Ha Woo Yi

Zerumbone suppresses EGF-induced CD44 expression through the inhibition of STAT3 in breast cancer cells.

Expression of the CD44 gene is upregulated in breast cancer cells and is correlated with patient survival. Aberrant CD44 expression promotes tumor progression and metastasis. In the present study, we investigated the role of zerumbone (ZER) on regulatory mechanisms of CD44 expression in breast cancer cells. Our results showed that CD44 expression was significantly increased by epidermal growth factor receptor (EGFR) ligands in SKBR3 breast cancer cells. In contrast, EGF-induced CD44 expression was decreased by a MEK1/2 inhibitor, UO126, or STAT3 inhibitor, STAT3 VI, respectively. Notably, ZER downregulated the basal level of CD44 expression in CD44+ breast cancer cells. In addition, the induction of CD44 expression by EGFR ligands, EGF or TGF-α, was markedly decreased by ZER treatment. Finally, we investigated the inhibitory mechanism of ZER on EGF-induced CD44 expression. Our results showed that EGF-induced phosphorylation of STAT3 was completely suppressed by ZER. Collectively, ZER suppressed EGF-induced CD44 expression through inhibition of the STAT3 pathway. Therefore, we suggested that ZER may act as a promising therapeutic drug for the treatment of breast cancer.

Independent Prognostic Factors for Overall Survival after Salvage Operation for Ipsilateral Breast Tumor Recurrence Following Breast-Conserving Surgery

Purpose Few studies address independent prognostic factors after ipsilateral breast tumor recurrence (IBTR) following breast-conserving surgery (BCS). Locoregional recurrence is associated with distant metastases and increased mortality rates. Therefore anticipating prognoses after IBTR and evaluating risk factors for overall survival following a second salvage operation are important. We evaluated independent prognostic factors affecting overall survival after a second operation for IBTR. Methods We retrospectively identified 11,073 patients who underwent breast cancer surgery between November 1995 and December 2011. Locoregional recurrence occurred in 787 patients. Among them, IBTR developed in 165 patients selected for analysis. Excluding eight patients who refused further treatment, we analyzed 157 patients who underwent a second operation (partial mastectomy, 28 [17.8%]; total mastectomy, 129 [82.2%]) for IBTR. Excluding 26 patients with incomplete data, we evaluated the clinicopathol-ogical features influencing overall survival at the first and the second operation in the 131 patients who underwent a second operation. Results The median age of patients at the first operation was 43.6 years (range, 27-69 years). The median duration from the first to the second operation was 45.0 months (range, 2.5-164.6 months). The 5-year overall survival rate after IBTR was 87.1%. In the multivariable analyses, duration from the first to the second operation, histopathology, lymph node status, and adjuvant chemotherapy, radiotherapy, and endocrine therapy at the first operation were independent prognostic factors for overall survival. Positive estrogen receptor status and endocrine therapy at the second operation were also associated with increased overall survival following salvage operations for IBTR. Conclusion The time interval to IBTR following BCS is related to overall survival after salvage operation for IBTR and it is important to undergo optimal adjuvant treatments according to risk factors after the first operation because those risk factors affect overall survival for IBTR following BCS.

Oncologic Outcomes after Immediate Breast Reconstruction Following Total Mastectomy in Patients with Breast Cancer: A Matched Case-Control Study

Purpose The use of immediate breast reconstruction (IBR) following total mastectomy (TM) has increased markedly in patients with breast cancer. As the indications for IBR have been broadened and more breast-conserving surgery-eligible patients are undergoing IBR, comparing the oncologic safety between TM only and IBR following TM becomes more difficult. This study aimed to analyze the oncologic outcomes between TM only and IBR following TM via a matched case-control methodology. Methods A retrospective review was conducted to identify all patients who underwent TM between 2008 and 2014. We excluded patients who underwent neoadjuvant chemotherapy, including palliative chemotherapy, and had a follow-up duration <12 months, inflammatory breast cancer, or incomplete data. We divided the remaining patients into two groups: those who underwent TM only (control group) and those who underwent IBR following TM (study group). The groups were propensity score-matched. Matched variables included age, pathologic stage, estrogen or progesterone receptor status, human epidermal growth factor receptor 2 status, and year of operation. Results After matching, 878 patients were enrolled in the control group and 580 patients in the study group. The median follow-up duration was 43.4 months (range, 11–100 months) for the control group and 41.3 months (range, 12–100 months) for the study group (p=1.000). The mean age was 47.3±8.46 years for the control group and 43.9±7.14 years for the study group (p>0.050). Matching was considered successful for the matching variables and other factors, such as family history, histology, multiplicity, and lymphovascular invasion. There were no significant differences in overall survival (log-rank p=0.454), disease-free survival (log-rank p=0.186), local recurrence-free survival (log-rank p=0.114), or distant metastasis-free survival rates (logrank p=0.537) between the two groups. Conclusion Our results suggest that IBR following TM is a feasible treatment option for patients with breast cancer.

