Whole-Brain Radiotherapy Alone vs Preceded by Bevacizumab, Etoposide, and Cisplatin for Untreated Brain Metastases From Breast Cancer: A Randomized Clinical Trial.

Importance: The incidence of brain metastasis is increasing in patients with metastatic breast cancer. Treatments to extend the control of brain metastasis are urgently required. Objective: To investigate whether the addition of an induction treatment of bevacizumab, etoposide, and cisplatin (BEEP) improves brain-specific progression-free survival (PFS) after whole-brain radiotherapy (WBRT). Design, Setting, and Participants: This open-label, randomized, multicenter clinical trial assessed patients with brain metastases from breast cancer (BMBC) in Taiwan from September 9, 2014, to December 24, 2018, with survival follow-up until December 31, 2021. Key inclusion criteria included metastatic brain tumors not suitable for focal treatment, WBRT naivety, age 20 to 75 years, and at least 1 measurable brain metastatic lesion. The primary end point was brain-specific PFS, with an expected hazard ratio of 0.60, a 2-sided α ≤ .20, and power of 0.8. Interventions: Eligible patients were randomly assigned at a ratio of 2:1 to the experimental arm, which involved 3 cycles of BEEP followed by WBRT, or the control arm, which involved WBRT alone. Main Outcomes and Measures: The primary end point was the determination of brain-specific PFS by local investigators according to the Response Evaluation Criteria in Solid Tumors, version 1.1, the initiation of other brain-directed treatment after WBRT, or death. Other key end points included brain-specific objective response rate after 8 weeks of BEEP treatment or WBRT and 8-month brain-specific PFS rate, PFS, and overall survival. Results: A total of 118 patients with BMBC were randomized, with the intention-to-treat cohort comprising 112 patients. The median age was 56 years (range, 34-71 years), and 61 patients (54.5%) had ERBB2 (formerly HER2 or HER2/neu)-positive disease. The median (range) brain-specific PFS was 8.1 (0.3-29.5) vs 6.5 (0.9-25.5) months in the experimental and control arms, respectively (hazard ratio, 0.71; 95% CI, 0.44-1.13; P = .15; significant at predefined α ≤ .20). The brain-specific objective response rate at 2 months was not significantly different (BEEP treatment vs WBRT, 41.9% vs 52.6%), but the 8-month brain-specific PFS rate was significantly higher in the experimental group (48.7% vs 26.3%; P = .03). Adverse events were generally manageable with prophylactic granulocyte colony-stimulating factor treatment. Conclusions and Relevance: The findings show that induction BEEP before WBRT may improve the control of BMBC compared with using upfront WBRT, which could address an unmet need for an effective systemic treatment for intractable brain and extracranial metastases from metastatic breast cancer. Trial Registration: ClinicalTrials.gov Identifier: NCT02185352.

The influence of chronic renal insufficiency on multi-therapeutic modalities for breast cancer: a single-center experience.

BACKGROUND: Due to the presence of other comorbidities and multi-therapeutic modalities in breast cancer, renally cleared chemotherapeutic regimens may cause nephrotoxicity. The aim of this retrospective study is to compare the chemotherapy types and outcomes in breast cancer patients with or without chronic renal disease. PATIENTS AND METHODS: We retrospectively enrolled 62 female patients with breast cancer and underlying late stages (stage 3b, 4, and 5) of chronic kidney disease (CKD) treated from 2000 to 2017. They were propensity score-matched 1:1 with patients in our database with breast cancer and normal renal function (total n = 124). RESULTS: The main subtype of breast cancer was luminal A and relatively few patients with renal impairment received chemotherapy and anti-Her-2 treatment. The breast cancer patients with late-stage CKD had a slightly higher recurrent rate, especially at the locally advanced stage. The 5-year overall survival was 90.1 and 71.2% for patients without and with late-stage CKD, but the breast cancer-related mortality rate was 88.9 and 24.1%, respectively. In multivariate analyses, dose-reduced chemotherapy was an independent negative predictor of 5-year recurrence-free survival and late-stage CKD was associated with lower 5-year overall survival rate. CONCLUSIONS: Breast cancer patients with late-stage CKD may receive insufficient therapeutic modalities. Although the recurrence-free survival rate did not differ significantly by the status of CKD, patients with breast cancer and late-stage CKD had shorter overall survival time but a lower breast cancer-related mortality rate, indicated that the mortality was related to underlying disease.

