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2020年的癌症统计数据显示,乳腺癌已取代肺癌成为全球第一大癌症,在我国女性患者中,乳腺癌的发病率占新发癌症的首位,癌症死亡人数占比位居第4[1]。乳腺癌治疗方案的制定、疗效评价及预后都与乳腺癌分子亚型密切相关[2-3]。除了外科手术及放化疗外,分子靶向药物和内分泌治疗在乳腺癌治疗中的应用越来越广泛。大量临床研究结果表明,曲妥珠单抗[Trastuzumab,商品名:赫赛汀(Hecepertin)]对高表达人表皮生长因子受体2 (human epidermal growth factor 2, HER-2)的转移性乳腺癌的疗效显著[4-7],明显延长了患者的生存期。相关研究结果表明,20%~30%的乳腺癌患者HER-2过表达,HER-2过表达常与乳腺癌的发生、发展密切相关,预示患者预后不良[8-10]。因此,及时准确地评判乳腺癌的HER-2表达状态对临床医师筛选曲妥珠单抗受试人群和预后预测至关重要。目前,临床医师需要通过对靶病灶进行组织病理学检查才能获得HER-2的表达情况,但这种方法存在有创、对标本要求高、操作难度大、容易漏诊等缺点;此外,由于肿瘤存在异质性,靶病灶的激素受体和HER-2的表达状态在时间和空间上经常存在差异[11-12]。因此,亟需一种更加安全有效的检查方法预估乳腺癌患者HER-2的表达状态,辅助临床医师更好地筛选曲妥珠单抗的受试人群,以减轻患者的经济负担,在进行个体化治疗的同时最大限度地改善患者预后。
18F-FDG PET/CT作为一种集解剖成像与功能代谢显像为一体的检查手段,在乳腺癌诊疗中的应用日益广泛。许多临床研究结果证实,SUV等代谢参数与乳腺癌患者的激素受体状态、分子亚型及预后具有相关性,但仍存在一定的分歧[13-18]。影像组学的兴起,让人们越来越深刻地认识到PET/CT图像可能包含比我们肉眼所能看到的更多有用信息。本研究评估PET代谢参数与乳腺癌HER-2表达状态的关系,建立并评估基于PET/CT图像的多元影像组学特征模型对乳腺癌原发灶HER-2表达的预测价值。
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在所有乳腺癌患者中,Luminal A型20例、Luminal B型167例、HER-2过表达型45例、三阴性(即TN)型41例。其他临床特征见表1。
项目 例数(%) 病理学类型 导管内癌 4(1.47) 浸润性导管癌 245(89.74) 浸润性小叶癌 3(1.10) 浸润性乳头状癌 5(1.83) 混合癌 14(5.13) 其他类型癌 2(0.73) 雌激素受体 阳性 181(66.30) 阴性 92(33.70) 孕激素受体 阳性 156(57.14) 阴性 117(42.86) HER-2 阳性 106(38.83) 阴性 167(61.17) Ki-67 <20% 34(12.45) ≥20% 239(87.55) 合并腋下淋巴结转移 是 222(81.32) 否 51(18.68) 肿瘤分期 Ⅰ期 19(6.96) Ⅱ期 139(50.92) Ⅲ期 60(21.98) Ⅳ期 55(20.14) 分子分型 Luminal A型 20(7.33) Luminal B(HER-2阴性)型 106(38.83) Luminal B(HER-2阳性)型 61(22.34) HER-2过表达型 45(16.48) 三阴性型 41(15.02) 注:HER-2为人表皮生长因子受体2;Ki-67为细胞增殖核抗原 表 1 273例原发性乳腺癌患者的临床特征
Table 1. Clinical characteristics of 273 patients with primary breast cancer
HER-2阳性组患者106例、阴性组患者167例,2组患者的临床特征比较见表2。2组患者在年龄、病理学类型及肿瘤分期间差异均无统计学意义(均P>0.05),而HER-2阴性组患者中合并腋下淋巴结转移的比例较HER-2阳性组患者稍高,且差异有统计学意义(P<0.05)。
临床特征 HER-2阳性组(n=106) HER-2阴性组(n=167) 检验值 P值 年龄( ,岁)$\bar x\pm s $ 51.8±11.4 51.7±10.5 t=−0.028 0.978 病理学类型[例(%)] χ2=5.429 0.366 导管内癌 2(1.89) 2(1.20) 浸润性导管癌 99(93.40) 146(87.43) 浸润性小叶癌 0 3(1.80) 浸润性乳头状癌 2(1.89) 3(1.80) 混合癌 3(2.83) 11(6.59) 其他类型癌 0 2(1.20) 合并腋下淋巴
结转移[例(%)]χ2=3.900 0.048 是 80(75.47) 142(85.03) 否 26(24.53) 25(14.97) 肿瘤分期[例(%)] χ2=1.891 0.595 Ⅰ期 5(4.72) 14(8.38) Ⅱ期 58(54.72) 81(48.50) Ⅲ期 23(21.70) 37(22.16) Ⅳ期 20(18.87) 35(20.96) 注:HER-2为人表皮生长因子受体 2 表 2 HER-2阳性组、阴性组原发性乳腺癌患者临床特征的比较
