Obesity May Lead to Aggressive Breast Cancer Tumor Biology

Biological differences may lead to aggressive tumor biology, according to data regarding racial disparities and the effect of obesity in patients with breast cancer from the observational FLEX study.

Data from this study, presented at the 2023 San Antonio Breast Cancer Symposium, included an analysis of tumors in 311 Latin American and 311 non-Hispanic White patients.

The researchers found that Latin American patients had a higher incidence of type 2 diabetes compared with White patients (23.3% versus 8.5%). Conversely, 8.5% of White patients had type 2 diabetes and 1.1% had type 1 diabetes.

No patients in the Latin American population were pre-diabetic and one patient in the White population was pre-diabetic. Notably, 76.4% of Latin American patients had no diabetes and 90% of White patients had no diabetes.

Latin American patients were more likely than White patients to have a body mass index (BMI) that is considered obese (49% versus 39.4%).

Additionally, regarding BMI, 35.1% of Latin American patients were overweight, 14.2% were of normal weight and 1.7% were underweight. Comparably, of the White patients, 30.1% were overweight, 28.1% were of normal weight and 2.3% were underweight.

Notably, IKZF1AGER and UTS2 immune-related genes and inflammatory response were found to be upregulated in Latin American patients. Downregulation of adipogenesis (accumulation of fat cells), oxidative phosphorylation (reduction of oxygen to form high-energy phosphate bonds) and MYC targets were also identified in Latin American patients.

“Based on these results, obesity seems to affect Latin American and Black breast cancer biology differently than (in) non-Hispanic White patients. Immune system differences derived from genetic ancestry may be involved,” Dr. Marcela Mazo-Canola, a medical oncologist and assistant professor of medicine at the University of Texas Health San Antonio in Texas, stated in a poster presentation of the data.

Compared with non-Hispanic White patients, Latin American patients are more likely to receive diagnoses with aggressive early-stage breast cancer due to metabolic and genetic factors.

Previous research has been conducted to address this unmet need. To expand this lack of research, researchers launched an evaluation of the clinical and transcriptomic profiles of breast tumors in Latin American and White patients to gain a deeper understanding of the factors contributing to these tumor biologies.

Investigators matched Latin American and White patients with breast cancer who were enrolled in the FLEX study and compared them by age, T stage, N stage and clinical subtype.

The goal of FLEX is to function as an extensive, population-based, forward-looking registry, in which patients with stages 1, 2 and 3 breast cancer who undergo MammaPrint (MP) and BluePrint (BP) testing (tumor and genetic testing, respectively) on their primary breast tumor are eligible.

Notably, FLEX allows for the incorporation of extra-targeted substudies and arms following the start of the initial study.

Patients are classified as low or high risk with MP, which is a 70-gene signature that assesses the risk of distant recurrence. Additionally, the 80-gene molecular subtyping signature, BP, categorizes tumors as Luminal-, HER2- or Basal-Type.

MP then groups the Luminal tumors into A (low risk) and B (high risk). Finally, ImPrint (IP), a 53-gene signature, predicts the likelihood of patients with hormone receptor-positive disease achieving pathological complete response with PD-1/PD-L1-targeted immune checkpoint inhibitors.

To complete this analysis, whole-transcriptome comparisons were conducted, employing the limma R package, in patients categorized by BP subtype BMI categories. A gene set enrichment analysis was also completed.

Regarding the genomic (study of genes) results, patients were categorized by an MP score of High 2 (Latin American, 23.8%; White, 19%), High 1 (30.9%; 32.2%), low (29.9%; 33.8%) and ultralow (15.4%; 15.1%).

Patients were further categorized by a BP classification of Luminal A or MP Low (Latin American, 45.3%; White, 48.9%), Luminal B or MP High (36.7%; 39.2%), Basal (14.8%; 9.3%) and HER2 (3.2%; 2.6%).

Notably, researchers also evaluated the matched tumor test results from Latin American and Black patients who were obese with Luminal B disease. This analysis yielded MP scores of High 2 (Latin American, 14.8%; Black, 16.4%) and High 1 (85.2%; 83.6).

Whole-transcriptome analyses showed that only tumor stratification by Luminal B and obesity resulted in differentially expressed genes, as Latin American patients had higher expression of more than two-fold change of 42 immunoglobulin genes compared with White patients, with only IGKV6-21 expression being statistically significant.

“Further studies with larger cohorts are needed to confirm and to further study these pathway responses in Latin American patients,” Mazo-Canola concluded.

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