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.
Breast cancer is a prevalent malignancy with increasing incidence, particularly in Asian countries. Classification based on estrogen receptor (ER), progesterone receptor (PR), and human epidermal ...growth factor receptor 2 (HER2) status is pivotal in determining treatment. Recent advances have challenged the traditional dichotomy in HER2 classification, prompting investigation into the HER2-low subtype’s characteristics and outcomes. This retrospective study analyzed 10,186 non-metastatic hormone receptor (HR)-positive, HER2-negative breast cancer cases treated from 2008 to 2020. Data encompassed clinical, pathological, and treatment information. Oncologic outcomes included disease-free survival (DFS), overall survival (OS), and breast cancer-specific survival (BCSS). In total, 56.5% were HER2-low cases. Differences in patient characteristics were noted, with more BRCA1/2 mutations and higher mastectomy rates in the HER2-low group (p = 0.002, p < 0.001, respectively). Fewer received adjuvant chemotherapy or radiation therapy, and fewer histologic and nuclear grade 1 tumors were identified (all p < 0.001). With a median follow-up of 64 months (range: 13–174), HER2-low cases exhibited better DFS, OS, and BCSS than HER2-0 cases (p = 0.012, p = 0.013, and p = 0.013, respectively). Notably, the prognosis differed between premenopausal and postmenopausal subgroups, with BCSS benefitting premenopausal patients (p = 0.047) and DFS and OS benefitting postmenopausal patients in the HER2-low group (p = 0.004, p = 0.009, respectively). Multivariate analysis confirmed HER2 status as an independent predictor of these outcomes (p = 0.010, p = 0.008, and p = 0.014, respectively). This extensive single-center study elucidates the favorable prognosis associated with HER2-low status in HR-positive breast cancer. However, this effect differs among premenopausal and postmenopausal patients, necessitating further research into the underlying tumor biology.
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. 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. 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. 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.
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.
Background:
It is important to identify factors predicting successful ovarian protection using gonadotropin-releasing hormone (GnRH) agonists during chemotherapy. However, only a few studies have ...prospectively assessed this issue in young breast cancer patients.
Objective:
This study evaluated the predictive factors for successful ovarian protection with GnRH agonists during chemotherapy in young estrogen receptor-negative breast cancer patients.
Materials and Methods:
This prospective study analyzed 67 estrogen receptor-negative breast cancer patients ≤40 years of age who were longitudinally assessed after receiving GnRH agonists during cyclophosphamide-based chemotherapy for ovarian protection. Associations between clinical characteristics or pretreatment hormones and successful ovarian protection resumption of menstruation and anti-Müllerian hormone (AMH) ≥1 ng/ml.
Results:
The mean age and pretreatment serum level of AMH were 33.2 years and 4.57 ng/ml, respectively. At 12 months after the completion of chemotherapy, most women (97%) experienced the resumption of menstruation. However, the proportion of patients with AMH ≥1 ng/ml at 12 months was 70.1%. In multivariate analyses, only the pretreatment serum AMH level (
P
< 0.001) was predictive for AMH ≥1 ng/ml at 12 months. Receiver operating characteristic curve analyses of pretreatment AMH exhibited an area under the curve of 0.866 (95% CI = 0.777–0.955) for AMH ≥1 ng/ml at 12 months. The cutoff value for the prediction of AMH concentration ≥1 ng/ml at 12 months was 2.87 ng/ml of pretreatment AMH with a sensitivity of 0.87 and a specificity of 0.75.
Conclusions:
Pretreatment AMH (2.87 ng/ml) is a useful predictor for AMH ≥1 ng/ml at 12 months after receiving GnRH agonists in young estrogen receptor-negative breast cancer patients. This finding can help improve decision-making regarding fertility preservation.
Several prognosis prediction models have been developed for breast cancer (BC) patients with curative surgery, but there is still an unmet need to precisely determine BC prognosis for individual BC ...patients in real time. This is a retrospectively collected data analysis from adjuvant BC registry at Samsung Medical Center between January 2000 and December 2016. The initial data set contained 325 clinical data elements: baseline characteristics with demographics, clinical and pathologic information, and follow-up clinical information including laboratory and imaging data during surveillance. Weibull Time To Event Recurrent Neural Network (WTTE-RNN) by Martinsson was implemented for machine learning. We searched for the optimal window size as time-stamped inputs. To develop the prediction model, data from 13,117 patients were split into training (60%), validation (20%), and test (20%) sets. The median follow-up duration was 4.7 years and the median number of visits was 8.4. We identified 32 features related to BC recurrence and considered them in further analyses. Performance at a point of statistics was calculated using Harrell's C-index and area under the curve (AUC) at each 2-, 5-, and 7-year points. After 200 training epochs with a batch size of 100, the C-index reached 0.92 for the training data set and 0.89 for the validation and test data sets. The AUC values were 0.90 at 2-year point, 0.91 at 5-year point, and 0.91 at 7-year point. The deep learning-based final model outperformed three other machine learning-based models. In terms of pathologic characteristics, the median absolute error (MAE) and weighted mean absolute error (wMAE) showed great results of as little as 3.5%. This BC prognosis model to determine the probability of BC recurrence in real time was developed using information from the time of BC diagnosis and the follow-up period in RNN machine learning model.