Factors Associated with Axillary Lymph Node Status in Clinically Node-Negative Breast Cancer Patients Undergoing Neoadjuvant Chemotherapy.

Adequate axillary lymph node (ALN) staging is critical for patients with invasive breast cancer. However, neoadjuvant chemotherapy (NAC) was associated with a lower risk of ALN metastasis compared with those who underwent primary surgery among clinically node-negative (cN0) patients. This study aimed to investigate the factors associated with ALN status among patients with cN0 breast cancer undergoing NAC. A total of 222 consecutive patients with cN0 breast cancer undergoing NAC between January 2012 and December 2021 were reviewed. Univariate and multivariate analyses were performed to compare factors associated with positive ALN status. Seventeen patients (7.7%) had ALNs metastases. Here, 90 patients (40.5%) achieved pathologic complete response in the breast (breast-pCR), and all had negative ALN status. Lymphovascular invasion (odds ratio: 29.366, p < 0.0001) was an independent risk predictor of ALN metastasis in all study populations. Among patients without breast-pCR, mastectomies were performed more frequently in patients with ALN metastasis (52.9%) than in those without metastasis (20.9%) (p = 0.013). Our findings support the omission of axillary surgery in patients who achieve breast-pCR. Prospective studies are needed to confirm the feasibility of a future two-stage surgical plan for breast-conserving surgery in patients who are likely to achieve breast-pCR during clinical evaluation.

Breast cancer larger than 2.5 cm with tumor-free radioisotope-hot sentinel nodes has higher risk of non-hot axillary lymph node metastasis.

BACKGROUND: Sentinel lymph node biopsy (SLNB) is the standard axillary staging approach for early breast cancer with clinically negative axillary involvement. Adequate SLNB should include the removal of not only radioactive tracer-labeled lymph nodes (hot nodes or SLNs) but also suspicious unlabeled nodes (non-hot nodes or non-SLNs). However, the biopsy of non-hot nodes is highly dependent on the surgeons' experiences. This article aims to facilitate the surgeon's decision making by elucidating parameters that correlate with non-hot node metastasis. METHODS: From 2013 to 2016, clinically node-negative (cN0) breast cancer patients receiving axillary SLNB using single Tc-99m tracer method at our institute were recruited. Patients were excluded if they had received prior neoadjuvant chemotherapy. Among them, cases that have at least one non-isotope-hot node biopsied were retrospectively reviewed with a particular focus on patients with pathologically negative isotope-hot SLNs. The correlation of clinicopathological data with metastasis to axillary lymph nodes and sentinel lymph nodes was analyzed with the Chi-squared test, Fisher's exact test, and multivariate logistic regression. Receiver operating curve (ROC) was applied for continuous variables that predicted non-hot node metastasis; relapse-free survival (RFS) and locoregional relapse-free survival (LRRFS) were compared by Kaplan-Meier analysis. RESULTS: In 632 isotope-hot SLN negative patients, T stage showed a correlation with non-isotope-hot SLN metastasis (p = 0.035, odds ratio (OR) 9.65). Tumors larger than 2.5 cm best predict non-isotope-hot SLN metastasis (area under curve (AUC) = 0.71). With a median follow up of 41.80 months, locoregional relapse-free survival was significantly worse in cases with non-hot node metastasis (66.2% vs. 69.0%, p = 0.001). CONCLUSION: In the setting of SLNB using single radioisotope tracer, non-hot node metastasis in cases with negative hot SLN still carries a higher locoregional recurrence rate (13.3%). For early breast cancer larger than 2.5 cm, removal of suspicious non-hot nodes should be included for a precision therapy.

Discrepancy of Breast and Axillary Pathologic Complete Response and Outcomes in Different Subtypes of Node-positive Breast Cancer after Neoadjuvant Chemotherapy.

