THSD4 is a novel mediator of T cell exclusion and anti-PD-1 resistance in hormone receptor-positive breast cancer

Background: Radiotherapy (RT) has shown promise in overcoming immune checkpoint inhibitor (ICI) resistance in breast cancer preclinical models and early-stage clinical trials. However, RT/ICI synergy is not observed in all tumors and the induction of systemic anti-tumor (i.e., “abscopal”) responses is relatively infrequent. The goal of this study was to identify targetable pathways that may guide patient selection and augment RT/ICI synergy by screening a panel of clinically representative breast cancer immune-competent mouse models. Our studies identify the mono-ADP-ribosyltransferase PARP7 as a biomarker of RT/ICI responsiveness that, when inhibited, results in significantly greater induction of interferon-stimulated genes (ISGs) and systemic anti-tumor immune responses. Methods: We profiled four Trp53-/- breast cancer syngeneic allograft tumor models (2250L, 2208L, 2336R, 2225L) in vivo for RT/ICI abscopal effects. Female BALB/c mice were bilaterally injected in the fourth mammary fat pad with tumor cells. Treatment began once the tumor reached 6mm, with mice being randomly divided into 4 groups: non-treated (NT), RT (3 x 8Gy), ICI (anti-PD-1, anti-CTLA4, both at 10mg/kg, 2x/week), and RT+ICI. RT was administered only to the left tumor and abscopal effects were based on measurement of the contralateral tumor relative to NT animals on day 10 after treatment initiation. Additional treatment arms were added for 2250L tumor: PARP7i (RBN-2397, 30mg/kg, daily for 10 days), RT+PARP7i, ICI+PARP7i, and RT+ICI+PARP7i. mRNA-sequencing was performed on the four syngeneic NT tumor models or 48h after treatment with RT (8Gy) +/- PARP1/2i (Olaparib, 1uM), using Illumina TruSeq stranded mRNA library prep on a NextSeq2000. DESeq2 was used for differential gene expression analysis of normalized read counts. A panel of three human (MDA-MB-231, MDA-MB-436, and MCF7) and six murine breast cancer models (2250L, 2336R, 2208L, 2225L, EO771, and mWnt) were profiled in vitro for ISG expression 48hr following treatment with RT (8Gy) +/- PARP7i (RBN-2397, 50nM) using RT-qPCR. Cells were transfected with synthetic nucleic acids using lipofectamine 3000 and RNA was isolated 6h post treatment for RT-qPCR. Statistical comparisons used two-tailed t-tests with a p<0.05 significance threshold. Results: All four syngeneic breast cancer models were ICI resistant, and only two demonstrated abscopal response when treated with RT/ICI (2250L, 2208L). RNA-sequencing of NT and RT samples identified genes in the PARP family as being significantly upregulated between abscopal responding models (2250L, 2208L) and non-abscopal models (2336R, 2225L), with PARP7 being uniformly higher expressed among the abscopal competent lines (p <0.000001). RT+PARP7i induced significantly greater IFNB1 levels compared to RT+PARP1/2i in 2250L cells (85-fold vs 6-fold, p<0.0001). Synergistic induction of ISGs by RT+PARP7i was observed across the panel of human and murine models (response additivity scores of 1.38-12.94). PARP7i enhanced IFNB1 induction in response to both ISD90 and poly(I:C) suggesting that PARP7 suppresses both RNA- and DNA- sensing pathways. In vivo, RT+ICI+PARP7i can overcome ICI resistance and induce a systemic immune response in the 2250L model, resulting in significantly smaller contralateral tumors compared to RT+ICI alone (p=.0483). Conclusion: Breast cancers that express PARP7 may be targetable with PARP7i in combination with RT/ICI to enhance ISG expression in the tumor microenvironment and overcome ICI resistance. Future studies will characterize the mechanism of this effect and its potential clinical translation. Citation Format: Lynn Lerner, Anna M. Goddard, Qinhong Wang, Kevin R. Mott, Charles M. Perou, Gaorav P. Gupta. PARP7 inhibition combined with radiotherapy overcomes ICI resistance in breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr PS12-05.

BackgroundResistance to immune checkpoint inhibitors (ICIs) is a significant barrier to improving cancer immunotherapy.1 To this end, we interrogated ICI-induced inflammation. One type of inflammation, driven by nuclear factor-kB (NF-kB)...

