Abstract
BackgroundMetastases from primary breast cancers can involve single or multiple organs at metastatic disease diagnosis. Molecular risk factors for particular patterns of metastastic spread in a clinical population are limited.MethodsA case-control design including 1357 primary breast cancers was used to study three distinct clinical patterns of metastasis, which occur within the first six months of metastatic disease: bone and visceral metasynchronous spread, bone-only, and visceral-only metastasis. Whole-genome expression profiles were obtained using whole genome (WG)-DASL assays from formalin-fixed paraffin-embedded (FFPE) samples. A systematic protocol was developed for handling FFPE samples together with stringent data quality controls to identify robust expression profiling data. A panel of published and novel gene sets were tested for association with these specific patterns of metastatic spread and odds ratios (ORs) were calculated.ResultsMetasynchronous metastasis to bone and viscera was found in all intrinsic breast cancer subtypes, while immunohistochemically (IHC)-defined receptor status and specific IntClust subgroups were risk factors for visceral-only or bone-only first metastases. Among gene modules, those related to proliferation increased the risk of metasynchronous metastasis (OR (95% CI) = 2.3 (1.1–4.8)) and visceral-only first metastasis (OR (95% CI) = 2.5 (1.2–5.1)) but not bone-only metastasis (OR (95% CI) = 0.97 (0.56–1.7)). A 21-gene module (BV) was identified in estrogen-receptor-positive breast cancers with metasynchronous metastasis to bone and viscera (area under the curve = 0.77), and its expression increased the risk of bone and visceral metasynchronous spread in this population. BV was further orthogonally validated with NanoString nCounter in primary breast cancers, and was reproducible in their matched lymph nodes metastases and an external cohort.ConclusionThis case-control study of WG-DASL global expression profiles from FFPE tumour samples, after careful quality control and RNA selection, revealed that gene modules in the primary tumour have differing risks for clinical patterns of metasynchronous first metastases. Moreover, a novel gene module was identified as a putative risk factor for metasynchronous bone and visceral first metastatic spread, with potential implications for disease monitoring and treatment planning.
Highlights
Metastases from primary breast cancers can involve single or multiple organs at metastatic disease diagnosis
Clinicians may pursue more aggressive therapy immediately in patients with bone metastasis who are at high likelihood of imminent visceral metastasis, or add bone-directed therapy in patients with visceral metastasis who are at high likelihood of imminent bone metastasis
RNA and whole genome (WG)-DASL data was performed to ensure that expression profiles could be obtained across the span of storage times and inferior-quality data were excluded from further analysis (Additional file 2: Figures S5-7)
Summary
Metastases from primary breast cancers can involve single or multiple organs at metastatic disease diagnosis. Clinicians may pursue more aggressive therapy immediately (e.g. chemotherapy instead of endocrine therapy) in patients with bone metastasis who are at high likelihood of imminent visceral metastasis, or add bone-directed therapy in patients with visceral metastasis who are at high likelihood of imminent bone metastasis. Identification of these patients at an early stage after primary diagnosis or during early metastatic disease is not well-established
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
