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Background/Aims: Transforming growth factor-beta proteins (TGF-βs) are multifunctional growth factors and powerful modulators of the epithelial-mesenchymal transition (EMT) in a variety of cancer types including breast and lung cancer cells. Here, we demonstrated the inhibitory effect of berberine (BBR) on tumor growth and metastasis of triple negative breast cancer (TNBC) cells via suppression of TGF-β1 expression. Methods: The levels of mRNA expression were analyzed by real-time PCR. The levels of MMP-2, MMP-9 and TGF-β1 protein expression were analyzed by zymography and confocal microscopy, respectively. Cell migration was analyzed by wound healing assay. Tumorigenicity of TNBC cells such as tumor growth and metastasis was analyzed using xenograft models. Results: In a clinical data set, aberrant TGF-β1 expression was associated with poor prognosis of breast cancer patients. Our in vitro results using TNBC cells showed that the expression levels of matrix metalloproteinase (MMP)-2 and MMP-9 and the capacity for cell migration were increased by TGF-β1 treatment. In contrast, basal levels of MMP-2 and MMP-9 were suppressed by a specific TGF-β receptor I inhibitor, SB431542. In addition, TGF-β1–induced MMP-2 and MMP-9 expression and cell migration were decreased by SB431542. Interestingly, we showed for the first time that BBR decreased the level of TGF-β1, but not TGF-β2, in TNBC cells. Furthermore, BBR significantly decreased the level of MMP-2 expression as well as the capacity for cell migration in TNBC cells. Finally, we examined the effect of BBR on in vivo tumor growth and lung metastasis in MDA-MB231 and 4T1 breast cancer xenograft models and showed that both were significantly decreased following BBR treatment. Conclusion: BBR suppresses tumorigenicity of TNBC cells through inhibition of TGF-β1 expression. Therefore, we demonstrate that BBR could be a promising drug for treatment of TNBC.

Objective: Recent trends involving increased screening have led to broad populations being diagnosed with atypical ductal hyperplasia (ADH) or ductal carcinoma in situ (DCIS); as a result, many patients have had to receive surgery followed by standard treatment for ADH or DCIS. The common interest in reducing the use of superfluous invasive treatment has led us to question the necessity of surgical treatment for ADH or DCIS patients in a retrospective review. This work is expected to be a particularly useful reference as there have yet to be any studies describing the outcomes of initial treatment with tamoxifen without curative surgery in Korea.Methods: The clinicopathological characteristics and oncologic outcomes of 36 patients with DCIS or ADH diagnosis who received initial treatment with tamoxifen between 2013 and 2019 were investigated.Results: Among 36 patients enrolled, 30 were diagnosed with DCIS and six were diagnosed with ADH. The median age in the included cohort was 47 years old (range, 26–81 years). There was a change in the follow-up strategy including the need for surgery in 13.9% of cases. The median time to surgery in those patients was 32 months (IQR, 17.5–63.5 months). Only one patient had upgraded to a higher nuclear grade, which was a case of ADH upgrading to intermediate DCIS. Three (8.3%) of 36 patients were upstaged to an invasive disease. Of them, two patients were upstaged to microinvasive ductal carcinoma, whereas one patient was diagnosed with metastatic invasive ductal carcinoma.Conclusion: The use of endocrine therapy without surgery could be a potential treatment strategy in patients with DCIS or ADH. Further validation in larger cohorts and in the context of clinical trials is needed.

Robotic nipple-sparing mastectomy (RNSM) provides better cosmetic outcomes and improves the quality of life of women with breast cancer. However, this has not been widely adapted due to the lack of well-structured training programs. The present study aimed to report the establishment of cadaveric and animal skill laboratory training programs for RNSM and the participants’ perception on the training programs. We performed 24 RNSMs using 11 cadavers and one porcine model. Then, the skill laboratory characteristics were reviewed. Five trainers and 10 trainees participated in the programs. The first four cadaveric RNSMs with latissimus dorsi flaps and implants were performed using the da Vinci Si® system. We performed 14 and six RNSMs using the Xi® and SP® systems, respectively. The scores for questionnaires on the satisfaction with the training consisted of the trainees’ perceived goals in attending the course, teaching/learning environment, and teaching staff performance. The scores were excellent. Cadaveric or porcine RNSM skill laboratory training may be essential programs that can provide safe and efficient training.

