Safety and Effectiveness of Trastuzumab Biosimilar SB3 in Korean Patients, a Post-Marketing Surveillance Study.

INTRODUCTION: SB3 is a trastuzumab biosimilar approved in Australia, Brazil, Canada, the European Union, the Republic of Korea, Switzerland, and the United States. This real-world study evaluated safety and effectiveness of SB3 as part of the Korean post approval safety management system. METHODS: This post-marketing surveillance in Korea included patients in line with approved indications, i.e. patients with early or metastatic breast cancer or metastatic gastric cancer. Safety outcomes were adverse events and adverse drug reactions. Effectiveness outcomes were tumor response and event-free survival. RESULTS: 424 patients were evaluated: 366 patients (86%) with early breast cancer, 53 patients (13%) with metastatic breast cancer, and 5 patients (1%) with metastatic gastric cancer. Among patients with breast cancer, adverse events (mostly mild) and adverse drug reactions were reported by 158 (37.7%) and 57 (13.6%) patients, respectively. Most patients with an AE (141, 75.9%) had no change in treatment schedule. Treatment was temporarily suspended in 14 (8.2%) patients with an AE and completely discontinued in 7 (3.7%). Among patients with early and metastatic breast cancer who were evaluated for efficacy, objective response rates were 82.7% and 38.3%, respectively. Pathological complete response was 64.6% in patients with early breast cancer. DISCUSSION/CONCLUSION: Safety and efficacy of SB3 demonstrated in this real-world study were comparable with previous studies of reference trastuzumab.

Characteristics and chronologically changing patterns of late-onset breast cancer in Korean women of age ≥ 70 years: A hospital based-registry study.

BACKGROUND: Women from Asian and western countries have vastly different ages of onset of breast cancer, with the disease tending to occur at an older age in the West. Through an investigation of the patterns of old-onset breast cancer (OBC) in Korean women, we aimed to identify the characteristics of Korean OBC and evaluate whether these patterns are changing in relation to increasing westernization. METHODS: This study retrospectively evaluated 102,379 patients who underwent surgical treatment of primary breast cancer between January 1, 2000 and December 31, 2013 in Korea. We used hospital -based breast cancer registry and analyzed data from these patients using multiple linear regression analysis to compare the characteristics and chronologically changing patterns between OBC (70 years of age or older) and non-OBC (40-69 years of age) patients in Korea. RESULTS: A total of 6% of the 102,379 patients had OBC. Overall, OBC had more favorable biological features, such as a higher incidence of luminal A subtype, than did non-OBC, except for a higher incidence rate of triple-negative breast cancer (TNBC). However, OBC also presented with a higher overall disease stage, including higher T and M stages. Although the incidence rates of both OBC and non-OBC have increased overtime, the relative proportion of OBC patients has slightly increased, whereas that of non-OBC has slightly decreased. The increase in the incidence of both OBC and non-OBC was primarily due to the luminal A subtype. CONCLUSIONS: Based on a hospital-based registry, overall, Korean OBC had favorable biological features but showed a higher rate of TNBC and advanced cancer stages. The incidence trend of breast cancer in Korea is slowly shifting toward an older age at onset, largely due to the luminal A subtype. Our results may provide novel insights into OBC in Asia, and aid in the development of optimal management of the disease in Asia. TRIAL REGISTRATION: Retrospectively registered.

Risk factors for level V metastasis in patients with N1b papillary thyroid cancer.

