Blood Test Detects Change from HER2- to+in Breast Cancer

描述（申请人提供）：本提案将检验以下假设：1.原发肿瘤为HER-2基因非扩增的患者和获得其CTC的HER-2基因扩增的患者的转移瘤和循环肿瘤细胞（CTC）的HER-2基因状态之间存在一致性。2.与对照组相比，这些患者对含曲妥珠单抗的治疗反应明显更好。目前，在CTC中获得HER-2基因扩增的患者很少被诊断出来，因此没有接受所需的靶向治疗。这是因为原发性肿瘤被认为是诊断HER-2基因扩增的“金标准”。这种假设应该受到质疑，因为肿瘤细胞的遗传不稳定克隆正在迅速突变，从而引起遗传变化。临床经验表明，出现了对所采用的特定化疗方案具有抗性的变体。因此，可以预测，随着肿瘤的进展，会出现使肿瘤细胞更具侵袭性和对化疗更具抵抗力的基因扩增。在涉及原发性乳腺癌患者的初步实验中，病理学家对原发性肿瘤的评估与CTC的FISH评估之间的一致性为97%水平（30名患者中的29名）。在原发肿瘤为HER-2基因未扩增的乳腺癌患者中，复发后37%的此类患者（24例中的9例）的CTC中存在HER-2基因扩增。其中4例患者接受了含曲妥珠单抗的治疗。3例患者缓解为PR或CR。原发性和转移性肿瘤与同时获得的CTC之间的一致性测试将扩展到275例患者，以获得统计学显著性结果。我们的肿瘤学家将对在CTC中获得HER-2基因扩增的患者进行靶向治疗。最后，一种新的免疫荧光方法定量HER-2的表达将进行研究。长期目标是验证CTC用于确定进行性癌症的免疫表型和基因型变化的用途，例如HER-2基因扩增的获得。这将确保在肿瘤中获得可治疗变化的患者将接受最佳靶向治疗。

DESCRIPTION (provided by applicant): This proposal will test the hypotheses that: 1.There is concordance between the HER-2 gene status of metastases and circulating tumor cells (CTCs) in patients with [sic] whose primary tumor was HER-2 gene nonamplified and who acquired HER-2 gene amplification of their CTCs. 2. Such patients can respond significantly better to trastuzumab-containing therapy compared to a control group. At present, patients who acquire HER-2 gene amplification in their CTCs are rarely diagnosed and therefore do not receive needed targeted treatment. This is because the primary tumor is considered the "gold standard" for making the diagnosis of HER-2 gene amplification. This assumption should be questioned because the genetically unstable clone of tumor cells is rapidly mutating giving rise to genetic changes. Clinical experience shows that variants appear which are resistant to the particular chemotherapeutic regimen that was employed. Hence, it would be predicted that amplification of genes that make tumor cells more aggressive and resistant to chemotherapy would emerge with tumor progression. In preliminary experiments involving patients with primary breast carcinoma, concordance between the pathologists' evaluation of the primary tumor and FISH evaluation of CTCs was at the 97% level (29 of 30 patients). Of the breast cancer patients whose primary tumor was HER-2 gene non-amplified, HER-2 gene amplification was present in the CTCs of 37% of such patients (9 of 24) after a recurrence. Four of these patients were treated with trastuzumab-containing therapy. Three patients responded with a PR or CR. Testing of concordance between primary and metastatic tumor with concomitantly obtained CTCs will be extended to 275 patients to obtain statistically significant results. Our oncologists will treat patients who have acquired HER-2 gene amplification in their CTCs with targeted treatment. Finally, a new immunofluorescence method for quantifying HER-2 expression will be studied. The long-term goal is to validate the use of CTCs for determination of changes in immunophenotype and genotype of progressive cancer such as acquisition of HER-2 gene amplification. This would ensure that patients who acquire treatable changes in their tumor will receive optimal targeted therapy.