Impact of pathogenic germline <i>BRCA1/2</i> and <i>PALB2</i> mutations and tumor aneuploidy in patients with HR+/HER2- metastatic breast cancer treated with CDK4/6 inhibitors.
Notice bibliographique
Résumé
1075 Background: CDK4/6 inhibitors lack established predictors of efficacy in HR + /HER2 - mBC. Pathogenic germline BRCA2 variants, somatic homologous recombination deficiency (HRD) and APOBEC signatures conferred worse survival in small series. Broader tumor DNA panels enable the detection of these and other parameters such as aneuploidy and tumor mutational burden. Methods: Clinical and molecular data from a single institution cohort of CDK4/6i-treated HR + /HER2 - mBC pts were analyzed. ECOG PS was 0-1. Clinical variables were collected retrospectively. Primary endpoints were progression-free survival (PFS) and overall survival (OS). Tumor-only sequencing was performed on clinical samples with 161-gene OCAv3, 523-gene TSO500 or 555-gene lab-developed NGS panels. HRD was assessed with the Signature Multivariate Analysis (SigMA) tool using a likelihood-based measure to estimate single base substitution signature 3. Aneuploidy scores were defined as the fraction of covered arms harboring arm-level somatic copy number alterations as determined by ASCETS v.1.1. Results: 153 pts were available for analysis. Median age was 54 y (29–88). 74% were postmenopausal, 28% de novo metastatic and 67% had visceral disease. Palbociclib was used in 80%, ribociclib in 17% and abemaciclib in 3%, mostly as early lines (1L 65%, 2L 22%). Median follow up was 46 mo (7–84) and median time from sample collection to CDK4/6i was 0.6 y (-18.5–+2.6). 76% of samples have been sequenced. The median number of mutations (muts) was 3 (1–32), most commonly in PIK3CA (37%), GATA3 (26%) and TP53 (20%). ESR1, KRAS and ARID1A, but not RB1 muts were numerically enriched in post–CDK4/6i mets (n=8). TP53 (HR 1.85 CI 1.02–3.33) and GATA3 (HR 0.48, CI 0.28–0.83) muts were associated with PFS. Germline ( g) testing was available in 68 (44%) pts, with 21 pts carrying pathogenic variants including 11 BRCA2, 2 BRCA1 and 2 PALB2. Cox regression showed a strong negative impact of gBRCA1/2-PALB2 on PFS (HR 4.0 CI 2.0–7.9) and OS (HR 3.5 CI 1.6–7.7) adjusted for age, visceral disease and prior chemo. In 1L, mPFS/OS was 9.9/28.1 mo for gBRCA1/2-PALB2 carriers, 26.8/NR mo for non-carriers and 23.7/49.2 mo for untested (Cox HR PFS 5.1 CI 2.1-14.0; HR OS 4.0 CI 1.4-11.2). Pts with gATM/ CHEK2/ BRIP1 had a 1L PFS/OS>15/45 mo. Among 36 pts assessed for HRD, 22 were HRDlow and 14 HRDhigh with no significant survival association. 3/4 known gBRCA1/2 carriers were HRDhigh and 7/8 gWT HRDlow. In these pts, higher aneuploidy was associated with shorter PFS and OS (Cox HR PFS 2.0 CI 0.9-4.3, p=0.07; HR OS 2.6 CI 1.0-7.1; p=0.05). Conclusions: Pathogenic gBRCA1/2- PALB2 and higher aneuploidy were associated with shorter survival. Profiling of aneuploidy, HRD, TMB and APOBEC in all pts is ongoing including 55 baseline ctDNA samples and 361 samples from the GENIE BPC cohort. Results will account for FDR, left truncation and optimal cutoffs.
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Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,001 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,002 | 0,000 |
| Bibliométrie | 0,000 | 0,001 |
| Études des sciences et des technologies | 0,000 | 0,001 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 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 tête enseignante, 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 ».