Influence of thyroid gland status on the thyroglobulin cutoff level in washout fluid from cervical lymph nodes of patients with recurrent/metastatic papillary thyroid cancer.

The influence of serum thyroglobulin (Tg) and thyroidectomy status on Tg in fine‐needle aspiration cytology (FNAC) washout fluid is unclear.

Abstract P1-11-01: Depression and anxiety after adjuvant ovarian function suppression in premenopausal breast cancer patients

Purpose The results of the Suppression of Ovarian Function Trial (SOFT) and the Tamoxifen and Exemestane Trial (TEXT) showed that ovarian function suppression (OFS) in premenopausal early breast cancer patients improves disease control. However, mood swings after OFS is one of the chief complaints to make patients stop undergoing endocrine therapy. Studies about complications of OFS in breast cancer patients are not established well. We designed this randomized controlled trial to evaluate psychological functioning of patients after undergoing adjuvant OFS by goserelin. Patients and Methods We randomly assigned 64 premenopausal women with hormone receptor positive early breast cancer to the tamoxifen or tamoxifen plus goserelin group for a period of 1 year. Participants were screened for depression and generalized anxiety disorder using Hamilton Rating Scale for Depression (HAMD), Hamilton Rating Scale for Anxiety (HAM-A), Anxiety Sensitivity Index (ASI) and Albany panic and phobia questionnaire (APPQ) at baseline, 6 months and 12 months. Brain-derived Neurotrophic Factor (BDNF) levels were measured, as well. The results were analyzed by using a linear mixed model and a generalized linear mixed model. Results Thirty two patients were distributed in each group, equally. Linear mixed-mixed model analyses revealed that, compared with HAM-A scores of each group at baseline, HAM-A scores at 12 months showed increments (p=0.0078). Among HAM-A questions, Questions for intellectual, sensory and autonomic status were scored significantly high at 12 months (p=0.0018, p=0.0132, p=0.0006). Platelet BDNF levels reported a statistically significant rise at 12 months (p=0.0006). There was no significant time-by-study group effect in all scales. Conclusion Compared with the patients without OFS, patients with Goserelin showed no difference in anxiety or depression scales. Thought the levels of anxiety of each group at 12 months were increased, they do not indicate medical interventions. Patients with increased levels of BDNF at 12 months are expected to have good recovery from anxious and depressive symptoms. Citation Format: Yi HW, Nam SJ, Kim SW, Lee JE, Lee SK, Bae SY, Park S, Paik H-J, Ryu JM. Depression and anxiety after adjuvant ovarian function suppression in premenopausal breast cancer patients. [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 P1-11-01.

Abstract P3-01-03: Optimal concentration of indocyanine green in near-infrared fluorescence guided sentinel lymph node biopsy in breast cancer

