Mithun Vinod Shah, Anne E. Wiktor, Reid G. Meyer, Kathleen S. Tenner, Karla V. Ballman, Stefan J, Green, William R. Sukov, Rhett P. Ketterling, Robert B. Jenkins, Mayo Clinic, Rochester, MN; and Edith A. Perez, Mayo Clinic, Jacksonville, FL.
J Clin Oncol. 2016 Oct 10;34(29):3502-3510. doi: 10.1200/JCO.2015.61.8983.
Purpose In 1998, the US Food and Drug Administration (FDA) approved human epidermal growth factor receptor 2 (HER2) testing guidelines to determine eligibility for HER2-directed therapy (HDT) in breast cancer. ASCO and the College of American Pathologists published immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) HER2 testing guidelines in 2007 (AC2007) and updated these guidelines in 2013 (AC2013). We compared the HER2 FISH amplification frequency using these three guidelines. Methods Patient samples that were sent to the Mayo Clinic cytogenetics laboratory for FISH testing (n = 2,851; from November 2013 to October 2014) were analyzed. Frequency of HER2 FISH amplification was examined and impact of AC2013 assessed. Results IHC results were available for 1,922 patient samples (67.4%), 137 of which were from Mayo Clinic. Distribution was 2.4% IHC 0, 7.9% IHC 1+, 84.8% IHC 2+, and 2.5% IHC 3+. Among IHC 2+ patients, HER2 FISH positivity was 11.8% (FDA), 9.4% (AC2007), and 24.1% (AC2013). Overall, 11.8% (n = 339) were positive with a FISH ratio ≥ 2.0, 1.3% (n = 35) with a FISH ratio ≥ 2.0 despite a HER2 signal < 4.0, and 3.0% (n = 86) with HER2 signal ≥ 6.0 despite FISH ratio < 2.0. Among 405 patients (14.2%) who were initially considered FISH-equivocal (ratio < 2.0 with HER2 signal ≥ 4.0, but < 6.0; AC2013), use of an alternative chromosome 17 probe reassigned 212 (7.4% overall) patients to FISH-positive and 36 (1.3% overall) patients to FISH-negative, whereas 157 (5.5% overall) patients remained equivocal. Final HER2 positivity with AC2013 (23.6%) was increased (P < .001) compared with FDA (13.1%) and AC2007 (11%) guidelines. Conclusion In a reference laboratory cohort that was highly enriched for IHC 2+ patient samples, AC2013 guidelines led to a larger number of FISH-equivocal patients. Approximately one half of these FISH-equivocal patients (7.4% overall) became HER2-positive upon alternative FISH probe testing. However, these patients would not have participated in the pivotal HDT trials. Clinical utility data on HDT benefit in these patients and other special subsets are needed.
目的
1998 年，美国食品和药物管理局（FDA）批准了人类表皮生长因子受体 2（HER2）检测指南，以确定乳腺癌患者接受 HER2 靶向治疗（HDT）的资格。美国临床肿瘤学会（ASCO）和美国病理学家协会（College of American Pathologists）于 2007 年发布了免疫组织化学（IHC）和荧光原位杂交（FISH）HER2 检测指南（AC2007），并于 2013 年进行了更新（AC2013）。我们比较了这三种指南中 HER2 FISH 扩增的频率。
方法
分析了 2013 年 11 月至 2014 年 10 月期间送往梅奥诊所细胞遗传学实验室进行 FISH 检测的 2851 例患者样本（n=2851；来自梅奥诊所的样本有 137 例）。检查了 HER2 FISH 扩增的频率，并评估了 AC2013 的影响。
结果
1922 例患者样本（67.4%）的 IHC 结果可用，其中 137 例来自梅奥诊所。分布为 IHC 0 2.4%、IHC 1+ 7.9%、IHC 2+ 84.8%和 IHC 3+ 2.5%。在 IHC 2+ 患者中，HER2 FISH 阳性率为 11.8%（FDA）、9.4%（AC2007）和 24.1%（AC2013）。总体而言，有 11.8%（n=339）的患者 FISH 比值≥2.0 阳性，有 1.3%（n=35）的患者 FISH 比值≥2.0 但 HER2 信号<4.0，有 3.0%（n=86）的患者 HER2 信号≥6.0 但 FISH 比值<2.0。在 405 例（14.2%）最初被认为 FISH 不确定（比值<2.0，HER2 信号≥4.0，但<6.0；AC2013）的患者中，使用替代的 17 号染色体探针重新分配了 212 例（总体 7.4%）患者为 FISH 阳性和 36 例（总体 1.3%）患者为 FISH 阴性，而 157 例（总体 5.5%）患者仍为不确定。使用 AC2013 时，最终的 HER2 阳性率（23.6%）高于 FDA（13.1%）和 AC2007（11%）指南（P<0.001）。
结论
在一个高度富集 IHC 2+ 患者样本的参考实验室队列中，AC2013 指南导致了更多的 FISH 不确定患者。大约一半的这些 FISH 不确定患者（总体 7.4%）在使用替代 FISH 探针检测后成为 HER2 阳性。然而，这些患者不会参加关键性的 HDT 试验。需要这些患者和其他特殊亚组接受 HDT 治疗的临床获益数据。
