Importance Tumor-infiltrating lymphocytes at diagnosis are reported to be prognostic in triple-negative breast cancer. Objective Here we evaluate the association of stromal tumor infiltrating lymphocytes (STILs) with recurrence-free survival (RFS) in N9831 HER2-positive patients treated with chemotherapy or chemotherapy plus trastuzumab. Design H&E tumor slides from patients on N9831 Arm A (standard AC→T chemotherapy) and Arm C (concurrent chemotherapy with trastuzumab) were assessed for STILs. STILs were quantitated in deciles and ≥60% STILs was used for the pre-specified categorical cutoff. The association between STILs and recurrence-free survival (RFS) was evaluated with Cox models. Setting Academic medical center Participants Tumor specimens from patients with early stage HER2+ breast cancer. Intervention(s) for clinical trials or exposure(s) for observational studies None. Main outcome measures Stromal tumor infiltrating lymphocytes (STILs) and their association with relapse-free survival. Results 489 pts from Arm A and 456 pts from Arm C were assessed with a median follow-up of 4.4 years. The 10 year Kaplan-Meier estimates for RFS in Arm A were 90.9% and 64.5% for patients with high STILs and low STILs, respectively (HR 0.23; 95%CI: 0.073 to 0.73; p=0.013). The 10 year estimates for RFS in Arm C were 80.0% and 80.1% for patients with high STILs and low STILs, respectively (HR 1.26; 95%CI: 0.5 to 3.2; p=0.63). The test for interaction between trastuzumab treatment and STILS status was statistically significant (p=0.026). In a multivariable analysis, STILs status remained significantly associated with RFS in Arm A and not significantly associated in Arm C (interaction p=0.042). Conclusions and relevance The analysis of N9831 patients found that STILs were prognostically associated with RFS in patients treated with chemotherapy alone, but not prognostically associated with RFS in patients treated with chemotherapy plus trastuzumab. High STILS were predictive of lack of trastuzumab benefit in contrast to a previously reported association between increased STILs and increased trastuzumab benefit in HER2 positive patients. Trial Registration Trial registration information: Clinicaltrials.gov, NCT00005970, https://clinicaltrials.gov/show/NCT00005970

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539 Background: An increased baseline sHER-2 concentration is an indicator of poor prognosis in the metastatic and adjuvant settings of HER-2+BC. This study evaluated the levels of sHER-2 during treatment and at time of recurrence in N9831. Methods: Aims were to describe sHER-2 levels during treatment and at time of recurrence in patients (pts) randomized to Arms A (standard chemotherapy) and C (standard chemotherapy with concurrent trastuzumab). Baseline serum samples of 1506 pts from both arms along with 86 recurrence serum samples were analyzed for sHER-2 (ng/mL). In addition, 556 serial samples were obtained in 148 patients over the treatment period. Median follow up was 4.5 years. Statistical methods included repeated measures linear models, Wilcoxon rank sum tests, and Cox regression models. Results: Analyzing serial sHER-2 levels during treatment, mean log sHER-2 remained constant in Arm C (estimated slope = 0.004, p = 0.44) while the estimated increase per month was 0.026 (on log e scale) for Arm A (p = 0.0003). Based on the linear model at 18 months, the mean log sHER-2 was 2.98 (95% CI: 2.87–3.09) and 2.55 (95% CI: 2.40–2.70) for Arms A and C, respectively. Among pts with disease recurrence, sHER-2 levels increased in Arm A from baseline to time of recurrence (mean = 72.9, median = 1.7, p =0.005) while sHER-2 levels remained unchanged in Arm C (mean = 9.2, median = -0.9, p = 0.65). While all 86 recurrence patients had baseline sHER2 levels <50, 24% (15/63) of Arm A patients had very high recurrence sHER-2 levels (≥50) as compared to 9% (2/23) on Arm C (p=0.10). Patients with recurrence sHER-2 levels ≥15 had shorter survival time following recurrence with 3 year overall survival of 51% compared to 76% for the <15 sHER-2 group (HR = 2.77; 95% CI: 1.20–6.43, p = 0.02). Conclusions: Based on serial specimens during treatment, the concurrent trastuzumab arm (C) had constant sHER-2 levels, whereas the standard chemotherapy arm (A) had increasing sHER-2 levels. In arm A, recurrence sHER-2 levels increased significantly from baseline while recurrence sHER-2 levels did not change in arm C. Additionally, pts with high sHER-2 levels at recurrence had shorter overall survival following recurrence. Partial support: CA25224, CA114740 , Genentech, Siemens, and the BCRF. [Table: see text]