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To report the results of a single-arm, prospective partial breast irradiation (PBI) trial from China mainland using a dose of 40.05 Gy in 15 fractions delivered with intensity-modulated radiation therapy (IMRT) technique for patients with early stage breast cancer. Patients aged ≥ 50 years who underwent breast-conserving surgery for unifocal non-lobular invasive breast cancer, with pathological T1 disease, clear margins, negative axillary nodes, and positive hormonal receptors, were recruited. The primary endpoint was 3-year cosmetic deterioration, and secondary endpoints included adverse events, ipsilateral breast tumor recurrence (IBTR), regional recurrence, and survivals. This trial is registered with ClinicalTrials.gov (registration No. NCT03411174). From Jan of 2015 to July of 2018, 208 out of 222 patients recruited were evaluable and included in final analysis. The median follow-up was 66.3 (range: 42.0-105.4) months. The 3-year overall cosmetic deterioration rate was 3.5%. The rates of grade 2 radiation dermatitis and breast induration was 5.8% and 1.5%, respectively. No one experienced ≥ grade 2 breast pain, edema, or telangiectasia. The 5-year cumulative incidence of IBTR and RR was 0.5%. No one developed DM. The 5-year DFS was 99.0%. Four patients died from non-breast cancer causes, and the 5- year OS was 97.9%. In conclusion, we observed lower rates of cosmetic deterioration, IBTR, and ≥ grade 2 acute/late normal tissue effects following PBI with a moderately hypofractionated regimen delivered with IMRT technique. Therefore, this regimen represents an attractive option when an external beam PBI approach is chosen to treat a patient with low-risk early breast cancer., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Introduction: Despite its therapeutic advantages, postmastectomy radiotherapy (PMRT) increases the risk of complications and often leads to poor cosmesis in women undergoing breast reconstruction. Preoperative radiotherapy followed by skin-sparing mastectomy and deep inferior epigastric perforator (DIEP) flap reconstruction is technically feasible, with low rates of surgical complications and good short-term oncological outcomes. Further evaluation in a randomised trial comparing preoperative radiotherapy versus conventional PMRT in breast reconstruction is required to assess both oncological and patient-reported outcomes (PROs)., Methods and Analysis: The CAPPELLA trial is a prospective, multicentre, open-label, randomised controlled trial across nine centres comparing PROs and safety outcomes between preoperative and postoperative radiotherapy in patients with locally advanced breast cancer requiring immediate DIEP flap reconstruction. Female patients aged >18 years with breast cancer who are treated with neoadjuvant systemic treatment, require both mastectomy and radiotherapy and are suitable for DIEP flap reconstruction will be included. Patients will be randomly assigned (1:1) to a preoperative radiotherapy group or a postoperative radiotherapy group. Stratification will be performed by cancer centre at initial diagnosis. The radiation volumes will include the ipsilateral breast/chest wall, supraclavicular lymph nodes, undissected axilla and internal mammary nodes. The dose regimen will be 42.56 Gy in 16 fractions. The primary endpoint will be satisfaction with the breast domain of the BREAST-Q at 2 years postoperatively. The secondary endpoints will include PROs at 3, 12 and 24 months postoperatively in both groups, aesthetic assessment, complication rates, rates of total pathological complete response (tpCR) and tumour safety. All patients will be followed up for 36 months postoperatively. The app software will be used to collect all data prospectively. Data will be analysed using SPSS and Stata software. The target sample size will be 80 participants., Ethics and Dissemination: This study will be performed according to the Helsinki Declaration. All patients will be asked to provide informed consent before enrolment. Approval for this study was provided by the independent ethics committee and institutional review board of Fudan University Shanghai Cancer Centre. We will present the study results at national and international meetings and publish them in a scientific peer-reviewed journal., Trial Registration Number: NCT05512286., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.)

Purpose: To assess the diagnostic performance of breast MRI for BI-RADS 4A microcalcifications on mammography and propose a potential clinical pathway to avoid unnecessary biopsies., Methods: Bibliometrics analysis of breast MRI and BI-RADS 4 was provided. A retrospective analysis was conducted on 139 women and 142 cases of BI-RADS 4A microcalcifications on mammography from Fudan University Shanghai Cancer Center. The mammographic BI-RADS level and the MRI reports were compared with the final pathological diagnosis., Results: Much attention has been given to breast MRI and BI-RADS 4 in the literature. However, studies on BI-RADS 4A are limited. Pathological results showed 117 cases (82.4%) were benign lesions, malignant cases of 25 (17.6%) in our study. The positive predictive values (PPV), specificity, sensitivity and negative predictive values (NPV) of MRI were 44.2% (23/52), 75.2% (88/117), 92.0% (23/25), and 97.8% (88/90), respectively. Therefore, 75.2% (88/117) of biopsies for benign lesions could potentially be avoided. There were 2.2% (2/90) malignant lesions missed. Logistic regression indicated that patients who are postmenopausal (HR = 2.655, p = 0.012), have a history of breast cancer (family history) (HR = 2.833, p = 0.029), and exhibit clustered microcalcifications (HR = 2.179, p = 0.046) are more likely to have a higher MRI BI-RADS level., Conclusions: Breast MRI has the potential to improve the diagnosis of BI-RADS 4A microcalcifications on mammography. We propose a potential clinical pathway that patients with BI-RADS 4A on mammography who are premenopausal, have no personal history of breast cancer (family history) or have non-clustered distribution of calcifications can undergo MRI to avoid unnecessary biopsies., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Breast cancer has the highest incidence rate among malignant tumors in China, with a trend of affecting younger women. The treatment has short- and long-term adverse effects such as damage to the ovaries, which may result in infertility. Such consequences then increase patients' concerns over future reproduction. At present, nor do medical staffs continuously assess their overall well-being, or ensure that they have the knowledge necessary to manage their reproductive concerns. This qualitative study aimed to explore psychological and reproductive decision-making experiences of young women who had experienced childbirth after their diagnosis., Methods: The phenomenological research, as a kind of qualitative study, was conducted on 12 young women who experienced childbirth after breast cancer diagnosis. Data collection was from September 2021 to January 2022 and content analysis method was used to analyze the data., Results: Five main themes were identified: (1) desire for childbearing from individual, familial, and social aspects after the diagnosis of breast cancer; (2) emotional experiences through pregnancy till raising children; (3) support needs from professionals, family, and peer; (4) self and doctors' influencing factors on reproductive decision-making; and (5) satisfaction with the outcome of reproductive decision-making., Conclusions: The desire for childbearing of young women should be considered during the reproductive decision-making process. A multidisciplinary team is suggested to be set up to provide professional support. During the reproductive process, professional and peer support should be strengthened to improve decision-making abilities, alleviate negative emotional experience, and smoothen the process of reproductive experience for young patients., (© 2023. The Author(s).)