BACKGROUND: Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer, and its incidence has increased. Lateral lymph node metastasis (LLNM) implies a worse prognosis than central lymph node metastasis, with a higher recurrence rate and decreased disease-free survival. The 2015 American Thyroid Association guidelines recommend compartmental node dissection in patients with LLNM to reduce the risk of recurrence and mortality. The purpose of this study was to identify the risk factors for level V lymph node (LN) metastasis in patients with N1b papillary thyroid cancer (PTC). METHODS: A total of 110 consecutive patients who underwent total thyroidectomy with lateral neck dissection for PTC between April 2016 and April 2022 were retrospectively enrolled. Based on level V metastasis, 94 patients were divided into two groups, and their clinicopathological characteristics were compared. Univariable analysis were used to assess the factors associated with level V metastasis. Spearman correlation analysis were used to assess the correlation between tumors and LN. The receiver operating characteristic (ROC) curve was used to determine the optimal cutoff value for the number of metastatic LNs at each level for level V metastasis. RESULTS: The number of metastatic LNs and lymph node ratio (LNR) in level II were significantly associated with level V metastasis (P = 0.011 and 0.001, respectively). The number of metastatic LNs in level II and those in the total number of levels correlated with the number of metastatic LNs in level V (rho = 0.331, 0.325, and P = 0.001, 0.001, respectively). The cutoff value for the number of metastatic LNs in level II was defined as 2.5 (area under the curve = 0.757, sensitivity = 50%, specificity = 82.5%, 95% confidence interval [CI] 0.626-0.889, P = 0.002). Simultaneous 3-level metastasis (level II, III, and IV) and 3-level with ≥ 2.5 metastatic LNs in level II were significantly associated with level V metastasis (P = 0.003 and 0.002). CONCLUSIONS: The number of metastatic LNs and LNR in level II, simultaneous 3-level metastasis (level II, III, and IV), and 3-level with ≥ 2.5 metastatic LNs in level II were significantly associated with level V metastasis. (P = 0.011, 0.001, 0.003, and 0.002, respectively). In the future, larger-scale multi-institutional studies were needed to find out predictors for level V metastasis.

Clinical impact of radioactive iodine dose selection based on the number of metastatic lymph nodes in patients with papillary thyroid carcinoma: A multicenter retrospective cohort study.

OBJECTIVE: The aim of this study is to investigate whether the number of metastatic lymph nodes (LNs) could be used as a basis in the radioactive iodine (RAI) dose selection for patients with papillary thyroid carcinoma (PTC). PATIENTS: A total of 595 patients with PTC who received first RAI therapy after total or near-total thyroidectomy and had no evidence of disease in treatment response assessment were retrospectively enroled from five hospitals. The patients were classified into two subgroups based on the number of metastatic LNs (>5). The multivariate Cox-proportional hazard model was performed to identify the significant factors for recurrence prediction in each group as well as all enroled patients. RESULTS: Overall, 22 (3.7%) out of 595 patients had the recurrent disease during the follow-up period. The number of metastatic LNs (>5) was only a significant factor for recurrence prediction in all enroled patients (odds ratio: 7.834, p < .001). In the subgroup with ≤5 metastatic LNs, the presence of extrathyroidal extension was only associated with recurrence (odds ratio: 7.333, p = .024) in multivariate analysis. RAI dose was significantly associated with recurrence rate in which the patients with high-dose RAI (3.7 GBq or higher) had less incidence of recurrence than those with low-dose RAI (1.11 GBq) in the subgroup with more than five metastatic LNs (odds ratio: 6.533, p = .026). CONCLUSIONS: High-dose RAI (≥3.7 GBq) therapy significantly lowered the recurrence rate in patients with more than five metastatic LNs. Therefore, RAI dose should be determined based on the number of metastatic LNs as well as conventional risk factors.

Prospective, Randomized, Comparative, Multicenter Study of the Hybrid Ultrasonic Advanced Bipolar Device and the Ultrasonic Coagulating Shears in Open Thyroidectomy.

Background. The hybrid ultrasonic advanced bipolar device (HUB) that integrates ultrasonic energy and advanced bipolar energy was recently developed and applied to thyroid surgery. The purpose of this study was to compare the efficacy and safety of HUB and ultrasonic coagulating shears for open thyroidectomy. Methods. A total of 200 patients were enrolled from April to September 2017 in this prospective, randomized, multicenter study. Patients were randomly assigned to an ultrasonic group (n = 101) or a hybrid group (n = 99). Results. Operation times were similar in the 2 study groups, that is, 54.2 ± 25.2 minutes in the ultrasonic group and 50.2 ± 21.6 minutes in the hybrid group. Postoperative surgical results and morbidities were no different in the 2 groups. However, the total amount of bleeding was significantly less in the hybrid group (13.0 ± 17.7 mg vs 8.6 ± 11.5 mg; P = .042). Conclusions. Our study showed that there was no significant difference between the 2 groups in postoperative surgical results and morbidity. The total bleeding amount was significantly less in the hybrid group. The study shows that HUB is comparable to the ultrasonic coagulating shears in terms of efficacy and safety during thyroid surgery.