Few studies have analyzed the discrepancy between breast pathologic complete response (B-pCR) and axillary node pCR (N-pCR) rates and their impact on survival outcomes in different intrinsic subtypes of early breast cancer after neoadjuvant chemotherapy (NAC). We retrospectively reviewed B-pCR, N-pCR, and total (breast and axillary node) pCR (T-pCR) after NAC to assess the discrepancy and outcomes between 2005 and 2017. A total of 968 patients diagnosed with cT1-4c, N1-2, and M0 breast cancer were enrolled in the study. The median age was 49 years and the median follow-up time was 45 months. Of these patients, 213 achieved T-pCR, 31 achieved B-pCR with axillary node pathologic non-complete response (N-non pCR), 245 achieved N-pCR with breast pathologic non-complete response (B-non pCR), and 479 achieved total (breast and axillary node) pathologic non-complete response (T-non pCR) after NAC. The highest B-pCR and N-pCR rates were found in the hormone receptor-negative, human epidermal growth factor receptor 2-positive HR(-)HER2(+) subtype, while the lowest B-pCR rate was found in the HR(+)HER2(-) subtype. The N-pCR rate was correlated to the B-pCR rate (P<0.001), but was higher than the B-pCR rate in all subtypes. The 5-year overall survival (OS) rates for patients with T-pCR, B-pCR, and N-pCR were 91.2%, 91.7%, and 91.9%, respectively. For non-pCR, non-pCR, and non-pCR, the 5-year OS rates were 73.6%, 78.9%, and 74.7%, respectively (P<0.0001). B-non pCR patients had a lower risk of recurrence than T-non pCR or N-non-pCR patients, although there were no differences in OS among them. In conclusion, the N-pCR rate was higher than the B-pCR rate after NAC in all intrinsic subtypes, and N-non pCR or T-non pCR patients had the worst outcomes.

Factors affecting locoregional recurrence in breast cancer patients undergoing surgery following neoadjuvant treatment.

BACKGROUND: Neoadjuvant chemotherapy (NAC) has been the standard treatment for locally advanced breast cancer for the purpose of downstaging or for conversion from mastectomy to breast conservation surgery (BCS). Locoregional recurrence (LRR) rate is still high after NAC. The aim of this study was to determine predictive factors for LRR in breast cancer patients in association with the operation types after NAC. METHODS: Between 2005 and 2017, 1047 breast cancer patients underwent BCS or mastectomy after NAC in Chang Gung Memorial Hospital, Linkou. We obtained data regarding patient and tumor characteristics, chemotherapy regimens, clinical tumor response, tumor subtypes and pathological complete response (pCR), type of surgery, and recurrence. RESULTS: The median follow-up time was 59.2 months (range 3.13-186.75 months). The mean initial tumor size was 4.89 cm (SD ± 2.95 cm). Of the 1047 NAC patients, 232 (22.2%) achieved pCR. The BCS and mastectomy rates were 41.3% and 58.7%, respectively. One hundred four patients developed LRR (9.9%). Comparing between patients who underwent BCS and those who underwent mastectomy revealed no significant difference in the overall LRR rate of the two groups, 8.8% in BCS group vs 10.7% in mastectomy group (p = 0.303). Multivariate analysis indicated that independent factors for the prediction of LRR included clinical N2 status, negative estrogen receptor (ER), and failure to achieve pCR. In subgroups of multivariate analysis, only negative ER was the independent factor to predict LRR in mastectomy group (p = 0.025) and hormone receptor negative/human epidermal growth factor receptor 2 positive (HR-/HER2 +) subtype (p = 0.006) was an independent factor to predict LRR in BCS patients. Further investigation according to the molecular subtype showed that following BCS, non-pCR group had significantly increased LRR compared with the pCR group, in HR-/HER2 + subtype (25.0% vs 8.3%, p = 0.037), and HR-/HER2- subtype (20.4% vs 0%, p = 0.002). CONCLUSION: Clinical N2 status, negative ER, and failure to achieve pCR after NAC were independently related to the risk of developing LRR. Operation type did not impact on the LRR. In addition, the LRR rate was higher in non-pCR hormone receptor-negative patients undergoing BCS comparing with pCR patients.

Long-Term Outcomes of Breast Cancer Patients Who Underwent Selective Neck Dissection for Metachronous Isolated Supraclavicular Nodal Metastasis.