Tumour-infiltrating lymphocytes and prognosis in different subtypes of breast cancer: a pooled analysis of 3771 patients treated with neoadjuvant therapy

Background: The KEYNOTE-522 (KN-522) regimen [chemotherapy (CT) + immune checkpoint inhibitor (ICI)] is the treatment of choice for patients with triple-negative breast cancer (TNBC) in the neoadjuvant setting. Addition of ICI could be associated with life-threatening immune related adverse events (irAEs). There is an unmet need to identify a subgroup of TNBC patients who would benefit from ICI, while sparing its use in the majority where CT alone may be sufficient. Our study aimed to compare the pathological complete response (pCR) rate between two matched cohorts (CT + ICI vs. CT alone), identify clinicopathologic variables that would predict benefit from ICI and study association of irAE with pCR. Methods: Patients treated with CT + ICI (n=128) were 1:1 matched to patients treated with CT alone (n=128) on age range (10 years), race, clinical-AJCC stage, and histologic type [metaplastic vs. no special type] from four US academic institutions. Additionally, data on Nottingham grade, degree of necrosis, and percentage of tumor infiltrating lymphocytes (TILs) was collected from pre-treatment core needle biopsy (CNB). To identify the clinicopathologic features of patients who could benefit from ICI, multivariable logistic regression models were used. Data on incidence of any grade irAEs was collected and its association with pCR was also analyzed using multivariable logistic regression models. Results: pCR was achieved in 64/128 (50%) patients treated with CT + ICI vs. 46/128 (35.9%) treated with CT alone (p = 0.02). The optimal threshold to predict pCR for TILs was 30% for both CT + ICI and CT alone groups, with AUC of 0.78 and 0.73, respectively (p<0.001 for both). In the CT group, lower TILs in CNB, non-Black race, metaplastic histology and higher degree of necrosis were associated with non-pCR; where the corresponding ROC curve had an AUC of 0.83. Patients who received CT were categorized into quartiles (Q) based on the predicted risk of non-pCR (Q1 representing the lowest risk, Q4 representing the highest risk of non-pCR (34/128 or 26.6%), and Q2 and Q3 representing intermediate levels of risk). In the Q4, the pCR rate with CT alone was only 2.9% (1/46) while it was 20% (6/64) in the CT + IT cohort (p=0.044). The following variables were associated with Q4 vs. Q1-3: non-Black race (96.9% vs. 88%, p=0.04), metaplastic histology (29.7% vs. 1.6%, p<0.01), lymph node (LN) positive disease (54.6% vs. 50%, p<0.01), Nottingham grade 2 (32.8% vs. 6.3%, p<0.01), and lower mean TILs (12.8 +/- 15.0 vs. 36.7 +/- 26.5, p<0.01). The incidence of any grade irAEs was 32% (41/128) in patients treated with CT + ICI. Among patients with an irAE, 63.4% achieved pCR vs. 43.7% without irAE who achieved pCR (p=0.04). There was a higher likelihood of pCR in patients treated with CT + ICI who experienced irAE (OR=3.34, 95% CI 1.17-9.58) while controlling for age, AJCC stage, nottingham grade, race, TILs, and number of ICI doses. Conclusions: In our real-world multicenter study, the pCR rate with neoadjuvant CT + ICI was lower than that reported in KN-522, with a similar irAE rate. We identified a subgroup of patients with TNBC likely to benefit from addition of neoadjuvant ICI to CT: those with metaplastic histology, non-Black race, LN positive disease, nottingham grade 2, or low TILs (<30%). Occurrence of any irAE was associated with increased likelihood of achieving pCR. Our results warrant validation in larger cohorts. Citation Format: Shipra Gandhi, Gary Tozbikian, Oluwole Fadare, Samira Syed, Briana To, Dionisia Quiroga, Song Yao, Kristopher Attwood, Yisheng Fang, Thaer Khoury. Clinicopathological features predictive of neoadjuvant immune checkpoint inhibitor benefit in triple-negative breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P2-11-11.