Background: Near-infrared (NIR) fluorescence-guided sentinel lymph node biopsy (SLNB) using indocyanine green (ICG) has been successfully applied in various kinds of cancers, especially in breast cancer. Optimizing the concentration of ICG without using human serum albumin in natural lymphatic system is still required. Methods: 25mg of ICG was diluted with distilled water (DW) or normal saline (NS). Dilution concentrations used for measurement were 0.25μg/mL, 0.5μg/mL, 2.5μg/mL, 5.0μg/mL, 25μg/mL, and 250μg/mL. The brightness of fluorescence was measured by an image system called Visual Navigator (SH System, Korea). We used graphic software (GIMP, version 2.8.14, The GIMP Team) to measure the brightness. We assumed that drained serous lymphatics from a breast cancer patient can reflect a natural lymphatic condition injected with ICG in the operation field. Drained lymphatics were mixed to reduce the concentration of ICG by half that was diluted with DW or NS. We also measured the brightness of fluorescence diluted with DW or NS that was mixed with drained lymphatics. After this screening test, we subdivided the range which brightness was measured as 100 and adjusted the intensity of illumination for more specific results. Results: Highest brightness values were measured as 100 between 2.5μg/mL and 25μg/mL concentration of ICG with DW dilution in screening settings, and the values of brightness were measured as 100 between 2.5μg/mL and 5.0μg/mL concentration of ICG with NS dilution. When drained lymphatics were mixed together, the values of brightness were measured as 100 between 2.5μg/mL and 25μg/mL concentration of ICG with DW or NS dilution. After subdividing the ICG concentration to 2.5μg/mL, 3.13μg/mL, 5.0μg/mL, 6.25μg/mL, 12.5μg/mL and 25μg/mL with adjusting the intensity of illumination, the highest brightness value was measured as 76 in 5.0μg/mL concentration of ICG with DW dilution. When diluting with NS, the highest brightness value was measured as 61 in 5.0μg/mL ICG concentration. After mixing with drained lymphatics, the highest brightness value was both 79 in 5.0μg/mL concentration of ICG with DW and NS dilution. Conclusions: This study showed a practically optimal ICG concentration range in fluorescence guided SLNB. The optimal range of ICG concentration is from 3.13μg/mL to 6.25μg/mL with DW or NS dilution. Although 5.0μg/mL met the best result, adjustment for individual settings may be considered. Citation Format: Paik H-J, Yi HW, Park S, Ryu JM, Nam SJ, Lee JE, Kil WH, Lee SK, Bae SY, Kim SW. Optimal concentration of indocyanine green in near-infrared fluorescence guided sentinel lymph node biopsy in breast cancer. [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 P3-01-03.

Abstract P3-01-08: Sentinel lymph node biopsy alone after neoadjuvant chemotherapy in patients with cytologically proven node-positive breast cancer

Background The purpose of this study was to identify the feasibility and accuracy of sentinel lymph node biopsy (SLNB) after neoadjuvant chemotherapy (NAC) in patients with axillary lymph node (ALN) metastasis at diagnosis. Methods This is a retrospective study of 332 patients who were diagnosed with invasive breast cancer and ALN metastasis and treated with NAC followed by curative surgery at Samsung Medical Center between January 2007 and December 2013. Patients were classified into five groups according to surgical procedure for the ALNs and pathologic results; group 1, patients with negative SLN status and no further dissection was performed; group 2, patients with negative SLN status undergoing further axillary lymph node dissection (ALND); group 3, patients with positive or undetected SLNs undergoing further ALND; group 4, patients without residual axillary metastasis undergoing complete ALND; and group 5, patients with pathologic nodal positive disease undergoing ALND. Results Sentinel lymph nodes identification rate after NAC was 99.1% and false negative rate was 24.1%. The median number of retrieved SLNs was 4 (range, 1–10). There was no difference in the overall survival among the groups (p=0.06). There was no significant difference in the disease-free survival rate between the SLNB only and complete ALN dissection groups who revealed a pathologic complete node response (79.6% versus 80.5%) and the rate of axillary recurrence demonstrated no significant differences among the groups. (p=0.225) There was a statistical difference of recurrence between group 1 versus 2, and group 1 versus 4 in hormone receptor-negative patients. (p=0.027) Conclusion SLNB after NAC in breast cancer patients with initial ALN metastasis may help identify downstaging to negative nodal status and thereby reduce the surgical morbidity by avoiding standard ALN dissection. Citation Format: Park S, Ryu JM, Paik H-J, Yi HW, Bae SY, Lee SK, Kil WH, Kim SW, Lee JE, Nam SJ. Sentinel lymph node biopsy alone after neoadjuvant chemotherapy in patients with cytologically proven node-positive breast cancer. [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 P3-01-08.

Comparison of prognosis and specific features according to tumor size in small-sized breast cancer with extensive lymph node involvement.

