Concordance analysis between tumor tissue HER2 status by immunohistochemistry (IHC) and in situ hybridization (ISH) and a translational analysis of plasma ctDNA in patients (pts) with biliary tract cancer (BTC): An exploratory analysis from the phase 2 HERIZON-BTC-01 trial.
Notice bibliographique
Résumé
4102 Background: HER2 is a target for precision oncology. HER2 protein overexpression and/or gene amplification is observed in a subset of pts with BTC. Zanidatamab (zani), a dual HER2-targeted bispecific antibody, received accelerated approval as a treatment for adults with previously treated, unresectable, or metastatic HER2-positive (IHC 3+) BTC based on the phase 2b HERIZON-BTC-01 trial. In this exploratory analysis, we evaluated concordance between tissue-based HER2 IHC and ISH in screened pts, and HER2 gene amplification between tissue-based HER2 ISH and plasma ctDNA by NGS in zani-treated pts. Methods: In HERIZON-BTC-01 (NCT04466891) pts were screened for HER2 gene-amplified tumors by ISH (VENTANA HER2 Dual ISH DNA Probe Cocktail assay) at a central laboratory. Pts with HER2 gene amplification were prospectively assigned to cohorts based on centrally determined HER2 IHC score (Ventana PATHWAY [4B5] IHC assay); cohort 1: IHC 2+ or 3+; cohort 2: IHC 0 or 1+. HER2 status was assessed in a fresh biopsy or an archived sample per ASCO/CAP guidelines, with gastric cancer algorithm. Enrolled pts received zani 20 mg/kg IV Q2W in 28-day cycles. Plasma ctDNA samples were collected prior to the first cycle of zani (baseline) and on-treatment at cycle 2 day 28 for testing with NGS Guardant360 (Guardant Health). Guardant360 Molecular Response (MR) scores were calculated based on changes in plasma ctDNA levels from baseline. Results: Overall, 756 screened pts had central results for both HER2 IHC and ISH. Nearly all pts (94%) with HER2 IHC 3+ BTC had HER2 -amplified tumors per ISH (Table). Among all 87 pts treated with zani across both cohorts, 48 samples from 25 pts were available for testing with NGS. The concordance between HER2 gene amplification by ISH and ctDNA NGS was 59%. Co-mutations at baseline in plasma ctDNA occurring in > 10% of pts included KRAS (n = 1 [3%]), HER2 S310F (n = 3 [9%]), and PIK3CA (n = 6 [18%]). Overall, 18/25 (72%) pts had a decrease in ctDNA levels from baseline at cycle 2 day 28; decreases > 90% were observed in pts with a best response of partial or stable disease. MR scores correlated with tumor response (ANOVA, P = 0.0189). Conclusions: In this analysis, there was a high concordance (94%) observed between tumor tissue HER2 IHC 3+ status and HER2 gene amplification among pts screened in HERIZON-BTC-01. Exploratory translational analysis shows that treatment with zani after 2 cycles was associated with a decrease in plasma ctDNA levels in the majority of pts. Clinical trial information: NCT04466891 . HER2 IHC and ISH status among screened patients. IHC Status ISH Status Amplification n/N (%) Amplified Non-Amplified Total 0 12 330 342 12/342 (3.5) 1+ 8 94 102 8/102 (7.8) 2+ 34 167 201 34/201 (16.9) 3+ 104 7 111 104/111 (93.7) Total 158 598 756 158/756 (20.9)
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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 | 0,003 | 0,003 |
| 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) | 0,001 | 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 ».