Abstract 5669: Differential prognosis of immune biomarkers in metastatic vs. early triple negative breast cancer (TNBC) settings
Authors: Kelly J. Dupree, Ching-Wei Chang, Meghna Das Thakur, Timothy R. Wilson, David Shames, David Cameron, Luciana Molinero
Journal: Cancer Research (2020)

Abstract Background: A pre-existing intratumoral immune response, as characterized by presence of tumor infiltrating lymphocytes or cytotoxic effector T cells, is linked to improved prognosis in early TNBC (eTNBC). Recent data in metastatic TNBC (mTNBC) suggest that immune rich tumors are not prognostic (Emens et al., SABCS 2018). Since different immune biomarkers were used across studies to make these observations, it is uncertain whether the T-cell immune biology has differential prognosis between eTNBC and mTNBC. The aim of this study was to evaluate the prognostic value of the T effector RNA gene signature (Teff), across two eTNBC and two mTNBC clinical studies using the same biomarker methodology. Methods: FFPE breast tumor samples from two adjuvant (BO20289 [n = 955] and NO17629 [n = 260]) and two front line metastatic (GO25632 [n = 62] and OAM4861G [n = 150]) TNBC clinical studies were evaluated for RNA gene expression by using customized Nanostring panels. Normalization was carried out across all 4 datasets combined, and Teff signature (CD8A, IFNG, PRF1, CXCL9 and CXCL10) values were generated using mean z-scores. Overall survival (OS) was evaluated in all the studies. Results: While levels of Teff were similar within the eTNBC studies (p = 0.43) and the mTNBC studies (p = 0.44), Teff score was significantly higher in eTNBC compared to the mTNBC studies (p &amp;lt;0.0001). Lymph node involvement in the eTNBC studies was the only baseline prognostic characteristic associated with Teff (p = 0.014 and 0.023) out of those assessed. Using the Teff global mean across the studies and adjusting for baseline characteristics, multivariate analysis showed that elevated Teff was associated with improved OS in the BO20289 and NO17629 eTNBC studies (HR 0.36 [95% CI 0.24-0.53] and 0.40 [95% CI 0.20-0.75], respectively), while no prognostic value was linked to the GO25632 or OAM4861G mTNBC trials (HR 1.28 [95% CI 0.35-3.91] and 1.01 [95% CI 0.57-1.73], respectively). Similar results were observed at different Teff cutoffs. Finally, Teff was lower in recurrent tumors compared to matched primary samples from the BO20289 study (n = 25, p = 0.002). Conclusions: Our data suggest that tumor immune biology, as assessed by Teff RNA gene expression 1) is lower in patients with mTNBC than eTNBC and 2) improves OS prognosis in patients with eTNBC but not in those with mTNBC. Using four clinical studies independently executed but simultaneously assessed increases the robustness of this analysis. Notably, eTNBC patients whose disease recurs are those with lower Teff levels, consistent with the finding that Teff is lower in mTNBC than the curative eTNBC setting. Taken together, our results highlight that the prognosis of immune biology in TNBC is not interchangeable between the metastatic and early disease settings. Finally, these results have implications for assessing clinical activity of immune checkpoint inhibitors in single arm studies. Citation Format: Kelly J. Dupree, Ching-Wei Chang, Meghna Das Thakur, Timothy R. Wilson, David Shames, David Cameron, Luciana Molinero. Differential prognosis of immune biomarkers in metastatic vs. early triple negative breast cancer (TNBC) settings [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5669.