A Survey of Practice Patterns for Clinical Nodal Staging Prior to Neoadjuvant Chemotherapy in Breast Cancer.

BACKGROUND: The importance of clinical staging in breast cancer has increased owing to the wide use of neoadjuvant systemic therapy (NST). This study aimed to investigate the current practice patterns regarding clinical nodal staging in breast cancer in real-world settings. MATERIALS AND METHODS: A web-based survey was administered to board-certified oncologists in Korea, including breast surgical, medical, and radiation oncologists, from January to April 2022. The survey included 19 general questions and 4 case-based questions. RESULTS: In total, 122 oncologists (45 radiation, 44 surgical, and 33 medical oncologists) completed the survey. Among them, 108 (88%) responded that clinical staging before NST was primarily performed by breast surgeons. All the respondents referred to imaging studies during nodal staging. Overall, 64 (52.5%) responders determined the stage strictly based on the radiology reports, whereas 58 (47.5%) made their own decision while noting radiology reports. Of those who made their own decisions, 88% referred to the number or size of the suspicious node. Of the 75 respondents involved in prescribing regimens for neoadjuvant chemotherapy, 58 (77.3%) responded that the reimbursement regulations in the selection of NST regimens affected nodal staging in clinical practice. In the case-based questions, high variability was observed among the clinicians in the same cases. CONCLUSIONS: Diverse assessments by specialists owing to the lack of a clear, harmonized staging system for the clinical nodal staging of breast cancer can lead to diverse practice patterns. Thus, practical, harmonized, and objective methods for clinical nodal staging and for the outcomes of post-NST response are warranted for appropriate treatment decisions and accurate outcome evaluation.

Association of Fat Graft with Breast Cancer Recurrence in Implant-Based Reconstruction: Does the Timing Matter?

PURPOSE: In two-stage prosthetic breast reconstruction, autologous fat graft (AFG) is often conducted simultaneously with the second-stage operation, which is usually performed shortly after mastectomy. There is a paucity of studies evaluating whether conducting AFG early, with a relatively short interval from the primary operation, is oncologically safe. This study aimed to evaluate potential associations of AFG with breast cancer prognosis, focusing on its timing. METHODS: Patients with invasive breast cancer who underwent immediate two-stage prosthetic reconstruction following mastectomy between 2011 and 2016 were identified. They were categorized into two groups by whether AFG was performed during the second-stage operation. Cumulative incidence of oncologic events was compared between the two groups, after stratifying patients by the time interval between mastectomy and the second-stage operation (≤ 12 months vs. > 12 months). RESULTS: Of 267 cases that met the selection criteria, 203 underwent the second-stage operation within 12 months of mastectomy. AFG was performed for 112 cases and was not performed in 91 cases. The two groups showed similar baseline characteristics including tumor stage and adjuvant treatments. Compared with the control, AFG was associated with lower locoregional recurrence-free survival and disease-free survival, and this difference remained significant after adjusting for other variables including tumor stage. In the 64 cases undergoing the operation after 12 months following mastectomy, oncologic outcomes did not differ between the two groups. CONCLUSION: Our results suggest that AFG timing in relation to mastectomy may be associated with risks for breast cancer recurrence.

Surgical margin status and survival outcomes of breast cancer patients treated with breast-conserving surgery and whole-breast irradiation after neoadjuvant chemotherapy.

PURPOSE: The definition of "no tumor on ink" is generally applied for clear resection margin (RM) after breast-conserving surgery (BCS). However, few studies reported the effect of RM in the setting of neoadjuvant chemotherapy (NAC). We investigated the association between RM status and survival outcomes for those who underwent BCS after NAC for breast cancer. METHODS: We retrospectively reviewed the data of 2,803 patients who underwent BCS and whole-breast irradiation after NAC between January 2008 and December 2016 from three institutions in South Korea. RESULTS: The 786 patients in the pathologic complete response group (RpCR) had significantly longer local recurrence-free survival (LRFS) than the 1,949 patients in clear or close RM and non-pCR group (R0) and the 68 patients in involved RM and non-pCR group (R1) (vs. R0, p = 0.001; vs. R1, p = 0.049). Patients in R0 showed no benefit in LRFS compared to R1 on both log-rank test (HR = 1.20; 95% C.I., 0.49-2.93; p = 0.692) and Cox regression analysis (HR = 2.05; 95% C.I., 0.64-6.58; p = 0.227). Subgroup analysis according to tumor subtypes revealed that there was no significant difference in LRFS, distant metastasis-free survival, and recurrence-free survival between the R0 and R1 group. Additionally, among 286 patients with pCR with residual ductal carcinoma in situ (DCIS) alone, RM status was not significantly associated with LRFS. CONCLUSION: Clear RM of specimen does not have benefit on LRFS after NAC. Additionally, for the patients showing pCR with residual DCIS in the breast, margin involvement also did not affect the risk of local recurrence.

