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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)

Emanuela Risi, Chiara Biagioni, Matteo Benelli, Ilenia Migliaccio, Amelia McCartney, Martina Bonechi, Cristina Guarducci, Florentine Hilbers, Serena Di Cosimo, Jens Huober, Dario Romagnoli, Giulia Boccalini, Stefania Vitale, Christos Sotiriou, Laura Biganzoli, Angelo Di Leo & Luca Malorni

abstract

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.
   
citation Risi E, Biagioni C, Benelli M, Migliaccio I, McCartney A, Bonechi M, Guarducci C, Hilbers F, Di Cosimo S, Huober J, Romagnoli D, Boccalini G, Vitale S, Sotiriou C, Biganzoli L, Di Leo A, Malorni L. 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). Ther Adv Med Oncol 2019; 11:1758835919891608.
   
type journal paper/review (English)
date of publishing 11-12-2019
journal title Ther Adv Med Oncol (11)
ISSN print 1758-8340
pages 1758835919891608
PubMed 31853266
DOI 10.1177/1758835919891608