We retrospectively enrolled 139 patients who developed metachronous isolated supraclavicular lymph node metastasis (miSLNM) from 8129 consecutive patients who underwent primary surgery between 1990 and 2008 at a single medical center. The median age was 47 years. The median follow-up time from date of primary tumor surgery was 73.1 months, and the median time to the date of neck relapse was 43.9 months in this study. Sixty-one (43.9%) patients underwent selective neck dissection (SND). The 5-year distant metastasis-free survival (DMFS), post-recurrence survival, and overall survival (OS) rates in the SND group were 31.1%, 40.3%, and 68.9%, respectively, whereas those of the no-SND group were 9.7%, 32.9%, and 57.7%, respectively (p = 0.001). No SND and time interval from primary tumor surgery to neck relapse ≤24 months were the only significant risk factors in the multivariate analysis of DMFS (hazard ratio (HR), 1.77; 95% confidence interval (CI), 1.23-2.56; p = 0.002 and HR, 1.76, 95% CI, 1.23-2.52; p = 0.002, respectively) and OS (HR, 1.77; 95% CI, 1.22-2.55; p = 0.003 and HR, 3.54, 95% CI, 2.44-5.16; p < 0.0001, respectively). Multimodal therapy, including neck dissection, significantly improved the DMFS and OS of miSLNM. Survival improvement after miSLNM control by intensive surgical treatment suggests that miSLNM is not distant metastasis.

Prognostic study for isolated local recurrence operated with salvage excision in hormone-receptor-positive patients with invasive breast cancer after primary breast surgery.

BACKGROUND: This study aimed to identify the factors that predict distant recurrence and survival outcome after patients with primary positive hormone receptor-positive (HR+) invasive breast cancer undergo complete excision for isolated local recurrence (ILR). METHODS: From January 2000 to December 2009, we performed a retrospective review of our database and identified 51 patients with HR + invasive breast cancer who underwent complete excision for ILR as a component of salvage therapy. The distant metastasis-free survival (DMFS) and overall survival (OS) from the time of ILR were calculated using the Kaplan-Meier method, and a Cox regression model was used for multivariate analysis. RESULTS: Of the 51 cases of ILR, 28 were of ipsilateral breast tumor recurrence and 23 were of chest wall recurrence. By receiver operating characteristic curve analyses, the cut-off time point for time to ILR was determined to be 29 months. According to time to ILR (≤29 vs. >29 months) and primary tumor size (≤2 vs. >2 cm), patients were divided into four risk groups as variables for analysis. On multivariate analysis, two independent prognostic factors for DMFS and OS after ILR were identified: risk groups (ILR≤29 months with primary tumor size >2 cm vs. ILR>29 months with primary tumor size ≤ 2 cm, HR = 8.53 for DMFS and HR = 11.18 for OS) and primary tumor grade (2/3 vs. 1, HR = 6.10 for DMFS and 4.27 for OS). CONCLUSION: We demonstrated that poor DMFS and OS are associated with high risk group defined as short time to ILR (≤29 months) with primary tumor size (>2 cm) and higher primary tumor grade (2/3) among patients with HR + invasive breast cancer treated with complete excision for ILR. Therapeutic strategies for ILR based on hormone therapy with new agents should be explored in future prospective studies, especially for patients with poor outcome.

Impact of Detection Method and Accompanying Ductal Carcinoma in Situ on Prognosis of T1a,bN0 Breast Cancer.

Background: T1a,bN0 breast cancer is not easily detected. Before mammography became widespread, most cases were discovered only after the development of symptoms. The presence of ductal carcinoma in situ (DCIS) affects the detectability of associated invasive cancer; however, the prognostic value of concomitant DCIS is controversial. This study compared the characteristics of screening-detected and symptom-detected T1a,bN0 breast cancer, and investigated the impact of accompanying DCIS on detection and prognosis. Patients and Methods: Data were collected from a single hospital between 2000 and 2009. Of 5,690 primary breast cancers patients, 438 met the criteria for T1a,bN0M0. Logistic regression models were used to identify prognostic indicators and their association with the detection method. Survival analyses were performed to estimate distant relapse-free survival (DRFS) and breast cancer-specific survival (BCSS). Results: Tumors in 79 and 359 patients were detected by screening and development of symptoms, respectively. Symptomatic cancer patients were younger, more likely to receive a mastectomy, and had larger accompanying DCIS lesions; their 10-year DRFS rates were worse than those of patients with screening-detected tumors (91.1% vs. 100% respectively, p=0.049). Patients with large accompanying DCIS (≥2 cm) had markedly worse 10-year DRFS (77.1% vs. 97.4%, p<0.001) and BCSS (94.3% vs. 98.9%, p<0.001). Conclusion: T1a,bN0 breast cancers detected owing to symptoms are more likely to have larger accompanying DCIS. T1a,bN0 patients with large accompanying DCIS have worse DRFS and BCSS. It is important to consider associated DCIS size when evaluating prognosis in T1a,bN0 breast cancer patients.

