Medical Oncology Unit, Oncology Center, Mansoura Faculty of Medicine, Mansoura, Egypt.
Clinical Pathology Department, Mansoura University, Mansoura, Egypt.
Curr Oncol. 2020 Oct;27(5):e444-e450. doi: 10.3747/co.27.6449. Epub 2020 Oct 1.
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).
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 plus cisplatin 75 mg/m 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.
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, = 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; = 0.001) and poor os (median: 14 months vs. 18 months; = 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 ( = 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 ( = 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%).
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.
癌症的发生通常是由于原癌基因的编码区发生突变，导致细胞生长和分裂失控，或者肿瘤抑制基因的编码区受到突变的影响，从而抑制了基因产物的活性。病理生理结果分别是细胞周期生长的过度放大或程序性细胞死亡的不足。骨桥蛋白（opn）是一种整合素结合磷酸蛋白，在正常细胞表面表达。骨桥蛋白在多种肿瘤成分中起主要作用，特别是那些与侵袭和转移有关的成分。在本研究中，我们旨在阐明 opn 作为乳腺癌（bca）的可能贡献者的价值。
这是一项前瞻性研究，纳入了 115 名新诊断为 bca 伴远处转移且伴有或不伴有骨转移的患者，这些患者均来自埃及曼苏拉大学肿瘤中心和曼苏拉大学医院临床肿瘤学和核医学系。入组患者均为有播散性内脏转移（内脏危机）的患者，无颅转移患者排除在研究之外。所有患者均接受一线化疗，方案为多西他赛 75mg/m2 加顺铂 75mg/m2 或卡铂 6 auc（曲线下面积），每 21 天 1 次，最多 6 个周期，或直至出现毒性。如果可能（如果政府援助或个人财务允许），则给予曲妥珠单抗（用于 her2 阳性疾病）。在开始治疗前，通过酶联免疫吸附试验（elisa）评估血清 opn 水平。纳入了 30 名匹配的健康女性，中位血清 opn 水平为 15ng/dL，因此将该水平定义为截断值。此外，还通过聚合酶链反应（pcr）确定 opn 基因突变。评估治疗前血清 opn 和 opn 基因突变与各种患者临床病理变量、对治疗的反应、无进展生存期（pfs）和总生存期（os）的相关性。
her2 扩增型 bca 患者的平均血清 opn 最高（64.4±42.3ng/dL），然后是三阴性 bca（55.9±34.7ng/dL），其次是 luminal B 和 A 亚型（38.4±33.1ng/dL 和 36.3±32.2ng/dL， = 0.017）。pcr 检测显示，三阴性 bca 中 opn 基因突变率最高（85%opn 突变型与 15%非突变型），其次是 her2 过表达型 bca（80%opn 突变型与 20%非突变型），其次是 luminal B 型 bca（61.9%opn 突变型与 38.1%非突变型）；luminal A 型 bca 表达最低（57.9%opn 突变型与 42.1%非突变型）。有趣的是，高血清 opn 和 opn 基因突变的患者均经历了较差的 pfs（中位：12 个月 vs. 14 个月； = 0.001）和较差的 os（中位：14 个月 vs. 18 个月； = 0.001）。此外，opn 基因突变的患者对治疗的反应较差：疾病进展患者中有 74%存在 opn 基因突变，26%存在未突变 opn（ = 0.04）。此外，高治疗前血清 opn 与治疗反应不良相关：疾病进展患者的血清 opn 水平为 49.1±33.8ng/dL，完全缓解、部分缓解或疾病稳定患者的血清 opn 水平为 35.5±34.3ng/dL（ = 0.05）。在 69 个肿瘤中发现高血清 opn 和 opn 基因突变之间有很强的一致性（79.3%），在 28 个肿瘤中发现正常或低血清 opn 和非突变 opn 之间有很强的一致性（60.8%）。
本前瞻性研究有助于突出 opn 作为转移性 bca 的有效预后生物标志物，并表明高治疗前血清 opn 和 opn 基因突变与不良反应和生存密切相关。elisa 和 pcr 结果之间的一致性表明，这两种方法都可用于 opn 的评估。三阴性 bca 中 opn 基因突变的增加可能有助于预测这种非常侵袭性肿瘤亚型的治疗反应，并可能成为未来研究中的靶向分子。
