■尽管在肿瘤患者中广泛使用了重复剂量的有效骨靶向剂(BTA),人们对它们在体内对骨稳态的影响知之甚少,骨质量,骨骼结构。传统上,使用带7mm“Bordier”芯针的经髂骨活检评估骨质量。我们研究了使用2mm“Jamshidi™”芯针作为更实用且侵入性较小的技术的可行性。
■根据骨转移的程度对在BTA上患有转移性乳腺癌的患者进行划分。对他们进行了2个疗程的四环素标记,然后进行了后路经髂环钻活检和骨髓穿刺。通过组织形态计量学分析样品的肿瘤侵袭程度以及骨转换和骨形成的参数。
■增加了12名患者,1没有骨转移,3例发生局限性骨转移(LSM)(<3个病灶),7例发生广泛骨转移(ESM)(>3个病灶)。多数原发肿瘤为雌激素受体(ER)/孕激素受体(PR)阳性。该程序耐受性良好。样品质量足以通过组织形态计量学分析12例患者中的11例的骨小梁结构和骨转换。成像数据与肿瘤侵袭的形态计量学分析之间存在良好的相关性。没有证据或骨转移轻微的患者没有肿瘤侵袭的证据。用BTA治疗时,大多数人抑制了骨转换,没有可检测的骨形成。相比之下,通过成像和骨髓中肿瘤细胞的证据,在7例具有广泛骨侵袭的患者中,有6例具有强烈的破骨细胞活性,如通过破骨细胞的数量所测量的。在这7名ESM患者中,用BTA处理图6的破骨细胞,显示对BTA的抗性,如存在的大量破骨细胞所证明的。这6名患者中有3名具有活跃的骨形成。基于成骨细胞活性和骨形成,与LSM的所有3例相比,6例ESM患者中有3例对BTA有反应。与未经治疗的患者相比,所有接受BTA治疗的患者均显示出抑制骨形成的趋势,通过四环素标签测量。用BTA处理的ESM和LSM之间也存在显着差异的趋势,尽管受到小样本量的限制,但高度暗示了耐药性。
■我们的结果表明,通过对骨组织进行形态计量分析,使用2mm环钻进行的髂骨活检显示,肿瘤侵袭的影像学评估与肿瘤负荷之间具有极好的相关性。此外,我们的方法提供了有关BTA治疗反应的额外机制信息,支持目前的临床理解,即大多数广泛骨受累的患者最终无法抑制骨转换(PetrutB,etal.2008).这表明随着疾病的进展,抗再吸收疗法变得不太有效。
BACKGROUND: Despite widespread use of repeated doses of potent bone-targeting agents (BTA) in oncology patients, relatively little is known about their in vivo effects on bone homeostasis, bone quality, and bone architecture. Traditionally bone quality has been assessed using a trans-iliac bone biopsy with a 7 mm \"Bordier\" core needle. We examined the feasibility of using a 2 mm \"Jamshidi™\" core needle as a more practical and less invasive technique.
METHODS: Patients with metastatic breast cancer on BTAs were divided according to the extent of bone metastases. They were given 2 courses of tetracycline labeling and then underwent a posterior trans-iliac trephine biopsy and bone marrow aspirate. Samples were analyzed for the extent of tumor invasion and parameters of bone turnover and bone formation by histomorphometry.
RESULTS: Twelve patients were accrued, 1 had no bone metastases, 3 had limited bone metastases (LSM) (<3 lesions) and 7 had extensive bone metastases (ESM) (>3 lesions). Most of the primary tumors were estrogen receptor (ER)/progesterone receptor (PR) positive. The procedure was well tolerated. The sample quality was sufficient to analyze bone trabecular structure and bone turnover by histomorphometry in 11 out of 12 patients. There was a good correlation between imaging data and morphometric analysis of tumor invasion. Patients with no evidence or minimal bone metastases had no evidence of tumor invasion. Most had suppressed bone turnover and no detectable bone formation when treated with BTA. In contrast, 6 out of 7 patients with extensive bone invasion by imaging and evidence of tumor cells in the marrow had intense osteoclastic activity as measured by the number of osteoclasts. Of these 7 patients with ESM, 6 were treated with BTA with 5 showing resistance to BTA as demonstrated by the high number of osteoclasts present. 3 of these 6 patients had active bone formation. Based on osteoblast activity and bone formation, 3 out of 6 patients with ESM responded to BTA compared to all 3 with LSM. Compared to untreated patients, all patients treated with BTA showed a trend towards suppression of bone formation, as measured by tetracycline labelling. There was also a trend towards a significant difference between ESM and LSM treated with BTA, highly suggestive of resistance although limited by the small sample size.
CONCLUSIONS: Our results indicate that trans-iliac bone biopsy using a 2 mm trephine shows excellent correlation between imaging assessment of tumor invasion and tumor burden by morphometric analysis of bone tissues. In addition, our approach provides additional mechanistic information on therapeutic response to BTA supporting the current clinical understanding that the majority of patients with extensive bone involvement eventually fail to suppress bone turnover (Petrut B, et al. 2008). This suggests that antiresorptive therapies become less effective as disease progresses.