Assessing the Relationship between Residual Cancer Burden and the Tumor Immune-Microenvironment in Early-Stage, Hormone Receptor-Positive Breast Cancer Following Preoperative Radiation Therapy in MC1732 Clinical Trial

Exploring the Potential of Breast Microbiota as Biomarker for Breast Cancer and Therapeutic Response

SummaryM2-tumor-associated macrophages (M2-TAMs) in the tumor microenvironment represent a prognostic indicator for poor outcome in triple-negative breast cancer (TNBC).Here we show that Prune-1 overexpression in human TNBC patients has positive correlation to lung metastasis and infiltrating M2-TAMs. Thus, we demonstrate that Prune-1 promotes lung metastasis in a genetically engineered mouse model of metastatic TNBC augmenting M2-polarization of TAMs within the tumor microenvironment. Thus, this occurs through TGF-β enhancement, IL-17F secretion, and extracellular vesicle protein content modulation.We also find murine inactivating gene variants in human TNBC patient cohorts that are involved in activation of the innate immune response, cell adhesion, apoptotic pathways, and DNA repair. Altogether, we indicate that the overexpression of Prune-1, IL-10, COL4A1, ILR1, and PDGFB, together with inactivating mutations of PDE9A, CD244, Sirpb1b, SV140, Iqca1, and PIP5K1B genes, might represent a route of metastatic lung dissemination that need future prognostic validations.

Predictive and prognostic value of stromal tumour-infiltrating lymphocytes before and after neoadjuvant therapy in triple negative and HER2-positive breast cancer

Akt-targeted therapy as a promising strategy to overcome drug resistance in breast cancer – A comprehensive review from chemotherapy to immunotherapy

PurposeThe microRNA-221/222 (miR-221/222) gene cluster has been reported to be associated with the promotion of epithelial-mesenchymal transition (EMT), downregulation of estrogen receptor-α, and tamoxifen resistance in breast cancer. We studied the expression of miR-222 in human breast cancer samples to analyze its relationship with clinicopathologic features of the tumor, including estrogen receptor status, expression of EMT markers, and clinical outcomes.MethodsQuantitative real-time polymerase chain reaction was performed to detect the expression of miR-222 in 197 invasive breast cancers. Expression of EMT markers (vimentin, smooth muscle actin, osteonectin, N-cadherin, and E-cadherin) was evaluated using immunohistochemistry.ResultsHigh miR-222 levels were associated with high T stage, high histologic grade, high Ki-67 proliferation index, and HER2 gene amplification. Its expression was significantly higher in the luminal B and human epidermal growth factor receptor 2-positive (HER2+) subtypes than in the luminal A and triple-negative subtypes. In the hormone receptor-positive subgroup, there was a significant negative correlation between miR-222 and estrogen receptor expression, and miR-222 expression was associated with EMT marker expression. In the group as a whole, high miR-222 expression was not associated with clinical outcome. However, subgroup analyses by hormone receptor status revealed that high miR-222 expression was a poor prognostic factor in the hormone receptor-positive subgroup, but not in the hormone receptor-negative subgroup.ConclusionThis study showed that miR-222 is associated with down-regulation of the estrogen receptor, EMT, and tumor progression in hormone receptor-positive breast cancer, indicating that miR-222 might be associated with endocrine therapy resistance and poor clinical outcome in hormone receptor-positive breast cancer.

