Young Up Cho

A hierarchical prognostic model for risk stratification in patients with early breast cancer according to 18F-fludeoxyglucose uptake and clinicopathological parameters

This study was to investigate a hierarchical prognostic model using clinicopathological factors and 18F‐fludeoxyglucose (FDG) uptake on positron emission tomography/computed tomography (PET/CT) for recurrence‐free survival (RFS) in patients with early breast cancer who underwent surgery without neoadjuvant chemotherapy. A total of 524 patients with early breast cancer were included. The Cox proportional hazards model was used with clinicopathological variables and maximum standardized uptake value (SUVmax) on PET/CT. After classification and regression tree (CART) modeling, RFS curves were estimated using the Kaplan–Meier method and differences in each risk layer were assessed using the log‐rank test. During a median follow‐up of 46.2 months, 31 (5.9%) patients experienced recurrence. The CART model identified four risk layers: group 1 (SUVmax ≤6.75 and tumor size ≤2.0 cm); group 2 (SUVmax ≤6.75 and Luminal A [LumA] or TN tumor >2.0 cm); group 3 (SUVmax ≤6.75 and Luminal B [LumB] or human epidermal growth factor receptor 2 [HER2]‐enriched] tumor >2.0 cm); group 4 (SUVmax >6.75). Five‐year RFS was as follows: 95.9% (group 1), 98% (group 2), 82.8% (group 3), and 85.4% (group 4). Group 3 or group 4 showed worse prognosis than group 1 or group 2 (group 1 vs. group 3: P = 0.040; group 1 vs. group 4: P < 0.001; group 2 vs. group 3: P = 0.016; group 2 vs. group 4: P < 0.001). High SUVmax (>6.75) in primary breast cancer was an independent factor for poor RFS. In patients with low SUVmax, LumB or HER2‐enriched tumor >2 cm was also prognostic for poor RFS, similar to high SUVmax.

Feasibility of Charcoal Tattooing of Cytology-Proven Metastatic Axillary Lymph Node at Diagnosis and Sentinel Lymph Node Biopsy after Neoadjuvant Chemotherapy in Breast Cancer Patients

Purpose Sentinel lymph node biopsy (SLNB) can be performed when node-positive disease is converted to node-negative status after neoadjuvant chemotherapy (NCT). Tattooing nodes might improve accuracy but supportive data are limited. This study aimed to investigate the feasibility of charcoal tattooing metastatic axillary lymph node (ALN) at presentation followed by SLNB after NCT in breast cancers. Materials and Methods Twenty patientswith cytology-proven node metastases prospectively underwent charcoal tattooing at diagnosis. SLNB using dual tracers and axillary surgery after NCT were then performed. The detection rate of tattooed node and diagnostic performance of SLNB were analyzed. Results All patients underwent charcoal tattooingwithout significant morbidity. Sentinel and tattooed nodes could be detected during surgery after NCT. Nodal pathologic complete response was achieved in 10 patients. Overall sensitivity, false-negative rate (FNR), negative predictive value, and accuracy of hot/blue SLNB were 80.0%, 20.0%, 83.3%, and 90.0%, respectively. Retrieving more nodes and favorable nodal response were associated with improved performance. The best accuracy was observed when excised tattooed node was calculated together (FNR, 0.0%). Cold/non-blue tattooed nodes of five patients were removed during non-sentinel axillary surgery but clinicopathological parameters did not differ compared to patients with hot/blue tattooed node detected during SLNB, suggesting the importance of the tattooing procedure itself to improve performance. Conclusion Charcoal tattooing of cytology-confirmed metastatic ALN at presentation is technically feasible and does not limit SLNB after NCT. The tattooing procedure without additional preoperative localization is advantageous for improving the diagnostic performance of SLNB in this setting.

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.nMethodsThe 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.