Routine sampling of internal mammary lymph nodes during microsurgical breast reconstruction-Experience based on 524 microsurgical breast reconstructions.

PURPOSE: Exploration of the internal mammary vessels during microsurgical reconstruction presents an ideal opportunity for identifying and sampling the internal mammary lymph node (IMLN) basin. METHODS: A retrospective review of patients undergoing microsurgical breast reconstruction using the internal mammary vessels as recipient vessels was conducted from March 2000 to December 2014. Patient demographics, tumor characteristics, preoperative lymph node mapping, reconstructive timing, and outcomes were studied. RESULTS: A total of 524 microsurgical breast reconstructions in 516 patients were performed using the internal mammary vessels. IMLNs were sampled in 53 immediate and 42 delayed breast reconstructions. Eight (seven in the immediate and one in the delayed group) of the sampled nodes were positive for cancer metastasis, for an incidence of 8.4% in identified lymph nodes. All patients with metastatic IMLNs subsequently received local-regional radiation and chemotherapy. All patients were alive, and six were disease-free at the conclusion of the study period, which had an average follow up of 67.3 months. CONCLUSION: Incidentally encountered IMLNs during microsurgical breast reconstruction are frequently positive. With negligible downside and the possibility to provide additional information for treatment, the procedure should be encouraged. J. Surg. Oncol. 2016;114:133-139. © 2016 Wiley Periodicals, Inc.

Expression of ROR1 has prognostic significance in triple negative breast cancer.

Overexpression of receptor tyrosine kinase-like orphan receptor (ROR1) in a variety of human malignancies is associated with aggressive behaviour. Therapeutic agents targeting ROR1 have shown promising results in vivo and in vitro studies. In breast cancer, high-level expression of ROR1 mRNA is associated with high-grade tumours and metastasis. We investigated the prevalence and prognostic significance of ROR1 expression in triple negative breast cancer (TNBC). ROR1 was immunohistochemically stained on full-face sections of 210 TNBC patient samples. Forty-seven TNBC cases (22.4 %) showed strong ROR1 expression, which was associated with shorter disease-free survival (DFS; P = 0.00015), distant metastasis-free survival (DMFS; P = 0.00013) and overall survival (OS; P = 0.026) in univariate analyses. Results were confirmed by multivariate analysis. Seventy TNBC cases (33.3 %) with medullary features showed longer OS (P = 0.00013). We divided the whole series into two subgroups based on the presence or absence of medullary features. Strong ROR1 expression retained a predictive value of shorter DFS and DMFS in both subgroups. Our study suggests that strong ROR1 expression might be an independent adverse prognostic factor in TNBC patients and may serve as a potential marker for patient selection in ROR1-targeted therapy. More large-scale studies are needed to clarify its potential usefulness.

Predictors of underestimation of malignancy after image-guided core needle biopsy diagnosis of flat epithelial atypia or atypical ductal hyperplasia.

Flat epithelial atypia (FEA) and atypical ductal hyperplasia (ADH) are precursors of breast malignancy. Management of FEA or ADH after image-guided core needle biopsy (CNB) remains controversial. The aim of this study was to evaluate malignancy underestimation rates after FEA or ADH diagnosis using image-guided CNB and to identify clinical characteristics and imaging features associated with malignancy as well as identify cases with low underestimation rates that may be treatable by observation only. We retrospectively reviewed 2,875 consecutive image-guided CNBs recorded in an electronic data base from January 2010 to December 2011 and identified 128 (4.5%) FEA and 83 (2.9%) ADH diagnoses (211 total cases). Of these, 64 (30.3%) were echo-guided CNB procedures and 147 (69.7%) mammography-guided CNBs. Twenty patients (9.5%) were upgraded to malignancy. Multivariate analysis indicated that age (OR = 1.123, p = 0.002, increase of 1 year), mass-type lesion with calcifications (OR = 8.213, p = 0.006), and ADH in CNB specimens (OR = 8.071, p = 0.003) were independent predictors of underestimation. In univariate analysis of echo-guided CNB (n = 64), mass with calcifications had the highest underestimation rate (p < 0.001). Multivariate analysis of 147 mammography-guided CNBs revealed that age (OR = 1.122, p = 0.040, increase of 1 year) and calcification distribution were significant independent predictors of underestimation. No FEA case in which, complete calcification retrieval was recorded after CNB was upgraded to malignancy. Older age at diagnosis on image-guided CNB was a predictor of malignancy underestimation. Mass with calcifications was more likely to be associated with malignancy, and in cases presenting as calcifications only, segmental distribution or linear shapes were significantly associated with upgrading. Excision after FEA or ADH diagnosis by image-guided CNB is warranted except for FEA diagnosed using mammography-guided CNB with complete calcification retrieval.

