Detalle Publicación

Gene expression profile at week 2 of neoadjuvant therapy course predicts outcome in HER2-positive breast cancer patients: an explorative analysis from NeoALTTO

Autores: Di Cosimo, S.; Pizzamiglio, S.; Sotiriou, C.; Ciniselli, C. M.; Triulzi, T.; De Cecco, L.; El-Abed, S.; Izquierdo, M.; De Azambuja, E.; Saura, C.; Huober, J.; Untch, M.; Lang, I.; Loi, S.; Tagliabue, E.; Rubio, Isabel Teresa; Vingiani, A.; Colombo, M. P.; Verderio, P.; Pruneri, G.
Título de la revista: EUROPEAN JOURNAL OF CANCER
ISSN: 0959-8049
Volumen: 175
Número: SUPPL 1
Páginas: S78
Fecha de publicación: 2022
Resumen:
Background: NeoALTTO showed increased pathological complete response (pCR) with paclitaxel combined with dual over single anti-HER2 blockade. The trial included six initial weeks of treatment with lapatinib (L), trastuzumab (T) or their combination (L+T) followed by chemotherapy (CHT). A tumor biopsy was planned during the CHT-free window at day14 ± 2. Herein, we tested the hypothesis that prognostication of clinical outcome is feasible through assessment of gene expression profile (GEP) following two weeks of anti-HER2 therapy. Patients and methods: RNA from matched baseline and day14 ± 2 biopsies were profiled using Clariom S microarray (ThermoFisher). The levels of the molecular classifier TRAR, which proved to identify HER2-addicted (HER2 high/ESR1 low, TRAR-low) and non HER2-addicted (TRAR high, Estrogen Receptor [ER]-dependent) primary tumors, and five immune-related metagenes, namely, the T-cell surrogate lymphocyte-specific kinase (LCK), the monocyte/myeloid lineage hemopoietic cell kinase (HCK), interferon (IFN), major histocompatibility complex II (MHCII), and signal transducer and activator of transcription 1 (STAT1) were computed. Logistic and Cox regression models were applied to evaluate the association between TRAR and immune-related metagenes with pCR and event free survival (EFS), at baseline and after two weeks of treatment with anti-HER 2 therapy. Results: Overall, 180 matched baseline and day14 ± 2 GEP samples were analyzed from patients treated with L (n = 65), T (n = 66), and L+T (n = 49). No significant differences in patient characteristics or outcomes were observed between the cohort included in our study and the whole NeoALTTO patient population. At baseline, none of the immune-related metagenes tested were informative of patient outcomes. After 2 weeks of treatment with anti-HER2, the expression levels of LCK (OR: 3.92, 95%CI: 1.96; 7.85), HCK (OR: 3.22, 95%CI: 1.55; 6.68), and MHCII (OR: 2.68, 95%CI: 1.37; 5.26) were significantly positively associated with pCR, independently from ER status and treatment arm. When considering changes from baseline, increased levels of LCK were also predictive (2.90, 95% CI:1.48;5.71), and those of HCK were associated with EFS regardless of pCR and nodal status (HR: 0.57, 95%CI: 0.34; 0.96). TRAR assessment at day 14 ± 2 was not predictive of response. However, both pre-treatment TRAR (Odds Ratio [OR]: 0.19, 95% CI: 0.08;0.47), and its increase during treatment (OR:3.99 95%CI1.90; 8.39) were independently associated with pCR. Conclusions: Biomarkers of early T-cell and monocyte-macrophage activation, as well as HER2 downregulation hold the potential to reliably identify patients likely to achieve a pCR and a favorable prognosis. New effective treatments need to be explored for cases lacking an early GEP response.
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