Gelber Richard D, Wang Xin V, Cole Bernard F, Cameron David, Cardoso Fatima, Tjan-Heijnen Vivianne, Krop Ian, Loi Sherene, Salgado Roberto, Kiermaier Astrid, Frank Elizabeth, Fumagalli Debora, Caballero Carmela, de Azambuja Evandro, Procter Marion, Clark Emma, Restuccia Eleonora, Heeson Sarah, Bines Jose, Loibl Sibylle, Piccart-Gebhart Martine
Dana-Farber Cancer Institute, Harvard Medical School, Harvard TH Chan School of Public Health, Frontier Science Foundation, Boston, MA, USA.
Dana-Farber Cancer Institute, Harvard TH Chan School of Public Health, Boston, MA, USA.
Eur J Cancer. 2022 May;166:219-228. doi: 10.1016/j.ejca.2022.01.031. Epub 2022 Mar 18.
The APHINITY trial showed that adding adjuvant pertuzumab (P) to trastuzumab and chemotherapy, compared with adding placebo (Pla), significantly improved invasive disease-free survival (IDFS) for patients with HER2+ early breast cancer both overall and for the node-positive (N+) cohort. We explored whether adding P could benefit some N- subpopulations and whether to consider de-escalation for some N+ subpopulations.
Subpopulation Treatment Effect Pattern Plot (STEPP) is an exploratory, graphical method that plots estimates of treatment effect for overlapping patient subpopulations defined by a covariate of interest. We used STEPP to estimate Kaplan-Meier differences in 6-year IDFS percentages (P minus Pla: Δ ± standard error [SE]), both overall and by nodal status, for overlapping subpopulations defined by (1) a clinical composite risk score, (2) tumour infiltrating lymphocytes (TILs) percentage, and (3) human epidermal growth factor receptor 2 (HER2) FISH copy number. Because of multiplicity, a Δ of at least three SE is required to warrant attention.
The average absolute gains in 6-year IDFS percentages were 2.8 ± 0.9 overall; 4.5 ± 1.2 for N+ and 0.1 ± 1.1 for N-. Largest gains were for patients with intermediate clinical composite risk (5.3 ± 1.9 overall; 6.9 ± 2.3 N+; 4.0 ± 3.0 N-), highest TILs percentage (6.3 ± 1.7 overall; 7.4 ± 2.4 N+; 3.2 ± 1.7 N-), and intermediate HER2 copy number (2.8 ± 1.9 overall; 7.4 ± 2.5 N+; -1.3 ± 1.9 N-), but clear evidence indicating a pattern of differential subpopulation treatment effects was lacking.
STEPP plots for N- did not identify subpopulations clearly benefiting from adding P, and those for N+ did not identify subpopulations warranting de-escalation. TILs percentage appeared to be more predictive of P treatment effect than clinical composite risk score.
clinicaltrials.gov Identifier NCT01358877.
APHINITY试验表明，与添加安慰剂（Pla）相比，在曲妥珠单抗和化疗基础上加用辅助性帕妥珠单抗（P）可显著提高HER2阳性早期乳腺癌患者的总无侵袭性疾病生存期（IDFS），以及淋巴结阳性（N+）队列患者的IDFS。我们探讨了加用P是否能使某些N-亚组患者获益，以及是否应考虑对某些N+亚组患者进行降阶梯治疗。
亚组治疗效应模式图（STEPP）是一种探索性的图形方法，用于绘制由感兴趣的协变量定义的重叠患者亚组的治疗效应估计值。我们使用STEPP来估计总体以及按淋巴结状态划分的、由以下因素定义的重叠亚组的6年IDFS百分比的Kaplan-Meier差异（P减去Pla：Δ±标准误[SE]）：（1）临床综合风险评分，（2）肿瘤浸润淋巴细胞（TILs）百分比，以及（3）人表皮生长因子受体2（HER2）荧光原位杂交（FISH）拷贝数。由于存在多重性，需要至少3个SE的Δ才值得关注。
6年IDFS百分比的平均绝对增益总体为2.8±0.9；N+为4.5±1.2，N-为0.1±1.1。增益最大的是临床综合风险为中等的患者（总体为5.3±1.9；N+为6.9±2.3；N-为4.0±3.0）、TILs百分比最高的患者（总体为6.3±1.7；N+为7.4±2.4；N-为3.2±1.7）以及HER2拷贝数为中等的患者（总体为2.8±1.9；N+为7.4±2.