Background: An international retrospective cohort study was conducted to clarify the survival advantage of combination therapy with locoregional and systemic therapy (ST) in oligometastatic breast cancer (BC)., Methods: Patients with oligometastatic BC diagnosed from 2007 to 2012 were enrolled in center hospitals in China, Korea and Japan. It was defined as a low-volume metastatic disease at up to five sites and not necessarily in the same organ. Cases with brain, pleural, peritoneal and pericardial metastases were excluded. The primary endpoint was overall survival (OS) from the initial diagnosis of oligometastases. OS was summarized using the Kaplan-Meier method. A multivariable Cox regression model was used to estimate the hazard ratio (HR) for clinicopathological factors., Results: Among 1,295 cases registered from February 2018 to May 2019, 932 remained for analysis after the exclusion of unavailable cases and locoregional recurrence. One metastatic site was found in 400 cases, 2 in 243, 3 in 130, 4 in 86 and 5 in 73. At the median follow-up of 4.5 years, 5-year OS was 54.7% and 39.7% for 321 cases in the combination therapy group and 611 cases in the ST group, respectively. An adjusted HR was 0.66 (95% confidence interval: 0.55, 0.79). Some types of ST without chemotherapy alone, younger age, ECOG performance status 0, early-stage BC, non-triple negative subtype, fewer metastatic sites and longer duration of surgery to relapse were significantly favorable prognostic factors., Conclusion: Combination therapy may be considered for longer survival under some conditions in oligometastatic BC., (© 2023. The Author(s), under exclusive licence to The Japanese Breast Cancer Society.)

Purpose: Changes in biological features and functional status make management decisions in older women with primary breast cancer complicated. We aimed to provide an overview of the clinicopathological characteristics and survival outcomes of older breast cancer patients based on the current treatment strategies., Methods: Female patients diagnosed with primary invasive breast cancer at Fudan University Shanghai Cancer Centre from 2008 to 2016 were included. Patients were divided into a younger group (<65 years) and older group (≥65 years). Propensity score matching was utilised to generate balanced cohorts., Results: A total of 13,707 patients met the study criteria. Compared with younger patients, older patients had a higher Charlson Comorbidity Index (p < 0.001), less lymph node metastasis (p = 0.009), more advanced tumour stage (p = 0.038), and a larger proportion of estrogen receptor-positive (p < 0.001) and epidermal growth factor receptor 2-negative (p < 0.001) tumours. Older patients were likely to receive mastectomy and axillary lymph node dissection in addition to a lower proportion of adjuvant chemotherapy. Adjuvant chemotherapy (HR [hazard ratio] 0.69, p = 0.039) was independently correlated with better overall survival in the older patients. This survival benefit (HR 0.58, p = 0.041) was confirmed in matched cohorts. Among the older patients with larger tumours (HR 0.48, p = 0.038) and more lymph node involvement (HR 0.44, p = 0.040), adjuvant chemotherapy was associated with a significant survival benefit., Conclusion: Older breast cancer patients showed less aggressive biological characteristics, intensive surgical and moderate medical preferences. The addition of adjuvant chemotherapy should be considered for older patients, especially for patients with large tumours and more lymph node involvement., Competing Interests: Declaration of competing interest None., (Copyright © 2022. Published by Elsevier Ltd.)

Purpose: Neoadjuvant therapy (NAT) is considered the standard of care for patients with HER2-positive breast cancer (BC). However, there is no proven survival benefit of NAT compared to adjuvant therapy for the survival of patients with early-stage HER2-positive BC. This study aimed to compare the prognosis of HER2-positive BC patients treated with NAT to that of patients treated with adjuvant therapy., Methods: This was a single-center real-world retrospective study. This study analyzed the disease-free survival (DFS) and overall survival (OS) of 538 HER2-positive BC patients treated with neoadjuvant therapy and 2684 patients treated with adjuvant therapy at Fudan University Shanghai Cancer Center (FUSCC) between 2012 and 2016. Patients with a clinical tumor size (cT) ≤5 cm or >5 cm were matched using the propensity score matching (PSM) method to prevent selection bias., Results: After PSM, among patients with cT ≤ 5 cm, there was no significant difference in DFS (P = 0.08) or OS (P = 0.11) between the two groups. The analysis of survival outcomes of patients treated with neoadjuvant and adjuvant therapy in the different chemotherapy subgroups yielded consistent results. According to multivariate analysis, lymph node status and response to NAT showed independent prognostic value for OS and DFS. Among patients with cT > 5 cm, the DFS (P = 0.25) and OS (P = 0.57) of patients treated with NAT were similar to those of patients treated with adjuvant therapy after PSM., Conclusion: We confirmed the equivalent effects of adjuvant therapy and NAT in HER2-positive BC patients. Neoadjuvant therapy should be used for patients with HER2-positive BC., (Copyright © 2022. Published by Elsevier Ltd.)