Table 2. Comparison of clinical characteristics between HER-2 positive group and HER-2 negative group of primary breast cancer patients
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由表3可知,HER-2阳性组患者的SUVmax、SUVmean、SUVpeak均略高于HER-2阴性组患者,但差异均无统计学意义(均P>0.05);2组患者的MTV和TLG间的差异也均无统计学意义(均P>0.05)。2组患者PET代谢参数差异的典型病例如图1所示。
组别 SUVmax SUVmean SUVpeak MTV(cm3) TLG(g) HER-2阳性组(n=106) 10.65±5.67 6.59±3.45 7.88±4.54 14.53±30.69 143.06±359.39 HER-2阴性组(n=167) 9.94±6.31 6.08±3.84 7.40±5.32 21.37±76.88 191.89±741.13 Z值 −1.508 −1.583 −1.549 −0.660 −0.064 P值 0.132 0.113 0.121 0.509 0.949 注:PET为正电子发射断层显像术;HER-2为人表皮生长因子受体2;SUVmax为最大标准化摄取值;SUVmean为平均标准化摄取值;SUVpeak为标准化摄取值峰值;MTV为肿瘤代谢体积;TLG为病灶糖酵解总量 表 3 HER-2阳性组、阴性组原发性乳腺癌患者PET代谢参数的比较(
)$\bar x\pm s $ Table 3. Comparison of PET metabolic parameters between HER-2 positive group and HER-2 negative group of primary breast cancer patients (
)$\bar x\pm s $ -
从PET/CT图像中提取了1 710个定量影像组学特征(基于PET图像和CT图像的组学特征各855个)。应用LASSO回归和十折交叉验证确定均方误差最低时的常数λ值为0.02099837,根据λ值筛选用于构建模型的PET/CT图像影像组学特征(图2)。最终筛选出具有较好预测价值的37个影像组学特征建立组学特征模型,其中,PET影像组学参数8个、CT影像组学参数29个(图3)。降维后每例患者的影像组学分数见图4。
图 2 原发性乳腺癌PET/CT代谢参数的最小绝对收缩选择算子十折交叉验证图(A)及影像组学特征降维图(B)
Figure 2. The least absolute shrinkage and selection operator cross validation diagram (A) and dimension reduction diagram of image omics characteristics (B) of PET/CT metabolic parameters of primary breast cancer
图 3 273例原发乳腺癌患者影像组学模型纳入特征及对应权重系数
Figure 3. Inclusion characteristics and corresponding weight coefficients of imaging omics model in 273 patients with primary breast cancer
图 4 273例原发性乳腺癌患者的影像组学分数散点图
Figure 4. Scatter plot of image omics scores of 273 primary breast cancer patients
由图5可见,基于18F-FDG PET/CT图像建立的多元影像组学特征模型在预测乳腺癌HER-2表达状态方面的表现显著优于传统PET代谢参数(SUVmax、SUVmean、SUVpeak、MTV和TLG)。在训练集中,该影像组学特征模型AUC、准确率、灵敏度和特异度分别为0.913(95%CI:0.871~0.954)、0.882(95%CI:0.832~0.922)、0.849(95%CI:0.759~0.910) 和0.910(95%CI:0.841~0.952);在测试集中,该影像组学特征模型AUC、准确率、灵敏度和特异度分别为0.820(95%CI:0.723~0.918)、0.830(95%CI:0.738~0.900)、0.875(95%CI:0.701~0.959)和0.807(95%CI:0.683~0.892)。
图 5 PET代谢参数和影像组学模型对乳腺癌HER-2表达状态预测性能的受试者工作特征曲线
Figure 5. Receiver operator characteristic curve of PET metabolic parameters and imaging omics model for predicting performance of HER-2 expression in breast cancer
为进一步验证其准确率和稳定性,使用十折交叉验证来计算该模型的平均预测性能。经验证,该预测模型的AUC、准确率、灵敏度、特异度的均值分别为0.818、0.847、0.908、0.764。
