Chumsri Saranya, Li Zhuo, Serie Daniel J, Norton Nadine, Mashadi-Hossein Afshin, Tenner Kathleen, Brauer Heather Ann, Warren Sarah, Danaher Patrick, Colon-Otero Gerardo, Partridge Ann H, Carey Lisa A, Hilbers Florentine, Van Dooren Veerle, Holmes Eileen, Di Cosimo Serena, Werner Olena, Huober Jens Bodo, Dueck Amylou C, Sotiriou Christos, Saura Cristina, Moreno-Aspitia Alvaro, Knutson Keith L, Perez Edith A, Thompson E Aubrey
Jacoby Center for Breast Health, Mayo Clinic, Jacksonville, FL, USA.
Department of Health and Human Services, Mayo Clinic, Jacksonville, FL, USA.
NPJ Breast Cancer. 2022 May 24;8(1):68. doi: 10.1038/s41523-022-00430-0.
Trastuzumab acts in part through the adaptive immune system. Previous studies showed that enrichment of immune-related gene expression was associated with improved outcomes in HER2-positive (HER2+) breast cancer. However, the role of the immune system in response to lapatinib is not fully understood. Gene expression analysis was performed in 1,268 samples from the North Central Cancer Treatment Group (NCCTG) N9831 and 244 samples from the NeoALTTO trial. In N9831, enrichment of CD45 and immune-subset signatures were significantly associated with improved outcomes. We identified a novel 17-gene adaptive immune signature (AIS), which was found to be significantly associated with improved RFS among patients who received adjuvant trastuzumab (HR 0.66, 95% CI 0.49-0.90, Cox regression model p = 0.01) but not in patients who received chemotherapy alone (HR 0.96, 95% CI 0.67-1.40, Cox regression model p = 0.97). This result was validated in NeoALTTO. Overall, AIS-low patients had a significantly lower pathologic complete response (pCR) rate compared with AIS-high patients (χ p < 0.0001). Among patients who received trastuzumab alone, pCR was observed in 41.7% of AIS-high patients compared with 9.8% in AIS-low patients (OR of 6.61, 95% CI 2.09-25.59, logistic regression model p = 0.003). More importantly, AIS-low patients had a higher pCR rate with an addition of lapatinib (51.1% vs. 9.8%, OR 9.65, 95% CI 3.24-36.09, logistic regression model p < 0.001). AIS-low patients had poor outcomes, despite receiving adjuvant trastuzumab. However, these patients appear to benefit from an addition of lapatinib. Further studies are needed to validate the significance of this signature to identify patients who are more likely to benefit from dual anti-HER2 therapy. ClinicalTrials.gov Identifiers: NCT00005970 (NCCTG N9831) and NCT00553358 (NeoALTTO).
曲妥珠单抗部分通过适应性免疫系统发挥作用。先前的研究表明，免疫相关基因表达的富集与HER2阳性（HER2+）乳腺癌患者预后改善相关。然而，免疫系统在对拉帕替尼反应中的作用尚未完全明确。对来自北中部癌症治疗组（NCCTG）N9831试验的1268份样本和NeoALTTO试验的244份样本进行了基因表达分析。在N9831试验中，CD45和免疫亚群特征的富集与预后改善显著相关。我们鉴定出一种新的17基因适应性免疫特征（AIS），发现其与接受辅助曲妥珠单抗治疗患者的无复发生存期（RFS）改善显著相关（风险比[HR]0.66，95%置信区间[CI]0.49 - 0.90，Cox回归模型p = 0.01），但在仅接受化疗的患者中并非如此（HR 0.96，95% CI 0.67 - 1.40，Cox回归模型p = 0.97）。这一结果在NeoALTTO试验中得到了验证。总体而言，AIS低的患者与AIS高的患者相比，病理完全缓解（pCR）率显著更低（χ检验p < 0.0001）。在仅接受曲妥珠单抗治疗的患者中，AIS高的患者pCR率为41.7%，而AIS低的患者为9.8%（比值比[OR]为6.61，95% CI 2.09 - 25.59，逻辑回归模型p = 0.003）。更重要的是，添加拉帕替尼后，AIS低的患者pCR率更高（51.1%对9.8%，OR 9.65，95% CI 3.24 - 36.09，逻辑回归模型p < 0.001）。尽管接受了辅助曲妥珠单抗治疗，AIS低的患者预后较差。然而，这些患者似乎从添加拉帕替尼中获益。需要进一步研究来验证这一特征的意义，以识别更可能从双重抗HER2治疗中获益的患者。临床试验.gov标识符：NCT00005970（NCCTG N9831）和NCT00553358（NeoALTTO）。