Introduction: Neoadjuvant chemotherapy (NAC) plays an important role in downgrading preoperative tumor size, providing information on regimen activity, and increases treatment efficacy in breast cancer patients. An increasing number of patients have sought Traditional Chinese Medicine (TCM) during NAC to relieve discomfort, regulate immune function, and improve survival. However, limited evidence is available on how concurrent TCM treatment combined with NAC affects tumor response. This study aims to assess the efficacy of Yanghe decoction, a classical warming Yang formula, on pathological complete response (pCR) and explore its mechanism via the phosphatidylinositol-3-kinase/ protein kinase B/nuclear factor kappa-B (PI3K/Akt/NF-κB) pathway-mediated immune-inflammation microenvironment., Methods: A single-center, randomized, placebo-controlled, double-blinded randomized control trial (RCT) was designed. This trial aims to recruit 128 participants with breast cancer scheduled to receive NAC in China. All participants will be randomly assigned (1:1) to the Neo-Yanghe group (Yanghe decoction plus NAC) or the control group (placebo plus NAC). The primary outcome will be evaluated by the proportion of participants achieving pCR. The secondary outcomes include the expression level of PI3K/Akt/NF-κB pathway-related proteins, the objective response rate, the time to response, serum level of immune-inflammatory indicators, quality of life, disease-free survival, and overall survival., Discussion: This study will be the first RCT to evaluate the efficacy of Yanghe decoction combined with NAC in treating breast cancer patients, and elucidate the antitumor mechanism via the PI3K/Akt/NF-κB pathway-mediated immune-inflammation microenvironment. If possible, Neo-Yanghe treatment pattern will be a better pharmacological intervention to manage breast cancer than chemotherapy alone. The results of the trial will provide research-based evidence for the development of integrated Chinese and Western medicine guidelines and expert consensus.Trial registration: Chinese Clinical Trial Registry ChiCTR-INR-2000036943. Registered on September 28, 2020 (https://www.chictr.org.cn/hvshowproject.aspx?id=57141)., Competing Interests: The authors have no conflict of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: To better understand the difference between traditional breast-conserving surgery (BCS) and oncoplastic surgery (OPS), we conducted a retrospective cohort study involving breast cancer patients who received neoadjuvant chemotherapy (NAC) and then underwent breast conservation at the Fudan University Shanghai Cancer Center., Methods: A retrospective chart review was conducted. All breast cancer patients who received NAC and then underwent traditional BCS or OPS at the Fudan University Shanghai Cancer Center from January 1, 2008, to December 31, 2019, were included., Results: Three hundred ninety-nine breast cancer patients received NAC and underwent traditional BCS, and 99 patients underwent OPS. The average age of the patients in the OPS group was younger than that in the BCS group (43 vs 48 years, P = 0.017). The size of the tumor assessed by ultrasonography at baseline in the OPS group was larger than that in the BCS group (31.3 vs 28.1 mm, P = 0.013). The same trend was observed in the clinical T stage and overall staging assessments before the administration of NAC in these 2 groups. Oncoplastic techniques were more frequently applied when tumors were located in areas with relatively few glands, such as the upper inner quadrant. There were no significant differences in the margins and distributions of pathological types and molecular subtypes between these 2 groups. The rates of pathological complete response were similar in the traditional BCS and OPS groups., Conclusions: Unlike traditional BCS, in breast cancer patients after NAC, the adoption of oncoplastic techniques makes breast conservation feasible, even in patients with large tumors, late stages, and unfavorable tumor locations., Competing Interests: Conflicts of interest and sources of funding: None of the authors has any funding received for this work from any of the following organizations: National Institutes of Health; Wellcome Trust; Howard Hughes Medical Institute; and others., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Early and accurate assessment of the response to neoadjuvant chemotherapy offers the potential to optimize treatment to obtain improved responses. We aimed to predict the response to neoadjuvant chemotherapy using a second breast core needle biopsy after a median of 2 cycles of neoadjuvant chemotherapy., Methods: We evaluated 805 consecutive patients undergoing neoadjuvant chemotherapy who had a second core needle biopsy between 2013 and 2017. The second core needle biopsy was performed after a median of 2 cycles of neoadjuvant chemotherapy. Pathologic response was evaluated after completion of all the chemotherapy cycles. Diagnostic values were compared and evaluated between the second core needle biopsy and contrast-enhanced magnetic resonance imaging in both the whole and the human epidermal growth factor receptor 2-positive populations., Results: Overall, 653 patients were eligible and underwent a median of 6 chemotherapy cycles. The second core needle biopsy predicted residual breast cancer earlier than the final contrast-enhanced magnetic resonance imaging, with a greater positive predictive value (positive predictive value: 0.856 vs 0.802, P = .028). Multivariate analysis revealed that a estrogen receptor status, human epidermal growth factor receptor 2 positivity, findings on the final contrast-enhanced magnetic resonance imaging and the pathologic findings of the second core needle biopsy pathology were independent predictive factors for treatment response. The superiority in diagnostic value of a second core needle biopsy pathology in human epidermal growth factor receptor 2-positive patients was consistent with that in the whole population, with a positive predictive value of 0.785 (95% confidence interval: 0.707-0.847). The second core needle biopsy predicted the response to neoadjuvant chemotherapy as early as after 2 cycles, but the accuracy increased from 0.744 to 0.872 if the procedure was performed after more cycles (P = .002)., Conclusion: The second core needle biopsy predicted the response to neoadjuvant chemotherapy after 2 cycles quite well, especially in human epidermal growth factor receptor 2-positive patients. The ability of the prediction of response improved if the second biopsy was performed after 3 or 4 cycles., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: The aim of this study was to investigate the predictive value of early changes in 18 F-fluoroestradiol (FES) positron emission tomography (PET)/computed tomography (CT) during fulvestrant 500 mg therapy in patients with estrogen receptor (ER)-positive metastatic breast cancer., Materials and Methods: Patients underwent 18 F-FES PET/CT scans at both baseline (scan 1) and day 28 (scan 2). The maximum standardized uptake value (SUVmax) of all metastatic sites was determined in each scan, and the percentage reduction in SUVmax (ΔSUVmax) was calculated as [(SUVmax on scan 1-SUVmax on scan 2)/ SUVmax on scan 1] * 100%., Results: In total, 294 18 F-FES-positive lesions from 36 patients were identified. The 18 F-FES SUVmax varied widely among lesions (median 5.7; range 1.8-32.4) and patients (median 5.1; range 2.5-13.2). After treatment, the median SUVmax among lesions and patients was 2.1 and 2.1, respectively. The ΔSUVmax ranged from -5.1% to 100%, with a median reduction of 61.3%. Using receiver operating characteristic analysis, the optimal cutoff point to discriminate patients who could derive clinical benefit from fulvestrant was determined to be 38.0%. Patients with a median ΔSUVmax ≥38.0% experienced significantly longer progression-free survival (PFS) than those with ΔSUVmax <38.0% (28.0 months vs. 3.5 months, p = .003). Multivariate analysis demonstrated that ΔSUVmax ≥38.0% was an independent predictor of PFS benefit in patients receiving fulvestrant therapy., Conclusion: Changes in SUVmax measured by serial imaging of 18 F-FES PET/CT could be used early to predict PFS benefit in patients receiving fulvestrant therapy., Implications for Practice: The aim of this study was to evaluate the role of 18 F-fluoroestradiol (FES) positron emission tomography (PET)/computed tomography (CT) in predicting response to fulvestrant 500 mg therapy in patients with hormone receptor-positive/human epidermal growth receptor 2-negative metastatic breast cancer. This study highlights the utility of FES PET/CT as a predictive factor to discriminate patients who might benefit from fulvestrant. Moreover, these findings showed that this molecular imaging technique might be a potential tool for physicians to make individualized treatment strategies., (© AlphaMed Press 2020.)

