Abstract P6-09-05: Prognostic and predictive values of high endothelial venules (HEV) and tumor infiltrating CD8+ lymphocytes (CD8) in tumors of patients included in the adjuvant PACS04 trial: HEV is predictive of outcome for HER2+ tumors exposed to trastuzumab
Authors: Roché HH , Lafouresse FF , Filleron T , Laffont R , Maisongrosse V , Pichery M , Le Guellec S , Penault-Llorca F , Lemonnier J , Lacroix-Triki M , Girard J-P 
Published: March 2017

Abstract
Background: HEV are specialized blood vessels that function as portals of entry for lymphocytes into lymphoid organs and tumor tissues (Moussion and Girard, Nature 2011, 479:542-546; Girard et al, Nature Rev Immunol 2012, 12:762-773). We retrospectively considered HEV and CD8 as potential prognostic and/or predictive factors in a large randomized adjuvant trial of node positive breast cancer patients (PACS04). This trial included 3010 node positive patients randomized between anthracyclins alone or anthracyclins and docetaxel chemotherapy. Patients with HER2+ expressing tumors had a second randomization with or without trastuzumab given sequentially for one year. With 59.5 median follow-up, metastatic free interval (MFI), the first end-point, was 84.5% at 5 years for the whole population.
Methods: 1660 tumor samples (9.7% triple negative, 67.5% HR+/HER2- and 22.8% HER2+) were collected and analyzed by immunostaining on full sections for HEV (MECA-79 mAb, BD Biosciences) and CD8 (C8/144B mAb, Dako). HEV densities were determined as previously described (Martinet et al., Cancer Res 2011, 71:5678-5687). CD8+ cells and tumor-infiltrating lymphocytes (TIL) were scored according to recently published guidelines. Univariate analyses were performed using cox proportional hazard model for continuous variable. Independent analyses for the predictive evaluation of trastuzumab outcome were performed in the HER2+ subgroup.
Results: MFI and overall survival at 5 years for this series are respectively of 84.9% (TN: 77.4%, HR+/HER2-: 89%, HER2+:75.8%) and 91% not different with the total group. The table shows expression of the different markers according to the subgroup of tumors.
Marker values according to sub molecular classification TNRH+/HER2-HER2+/RH-Number1601119378Metastatic events3411990HEV/mm2(median,range)0.51 (0, 7.73)0.13 (0, 10.23)0.38 (0, 13.63)CD8score (median, range)2 (0, 3)1 (0, 3)2 (0, 3)Table 1
No difference in univariate analysis was observed in TN and HR+/HER2- subgroups in terms of relationship between marker expression and outcomes. For the HER2+ group, HEV and CD8 were correlated to better outcome (HEV: HR=0.73, p =0.011; CD8: HR=0.64; p=0.006). For HER2+ patients not receiving trastuzumab (222 pts, 55 events), CD8 was predictive of metastasis risk (HR: 0.65, p=0.032), but not HEV (HR:0.82, p=0.09). Conversely, in the trastuzumab treated group (156 pts, 35 events), HEV was significantly correlated with a lower risk of relapse (HR: 0.45, p=0.02), but CD8 was not (HR:0.63, p=0.07). TIL counts are still ongoing and will be reported at time of presentation.
Conclusions: HEV and CD8 are associated with better prognosis in the HER2+ tumor group. Interestingly, HEV presence in the tumor seems to be a significant predictive factor of trastuzumab efficacy.
Citation Format: Roché HH, Lafouresse FF, Filleron T, Laffont R, Maisongrosse V, Pichery M, Le Guellec S, Penault-Llorca F, Lemonnier J, Lacroix-Triki M, Girard J-P. Prognostic and predictive values of high endothelial venules (HEV) and tumor infiltrating CD8+ lymphocytes (CD8) in tumors of patients included in the adjuvant PACS04 trial: HEV is predictive of outcome for HER2+ tumors exposed to trastuzumab [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-09-05.