Visit us at EACR Congress 2022

Marta Casarrubios

The advance of chemoimmunotherapy in locally advanced stages of lung cancer has positioned complete pathologic responses as a new relevant clinical entity, with implications for both the differential biology behind these responses and their possible use as an endpoint for assessing therapy efficacy. Characterisation of the T-cell receptor (TCR) repertoire has become a novel approach to monitor immunotherapy responses, however  there is lack of knowledge about its clinical relevance as a predictive biomarker of pathological response in neoadjuvant chemoimmunotherapy. In this exploratory analysis of the NADIM clinical trial, two biomarkers (Top 1% clonal space and TCR evenness), associated with T-cell repertoire imbalance, outperformed the established biomarkers PD-L1 and TMB, regarding CPR prediction after chemoimmunotherapy in this cohort of patients. Additionally, some mechanistic insights are revealed, that imply a higher immunogenicity of tumours with high Top 1% clonal space, as well as the presence of a distinctive peripheral immunosurveillance of pre-treatment tissue top 1% clones, in patients achieving CPR.

Dr. Matteo Allegretti PhD

Breast carcinomas of the HER2-positive subtype (HER2 BC) are oncogene addicted, e.g. they rely on a single dominant cancer driver that sustains pathways hyperactivation, cell proliferation and tumour spreading. At least in the first phases of the disease, this is successfully counteracted by a variety of therapeutic agents (small molecules and monoclonal antibodies) mostly in association with chemotherapy. Among anti-HER2 therapies, T-DM1 has been for many years standard of care in advanced HER2 BC following Trastuzumab/Pertuzumab although lesser than expected objective responses were observed. Pharmacological resistance to T-DM1 has been associated with several direct or bypass alterations of the HER2 pathway but most of these has been documented only in preclinical models. We developed the LiqBreasTrack, a multicentre Italian study, to investigate whether liquid biopsy (LB) may provide opportunities to non-invasively capture resistance traits in the clinical setting. Longitudinal profiling of a uniformly treated patient cohort (n=35) showed that LB accurately identifies drivers of T-DM1 escape that gradually replace HER2 dependency. Predictors of cancer progression appeared into the blood weeks to months before clinical manifestations, allowing the anticipation of relapse with a median of 3.5 months as compared to standard imaging. In most of the cases, molecular findings were actionable mutations or amplifications other than HER2 that may be further exploited through clinical trials of new treatments, alone or in combination with standard anti-HER2 therapies. Additionally, LB profiling highlighted tumor alterations that were sensitive to the treatment, identifying a group of patients with a sustained response to T-DM1).