Background: The purpose of this study was to investigate the value of 18 [F]-fluorodeoxyglucose ( 18 F-FDG) positron emission tomography/computed tomography (PET/CT) in tailoring axillary surgery by predicting nodal response among patients with node-positive breast cancer after neoadjuvant chemotherapy (NAC)., Methods: One hundred thirty-three patients with breast cancer with biopsy-confirmed nodal metastasis were prospectively enrolled. 18 F-FDG PET/CT scan was performed before NAC (a second one after two cycles with baseline maximum standardized uptake value [SUV max ] ≥2.5), and a subset of patients underwent targeted axillary dissection (TAD). All the patients underwent axillary lymph node dissection (ALND). The accuracy was calculated by a comparison with the final pathologic results., Results: With the cutoff value of 2.5 for baseline SUV max and 78.4% for change in SUV max , sequential 18 F-FDG PET/CT scans demonstrated a sensitivity of 79.0% and specificity of 71.4% in predicting axillary pathologic complete response with an area under curve (AUC) of 0.75 (95% confidence interval, 0.65-0.84). Explorative subgroup analyses indicated little value for estrogen receptor (ER)-negative, human epidermal growth factor receptor 2 (HER2)-positive patients (AUC, 0.55; sensitivity, 56.5%; specificity, 50.0%). Application of 18 F-FDG PET/CT could spare 19 patients from supplementary ALNDs and reduce one of three false-negative cases in TAD among the remaining patients without ER-negative/HER2-positive subtype., Conclusion: Application of the subtype-guided 18 F-FDG PET/CT could accurately predict nodal response and aid in tailoring axillary surgery among patients with node-positive breast cancer after NAC, which includes identifying candidates appropriate for TAD or directly proceeding to ALND. This approach might help to avoid false-negative events in TAD., Implications for Practice: This feasibility study showed that 18 [F]-fluorodeoxyglucose ( 18 F-FDG) positron emission tomography/computed tomography (PET/CT) could accurately predict nodal response after neoadjuvant chemotherapy (NAC) among patients with breast cancer with initial nodal metastasis except in estrogen receptor-negative, human epidermal growth factor receptor 2-positive subtype. Furthermore, the incorporation of 18 F-FDG PET/CT can tailor subsequent axillary surgery by identifying patients with residual nodal disease, thus sparing those patients supplementary axillary lymph node dissection. Finally, we have proposed a possibly feasible flowchart involving 18 F-FDG PET/CT that might be applied in post-NAC axillary evaluation., (© AlphaMed Press 2019.)

Purpose: To investigate whether digital breast tomosynthesis (DBT) and subsequently generated synthesized mammography (SM) images show a better performance than full-field digital mammography (FFDM) images for diagnosing malignant breast lesions. In addition, the radiation doses for SM using different procedures were compared., Materials and Methods: This prospective study enrolled 212 women (age ≥ 25 years) with clinically suspicious breast lesions. All participants underwent FFDM and DBT with the same breast compression. Finally, 222 lesions were confirmed by pathological analysis. The mammogram results were evaluated according to the BI-RADS criteria and compared with the pathological results. The diagnostic performances, morphological features and average glandular doses (AGDs) were compared., Results: In total, 141 malignant lesions and 81 benign lesions were confirmed by pathological analysis. The overall AGD showed no significant difference between FFDM and DBT. Compared with 2D imaging, the AUC values of FFDM plus DBT and SM plus DBT were both significantly different overall (P = 0.0002) and remained significantly different in dense breasts (P < 0.0001). In terms of morphologic characteristics, lesions showed similar morphology between FFDM and SM, while the lesion characteristics were discordant from 2D imaging to DBT in 33 lesions in dense breasts., Conclusions: Compared to FFDM, 2D SM images generated from DBT had significantly improved diagnostic efficacy for detecting malignant breast lesions without increasing radiation doses. This new procedure is useful for characterizing breast lesions, particularly in dense breasts.

Purpose: How the neddylation pathway functions in breast tumor and regulation of estrogen receptor (ER) expression is rarely reported. The purpose of this study was to identify the role of neddylation in breast cancer and ER expression, and further explore the underlying mechanisms., Experimental Design: Expression patterns of nedd8-activating enzyme (NAE) and nedd8, two key proteins in the neddylation pathway, were examined in human breast specimens. ER-α expression was investigated using animal 18F-FES-PET/CT and immunoblotting upon NAE inhibitor MLN4924 treatment. Chromatin immunoprecipitation assay, luciferase reporter promoter assay, and the CRISPR-Cas9 system were used to elucidate the mechanism of ER-α regulation by MLN4924. The ER-positive breast cancer mouse model was used to determine the synergetic effect of MLN4924 and fulvestrant on tumor growth. All statistical tests were two-sided., Results: Both NAE1 and nedd8 expressions were higher in the ER-positive subgroup. Higher expressions of NAE1 and nedd8 indicated poorer prognosis. Importantly, ER-α expression was significantly downregulated upon MLN4924 treatment in vitro and in vivo . Mechanistically, MLN4924 treatment delayed serum and glucocorticoid-induced protein kinase (SGK) degradation and induced Forkhead box O3a (FOXO3a) nuclear export as well as decreased binding to the ESR1 promoter. Importantly, MLN4924 single or synergized with fulvestrant significantly suppressed the growth of ER-positive breast cancer in vitro and in vivo ., Conclusions: Our proof-of-principle study determines the activation of neddylation in breast tumor tissues for the first time and reveals a new ER-α regulatory mechanism, as well as further explores an effective approach to improve fulvestrant sensitivity through a neddylation inactivation combination., (©2019 American Association for Cancer Research.)