Despite effective therapeutic strategies for treating hormone receptor-positive (HR+) breast cancer, resistance to endocrine therapy that is either de novo or acquired still occurs. We investigated epidermal growth factor receptor (EGFR) as a therapeutic target for overcoming endocrine resistance in HR+ breast cancer models.BACKGROUND/AIMSDespite effective therapeutic strategies for treating hormone receptor-positive (HR+) breast cancer, resistance to endocrine therapy that is either de novo or acquired still occurs. We investigated epidermal growth factor receptor (EGFR) as a therapeutic target for overcoming endocrine resistance in HR+ breast cancer models.Using clinical data from 2,166 patients who had HR+ breast tumors and received tamoxifen, we analyzed survival rates. Levels of mRNA and protein expression were analyzed by real-time PCR and western blotting, respectively. Cell viability was analyzed by MTT assays and anchorage-independent growth by soft agar colony-formation assays. Efficacy of tamoxifen and/or gefitinib was analyzed using orthotopic xenograft mouse models.METHODSUsing clinical data from 2,166 patients who had HR+ breast tumors and received tamoxifen, we analyzed survival rates. Levels of mRNA and protein expression were analyzed by real-time PCR and western blotting, respectively. Cell viability was analyzed by MTT assays and anchorage-independent growth by soft agar colony-formation assays. Efficacy of tamoxifen and/or gefitinib was analyzed using orthotopic xenograft mouse models.EGFR expression was significantly associated with more advanced stage and higher grade. EGFR expression was different in luminal A-like (Lum A, 1.3%) versus luminal B-like (Lum B, 11.4%) subtypes. On multivariate analyses for survival Lum B subtype EGFR+ tumors showed a hazard ratio (HR) of 5.22 (95% CI, 1.29-21.15, P = 0.020) for overall survival (OS) and HR of 2.91 (95% CI, 1.35-6.28, P = 0.006) for disease-free survival (DFS). Levels of EGFR inversely correlated with ER-α expression. Basal ER-α level was completely blocked by TGFA or EGF treatment. With TGFA pretreatment, ER+ breast cancer cells were resistant to 4-hydroxytamoxifen (4-OHT). Conversely, downregulation of ER-α by TGFA was reversed by gefitinib with recovered sensitivity to 4-OHT. Tumorigenicity of EGFR and ER+ breast cancer cells were significantly decreased by combined tamoxifen and gefitinib.RESULTSEGFR expression was significantly associated with more advanced stage and higher grade. EGFR expression was different in luminal A-like (Lum A, 1.3%) versus luminal B-like (Lum B, 11.4%) subtypes. On multivariate analyses for survival Lum B subtype EGFR+ tumors showed a hazard ratio (HR) of 5.22 (95% CI, 1.29-21.15, P = 0.020) for overall survival (OS) and HR of 2.91 (95% CI, 1.35-6.28, P = 0.006) for disease-free survival (DFS). Levels of EGFR inversely correlated with ER-α expression. Basal ER-α level was completely blocked by TGFA or EGF treatment. With TGFA pretreatment, ER+ breast cancer cells were resistant to 4-hydroxytamoxifen (4-OHT). Conversely, downregulation of ER-α by TGFA was reversed by gefitinib with recovered sensitivity to 4-OHT. Tumorigenicity of EGFR and ER+ breast cancer cells were significantly decreased by combined tamoxifen and gefitinib.Aberrant EGFR expression was associated with poor prognosis in ER+ breast cancers, especially the Lum B subtype. Loss of ER by EGFR activation induced tamoxifen resistance. Therefore, EGFR could be a therapeutic target for overcoming recurrence of ER+ breast cancer with high EGFR expression.CONCLUSIONAberrant EGFR expression was associated with poor prognosis in ER+ breast cancers, especially the Lum B subtype. Loss of ER by EGFR activation induced tamoxifen resistance. Therefore, EGFR could be a therapeutic target for overcoming recurrence of ER+ breast cancer with high EGFR expression.

