Whole-transcriptome analysis links trastuzumab sensitivity of breast tumors to both HER2 dependence and immune cell infiltration.
While results thus far demonstrate the clinical benefit of trastuzumab, some patients do not respond to this therapy. To identify a molecular predictor of trastuzumab benefit, we conducted whole-transcriptome analysis of primary HER2+ breast carcinomas obtained from patients treated with trastuzumab-containing therapies and correlated the molecular portrait with treatment benefit. The estimated association between gene expression and relapse-free survival allowed development of a trastuzumab risk model (TRAR), with ERBB2 and ESR1 expression as core elements, able to identify patients with high and low risk of relapse. Application of the TRAR model to 24 HER2+ core biopsies from patients treated with neo-adjuvant trastuzumab indicated that it is predictive of trastuzumab response. Examination of TRAR in available whole-transcriptome datasets indicated that this model stratifies patients according to response to trastuzumab-based neo-adjuvant treatment but not to chemotherapy alone. Pathway analysis revealed that TRAR-low tumors expressed genes of the immune response, with higher numbers of CD8-positive cells detected immunohistochemically compared to TRAR-high tumors. The TRAR model identifies tumors that benefit from trastuzumab-based treatment as those most enriched in CD8-positive immune infiltrating cells and with high ERBB2 and low ESR1 mRNA levels, indicating the requirement for both features in achieving trastuzumab response.
Department of Experimental Oncology and Molecular Medicine, Molecular Targeting Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Tiziana
T
Triulzi
Department of Experimental Oncology and Molecular Medicine, Functional Genomics Core Facility, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Loris
L
De Cecco
Department of Experimental Oncology and Molecular Medicine, Molecular Targeting Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Marco
M
Sandri
Translational Genomics Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain.|Medical Oncology Department, Hospital Clínic i Provincial, Barcelona, Spain.
Aleix
A
Prat
Department of Experimental Oncology and Molecular Medicine, Molecular Targeting Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Marta
M
Giussani
Department of Pathology, Anatomic Pathology A Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Biagio
B
Paolini
Department of Pathology, Anatomic Pathology A Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Marialuisa L
ML
Carcangiu
Department of Experimental Oncology and Molecular Medicine, Functional Genomics Core Facility, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Silvana
S
Canevari
Dipartimento di Terapia Molecolare e Farmacogenomica, Istituti Ospitalieri di Cremona, Italy.
Alberto
A
Bottini
Department of Experimental Oncology and Molecular Medicine, Molecular Targeting Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.|Dipartimento di Scienze Biomediche per la Salute, Università degli Studi di Milano, Italy.
Andrea
A
Balsari
Department of Experimental Oncology and Molecular Medicine, Molecular Targeting Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Sylvie
S
Menard
Dipartimento di Terapia Molecolare e Farmacogenomica, Istituti Ospitalieri di Cremona, Italy.
Daniele
D
Generali
Department of Experimental Oncology and Molecular Medicine, Molecular Targeting Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Manuela
M
Campiglio
Department of Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Serena
S
Di Cosimo
Department of Experimental Oncology and Molecular Medicine, Molecular Targeting Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Elda
E
Tagliabue
D000970:Antineoplastic Agents / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D017024:Chemotherapy, Adjuvant; D015331:Cohort Studies; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008957:Models, Genetic; D020360:Neoadjuvant Therapy; D009364:Neoplasm Recurrence, Local; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D012307:Risk Factors; D000068878:Trastuzumab / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D047628:Estrogen Receptor alpha; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C506487:ESR1 protein, human; C508053:ERBB2 protein, human
breast cancer; gene expression profiling; lymphocytes; trastuzumab benefit