Gene Expression Patterns Prognostic For Response In NeoALTTO Patients

Gene markers of oestrogen signalling and tumour microenvironment predict pathological complete response in patients with human epidermal growth factor receptor 2-positive breast cancer given neoadjuvant trastuzumab and/or lapatinib

medwireNews: The likelihood of a pathological complete response (pCR) in patients with early-stage human epidermal growth factor receptor (HER)2-positive breast cancer given dual HER2 blockade can be predicted by RNA sequencing, suggest the NeoALTTO trial investigators.

“The results of this study support the existence of significant molecular heterogeneity among HER2-positive breast cancers and the influence of both estrogen signaling and tumor microenvironment in the response to anti-HER2 therapies”, say Christos Sotiriou, from Université Libre de Bruxelles in Belgium, and co-authors.

“Future studies should take this knowledge into account and aim to determine how these factors could be used to individualize the treatment of patients with HER2-positive disease”, they write in JAMA Oncology.

The preplanned secondary analysis included RNA sequencing results for 56% of patients in the phase III trial comparing neoadjuvant trastuzumab , lapatinib or combined therapy for 6 weeks, followed by 12 weeks of paclitaxel , and three postoperative cycles of fluorouracil , epirubicin and cyclophosphamide .

The strongest correlation was between pCR and RNA expression of ESR1 and ERBB2/HER2, with the 45% of patients with low ERS1 and high ERBB2/HER2 accounting for most of the pCRs, at a rate of 47%.

By contrast, 35% of patients had high ESR1 and high ERBB2/HER2 expression and 20% of patients had low expression of both biomarkers, and pCR occurred in just 32% and 9% of these groups, respectively.

“The fact that in our study the level of expression of ESR1 remained significant after accounting for the ER [oestrogen receptor] status determined using [immunohistochemistry], and not the opposite, suggests that […]in this case ESR1 mRNA levels are more predictive than its protein levels”, the researchers comment.

“[H]owever, we cannot exclude that this finding is due to the ER testing being performed only in local laboratories in the NeoALTTO trial”, they observe.

pCR rate also varied with the PAM50 classifier, with the 43% of patients designated as HER2 enriched significantly more likely to achieve a pCR than those with the other classifier subtypes.

The researchers also looked for correlations between pCR and three immune-related genetic signatures, two proliferation-related genetic signatures and two stroma-related genetic signatures. Both the immune signatures and one of the stroma signatures were linked to pCR in patients given combined HER2 blockade, whereas pCR in patients given lapatinib was linked to one of the proliferation markers, the Genomic Grade Index.

After adjusting for a raft of clinicopathological parameters and treatment arm, the researchers found the odds ratio (OR) of pCR was significantly predicted by ESR1 expression (OR=0.53), ERBB2/HER2 expression (OR=3.1), HER2 enriched classification on PAM50 (OR=3.2), two of the immune signatures (OR=1.3 for both), and both the Genomic Grade Index (OR=1.5) and Aurka (OR=1.3) proliferation signatures.

The researchers note, however, that after correction for multiple testing, no significant correlation was found between any of the gene expression markers used in the study and event-free survival (EFS). Nor was there any evidence for an interaction between EFS and treatment received.

“The NeoALTTO trial was not originally powered to evaluate the difference between the treatment arms in terms of EFS, and our findings could be weakened by the low statistical power”, they suggest.


Fumagalli D, Venet D, Ignatiadis M, et al. RNA sequencing to predict response to neoadjuvant anti-HER2 therapy. A secondary analysis of the NeoALTTO randomized clinical trial. JAMA Oncol; Advance online publication 29 September 2016. doi:10.1001/jamaoncol.2016.3824

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