Abstract P6-01-05: Platelet-derived growth factor-CC expression in primary triple-negative breast cancer is associated with the basal-like molecular subtype and increased immune infiltrate
Authors: Lehn Sophie , Pekar Gyula , Balbas Paulina Bolivar , Staaf Johan , Möller Christina , Lövgren Kristina , Ehinger Anna , Campos Ana Bosch , Borg Åke , Pietras Kristian 
Published: March 2023

Around 10-15% of all breast cancers are categorized clinically as triple-negative breast cancer (TNBC). TNBC is defined by lack of protein expression or over expression of treatment targets such as the Estrogen Receptor α (ER) and Human Epidermal Growth Factor Receptor-2 (HER2), and the prognostic factor PR (Progesterone Receptor). The negative definition of TNBC results in a heterogeneous mix of tumors with variable molecular characteristics and prognosis. Defining TNBC molecular subtypes in detail is of importance to improve prognostication and find new treatment options. Expression of Platelet-derived growth factor-CC (PDGF-CC) has previously been correlated with the TNBC subtype, and paracrine PDGF-CC signaling has been reported to be of importance for maintaining TNBC tumor cell phenotype. We aimed to characterize PDGF-CC expression within the TNBC patient population by combining studies of PDGF-CC in tissue microarrays (TMAs) with matching RNAseq data and clinical follow-up; all variables originating from the SCAN-B (Sweden Cancerome Analysis Network – Breast) clinical study (ClinicalTrials.gov: NCT02306096). TMAs constructed of primary TNBC patient samples were stained for PDGF-CC using the Dako PT Autostainer system. Tumor cell-specific expression of PDGF-CC intensity was scored as either absent (N=11), weak (N=86), intermediate (N=81) or strong (N=70), and the scores were used to create corresponding TNBC PDGF-CC subgroups. We then explored associations of these subgroups with clinicopathological variables and time-to-event outcomes. Intermediate and strong PDGF-CC scores were associated with Nottingham Histological Grade 3 (p=0.001), increased proliferation (p&lt; 0.001) and younger patient age at diagnosis (p=0.002). RNAseq data corresponding to tumors included in the TMAs was then retrieved, and differentially expressed genes were identified and used to perform Gene Set Enrichment Analysis (GSEA) comparing the TMA-derived PDGF-CC subgroups. Immune-related signatures were found to be enriched in the strong PDGF-CC subgroup vs. intermediate. Interestingly, strong PDGF-CC intensity was associated with a decreased risk of recurrence in the chemotherapy treated patient group (HR 0.28, 95% CI 0.10-0.80, p=0.017). Finally, patient samples were assigned a PAM50 subtype and a TNBC molecular subtype by the TNBCtype algorithm. Ninety-four percent of tumors in the strong PDGF-CC subgroup were classified as basal-like, whereas the corresponding number in the weak and intermediate PDGF-CC subgroups were 51% and 84%, respectively. The TNBC molecular subtype termed ‘Immunomodulatory’ was more frequently represented in the strong PDGF-CC subgroup compared to weak and intermediate (33% vs. 13% and 16%, respectively). In conclusion, strong PDGF-CC protein expression identified basal-like TNBCs, with an increase in immune cell infiltrate shown by RNAseq analysis. Whether or not PDGF-CC has a direct effect on influx of immune cells into tumors remains to be investigated. Analyses are currently ongoing to better understand the improved outcome associated with strong PDGF-CC intensity and on the contrary, the worse outcome associated with weak and intermediate PDGF-CC intensity, and if paracrine PDGF-CC signaling may explain the discrepancy observed.

Citation Format: Sophie Lehn, Gyula Pekar, Paulina Bolivar Balbas, Johan Staaf, Christina Möller, Kristina Lövgren, Anna Ehinger, Ana Bosch Campos, Åke Borg, Kristian Pietras. Platelet-derived growth factor-CC expression in primary triple-negative breast cancer is associated with the basal-like molecular subtype and increased immune infiltrate [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-01-05.