Liu Yuhong, Gan Yixiang, AiErken NiJiati, Chen Wei, Zhang Shiwei, Ouyang Jie, Zeng Leli, Tang Di
The Seventh Affiliated Hospital of Sun Yat-Sen University, General Surgery, Shenzhen 518107, China.
School of Medicine, Sun Yat-Sen University, Shenzhen 518107, China.
J Oncol. 2022 Aug 22;2022:9390912. doi: 10.1155/2022/9390912. eCollection 2022.
Estrogen receptor-positive (ER+) breast cancer (BC) is a common subtype of BC with a relatively good prognosis. However, recurrence and death from ER+ BC occur because of tumor heterogeneity. This study aimed to explore tumor heterogeneity using next-generation sequencing (NGS) and tumor-organoid models to promote BC precise therapy. We collected needle biopsy, surgical excision, and cerebrospinal fluid (CSF) samples to establish tumor organoids. We found that the histological characteristics of organoids were consistent with original lesions and recapitulated their heterogenicity. In addition, the NGS results showed that PIK3CA and TP53 genes had detrimental mutations. BAP1, RET, AXIN2, and PPP2R2A genes had mutations with unknown function. The score for homologous recombination deficiency (HRD) of genome was 56, indicating that the tumor was likely sensitive to PARPi. The mutant-allele tumor heterogeneity (MATH) value of the tumor genome was 68.03, indicating high tumor heterogeneity. At last, we performed a drug screening on organoids. The toxicity of different drugs toward BC organoids originated from needle biopsy and surgical excision was tested, respectively. The IC values in the needle biopsy groups were paclitaxel 2.83 M, carboplatin 61.47 M, neratinib 0.8 M, lapatinib >100 M; in the surgical excision groups: trastuzumab >100 M, docetaxel 0.036 M, tamoxifen 20.54 M, olaparib 5.478 M, BYL719 < 0.1 M. The toxicity data showed that the BC organoids could show dynamic characteristics of tumor progression and reflect the heterogeneity of BC. Our study demonstrates that the combined use of tumor organoids and NGS is a potential way to test tumor heterogeneity and predict drug response in ER + BC, which contributes to the development of personalized therapy.
雌激素受体阳性（ER+）乳腺癌（BC）是BC的一种常见亚型，预后相对较好。然而，由于肿瘤异质性，ER+ BC会出现复发和死亡。本研究旨在使用下一代测序（NGS）和肿瘤类器官模型探索肿瘤异质性，以促进BC的精准治疗。我们收集了针吸活检、手术切除和脑脊液（CSF）样本以建立肿瘤类器官。我们发现类器官的组织学特征与原始病变一致，并概括了它们的异质性。此外，NGS结果显示PIK3CA和TP53基因存在有害突变。BAP1、RET、AXIN2和PPP2R2A基因存在功能未知的突变。基因组同源重组缺陷（HRD）评分为56，表明该肿瘤可能对PARPi敏感。肿瘤基因组的突变等位基因肿瘤异质性（MATH）值为68.03，表明肿瘤异质性高。最后，我们对类器官进行了药物筛选。分别测试了不同药物对源自针吸活检和手术切除的BC类器官的毒性。针吸活检组的IC值分别为：紫杉醇2.83μM、卡铂61.47μM、来那替尼0.8μM、拉帕替尼>100μM；手术切除组：曲妥珠单抗>100μM、多西他赛0.036μM、他莫昔芬20.54μM、奥拉帕利5.478μM、BYL719<0.1μM。毒性数据表明，BC类器官可以显示肿瘤进展的动态特征，并反映BC的异质性。我们的研究表明，肿瘤类器官和NGS的联合使用是测试ER+ BC肿瘤异质性和预测药物反应的一种潜在方法，有助于个性化治疗的发展。