81 Background: As known, larger tumor size and more extensive lymph node (LN) involvement have been considered an independent factor for poor prognosis of breast cancer. We evaluated if very small tumor size may be a factor of worse prognosis compared to larger tumor in small sized breast cancer with LN involvement. METHODS A retrospective analysis was made in a single center of all 1400 patients with small (below 2cm, T1) sized and LN involved (N1~N3) breast cancer without metastasis diagnosed between 2004 and 2014. Their ages ranged from 23 to 88 years (mean age 49.1 ± 9.9 years) and mean follow-up was 31 months. All patients were performed with surgery including axillary LN dissection without neo-adjuvant chemotherapy. We subdivided their tumor size to 4 group (T1m, T1a, T1b and T1c) grading by 7th AJCC cancer staging. The number of patients in each group is as follows: T1m = 17, T1a = 63, T1b = 214, T1c = 1106. The specific features related to mortality were analyzed according to the minor groups and they were compared with one another by Chi-square test and Kaplan-Meier analysis. RESULTS Total expired patients were 39 (2.8%) and the number (the rate in each group) of the minor groups is as follows: T1m = 1 (5.9%), T1a = 1 (1.6%), T1b = 7 (3.3%), T1c = 22 (2.0%). Overall survival of smaller sized tumor groups ( ≤ 1cm, T1m+T1a+T1b) are significantly decreased than the other larger sized group T1c in T1N1 staged patients (p = 0.004). There are significant differences in estrogen receptor, progesterone receptor, nuclear grade, recurrence among the 4 minor groups in whole patients group. In the analysis of nuclear grade, the results show higher grade in T1m than T1a, T1m than T1b, T1b than T1c. Especially, recurrence of T1m is significantly more frequent than T1a (17.6% vs 3.2%, P = 0.03) or T1b (17.6% vs 4.2%, p = 0.016). CONCLUSIONS In conclusion, this study indicates smaller sized tumor with LN involvement can progress worse compared to larger tumor. This result supports very small size can be another predictive factor for prognosis in small sized breast cancer with LN involvement.

Abstract P4-11-43: Ki-67 and p53 are useful factors to predict long term survival in low-risk luminal A breast cancer patients

Overexpression of p53 is the most frequent genetic alteration in breast cancer. Recently, many studies have shown that the expression of mutant p53 differs for each subtype of breast cancer and is associated with different prognoses. In this study, we aimed to determine the suitable cut-off value to predict the clinical outcome of p53 overexpression and its usefulness as a prognostic factor in each subtype of breast cancer, especially in luminal A breast cancer. Approval was granted by the Institutional Review Board of Samsung Medical Center. We analyzed a total of 7739 patients who were surgically treated for invasive breast cancer at Samsung Medical Center between Dec 1995 and Apr 2013. Luminal A subtype was defined as ERaPR + and HER2- and was further subclassified according to Ki-67 and p53 expression as follows: luminal A (Ki-67-,p53-), luminal A (Ki-67+, p53-), luminal A (Ki-67 -, p53+) and luminal A (Ki-67+, p53+). Low-risk luminal A subtype was defined as negative for both Ki-67 and p53 (luminal A (ki-67-, p53-)), and others subtypes were considered to be high-risk luminal A breast cancer. A cut-off value of 10% for p53 was a good predictor of clinical outcome in all patients and luminal A breast cancer patients. The prognostic role of p53 overexpression for OS and DFS was only significant in luminal A subtype. The combination of p53 and Ki-67 has been shown to have the best predictive power as calculated by the area under curve (AUC), especially for long-term overall survival. In this study, we have shown that overexpression of p53 and Ki-67 could be used to discriminate low-risk luminal A subtype in breast cancer. Therefore, using the combination of p53 and Ki-67 expression in discriminating low-risk luminal A breast cancer may improve the prognostic power and provide the greatest clinical utility. Citation Format: Ha Woo Yi, Se Kyung Lee, Soo Youn Bae, Jun Ho Lee, Hyun-Chul Lee, Won Ho Kil, Jeong Eon Lee, Seok Won Kim, Seok Jin Nam. Ki-67 and p53 are useful factors to predict long term survival in low-risk luminal A breast cancer patients [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-11-43.