Construction of an engineered biocatalyst system for the production of medium-chain α,ω-dicarboxylic acids from medium-chain ω-hydroxycarboxylic acids.

Medium-chain α,ω-dicarboxylic acids produced from renewable long-chain fatty acids are valuable as precursors in the chemical industry. However, they are difficult to produce biologically at high concentrations. Although improved biocatalyst systems consisting of engineering of Baeyer-Villiger monooxygenases are used in the production of ω-hydroxycarboxylic acids from long-chain fatty acids, the engineering of biocatalysts involved in the production of α,ω-dicarboxylic acids from ω-hydroxycarboxylic acids has been rarely attempted. Here, we used highly active bacterial enzymes, Micrococcus luteus alcohol dehydrogenase and Archangium violaceum aldehyde dehydrogenase, for the efficient production of α,ω-dicarboxylic acids from ω-hydroxycarboxylic acids and constructed a biocatalyst with cofactor regeneration system by introducing NAD(P)H flavin oxidoreductase as the NAD(P)H oxidase. The inhibition of the biocatalyst by hydrophobic substrates was attenuated by engineering a biocatalyst system with an adsorbent resin, which allowed us to obtain 196 mM decanedioic, 145 mM undecanedioic, and 114 mM dodecanedioic acid from 200 mM of C10, C11, and C12 hydroxyl saturated carboxylic acids, respectively, and 141 mM undecanedioic acid from 150 mM C11 unsaturated carboxylic acids, with molar conversions of 98%, 97%, 95%, and 94%, respectively. The concentration of undecanedioic acid obtained was approximately 40-fold higher than that in the previously highest results. Our results from this study can be applied for the industrial production of medium-chain α,ω-dicarboxylic acids from renewable long-chain fatty acids.

Correlation between 5-α reductase type 2 protein expression and methylation of 5-α reductase type 2 promotor gene of benign prostatic hyperplasia.

PURPOSE: The enzyme 5-α reductase type 2 (5-AR 2) plays a key role in the development and maintenance of the prostate gland. We evaluated the level 5-AR 2 protein expression and the relationship between methylation of the 5-AR 2 gene-promoter and 5-AR 2 protein expression of benign prostatic hyperplasia (BPH). MATERIALS AND METHODS: A total of 37 prostate samples were evaluated. These included 22 samples from men undergoing transurethral prostate resections and 15 non-cancerous transition-zone human prostate tissue samples taken following radical prostatectomy. We quantified 5-AR 2 protein expression and gene-promoter methylation status using common assay procedures. Clinical variables included age, body mass index (BMI), prostate-specific antigen (PSA) levels, lipid profiles, and prostate volumes. Univariate and multivariate statistical analyses were performed followed by stepwise logistic regression modeling. RESULTS: We were able to extract DNA from 36 of the 37 tissue samples and 10 of these (28%) did not express the 5-AR 2 protein. In total, 26 patients (72%) had methylated 5-AR 2 promoter-regions. There was a strong correlation between methylation of the 5-AR 2 promoter-regions and low-absent 5-AR 2 protein expression (p = 0.0003). Increasing age significantly predicted methylation status and protein expression level (p = 0.013). CONCLUSIONS: The level of 5-AR 2 protein expression varies among prostate tissue samples. Methylation of the 5-AR 2 gene-promoter may account for low or absent expression of 5-AR 2 in adult human prostate tissues. Increased age correlates with increased 5-AR 2 gene-promoter methylation and decreased protein expression in men with BPH.

Enzymatic Biotransformation of Balloon Flower Root Saponins into Bioactive Platycodin D by Deglucosylation with Caldicellulosiruptor bescii ß-Glucosidase.

