Messaggi chiave
- È stato condotto uno studio retrospettivo volto a valutare l’efficacia delle terapie anti-HER2 in pazienti con carcinoma mammario con discrepanza dei dati immunoistochimici (IHC) e di ibridazione in situ (ISH) o con pattern ISH non comuni (gruppi 2, 3 o 4 secondo le linee guida ASCO/CAP). A questo scopo, sono stati analizzati i dati di 144.013 pazienti del National Cancer Database con diagnosi ricevuta nel periodo 2013-2021.
- I pazienti classicamente HER2+ (IHC 2-3+, rapporto HER2/CEP17 ≥2 con numero di copie di HER2 ≥4) e i pazienti del gruppo 2 (rapporto ≥2, numero di copie <4) trattati con terapie anti-HER2 hanno mostrato tassi di risposta patologica completa significativamente superiori rispetto ai controlli HER2-, con odds ratio aggiustati pari a 2,9 (IC 95%, 2,65-3,18; p <0,001) e 2,38 (IC 95%, 1,42-3,96; p <0,001), rispettivamente. È stato osservato un beneficio anche nel gruppo 3, ma solo in presenza di un numero di copie ≥8, e nei casi con risultati discordanti ISH+/IHC-, ma solo in presenza di un rapporto HER2/CEP17 ≥3. Infine, non è emerso alcun beneficio nel gruppo 4 e nei casi ISH-/IHC+.
- Lo studio dimostra come una porzione significativa di pazienti tradizionalmente classificati come HER2+ tragga in realtà scarso beneficio dai farmaci mirati a HER2 e necessiti pertanto di strategie terapeutiche alternative.
Abstract
Purpose
- Human epidermal growth factor receptor 2 (HER2)-targeted therapy improves outcomes in HER2+ breast cancer, but efficacy in cases with discordant immunohistochemistry (IHC) and in situ hybridization (ISH) results or with ASCO/College of American Pathologists (CAP) group 2-4 ISH results remains uncertain.
Methods
- This retrospective study included patients from the National Cancer Database diagnosed from 2013 to 2021.
- Cases were classified as classically HER2+ (HER2/centromeric region of chromosome 17 [CEP17] ratio ≥2 with HER2 copy number ≥4, IHC 2-3+), HER2- (ratio <2, copy number <4, IHC 0-2+), discordant ISH/IHC, or HER2+ with ISH group 2 (ratio ≥2, copy number <4), group 3 (ratio <2, copy number ≥6), or group 4 (ratio <2, copy number ≥4 and <6) per ASCO/CAP guidelines.
- Adjusted odds ratio (aOR) for pathologic complete response (pCR) for these subgroups receiving HER2-targeted therapy was calculated compared with HER2- controls.
Results
- We identified N = 144,013 patients with IHC and dual-probe ISH.
- Of HER2 IHC 3+ cases (n = 8,579), 8.2%, 2.8%, 4.2%, and 8.8% had ISH categorized as groups 2, 3, 4, and 5 (discordant negative), respectively.
- Classically, HER2+ (aOR, 2.9 [95% CI, 2.65 to 3.18], p <0.001) and group 2 (aOR, 2.38 [95% CI, 1.42 to 3.96], p <0.001) treated with HER2-targeted therapy had higher pCR than HER2- controls.
- Benefit was also seen in group 3 (aOR, 1.63 [95% CI, 1.24 to 2.13], p <0.001) and cases with discordant ISH+/IHC- (aOR, 1.61 [95% CI, 1.13 to 2.30], p = 0.008) – but this was only significant in group 3 cases with copy number ≥8 and discordant ISH+/IHC- cases with HER2/CEP17 ratio ≥3.
- Group 4 ISH cases and cases with ISH-/IHC+ did not benefit.
Conclusions
- Patients with ASCO/CAP group 4, discordant ISH-/IHC+ results, and weakly amplified group 3 and discordant ISH+/IHC- have low benefit from HER2 therapy, and alternative approaches for such patients are needed.