Background: For breast cancer patients, a false-negative rate lower than 10% can be achieved if targeted axillary dissection (TAD) is performed, which includes the excision of both biopsy-proven positive lymph nodes (BxLNs) and sentinel lymph nodes (SLNs). However, little evidence exists on the accuracy of intraoperative touch imprint cytology (ITPC) applied in TAD after neoadjuvant chemotherapy (NAC) for breast cancer patients with initial axillary metastasis. This study aimed to investigate the accuracy of ITPC in TAD after NAC., Methods: Breast cancer patients with biopsy-confirmed nodal metastasis were prospectively enrolled in the study. After completion of NAC, all patients underwent TAD followed by axillary lymph node dissection (ALND). Then ITPC was performed to evaluate BxLNs and SLNs. The accuracy of TAD and ITPC was calculated in comparison with hematoxylin and eosin (H&E) staining of ALNs. The results of ITPC during 6 months at our center in the adjuvant setting were used for comparison ., Results: Overall, the false-negative rate of TAD was 10.8%. In a test with 92 patients, ITPC had an accuracy of 92.4%, a sensitivity of 87.9%, and a specificity of 94.9%. In the non-NAC group, ITPC showed similar accuracy (91.2%) and specificity (97.9%) but significantly lower sensitivity (68.9%; P = 0.03)., Conclusions: The use of ITPC was feasible for TAD among breast cancer patients with biopsy-confirmed axillary metastasis who were treated with NAC. All the misses in the ITPC involved patients with micrometastases or isolated tumor cells. Use of ITPC can help decrease the number of second operations for patients with residual disease in ALNs after NAC.

Background Several recent studies have focused on the association between background parenchymal enhancement (BPE) and tumor response to neoadjuvant chemotherapy (NAC), but early prediction of tumor response based on BPE has yet not been investigated. Purpose To retrospectively investigate whether changes in the BPE of the contralateral breast following NAC could help predict tumor response in early stage HER2-positive breast cancer. Material and Methods Data from 71 patients who were diagnosed with unilateral HER2 positive breast cancer and then underwent NAC with trastuzumab before surgery were analyzed retrospectively. Two experienced radiologists independently categorized the patients' levels of BPE of the contralateral breast into four categories (1 = minimal, 2 = mild, 3 = moderate, 4 = marked) at baseline and after the second cycle of NAC. After undergoing surgery, 34 patients achieved pathologic complete response (pCR) and 37 patients had residual disease (non-pCR). The association between BPE and histopathologic tumor response was analyzed. Result The level of BPE was higher in premenopausal than post-menopausal women both at baseline and after the second cycle of NAC ( P < 0.005). A significant reduction in BPE ( P < 0.001) was observed after the second NAC cycle; however, a more obvious decrease in BPE was identified in premenopausal relative to post-menopausal women ( P = 0.041). No significant association was identified between pCR and baseline BPE ( P = 0.287). However, after the second NAC cycle, decreased BPE was significantly associated with pCR ( P = 0.003). Conclusion For HER2-positive patients, changes in BPE may serve as an additional imaging biomarker of treatment response at an early stage.

Previous studies have reported that hypoxia-inducible factor (HIF)-1α confers endocrine resistance and that zoledronic acid (ZOL) decreases HIF‑1α expression in estrogen receptor‑positive breast cancer. The present study investigated the effect of the combination treatment with ZOL and fulvestrant and its possible mechanism for HIF‑1α inhibition in vitro and in vivo. First, cell proliferation, clonogenic ability and HIF‑1α expression by western blotting were determined in MCF‑7 breast cancer cells stably expressing HIF‑1α in vitro. Next, a mouse xenograft model was established with the HIF‑1α‑overexpressing MCF‑7 breast cancer cells, and treated with PBS, fulvestrant, ZOL or fulvestrant plus ZOL. Tumor volumes were compared and animal [18F]‑fluoromisonidazole (FMISO) positron emission tomography‑computer tomography (PET‑CT) was used to detect the hypoxic status of the xenograft tumors. Protein expression levels of HIF‑1α in the xenograft tumors were detected by immunohistochemistry and western blotting. The results demonstrated that the HIF-1α-overexpressing xenograft tumors grew faster and larger compared with control tumors. The animal [18F]‑FMISO PET‑CT also confirmed these results. [18F]‑FMISO uptake was significantly higher in HIF‑1α‑overexpressing xenograft tumors compared with control tumors. In addition, the combination treatment with ZOL and fulvestrant acted synergistically in the mouse xenograft model in vivo to significantly reduce tumor burden. Similarly, combination of ZOL and fulvestrant significantly reduced tumor cell growth in vitro. ZOL alone did not inhibit the tumor growth of MCF‑7 cells stably expressing HIF‑1α. Furthermore, ZOL significantly inhibited extracellular signal‑regulated kinase (ERK) 1/2 phosphorylation, while phosphoinositide 3‑kinase/AKT signaling was not affected. In conclusion, the present study demonstrated that ZOL significantly increased the sensitivity of breast cancer cells to fulvestrant through inhibition of the ERK/HIF-1α pathway.

