Publication
An RB-1 loss of function gene signature as a tool to predict response to neoadjuvant chemotherapy plus anti-HER2 agents: a substudy of the NeoALTTO trial (BIG 1-06)
Journal Paper/Review - Dec 11, 2019
Risi Emanuela, Di Leo Angelo, Biganzoli Laura, Sotiriou Christos, Vitale Stefania, Boccalini Giulia, Romagnoli Dario, Huober Jens, Di Cosimo Serena, Hilbers Florentine, Guarducci Cristina, Bonechi Martina, McCartney Amelia, Migliaccio Ilenia, Benelli Matteo, Biagioni Chiara, Malorni Luca
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Brief description/objective
Background
Chemotherapy added to anti-HER2 agents (H) is the treatment of choice in patients with HER2+ early breast cancer. However, HER2+ tumours are clinically and biologically heterogeneous, and treatment response varies significantly by hormone receptor (HR) status and molecular subtype. Predictive biomarkers are needed in this context. This study assessed whether an RB-1 loss of function gene signature (RBsig) is predictive of response to neoadjuvant chemotherapy in combination with trastuzumab, lapatinib or both, within the NeoALTTO trial.
Methods
We collected RNA-sequencing data from pretreatment biopsies derived from the NeoALTTO trial. RBsig expression was computed retrospectively and correlated with pathological complete response (pCR) using receiver-operating characteristic (ROC) curves. The RBsig was dichotomised as High/Low in correspondence to the 25th percentile. Reported values resulted from Fisher's exact test.
Results
Of 455 NeoALTTO patients, 244 were eligible for this substudy (HR+ = 129; HR- = 115). Overall, pCR rate was significantly higher in patients with RBsig High tumours than those with RBsig Low (35% 18% respectively; = 0.01). The area under the ROC curve (AUC) was 0.60 (95% CI 0.52-0.67). A remarkably low pCR rate of 11% was seen in HR+/RBsig Low patients 28% in HR+/RBsig High.
Conclusions
These results indicate RBsig may add valuable information to HER2 and HR expression, which may in turn inform treatment choices. HR+/HER2+/RBsig Low breast cancers exhibited the poorest pathological response following chemotherapy plus H. Accordingly, in such patients, endocrine therapy in combination with H and, possibly, a CDK4/6 inhibitor, may potentially prove to be a more effective treatment.