Platycodin D (PD), a major saponin (platycoside) in Platycodi radix (balloon flower root), has higher pharmacological activity than the other major platycosides; however, its content in the plant root is only approximately 10% (w/w) and the productivities of PD by several enzymes are still too low for industrial applications. To rapidly increase the total PD content, the ß-glucosidase from Caldicellulosiruptor bescii was used for the deglucosylation of the PD precursors platycoside E (PE) and platycodin D3 (PD3) in the root extract into PD. Under the optimized reaction conditions, the enzyme completely converted the PD precursors into PD with the highest productivity reported so far, increasing the total PD content to 48% (w/w). In the biotransformation process, the platycosides in Platycodi radix were hydrolyzed by four pathways: deapiosylated (deapi)-PE → deapi-PD3 → deapi-PD, PE → PD3 → PD, polygalacin D3 → polygalacin D, and 3″-O-acetyl polygalacin D3 → 3″-O-acetyl polygalacin D.

Prognostic Value of Tumor-Infiltrating Lymphocyte Density Assessed Using a Standardized Method Based on Molecular Subtypes and Adjuvant Chemotherapy in Invasive Breast Cancer.

BACKGROUND: This study investigated the prognostic value of tumor-infiltrating lymphocyte (TIL) density as determined by molecular subtype and receipt of adjuvant chemotherapy in invasive breast cancer (IBC). METHODS: Stromal TIL densities were evaluated in 1489 IBC samples using recommendations proposed by the International TILs Working Group. Cases were allocated to high- and low-TIL density groups using a cutoff of 10%. RESULTS: Of the 1489 IBC patients, 427 (28.7%) were assigned to the high-TIL group and 1062 (71.3%) to the low-TIL group. High TIL density was found to be significantly associated with large tumor size (p = 0.001), high histologic grade (p < 0.001), and high Ki-67 labeling index (p < 0.001). Triple-negative and human epidermal growth factor receptor 2 (HER2)-positive subtypes had significantly higher TIL densities than luminal A or B (HER2-negative) subtypes (p < 0.001). High TIL density was significantly associated with prolonged disease-free survival (DFS) by univariate (p < 0.001) and multivariate (p < 0.001) analyses. In the low-TIL-density group, the patients who did not receive adjuvant chemotherapy showed better DFS (p < 0.001), but no such survival difference was observed in the high-TIL group (p = 0.222). For the patients who received adjuvant anthracycline, high-TIL density was found to be an independent prognostic factor of favorable DFS in the luminal B (HER2-negative; p = 0.003), HER2-positive (p = 0.019), and triple-negative (p = 0.017) subtypes. CONCLUSION: Measurements of TIL density in routine clinical practice could give useful prognostic information for the triple-negative, HER2-positive, and luminal B (HER2-negative) IBC subtypes, especially for patients administered adjuvant anthracycline.

Characterization of L-rhamnose isomerase from Clostridium stercorarium and its application to the production of D-allose from D-allulose (D-psicose).

OBJECTIVE: To characterize L-rhamnose isomerase (L-RI) from the thermophilic bacterium Clostridium stercorarium and apply it to produce D-allose from D-allulose. RESULTS: A recombinant L-RI from C. stercorarium exhibited the highest specific activity and catalytic efficiency (k cat/K m) for L-rhamnose among the reported L-RIs. The L-RI was applied to the high-level production of D-allose from D-allulose. The isomerization activity for D-allulose was maximal at pH 7, 75 °C, and 1 mM Mn2+ over 10 min reaction time. The half-lives of the L-RI at 65, 70, 75, and 80 °C were 22.8, 9.5, 1.9, and 0.2 h, respectively. To ensure full stability during 2.5 h incubation, the optimal temperature was set at 70 °C. Under the optimized conditions of pH 7, 70 °C, 1 mM Mn2+, 27 U L-RI l-1, and 600 g D-allulose l-1, L-RI from C. stercorarium produced 199 g D-allose l-1 without by-products over 2.5 h, with a conversion yield of 33% and a productivity of 79.6 g l-1 h-1. CONCLUSION: To the best of our knowledge, this is the highest concentration and productivity of D-allose reported thus far.

Prognostic significance of CD9 expression differs between tumour cells and stromal immune cells, and depends on the molecular subtype of the invasive breast carcinoma.