The kinetic expression of lipopolysaccharide-binding protein and CD14 gene in obstructive jaundice.

BACKGROUND: Binding lipopolysaccharide (LPS) with high-affinity, lipopolysaccharide-binding protein (LBP) and CD14 lower the threshold stimulatory concentrations of LPS dramatically and enhance the rate of cytokine production markedly. This study aimed to investigate the kinetic expression of LBP/CD14 and its possible relationship with tumor necrosis factor alpha (TNF-α) to better understand the pathophysiology of obstructive jaundice. MATERIALS AND METHODS: The tissues (liver, spleen, intestine, and lung) of male Sprague-Dawley rats were harvested at pre-bile duct ligation in controls and at specific time points (24, 48, 72, 96, and 120 hr) after bile duct ligation. LBP, CD14, and TNF-α mRNA expression were measured in tissues harvested from controls and at the specific time points. RESULTS: Hepatic LBP mRNA expression increased significantly at five days after bile duct ligation. CD 14 mRNA expression increased significantly after five days of bile duct ligation in liver, lung, spleen, and ileum. TNF-α mRNA expression increased significantly in all four organs (liver, lung, spleen, and ileum) after four days of bile duct ligation. CONCLUSION: Five days of bile duct ligation upregulated CD 14 mRNA expression in liver, lung, spleen, and ileum and increased TNF-α mRNA expression simultaneously in the liver, lung, spleen, and ileum. In addition, five days of bile duct ligation also upregulated LBP mRNA expression in the liver and increased hepatic TNF-α mRNA expression simultaneously. The kinetic expressions of LBP and CD 14 in obstructive jaundice are intriguing and further evaluation is warranted.

MART-10, a less calcemic vitamin D analog, is more potent than 1α,25-dihydroxyvitamin D3 in inhibiting the metastatic potential of MCF-7 breast cancer cells in vitro.

With the recent advance in breast cancer therapy, the survival rate of breast cancer patients has improved greatly. In spite of the progress, 25-50% of breast cancer patients eventually will develop metastasis. Due to limited early detection methods, metastasis is usually diagnosed at the late stages beyond recovery likely due to resistance to currently available breast cancer therapies. Thus, a new strategy to prevent cancer cell growth and repress tumor metastasis is desirable. The active form of vitamin D3, 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3], has anti-invasion and anti-migration properties in pre-clinical studies, yet its clinical application has been hampered by its hypercalcemic side effect. Previously, we have demonstrated that a new class of less-calcemic vitamin D analog, 19-nor-2α-(3-hydroxypropyl)-1α,25-dihydroxyvitamin D3 (MART-10), is 1000-fold more active than 1α,25(OH)2D3 in suppressing MCF-7 cells growth through cell cycle arrest and apoptosis induction. In the current study, we show for the first time that MART-10 is more active than 1α,25(OH)2D3 in preventing MCF-7 cell invasion and migration likely mediated through the upregulation of E-cadherin, and the downregulation of Snail, Slug, and Twist, the transcription factors implicated in epithelial-mesenchymal transition (EMT), as well as MMP-13. Based on the current in vitro and the highly anti-tumor characteristics of MART-10 in a pancreatic xenograft model, MART-10 is deemed as a promising candidate for breast cancer treatment. Further in vivo animal study comparing MART-10 with 1α,25(OH)2D3 and other potent and less calcemic analogs of vitamin D is warranted.

Low re-excision rate for positive margins in patients treated with ultrasound-guided breast-conserving surgery.

