Abstract 2316
Background
Neoadjuvant chemotherapy (NACT) is the treatment option for locally advanced breast cancer (BC). However, more than half of the patients have no response. Thus, there is an urgent need to find biomarkers of NACT response and personalized therapies for non-responders. Recently, we described a biomarker of NACT response, assessed both in biopsy and blood - HLA-DR expressing cytotoxic T cells (CTLs) with a sensitivity and specificity of 94.12% and 100%, respectively. HLA-DR is associated with CTLs’ cytotoxicity, and it was only observed in NACT-responders, suggesting that functional CTLs are required in the tumor for NACT success. Now, we are validating these results in an independent cohort. Simultaneously, we are establishing 3D spheroid co-culture platforms to tackle new therapeutic options for NACT non-responders.
Methods
MCF7 BC cell line was used to spontaneously form a spheroid in agarose coated plates. Peripheral blood mononuclear cells (PBMCs) from NACT-responders or non-responders were added after spheroid formation and they were able to infiltrate the structure. Doxorubicin (doxo), anti-PD-1 and anti-PD-L1 were added in different combinations.
Results
The validation of HLA-DR level in CTLs to predict NACT response has been in agreement with the first cohort. Regarding the BC spheroids, doxo alone or in combination with NACT non-responders PBMCs (low HLA-DR in CTLs) did not affect them. However, when PBMCs from NACT responders (high HLA-DR in CTLs) were added in combination with doxo, the viability and proliferation of MCF7 cells reduced significantly. Notably, when PBMCs from NACT non-responders were stimulated ex vivo, to increase CTLs’ HLA-DR level and IFN-γ production (p = 0.002), MCF7 cells viability decreased (p = 0.0007). Considering that in biopsies of non-responders, the low HLA-DR level in CTLs was negatively correlated with the expression of tumor PD-L1, we are also exploring this platform to inhibit the PD-1/PD-L1 axis in order to stimulate the PBMCs and decrease BC cells viability.
Conclusions
Besides determining if BC patients will respond to NACT, by analysing HLA-DR levels in CTLs, we will now be able to define the best therapy to NACT non-responders, hopefully improving the BC treatment.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Fundação para a Ciência e Tecnologia (FCT) - PD/BD/114023/2015 and PTDC/BBB-BMD/4497/2014. Liga Portuguesa Contra o Cancro - LPCC-NRS/Terry Fox 2019/2020.
Disclosure
All authors have declared no conflicts of interest.
Resources from the same session
3264 - A novel preclinical model of RAF-independent MEK1 mutant tumors and its treatment with novel ATP competitive MEK inhibitor
Presenter: Luca Hegedus
Session: Poster Display session 3
Resources:
Abstract
4918 - HER2 inhibition in Aggressive Squamous Cell Carcinomas driven by a common MET Sema Domain Polymorphism
Presenter: Nur Afiqah Mohamed Salleh
Session: Poster Display session 3
Resources:
Abstract
2426 - ADAM9 as a target for lung cancer treatment
Presenter: Yuh-pyng Sher
Session: Poster Display session 3
Resources:
Abstract
5537 - Novel polyurea/polyurethane nanocapsules loaded with a tambjamine analog to improve cancer chemotherapy delivery and safety in lung cancer
Presenter: Marta Perez Hernandez
Session: Poster Display session 3
Resources:
Abstract
1597 - Discovery of Clinical Candidate DBPR112, a Furanopyrimidine-based Epidermal Growth Factor Receptor Inhibitor for the Treatment of Non-Small Cell Lung Cancer
Presenter: Hsing-pang Hsieh
Session: Poster Display session 3
Resources:
Abstract
3543 - Molecular characteristics in lung squamous cell carcinomas dependent on TP53 status – putative targets
Presenter: Vilde Haakensen
Session: Poster Display session 3
Resources:
Abstract
4111 - Comparison of molecular profiles between primary tumour and matched metastasis in non-small cell lung cancer
Presenter: Asuka Kawachi
Session: Poster Display session 3
Resources:
Abstract
4559 - Treatment with BLU-667, a potent and selective RET inhibitor, provides rapid clearance of ctDNA in Patients with RET-altered Non-Small Cell Lung Cancer (NSCLC) and Thyroid Cancer
Presenter: Giuseppe Curigliano
Session: Poster Display session 3
Resources:
Abstract
2501 - Triple MET/SRC/PIM inhibition in MET addicted tumors
Presenter: Ilaria Attili
Session: Poster Display session 3
Resources:
Abstract
5655 - Bioactivation of napabucasin triggers reactive oxygen species–mediated cancer cell death
Presenter: Fieke Froeling
Session: Poster Display session 3
Resources:
Abstract