AIMS: CD9, a tetraspanin transmembrane protein, modulates cell motility, migration, and proliferation. The aim of this study was to investigate the prognostic significance of CD9 expression in patients with invasive breast carcinoma (IBC). METHODS AND RESULTS: CD9 expression was evaluated in tissue microarrays of 1349 IBC samples via immunohistochemistry. CD9 expression in tumour cells (T-CD9 expression) and CD9 expression in stromal immune cells (S-CD9 expression) were analysed separately. T-CD9 expression was observed in 732 (54.3%) cases, and was associated with lymph node metastasis, histological type, lymphovascular invasion, high histological grade, HER2 positivity, a high Ki67 labelling index, and distant metastasis. S-CD9 expression was observed in 833 (61.7%) cases, and was associated with large tumour size, histological type, high histological grade, negative hormone receptors, HER2 positivity, a high Ki67 labelling index, and tumour-infiltrating lymphocytes. Patients with T-CD9 expression had shorter disease-free survival (DFS) than those without T-CD9 expression in the univariate and multivariate analyses. However, S-CD9 expression correlated significantly with a favourable DFS in the univariate and multivariate analyses. In the subgroup analysis, T-CD9 expression and S-CD9 expression were independent markers for DFS in luminal A and luminal B (HER2-negative) subgroups, respectively. CONCLUSIONS: T-CD9 expression could be a biomarker for poor prognosis in luminal A IBC, whereas S-CD9 expression could be a marker of good prognosis in luminal B (HER2-negative) IBC. Therefore, tumour compartment-specific analyses considering molecular subtypes are necessary to study the prognostic significance of CD9 expression in IBC.

RGS2 suppresses breast cancer cell growth via a MCPIP1-dependent pathway.

Regulator of G protein signaling 2 (RGS2) is a member of a family of proteins that functions as a GTPase-activating protein (GAP) for Gα subunits. RGS2 mRNA expression is lower in breast cancerous tissues than in normal tissues. In addition, expression of RGS2 is also lower in MCF7 (cancerous breast cells) than in MCF10A (normal breast cells). Here we investigated whether RGS2 inhibits growth of breast cancer cells. RGS2 overexpression in MCF7 cells inhibited epidermal growth factor- or serum-induced proliferation. In HEK293T cells expressing RGS2, cell growth was also significantly suppressed (In addition, exogenous expression of RGS2 in HEK293T cells resulted in the significant suppression of cell growth). These results suggest that RGS2 may have a tumor suppressor function. MG-132 treatment of MCF7 cells increased endogenous or exogenous RGS2 levels, suggesting a post-transcriptional regulatory mechanism that controls RGS2 protein levels. RGS2 protein was degraded polyubiquitinated the K71 residue, but stabilized by deubiquitinase monocyte chemotactic protein-induced protein 1 (MCPIP1), and not affected by dominant negative mutant (C157A) of MCPIP1. Gene expression profiling study showed that overexpression of RGS2 decreased levels of testis specific Y encoded like protein 5 (TSPYL5), which plays a causal role in breast oncogenesis. TSPYL5 protein expression was low in MCF10A and high in MCF7 cells, showing the opposite aspect to RGS2 expression. Additionally, RGS2 or MCPIP1 overexpression in MCF7 cells decreased TSPYL5 protein level, indicating that RGS2 stabilized by MCPIP1 have diminished TSPYL5 protein levels, thereby exerting an inhibitory effect of breast cancer cell growth.

Androgen receptor expression predicts decreased survival in early stage triple-negative breast cancer.

BACKGROUND: A subset of triple-negative breast cancer (TNBC) has been reported to express androgen receptor (AR); however, the clinical significance of AR expression in TNBC is unclear. METHODS: We examined immunohistochemical expression of AR in a large cohort of TNBC cases and correlated its expression with clinicopathologic features and clinical outcome. RESULTS: AR expression was found in 17.7% (87/492) of TNBCs. Positive expression of AR showed significant correlation with older age (p < 0.001), apocrine histology (p = 0.001), and lower histologic grade (p < 0.001). AR was a poor prognostic marker for overall survival (OS) in univariate (p = 0.026) and multivariate (p = 0.008) analyses. In the lymph node-negative (n = 316) subgroup, AR expression was a significant predictor of worse OS and disease-free survival (DFS) in both univariate (p = 0.028 and 0.011) and multivariate (p = 0.024 and 0.01, respectively) analyses. AR expression also was a prognostic factor in pT1 subgroup (OS, p = 0.007; DFS, p = 0.01); however, its prognostic value was not observed in TNBC patients with lymph node metastasis or tumor size larger than pT1. CONCLUSIONS: AR-expressing TNBCs represent a distinct breast cancer subgroup with adverse clinical outcome and AR blockade could be a potential endocrine therapy for these TNBC patients. Evaluation of AR status may provide additional information on prognosis and treatment in patients with TNBC.

