCs) using CellSearch™. Cohort 2 included patients who, as part of routine care, had circulating tumor DNA (ctDNA) sequenced by the Guardant360™ assay. Clinicopathologic data were collected from retrospective review to compare disease features between premenopausal and postmenopausal women., Results: Premenopausal women represented 26% of 138 patients in Cohort 1 and 21% of 253 patients in Cohort 2. In Cohort 1, younger patients had a shorter time to metastases and a higher prevalence of lung and brain metastases. Overall, there were similar rates of ≥ 5 CTCs/7.5 mL, HER2 + CTC expression, and CTC clusters between pre- and postmenopausal women. However, for those with triple negative breast cancer, premenopausal women had a higher proportion of ≥ 5 CTCs/7.5 mL. In Cohort 2, premenopausal women had a higher incidence of FGFR1 (OR 2.75, p = 0.022) and CCND2 (OR 6.91, p = 0.024) alterations. There was no difference in the ctDNA mutant allele frequency or the number of detected alterations between these age groups., Conclusions: Our data reveal that premenopausal women diagnosed with MBC have unique clinical, pathologic, and molecular features when compared to their postmenopausal counterparts. Our results highlight FGFR1 inhibitors as potential therapeutics of particular interest among premenopausal women.

Background: Liquid biopsy provides real-time data about prognosis and actionable mutations in metastatic breast cancer (MBC). The aim of this study was to explore the combination of circulating tumour DNA (ctDNA) analysis and circulating tumour cells (CTCs) enumeration in estimating target organs more susceptible to MBC involvement., Methods: This retrospective study analysed 88 MBC patients characterised for both CTCs and ctDNA at baseline. CTCs were isolated through the CellSearch kit, while ctDNA was analysed using the Guardant360 NGS-based assay. Sites of disease were collected on the basis of imaging. Associations were explored both through uni- and multivariate logistic regression and Fisher's exact test and the random forest machine learning algorithm., Results: After multivariate logistic regression, ESR1 mutation was the only significant factor associated with liver metastases (OR 8.10), while PIK3CA was associated with lung localisations (OR 3.74). CTC enumeration was independently associated with bone metastases (OR 10.41) and TP53 was associated with lymph node localisations (OR 2.98). The metastatic behaviour was further investigated through a random forest machine learning algorithm. Bone involvement was described by CTC enumeration and alterations in ESR1, GATA3, KIT, CDK4 and ERBB2, while subtype, CTC enumeration, inflammatory BC diagnosis, ESR1 and KIT aberrations described liver metastases. PIK3CA, MET, AR, CTC enumeration and TP53 were associated with lung organotropism. The model, moreover, showed that AR, CCNE1, ESR1, MYC and CTC enumeration were the main drivers in HR positive MBC metastatic pattern., Conclusions: These results indicate that ctDNA and CTCs enumeration could provide useful insights regarding MBC organotropism, suggesting a possible role for future monitoring strategies that dynamically focus on high-risk organs defined by tumourbiology., Competing Interests: Conflict of interest statement AAD reports non-financial support from Menarini Silicon Biosystems, outside the submitted work; LG reports non-financial support from Menarini Silicon Biosystems, personal fees from Lilly, outside the submitted work; MC reports grants from National Institutes of Health, during the conduct of the study; personal fees from Pfizer, personal fees from Merus, personal fees from Novartis, personal fees from CytoDyn, outside the submitted work; FP reports grants from AstraZeneca, grants from Eisai, outside the submitted work; all other authors declare no conflict of interest., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)