The relationships between serum levels of trace elements and breast cancer remain relatively unknown. In this study, we investigate serum levels of seven trace elements in Korean breast cancer ...patients compared to controls without breast cancer. Serum trace element levels were determined using inductively coupled plasma mass spectrometry in Korean breast cancer patients before initiation of breast cancer treatment. Korean females without breast cancer served as a control group. Trace element levels were measured in the discovery cohort (
= 287) and were validated in an independent cohort (
= 142). We further investigated possible associations between trace element levels and the presence of lymph node metastasis, distant metastasis, or triple-negative breast cancer among breast cancer patients in subgroup analyses. Serum manganese and molybdenum levels were significantly higher (
< 0.05) in breast cancer patients than in controls. Serum copper levels were significantly higher in breast cancer patients with distant metastasis, while selenium levels were significantly lower. Other trace elements were neither significantly different between breast cancer patients and controls nor between subgroups of breast cancer patients. Our study provides insights about the potential roles and impacts of trace elements through an assessment of the associations between trace elements and breast cancer.
TNBC is noted for its aggressive behavior and poor prognosis. Recently developed HER2 target agents have shown potential benefit even in HER2-low expressing breast cancers. This study retrospectively ...analyzed 2542 non-metastatic TNBC patients from 2008 to 2020, revealing that 26.0% were HER2-low. Data on demographics, tumor characteristics, pathologic complete response (pCR) rates and disease-free survival (DFS), distant metastasis-free survival (DMFS), overall survival (OS), and breast cancer-specific survival (BCSS) were analyzed. The HER2-low group, compared to the HER2-0 group, showed significantly better DFS, DMFS, OS, BCSS (p = 0.0072, p = 0.0096, p = 0.0180, and p = 0.0001, respectively) with older age and higher rates of postmenopausal status (p < 0.0001). No significant differences in pCR rates were observed. Multivariate analyses identified HER2 status as a significant prognostic factor for DFS (p = 0.048), DMFS (p = 0.018), OS (p = 0.049), and BCSS (p = 0.008). Subgroup analysis revealed that these effects varied with menopausal status, showing more pronounced benefits in postmenopausal women. Our findings suggest that HER2-low TNBC patients exhibit a distinct clinical profile and improved survival compared to HER2-0 TNBC patients, especially in postmenopausal patients. Further research on estrogen and HER2 interaction is needed.
Abstract
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.
This study aimed to evaluate the role of post-mastectomy radiotherapy (PMRT) in T1-2N1 breast cancer. Between 2006 and 2014, a total of 504 patients with T1-2N1 breast cancer were analyzed. PMRT was ...administered to 71 patients, and 1:2 propensity score matching (PSM) was performed between the PMRT and non-PMRT groups. Loco-regional control (LRC), disease-free survival (DFS), and overall survival (OS) rates were compared according to PMRT status. Thirteen and one loco-regional recurrences were observed in the PMRT and non-PMRT groups, respectively. Before PSM, the 8-year LRC, DFS, and OS rates in the non-PMRT and PMRT groups were 98.5% and 96.5% (p = 0.426), 89.7% and 91.2% (p = 0.700), and 91.5% and 92.1% (p = 0.679), respectively. Corresponding rates were 95.6% and 96.5% (p = 0.365), 84.1% and 91.2% (p = 0.185), and 88.4% and 92.1% (p = 0.276), respectively, after PSM. Multivariate analysis showed that three lymph node metastases were prognostic for LRC and DFS rates and LVI for OS rate. Arm lymphedema developed in 32.4% of patients who received PMRT, which was significantly higher than the non-PMRT group (p < 0.001). Contributions of PMRT for improvement of treatments outcomes in T1-2N1 breast cancer patients were not evident, while the incidence of arm lymphedema significantly increased after PMRT. Further prospective trials are required to re-evaluate the role of PMRT.
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