Relationship between body mass index and the expression of hormone receptors or human epidermal growth factor receptor 2 with respect to breast cancer survival.

BACKGROUND: The association between body mass index (BMI) at the time of breast cancer diagnosis and the prognosis of breast cancer patients remains controversial. Furthermore, the association between BMI and prognosis with respect to different breast cancer subtypes is not clearly defined. METHODS: We analyzed data from 41,021 invasive breast cancer patients between January 1988 and February 2008 from the Korean Breast Cancer Registry (KBCR) database. Overall survival (OS) and breast cancer-specific survival (BCSS) were analyzed using the Kaplan-Meier method and Cox's proportional hazard regression model among all patients and specific breast cancer subtypes with respect to BMI categories. RESULTS: A U-shaped association between BMI and mortality was observed in the total cohort. Underweight and obese individuals exhibited worse OS (hazard ratio, 1.23 [95 % confidence interval {CI}, 1.05 to 1.44] and 1.29 [1.13 to 1.48], respectively) and BCSS (1.26 [1.03 to 1.54] and 1.21 [1.02 to 1.43], respectively) than normal-weight individuals. In the estrogen receptor (ER) and/or progesterone receptor (PR)+/human epidermal growth factor receptor 2 (HER2) - subgroup, obese individuals exhibited worse OS (1.48 [1.18 to 1.85]) and BCSS (1.31 [1.13 to 1.52]) than normal-weight individuals. Conversely, in the ER and PR-/HER2+ subgroup, underweight individuals exhibited worse OS (1.68 [1.12 to 2.47]) and BCSS (1.79 [1.11 to 2.90]) than normal-weight individuals. CONCLUSIONS: We observed a U-shaped relationship between BMI at diagnosis and poor OS and BCSS among all breast cancer patients. However, obesity in the ER and/or PR+/HER2- subgroup and underweight in the ER and PR-/HER2+ subgroup were poor prognostic factors. Therefore, BMI at diagnosis and breast cancer subtype should be considered simultaneously in various treatment decision processes and surveillance schedules.

Neuroendocrine differentiation correlates with hormone receptor expression and decreased survival in patients with invasive breast carcinoma.

AIMS: Invasive breast carcinoma (IBC) with neuroendocrine (NE) differentiation has been controversial in terms of its definition and clinical outcome. We investigated the incidence and clinical significance of NE differentiation in patients with IBC. METHODS AND RESULTS: We performed immunohistochemistry for NE markers, chromogranin-A and synaptophysin on 1428 IBC samples using tissue microarrays and classified cases with NE differentiation into two groups, focal (1-49% tumour cells positive for any NE marker) and diffuse (≥50% tumour cells positive) groups. Fifty-nine cases (4.1%) showed NE differentiation immunohistochemically, and the majority did not show typical NE morphology. The presence of NE differentiation showed a significant association with positive oestrogen receptor (P = 0.001) and progesterone receptor (P = 0.008) status. Patients with NE differentiation showed worse overall survival (OS) and disease-free survival (DFS) than those without NE differentiation in both univariate (P < 0.001 for both) and multivariate (OS, P = 0.004; DFS, P < 0.001) analyses. CONCLUSIONS: IBC with NE differentiation is a distinct subtype of mammary carcinoma with an aggressive clinical outcome.

Prognostic significance of Bcl-2 expression in non-basal triple-negative breast cancer patients treated with anthracycline-based chemotherapy.

