A Comparison of PAM50 Intrinsic Subtyping with Immunohistochemistry and Clinical Prognostic Factors in Tamoxifen-Treated Estrogen Receptor–Positive Breast Cancer

Abstract

Purpose: To compare clinical, immunohistochemical (IHC), and gene expression models of prognosis applicable to formalin-fixed, paraffin-embedded blocks in a large series of estrogen receptor (ER)-positive breast cancers from patients uniformly treated with adjuvant tamoxifen.Experimental Design: Quantitative real-time reverse transcription-PCR (qRT-PCR) assays for 50 genes identifying intrinsic breast cancer subtypes were completed on 786 specimens linked to clinical (median follow-up, 11.7 years) and IHC [ER, progesterone receptor (PR), HER2, and Ki67] data. Performance of predefined intrinsic subtype and risk-of-relapse scores was assessed using multivariable Cox models and Kaplan-Meier analysis. Harrell's C-index was used to compare fixed models trained in independent data sets, including proliferation signatures.Results: Despite clinical ER positivity, 10% of cases were assigned to nonluminal subtypes. qRT-PCR signatures for proliferation genes gave more prognostic information than clinical assays for hormone receptors or Ki67. In Cox models incorporating standard prognostic variables, hazard ratios for breast cancer disease-specific survival over the first 5 years of follow-up, relative to the most common luminal A subtype, are 1.99 [95% confidence interval (CI), 1.09-3.64] for luminal B, 3.65 (95% CI, 1.64-8.16) for HER2-enriched subtype, and 17.71 (95% CI, 1.71-183.33) for the basal-like subtype. For node-negative disease, PAM50 qRT-PCR-based risk assignment weighted for tumor size and proliferation identifies a group with >95% 10-year survival without chemotherapy. In node-positive disease, PAM50-based prognostic models were also superior.Conclusion: The PAM50 gene expression test for intrinsic biological subtype can be applied to large series of formalin-fixed, paraffin-embedded breast cancers, and gives more prognostic information than clinical factors and IHC using standard cut points. Clin Cancer Res; 16(21); 5222-32. ©2010 AACR.

Tumor mutational burden is a determinant of immune-mediated survival in breast cancer

“…The 1,100 BRCA cases with RNAseq data were filtered to exclude male and gender “unknown” samples (n = 13), metastatic tissue samples (n = 7) and one errant skin cancer sample yielding 1,079 female primary breast tumor samples for downstream expression analysis. PAM50 intrinsic molecular subtype assignments and PAM50 proliferation scores were computed as previously described, 48,49 and are available in eWorksheet 1 in Supplement 2. The subtypes segregate as follows: Basal-like (n = 189), HER2E (n = 82), LumA (n = 559), LumB (n = 209) and Normal-like (n = 40).…”

A survey of immunohistochemical biomarkers for basal-like breast cancer against a gene expression profile gold standard

“…The development of the PAM50 assay, a gene expression assay applicable to formalinfixed paraffin-embedded blocks, 33,34 now greatly facilitates such endeavors. Specifically, this 50-gene bioclassifier stratifies breast cancers into prognostic groups that can be used to aid clinicians in making treatment decisions.…”

“…Specifically, this 50-gene bioclassifier stratifies breast cancers into prognostic groups that can be used to aid clinicians in making treatment decisions. 33,34,142 Furthermore, the PAM50 assay identifies breast cancer intrinsic subtypes (luminal A, luminal B, HER2-enriched or basal-like) with prognostic and predictive implications. 142,143 This study presents an immunohistochemical assessment of several dozen published biomarkers of the aggressive basal-like subtype of breast cancer in a cohort of molecularly defined breast cancer specimens.…”

“…In line with current pathology practices that rely on immunohistochemistry and concurrent morphological examination, we sought to evaluate 72 proposed basal-like biomarkers, drawn from recent gene expression profile data and published literature, on sections from the same breast cancer tissue microarray in which intrinsic subtype has been assigned by a PAM50 gene expression profile assay. 33,34 In doing so we sought to identify the best individual immunohistochemical biomarkers for this aggressive form of breast cancer.…”

General St. Gallen-2015 guidelines for the treatment of early breast cancer (adapted by the experts of the Russian Society of Breast Oncologists)

“…В этих целях используется несколько мультипараме-трических молекулярных маркеров [18,19]. Посколь-ку в большин стве стран мира такие тесты неприме-нимы из-за логистических или финансовых причин, разработаны суррогатные подходы, использующие приемлемые иммуногистохимические (ИГХ) тесты для рецепторов эстрогенов (ER), рецепторов проге-стерона (PR), индекса Ki-67 и сверхэкспрессии или амплификации HER-2 с помощью in situ гибри-дизации (FISH), хотя с меньшей прогностической информацией, чем формальное молекулярное тести-рование [20,21]. Стандартные патоморфологические характеристики представляются адекватными для выделения клинически полезных групп, таких как трижды негативный, HER-2-позитивный гормон-рецептор-негативный и HER-2-позитивный гор мон-рецептор-позитивный РМЖ, для которых лечебные рекомендации обычно не являются спор ными.…”