J Breast Cancer.  2017 Jun;20(2):142-149. 10.4048/jbc.2017.20.2.142.

CD49f Can Act as a Biomarker for Local or Distant Recurrence in Breast Cancer

• Ye F
• Zhong X
• Qiu Y
• Yang L
• Wei B
• Zhang Z
• Bu H

• KMID: 2389751
• DOI: http://doi.org/10.4048/jbc.2017.20.2.142

Abstract

PURPOSE
Metastasis and local recurrence are the primary causes of treatment failure and patient death in breast cancer. The aim of this study was to validate a metastasis- and local recurrenceassociated biomarker for prognostic evaluation and planning treatment strategies.
METHODS
Formalin-fixed, paraffin-embedded tissues from a cohort of 312 patients (all stage II and III) were used. The prevalence of CD49f⁺ cells in the patients' tumors was analyzed and correlated with clinical characteristics to determine its prognostic and clinical implications.
RESULTS
CD49f⁺ tumor cells were found in a minority of tumors, with 62.8% of the samples showing not a single cell of this subtype. In the clinical characteristics analysis, which were performed with t-tests, CD49f⁺ tumors were not associated with age, tumor size, World Health Organization grade, nodal status, human epidermal growth factor receptor 2 status, progesterone receptor status, or estrogen receptor status, although they were significantly associated with disease recurrence (distant metastasis or/and local recurrence). Univariate survival analysis using the Kaplan-Meier method showed that CD49f⁺ tumors were associated with markedly decreased disease-free survival (DFS); the same result was found using multivariate Cox analysis, even when only chemotherapy-treated patients were analyzed.
CONCLUSION
Our results indicated that breast tumors with CD49f⁺ cancer cells are associated with an increased risk for disease recurrence after initial surgery with poor clinical outcomes (decreased DFS). Therefore, as it requires testing for only one additional protein, adding CD49f testing to conventional surgical pathology is a strategy that has great potential for prognostic and treatment-guidance purposes.

Keyword

Breast neoplasms; Integrin alpha6; Metastasis; Neoplastic stem cells; Prognosis

MeSH Terms

Breast Neoplasms*
Breast*
Cohort Studies
Disease-Free Survival
Estrogens
Humans
Integrin alpha6
Methods
Neoplasm Metastasis
Neoplastic Stem Cells
Pathology, Surgical
Prevalence
Prognosis
Receptor, Epidermal Growth Factor
Receptors, Progesterone
Recurrence*
Treatment Failure
World Health Organization
Estrogens
Integrin alpha6
Receptor, Epidermal Growth Factor
Receptors, Progesterone

Figure

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  Figure 1 Flowchart showing the inclusion criteria used in this study. IDC=invasive ductal carcinoma; IHC=immunohistochemistry.

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  Figure 2 Immunohistochemistry staining on tissue microarray (TMA) slides. Immunohistochemistry staining with primary antibodies against CD49f for all formalin-fixed paraffin-embedded TMA tissues was performed. The prevalence of CD49f positive cells was clearly different for inter- and intra-tumors. To quantify the prevalence of CD49f positive cells, we scored all tumors as either 0 (0% positive cells) (A), 1 (1%–10% positive cells) (B), 3 (51%–75% positive cells) (C), and 4 score (76%–100% positive cells) (D) (×200).

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  Figure 3 Prevalence of CD49f+ and histopathological characteristics. Analysis of 312 breast cancer patient tumor samples stained for CD49f and stratified for tumor age (A), WHO grade (low=grade 1 and 2, high=grade 3) (B), node status (C), tumor size (D), HER2 status (E), ER expression (F), distant metastasis (G), local recurrence (H), and disease recurrence (I). Tumors containing CD49f+ cells were associated with disease recurrence (distant metastasis or/and recurrence) (p=0.009). WHO=World Health Organization; HER2=human epidermal growth factor receptor 2; ER=estrogen receptor.

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  Figure 4 Univariate survival analysis of CD49f+ with disease-free survival (DFS) and overall survival (OS) for total and chemotherapy-treated patients. Univariate survival analysis of CD49f+ cells with DFS and OS for total (A, B) and chemotherapy-treated patients (C, D). The presence of CD49f+ tumor cells had a significant negative association with DFS in both the total patient (A) and the chemotherapy-treated patient (C) groups. The present of CD49f+ tumor cells had no significant association with OS in the total patient (B) or the chemotherapy-treated patient (D) groups.

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  Figure 5 Identification of breast cancer stem cells (BCSCs) for treatment significance. (A) Although regular treatment involving bulk tumor excision can remove most of the tumor cells, BCSCs remain behind after treatment. These residual cells are the cellular source of recurrence and distant metastasis. (B) Targeting BCSCs along with conventional treatment of normal tumor cells may completely eradicate tumor cells in the patient.

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