Thompson, E. Aubrey

530 Background: Therapeutic efficacy of H involves activation of the immune system.Age-dependent progressive deterioration of the immune response is referred as immunosenescence. In HER2+ breast cancer, the effects of aging and the ability of H to activate endogenous anti-tumor immunity is unknown. A previous report from HERA trial showed no significant increase in risk of early recurrence with age (≤ or > 40). We evaluated the long-term outcome of HER2+ patients (pt) related to age and immune landscape. Methods: 1,392 pt from N9831 trial were evaluated. Stromal tumor infiltrating lymphocytes (sTIL) were evaluated in H&E slides. Lymphocyte predominant breast cancer (LPBC) was defined as sTIL ≥ 50%. Molecular TIL (mTIL) and immune subset signatures were evaluated using NanoString research CodeSets. Cox proportional hazard ratio (HR) was used for analysis. Results: There were 1,111 (79.8%) pt > 40 years old (yo) and 281 (20.2%) pt ≤ 40 yo. Younger age was significantly associated with hormone receptor positivity (p 0.00011) and luminal B subtype (p 0.011). With a median follow up of 10.6 years, there was no significant difference in long-term outcome among pt ≤ 40 vs. > 40 yo who received H (HR = 0.88 (0.62-1.24), p = 0.45). Similar findings were observed when age was dichotomized at 50 and 60 yo. While there was no association between sTIL and age, a small but significant increase in mTIL CD45 expression with age (p 0.003) was observed. Similar small increases in cytotoxic cell (p 0.007) and T cell (p 0.015) immune scores were also observed with increasing age. Among pt who received chemotherapy alone, pt > 40 yo with LPBC (n 55) had excellent outcome with 92.4% recurrence free survival (RFS) at 10 years. However, there was no significant difference in RFS among pt ≤ 40 yo with or without LPBC. Conclusions: Among pt treated with H, there was no significant difference in outcome related to age. In contrast to a decline expected from immunosenescence, we observed small but significant increases in mTIL signatures for total lymphocytes, cytotoxic, and T cell subsets. Among patients who received chemotherapy alone, our data suggested that pt > 40 yo with LPBC had excellent prognosis, compared to pt > 40 yo without LPBC.

TPS17 Background: Emerging studies suggest that breast cancer, particularly triple negative breast cancer (TNBC), may be sensitive to immunotherapy. However, the response rate of single agent immune checkpoint blockade agent in TNBC is rather low. Previous genomic study in residual tumor after neoadjuvant chemotherapy showed inverse correlations between MEK activation signature and the amount of tumor infiltrating lymphocytes (TILs) in residual disease samples as well as poor outcome. Preclinical study also showed that the combination of MEK inhibitor and anti-PD-L1 antibody in mouse model can eradicate TNBC tumors. Methods: This is a single arm, Phase I/II trial of Pembrolizumab (P) in combination with Binimetinib (B) in patients with unresectable locally advanced or metastatic TNBC. This trial is currently opened for accrual at Mayo Clinic in Florida and Minnesota. Patients with TNBC defined as ER ≤ 10% and PR ≤ 10% who received ≤ 3 prior lines with measurable disease will be enrolled. The primary objective of the Phase I part is to determine the maximum tolerated dose of B in combination with P and for the Phase II part is objective response rate (ORR) by RECIST criteria. The secondary endpoints include ORR by irRECIST, progression free survival, and overall survival. The total sample size is 15-38 patients with 6-12 patients in Phase I with 2 dose levels and 9-26 patients in Phase II. Simon’s Two-Stage Optimal Design is used to test the null hypothesis that this two-drug combination has an ORR of at most 15% vs. the alternative hypothesis that it has an ORR of at least 35%. Patients will receive single agent B for 2 weeks prior to starting P. A mandatory biopsy will be performed before starting B and an optional biopsy will be performed after 2 weeks of B. Tumor tissue will be evaluated for the amount and phenotypes of TILs, PD-L1 expression, and gene expression analysis using PanCancer Immune Profiling Panel, and PDJ amplification. Peripheral blood will be evaluated for circulating immunoregulatory cells, cytokine profiling, circulating tumor cells (CTCs), as well as p-ERK and PD-L1 expression on CTCs. Clinical trial information: NCT03106415.

