Messaggi chiave
- È stata condotta un’analisi secondaria di PALLAS, lo studio in aperto di fase III che ha valutato l’aggiunta di palbociclib all’endocrinoterapia adiuvante in pazienti con carcinoma mammario (BC) ER+/HER2- in stadio II-III, volta ad accertare il possibile ruolo prognostico e predittivo dello stato HER2-low. L’analisi ha incluso un totale di 5304 pazienti (92,2% della popolazione intent-to-treat originale).
- Il 42,5 e 57,5% dei pazienti inclusi nell’analisi presentava una malattia rispettivamente HER2-0 e HER2-low. Il follow-up mediano è stato di 59,8 mesi. La prevalenza di HER2-low è risultata significativamente diversa tra i Paesi partecipanti (range, 16,7-75,6%; p <0,001), maggiore nei pazienti arruolati presso centri nordamericani (63,1%) rispetto a Europa (53,4%) o altre regioni (53,4%) (p <0,001). Il modello multivariato di Cox non ha evidenziato alcuna associazione significativa dello stato di HER2 con la sopravvivenza libera da malattia invasiva (IDFS) (hazard ratio, 0,93; IC 95%, 0,81-1,06). Non sono altresì emerse interazioni significative tra braccio di trattamento e stato di HER2 in relazione agli esiti di IDFS (p = 0,43), sopravvivenza libera da recidiva a distanza e sopravvivenza globale.
- In questa coorte prospettica globale, non sono state osservate differenze nella prognosi né è stato individuato alcun beneficio differenziale del trattamento con palbociclib in base ai livelli di espressione di HER2. L’ampia variabilità geografica nella prevalenza dello stato HER2-low suggerisce un elevato grado di eterogeneità nella valutazione patologica dell’espressione di HER2, senza alcun impatto sugli esiti.
Abstract
Background
- Bidirectional crosstalk between HER2 and estrogen receptor (ER) pathways may influence outcomes and the efficacy of endocrine therapy (ET).
- Low HER2 expression levels (HER2-low) have emerged as a predictive biomarker in patients with breast cancer (BC).
Methods
- PALLAS is an open, international, phase 3 study evaluating the addition of palbociclib for 2 years to adjuvant ET in patients with stage II-III ER-positive/HER2-negative BC.
- To assess the impact of HER2 expression on patient outcomes in the phase III PALLAS trial, we analyzed (1) the association between rate of HER2-low with demographic and clinicopathological parameters, (2) the prognostic value of HER2-low status on invasive disease-free survival (iDFS), distant relapse-free survival (DRFS), and overall survival (OS) and (3) HER2 expression’s value as a predictive biomarker of response to palbociclib.
- HER2-low was defined as HER2 immunohistochemistry (IHC) 1 + or IHC 2 + with negative in situ hybridization (ISH).
- All pathologic evaluation was performed locally.
- Prognostic and predictive power of HER2 were assessed with Cox models.
Results
- From the original PALLAS intention-to-treat population (N = 5753), 5304 patients (92.2%) were included in this analysis.
- Among these, 2254 patients (42.5%) were classified as having HER2 IHC 0 (HER2-0), and 3050 (57.5%) as having HER2-low disease (1838 with IHC 1 + and 1212 with IHC 2 +).
- Median follow-up was 59.8 months.
- HER2-low prevalence varied significantly across 21 participating countries (range 16.7% to 75.6%; p <0.001) and was more frequent in patients enrolled in North America (63.1%) than in Europe (53.4%) or other regions (53.4%) (p <0.001).
- HER2 status was not significantly associated with iDFS in a multivariable Cox model (hazard ratio 0.93, 95% confidence interval 0.81 – 1.06).
- No significant interaction was observed between treatment arm and HER2 status for iDFS (p = 0.43).
- Similar results were obtained for DRFS and OS.
Conclusions
- In this large, prospective, global patient cohort, no differences were observed in clinical parameters, prognosis, or differential benefit from palbociclib between HER2-0 and HER2-low tumors.
- Significant geographic variability was observed in the prevalence of HER2-low status, suggesting a high degree of variation in pathologic assessment of HER2 expression without impact on outcomes.