Department of Pathology, University of California San Diego, San Diego, CA.
Am J Surg Pathol. 2018 Sep;42(9):1208-1215. doi: 10.1097/PAS.0000000000001106.
At our institution, breast cancer cases that generate an equivocal HER2/neu (HER2) result by fluorescence in situ hybridization (FISH) using the dual HER2/chromosome enumeration probe (CEP17) are reflexed to an assay that utilizes an alternative control probe (lissencephaly gene1 [LIS1] [17p13.3]/retinoic acid receptor α [RARA] [17q21.2]). This study examines whether cancers that are classified as HER2-amplified with an alternate probe are clinicopathologically similar to those that are classified as such using the HER2/CEP17 probe. Reports for 1201 breast cancers were reviewed, and clinicopathologic findings were compared between HER2/CEP17-equivocal cases that became HER2-amplified using the alternate probe (group A: n=48), HER2-amplified cases using the HER2/CEP17 probe (group B: n=169), and HER2-nonamplified cases using the HER2/CEP17 probe (group C: n=910). Of 1201 cases tested using the HER2/CEP17 probe, 169 (14%) were HER2-amplified, 122 (10%) were equivocal, and 910 (76%) were nonamplified. Additional testing with the alternative probe on the 122 equivocal cases reclassified 48 (39%) of them to HER2-amplified, and such cases comprised 22% of all HER2-amplified tumors. A higher proportion of tumors with HER2 copy number between 5.0 and 5.9 became positive upon additional testing when compared with those with a priori HER2 copy numbers between 4.0 and 4.9 (P=0.0362). Group A cases, compared with group B cases, were more frequently positive for estrogen receptor (97.91% vs. 72.18%, P<0.0001) and progesterone receptor (85.41% vs. 59.17%, P=0.0009). Most group A cases (71%) were HER2 equivocal (score 2+) by immunohistochemistry, whereas most group B cases (60%) were positive (score 3+). Groups A and B showed no significant differences regarding patient age, lymph node status, tumor grade, histotype, and stage distribution. In summary, among our HER2-amplified cohort of breast cancers, alternative probe-detected cases were more frequently estrogen receptor and progesterone receptor positive than HER2/CEP17-detected cases, and were more frequently discordant with HER2 immunohistochemistry results. These findings raise the possibility of underlying biologic differences between these 2 groups, which warrants further study. However, the tumors were largely comparable regarding all other clinicopathologic variables. As it is unknown whether HER2-targeted therapy is truly beneficial in this subgroup of patients, future clinical trials should specifically evaluate this subset.
在我们的机构中，使用双重 HER2/染色体计数探针（CEP17）进行荧光原位杂交（FISH）后 HER2/neu（HER2）结果不确定的乳腺癌病例会被重新进行使用替代对照探针（无脑回基因 1 [LIS1] [17p13.3]/维甲酸受体 α [RARA] [17q21.2]）的检测。本研究旨在探讨使用替代探针分类为 HER2 扩增的癌症与使用 HER2/CEP17 探针分类为 HER2 扩增的癌症在临床病理方面是否相似。对 1201 例乳腺癌的报告进行了回顾，比较了使用替代探针（A 组：n=48）HER2/CEP17 不确定病例成为 HER2 扩增、HER2/CEP17 探针（B 组：n=169）HER2 扩增和 HER2/CEP17 探针（C 组：n=910）HER2 非扩增病例的临床病理发现。在使用 HER2/CEP17 探针检测的 1201 例病例中，169 例（14%）为 HER2 扩增，122 例（10%）为不确定，910 例（76%）为非扩增。对 122 例不确定病例使用替代探针进行额外检测，其中 48 例（39%）重新分类为 HER2 扩增，此类病例占所有 HER2 扩增肿瘤的 22%。与先验 HER2 拷贝数为 4.0 至 4.9 的肿瘤相比，HER2 拷贝数在 5.0 至 5.9 之间的肿瘤在进一步检测时更有可能呈阳性（P=0.0362）。与 B 组相比，A 组的雌激素受体（97.91% vs. 72.18%，P<0.0001）和孕激素受体（85.41% vs. 59.17%，P=0.0009）的阳性率更高。大多数 A 组病例（71%）的免疫组织化学检查结果为 HER2 不确定（评分 2+），而大多数 B 组病例（60%）为阳性（评分 3+）。A 组和 B 组在患者年龄、淋巴结状态、肿瘤分级、组织类型和分期分布方面无显著差异。总之，在我们的 HER2 扩增乳腺癌队列中，与 HER2/CEP17 检测病例相比，替代探针检测的病例更常表达雌激素受体和孕激素受体，且与 HER2 免疫组化结果更不一致。这些发现提示这两组之间可能存在潜在的生物学差异，这需要进一步研究。然而，这些肿瘤在所有其他临床病理变量方面基本相似。由于尚不清楚针对这组患者的 HER2 靶向治疗是否真正有益，未来的临床试验应专门评估这一亚组。