基于18F-FDG PET/CT图像建立的多元影像组学模型对乳腺癌原发灶HER-2表达状态的预测价值
The predictive value of 18F-FDG PET/CT derived multivariate radiomic mdodel in HER-2 status for primary breast cancer
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摘要:
目的 评估基于18F-氟脱氧葡萄糖(FDG) PET/CT图像建立的多元影像组学模型对乳腺癌原发灶人表皮生长因子受体2(HER-2)表达状态的预测价值。 方法 回顾性分析2010年1月1日至2019年12月31日于天津医科大学肿瘤医院行18F-FDG PET/CT检查的273例女性乳腺癌患者的临床和影像学资料,年龄26~78(51.8±10.8)岁。根据乳腺癌原发灶HER-2表达状态的不同将患者分为HER-2阳性组和HER-2阴性组,比较2组患者的临床特征和PET/CT代谢参数的差异。勾画原发灶的感兴趣区,提取所有影像组学特征并建立基于PET/CT图像的影像组学特征模型,将样本中70%的患者作为训练集,剩余30%的患者作为测试集,采用受试者工作特征曲线比较PET/CT代谢参数及影像组学模型对乳腺癌原发灶HER-2表达状态的预测能力,采用十折交叉验证计算预测模型的平均性能。采用Wilcoxon秩和检验比较组间各PET代谢参数是否存在差异。计数资料的比较采用χ2检验,计量资料的比较采用两独立样本t检验和Mann-Whitney U秩和检验。 结果 HER-2阳性组患者106例、阴性组患者167例。HER-2阴性组患者合并腋下淋巴结转移的比例较HER-2阳性组患者高[85.03%(80/106)对75.47%(142/167)],且差异有统计学意义(χ2=3.900,P<0.05)。除腋下淋巴结转移情况外,2组患者的年龄、病理学类型及肿瘤分期间的差异均无统计学意义(t=−0.028,χ2=5.429、1.891,均P>0.05)。2组患者的PET代谢参数最大标准化摄取值、平均标准化摄取值、标准化摄取值峰值、肿瘤代谢体积、病灶糖酵解总量之间的差异均无统计学意义(Z=−1.583~−0.064,均P>0.05)。最终筛选出具有较好预测价值的37个影像组学特征建立组学特征模型,其中,PET影像组学参数8个、CT影像组学参数29个。在训练集中,影像组学特征模型曲线下面积(AUC)、准确率、灵敏度和特异度分别为0.913(95% CI:0.871~0.954)、0.882(95%CI:0.832~0.922)、0.849(95%CI:0.759~0.910)和0.910(95%CI:0.841~0.952);在测试集中,影像组学特征模型AUC、准确率、灵敏度和特异度分别为0.820(95%CI:0.723~0.918)、0.830(95%CI:0.738~0.900)、0.875(95%CI:0.701~0.959)和0.807(95%CI:0.683~0.892);经十折交叉验证后,影像组学模型的AUC、准确率、灵敏度、特异度的均值分别为0.818、0.847、0.908、0.764。 结论 相较于传统的PET代谢参数,基于18F-FDG PET/CT图像建立的多元影像组学模型对乳腺癌原发灶HER-2表达状态有较好的预测价值,有助于临床医师筛选曲妥珠单抗受试人群,改善患者预后。 -
关键词:
- 乳腺肿瘤 /
- 正电子发射断层显像术 /
- 体层摄影术,X线计算机 /
- 氟脱氧葡萄糖F18 /
- 分子亚型 /
- 影像组学 /
- HER-2
Abstract:Objective To evaluate the predictive value of 18F-FDG PET/CT derived multivariate radiomic model in human epidermal growth factor 2 (HER-2) status for primary breast cancer (BC). Methods A total of 273 BC patients aged 26−78(51.8±10.8) years with complete clinical data and imaging data who underwent 18F-FDG PET/CT imaging before any treatment from January 1, 2010, to December 31, 2019, were included in the retrospective study. According to HER-2 status in primary BC lesion, the BC patients were classified into HER-2 positive group and HER-2 negative group. The differences in clinical characteristics and PET/CT metabolic parameters between the two groups were compared. For radiomic analysis, a