Immediate breast reconstruction has no impact on the oncologic outcomes of patients treated with post-mastectomy radiation therapy: a comparative analysis based on propensity score matching.

PURPOSE: To investigate the impact of immediate breast reconstruction (iBR) on patients treated with post-mastectomy radiation therapy (PMRT) using propensity score matching (PSM). METHODS: After a retrospective review of patients treated with PMRT between 2008 and 2017, we included 153 patients who underwent iBR and 872 patients who did not undergo iBR. Among the 153 patients who underwent iBR, 34 received one-stage iBR with autologous tissue and 119 received two-stage iBR. Conventional fractionated PMRT with a total dose of 50-50.4 Gy in 25-28 fractions was performed in all patients. Propensity scores were calculated via logistic regression. RESULTS: Patients who underwent iBR were younger, had early stage disease, and had more frequent hormone receptor-positive tumor than those who did not undergo iBR. After PSM, 127 patients from each group with well-balanced characteristics were selected. With a median follow-up of 67.5 months, iBR led to better 6-year disease-free survival rates compared to no iBR before PSM (84.8% vs. 71.4%, p = 0.003); after PSM, there was no significant difference (84.8% vs. 75.5%, p = 0.130). On multivariable analysis in the matched cohort, iBR was not associated with inferior disease-free survival (hazard ratio, 0.67; p = 0.175). In the sensitivity analysis, iBR was not associated with a lower disease-free survival across all prognostic groups. The 5-year cumulative incidence of iBR failure was 15.0%. CONCLUSION: In patients with adverse pathologic factors planning to receive PMRT, iBR did not compromise oncologic outcomes. In addition, iBR can be considered in patients treated with PMRT with several clinicopathologic risk factors.

Divorce after breast cancer diagnosis and its impact on quality of life.

OBJECTIVE: This study aims to identify factors associated with divorce following breast cancer diagnosis and measures the impact of divorce on the quality of life (QoL) of patients. METHODS: We used cross-sectional survey data collected at breast cancer outpatient clinics in South Korea from November 2018 to April 2019. Adult breast cancer survivors who completed active treatment without any cancer recurrence at the time of the survey (N = 4,366) were included. The participants were classified into two groups: "maintaining marriage" and "being divorced," between at the survey and at the cancer diagnosis. We performed logistic regression and linear regression to identify the factors associated with divorce after cancer diagnosis and to compare the QoL of divorced and nondivorced survivors. RESULTS: Approximately 11.1/1,000 of married breast cancer survivors experienced divorce after cancer diagnosis. Younger age, lower education, and being employed at diagnosis were associated with divorce. Being divorced survivors had significantly lower QoL (Coefficient [Coef] = -7.50; 95% CI = -13.63, -1.36), social functioning (Coef = -9.47; 95% CI = -16.36, -2.57), and body image (Coef = -8.34; 95% CI = -6.29, -0.39) than survivors who remained married. They also experienced more symptoms including pain, insomnia, financial difficulties, and distress due to hair loss. CONCLUSION: Identifying risk factors of divorce will ultimately help ascertain the resources necessary for early intervention.

Does chemotherapy or radiotherapy affect the postoperative complication in breast cancer patients who underwent immediate breast reconstruction with tissue expander?

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.

Hormone Resistance.

Hormone therapy is a major therapy for hormone receptor-positive breast cancer that improves survival. However, despite these hormone treatments, there are de novo or acquired resistance of breast cancer. Many studies revealed these resistance mechanisms, which are related to hormonal receptors including low expression or mutation of estrogen receptor alpha(ERα), co-factors and progesterone receptor, and with activation of growth signaling pathways such as PIK3A/Akt/mTOR pathway or cell cycle pathway. To overcome endocrine resistance based on these mechanisms, there have been many efforts in clinical studies of new agents which are representative of steroidal selective estrogen receptor down-regulator, cyclin-dependent kinase (CDK) 4/6 inhibitors, inhibitors of the PI3K/AKT/mTOR Pathway and histone deacetylase (HDAC) Inhibitors. Our studies at LBCB focused the endocrine resistance in young age and showed that age under 35 years is poor prognostic factor on not only single-center data but also Korean Breast Cancer Registry Data and that women with hormone receptor-positive breast cancer who were younger than 35 years of age had less response to anti-hormonal therapy. Also, a study for gene expression in hormone receptor-positive breast cancer at a very young age (<35) revealed that expression of cell cycle-related genes increased higher than that of premenopausal women in their forties. There have been a lot of studies and clinical trials to investigate the mechanisms of resistance to endocrine treatment and to overcome them with new drugs. However, many still do not know the precise mechanism of recurrence of breast cancer after endocrine treatment. In particular, the identification of the mechanism of endocrine resistance in young women, and the combination of drugs and clinical trials to overcome this require much effort.

