Molecular stratification within triple-negative breast cancer subtypes

Area of Science:

• Oncology
• Genomics
• Molecular Biology

Background:

• Triple-negative breast cancer (TNBC) comprises six subtypes: BL1, BL2, M, MSL, IM, and LAR.
• A specific TNBC subgroup with PTEN loss, low microRNAs, TP53 mutation, RB1 loss, and high MYC/WNT signaling shows poor outcomes.
• This subgroup clusters with the BL1 TNBC subtype.

Purpose of the Study:

• To identify novel prognostic markers for distinct TNBC subtypes.
• To stratify TNBC patients based on molecular alterations for potential therapeutic targeting.
• To investigate the prognostic significance of PTEN, RhoA, AKT1, and PD1 in specific TNBC subtypes.

Main Methods:

• Subtyping of TNBC based on molecular characteristics.
• Analysis of PTEN, microRNA, TP53, RB1, MYC, WNT, RhoA, AKT1, and PD1 expression.
• Statistical analysis including hazard ratios (HR) to assess prognostic significance in training and test cohorts.

Main Results:

• PTEN-low/RhoA-signalling-high TNBC (BL1) showed significant poor prognosis (HRs of 8.2 and 4.87).
• AKT1 copy gain/high mRNA expression was a surrogate for poor prognosis in BL2 TNBC (HRs of 3.9 and 6.1).
• Elevated programmed cell death 1 (PD1) in IM TNBC predicted poor prognosis (HRs of 5.3 and 3.5).
• Additional alterations like E2F2, TGFβ, CXCL8, IFNα/γ, CTLA4, and EGFR were noted but lacked prognostic power.

Conclusions:

• PTEN-low/RhoA-signalling-high, high AKT1, and high PD1 expression are potent prognosticators for BL1, BL2, and IM TNBC subtypes, respectively.
• These findings reveal significant survival differences, highlighting the prognostic value of these markers.
• The intrinsic heterogeneity of TNBC can be leveraged for patient prioritization in precision medicine strategies.