Decision to undergo risk-reducing mastectomy (RRM) needs to consider several factors, including patient’s preference, surgeon’s preference, family history, and genetic predisposition. The aim of this study was to examine whether preoperative diagnosis of BRCA1/2 mutation status could influence surgical decision-making in newly diagnosed breast cancer patients. We retrospectively reviewed ipsilateral breast cancer patients with BRCA1/2 mutation who underwent primary surgery between January 2008 and November 2019 at a single institution in Korea. Of 344 eligible patients, 140 (40.7%) patients were aware of their mutation status ‘prior to surgery’, while 204 (59.3%) did not. Contralateral RRM rate was significantly higher in the group with BRCA1/2 mutation status identified ‘prior to surgery’ compared to the group with mutation status identified ‘after surgery’ [45.0% (63/140) vs. 2.0% (4/204)] ( p  < 0.001). Reduced turnaround time of BRCA1/2 testing ( p  < 0.001) and the use of neoadjuvant chemotherapy ( p  < 0.001) were associated with BRCA1/2 mutation status identified prior to surgery. Although not statistically significant, higher incidence of developing contralateral breast cancer for BRCA1/2 mutation carriers who underwent ipsilateral surgery-only compared to those who underwent contralateral RRM was observed [12.1% (95% CI: 7.7–17.7%)] ( p  = 0.1618). Preoperative diagnosis of BRCA1/2 mutation could impact surgical decision-making for breast cancer patients to undergo risk-reducing surgery at the time of initial surgery.

Background Immediate breast reconstruction with tissue expander in breast cancer patients who were expected to receive adjuvant therapy, such as chemotherapy or radiotherapy, has been a topic of debate. Postoperative complications from tissue expander procedures can delay the timing of adjuvant treatment and subsequently increase the probability of recurrence. The purpose of this study was to identify the impact of chemotherapy and radiotherapy on postoperative complications in patients who underwent immediate reconstruction (IR) using tissue expander. Methods We conducted a retrospective study of 1081 breast cancer patients who underwent mastectomy and IR using tissue expander insertion between 2012 and 2017 in Samsung Medical Center. The patients were divided into two groups based on complications (complication group vs. no complication group). Complication group was regarded to have surgical removal or conservative treatment based on clinical findings such as infection, capsular contracture, seroma, hematoma, rupture, malposition, tissue viability, or cosmetic problem. The complication group had 59 patients (5.5%) and the no complication group had 1022 patients (94.5%). Results In univariate analysis, adjuvant radiotherapy and adjuvant chemotherapy were significantly associated with postoperative complications. In multivariate analysis, however, only higher pathologic N stage was significantly associated with postoperative complications ( p  < 0.001). Chemotherapy ( p  = 0.775) or radiotherapy ( p  = 0.825) were not risk factors for postoperative complications. Conclusions IR with tissue expander after mastectomy may be a treatment option even when the patients are expected to receive adjuvant chemotherapy or radiotherapy. These results will aid patients who are concerned about the complications of IR caused by chemotherapy or radiotherapy determine whether or not to have IR. Trial registration Patients were selected and registered retrospectively, and medical records were evaluated.

PurposeTriple-negative breast cancer (TNBC) accounts for 10–20% of all diagnosed BCs and it is enriched in BRCA1 mutation. Guidelines for Western countries suggest that BRCA 1/2 genetic testing should be done for patients with TNBC diagnosed less than 60 years, but there is lack of evidence supporting genetic testing in Asian populations. We determined the prevalence of germline BRCA 1/2 mutations among unselected Korean patients with TNBC and analyzed oncologic outcomes.MethodsFrom among 1628 women with TNBC who underwent surgery at Samsung Medical Center (SMC) between Jul 2008 and Jan 2016, 999 samples were available in the SMC biobank for testing germline BRCA 1/2 mutations using next-generation DNA sequencing.ResultsOverall, 131 Korean patients (13.1%) had BRCA 1/2 mutations: 97 (9.7%) were in BRCA 1, and 35 (3.5%) were in BRCA 2. One patient had both BRCA 1 and BRCA 2 mutations. Overall, 68 distinct pathologic or likely pathogenic variants (43 BRCA1 and 25 BRCA2) were found. Among those diagnosed at ≤ 60 years, the prevalence of BRCA 1/2 mutation was 14.5%. The mean age of diagnosis of BRCA1/2 mutation carriers was significantly younger than that of non-carriers (45.6 vs. 50.1 years, p < 0.0001). The median follow-up duration was 53.6 months. There were no significant differences in disease-free survival, overall survival, or breast cancer-specific survival (p = 0.799, 0.092, and 0.124, respectively) between BRCA 1/2 carriers and non-carriers, although BRCA 1/2 carriers showed significantly worse contralateral breast cancer-free survival (p < 0.0001) than non-carriers.ConclusionIn unselected TNBC patients, we found BRCA 1/2 mutations in 13.1% of overall patients and 14.5% of patients ≤ 60 years. We suggest that Korean women with TNBC diagnosed at ≤ 60 years should be tested for BRCA1/2 mutation.

