Abstract
FN14 has been implicated in many intracellular signaling pathways, and GRP94 is a well-known endoplasmic reticulum protein regulated by glucose. Recently, both have been associated with metastasis progression in breast cancer patients. We studied the usefulness of FN14 and GRP94 expression to stratify breast cancer patients according their risk of brain metastasis (BrM) progression. We analyzed FN14 and GRP94 by immunohistochemistry in a retrospective multicenter study using tissue microarrays from 208 patients with breast carcinomas, of whom 52 had developed BrM. Clinical and pathological characteristics and biomarkers expression in Luminal and non-Luminal patients were analyzed using a multivariate logistic regression model adjusted for covariates, and brain metastasis-free survival (BrMFS) was estimated using the Kaplan–Meier method and the Cox proportional hazards model. FN14 expression was associated with BrM progression mainly in Luminal breast cancer patients with a sensitivity (53.85%) and specificity (89.60%) similar to Her2 expression (46.15 and 89.84%, respectively). Moreover, the likelihood to develop BrM in FN14-positive Luminal carcinomas increased 36.70-fold (3.65–368.25, p = 0.002). Furthermore, the worst prognostic factor for BrMFS in patients with Luminal carcinomas was FN14 overexpression (HR = 8.25; 95% CI: 2.77–24.61; p = 0.00015). In these patients, GRP94 overexpression also increased the risk of BrM (HR = 3.58; 95% CI: 0.98–13.11; p = 0.054—Wald test). Therefore, FN14 expression in Luminal breast carcinomas is a predictive/prognostic biomarker of BrM, which combined with GRP94 predicts BrM progression in non-Luminal tumors 4.04-fold (1.19–8.22, p = 0.025), suggesting that both biomarkers are useful to stratify BrM risk at early diagnosis. We propose a new follow-up protocol for the early prevention of clinical BrM of breast cancer patients with BrM risk.
Highlights
Identification of molecular subtypes has enhanced our understanding of breast cancer biology [1], overcoming one of the main barriers to improving the progression, prognosis, and treatment of breast cancer, namely, its clinical and genetic heterogeneity
Our results indicate that FN14 is the most useful predictive/prognostic biomarker of brain metastasis (BrM) in breast cancer patients with Luminal (Luminal A, Luminal B, and Luminal/Her2+) carcinomas
We studied patient characteristics according to three different groups of progression patterns (Table S1 in Supplementary Material): brain metastases (BrM), with or without metastases (WoM) at other sites; non-brain distant metastases (NBrM), patients with metastasis in bones and/or liver and/or lungs and/ or non-regional lymph nodes, but not in brain; and patients WoM
Summary
Identification of molecular subtypes has enhanced our understanding of breast cancer biology [1], overcoming one of the main barriers to improving the progression, prognosis, and treatment of breast cancer, namely, its clinical and genetic heterogeneity. One of the important differences between subtypes as regards clinical progression is that hormone receptor-positive tumors, such as Luminal A, have a better prognosis for survival compared with Her overexpression and TN subtypes [4, 5] and the lowest risk of lymph node metastasis, whereas the Luminal-Her2+ subtype has the highest risk [6]. Hormone receptor-positive subtypes such as Luminal A and Luminal B should be considered different oncologic entities sharing similarities when studying their pattern of response to therapy [7]. The Luminal/Her2+ and Her2-enriched subtypes are associated with a significantly higher rate of brain, lung, and liver metastases in comparison with the Luminal A subtype, whereas TN patients are associated with a higher rate of brain, lung and distant nodal metastases [11,12,13,14]
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