B cell lymphoma/leukemia-2 (Bcl-2) expression has generally been associated with estrogen receptor positivity and favorable prognosis in breast cancer. We examined immunohistochemical expression of Bcl-2 in 492 triple-negative breast cancers (TNBCs) using tissue microarrays and investigated its correlation with clinicopathologic features and clinical outcome. A total of 47 (9.5 %) TNBCs showed Bcl-2 expression. Bcl-2 expression was not associated with any of the clinicopathologic parameters and did not affect patient survival in TNBCs (Bcl-2-positive vs Bcl-2-negative TNBCs; overall survival (OS), P = 0.258; disease-free survival (DFS), P = 0.436). When TNBCs were divided into basal (cytokeratin 5/6 (CK5/6)+ and/or epidermal growth factor receptor (EGFR)+) and non-basal (CK5/6- and EGFR-) subgroups, Bcl-2 expression showed a significant association with worse OS (P = 0.002) and DFS (P = 0.002) in the non-basal subgroup. Among patients treated with an anthracycline, Bcl-2 expression also showed an association with decreased survival (OS, P = 0.004; DFS, P = 0.003) in the non-basal subgroup. In multivariate analyses, Bcl-2 expression was an independent poor prognostic factor for OS (P = 0.003) and DFS (P = 0.002) in this subgroup of TNBCs. Our results suggest that positive expression of Bcl-2 predicts no benefit from adjuvant anthracycline-based chemotherapy in non-basal TNBC patients. In conclusion, Bcl-2 status showed both prognostic and predictive values in non-basal TNBCs; therefore, assessment of Bcl-2 status and basal phenotype can provide information on prognostic and therapeutic classifications of TNBCs.

Breast density reduction as a predictor for prognosis in premenopausal women with estrogen receptor-positive breast cancer: an exploratory analysis of the updated ASTRRA study.

BACKGROUND: While the relationship between mammographic breast density reduction (MDR) and endocrine therapy efficacy has been reported in estrogen receptor (ER)-positive breast cancer, it is still unclear in premenopausal women, especially in the case of adding ovarian function suppression (OFS) to antihormone therapy. The authors investigated the impact of MDR on prognosis stratified by treatment based on the updated results of the ASTRRA trial. MATERIALS AND METHODS: The ASTRRA trial, a randomized phase III study, showed that adding OFS to tamoxifen (TAM) improved survival in premenopausal women with estrogen receptor-positive breast cancer after chemotherapy. The authors updated survival outcomes and assessed mammography before treatment and the annual follow-up mammography for up to 5 years after treatment initiation. Mammographic density (MD) was classified into four categories based on the Breast Imaging-Reporting and Data System. MDR-positivity was defined as a downgrade in MD grade on follow-up mammography up to 2 years after randomization, with pretreatment MD grade as a reference. RESULTS: The authors evaluated MDR in 944 of the 1282 patients from the trial, and 813 (86.2%) had grade III or IV MD. There was no difference in the MDR-positivity rate between the two treatment groups [TAM-only group (106/476 (22.3%)) vs. TAM+OFS group (89/468 (19.0%)); P =0.217). MDR-positivity was significantly associated with better disease-free survival (DFS) in the TAM+OFS group (estimated 8-year DFS: 93.1% in MDR-positive vs. 82.0% in MDR-negative patients; HR: 0.37; 95% CI: 0.16-0.85; P =0.019), but not in the TAM-only group ( Pinteraction =0.039). MDR-positive patients who received TAM+OFS had a favorable DFS compared to MDR-negative patients who received only TAM (HR: 0.30; 95% CI: 0.13-0.70; P =0.005). CONCLUSION: Although the proportion of MDR-positive patients was comparable between both treatment groups, MDR-positivity was independently associated with favorable outcomes only in the TAM+OFS group.

Prediction of Oncotype DX Recurrence Score Using Clinicopathological Variables in Estrogen Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative Breast Cancer.

PURPOSE: Oncotype DX (ODX) is a well-validated multigene assay that is increasingly used in Korean clinical practice. This study aimed to develop a clinicopathological prediction (CPP) model for the ODX recurrence scores (RSs). METHODS: A total of 297 patients (study group, n = 175; external validation group, n = 122) with estrogen receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative, T1-3N0-1M0 breast cancer, and available ODX test results were included in the study. Risk categorization as determined by ODX RSs concurred with the TAILORx study (low-risk, RS ≤ 25; high-risk, RS > 25). Univariate and multivariate logistic regression analyses were used to assess the relationships between clinicopathological variables and risk stratified by the ODX RSs. A CPP model was constructed based on regression coefficients (ß values) for clinicopathological variables significant by multivariate regression analysis. RESULTS: Progesterone receptor (PR) negativity, high Ki-67 index, and nuclear grade (NG) 3 independently predicted high-risk RS, and these variables were used to construct the CPP model. The C-index, which represented the discriminatory ability of our CPP model for predicting a high-risk RS, was 0.915 (95% confidence interval [CI], 0.859-0.971). When the CPP model was applied to the external validation group, the C-index was 0.926 (95% CI, 0.873-0.978). CONCLUSION: Our CPP model based on PR, Ki-67 index, and NG could aid in the selection of patients with breast cancer requiring an ODX test.