BACKGROUND: Re-excision is a necessary procedure in obtaining clean margins for breast-conserving surgery (BCS)-treated patients. Re-excision rates vary widely among different breast cancer management procedures. The aim of this study was to evaluate the efficacy of ultrasound (US)-guided BCS to decrease the re-excision rate in patients with US-detectable breast cancer, as well as the relationship between positive margins and ultrasonographic characteristics of tumor. METHODS: Between 2008 and 2009, we identified consecutive patients who underwent initial US-guided BCS for breast in situ or invasive carcinoma, which was preoperatively detected using US examination and on the basis of image-guided biopsy findings. The margins achieved after BCS were separately assessed by performing frozen section analysis of shaved margins. The negative margin and positive margin groups were compared for clinicopathological features and ultrasonographic findings. RESULTS: Of 381 patients undergoing US-guided BCS, 126 (33.1%) had palpable tumors and 255 (66.9%) had nonpalpable tumors. Positive margins were noted in 35 patients (9.2%). These patients underwent re-excision and were margin-free; no further surgery was required for these patients. There were no significant intergroup differences in clinicopathological features and ultrasonographic findings. CONCLUSION: Breast US is an effective modality for intraoperative tumor localization and can thus help obtain clean margins and reduce the re-excision rate in cases in which breast-conserving therapy has been performed. Furthermore, frozen section analysis of cavity shaved margins is a feasible method for minimizing the need for further surgery.

Phosphorylated mTOR expression correlates with poor outcome in early-stage triple negative breast carcinomas.

The mammalian target of rapamycin (mTOR) plays an important role in cell growth, proliferation, and metabolism. Some studies have associated phosphorylated mTOR (p-mTOR) expression with worse outcome in breast cancers. However, the significance of p-mTOR expression specifically in triple negative breast carcinoma (TNBC) is unknown. In this study, p-mTOR expression was evaluated by immunohistochemistry in 172 TNBCs and the result was correlated with clinicopathologic variables and disease outcome. The majority of tumors (72.1%) were p-mTOR positive; p-mTOR expression did not correlate with age, tumor size, grade, lymph node status, or tumor stage. In patients at stage 1 and 2 disease, those with p-mTOR expression had significantly worse overall as well as recurrence-free survival compared to those without p-mTOR expression. p-mTOR expression appears to be an adverse prognostic indicator in early-stage TNBCs. The assessment of p-mTOR expression in these tumors may also help to stratify patients for future target therapy studies.

Favorable outcome of secondary axillary dissection in breast cancer patients with axillary nodal relapse.

PURPOSE: Little evidence can be found about the long-term outcome of breast cancer patients after axillary lymph node recurrence (ALNR) and its survival benefit after different kinds of management. The present study intends to evaluate the risk factors associated with axillary recurrence after definite surgery for primary breast cancer. The prognosis after ALNR and particularly outcome of different management methods also were studied. METHODS: We retrospectively reviewed data from 4,473 patients who were diagnosed with primary breast cancer and received surgical intervention in a single institute from January 1990 to December 2002. Medical files were reviewed and data on survival were updated annually. Risk factors and prognosis of patients with axillary recurrence were analyzed. Breast-cancer-specific survival of patients with ALNR and outcomes after different management methods also were studied. RESULTS: After a median follow-up of 70.2 months, axillary recurrence developed in 0.8% of patients. Factors associated with ALNR included: age younger than 40 years, medial tumor location, no initial standard level I & II axillary dissection, and not receiving hormonal therapy. The 5-year breast-cancer-specific survival after ALNR was 57.9%. For patients who received further axillary dissection, the 5-year survival rate was 82.5% compared with 44.9% for patients who did not receive further dissection. CONCLUSIONS: ALNR is a rare event in treating breast cancer. Young age at diagnosis and medially located tumor are associated with higher risk, but standardized initial axillary dissection to level II and adjuvant hormonal therapy is protective against ALNR. In patients with ALNR, the outcome is not dismal and survival may be improved if further axillary dissection is given.

MART-10, a New Generation of Vitamin D Analog, Is More Potent than 1α,25-Dihydroxyvitamin D(3) in Inhibiting Cell Proliferation and Inducing Apoptosis in ER+ MCF-7 Breast Cancer Cells.