Background: Tripartite motif-containing protein 37 (TRIM37) is an oncogenic histone H2A ubiquitin ligase that is overexpressed in a subset of breast cancers. TRIM37 was suggested to be associated with chemotherapy resistance and metastasis of triple-negative breast cancer (TNBC) in in vivo and in vitro studies. Breast cancer with TRIM37 amplification is sensitive to polo-like kinase 4 (PLK4) inhibition. On the other hand, clinical relevance of TRIM37 in breast cancer was never investigated. Material and Methods: Total of 6836 breast cancer patients from three large patient cohorts (Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), The Cancer Genome Atlas (TCGA), GSE96058, GSE25066 and GSE20194. Gene set enrichment analysis (GSEA) was performed. The high and low expression of TRIM37 gene were divided by median. Results: TRIM37 expression was significantly associated with worse survival (disease-free (DFS), disease-specific (DSS), and overall survival (OS)) in ER-positive/HER2-negative breast cancer (p=0.012, p=0.011, and p=0.003, respectively), but not in the other subtypes. TRIM37 expression was higher in HER2-positive among the subtypes. TRIM37 expression correlated with Nottingham histological grade (p<0.001), and with MKI-67 expression (p<0.001) consistently in METABRIC and GSE96058 cohorts. TRIM37 high expression enriched cell proliferation-related gene sets; E2F targets, G2M checkpoints, mitotic spindle, and MYC targets v1 and v2, as well as DNA repair gene sets regardless of subtypes. TRIM37 high expression was also associated with RAD51C and/or PLK4 expression, which are DNA repair related genes. In agreement, silent and non-silent mutation rate and altered fraction were all significantly elevated in TRIM37 high tumors regardless of subtypes. TRIM37 expression correlated with response to Cisplatin, Paclitaxel, and Tamoxifen in breast cancer cell line study (r=0.655, r=0.446, and r=0.9, respectively). TRIM37 high tumors demonstrated significantly worse pathological complete response after neoadjuvant chemotherapy in ER-positive/HER2-negative patients (p=0.002), but the opposite in TNBC (p=0.025) in GSE25066 cohort, but this result was not validated by GSE20194, a cohort with very small samples size. Interestingly, TRIM37 low expression enriched immune related gene sets; inflammatory response, IL2 signaling, IL6 signaling, TNF-a signaling, and allograft rejection in ER-positive/HER2-negative patients, but not in TNBC. Indeed, CD8 central memory T cells and CD4 effector memory T cells are highly infiltrated in TRIM37 low tumors consistently in both METABRIC and GSE96058 in ER-positive/HER2-negative patients, but not in TNBC. Taken together, TRIM37 high expression was associated with cell proliferation regardless of subtypes, but TRIM37 low expression was associated with high tumor infiltrating lymphocytes and immune response that may have contributed to the survival difference in ER-positive/HER2-negative patients, but not in TNBC. Conclusions: In conclusion, TRIM37 expression is associated with cell proliferation and DNA repair, less tumor infiltrating lymphocytes and immune response, and with worse survival in ER-positive/HER2-negative breast cancer. Citation Format: Junko Tsuchida, Rongrong Wu, Maiko Endo, Kazuki Moro, Chie Toshikawa, Yu Koyama, Hiroshi Ichikawa, Takaaki Hanyu, Yamato Takabe, Kazuyasu Takizawa, Yoshifumi Shimada, Takashi Kobayashi, Takashi Ishikawa, Jun Sakata, Toshifumi Wakai, Kazuaki Takabe. Clinical relevance of TRIM37 gene expression in breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-01-15.

Background: There is a strong evidence indicating that locoregional control of early-stage breast cancer either by lumpectomy with radiation therapy or by mastectomy yields similar rates of disease-free survival (DFS) and overall survival (OS). Recent retrospective review of a Danish prospective database demonstrated a strong favorable interaction between radiotherapy (RT) and all breast cancer subtypes that contain high amount of tumor infiltrating lymphocytes (TILs). Objective: We aim to compare the DFS and OS rates in patients with early-stage triple negative breast cancer (TNBC), whose tumors demonstrate high involvement by TILs after locoregional management by either mastectomy or lumpectomy and whole breast radiotherapy. Methods: We retrospectively reviewed the charts and histopathology slides of patients with TNBC with the clinical stage of T1-T2 N0 who were treated in our center between January 2009 and December 2018. Locoregional management included either mastectomy (no radiation group) or lumpectomy with whole breast irradiation (radiation group). Stromal TILs were estimated by 3 pathologists independently using hematoxylin-eosin staining, following the recommendations of the TILs working group 2014. A competing risk model, Kaplan-Meier analysis and multivariate Cox regression analysis were used to analyze correlations between TILs and clinical outcome. Results: A total of 101 charts were reviewed and 91 were included in the final analysis. Patients were dichotomized into groups of “low TILs” and “high TILs” using a 40% cut off. Approximately 26% of patients (24/91) were “high TILs”. About 46% of the “high TILs” group and 52% of “low TILs” group received RT. In patients with high TILs, 82% received chemotherapy in the "radiation group" and 100% in "no radiation group". In the patients with low TILs, 77% received chemotherapy in the "RT group" and 75% in "no RT group”. Table 1 and 2 depict the 5-year DFS and 5-year OS in "high TILs" and "low TILs" groups in relation to RT, respectively. Conclusion: Our data indicate that in a selected group of high TILs TNBC, RT is associated with significant improvement of 5-year DFS and OS. This improvement is unlikely to be due to improved locoregional control as local failure was rare in all patient groups. This study is limited by its retrospective nature and the low number of subjects. Despite that, our results are important and deserve further confirmation using larger prospective clinical trials. Table 1. 5-year DFS5-year DFSHigh TILsLow TILsRT group100%83.9%No RT group47.1%79.3%p-value0.010.96 Table 2. 5-year OS5-year OSHigh TILsLow TILsRT group100%83.7%No RT group65.6%76.7%p-value0.050.98 Citation Format: Jason Aboudi Mouabbi, Momal Chand, Ramen Sakhi, Daniel Ockner, Susan Szpunar, Carrie L Dul, Tarik Hadid, Zyad Kafri, Amr Aref. Improvement of survival with radiation therapy in early stage triple negative breast cancer patients with high level of tumor infiltrating lymphocytes [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-12-09.