Background Although several studies have evaluated health-related quality of life (HRQoL) in breast cancer survivors, few have compared HRQoL between breast cancer survivors and an age-matched general population in terms of improvement patterns according to time after surgery. Thus, we compared the postoperative changes in HRQoL in breast cancer survivors with those of age-matched general population groups using the EuroQoL five-dimension three-level questionnaire (EQ-5D-3 L). Methods EQ-5D-3 L questionnaires were obtained from 686 breast cancer survivors during follow-up visits. They were divided into five groups according to time after surgery: 0–5 months, 6–11 months, 12–35 months, 36–59 months, and ≥ 60 months. Their EQ-5D-3 L data, covering five dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression), were compared with those of age-matched general population groups. Results The mean EQ-5D-3 L index of breast cancer survivors was high in group with longer time after surgery and the mean EQ-5D-3 L index of breast cancer group over 5 years after surgery was similar to that of an age-matched general population (0.919 vs 0.928, p  = 0.305). Although there were deficits in all dimensions of breast cancer survivors, motility eventually exceeded that of general population groups and self-care and usual activities of groups over 3 years after surgery matched those of general population however, pain/discomfort and anxiety/depression of survivors over 5 years after surgery remained worse than those of the general population ( p  = 0.028, p  < 0.001). Conclusions Motility, self-care, and usual activities decreased in the early postoperative period for breast cancer survivors but showed recovery after 3 years. However, pain/discomfort and anxiety/depression remained poorer in these patients than in the general population for many years.

Triple-negative breast cancer (TNBC) patients are more likely to have BRCA1/2 mutations, with a prevalence rate of about 10–20%. Although several studies have analyzed the oncologic outcomes between BRCA1/2 carriers and non-carriers, the impact on breast cancer patients is still unclear. A retrospective review was performed to determine the long-term outcomes of TNBC patients, focusing on the impact of BRCA1/2 mutations. A total of 953 TNBC patients who underwent primary breast cancer surgery from June 2008 to January 2016 were included. We examined long-term outcomes, including contralateral breast cancer (CBC) incidence, recurrence patterns, and survival rates over a median follow-up of 80.9 months (range 3–152 months). 122 patients (12.8%) had BRCA1/2 mutations. BRCA1/2 mutation carriers were significantly younger at diagnosis and more likely to have a family history of breast/ovarian cancer. CBC incidence at 60, 120, and 150 months was significantly higher in BRCA1/2 mutation carriers compared to non-carriers ( P  = 0.0250, 0.0063, and 0.0184, respectively). However, there were no significant differences in disease-free survival, overall survival, breast cancer-specific survival, or distant-metastasis-free survival between the two groups. BRCA1/2 mutation status was a significant risk factor for CBC (HR = 6.242, P  < 0.0001). Interestingly, among 29 patients with CBC recurrence, 24 patients (82.8%) had recurring TNBC subtype and among the CBC recurrence patients, 19 patients (65.5%) resumed chemotherapy. In the TNBC subtype, appropriate genetic testing and counseling are pivotal for surgical decisions like risk-reducing mastectomy (RRM). Furthermore, long-term surveillance is warranted, especially in BRCA1/2 carriers who did not receive RRM.

We previously reported that the level of EGFR expression is directly associated with the survival rate of estrogen receptor-positive (ER+) breast cancer patients. Here, we investigated how ER activation by 17β-estradiol (E2), the most potent form of estrogen, affects the expression or activity of EGFR or EGFR-related genes in ER+ breast cancer cells. As expected, E2 enhanced cell proliferation, the induction of S phase, and tumor growth in ER+ breast cancer models. E2 also increased the expression of secretory proteins, including amphiregulin (AREG), angiogenin, artemin, and CXCL16. We focused on AREG, which is a ligand of the epidermal growth factor receptor (EGFR). The levels of AREG expression were positively correlated with ESR1 expression. Our results also showed higher AREG mRNA expression levels in ER+ breast cancer cells than in ER- breast cancer cells. We treated ER+ breast cancer cells with lapatinib to inhibit the AREG/EGFR signaling pathway and then completely inhibited E2-induced cell proliferation and S-phase induction. Similar to the lapatinib treatment, cell proliferation, S-phase induction, cell migration, and tumor growth were suppressed by AREG knockdown. Taken together, we demonstrated that the induction of AREG by E2 contributes to EGFR activation, which then affects cell proliferation and tumor growth. Therefore, we suggest that AREG acts as an intermediary between EGFR and ER and targeting both ERs and EGFRs through combination therapy could prevent tumor progression in EGFR+ ER+ breast cancer patients.