ORCID Profile
0000-0001-5167-4468
Current Organisation
CSIRO, Australian Animal Health Laboratory
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Publisher: Springer Science and Business Media LLC
Date: 18-08-2020
DOI: 10.1186/S13058-020-01328-0
Abstract: Metastatic breast cancer remains incurable. Next-generation sequencing (NGS) offers the ability to identify actionable genomic alterations in tumours which may then be matched with targeted therapies, but the implementation and utility of this approach is not well defined for patients with metastatic breast cancer. We recruited patients with advanced breast cancer of any subtype for prospective targeted NGS of their most recent tumour s les, using a panel of 108 breast cancer-specific genes. Genes were classified as actionable or non-actionable using the European Society of Medical Oncology Scale for Clinical Actionability of Molecular Targets (ESCAT) guidelines. Between February 2014 and May 2019, 322 patients were enrolled onto the study, with 72% ( n = 234) of patients successfully sequenced ( n = 357 s les). The majority (74%, n = 171) of sequenced patients were found to carry a potentially actionable alteration, the most common being a PIK3CA mutation. Forty-three percent ( n = 74) of patients with actionable alterations were referred for a clinical trial or referred for confirmatory germline testing or had a change in therapy outside of clinical trials. We found alterations in AKT1 , BRCA2 , CHEK2, ESR1 , FGFR1 , KMT2C , NCOR1 , PIK3CA and TSC2 to be significantly enriched in our metastatic population compared with primary breast cancers. Concordance between primary and metastatic s les for key driver genes ( TP53 , ERBB2 lification) was 75%. Additionally, we found that patients with a higher number of mutations had a significantly worse overall survival. Genomic profiling of patients with metastatic breast cancer can have clinical implications and should be considered in all suitable patients.
Publisher: Wiley
Date: 08-03-2019
DOI: 10.1002/PATH.5251
Abstract: Breast cancer (BC) diagnosed after a negative mammogram but prior to the next screening episode is termed an 'interval BC' (IBC). Understanding the molecular differences between IBC and screen-detected BCs (SDBC) could improve mammographic screening and management options. Therefore, we assessed both germline and somatic genomic aberrations in a prospective cohort. Utilising the Lifepool cohort of >54 000 women attending mammographic screening programs, 930 BC cases with screening status were identified (726 SDBC and 204 IBC). Clinico-pathological and family history information were recorded. Germline and tumour DNA were collected where available and sequenced for BC predisposition and driver gene mutations. Compared to SDBC, IBCs were significantly associated with a younger age at diagnosis and tumour characteristics associated with worse prognosis. Germline DNA assessment of BC cases that developed post-enrolment (276 SDBCs and 77 IBCs) for pathogenic mutations in 12 hereditary BC predisposition genes identified 8 carriers (2.27%). The germline mutation frequency was higher in IBC versus SDBC, although not statistically significant (3.90% versus 1.81%, p = 0.174). Comparing somatic genetic features of IBC and SDBC matched for grade, histological subtype and hormone receptor revealed no significant differences, with the exception of higher homologous recombination deficiency scores in IBC, and copy number changes on chromosome Xq in triple negative SDBCs. Our data demonstrates that while IBCs are clinically more aggressive than SDBC, when matched for confounding clinico-pathological features they do not represent a unique molecular class of invasive BC, but could be a consequence of timing of tumour initiation and mammographic screening. Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Publisher: Public Library of Science (PLoS)
Date: 10-2020
No related grants have been discovered for Keilly Kuykhoven.