Changes in Korean National Healthcare Insurance Policy and Breast Cancer Surgery Trend in Korea.

BACKGROUND: Since April 2015, the Korean National Health Insurance (NHI) has reimbursed breast cancer patients, approximately 50% of the cost of the breast reconstruction (BR) procedure. We aimed to investigate NHI reimbursement policy influence on the rate of immediate BR (IBR) following total mastectomy (TM). METHODS: We retrospectively analyzed breast cancer data between April 2011 and June 2016. We divided patients who underwent IBR following TM for primary breast cancer into "uninsured" and "insured" groups using their NHI statuses at the time of surgery. Univariate analyses determined the insurance influence on the decision to undergo IBR. RESULTS: Of 2,897 breast cancer patients, fewer uninsured patients (n = 625) underwent IBR compared with those insured (n = 325) (30.0% vs. 39.8%, P < 0.001). Uninsured patients were younger than those insured (median age [range], 43 [38-48] vs. 45 [40-50] years; P < 0.001). Pathologic breast cancer stage did not differ between the groups (P = 0.383). More insured patients underwent neoadjuvant chemotherapy (P = 0.011), adjuvant radiotherapy (P < 0.001), and IBR with tissue expander insertion (P = 0.005) compared with those uninsured. CONCLUSION: IBR rate in patients undergoing TM increased after NHI reimbursement.

Breast cancer screening disparities between women with and without disabilities: A national database study in South Korea.

BACKGROUND: Health disparities among individuals with disabilities remain underrecognized. The objective of the current study was to investigate: 1) whether disparities exist in breast cancer screening rates among women with disabilities compared with women without disabilities; 2) whether breast cancer screening rates vary according to the type and severity of disabilities; and 3) trends in breast cancer screening disparities according to disability status over time. METHODS: Using national administrative databases concerning disability status and national cancer screening programs in Korea, age-standardized participation rates were calculated according to the type and severity of disabilities. RESULTS: The age-standardized rate for breast cancer screening in individuals with disabilities increased from 30.2% in 2006 to 53.7% in 2015 (change of +23.5%), whereas that among those without a disability increased from 29.3% to 60.1% (change of +30.8%). In general, disability was associated with slightly lower breast cancer screening rates (adjusted odds ratio [aOR], 0.824; 95% CI, 0.820-0.828). However, screening rates were especially low in women with severe disabilities (aOR, 0.465; 95% CI, 0.461-0.469) and among women with autism (aOR, 0.235; 95% CI, 0.143-0.388), renal failure (aOR, 0.342; 95% CI, 0.337-0.348), brain injury (aOR, 0.349; 95% CI, 0.346-0.352), intellectual disabilities (aOR, 0.403; 95% CI, 0.397-0.410), mental disorders (aOR, 0.494; 95% CI, 0.488-0.501), or ostomies (aOR, 0.529; 95% CI, 0.512-0.546). CONCLUSIONS: Even without a cost barrier, significant disparities were found in breast cancer screening participation, especially in women with severe disabilities and brain-related and/or mental disabilities. Policy efforts, such as ensuring the accessibility of information and equipment, transportation support, and access to a usual source of care, should be made to decrease this disparity.

Prognosis of BRCA1/2-negative breast cancer patients with HBOC risk factors compared with sporadic breast cancer patients without HBOC risk factors.

