Samraj, Lavanya

Abstract Background: Latin Americans are more likely to be diagnosed with aggressive early-stage breast cancer compared to Non-Hispanic White. Multiple factors may contribute to this, including metabolic factors and ancestry. In a previous study, we identified upregulated immune pathway genes in Luminal B tumors from obese Black patients compared to matched White patients. In this study, we report clinical and transcriptomic profiles of breast tumors from Latin and White patients to enhance understanding of factors contributing to aggressive tumor biology in Latin patients. Methods: We matched 311 Latin and 311 White breast cancer patients enrolled in FLEX by age, T stage, N stage and clinical subtype (ER/PR and HER2 status). FLEX (NCT03053193) is a prospective, observational trial that includes stage I-III breast cancer patients who receive MammaPrint (with or without BluePrint) as standard of care and consent to whole transcriptome and clinical data collection. MammaPrint is a 70-gene risk of distant recurrence signature that classifies patients as Low Risk or High Risk. BluePrint is an 80-gene molecular subtyping signature, categorizes tumors as Luminal-, HER2- or Basal-Type. MammaPrint further groups Luminal into A (Low Risk) and B (High Risk). ImPrint is a 53-gene signature that has been shown to predict the likelihood of achieving pCR with PD1-PDL1 immune checkpoint inhibitors. Statistical analyses on groups were conducted using arsenal R package and p-value < 0.05 was considered significant. Whole transcriptome comparisons were made, using limma R package, between Latin and White patients stratified by BluePrint subtype Luminal and weight categories normal (body-mass-index (BMI) 18.5 to < 25) and obese (BMI ≥30). Significant differentially expressed genes had an adjusted p-value < 0.05. Gene set enrichment analysis (GSEA) was conducted using fgsea R package. Results: Latin patients had significantly higher percentage of type 2 diabetes (23.3% vs 8.5%), BMI obese (49.0% vs 39.4%), BluePrint Basal (14.8% vs 9.3%) and ImPrint Immune Sensitive (12.0% vs 5.1%) compared to matched White patients. When comparing whole transcriptome of tumors from Latin and White patients, only tumors stratified by Luminal B and obesity resulted in differentially expressed genes: Latin patients had higher expression (>2-fold change) of 42 immunoglobulin genes compared to White, with only IGKV6-21 being statistically significant. Additional immune related genes such as IKZF1 and AGER, as well as UTS2 (gene encoding a vasoconstrictor agent and contributor of angiogenesis) were significantly upregulated in Latin patients. Upregulation of immune related pathways such as inflammatory response, interferon alpha/gamma response and downregulation of adipogenesis, oxidative phosphorylation and MYC targets were identified in Latin patients compared to White using GSEA Hallmarks gene sets. Conclusion: There were additional clinical and genomic differences between tumors from Latin and White patients, even when controlling for age, T stage, N stage and clinical subtype. Particularly, there were more type 2 diabetes, BMI obese, BluePrint Basal, and ImPrint Immune Sensitive among Latin patients. In addition, transcriptomic differences between obese Latin and matched White patients were found in Luminal B subgroup that may contribute to the aggressive tumor biology; immunoglobulin genes and immune related pathways were associated with higher expression in Latin patients. This study suggests that biological differences in breast tumors, particularly from obese patients, may result from shared background and reflects the need for inclusion of diverse patient groups in clinical trials. Citation Format: Marcela Mazo-Canola, Virginia Kaklamani, Pooja Advani, Sailaja Kamaraju, Alfredo A. Santillan-Gomez, Robert Maganini, Julie Barone, Sahra Uygun, Lavanya Samraj, William Audeh, Joyce O'Shaughnessy, FLEX Investigators' Group. Racial disparities in breast cancer and effect of obesity: MammaPrint, BluePrint and whole transcriptome analyses of tumors in Latin American patients in FLEX trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS18-04.

3134 Background: Mucinous breast cancer (MuBC) is a rare subtype of invasive ductal carcinoma (IDC) that accounts for less than 2% of all breast cancers and is associated with a favorable prognosis. Since MuBCs are rare in clinical trials, current treatment guidelines are extrapolated from IDC-no special type (IDC-NST). To provide better understanding of MuBCs and factors contributing to their clinical behavior, we examined the transcriptomic profiles of MuBCs in our FLEX study. Methods: The prospective, observational FLEX Study (NCT03053193) includes stage I-III breast cancer patients who receive MammaPrint (MP)/BluePrint (BP) testing and consent to full transcriptome and clinical data collection. For this study, histologically confirmed MuBCs (n = 102) in the FLEX database were included. All patients examined were ER+/HER2- by immunohistochemistry and Luminal by BP. MuBC was compared with IDC matched for Age, MP, and BP index (n = 97). Differential gene expression analyses (DGEA) were performed with R package ‘limma’ and differentially expressed genes (DEGs) were considered significant if they had an adjusted p < 0.05 and fold change ≥ 2. Results: DGEA comparing MuBC (n = 102) with IDC (n = 97) revealed 60 DEGs, regardless of the genomic risk, of which 42 genes were upregulated and 18 were downregulated in MuBC relative to IDC. Genes associated with MuBC, such as MUC2, TFF1, CARTPT were among the upregulated genes. Of the 102 MuBC patients, 56 were Luminal A (MP Low Risk-LR) and 46 were Luminal B (MP High Risk-HR) by MammaPrint and BluePrint. Comparison of LR MuBC with LR IDC revealed 111 DEGs. Functional enrichment showed upregulation of pathways involved in estrogen response (early & late) and androgen response and a downregulation of the epithelial to mesenchymal transition (EMT) and E2F pathways in LR MuBC compared to LR IDC. DGEA between HR MuBC and HR IDC revealed only 22 DEGs with immune pathways being downregulated in HR MuBC. DGEA comparing LR MuBC with HR MuBC resulted in 63 DEGs, indicating LR and HR MuBC are biologically distinct types. Interestingly in LR MuBC, the tumor suppressor marker SCUBE2 is upregulated. Over expression of SCUBE2 is associated with better prognosis. Conclusions: Although MuBCs are often expected to have low clinical risk, MP revealed that half of the MuBCs examined in this study were MP High Risk (Luminal B). MP low risk MuBC is biologically different from MP low risk IDC, and downregulation of E2F and EMT pathways might lead to favorable prognoses in MP low risk MuBC. MP high risk MuBC showed limited DEGs compared to high-risk IDCs indicating these tumor types are highly genomically similar and likely to benefit from chemotherapy. The downregulation of immune pathways in MP high risk MuBC may lead to immune surveillance escape resulting in metastasis and further investigation is needed. Clinical trial information: NCT03053193.