拉帕替尼可改善乳腺癌新辅助治疗结局
对于肿瘤较大、复发风险较高或难以手术的HER2阳性早期乳腺癌，紫杉醇＋曲妥珠单抗是术前新辅助治疗标准方案之一，可显著提高手术的可行性和成功率。2016年，CALGB 40601研究主要终点分析报告表明，对于激素受体阴性、HER2基因扩增、p53基因突变、某些免疫细胞浸润的HER2阳性早期乳腺癌，HER1和HER2酪氨酸酶抑制剂拉帕替尼可显著提高紫杉醇＋曲妥珠单抗新辅助治疗病理完全缓解率。不过，HER2阳性早期乳腺癌术前紫杉醇＋曲妥珠单抗＋拉帕替尼新辅助治疗长期结局以及疗效预测指标尚不明确。
CALGB 40601: Randomized Phase III Trial of Paclitaxel + Trastuzumab + Lapatinib Versus Paclitaxel + Trastuzumab as Neoadjuvant Treatment of HER2-Positive Primary Breast Cancer (NCT00770809)
2020年10月23日，美国临床肿瘤学会《临床肿瘤学杂志》在线发表北卡罗来纳大学教堂山总校、哈佛大学达纳法伯癌症研究院、梅奥医学中心、密歇根大学罗格尔癌症中心、纽约纪念医院斯隆凯特林癌症中心、国家癌症研究所、德克萨斯大学MD安德森癌症中心、芝加哥大学的CALGB 40601研究次要终点分析报告，比较了HER2阳性早期乳腺癌术前紫杉醇＋曲妥珠单抗±拉帕替尼新辅助治疗无复发生存和总生存结局，以及预测病理完全缓解和生存结局的基因表达特征。
该多中心随机对照三期临床研究于2008年12月～2012年2月从全国23家医院入组HER2阳性早期（II或III期）乳腺癌治疗前女性305例，按2∶2∶1随机分为3组：每周紫杉醇＋曲妥珠单抗＋拉帕替尼118例、每周紫杉醇＋曲妥珠单抗120例、每周紫杉醇＋拉帕替尼67例。主要终点为病理完全缓解，次要终点包括无复发生存、总生存和基因表达分析。对264例治疗前乳腺肿瘤标本进行基因转录信使核糖核酸测序，分析688个基因表达特征。
结果，中位随访6.9年，紫杉醇＋曲妥珠单抗＋拉帕替尼与紫杉醇＋曲妥珠单抗相比：
复发死亡风险低68%（风险比：0.32，95%置信区间：0.14～0.71，P=0.005）
全因死亡风险低66%（风险比：0.34，95%置信区间：0.12～0.94，P=0.037）
紫杉醇＋曲妥珠单抗与紫杉醇＋拉帕替尼相比，复发死亡风险和全因死亡风险相似。
215个基因与病理完全缓解显著相关，45个基因与无复发生存率显著相关，仅22个（3.2%）基因与病理完全缓解和无复发生存率显著相关。8种免疫特征与病理完全缓解和无复发生存率显著相关。对于残留病变亚组患者，IgG高表达与低表达相比，无复发生存时间显著较长；而HER2基因扩增与未扩增相比，无复发生存时间显著较短。
因此，该研究结果表明，对于HER2阳性早期乳腺癌女性，HER2双靶向药物可显著改善术前新辅助治疗的无复发生存和总生存结局。结合分子亚型和免疫特征可预测病理完全缓解和无复发生存，无论对全部患者还是残留病变亚组患者。这些方法可为HER2阳性乳腺癌合理升级或降级治疗策略提供手段。
J Clin Oncol. 2020 Oct 23. Online ahead of print.
Survival, Pathologic Response, and Genomics in CALGB 40601 (Alliance), a Neoadjuvant Phase III Trial of Paclitaxel-Trastuzumab With or Without Lapatinib in HER2-Positive Breast Cancer.
Fernandez-Martinez A, Krop IE, Hillman DW, Polley MY, Parker JS, Huebner L, Hoadley KA, Shepherd J, Tolaney S, Henry NL, Dang C, Harris L, Berry D, Hahn O, Hudis C, Winer E, Partridge A, Perou CM, Carey LA.
University of North Carolina, Chapel Hill, NC; Dana-Farber/Partners CancerCare, Boston, MA; Mayo Clinic, Rochester, MN; University of Michigan Rogel Cancer Center, Ann Arbor, MI; Memorial Sloan Kettering Cancer Center, New York, NY; National Cancer Institute, Cancer Diagnostics Program, Bethesda, MD; MD Anderson Cancer Center, Houston, TX; University of Chicago, Chicago, IL.
PURPOSE: CALGB 40601 assessed whether dual versus single human epidermal growth factor receptor 2 (HER2) -targeting drugs added to neoadjuvant chemotherapy increased pathologic complete response (pCR). Here, we report relapse-free survival (RFS), overall survival (OS), and gene expression signatures that predict pCR and survival.
PATIENTS AND METHODS: Three hundred five women with untreated stage II and III HER2-positive breast cancer were randomly assigned to receive weekly paclitaxel combined with trastuzumab plus lapatinib (THL), trastuzumab (TH), or lapatinib (TL). The primary end point was pCR, and secondary end points included RFS, OS, and gene expression analyses. mRNA sequencing was performed on 264 pretreatment samples.
RESULTS: One hundred eighteen patients were randomly allocated to THL, 120 to TH, and 67 to TL. At more than 7 years of follow-up, THL had significantly better RFS and OS than did TH (RFS hazard ratio, 0.32; 95% CI, 0.14 to 0.71; P = .005; OS hazard ratio, 0.34; 95% CI, 0.12 to 0.94; P = .037), with no difference between TH and TL. Of 688 previously described gene expression signatures, significant associations were found in 215 with pCR, 45 with RFS, and only 22 with both pCR and RFS (3.2%). Specifically, eight immune signatures were significantly correlated with a higher pCR rate and better RFS. Among patients with residual disease, the immunoglobulin G signature was an independent, good prognostic factor, whereas the HER2-enriched signature, which was associated with a higher pCR rate, showed a significantly shorter RFS.
CONCLUSION: In CALGB 40601, dual HER2-targeting resulted in significant RFS and OS benefits. Integration of intrinsic subtype and immune signatures allowed for the prediction of pCR and RFS, both overall and within the residual disease group. These approaches may provide means for rational escalation and de-escalation treatment strategies in HER2-positive breast cancer.
PMID: 33095682
DOI: 10.1200/JCO.20.01276