OBJECTIVE: Demands for genetic counseling with BRCA1/2 examination have markedly increased. Accordingly, the incidence of uninformative results on BRCA1/2 mutation status has also increased. Because most patients examined for BRCA1/2 mutation have a high risk of hereditary breast and/or ovarian cancer, many patients suffer psychological distress even when the BRCA1/2 result is negative. We compared oncological outcomes between BRCA1/2-negative breast cancer with high risk of hereditary breast and/or ovarian cancer and sporadic breast cancer without risk of hereditary breast and/or ovarian cancer. METHODS: The criteria for high risk for hereditary breast and/or ovarian cancer were defined as family history of breast and/or ovarian cancer in first- or second-degree relative, early onset breast cancer at <35 years old and bilateral breast cancer. Patients were matched maximally 1:3 into those who identified as negative for BRCA1/2 mutation with risk of hereditary breast and/or ovarian cancer (study group) and those who were not examined for BRCA1/2 mutation without risk for hereditary breast and/or ovarian cancer (control group). Matched variables were pathologic stage, estrogen receptor, progesterone receptor and human epidermal growth factor receptor-2 status. RESULTS: All matching variables were successfully matched. Median follow-up duration was 57.8 months. There was no significant difference between the groups in disease-free survival (log-rank P = 0.197); however, the study group showed significantly better overall survival and breast cancer-specific survival (both P < 0.0001). We conducted subgroup analysis in the middle-aged group (36-54) and showed no significant difference for disease-free survival (P = 0.072) but significantly better overall survival and breast cancer-specific survival in the study group (P = 0.002 and P < 0.0001). CONCLUSIONS: BRCA1/2-negative breast cancer patients who had hereditary breast and/or ovarian cancer risk factors showed similar disease-free survival and better overall survival and breast cancer-specific survival compared with those with sporadic breast cancer without hereditary breast and/or ovarian cancer risk factors.

Correction to: ECM1 regulates cell proliferation and trastuzumab resistance through activation of EGF-signaling.

After the publication of this work [1] errors were found in Figs. 1a and 5d.

EGFR is a Therapeutic Target in Hormone Receptor-Positive Breast Cancer.

BACKGROUND/AIMS: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Prediction of axillary pathologic response with breast pathologic complete response after neoadjuvant chemotherapy.

PURPOSE: Many breast cancer patients receive sentinel lymph node biopsy after neoadjuvant chemotherapy (NAC). We evaluated the axillary pathologic complete response (pCR) in relation to achievement of breast pCR. METHODS: We evaluated 1044 patients who were diagnosed with invasive breast cancer and were treated with NAC followed by curative surgery at the Samsung Medical Center between January 2008 and December 2016. The pathologic node-positive rates in breast pCR patients were compared for different breast cancer subtypes and clinical nodal stages. RESULTS: Axillary pCR was achieved in 51.9% of the patients after NAC. In this case, the axillary pCR was associated with a biologic subtype (P < 0.0001), initial clinical tumor stage (P < 0.0001), clinical nodal stage (P = 0.0071), and breast pCR (P < 0.0001). In particular, axillary pCR correlated more than 80% with breast pCR (87.1%) or clinical nodal stage N0 (81.0%). Patients with breast pCR had 96.4% axillary pCR in clinical nodal stage N0, 86.1% in N1, and 84.7% in N2/N3. CONCLUSION: Our study may help to predict node-positive rates in patients with breast pCR after NAC according to clinical node stage. Patients with a high probability of achieving pCR might be suitable candidates for more minimal surgery.

A nomogram to predict pathologic complete response (pCR) and the value of tumor-infiltrating lymphocytes (TILs) for prediction of response to neoadjuvant chemotherapy (NAC) in breast cancer patients.

PURPOSE: The value of tumor-infiltrating lymphocytes (TILs) for prediction of pathologic complete response (pCR) in breast cancer (BC) patients treated with neoadjuvant chemotherapy (NAC) has received increasing attention. In human epidermal growth factor receptor 2 (HER2)-positive BC, advances in HER2-targeted therapy have not yet clarified the clinical implications of pre-NAC TILs. Likewise, the prognostic role of TILs for long-term survival is not well established. METHODS: Pre- and post-NAC TIL levels were evaluated in 248 pair-matched pre-NAC biopsy and post-NAC resection samples, and analyzed for predictive and prognostic significance with other clinicopathologic parameters. Additional 60 pre-NAC biopsy samples of HER2-positive BC treated with a TCHP regimen (docetaxel, carboplatin, and a combination of trastuzumab and pertuzumab) were also assessed. RESULTS: High pre-NAC TILs, clinical nodal stage 0-1 (cN0-1), and negative ER expression were shown to be strong predictive markers for pCR. A nomogram based on these significant clinicopathologic predictors was developed, providing integrated probability of achieving pCR after NAC. The association between high pre-NAC TIL levels and significantly increased pCR rate was also confirmed in HER2-positive BC patients treated with a TCHP regimen. After chemotherapy, increased quantity of post-NAC TILs was shown to have extended BC-specific survival and disease-free survival in univariable and multivariable analyses. CONCLUSIONS: High pre-NAC TIL levels were significantly predictive of pCR in BC, and can act as a surrogate marker for predicting therapeutic effects of a TCHP regimen for HER2-positive BC. Post-NAC TILs in residual disease were a new prognostic marker of risk stratification for long-term survival.