Objective: To investigate ovarian function and therapeutic efficacy among estrogen receptor (ER)-positive, premenopausal breast cancer patients treated with gonadotropin-releasing hormone agonist (GnRHa) and chemotherapy simultaneously or sequentially., Method: This study was a phase 3, open-label, parallel, randomized controlled trial (NCT01712893). Two hundred sixteen premenopausal patients (under 45 years) diagnosed with invasive ER-positive breast cancer were enrolled from July 2009 to May 2013 and randomized at a 1:1 ratio to receive (neo)adjuvant chemotherapy combined with sequential or simultaneous GnRHa treatment. All patients were advised to receive GnRHa for at least 2 years. The primary outcome was the incidence of early menopause, defined as amenorrhea lasting longer than 12 months after the last chemotherapy or GnRHa dose, with postmenopausal or unknown follicle-stimulating hormone and estradiol levels. The menstrual resumption period and survivals were the secondary endpoints., Result: The median follow-up time was 56.9 months (IQR 49.5-72.4 months). One hundred and eight patients were enrolled in each group. Among them, 92 and 78 patients had complete primary endpoint data in the sequential and simultaneous groups, respectively. The rates of early menopause were 22.8% (21/92) in the sequential group and 23.1% (18/78) in the simultaneous group [simultaneous vs. sequential: OR 1.01 (95% CI 0.50-2.08); p = 0.969; age-adjusted OR 1.13; (95% CI 0.54-2.37); p = 0.737]. The median menstruation resumption period was 12.0 (95% CI 9.3-14.7) months and 10.3 (95% CI 8.2-12.4) months for the sequential and simultaneous groups, respectively [HR 0.83 (95% CI 0.59-1.16); p = 0.274; age-adjusted HR 0.90 (95%CI 0.64-1.27); p = 0.567]. No significant differences were evident for disease-free survival (p = 0.290) or overall survival (p = 0.514) between the two groups., Conclusion: For ER-positive premenopausal patients, the sequential use of GnRHa and chemotherapy showed ovarian preservation and survival outcomes that were no worse than simultaneous use. The application of GnRHa can probably be delayed until menstruation resumption after chemotherapy.

Objective: This study was designed to evaluate the utility of textural features for predicting pathological complete response (pCR) to neoadjuvant chemotherapy (NAC)., Methods: Sixty-one consecutive patients with locally advanced breast cancer underwent 18 F-FDG PET/CT scanning at baseline and after the second course of NAC. Changes to imaging parameters [maximum standardized uptake value (SUV max ), metabolic tumor volume (MTV), total lesion glycolysis (TLG)] and textural features (entropy, coarseness, skewness) between the 2 scans were measured by two independent radiologists. Pathological responses were reviewed by one pathologist, and the significance of the predictive value of each parameter was analyzed using a Chi-squared test. Receiver operating characteristic curve analysis was used to compare the area under the curve (AUC) for each parameter., Results: pCR was observed more often in patients with HER2-positive tumors (22 patients) than in patients with HER2-negative tumors (5 patients) (71.0 vs. 16.7%, p < 0.001). ∆ %SUV max , ∆ %entropy and ∆ %coarseness were significantly useful for differentiating pCR from non-pCR in the HER2-negative group, and the AUCs for these parameters were 0.928, 0.808 and 0.800, respectively (p = 0.003, 0.032 and 0.037). In the HER2-positive group, ∆ %SUV max and ∆ %skewness were moderately useful for predicting pCR, and the respective AUCs were 0.747 and 0.758 (p = 0.033 and 0.026). Although there was no significant difference in the AUCs between groups for these parameters, an additional 3/22 patients in the HER2-positive group with pCR were identified when ∆ %skewness and ∆ %SUV max were considered together (p = 0.031). The absolute values for each parameter before NAC and after 2 cycles cannot predict pCR in our patients. Neither ∆ %MTV nor ∆ %TLG was efficiently predictive of pCR in any group., Conclusions: The early changes in the textural features of 18 F-FDG PET images after two cycles of NAC are predictive of pCR in both HER2-negative and HER2-positive patients; this evidence warrants confirmation by further research.

A recent randomized controlled trial firstly demonstrated that cavity shaving significantly decreased the rate of positive margins and re-excision among partial mastectomy (PM) patients. However, it remains unknown whether cavity shaving should be routinely applied to Chinese breast cancer patients undergoing PM. A total of 408 PM patients undergoing 410 PMs among 1796 surgically treated breast cancer patients at Fudan University Shanghai Cancer Centre from January 2015 to June 2015 were included in our study. Data were analysed with univariate or multivariate analysis. Overall, 11 of 410 cases (2.7%) had positive margins postoperatively. Moreover, only 24.6% of the cases (P<0.05) presented with ductal carcinoma in situ (DCIS), among whom 10.0% obtained positive margins. In multivariate logistic regression analysis, presence of mammographic calcifications was significantly associated with margin positivity (P<0.05, OR=6.06, 95% CI: 1.53-23.91). In conclusion, cavity shaving during PM should not be routinely performed in Chinese breast cancer patients, particularly in highly selected cases with a low prevalence of DCIS. PM patients with preoperative mammographic calcifications were more likely to have positive margins and might benefit more from cavity shaving.

Background: Studies have demonstrated that cysteine-rich 61 (CYR61) may be involved in tumor proliferation and invasion. However, the role of CYR61 plays in endocrine therapy response is largely unknown., Patients and Methods: We tested the levels of CYR61 expression of 36 primary breast cancer patients who received neo-adjuvant endocrine therapy for at least 3 months by immunohistochemistry staining before and after administrating letrozole, an oral non-steroidal aromatase inhibitor (AI) for the treatment of hormone-responsive breast cancer. The expression levels of CYR61 and ki67 were compared between pre-treatment and post-treatment samples by using the paired t test. Chi-square test was used to determine the relationship between baseline CYR61 expression and clinical response., Results: In the clinical case series analysis, a positive correlation was observed between baseline CYR61 expression and clinical outcomes (p=0.02). CYR61 expression was significantly increased in the residual tumors after treatment (indicating insensitivity to endocrine therapy) compared with that in the baseline biopsy samples, which was irrespective of the efficacy of primary endocrine treatment. In addition, the ki67 level was significantly decreased after neo-adjuvant endocrine therapy, compared with that in the baseline samples., Conclusion: This study provides evidence that CYR61 may confer the sensitivity to letrozole treatment and may offer an opportunity to target CYR61 to improve endocrine resistance in ER-positive breast cancer., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Purpose: The Great Chinese Famine afflicted almost all Chinese people between 1959 and 1961. No study has explicitly assessed the association between an exposure to Chinese Famine and risk of overall breast cancer and tumor subtype. We evaluated the unique historical environmental influences of famine exposure on breast cancer subtypes., Methods: 16,469 Chinese women who were diagnosed with invasive breast cancer in the Fudan University Shanghai Cancer Center (FUSCC) from 1999 to 2014 were analyzed. Four tumor subtypes were defined by both estrogen-receptor (ER) and progesterone-receptor (PR) status. Multinomial logistic regression models were used to estimate the odds ratios (ORs) of ER-PR-, ER+PR-, and ER-PR+ relative to ER+PR+ breast cancer for exposure to famine and age at the exposure., Results: Compared with cases not exposed to the Famine, exposed cases were more likely to be diagnosed with ER-PR- (OR 1.60, 95 % CI 1.43-1.81), ER-PR+ (OR 4.85, 95 % CI 3.80-6.19), and ER+PR- (OR 1.99, 95 % CI 1.67-2.37) than ER+PR+ breast cancer after controlling for established breast cancer risk factors. Women exposed to Famine after first birth had a higher risk of EP-PR- (OR 1.66, 95 % CI 1.28-2.15), ER-PR+ (OR 9.75, 95 % CI 5.85-16.25), and ER+PR- (OR 2.35, 95 % CI 1.69-3.26) compared to those with ER+PR+ breast cancer., Conclusions: Women exposed to the Famine, particularly those exposed after first birth, were more likely to be diagnosed with ER-PR-, ER-PR+, and ER+PR- breast cancer. This retrospective analysis suggests that famine, malnutrition, or the associated lack of fruit and vegetable consumption in adulthood may be related to epidemiological heterogeneity within breast cancer subtypes.