BRCA1/ 2-negative, high-risk breast cancers ( BRCAX ) for Asian women: genetic susceptibility loci and their potential impacts

Abstract“BRCAX” refers breast cancers occurring in women with a family history predictive of being a BRCA1/2 mutation carrier, but BRCA1/2 genetic screening has failed to find causal mutations. In this study, we report the findings of the genetic architecture of BRCAX with novel and redefined candidate loci and their potential impacts on preventive strategy. We performed a genome-wide association study involving 1,469 BRCAX cases from the Korean Hereditary Breast Cancer study, and high-risk breast cancer cases (1,482 Asians and 9,902 Europeans) from the Breast Cancer Association Consortium. We also evaluated the previously reported susceptibility loci for their roles in the high-risk breast cancers. We have identified three novel loci (PDE7B, UBL3, and a new independent marker in CDKN2B-AS1) associated with BRCAX, and replicated previously reported SNPs (24 of 92) and moderate/high-penetrance (seven of 23) genes for Korean BRCAX. For the novel candidate loci, evidence supported their roles in regulatory function. We estimated that the common low-penetrance loci might explain a substantial part of high-risk breast cancer (39.4% for Koreans and 24.0% for Europeans). Our study findings suggest that common genetic markers with lower penetrance constitute a part of susceptibility to high-risk breast cancers, with potential implications for a more comprehensive genetic screening test.

External validation of IBTR! 2.0 nomogram for prediction of ipsilateral breast tumor recurrence

Purpose IBTR! 2.0 nomogram is web-based nomogram that predicts ipsilateral breast tumor recurrence (IBTR). We aimed to validate the IBTR! 2.0 using an external data set. Materials and Methods The cohort consisted of 2,206 patients, who received breast conserving surgery and radiation therapy from 1992 to 2012 at our institution, where wide surgical excision is been routinely performed. Discrimination and calibration were used for assessing model performance. Patients with predicted 10-year IBTR risk based on an IBTR! 2.0 nomogram score of <3%, 3%–5%, 5%–10%, and >10% were assigned to groups 1, 2, 3, and 4, respectively. We also plotted calibration values to observe the actual IBTR rate against the nomogram-derived 10-year IBTR probabilities. Results The median follow-up period was 73 months (range, 6 to 277 months). The area under the receiver operating characteristic curve was 0.607, showing poor accordance between the estimated and observed recurrence rate. Calibration plot confirmed that the IBTR! 2.0 nomogram predicted the 10-year IBTR risk higher than the observed IBTR rates in all groups. High discrepancies between nomogram IBTR predictions and observed IBTR rates were observed in overall risk groups. Compared with the original development dataset, our patients had fewer high grade tumors, less margin positivity, and less lymphovascular invasion, and more use of modern systemic therapies. conclusions IBTR! 2.0 nomogram seems to have the moderate discriminative ability with a tendency to over-estimating risk rate. Continued efforts are needed to ensure external applicability of published nomograms by validating the program using an external patient population.

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.

Assessment of Quality of Life and Safety in Postmenopausal Breast Cancer Patients Receiving Letrozole as an Early Adjuvant Treatment

Purpose There are few reports from Asian countries about the long-term results of aromatase inhibitor adjuvant treatment for breast cancer. This observational study aimed to evaluate the long-term effects of letrozole in postmenopausal Korean women with operable breast cancer. Methods Self-reported quality of life (QoL) scores were serially assessed for 3 years during adjuvant letrozole treatment using the Korean version of the Functional Assessment of Cancer Therapy-Breast questionnaires (version 3). Changes in bone mineral density (BMD) and serum cholesterol levels were also examined. Results All 897 patients received the documented informed consent form and completed a baseline questionnaire before treatment. Adjuvant chemotherapy was administered to 684 (76.3%) subjects, and 410 (45.7%) and 396 (44.1%) patients had stage I and II breast cancer, respectively. Each patient completed questionnaires at 3, 6, 12, 18, 24, 30, and 36 months after enrollment. Of 897 patients, 749 (83.5%) completed the study. The dropout rate was 16.5%. The serial trial outcome index, the sum of the physical and functional well-being subscales, increased gradually and significantly from baseline during letrozole treatment (p<0.001). The mean serum cholesterol level increased significantly from 199 to 205 after 36 months (p=0.042). The mean BMD significantly decreased from −0.39 at baseline to −0.87 after 36 months (p<0.001). Conclusion QoL gradually improved during letrozole treatment. BMD and serum cholesterol level changes were similar to those in Western countries, indicating that adjuvant letrozole treatment is well tolerated in Korean women, with minimal ethnic variation.

Factors predictive of occult nipple-areolar complex involvement in patients with carcinoma in situ of the breast

To investigate predictors of occult nipple‐areolar complex (NAC) involvement in patients with carcinoma in situ (CIS) and to validate an online probability calculator (CancerMath; www.lifemath.net/cancer/breastcancer/nipplecalc/index.php).

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