Although gene expression-derived intrinsic subtypes were reported in Latin American breast cancer patients, most studies did not adequately represent the unique and diverse genetic admixture of our population. We assessed the general distribution and prognostic performance of PAM50-based intrinsic and immunohistochemistry (IHC)-based surrogate subtype classifications in women included in a Breast Cancer Study initiative of the US-Latin America Cancer Research Network comprising institutions of Argentina, Brazil, Chile, Mexico and Uruguay. Eligible enrolled patients were characterized clinically, pathologically and epidemiologically and followed-up for 5 years. IHC subtypes were assessed according to St Gallenʼs 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. The 5-year prognostic ability of PAM50 and IHC classifications was also evaluated. PAM50-derived risks of recurrence(RORs), was used to discriminate risk into low, intermediate and high-risk groups. Transcriptomic pathway analysis was performed to identify the driven pathways in each subgroup and compared with TCGA stage matched samples. Current studies using molecular ancestry assignation may help to reveal subtler differences in this heterogeneously admixed population.
Mammographic breast density -the biological and clinical consequences of an opaque breast?
Understanding Mammography (MBD) is crucial in the etiology and management of breast cancer (BCa). MBD is the expression of the fibroglandular:adipose content of the breast and is associated with the risk of developing BCa and the sensitivity of mammography (MMG). Although there are racial differences in the expression of MBD; the correlation of high MBD with an increased risk BCa is uniform. The common thinking is that high MBD is a normal variant; I would challenge this hypothesis. Without reproductive hormones high MBD does not occur. HRT usage can increase MBD and lead to an increased risk of developing BCa. Conversely when MBD is reduced, as with tamoxifen, the risk of developing BCa is reduced. Is this a causative change or just an association? Clearly, hormonal changes in the breast are critical in generating carcinogenesis. These changes start at a very early age in a woman’s reproductive life and how we let the breast be exposed to these changes are critical if we are to alter the incidence of BCa.
The following issues will be covered;
• Measurement of MBD
• Can high MBD be changed?
• Can MBD be used as a surrogate marker in prevention trials?
• What hormones are “good” for MBD?
• How is MBD influenced by the hormone/immune interface?
• Is MMG obsolete in high MBD?
A breast cancer patient-derived xenograft biobank for precision medicine studies in Argentina
Patient-derived tumor xenografts (PDX) are generated by implanting tumor fragments directly from patients into immune-deficient mice. PDX reflect more accurately the human tumor biology as compared with cell line xenografts, since the latter have acquired different portraits due to long term culturing. Our aim was to establish a bank of genetically characterized breast cancer PDX models for precision medicine studies. The study was approved by Institutional IRB (021-2017). Surgical specimens from patients that attended “Magdalena V de Martinez Hospital” from General Pacheco were transplanted sc by trocar into estradiol (E2)-treated (0.5 mg pellets, sc) or untreated female NSG mouse. Once the tumors reached 0.8 cm in diameter (long axis), they were excised, frozen, formalin-embedded for diagnosis, and passaged in E2-treated or untreated mice. A total of 95 samples were transplanted, and 9 PDX were developed: 2 luminal B, 1 luminal B that changed to triple negative (TN), 1 HER2 and 5 TN. Seven PDX were studied by Exome-Seq. Relevant mutations in FGFR1, ERBB2, STAT5A, FOXA1, BRCA1, PIK3CA, WNT4 and others were registered in the different PDXs. MUC2-19, HDAC6, HDAC7, Serpina2, LAIR1 among others were mutations present in almost all PDX. We conclude that these models are valid preclinical tools to test therapeutic efficacy of existing or novel drugs to guide breast cancer treatment.