multivariate radiomic model based on PET/CT was established after lesion segmentation and radiomic feature extraction. Furthermore, all the candidates were randomly divided into the training set and testing set at a ratio of 7∶3. Receiver operator characteristic curve analysis was used to determine the predictive power of PET metabolic parameters and develop a radiomic model in HER-2 status. Furthermore, the average performance of the radiomic model in the prediction of HER-2 status was determined after tenfold cross-validation. The Wilcoxon rank sum test was performed to compare the differences in PET metabolic parameters between the two groups. Chi-square test was used for qualitative data, whereas two independent sample t test was used for quantitative data with normal distribution. Mann-Whitney U rank sum test was employed for quantitative data that did not obey normal distribution. Results A total of 106 patients were classified in HER-2 positive group, and 167 patients were in the negative group. The proportion of patients with axillary lymph node metastasis in the HER-2 negative group was higher than that in the HER-2 positive group (85.03%(80/106) vs. 75.47%(142/167)), and the difference was statistically significant (χ2=3.900, P<0.05). By contrast, no significant difference was found in age, pathological type, and tumor stage between the two groups (t=−0.028, χ2=5.429, 1.891; all P>0.05). For the five PET metabolic parameters between the two groups, namely, maximum standard uptake value, mean standard uptake value, peak of standard uptake value, metabolic tumor volume, and total lesion glycolysis, no statistically significant difference was found in the study (Z=−1.583 to −0.064, all P>0.05). In the training set, the area under the curve (AUC), accuracy, sensitivity, and specificity of the radiomic model were 0.913(95%CI: 0.871–0.954), 0.882(95%CI: 0.832–0.922), 0.849(95%CI: 0.759–0.910), and 0.910(95%CI: 0.841–0.952), respectively. In the testing set, the AUC, accuracy, sensitivity, and specificity of the radiomic model were 0.820(95%CI: 0.723–0.918), 0.830(95%CI: 0.738–0.900), 0.875(95%CI: 0.701–0.959), and 0.807(95%CI: 0.683–0.892), respectively. After tenfold cross-validation, the average AUC, accuracy, sensitivity, and specificity of