Purpose: The purpose of this study was to directly compare mutation profiles in multiple single circulating tumor cells (CTC) and cell-free DNA (cfDNA) isolated from the same blood samples taken from patients with metastatic breast cancer (MBC). We aimed to determine whether cfDNA would reflect the heterogeneity observed in 40 single CTCs.Experimental Design: CTCs were enumerated by CELL-SEARCH. CTC count was compared with the quantity of matched cfDNA and serum CA15-3 and alkaline phosphatase (ALP) in 112 patients with MBC. In 5 patients with !100 CTCs, multiple individual EpCAM-positive CTCs were isolated by DEPArray and compared with matched cfDNA and primary tumor tissue by targeted next-generation sequencing (NGS) of about 2,200 mutations in 50 cancer genes.Results: In the whole cohort, total cfDNA levels and cell counts (!5 CTCs) were both significantly associated with overall survival, unlike CA15-3 and ALP. NGS analysis of 40 individual EpCAMpositive CTCs from 5 patients with MBC revealed mutational heterogeneity in PIK3CA, TP53, ESR1, and KRAS genes between individual CTCs. In all 5 patients, cfDNA profiles provided an accurate reflection of mutations seen in individual CTCs. ESR1 and KRAS gene mutations were absent from primary tumor tissue and therefore likely either reflect a minor subclonal mutation or were acquired with disease progression.Conclusions: Our results demonstrate that cfDNA reflects persisting EpCAM-positive CTCs in patients with high CTC counts and therefore may enable monitoring of the metastatic burden for clinical decision-making.
BACKGROUND: Breast cancer tissues are heterogeneous and show diverse somatic mutations and somatic copy number alterations (CNAs). We used a novel targeted next generation sequencing (NGS) panel to examine cellfree DNA (cfDNA) to detect somatic mutations and gene amplification in women with metastatic breast cancer (MBC).
Cancer burden is increasing in kidney transplant recipients, but differences in mortality compared to the general population remain unclear. We sought to compare cancer mortality in paediatric and adult kidney transplant recipients with the general population and describe any differences, by site, age and sex, country and over time. We included kidney transplant recipients from the Australian and New Zealand Dialysis and Transplantation Registry, 1980–2013. Date of death and underlying cause of death were ascertained by data‐linkage and classified using ICD10AM codes. Indirect standardisation was used to estimate standardised mortality ratios (SMR). There were 5,284 deaths in 17,628 kidney transplant recipients over 175,084 person‐years of observation, including 1,061 (20%) cancer deaths. Relative cancer mortality was higher than the general population for all‐site (SMR 2.9, 95% CI 2.7–3.1) cancer and highest for nonmelanoma skin cancer (SMR 50.9, 95% CI 43.5–59.6) and lymphoma (SMR 42.2, 95% CI 35.3–50.5). Relative cancer mortality decreased with increasing age in men (p < 0.001) and women (p = 0.001) but never reached parity with the general population. Relative mortality did not change with age for skin and lip, or colorectal cancers (p‐value >0.1). Only relative colorectal cancer mortality increased over time (p = 0.002). Our study shows cancer mortality in kidney transplant recipients was higher than expected in the general population. The magnitude of excess mortality varied by cancer site, age and sex. Further evidence is needed to identify whether this variation is due to differences at diagnosis or access and effectiveness of cancer treatments in this population.
Background: Blood-borne viral infections can complicate organ transplantation. Systematic monitoring to distinguish donor-transmitted infections from other new infections post transplant is challenging. Administrative health data can be informative. We aimed to quantify post-transplant viral infections, specifically those transmitted by donors and those reactivating or arising new in recipients. Methods: We linked transplant registries with administrative health data for all solid organ donor-recipient pairs in New South Wales, Australia, 2000-2015. All new recipient notifications of hepatitis B (HBV), C (HCV), or human immunodeficiency virus (HIV) after transplant were identified. Proven/probable donor transmissions within 12 months of transplant were classified using an international algorithm. Results: Of 2120 organ donors, there were 72 with a viral infection (9/72 active, 63/72 past). These 72 donors donated to 173 recipients, of whom 24/173 already had the same infection as their donor, and 149/173 did not, so were at risk of donor transmission. Among those at risk, 3/149 recipients had proven/probable viral transmissions (1 HCV, 2 HBV); none were unrecognized by donation services. There were no deaths from transmissions. There were no donor transmissions from donors without known blood-borne viruses. An additional 68 recipients had new virus notifications, of whom 2/68 died, due to HBV infection. Conclusion: This work confirms the safety of organ donation in an Australian cohort, with no unrecognized viral transmissions and most donors with viral infections not transmitting the virus. This may support targeted increases in donation from donors with viral infections. However, other new virus notifications post transplant were substantial and are preventable. Data linkage can enhance current biovigilance systems.
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