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Integrative multi-omic analysis: towards treatment de-escalation for early stage HER2-positive breast cancer

par Rediti, Mattia
Président du jury Le Moine, Alain
Promoteur Sotiriou, Christos
Publication Non publié, 2023-11-09

Thèse de doctorat

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Résumé :

Human Epidermal growth factor Receptor 2 (HER2)-positive breast cancer accounts for approximately 15-20% of all breast cancer cases. The HER2-targeting monoclonal antibody trastuzumab revolutionized HER2-positive breast cancer prognosis and was followed by the development of additional anti-HER2 agents. Nonetheless, despite these major therapeutic advances, response to anti-HER2 treatments is heterogeneous. Indeed, dual HER2-blockade in the (neo)adjuvant setting led only to a limited reduction in the risk of recurrence, and disease relapse is still observed in approximately 5-20% of patients in the early disease setting. In addition, after neoadjuvant therapy 40-60% of the patients present residual disease and, consequently, experience worse long-term outcomes compared to those achieving pathological complete response (pCR). In the last years, the concepts of escalation and de-escalation strategies have become an important topic of discussion for the management of patients with early stage HER2-positive breast cancer, as some of them present excellent outcome and may avoid escalation treatment approaches, sparing them from unnecessary toxicities. The main objective of this thesis was to identify biomarkers of treatment resistance and disease recurrence in patients with early stage HER2-positive breast cancer, in order to develop stratification models able to identify patients with excellent prognosis who may benefit from treatment de-escalation approaches. For this purpose, we aimed to analyze “omics” data, immune-related features and clinicopathological characteristics in patients enrolled in the Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimisation (NeoALTTO) phase 3 trial, as well as in patients treated with trastuzumab alone in the context of the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation (ALTTO) phase 3 trial. In the first study, we investigated the role of copy number aberrations in predicting pCR and survival outcomes in the NeoALTTO clinical trial. We showed that ERBB2 copy number levels were significantly associated with pCR. However, ERBB2 expression levels outperformed ERBB2 copy number levels in predicting pCR. GISTIC2.0 analysis revealed 159 recurrent CNA regions. Lower copy number levels of the 6q23-24 locus predicted absence of pCR in the whole cohort and in the estrogen receptor-positive subgroup. Moreover, 6q23-24 deletion was significantly more frequent in TP53 wild-type (WT) compared with TP53-mutated, and 6q23-24 copy number levels were significantly associated with lack of pCR only in the TP53 WT subgroup. Interestingly, a gene-ontology analysis highlighted several immune processes correlated to 6q23-24 copy number deletions suggesting an immune evasion mechanism. In the second study we focused on characterizing the immune response by studying the complexity of B and T cell receptor (BCR and TCR) repertoires, reflecting antigen-specific immune response in the NeoALTTO trial. BCR/TCR features were heterogeneous, and we demonstrated the prognostic value of BCR measures describing B cell clonal expansion. Building on these results, we developed a model to predict event-free survival (EFS) by integrating hormone receptor and clinical nodal status, breast pCR as well as tumor-infiltrating lymphocytes and BCR evenness, measuring the equality of BCR clonal distribution. These findings were independently validated in the neoadjuvant CALGB 40601 clinical trial. A score derived from the model (HER2-EveNT) allowed the identification of patients with 5-year EFS > 90%, and, in those not achieving pCR, of a subgroup of immune-enriched tumors with an excellent outcome despite residual disease. Finally, in the third study, we aimed to explore biological processes associated with risk of distant recurrence in patients with HER2-positive breast cancer treated with adjuvant trastuzumab in the context of the ALTTO clinical trial. By performing gene expression profiling, we identified 5 novel molecular subtypes associated with prognosis, namely immune-enriched (IM), proliferative/metabolic-enriched (P/Met), mesenchymal/stroma-enriched (Mes/S), luminal (LUM) and ERBB2-enriched (ERBB2-E). We next validated the biological profiles of the subtypes and explored their prognostic/predictive value in external cohorts, namely the NeoALTTO trial, SCAN-B, I-SPY2, METABRIC and TCGA. IM tumors presented better survival outcomes, in contrast to Mes/S and P/Met tumors, while LUM tumors and ERBB2-E were characterized by low and high rates of pCR, respectively. Of note, these molecular subtypes provide the rationale for novel treatment approaches leveraging the heterogeneous biology of HER2-positive breast cancer. In conclusion, in these studies we provide novel insights into the biology of HER2-positive breast cancer, and we identify biomarkers of sensitivity and resistance to anti-HER2 which could help in optimizing treatment strategies in patients affected by HER2-positive breast cancer.