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Whole-genome sequencing of triple-negative breast cancers in a population-based clinical study

Staaf, Johan LU orcid ; Glodzik, Dominik LU ; Bosch, Ana LU ; Vallon-Christersson, Johan LU orcid ; Reuterswärd, Christel LU ; Häkkinen, Jari LU orcid ; Degasperi, Andrea ; Amarante, Tauanne Dias ; Saal, Lao H LU orcid and Hegardt, Cecilia LU , et al. (2019) In Nature Medicine 25. p.1526-1533
Abstract

Whole-genome sequencing (WGS) brings comprehensive insights to cancer genome interpretation. To explore the clinical value of WGS, we sequenced 254 triple-negative breast cancers (TNBCs) for which associated treatment and outcome data were collected between 2010 and 2015 via the population-based Sweden Cancerome Analysis Network-Breast (SCAN-B) project (ClinicalTrials.gov ID:NCT02306096). Applying the HRDetect mutational-signature-based algorithm to classify tumors, 59% were predicted to have homologous-recombination-repair deficiency (HRDetect-high): 67% explained by germline/somatic mutations of BRCA1/BRCA2, BRCA1 promoter hypermethylation, RAD51C hypermethylation or biallelic loss of PALB2. A novel mechanism of BRCA1 abrogation was... (More)

Whole-genome sequencing (WGS) brings comprehensive insights to cancer genome interpretation. To explore the clinical value of WGS, we sequenced 254 triple-negative breast cancers (TNBCs) for which associated treatment and outcome data were collected between 2010 and 2015 via the population-based Sweden Cancerome Analysis Network-Breast (SCAN-B) project (ClinicalTrials.gov ID:NCT02306096). Applying the HRDetect mutational-signature-based algorithm to classify tumors, 59% were predicted to have homologous-recombination-repair deficiency (HRDetect-high): 67% explained by germline/somatic mutations of BRCA1/BRCA2, BRCA1 promoter hypermethylation, RAD51C hypermethylation or biallelic loss of PALB2. A novel mechanism of BRCA1 abrogation was discovered via germline SINE-VNTR-Alu retrotransposition. HRDetect provided independent prognostic information, with HRDetect-high patients having better outcome on adjuvant chemotherapy for invasive disease-free survival (hazard ratio (HR) = 0.42; 95% confidence interval (CI) = 0.2-0.87) and distant relapse-free interval (HR = 0.31, CI = 0.13-0.76) compared to HRDetect-low, regardless of whether a genetic/epigenetic cause was identified. HRDetect-intermediate, some possessing potentially targetable biological abnormalities, had the poorest outcomes. HRDetect-low cancers also had inadequate outcomes: ~4.7% were mismatch-repair-deficient (another targetable defect, not typically sought) and they were enriched for (but not restricted to) PIK3CA/AKT1 pathway abnormalities. New treatment options need to be considered for now-discernible HRDetect-intermediate and HRDetect-low categories. This population-based study advocates for WGS of TNBC to better inform trial stratification and improve clinical decision-making.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Nature Medicine
volume
25
pages
1526 - 1533
publisher
Nature Publishing Group
external identifiers
  • pmid:31570822
  • scopus:85074205529
ISSN
1546-170X
DOI
10.1038/s41591-019-0582-4
project
Sweden Cancerome Analysis Network - Breast (SCAN-B): a large-scale multicenter infrastructure towards implementation of breast cancer genomic analyses in the clinical routine
Genomisk karakterisering av trippelnegativ bröstcancer (TNBC)
language
English
LU publication?
yes
id
bc152eea-fc0b-4da6-9189-512f03a17c99
date added to LUP
2019-10-14 17:39:05
date last changed
2023-11-19 16:45:03
@article{bc152eea-fc0b-4da6-9189-512f03a17c99,
  abstract     = {{<p>Whole-genome sequencing (WGS) brings comprehensive insights to cancer genome interpretation. To explore the clinical value of WGS, we sequenced 254 triple-negative breast cancers (TNBCs) for which associated treatment and outcome data were collected between 2010 and 2015 via the population-based Sweden Cancerome Analysis Network-Breast (SCAN-B) project (ClinicalTrials.gov ID:NCT02306096). Applying the HRDetect mutational-signature-based algorithm to classify tumors, 59% were predicted to have homologous-recombination-repair deficiency (HRDetect-high): 67% explained by germline/somatic mutations of BRCA1/BRCA2, BRCA1 promoter hypermethylation, RAD51C hypermethylation or biallelic loss of PALB2. A novel mechanism of BRCA1 abrogation was discovered via germline SINE-VNTR-Alu retrotransposition. HRDetect provided independent prognostic information, with HRDetect-high patients having better outcome on adjuvant chemotherapy for invasive disease-free survival (hazard ratio (HR) = 0.42; 95% confidence interval (CI) = 0.2-0.87) and distant relapse-free interval (HR = 0.31, CI = 0.13-0.76) compared to HRDetect-low, regardless of whether a genetic/epigenetic cause was identified. HRDetect-intermediate, some possessing potentially targetable biological abnormalities, had the poorest outcomes. HRDetect-low cancers also had inadequate outcomes: ~4.7% were mismatch-repair-deficient (another targetable defect, not typically sought) and they were enriched for (but not restricted to) PIK3CA/AKT1 pathway abnormalities. New treatment options need to be considered for now-discernible HRDetect-intermediate and HRDetect-low categories. This population-based study advocates for WGS of TNBC to better inform trial stratification and improve clinical decision-making.</p>}},
  author       = {{Staaf, Johan and Glodzik, Dominik and Bosch, Ana and Vallon-Christersson, Johan and Reuterswärd, Christel and Häkkinen, Jari and Degasperi, Andrea and Amarante, Tauanne Dias and Saal, Lao H and Hegardt, Cecilia and Stobart, Hilary and Ehinger, Anna and Larsson, Christer and Rydén, Lisa and Loman, Niklas and Malmberg, Martin and Kvist, Anders and Ehrencrona, Hans and Davies, Helen R and Borg, Åke and Nik-Zainal, Serena}},
  issn         = {{1546-170X}},
  language     = {{eng}},
  pages        = {{1526--1533}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Medicine}},
  title        = {{Whole-genome sequencing of triple-negative breast cancers in a population-based clinical study}},
  url          = {{http://dx.doi.org/10.1038/s41591-019-0582-4}},
  doi          = {{10.1038/s41591-019-0582-4}},
  volume       = {{25}},
  year         = {{2019}},
}