In neoadjuvant trials, treatment of human epidermal growth factor
receptor 2 (HER2)-positive breast cancers with dual HER2 blockade
resulted in increased pathologic complete response (pCR) rates
compared with each targeted agent alone. Amplification and/or
overexpression of HER2 currently remains the only biomarker for
therapeutic decisions, but it is insufficient to explain the
heterogeneous response to anti-HER2 agents.
To investigate the ability of clinically and biologically relevant
genes and gene signatures (GSs) measured by RNA sequencing to
predict the efficacy of anti-HER2 agents.
Design, Setting, and Participants
The neoadjuvant NeoALTTO trial randomized 455 women with
HER2-positive early-stage breast cancer to trastuzumab, lapatinib,
or the combination for 6 weeks followed by the addition of weekly
paclitaxel for 12 weeks, followed by 3 cycles of fluorouracil,
epirubicin, and cyclophosphamide after surgery. The present
substudy, which was planned in the NeoALTTO main protocol, evaluated
the association of pretreatment gene expression levels defined using
RNA sequencing with pCR and event-free survival (EFS).
Main Outcomes and Measures
Gene expression-based biomarkers using RNA sequencing were examined
for their association with response to anti-HER2 therapy and
Sequencing data were available for 254 (56%) of the NeoALTTO
participants (mean [SD] age of substudy participants, 48.8 [11.2]
years). The expression of ERBB2/HER2 was the most significant
predictor of pCR, followed by HER2-enriched subtype, ESR1, treatment
arm, ER immunohistochemical analysis scores, Genomic Grade Index,
immune, proliferation, and AKT/mTOR GSs. Adjusting for
clinicopathological variables and treatment arms, ERBB2/HER2,
HER2-enriched subtype, ESR1, and Genomic Grade Index remained
significant. Immune GSs were associated with higher pCR only in the
combination arm (odds ratio, 2.1; 95% CI, 1.2-4.0; interaction test
P = .01), while the stroma GSs were significantly
associated with higher pCR in the single arms and with lower pCR in
the combination arm (odds ratio, 0.46; 95% CI, 0.25-0.84;
P = .009). None of the evaluated variables was
associated with EFS after correction for multiple testing, but this
analysis was underpowered.
Conclusions and Relevance
High levels of ERBB2/HER2 and low levels of ESR1 were associated
with pCR in all treatment arms. In the combination arm, high
expression of immune and stroma GSs were significantly associated
with higher and lower pCR rates, respectively, and should be further
explored as candidate predictive markers.
clinicaltrials.gov Identifier: NCT00553358.
Fumagalli D, Venet D, Ignatiadis M, Azim H A, Maetens M, Rothé F,
Salgado R, Bradbury I, Pusztai L, Harbeck N, Gomez H, Chang T W,
Coccia-Portugal M A, Di Cosimo S, de Azambuja E, de la Pena L,
Nuciforo P, Brase J C, Huober J, Baselga J, Piccart M, Loi S,
Sotiriou C. RNA Sequencing to Predict Response to Neoadjuvant
Anti-HER2 Therapy: A Secondary Analysis of the NeoALTTO Randomized
Clinical Trial. JAMA Oncol 2017; 3:227-234.