Background: Cancer initiation typically occurs when a proto-oncogene’s coding region undergoes mutation, resulting in uncontrollable cell growth and division, or when a tumour suppressor gene’s coding region is affected by a mutation that inhibits activity of the resulting gene product. The pathophysiologic result is, respectively, exaggerated cell-cycle growth or deficient programmed cell death. Osteopontin (
opn) is an integrin-binding phosphoprotein that is expressed on the surface of normal cells. Osteopontin has a major role in diverse tumour components, especially those implicated in invasion and metastasis. In the present study, we aimed to illustrate the value of
opn as a possible contributor in breast cancer (
bca).
Methods: This prospective study included 115 patients newly diagnosed with
bca and distant metastasis who were recruited from the Oncology Center, Mansoura University, and the Department of Clinical Oncology and Nuclear Medicine, Mansoura University Hospital, Egypt. The patients recruited had been diagnosed with disseminated visceral metastasis (visceral crisis), with or without bone metastasis; patients with cranial metastasis were excluded from the study. All patients received first-line chemotherapy with docetaxel 75 mg/m
2 plus cisplatin 75 mg/m
2 or carboplatin 6
auc (area under the curve) on day 1 every 21 days for a maximum of 6 cycles or till development of toxicity. Trastuzumab (in cases of
her2-positive disease) was given whenever possible (if government assistance or personal finances permitted). Serum levels of
opn were assessed by enzyme-linked immunosorbent assay (
elisa) before treatment was started. A group of 30 matched healthy women whose median serum
opn level was 15 ng/dL were included, and that level was therefore defined as the cut-off value. In addition,
opn gene mutation was determined by polymerase chain reaction (
pcr). Correlations of pretreatment serum
opn and
opn gene mutation with various patient clinicopathologic variables, response to the treatment, progression-free survival (
pfs), and overall survival (
os) were assessed.
Results: Mean serum
opn was highest in
her2-amplified
bca (64.4 ± 42.3 ng/dL), and then in triple-negative
bca (55.9 ± 34.7 ng/dL), followed by the luminal B and A subtypes (38.4 ± 33.1 ng/dL and 36.3 ± 32.2 ng/dL respectively,
p = 0.017). Testing by
pcr revealed that
opn gene mutation was highest in triple-negative
bca (85%
opn mutant vs. 15% non-mutant), and then in
her2-overexpressed
bca (80%
opn mutant vs. 20% non-mutant), followed by luminal B
bca (61.9%
opn mutant vs. 38.1% non-mutant); the least expression was detected in luminal A
bca (57.9%
opn mutant vs. 42.1% non-mutant). Interestingly, patients with high serum
opn and
opn gene mutation experienced both poor
pfs (median: 12 months vs. 14 months;
p = 0.001) and poor
os (median: 14 months vs. 18 months;
p = 0.001). Moreover, participants with
opn gene mutation experienced a poor response: of those with progressive disease, 74% had
opn mutation and 26% had unmutated
opn (
p = 0.04). Additionally, high pretreatment serum
opn was correlated with poor treatment response: 49.1 ± 33.8 ng/dL in patients with progressive disease and 35.5 ± 34.3 ng/dL in those who achieved a complete response, a partial response, or stable disease (
p = 0.05). Strong concordance was found between high serum
opn and
opn gene mutation in 69 tumours (79.3%), and strong concordance was detected between normal or low serum
opn and non-mutant
opn in 28 tumours (60.8%).
Conclusions: The current prospective work helps to highlight
opn as a valid prognostic biomarker for patients with metastatic
bca and reveals that high pretreatment serum
opn and
opn gene mutation are both strongly linked with poor response and survival. Concordance between
elisa and
pcr results indicates that either method can be used for the evaluation of
opn. Increased
opn gene mutation in triple-negative
bca could assist in tailoring the treatment response in this very aggressive tumour subtype and could be considered a targetable molecule in future studies.
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