Molecular features of breast cancer involved in classification and prognosis of a multi-country Latin American cohort: The US-LACRN-MPBCS breast cancer cohort

ANDREA S LLERA; ELMER A FERNÁNDEZ; MIEMBROS US-LACRN

Congreso; AACR Annual Meeting 2021; 2022

American Association for Cancer Research.Aller

Although gene expression-derived PAM50 intrinsic subtypes (LumA, LumB, HER2E and Basal) were reported in Latin American breast cancer, most studies did not adequately represent the unique and diverse genetic admixture of the Latin American population and/or included a small number of individuals. As a result of these limitations, confirmation of the prognostic value of available intrinsic subtype classification signatures in a diverse cohort of Latin American women is of utmost importance. We assessed the general distribution and prognostic performance of PAM50-based intrinsic and immunohistochemistry (IHC)-based surrogate subtype classifications in Latin American women included in the Molecular Profile of Breast Cancer Study (MPBCS), an initiative of the US-Latin America Cancer Research Network (US-LACRN) comprising institutions of Argentina, Brazil, Chile, Mexico and Uruguay. MPBCS focused on stage II-III breast cancer in Latin American women. Eligible enrolled patients (n=1300) were characterized clinically, pathologically and epidemiologically and followed-up for 5 years. IHC subtypes were assessed according to St Gallen's 2013 criteria, using Ki67 to discriminate LumB from LumA tumors. A total of 1071 tumors were characterized by gene-expression microarrays. PAM50 classification defined 45% of tumors as LumA, 19.7% as LumB, 13.8% as HER2E and 17.5% as Basal. Normal-like tumors (6.3%) were excluded from the analysis. The 5-year prognostic ability of PAM50 and IHC classifications, both at the cancer-specific (OS) and progression-free survival (PFS), was tested. The prognosis for LumA tumors was significantly better than for other subtypes, while Basal-like tumors had the worst prognosis. The prognostic power of IHC-based subtypes (C-index 0.698 for OS, 0.635 for PFS) was very similar to that of PAM50 (C-index 0.678 for OS, 0.639 for PFS), indicating that in US-LACRN-MPBCS, contrary to other cohorts, surrogate subtypes are as useful as PAM50 for discriminating recurrence risk. PAM50-derived risks of recurrence (RORs), in particular ROR-S (C-index 0.699 for OS, 0.649 for PFS), clearly discriminated risk into low, intermediate and high-risk groups. Transcriptomic pathway analysis showed high proliferation (i.e. cell cycle control and DNA damage repair) associated with LumB, HER2E and Basal tumors, and a strong dependency on the estrogen pathway for LumA. Overall, a general concordance of the molecular features of US-LACRN-MPBCS breast cancer tumors with those of other cohorts was confirmed. The shift towards non-luminal subtypes could be partly attributable to the recruitment bias towards advanced stages. Further refinement of analyses using molecular ancestry assignation may help to reveal more subtle differences in this heterogeneously admixed population.