Abstract P5-13-30: Analysis of αβ and γδ circulating T cells in the PHERGain randomized phase 2 trial for patients with HER2-positive early breast cancer receiving neoadjuvant trastuzumab and pertuzumab without chemotherapy: LINGain
Authors: Andreu-Ballester Juan Carlos , Pérez-García José Manuel , Bermejo Begoña , Carañana Vicente , Iranzo Vega , Gavilà Joaquín , Santaballa Ana , Gómez-Soler María Carmen , Sampayo-Cordero Miguel , Malfettone Andrea , Cortes Javier , Llombart-Cussac Antonio 
Published: March 2022

Abstract
Background: The presence of stromal tumor-infiltrating lymphocytes (TILs) represents an independent prognostic factor in HER2-positive early-stage breast cancer (EBC) treated with trastuzumab/pertuzumab-containing regimens. Among distinct subsets of TILs, conventional CD8+ αβ T cells require TCR signaling as a part of adaptive immunity, while γδ T cells display also innate-like activity via the NKG2D receptor contributing to a very rapid tumor immunosurveillance. Specific γδ T cell subsets were associated with remission and improved overall survival of patients with triple-negative breast cancer. However, very little is known about circulating αβ and γδ T cells and their immunological status in HER2-positive breast cancer. In this substudy, we aimed to characterize the αβ and γδ T cell subsets and the association with clinical outcome in peripheral blood of patients with HER2-positive EBC enrolled in the PHERGain trial, which assessed the possibility of chemotherapy de-escalation with neoadjuvant dual HER2 blockade with trastuzumab and pertuzumab using an 18F-fluorodeoxyglucose-PET and pathological response-adapted strategy. Methods: Peripheral blood was obtained from 24 consecutive patients who were assigned to the trastuzumab and pertuzumab group (+/- endocrine therapy as per hormone receptor status) before randomization (baseline) and after 2 treatment cycles (6 weeks). Blood samples were also collected from 48 age-matched healthy donors who represented the control group. Absolute numbers of CD3+, CD3+/CD4+, CD3+/CD8+, and CD3+/CD56+ according to the TCR expression, and annexin V apoptotic rate on αβ and γδ T cells were evaluated by flow cytometry. Subset distribution of T cell differentiation within naïve, central memory, effector memory, and terminally differentiated effector memory cells was also determined. The changes in the frequency of peripheral T cells and rate of apoptotic subsets between timepoints, patients, and healthy donors were compared with Wilcoxon test. The analyses were set at two-sided 0.05 level of significance. Results: Among 24 patients with evaluable blood samples at both timepoints, median age was 50.5 years (IQR 45.8-61), 45.8% had node-positive disease, 79.2% had hormone receptor-positive status, 79.2% had tumors with HER2 IHC 3+ status, and 54.2% achieved a pathological complete response (ypT0/is ypN0) after treatment. At baseline, levels of αβ and γδ T cells in EBC patients were significantly lower than levels in healthy subjects (P ≤0.05). After 6 weeks of study treatment, these levels in EBC patients did not significantly differ from those at baseline. Baseline rates of apoptotic subsets were higher in EBC patients than rates in healthy subjects (P &lt;0.01), but after 6 weeks of study treatment all apoptotic subsets were significantly reduced in EBC patients compared with those at baseline (P ≤0.05). No evidence of association was found between peripheral T cells and pathological complete response in EBC patients. Conclusions: These data suggest a potential involvement of T cell apoptosis on the mechanism of action mediated by dual HER2 blockade with trastuzumab and pertuzumab in patients with HER2-positive EBC. However, further validation is required. Additional data on the subset distribution of T cell differentiation status will be presented at the meeting.
Citation Format: Juan Carlos Andreu-Ballester, José Manuel Pérez-García, Begoña Bermejo, Vicente Carañana, Vega Iranzo, Joaquín Gavilà, Ana Santaballa, María Carmen Gómez-Soler, Miguel Sampayo-Cordero, Andrea Malfettone, Javier Cortes, Antonio Llombart-Cussac. Analysis of αβ and γδ circulating T cells in the PHERGain randomized phase 2 trial for patients with HER2-positive early breast cancer receiving neoadjuvant trastuzumab and pertuzumab without chemotherapy: LINGain [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-13-30.