the imaging omics model were 0.818, 0.847, 0.908, and 0.764, respectively. Conclusions The established multivariate radiomic model based on 18F-FDG PET/CT images outperformed the traditional PET metabolic parameters in the prediction of HER-2 status for primary BC. This model can contribute to the clinical screening of a potential sensitive population for trastuzumab monoclonal antibody treatment and finally improve the prognosis for BC. -
表 1 273例原发性乳腺癌患者的临床特征
Table 1. Clinical characteristics of 273 patients with primary breast cancer
项目 例数(%) 病理学类型 导管内癌 4(1.47) 浸润性导管癌 245(89.74) 浸润性小叶癌 3(1.10) 浸润性乳头状癌 5(1.83) 混合癌 14(5.13) 其他类型癌 2(0.73) 雌激素受体 阳性 181(66.30) 阴性 92(33.70) 孕激素受体 阳性 156(57.14) 阴性 117(42.86) HER-2 阳性 106(38.83) 阴性 167(61.17) Ki-67 <20% 34(12.45) ≥20% 239(87.55) 合并腋下淋巴结转移 是 222(81.32) 否 51(18.68) 肿瘤分期 Ⅰ期 19(6.96) Ⅱ期 139(50.92) Ⅲ期 60(21.98) Ⅳ期 55(20.14) 分子分型 Luminal A型 20(7.33) Luminal B(HER-2阴性)型 106(38.83) Luminal B(HER-2阳性)型 61(22.34) HER-2过表达型 45(16.48) 三阴性型 41(15.02) 注:HER-2为人表皮生长因子受体2;Ki-67为细胞增殖核抗原 表 2 HER-2阳性组、阴性组原发性乳腺癌患者临床特征的比较
Table 2. Comparison of clinical characteristics between HER-2 positive group and HER-2 negative group of primary breast cancer patients
临床特征 HER-2阳性组(n=106) HER-2阴性组(n=167) 检验值 P值 年龄( ,岁)$\bar x\pm s $ 51.8±11.4 51.7±10.5 t=−0.028 0.978 病理学类型[例(%)] χ2=5.429 0.366 导管内癌 2(1.89) 2(1.20) 浸润性导管癌 99(93.40) 146(87.43) 浸润性小叶癌 0 3(1.80) 浸润性乳头状癌 2(1.89) 3(1.80) 混合癌 3(2.83) 11(6.59) 其他类型癌 0 2(1.20) 合并腋下淋巴
结转移[例(%)]χ2=3.900 0.048 是 80(75.47) 142(85.03) 否 26(24.53) 25(14.97) 肿瘤分期[例(%)] χ2=1.891 0.595 Ⅰ期 5(4.72) 14(8.38) Ⅱ期 58(54.72) 81(48.50) Ⅲ期 23(21.70) 37(22.16) Ⅳ期 20(18.87) 35(20.96) 注:HER-2为人表皮生长因子受体 2 表 3 HER-2阳性组、阴性组原发性乳腺癌患者PET代谢参数的比较(
)$\bar x\pm s $ Table 3. Comparison of PET metabolic parameters between HER-2 positive group and HER-2 negative group of primary breast cancer patients (
)$\bar x\pm s $ 组别 SUVmax SUVmean SUVpeak MTV(cm3) TLG(g) HER-2阳性组(n=106) 10.65±5.67 6.59±3.45 7.88±4.54 14.53±30.69 143.06±359.39 HER-2阴性组(n=167) 9.94±6.31 6.08±3.84 7.40±5.32 21.37±76.88 191.89±741.13 Z值 −1.508 −1.583 −1.549 −0.660 −0.064 P值 0.132 0.113 0.121 0.509 0.949 注:PET为正电子发射断层显像术;HER-2为人表皮生长因子受体2;SUVmax为最大标准化摄取值;SUVmean为平均标准化摄取值;SUVpeak为标准化摄取值峰值;MTV为肿瘤代谢体积;TLG为病灶糖酵解总量 -
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