Chemotherapy (CT) combined with anti-HER2 drugs (H) is the treatment of choice for HER2+ early breast cancer (BC) patients (pts). However HER2+ tumors are clinically and biologically heterogeneous, and treatment response largely varies according to ER status. Predictive biomarkers are urgently needed in this context. We have recently developed a meta-dataset of clinical trials of neoadjuvant CT +/− H (trastuzumab, lapatinib, or both) in HER2+ BC pts annotated for gene expression, hormone receptor status and pathological complete response (pCR) rates. We have shown that a gene-signature (GS) of RB-1 loss-of-function (RBsig) seems to be predictive of response to neoadjuvant CT +/− H in ER+/HER2+ BC pts in this meta-dataset. Here we report the results of additional analyses aimed to evaluate RBsig’s predictive value against 10 previously developed GSs in the subset of ER+/HER2+ BC pts.
The association of RBsig with pCR was evaluated in comparison with previously described GSs of: low ER signaling, p53 mutation, high PI3K pathway signaling, high expression of HER2 amplicon genes, PAM 50 and 5 immune-related GSs. For each GS, samples were classified as High or Low group using a previously described classifier. Odds Ratio (OR) performance was calculated using the ROCR (v. 1.0) package in R and plotted by forest plot using the survcomp (v. 1.24) package.
RBsig and the HER2 amplicon GS were best at predicting response to neoadjuvant CT +/− H (211 pts; p:0.017). In the subgroup of pts treated with CT alone (n = 94), only the PI3K pathway GS was significantly associated with pCR (p:0.026). In pts treated with CT + H (n = 117) only the HER2 amplicon GS significantly correlated with pCR (p:0.042). RBsig showed a similar trend in both these subgroups (p: 0.078 and 0.104, respectively) The immune GSs and PAM50 were not associated with pCR, independent of treatment received.
RBsig and HER2 amplicon GS are strongly associated with pCR in ER+/HER2+ tumors unselected for treatment. These results support the potential use of such GSs as predictive markers of response to CT +/−H in ER+/HER2+ BC pts. Validation studies are warranted.
Clinical trial identification
Legal entity responsible for the study
Angelo Di Leo
A. Di Leo: Consultant/Advisory Board: Novartis, Pfizer, Lilly. All other authors have declared no conflicts of interest.