Hormone antagonist therapy for estrogen receptor positive (ER+) breast cancer patients post radical surgery and radiation therapy has a poor prognosis and also causes bone loss. 1α,25-dihydroxyvitamin D(3) [1α,25(OH)(2)D(3)] is a potent antitumor agent in pre-clinical studies, but caused hypercalcemia when its effective antitumor doses were used. Therefore, we investigated the effects of a less-calcemic 1α,25(OH)(2)D(3) analog, 19-nor-2α-(3-hydroxypropyl)-1α,25-dihydroxyvitamin D(3 )(MART-10), on ER+MCF-7 cells. We demonstrate that MART-10 is 500- to 1000-fold more potent than 1α,25(OH)(2)D(3) in inhibiting cell growth in a dose- and time-dependent manner. MART-10 is also much more potent in arresting MCF-7cell cycle progression at G(0)/G(1) phase as compared to 1α,25(OH)(2)D(3), possibly mediated by a greater induction of p21 and p27 expression. Moreover, MART-10 is more active than 1α,25(OH)(2)D(3) in causing cell apoptosis, likely through a higher BAX/Bcl expression ratio and the subsequent cytochrome C release from mitochondria to cytosol. Based on our in vitro findings, MART-10 could be a promising vitamin D analog for the potential treatment of breast cancer, for example, ER+ patients, to decrease the tumor relapse rate and the side effect on bone caused by antihormone regimens. Thus, further in vivo animal study is warranted.

Low body mass index is an independent risk factor of locoregional recurrence in women with breast cancer undergoing breast conserving therapy.

BACKGROUND: To investigate the risk factors and prognosis for locoregional recurrence (LRR) after breast conserving treatment (BCT) in women with early breast cancer. METHODS: Women who had undergone BCT from 1998 to 2005 at Chang Gung Memorial Hospital were retrospectively reviewed. LRR was defined as the reappearance of invasive carcinoma in the treated breast and/or ipsilateral axillary lymph node (ALN). The appearance of carcinoma outside this area was defined as distant metastasis (DM). Patient characteristics, tumor characteristics, treatment modality, and follow-up clinical evaluations were analyzed. Survival was estimated by the Kaplan-Meier method and compared with the log-rank test. A multivariate model was built by the Cox regression method. RESULTS: This study included 858 patients, and the median follow up time was 36 (range 6-193) months. Twenty seven patients developed LRR for a crude LRR rate of 3.1%. The 5-year cumulative incidence of LRR was 5.0%. The mean age of patients at the primary operation was 45 (+/-9.8) years old. Their median body mass index (BMI) was 23 (range 16-40) kg/m(2). Univariate analysis of locoregional recurrence free survival (LRRFS) revealed that age < or =40 years, a low BMI (< or =24 kg/m(2)) and omission of postoperation radiotherapy were unfavorable factors. Low BMI and young age were independent prognostic factors for LRRFS in multivariate analysis. The five-year overall survival of patients with no recurrence, LRR and DM were 97.4%, 63.2% and 41.6%, respectively (p < 0.001). CONCLUSIONS: BCT in a young population can result in good locoregional control after careful preoperative evaluation. Women with a low BMI are at high risk of LRR.

High pathologic complete response in HER 2-positive locally advanced breast cancer after primary systemic chemotherapy with weekly docetaxel and epirubicin.

BACKGROUND: To evaluate pathological complete response rate and to identify the predictor of response after primary systemic chemotherapy (PST) with weekly docetaxel and epirubicin for locally advanced breast cancer. METHODS: Sixty-three patients with locally advanced breast cancer received three cycles PST on day 1 and 8 of each 3-week cycle with epirubicin and docetaxel (epirubicin 45 mg/m(2) intravenous bolus, docetaxel 35 mg/m(2) in 100 ml normal saline infused 1 h), followed by surgery and adjuvant chemotherapy with cyclophosphamide, epirubicin and 5-fluorouracil. The pathological complete response was defined as no invasive carcinoma in breast and axillary nodes after PST. RESULTS: The median tumor sizes (by ultrasound) before and after PST were 6.2 and 2.5 cm, respectively. The negative estrogen receptor (ER) by immunochemical stain was found in 33 (52.4%) patients and HER-2/neu-overexpression in 12 (19.0%) patients. Clinical overall response rate (ORR) was 89% (95% confidence intervals (95% CI: 81-97), including 38% complete response (95% CI: 26-50), sonographical ORR was 97% (95% CI: 93-100). The pathological complete response were found in 11 patients (18%, 95% CI: 9-27), and 15(24%, 95% CI: 13-35) patients achieved breast only pathological complete response. Nine (27.3%) of thirty-three ER (-) patients and 5 (41.7%) of 12 HER2-positive patients achieved pathological complete response. CONCLUSION: PST with weekly docetaxel and epirubicin were well-tolerated and very high pathological complete response rate was achieved in HER-2/neu-overexpression tumors.