Background: This study aims to understand the quality of life (QOL) and psychological state (PS) of Chinese breast cancer patients who received BRCA1/2 genetic testing; to examine the psychological changes between BRCA1/2 mutation carriers and non-carriers; and to further explore the psychological experience of BRCA1/2 mutation carriers., Methods: This study was combined with quantitative and qualitative designs. First, we performed a quantitative investigation using FACT-B (Chinese version) and Irritability, Depression and Anxiety scale (IDA) to assess the QOL and PS in breast cancer patients who received BRCA1/2 genetic testing. Then semi-structured in-depth qualitative interviews among 13 mutation carriers were conducted in hospital., Results: Results from the quantitative study showed QOL scores were relatively high and the IDA scores were relatively low among the patients, and there was no significant difference in the QOL or IDA scores between non-carriers and carriers. Based on the qualitative analysis, four main themes emerged: (1) Finding the reason for having breast cancer; (2) Negative emotions; (3) Behavioral changes; (4) Lack of information., Conclusions: The present study showed that QOL and PS are good among the breast cancer patients who received genetic testing. Genetic testing itself does not cause long psychosocial effects. BRCA1/2 mutation carriers may have certain negative emotions at the first stage they knew the testing results and may initiate behavioral and lifestyle changes. The patients with a BRCA1/2 mutation desire knowledge with regard to genetic aspects in mainland China. Professional information and advice can be provided to relieve the patients' negative emotions when they were informed of gene defect.

Objective: To evaluate the role of germline mutations of TP53 gene among a Chinese population with high risk for breast cancer., Methods: A total of 81 BRCA-negative breast cancer probands from cancer families were analyzed using targeted capture and next-generation sequencing. Candidate mutations were verified with Sanger sequencing. Co-segregation analyses were carried out to explore the likely pathogenicity of the mutation., Results: Of the 81 BRCA-negative patients, 3 exonic mutations in the TP53 gene were identified in 3 breast cancer patients. Of these, 2 mutations were previously reported and 1 was novel. One family with TP53 mutation has met the criteria for Li-Fraumeni syndrome (LFS) and accounted for 9.1% of all families who fulfilled the diagnostic criteria for LFS. Two of the carriers were diagnosed with breast cancer under the age of 30, and have accounted for 11.8% (2/17) of all very young (≤30 years) breast cancer patients in our study., Conclusion: The TP53 germline mutation is more common in Chinese population with a high risk for breast cancer than previously thought. TP53 gene mutation screening should be considered particularly for patients with a family history of LFS and very young age of onset.

Objective: To evaluate the cost-effectiveness of two breast cancer screening modalities conducted in Minhang district of Shanghai, China., Methods: An organized and an opportunistic breast screening programs were implemented among women aged 35-74 years in Minhang district of Shanghai between May 2008 and Oct 2010, and were compared with the results obtained without screening. Costs related to screening were obtained by access to finance data of the screening programs, and costs of first treatment were collected through patient survey and medical reimbursement system query. Information on breast cancer stage was obtained from Shanghai Cancer Registry and confirmed by medical chart review. The effectiveness of screening was evaluated by breast cancer stage improvement.Cost-effectiveness ratios (CERs) were computed as costs of gaining a stage improvement from a specified screening strategy when compared with the results obtained without screening. Incremental cost-effectiveness (ICER) which compares the two screening strategies was calculated by dividing the difference in total net costs and the difference in stages improved between the two screening strategies., Results: Thirty-five, one hundred and ninety-three and four hundred and seventy-nine breast cancer cases were identified in the organized screening, opportunistic screening and control groups, with an early detection rate of 46.9%, 40.7% and 38.9%, respectively. The costs of screening were 208 yuan per person or 72 453 yuan per case detected in the organized screening group and were 21 yuan per person or 11 640 yuan per case detected in the opportunistic screening group. The total cost was 103 650 yuan per case in the organized screening group, significantly higher than 50 712 yuan in the opportunistic screening group and 35 413 yuan in the control group. However, the average direct medical cost was significantly lower in the organized screening group than that in the opportunistic screening group and control group, with median costs of 11 024 yuan, 13 465 yuan and 14 243 yuan per case, respectively (P<0.001). The additional cost per case detected was 68 237 yuan for the organized screening and 15 299 yuan for opportunistic screening. The CERs were 135 291 yuan and 152 179 yuan per stage improved in the organized screening and opportunistic screening relative to the control group, with ICER of organized versus opportunistic screening being 131 086 yuan per stage improved., Conclusions: The organized screening modality and the opportunistic one are both effective in early detecting breast cancer in Chinese women. The organized screening costs more than opportunistic screening, but with a better cost-effectiveness. It may be used as an option in economically developed areas of China.