Insight into the mechanism of docetaxel resistance in breast cancer may help to improve prognosis. We aimed to investigate the role of N6-methyladenosine (m6A) and the METTL3/LINC00662/miR-186-5p pathway in regulating docetaxel resistance in triple negative breast cancer (TNBC). We have recruited 193 pathologically diagnosed TNBC patients from 2016 to 2017 in our hospital. Quantitative real-time PCR was used to evaluate the expression of LINC00662 and miR-186-5p both in vivo and in vitro. CCK8 tests were used to assess cell viability. ELISA was used for protein expression evaluation. Dual luciferase reporter gene assay and RNA pull-down were used to evaluate the interaction between LINC00662 and miR-186-5p. m6A levels were enhanced in breast cancer tissues and cells. LINC00662, miR-186-5p and METTL3 were differentially expressed in vivo, and METTL3 expression was associated with LINC00662 and miR-186-5p expression. LINC00662 and miR-186-5p were differentially expressed in vitro; LINC00662 promoted cell viability and decreased the apoptosis rate, whereas miR-186-5p inhibited cell viability and increased the apoptosis rate. Furthermore, we found that METTL3 regulated m6A levels in docetaxel-resistant breast cancer cells by regulating the expression of LINC00662. Moreover, LINC00662 and miR-186-5p regulated the cell viability rate of docetaxel-resistant breast cancer cells. Further experiments showed that LINC00662 directly interacted with miR-186-5p to exert biological functions; besides miR-186-5p could regulate the expression of METTL3. METTL3 promotes m6A levels and docetaxel resistance in breast cancer by regulating the expression of LINC00662 and miR-186-5p; more experiments are needed to clarify the role of m6A regulation in drug resistance.

Background:Tumor-infiltrating lymphocytes (TILs), one of immunological biomarkers have been investigated in breast cancer and other cancers. High levels of TILs or lymphocyte-predominant breast cancer subgroup (LPBC) were associated with better prognosis in HER2 positive and triple negative breast cancers from various studies. Recently, TILs is also the predictive biomarker for response to neoadjuvant chemotherapy. Clinical utility of TILs has been recommended in routine clinical practice for breast cancer patients. However, limitation of TILs in HER2 positive women in Thai ethnicity was reported. So, the aim of this study was to evaluate TILs in combination with clinical values as the prognostic value for predicting the recurrent breast cancer in Thai population. Methods: Four hundred and eighty-six patients with early stage HER-2 positive breast cancer who were diagnosed and treated at King Chulalongkorn Memorial Hospital from January 2005 to December 2016 were reviewed retrospectively. Clinico-pathological features, stromal TILs classified as low, intermediate and high, and survival outcomes were analyzed. Results: The median age was 52 years (26-85). Of the 486 HER2 positive women, 56% had postmenopause, 54.5% had T2 tumor, 47.7% had node negative, 66.8% had stage I-II, 44.6% had lymphovascular invasion, and 47.5% had positive hormonal receptor. For the primary treatment, 67.3% underwent modified radical mastectomy, 96.5% received neoadjuvant/adjuvant chemotherapy, 69.7% received adjuvant trastuzumab, 46.7% received adjuvant hormonal therapy. In 92 recurrent patients (18.9%), distant metastasis was identified in 67.4%. In 100 available tissues for evaluating stromal TILs, only 14 (14%) had high stromal TILs (at least 50%) and 46 patients (46%) had recurrent disease. Twenty three of 39 (59%)in low stromal TILs group had disease recurrence while only 4 out of 14 (28.6%) in high stromal TILs had recurrent disease. Median percentage of stromal TILs in recurrent and non-recurrent group was 17.5% and 27.5%, respectively. From multivariate analysis, high stromal TILs (HR 0.52 [95%CI 0.32-0.85]; p = 0.01) and trastuzumab used (HR 0.39 [95%CI 0.25-0.61]; p <0.001) were associated with decreased risk of recurrences. After median follow up of 4.1 years, 5-years disease free survival (DFS) and 5-years overall survival (OS) were 80.9%, 86.8%, 69% and 92.6%, 91.5%, 94.5% in overall populations, trastuzumab and non-trastuzumab used group, respectively. Additionally, 5-year DFS and 5-year OS were 34.3%, 60.8%, 75.7% and 86.2%, 82.5%, 83.1% in low, intermediate and high stromal TILs subgroup, respectively. Conclusion: High stromal TILs and trastuzumab used were statistically significant prognostic values for predicting disease recurrence in HER-2 positive early breast cancer. Stromal TILs together with clinical values established clinical utility in Thai HER2 positive breast cancer women. Level of Stromal TILs in Overall PatientsStromal TILsTotal (n = 100)No recurrence (n = 54)Recurrence (n = 46)P valueLow (0-15%)39(39%)16(41%)23(59%)0.03Intermediate (20-40%)47(47%)28(59.6%)19(40.4%) LPBC (50-90%)14(14%)10(71.4%)4(28.6%) Citation Format: Prapatsornvichit S, Atikankul T, Sriuranpong V, Poovorawan N, Parinyanitikul N. Prognostic value of tumor-infiltrating lymphocytes (TILs) and clinical values for prediction of breast cancer recurrence in HER2 positive early breast cancer after surgery in King Chulalongkorn Memorial Hospital [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-08-46.

