RNA Sequencing to Predict Response to Neoadjuvant Anti-HER2 Therapy: A Secondary Analysis of the NeoALTTO Randomized Clinical Trial.
OBJECTIVE
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.


OBJECTIVE
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.


METHODS
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).


METHODS
Gene expression-based biomarkers using RNA sequencing were examined for their association with response to anti-HER2 therapy and long-term outcome.


RESULTS
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
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.


BACKGROUND
clinicaltrials.gov Identifier: NCT00553358.
Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
Debora
D
Fumagalli
Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
David
D
Venet
Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
Michail
M
Ignatiadis
Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
Hatem A
HA
Azim
Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
Marion
M
Maetens
Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
Françoise
F
Rothé
Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
Roberto
R
Salgado
Frontier Science Scotland, Kincraig, Inverness-shire, Scotland.
Ian
I
Bradbury
Breast Medical Oncology Section, Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut.
Lajos
L
Pusztai
Breast Center, Department of Obstetrics and Gynecology, University of Munich, Munich, Germany.
Nadia
N
Harbeck
Department of Medical Oncology, Instituto Nacional de Enfermedades Neoplasicas, Lima, Peru.
Henry
H
Gomez
Department of Surgery, National Cheng Kung University Hospital, Tainan, Taiwan.
Tsai-Wang
TW
Chang
Clinical Trial Department, Eastleigh Breast Care Centre, Pretoria, South Africa.
Maria Antonia
MA
Coccia-Portugal
Department of Oncology, Istituto Nazionale Tumori, Milan, Italy.
Serena
S
Di Cosimo
Breast European Adjuvant Study Team, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
Evandro
E
de Azambuja
SOLTI-Breast Cancer Research Group, Barcelona, Spain.
Lorena
L
de la Peña
Molecular Oncology Laboratory, Vall d'Hebron Institute of Oncology, Barcelona, Spain.
Paolo
P
Nuciforo
Novartis Pharmaceutical, Basel, Switzerland.
Jan C
JC
Brase
Department of Obstetrics and Gynecology, University of Ulm, Ulm, Germany.
Jens
J
Huober
Breast Medicine Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
José
J
Baselga
Department of Medical Oncology, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
Martine
M
Piccart
Division of Cancer Medicine and Research, Peter MacCallum Cancer Center, East Melbourne, Victoria, Australia.
Sherene
S
Loi
Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium15Department of Medical Oncology, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
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