Abstract 2473: Breast cancer whole genomes link homologous recombination deficiency (HRD) with therapeutic outcomes
Notice bibliographique
Résumé
Abstract Background: Homologous recombination deficiency (HRD) is common in cancer - germline BRCA1 & BRCA2 mutations account for 5-10% of breast cancers and confer 85% lifetime risk. HRD cancers exhibit genomic instability and sensitivity to platinum-based therapy and PARP inhibitors. While not all causes of HRD are known, recent sequencing efforts have revealed genome-wide somatic mutation signatures that characterize the HRD genomic instability phenotype, also known as “BRCA-ness”. This provides a promising new assay to predict sensitivity to platinum-based therapy. Here, we integrate two whole-genome sequencing metrics to assess their association with therapeutic outcomes in a breast cancer cohort. Methods: Whole-genome sequencing of 47 breast cancer tumors (100x coverage) and matched normals (60x) was performed on an Illumina HiSeq. Alignment, assembly, SNV calling, and loss of heterozygosity (LOH) detection were performed with BWA, ABySS, Strelka, and APOLLOH respectively. SNV signatures were deciphered by non-negative matrix factorization with Monte Carlo resampling. An HRD score comprised of LOH, telomeric allelic imbalance (TAI), and large scale transition (LST) counts was computed. Clinical endpoints were obtained by retrospective review of treatment and imaging reports. Analysis is ongoing in an independent validation cohort of 62 sequenced cases. Results: The HRD-linked SNV signature was significantly associated with radiographic clinical response (CR) to platinum-based therapy (p=0.015). Logistic regression demonstrated a 59% improved odds of CR to platinum-based therapy per 1000 somatic SNVs attributed to HRD (odds ratio 1.16-2.50). Tumors carried up to 10,246 such SNVs and all patients with CR were among the top quartile. The LOH-TAI-LST score was correlated with SNV signature (r=0.6, p=7×10-6) and associated with CR (p=0.025). Notably, elevated HRD signatures associated with CR were identified in tumors with wild-type BRCA1/BRCA2 or variants of unknown significance. Tumors with above median HRD signatures were associated with a 69-day longer time to treatment failure and an 18% daily decreased probability of treatment failure per 1000 HRD-attributed SNVs (hazard ratio 0.71-0.95, p = 0.007). Discussion: We found that HRD mutation signatures are associated with clinical response and longer time to treatment failure with platinum-based therapy. While similar benefits were observed in patients with somatic bi-allelic loss of BRCA1/BRCA2, such cases are less common (8% of our cohort) compared to those with elevated HRD signature. Thus, mutation signature methods may identify patients who stand to benefit from platinum-based therapy missed by BRCA screening alone. Citation Format: Eric Y. Zhao, Yaoqing Shen, Erin Pleasance, Katayoon Kasaian, Martin R. Jones, Carolyn Ch'ng, Caralyn Reisle, Peter Eirew, Karen Mungall, Nina Thiessen, Yussanne Ma, Alexandra Fok, Andrew J. Mungall, Yongjun Zhao, Richard Moore, Diego Villa, Tamara Shenkier, Caroline Lohrisch, Stephen Chia, Stephen Yip, Karen Gelmon, Howard Lim, Sophie Sun, Kasmintan A. Schrader, Sean Young, Aly Karsan, Robyn Roscoe, Janessa Laskin, Marco A. Marra, Steven J. Jones. Breast cancer whole genomes link homologous recombination deficiency (HRD) with therapeutic outcomes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2473. doi:10.1158/1538-7445.AM2017-2473
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,001 | 0,002 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,001 | 0,001 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,001 | 0,000 |
| Science ouverte | 0,000 | 0,001 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,003 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».