Impacts of Subtype on Clinical Feature and Outcome of Male Breast Cancer: Multicenter Study in Korea (KCSG BR16-09).

PURPOSE: The treatment of male breast cancer (MBC) has been extrapolated from female breast cancer (FBC) because of its rarity despite their different clinicopathologic characteristics. We aimed to investigate the distribution of intrinsic subtypes based on immunohistochemistry, their clinical impact, and treatment pattern in clinical practice through a multicenter study in Korea. MATERIALS AND METHODS: We retrospectively analyzed clinical data of 248 MBC patients from 18 institutions across the country from January 1995 to July 2016. RESULTS: The median age of MBC patients was 63 years (range, 25 to 102 years). Among 148 intrinsic subtype classified patients, 61 (41.2%), 44 (29.7%), 29 (19.5%), and 14 (9.5%) were luminal A, luminal B, human epidermal growth factor receptor 2, and triple-negative breast cancer, respectively. Luminal A subtype showed trends for superior survival compared to other subtypes. Most hormone receptor-positive patients (166 patients, 82.6%) received adjuvant endocrine treatment. Five-year completion of adjuvant endocrine treatment was associated with superior disease-free survival (DFS) in patients classified with an intrinsic subtype (hazard ratio [HR], 0.15; 95% confidence interval [CI], 0.04 to 0.49; p=0.002) and in all patients (HR, 0.16; 95% CI, 0.05 to 0.54; p=0.003). CONCLUSION: Distribution of subtypes of MBC was similar to FBC and luminal type A was most common. Overall survival tended to be improved for luminal A subtype, although there was no statistical significance. Completion of adjuvant endocrine treatment was associated with prolonged DFS in intrinsic subtype classified patients. MBC patients tended to receive less treatment. MBC patients should receive standard treatment according to guidelines as FBC patients.

Adding Ovarian Suppression to Tamoxifen for Premenopausal Women With Hormone Receptor-Positive Breast Cancer After Chemotherapy: An 8-Year Follow-Up of the ASTRRA Trial.

PURPOSE: To determine the updated long-term outcomes of the Addition of Ovarian Suppression to Tamoxifen in Young Women With Hormone-Sensitive Breast Cancer Who Remain Premenopausal or Regain Vaginal Bleeding After Chemotherapy (ASTRRA) trial. PATIENTS AND METHODS: This study is a post-trial follow-up of the ASTRRA trial, involving 1,483 premenopausal women younger than 45 years treated with definitive surgery after completing adjuvant or neoadjuvant chemotherapy for estrogen receptor-positive breast cancer. Patients were randomly assigned in a 1:1 ratio to complete 5 years of tamoxifen (TAM) alone (TAM-only) or 5 years of TAM with ovarian function suppression (OFS) for 2 years (TAM + OFS). The primary end point was disease-free survival (DFS), and the secondary end point was overall survival (OS). RESULTS: At 106.4 months of median follow-up, there was a continuous significant reduction in the DFS event rate in the TAM + OFS group. The 8-year DFS rate was 85.4% in the TAM + OFS group and 80.2% in the TAM-only group (hazard ratio [HR], 0.67; 95% CI, 0.51 to 0.87). There were no significant differences in OS between the two groups. The OS rate was 96.5% in the TAM + OFS group and 95.3% in the TAM-only group (HR, 0.78; 95% CI, 0.49 to 1.25). CONCLUSION: Adding OFS for 2 years to adjuvant TAM with a longer follow-up resulted in consistent DFS benefits, suggesting that adding OFS to TAM should be considered for patients who remain in a premenopausal state or resume ovarian function after chemotherapy.