Joo Heung Kim

Expression of T-Lymphocyte Markers in Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer.

Purpose The present study aimed to examine the clinical implications of CD4, CD8, and FOXP3 expression on the prognosis of human epidermal growth factor receptor 2 (HER2)-positive breast cancer using a web-based database, and to compare the immunohistochemical expression of T-lymphocyte markers using primary and metastatic HER2-positive tumor tissues before and after HER2-targeted therapy. Methods Using the cBioPortal for Cancer Genomics and Kaplan-Meier plotter, the mRNA expression, association between T-lymphocyte markers, and survival in HER2-positive cancers were investigated according to various cutoff levels. Immunohistochemistry analysis was performed using paired primary and metastatic tissues of 29 HER2-positive tumors treated with systemic chemotherapy and HER2-directed therapy. Results HER2 mRNA was mutually exclusive of T-lymphocyte markers, and a significant correlation between T-cell markers was observed in the cBioPortal for Cancer Genomics. According to analysis of the Kaplan-Meier plotter, the impact of T-lymphocyte marker expression on survival was statistically insignificant in clinical HER2-positive tumors, irrespective of the cutoff levels. However, in the intrinsic HER2-positive subtype, the individual analyses of T-cell markers except for FOXP3 and combined analysis showed significantly favorable survival irrespective of cutoff points. Although the small clinical sample size made it difficult to show the statistical relevance of immunohistochemistry findings, good responses to neoadjuvant treatments might be associated with positive expression of combined T-lymphocyte markers, and approximately half of the samples showed discordance of combined markers between baseline and resistant tumors. Conclusion T-lymphocyte markers could be favorable prognostic factors in HER2-positive breast cancers; however, a consensus on patient section criteria, detection methods, and cutoff value could not be reached. The resistance to HER2-directed therapy might involve different and personalized mechanisms, and further research is required to understand the association between immune function and HER2 expression and to overcome the resistance mechanisms to HER2-targeted therapies.

Impact of Micrometastatic Axillary Nodes on Survival of Breast Cancer Patients with Tumors ≤2 cm

AbstractBackgroundThis study investigated the impact of pN1mi disease on the survival of T1 breast cancer patients and examined the clinical usefulness of the online PREDICT tool and updated staging system. MethodsThe node stages of 2344 patients were divided into pN0, pN1mi, and pN1a. Clinicopathological parameters and survival outcomes were retrospectively analyzed. Data for 111 micrometastatic diseases were applied to the PREDICT version 2.0 and re-classified using the 8th edition of the cancer staging manual.ResultsUnivariable analyses demonstrated worse disease-free and overall survival rates for patients with node-positive cancer; however, the significance was not maintained in multivariable analyses. Chemotherapy improved outcomes in patients with node-positive and non-luminal A-like subtype cancers. The PREDICT tool demonstrated good performance when estimating the 5-year overall survival for pN1mi disease (area under the receiver operating characteristic curve, 0.834). According to the updated staging system, 74% of cases were down-staged to IA, and clearly splitting survival curves were identified.ConclusionpN1mi disease alone did not adversely affect survival outcomes. Biologic and treatment factors determined outcomes in cases of small-volume node micrometastasis. The PREDICT tool or new staging classification could help predict the survival of patients with micrometastatic sentinel nodes.

Gasless Robot-Assisted Nipple-Sparing Mastectomy: A Case Report

Robotic surgical systems enhance surgical accuracy and efficiency by applying advanced technologies such as artificial arm joints to provide higher degrees of freedom of movement and high-quality three-dimensional images. However, the application of robotic surgical systems to breast surgery has not been widely attempted. The robotic system would improve cosmesis by enabling surgery using a single small incision. We report the first case of a gasless robot-assisted nipple-sparing mastectomy and immediate reconstruction in a patient with early breast cancer.

