Defining breast cancer prognosis based on molecular phenotypes: results from a large cohort study

Abstract

The objective of this study is to define the survival outcomes associated with distinct molecular phenotypes defined by immunohistochemical staining of paraffin-embedded tissues among invasive breast cancer cases identified from the Nurses’ Health Study (NHS). Tissue microarrays were constructed from archived tissue blocks of women diagnosed with breast cancer in the NHS (1976–1997). Invasive non-metastatic breast cancer tumors (n = 1,945) were classified into 1 of 5 molecular phenotypes based on immunohistochemistry assays for estrogen receptor (ER), progesterone receptor (PR), HER2, cytokeratin (CK) 5/6, epidermal growth factor receptor (EGFR) and grade. Survival outcomes were estimated using the Kaplan–Meier product limit method. Cox-proportional hazards models were fitted to determine the association of molecular phenotype with survival outcomes after adjusting for covariates. 1,279 (65.8%) tumors were classified as luminal A, 279 (14.3%) as luminal B, 95 (4.9%) as HER2 type, 203 (10.4%) as basal-like and 89 (4.6%) tumors were unclassified. The 5-year breast cancer-specific survival estimates for women with luminal A, luminal B, HER2-type, basal-like and unclassified tumors were 96, 88, 81, 89 and 85%, respectively. In the multivariable model, compared to cases with luminal A tumors, cases with luminal B (HR 1.90, 95% CI 1.33–2.71), HER2-type (HR 1.36, 95% CI 0.87–2.12), basal-like (HR 1.58, 95% CI 1.05–2.39) and unclassified (HR 1.38, 95% CI 0.87–2.20) tumors had higher hazard of breast cancer death. Similar trends were observed for both overall and recurrence-free survival. In conclusion, compared to women who have luminal A tumors those with luminal B, HER2-type, basal-like and unclassified tumors had a worse prognosis, when tumor subtype was defined by immunohistochemistry. This method may provide a cost-effective means of determining prognosis in the clinical setting.

NKX3.1 is expressed in ER-positive and AR-positive primary breast carcinomas

“…Hormone receptor status is a critical component of breast carcinoma prognosis and predicts response to therapy. ER and PR-positive breast carcinomas have a better clinical outcome than ER or PR-negative carcinomas,8 24 and it is increasingly understood that androgens also have an important role in breast cancer progression. AR-positive carcinomas also have a better overall clinical outcome,12 13 and loss of AR expression is associated with breast cancer metastases14 and the development of early recurrence 15…”

Molecular subtyping of male breast cancer using alternative definitions and its prognostic impact

“…IHC markers are often used as a surrogate for gene expression subtyping, and different combinations with similar prognostic information have been validated in FBC [5][6][7] .The different subtypes in FBC using IHC are luminal A in 44-66%, luminal B or luminal/HER2 in 6-19%, basal-like in 10-17% and HER2-like in 8-10% of cases. In MBC, the corresponding prevalences are luminal A in 75-98%, luminal B in 0-21%, basal-like in 0-4%, but no cases of HER2-like, keeping in mind the small sample sizes in these studies [11][12][13].…”

“…IHC markers were used to classify tumors into subgroups matching the "intrinsic" gene expression classification. Three different, previously used classifications for luminal tumors were evaluated; the "five biomarker classification" [18] in which the division into luminal tumors was based on HER2 status, "classification/NHG" [6] in which information on tumor grade was added and "classification/Ki-67" in which hormone receptor positive and HER2 negative tumors were divided according to high or low Ki-67 while hormone receptor positive and HER2 positive tumors were classified as a third luminal group (Table II) [7].…”

“…Transcriptional microarray profiling studies based on the "intrinsic" gene set have identified five distinct subtypes in FBC (luminal A/B, HER2-like, basal-like and normal-like) associated with significant differences in relapse-free survival [4]. Immunohistochemical (IHC) markers broadly matching the "intrinsic" gene expression subtypes have been identified and may be more feasible in clinical routine [5][6][7].…”

Are Breast Cancer Subtypes Prognostic for Nodal Involvement and Associated with Clinicopathologic Features at Presentation in Early-Stage Breast Cancer?

“…Specifically, molecular gene expression for estrogen receptor (ER), progesterone receptor (PR), and HER-2/neu (HER-2) allows a higher order of classification that has been correlated to outcomes (4,5). Subsequently, the use of immunohistochemical analysis as a surrogate for molecular profiling has been verified to estimate the prevalence of these molecular subtypes (18,36), allowing for more widespread utilization of this higher order of tumor distinction in the clinical setting to provide important insight into management strategies and risk of distant metastasis (13,32). …”