Identification of Markers to Predict Benefit from Trastuzumab Treatment

Triulzi, Tiziana (2017). Identification of Markers to Predict Benefit from Trastuzumab Treatment. PhD thesis The Open University.



Despite the clinical benefit of trastuzumab, some patients do not respond to this therapy. Aims of this study are to identify new predictive biomarkers to distinguish responsive from de novo resistant tumours and to have new insights into the biological characterisation of trastuzumab activity.

Whole-transcriptome analysis of primary HER2-positive breast carcinomas (BCs) treated with adjuvant trastuzumab identified a tumour subgroup, characterised by high ERBB2/low ESR1 expression, with good clinical outcome, and allowed the development of a trastuzumab risk model (TRAR) able to identify patients with high- and low-risk of relapse. Application of TRAR model to available datasets and to a new series of HER2-positive BC patients treated with neoadjuvant trastuzumab designated TRAR as predictive of response rather than associated to low aggressiveness. Our analyses showed that tumours exquisitely sensitive to treatment are addicted to HER2, enriched in immune pathways and have a peculiar circulating NK profile, characterised by high expression of the NKG2D receptor. Enrichment of immune system- and tyrosine kinase receptor signaling-related pathways was found associated also with response to trastuzumab monotherapy in clinical samples, suggesting the possibility to treat HER2-addicted tumours with trastuzumab monotherapy. Accordingly TRAR-low, high-NKG2D- and -MHC-II-expressing tumours were associated with response to one cycle of trastuzumab alone. In addition, increase of MHC-II gene expression upon a single cycle of trastuzumab characterised patients who benefit from the following combination with chemotherapy. Characterisation of biological features of TRAR-low tumours showed high infiltration of macrophages and CD8+ T cells, together with the expression of chemokines involved in their recruitment and of immune checkpoint ligands. In vitro analysis demonstrated a direct regulation of CCL2 and PD-L1 by HER2 signals.

Overall, we described a tool able to identify BCs responsive to trastuzumab and understood that in these tumours HER2 is crucial for tumour growth, for infiltration of pro-trastuzumab immune cells and their suppression.

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