Abstract BACKGROUND Clinical trials NRG/NSABP B-31 and Alliance/NCCTG N9831 demonstrated that trastuzumab added to chemotherapy extended disease-free survival (DFS) in breast cancer patients (pts) in the adjuvant setting (Romond et al). However, the degree of trastuzumab benefit varies among pts. We previously described an 8-gene model that was predictive for trastuzumab benefit, which was validated in an independent cohort of B-31 patients (Pogue-Geile 2013). The 8-gene signature subtyped B-31 pts in an independent validation cohort into three trastuzumab benefit groups: one with large benefit HR=0.27, one with medium benefit HR=0.56, and one with little to no benefit HR=1.56. The purpose of this study was to validate the 8-gene model in pts enrolled into N9831, which tested the efficacy of adding trastuzumab to doxorubicin plus cyclophosphamide → paclitaxel by randomizing pts into one of three arms: chemotherapy only (Arm A), trastuzumab given after chemotherapy (Arm B), or trastuzumab given concurrently with chemotherapy (Arm C). METHODS NCounter data, consisting of 8 predictive genes and 4 house-keeping genes, for 1,379 patients enrolled into N9831 were used to assign each patient to one of the three benefit groups. Assignments to one of the three trastuzumab benefit groups based on the 8-gene model were made by the NSABP/NRG Pathology Laboratory Biostatistician, who was blinded to outcome data. Predictions were sent to N9831 investigators and accuracy of predictions were tested in pts enrolled into arms A and C (N=892) using Cox models adjusted for age, nodes, ER/PR status, tumor size, and grade. Recurrence-free survival (RFS) and DFS were used as endpoints. RESULTS Tumors from N9831were placed into one of the three trastuzumab benefit groups based on the 8-gene signature. The N9831 pts in the predicted-large benefit group had a hazard ratio (HR) of 0.47, P=0.0006, pts in the predicted-medium benefit group had an HR of 0.6, P=0.02, and the predicted-low benefit group had an HR of 1.54, P=0.375. The interaction P value was significant at 0.019 in adjusted Cox models. The RFS at 10 years for trastuzumab-treated pts was 72%, 83%, and 83% in the low, medium, and large benefit groups, respectively. CONCLUSIONS The 8-gene signature developed in a discovery cohort and validated in an independent cohort of B-31 pts has now been validated in N9831. Many anti-HER2 therapies such as lapatinib, afatinib, neratinib, pertuzumab, and TDM-1 have been approved for treatment in metastatic breast cancer pts and although these agents have shown responses, the actual improvements in outcomes in pts is variable and it is not known which pts actually receive benefit. Thus this signature may be clinically useful in identifying pts who may benefit from additional treatment beyond trastuzumab or for stratification of pts enrolled into clinical trials testing new anti-HER2 therapies. SUPPORT U10CA180868, -180822, UG1CA189867, U24CA196067, the PA DOH, which disclaims certain responsibilities, Genentech, Inc., and the Breast Cancer Research Foundation. Citation Format: Pogue-Geile KL, Song N, Serie DJ, Thompson EA. The NSABP/NRG 8-gene signature accurately predicts degree of benefit from trastuzumab in Alliance/NCCTG N9831: Validation of the 8-gene signature in an independent clinical trial [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD3-18.

We previously reported an extremely rare case of follicular dendritic cell sarcoma (FDCS) presented as a thyroid mass. Given the rarity of this disease, there are no personalized and molecularly targeted treatment options due to the lack of knowledge in the genomic makeup of the tumor. A 44-year-old white woman was diagnosed with an extranodal FDCS in thyroid. The patient underwent a total thyroidectomy, central compartment dissection, parathyroid re-implantation, and adjuvant radiation therapy. Tumor DNA sequencing of 236 genes by FoundationOne panel found truncating mutations in PTEN and missense mutations in RET and TP53. However, patient-matched germline DNA was not sequenced which is critical for identification of true somatic mutations. Furthermore, the FoundationOne panel doesn't measure genomic rearrangements which have been shown to be abundant in sarcomas and are associated with sarcoma tumorigenesis and progression. In the current study, we carried out comprehensive genomic sequencing of the tumor, adjacent normal tissues, and patient-matched blood, in an effort to understand the genomic makeup of this rare extranodal FDCS and to identify potential therapeutic targets. Eighty-one somatic point mutations were identified in tumor but not in adjacent normal tissues or blood. A clonal truncating mutation in the CLTCL1 gene, which stabilizes the mitotic spindle, was likely a driver mutation of tumorigenesis and could explain the extensive copy number aberrations (CNAs) and genomic rearrangements in the tumor including a chr15/chr17 local chromothripsis resulted in 6 expressed fusion genes. The fusion gene HDGFRP3→SHC4 led to a 200-fold increase in the expression of oncogene SHC4 which is a potential target of the commercial drug Dasatinib. Missense mutations in ATM and splice-site mutation in VEGFR1 were also detected in addition to the TP53 missense mutation reported by FoundationOne.