Association between Changes in Serum 25-Hydroxyvitamin D Levels and Survival in Patients with Breast Cancer Receiving Neoadjuvant Chemotherapy

Purpose We investigated the changes in serum 25-hydroxyvitamin D (25[OH]D) levels before and after neoadjuvant chemotherapy (NCT) and the associations with pathologic complete response (pCR) and survival in patients with breast cancer. Methods Serum 25(OH)D concentrations were measured pre- and post-NCT in 374 patients between 2010 and 2013. Based on a cutoff of 20 ng/mL, patients were categorized into “either sufficient” or “both deficient” groups. The associations with clinicopathological data, including pCR and survival, were analyzed using multivariable analyses. Results Patients with either pre- or post-NCT sufficient 25(OH)D levels accounted for 23.8%, and the overall pCR rate was 25.9%. Most patients showed 25(OH)D deficiency at diagnosis and 65.8% showed decreased serum levels after NCT. Changes in 25(OH)D status were associated with postmenopause status, rural residence, baseline summer examination, and molecular phenotype, but not pCR. No association between survival and 25(OH)D status was found, including in the subgroup analyses based on molecular phenotypes. Conclusion Most Korean patients with breast cancer showed vitamin D deficiency at diagnosis and a significant decrease in the serum concentration after NCT. No association with oncologic outcomes was found. Therefore, although optimal management for vitamin D deficiency is urgent for skeletal health, further research is warranted to clearly determine the prognostic role of vitamin D in patients with breast cancer who are candidates for NCT.

Abstract 5613: PD-1 and TIGIT are major immune checkpoint receptors expressed in breast cancer-infiltrating T cells

Immune checkpoint blockers, which target co-inhibitory receptors of T cells, have provided promising responses against various tumors. However, the expression of immune checkpoint receptors (ICRs) in breast cancer remains poorly understood. We aimed to investigate the expression pattern of multiple ICRs in tumor-infiltrating and peripheral blood (PB) lymphocytes in human breast cancer. We isolated lymphocytes from fresh breast tumor and paired PB from 21 patients who underwent surgery between July 2016 and November 2016. Multi-color flow cytometry was performed primarily focusing on expression of multiple ICRs in CD8+ T cells and regulatory T cells (Tregs). In CD8+ T cell subsets, PD-1+ or TIGIT+ cells were more frequently observed in tumor-infiltrating CD8+ T cells than in PB CD8+ T cells (p 70% of PD-1+ tumor-infiltrating CD8+ T cells co-expressed TIGIT, indicating that functional exhaustion of breast tumor-infiltrating CD8+ T cells might be mediated not by PD-1 alone but by multiple receptors including TIGIT. However, the expression of PD-1 and TIGIT showed different patterns in detail. PD-1 was frequently expressed by CCR7-CD45RA- effector memory T cells (TEM) (p=0.001) whereas TIGIT was frequently expressed by CCR7-CD45RA+ effector memory RA T cells (TEMRA) (p=0.03), suggesting that TIGIT is expressed during terminal differentiation of CD8+ T cells. Next, we examined breast tumor-infiltrating Tregs. The frequency of CD25+FoxP3+ Tregs among CD4+ T cells were higher in tumor than in PB (16.60% vs. 7.86%; p=0.002). In particular, CD45RA-FoxP3hi activated suppressive Tregs account for 77.6% of tumor-infiltrating Tregs (vs. PB 32.2%; p=0.005). Tumor-infiltrating Tregs showed higher expression of CD39 (p=0.005), a marker of the suppressive activity of Tregs. We also examined the expression of ICRs on Tregs as upregulation of these receptors is associated with enhanced suppressive activity of Tregs. CD4+CD25+FoxP3+ Tregs in tumors showed higher expression levels of PD-1, TIGIT and CTLA-4 compared to PB Tregs (p There were no noteworthy correlations between ICR expression and clinical features, such as age, stage and subtype. We show that PD-1 and TIGIT are major ICRs expressed in breast tumor-infiltrating CD8+ T cells. Moreover, we found that CD4+CD25+FoxP3+ Tregs are abundant in breast tumors and overexpress PD-1, TIGIT and CTLA-4. Our data provide an understanding of comprehensive phenotypes of immune checkpoint expression on T cells in breast cancer. Functional changes of CD8+ T cells and Tregs by blocking of single or multiple ICRs are being investigated. Citation Format: Jee Ye Kim, Minsuk Kwon, Sung Mook Lim, Joo Heung Kim, Hyung Seok Park, Seho Park, Seung Il Kim, Young Up Cho, Soonmyung Paik, Eui-Cheol Shin. PD-1 and TIGIT are major immune checkpoint receptors expressed in breast cancer-infiltrating T cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5613. doi:10.1158/1538-7445.AM2017-5613