新辅助HER2靶向治疗的分子学异质性与疗效：紫杉醇＋曲妥珠单抗±拉帕替尼随机Ⅲ期临床试验（CALGB40601）

　　双HER2靶向疗法的病理学完全缓解（pCR）并不显著高于单HER2靶向疗法，但是激素受体阴性亚组除外。组织分析表明有关肿瘤基因组学和肿瘤微环境（如HER2扩增基因表达、p53基因突变标记和免疫细胞标记）的肿瘤间高度异质性显著影响pCR率。在HER2阳性疾病试验的解释和设计时应该考虑这些因素。

J Clin Oncol. 2016 Feb 20;34(6):542-9.

Molecular Heterogeneity and Response to Neoadjuvant Human Epidermal Growth Factor Receptor 2 Targeting in CALGB 40601, a Randomized Phase III Trial of Paclitaxel Plus Trastuzumab With or Without Lapatinib.

Carey LA, Berry DA, Cirrincione CT, Barry WT, Pitcher BN, Harris LN, Ollila DW, Krop IE, Henry NL, Weckstein DJ, Anders CK, Singh B, Hoadley KA, Iglesia M, Cheang MC, Perou CM, Winer EP, Hudis CA.

University of North Carolina Chapel Hill, Chapel Hill.

Alliance Statistics and Data Center, Duke University, Durham, NC.

Alliance Statistics and Data Center, MD Anderson, Houston, TX.

Alliance Statistics and Data Center, Dana-Farber Cancer Institute.

Dana-Farber Cancer Institute, Boston, MA.

University Hospitals of Cleveland, Cleveland, OH.

University of Michigan, Ann Arbor, MI.

New Hampshire Hematology-Oncology, Hooksett, NH.

New York University.

Memorial Sloan-Kettering Cancer Center, New York, NY.

Clinical Trials and Statistics Unit, Institute of Cancer Research, Belmont, United Kingdom.

PURPOSE: Dual human epidermal growth factor receptor 2 (HER2) targeting can increase pathologic complete response rates (pCRs) to neoadjuvant therapy and improve progression-free survival in metastatic disease. CALGB 40601 examined the impact of dual HER2 blockade consisting of trastuzumab and lapatinib added to paclitaxel, considering tumor and microenvironment molecular features.

PATIENTS AND METHODS: Patients with stage II to III HER2-positive breast cancer underwent tumor biopsy followed by random assignment to paclitaxel plus trastuzumab alone (TH) or with the addition of lapatinib (THL) for 16 weeks before surgery. An investigational arm of paclitaxel plus lapatinib (TL) was closed early. The primary end point was pCR in the breast; correlative end points focused on molecular features identified by gene expression-based assays.

RESULTS: Among 305 randomly assigned patients (THL, n = 118; TH, n = 120; TL, n = 67), the pCR rate was 56% (95% CI, 47% to 65%) with THL and 46% (95% CI, 37% to 55%) with TH (P = .13), with no effect of dual therapy in the hormone receptor-positive subset but a significant increase in pCR with dual therapy in those with hormone receptor-negative disease (P = .01). The tumors were molecularly heterogeneous by gene expression analysis using mRNA sequencing (mRNAseq). pCR rates significantly differed by intrinsic subtype (HER2 enriched, 70%; luminal A, 34%; luminal B, 36%; P < .001). In multivariable analysis treatment arm, intrinsic subtype, HER2 amplicon gene expression, p53 mutation signature, and immune cell signatures were independently associated with pCR. Post-treatment residual disease was largely luminal A (69%).

CONCLUSION: pCR to dual HER2-targeted therapy was not significantly higher than single HER2 targeting. Tissue analysis demonstrated a high degree of intertumoral heterogeneity with respect to both tumor genomics and tumor microenvironment that significantly affected pCR rates. These factors should be considered when interpreting and designing trials in HER2-positive disease.

PMID: 26527775

PII: JCO.2015.62.1268

DOI: 10.1200/JCO.2015.62.1268