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

描述（由申请人提供）：本提案将测试以下假设：1。在原发肿瘤为HER-2基因未扩增和获得HER-2基因扩增的CTCs患者中，转移灶和循环肿瘤细胞（CTCs）的HER-2基因状态存在一致性。2. 与对照组相比，此类患者对含曲妥珠单抗治疗的反应明显更好。目前，在ctc中获得HER-2基因扩增的患者很少被诊断出来，因此没有得到所需的靶向治疗。这是因为原发肿瘤被认为是诊断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发生突变，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耐药性的变体。因此，可以预测，随着肿瘤的进展，使肿瘤细胞更具侵袭性和耐化疗的基因扩增将会出现。在涉及原发性乳腺癌患者的初步实验中，病理学家对原发肿瘤的评价与FISH对ctc的评价之间的一致性为97%（30例患者中有29例）。在原发肿瘤为HER-2基因未扩增的乳腺癌患者中，复发后37%的患者（24例中有9例）的CTCs中存在HER-2基因扩增。其中4例患者接受含曲妥珠单抗的治疗。3例患者出现PR或CR反应。原发性和转移性肿瘤合并ctc的一致性测试将扩展到275例患者，以获得具有统计学意义的结果。我们的肿瘤学家将对在CTCs中获得HER-2基因扩增的患者进行靶向治疗。最后，我们将研究一种新的定量HER-2表达的免疫荧光方法。长期目标是验证ctc用于确定进展性癌症的免疫表型和基因型变化，例如获得HER-2基因扩增。这将确保获得可治疗的肿瘤变化的患者将获得最佳的靶向治疗。

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.