在 neo-ALTTO 试验中，通路水平的改变而不是单个基因的突变可预测对 HER2 靶向治疗的反应。
Pathway level alterations rather than mutations in single genes predict response to HER2-targeted therapies in the neo-ALTTO trial.
机构信息
Department of Breast Medical Oncology, Yale University, Yale Cancer Center, New Haven, USA.
Vall d'Hebron Institute of Oncology, Barcelona, Spain.
出版信息
Ann Oncol. 2017 Jan 1;28(1):128-135. doi: 10.1093/annonc/mdw434.
BACKGROUND
We performed whole-exome sequencing of pretreatment biopsies and examined whether genome-wide metrics of overall mutational load, clonal heterogeneity or alterations at variant, gene, and pathway levels are associated with treatment response and survival.
PATIENTS AND METHODS
Two hundred and three biopsies from the NeoALTTO trial were analyzed. Mutations were called with MuTect, and Strelka, using pooled normal DNA. Associations between DNA alterations and outcome were evaluated by logistic and Cox-proportional hazards regression.
RESULTS
There were no recurrent single gene mutations significantly associated with pathologic complete response (pCR), except PIK3CA [odds ratio (OR) = 0.42, P = 0.0185]. Mutations in 33 of 714 pathways were significantly associated with response, but different genes were affected in different individuals. PIK3CA was present in 23 of these pathways defining a ‘trastuzumab resistance-network’ of 459 genes. Cases with mutations in this network had low pCR rates to trastuzumab (2/50, 4%) compared with cases with no mutations (9/16, 56%), OR = 0.035; P < 0.001. Mutations in the ‘Regulation of RhoA activity’ pathway were associated with higher pCR rate to lapatinib (OR = 14.8, adjusted P = 0.001), lapatinib + trastuzumab (OR = 3.0, adjusted P = 0.09), and all arms combined (OR = 3.77, adjusted P = 0.02). Patients (n = 124) with mutations in the trastuzumab resistance network but intact RhoA pathway had 2% (1/41) pCR rate with trastuzumab alone (OR = 0.026, P = 0.001) but adding lapatinib increased pCR rate to 45% (17/38, OR = 1.68, P = 0.3). Patients (n = 46) who had no mutations in either gene set had 6% pCR rate (1/15) with lapatinib, but had the highest pCR rate, 52% (8/15) with trastuzumab alone.
CONCLUSIONS
Mutations in the RhoA pathway are associated with pCR to lapatinib and mutations in a PIK3CA-related network are associated with resistance to trastuzumab. The combined mutation status of these two pathways could define patients with very low response rate to trastuzumab alone that can be augmented by adding lapatinib or substituting trastuzumab with lapatinib.
背景
我们对预处理活检进行了全外显子组测序，并研究了全基因组突变负荷、克隆异质性或变异、基因和通路水平的改变指标是否与治疗反应和生存相关。
方法
对 NeoALTTO 试验中的 203 个活检标本进行了分析。使用混合正常 DNA 用 MuTect 和 Strelka 进行突变检测。通过逻辑和 Cox 比例风险回归评估 DNA 改变与结局之间的关系。
结果
除了 PIK3CA（比值比[OR] = 0.42，P = 0.0185）外，没有任何单个基因的复发突变与病理完全缓解（pCR）显著相关。714 条通路中的 33 条通路的突变与反应显著相关，但不同个体中受影响的基因不同。PIK3CA 存在于这些通路定义的 459 个基因的“曲妥珠单抗耐药网络”中。在这个网络中存在突变的病例接受曲妥珠单抗治疗的 pCR 率较低（50 例中有 2 例，4%，9/16，56%，OR = 0.035；P < 0.001）。“RhoA 活性调节”通路的突变与拉帕替尼（OR = 14.8，调整后 P = 0.001）、拉帕替尼+曲妥珠单抗（OR = 3.0，调整后 P = 0.09）和所有治疗组（OR = 3.77，调整后 P = 0.02）的 pCR 率较高相关。在曲妥珠单抗耐药网络中有突变但 RhoA 通路完整的患者（n = 124）单独使用曲妥珠单抗的 pCR 率为 2%（41 例中有 1 例，OR = 0.026，P = 0.001），但加用拉帕替尼可将 pCR 率提高至 45%（38 例中有 17 例，OR = 1.68，P = 0.3）。在这两个基因集均无突变的患者（n = 46）中，单独使用拉帕替尼的 pCR 率为 6%（15 例中有 1 例），但单独使用曲妥珠单抗的 pCR 率最高，为 52%（15 例中有 8 例）。
结论
RhoA 通路的突变与拉帕替尼的 pCR 相关，而与 PIK3CA 相关网络的突变与曲妥珠单抗的耐药性相关。这两个通路的联合突变状态可以确定对曲妥珠单抗单独治疗反应率非常低的患者，这些患者可以通过加用拉帕替尼或用拉帕替尼替代曲妥珠单抗来增强疗效。
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