Prevalence and oncologic outcomes of BRCA 1/2 mutations in unselected triple-negative breast cancer patients in Korea.

PURPOSE: Triple-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. METHODS: From 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. RESULTS: Overall, 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. CONCLUSION: In 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.

Is the high proportion of young age at breast cancer onset a unique feature of Asian breast cancer?

PURPOSE: Women with breast cancer in Asian and Western countries are similar in many respects, but there are also differences, such as in the age at onset and the proportion of breast cancer occurring at younger ages. There is controversy as to whether these differences are due to inter-racial genetic differences or to environmental or other factors. METHODS: Using the Korean Breast Cancer Society's large breast cancer registry, we investigated the causes of Koreans' unique breast cancer characteristics by examining the changes in the incidence and proportion of young-onset breast cancer (YBC) in Korea over time. We analyzed data from 108,894 patients to compare characteristics between patients with YBC and non-YBC. For a subtype analysis, we analyzed data from 85,691 patients from 2000. RESULTS: Among the 108,894 patients, 17,877 (15.5%) had YBC. The tumors associated with YBC showed aggressive clinicopathologic features. The incidence of breast cancer in Korea has increased over time, and while both YBC and non-YBC increased each year, the increase in non-YBC was more pronounced; thus, the proportion of YBC has decreased over time. By 2020, it appears that the ratio of YBC in Korea will be similar to that in Western countries. The increase in YBC was mainly due to an increase in the luminal A subtype. The incidence of other YBC subtypes did not change over time. CONCLUSIONS: Our data suggest that the current high proportion of YBC is probably not a unique feature of breast cancer in Asia but rather a transient phenomenon. Additionally, our results indirectly suggest that there were different causes for breast cancer in different age groups, suggesting the importance of using different approaches for different age groups to establish policies for preventing breast cancer.

Berberine Suppresses Cell Motility Through Downregulation of TGF-ß1 in Triple Negative Breast Cancer Cells.

BACKGROUND/AIMS: Transforming growth factor-beta proteins (TGF-ßs) 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-ß1 expression. METHODS: The levels of mRNA expression were analyzed by real-time PCR. The levels of MMP-2, MMP-9 and TGF-ß1 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-ß1 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-ß1 treatment. In contrast, basal levels of MMP-2 and MMP-9 were suppressed by a specific TGF-ß receptor I inhibitor, SB431542. In addition, TGF-ß1-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-ß1, but not TGF-ß2, 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-ß1 expression. Therefore, we demonstrate that BBR could be a promising drug for treatment of TNBC.

Only estrogen receptor "positive" is not enough to predict the prognosis of breast cancer.

PURPOSE: Beginning in 2018, biomarkers including estrogen receptor (ER) status were incorporated in the 8th AJCC staging system. ER expression levels were not considered in these changes. We hypothesized that the levels of ER expression could affect the prognosis of breast cancer. METHODS: A retrospective review was conducted to identify all female patients with invasive breast cancer between 2003 and 2012. ER negative (group I), weakly ER-positive (group II), and strongly ER-positive (group III) were defined as Allred total scores of 0-2, 3-5, and 6-8, respectively. We examined a multigene panel, designated the BCT score, which is a newly developed prognostic model for predicting the risk of a distant metastasis. RESULTS: Among the 4949 patients enrolled in this study, 1310 (26.5%), 361 (7.3%), and 3277 (66.2%) were categorized as group I, II, and III, respectively. Median F/U duration was 57.8 months. Compared to group III, patients in group II were younger, had larger tumors, and were also more likely to have PR-negative tumors, HER-2 amplification, high Ki-67, and high nuclear grade. Between group II and III, there was a significant difference in OS (P = 0.0764, 0.909, and 0.010, respectively). After adjusting for additional factors that may affect OS, the HR for OS showed higher in group II than in group III. The baseline median BCT score indicated that lower ER expression was associated with significantly higher BCT score (P < 0.0001) and significantly more likely to have high risk group (P < 0.0001) relative to higher levels of ER expression group. CONCLUSION: ER expression levels affect the prognosis of breast cancer. The risk for patients with weakly ER-positive breast cancer should not be underestimated.

Uneven recovery patterns of compromised health-related quality of life (EQ-5D-3 L) domains for breast Cancer survivors: a comparative study.

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.