Background:Prognostic significance of stromal TILs in metastatic BC has been suggested in various BC subtypes. However, predictive role of stromal TILs for the efficacy of trastuzumab has not been established in patients with HER2-positive BC. This study was performed to evaluate whether the stromal TILs are associated with the efficacy of trastuzumab in patients with metastatic HER2-positve BC. Method:Between June 2006 and March 2013, a total of 60 women with recurrent or metastatic HER2-positive BC treated with trastuzumab were included in this retrospective analysis. In these patients, trastuzumab was administered either as single agent or combination with taxanes. Stromal TILs were assessed using immunohistochemistry in surgical specimen (n=39, 65%) and biopsy specimen of metastatic lesion (n=21, 35%) by the academic pathologist (HJL). Primary endpoint of this study was progression-free survival (PFS), and secondary endpoints were response rate and overall survival (OS). Result:Median age was 54 year old (range, 36-76), and all patients had invasive ductal carcinoma. Hormone receptor was positive in 34 patients (57%) and 18 patients (30%) initially presented with metastatic disease. Nine patients (15%) received cytotoxic chemotherapy without trastuzumab before the administration of trastuzumab. Patients were grouped according to the TILs (< 10% [n=50] and >10% [n=10]), and there was no significant difference in age (p=0.68), histologic grade (p=1.00), metastatic sites (p>0.05), and number of lines of chemotherapy before the administration of trastuzumab(p=0.33) among patients with low and high stromal TILs. High TILs were more common in hormone receptor (HR)-negative tumor compared with HR–positive tumor (31% vs 6%; p=0.02). In overall, median PFS and OS were 15.0 months (95% CI, 9.7-20.2) and 35.0 months (95% CI, 29.8-40.2), respectively. Median PFS in patients with high stromal TILs were numerically longer than that in those with low TILs (22.0 months [95% CI, 9.6-34.4] vs 14.0 months [95% CI, 9.6-18.4]; p=0.057). There was no difference in response rates (p=0.43) and OS (p=0.94) according to the stromal TILs. FcR genotype was not significantly correlated with objective response rate, PFS and OS. Conclusion:This study suggests that the stromal TILs might be associated with the clinical outcomes of HER2-targeted therapy in patients with metastatic HER2-positive BC. Our finding should be validated in future studies based on a large sample size. Keywords: Breast cancer, tumor infiltrating lymphocyte. Trastzumab, HER2. Citation Format: Yoon JA, Yoo C, Lee HJ, Kim K-P, Kim J, Ahn J-H, Jung KH, Gong G, Kim S-B. Predictive role of stromal tumor infiltrating lymphocytes (TILs) in patients with metastatic HER2-positive breast cancer (BC) treated with trastuzumab. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-07-34.