The aim of this prospective study was to assess the ability of 18F-fluorodeoxyglucose ((18)FDG) positron emission tomography/computed tomography (PET/CT) scanning to predict pathological complete response (pCR) in breast cancer, and to investigate whether timing of the scan and trastuzumab treatment influence the accuracy of pCR prediction in human epidermal growth factor receptor 2 (HER2) positive breast cancer patients. We treated 81 locally advanced breast cancer patients with four cycles of neoadjuvant chemotherapy (NAC). HER2-negative breast cancer patients received NAC alone, while HER2-positive breast cancer patients received NAC plus trastuzumab. (18)FDG PET/CT scans were scheduled at baseline and after the second cycle of NAC. Axillary lymph node (ALN) dissection was performed after the last cycle of neoadjuvant therapy. Relative changes in standardized uptake values (SUV) between the two PET/CT scans (ΔSUV) in primary tumors and ALN metastases were calculated. There were 75 patients with 150 PET/CT scans in the final analysis, including 41 HER2-negative and 34 HER2-positive cases. In the HER2-negative group, the ΔSUV predicted overall and ALN pCR; the receiver operating characteristics-areas under curve (ROC-AUC) were 0.87 and 0.80 (P = 0.0014 and 0.031, respectively) and the negative predictive values were 94% and 89% respectively. However, in the HER2-positive group, ΔSUV could predict neither overall nor ALN pCR; the ROC-AUCs were only 0.56 and 0.53, with P = 0.53 and 0.84, respectively. Hence, the ΔSUV after two cycles of neoadjuvant therapy could predict pCR in HER2-negative patients treated with NAC alone, but not in HER2-positive patients treated with NAC plus trastuzumab.

The prognosis for breast cancer occurs in young women is usually poor. The impact of different reproductive factors on disease characteristics is still largely unknown. We analyzed 261 patients aged ≤35 years old who were treated at the Cancer Hospital of Fudan University, Shanghai, China. The relationships between certain reproductive factors (age at menarche, parity, number of children, breastfeeding, history of abortion, age at first full-term pregnancy and oral contraceptive (OC) use) and disease characteristics were evaluated. Compared with patients who experienced fewer full-term pregnancies (<2 times), the patients with more full-term pregnancies (≥2 times) exhibited higher percentage of ER-positive tumors (61.5%) (P = 0.015), and patients whose age of menarche was ≥15 years exhibited a greater chance of PR-positive tumors (64.8%) (P = 0.036) compared with those whose age of menarche was <15 years old. Additionally, patients who had taken OCs were more likely to present with late-stage tumors (II stage or later) (87.5%) (P = 0.002) than patients who had never taken OCs. Our study provides evidence that women with more full-term pregnancies and later age at menarche are more possible to exhibit hormone receptor-positive tumors. Additionally, patients who have taken OCs are more likely to present with advanced disease.

There has not been a clear answer about the efficacy of intraoperative radiotherapy (IORT) for women with early-stage breast cancer.The aim of this meta-analysis was to summarize the available evidence comparing the efficacy and safety of IORT with those of whole-breast external beam radiotherapy (EBRT) for women with early-stage breast cancer.MEDLINE, EMBASE, the Web of Science, and the Cochrane Library were searched up to October 2014. Two authors independently conducted the literature selection and data extraction.Studies that compared IORT with whole-breast EBRT were included in the systematic review. IORT was defined as a single dose of irradiation to the tumor bed during breast-conserving surgery rather than whole-breast irradiation.Qualities of RCTs were evaluated according to the PEDro scale. Qualities of non-RCTs were evaluated according to the Methodological Index for Non-Randomized Studies (MINORS). The risk ratios (RRs) of ipsilateral breast tumor recurrence, overall mortality, breast cancer mortality, non-breast cancer mortality, and distant metastasis were pooled using a random-effects model.Four studies with 5415 patients were included in this meta-analysis, including 2 randomized controlled trials (RCTs) and 2 non-RCTs. Ipsilateral breast tumor recurrence was significantly higher in patients with IORT compared to those with whole-breast EBRT (RR 2.83, 95% CI 1.23-6.51), but with significant heterogeneity (I = 58.5%, P = 0.065). Comparing IORT with whole-breast EBRT, the pooled RRs for overall mortality, breast cancer mortality, non-breast cancer mortality, and distant metastasis were 0.88 (95% CI: 0.66-1.17), 1.20 (95% CI: 0.77-1.86), 0.76 (95% CI: 0.44-1.31), and 0.95 (95% CI: 0.61-1.49), respectively.IORT had a significantly higher risk of ipsilateral breast tumor recurrence than whole-breast EBRT. Overall mortality did not differ significantly. IORT should be used in conjunction with the prudent selection of suitable patients. It is imperative to identify women with a low risk of local recurrence.

Resistance is an obstacle to endocrine therapy for breast cancer. We measured levels of hypoxia-inducible factor (HIF)-1α in 52 primary breast cancer patients before and after receiving neoadjuvant endocrine therapy with letrozole for at least 3 months. Pre-treatment levels of HIF-1α were associated with negative clinical outcome. Furthermore, levels of HIF-1α were increased in post-treatment residual tumors compared with those in pre-treatment biopsy samples. In animal studies, xenografts stably expressing HIF-1α were resistant to endocrine therapy with fulvestrant compared with the effects in control xenografts. Additionally, HIF-1α transcription was inhibited by zoledronic acid, a conventional drug for the treatment of postmenopausal osteoporosis, and was accompanied by a marked inhibition of the RAS/MAPK/ERK1/2 pathway. HIF-1α is a determinant of resistance to endocrine therapy and should be considered as a potential therapeutic target for overcoming endocrine resistance in estrogen receptor (ER)-positive breast cancer. In addition, zoledronic acid may overcome endocrine resistance in ER-positive human breast cancer by targeting HIF-1α transcription through inhibition of the RAS/MAPK/ERK1/2 pathway. Clinical studies on the administration of zoledronic acid as a second line treatment in patients who failed endocrine therapy should be considered to improve therapeutic outcomes in breast cancer patients.

To evaluate whether chemotherapy is indispensable in elderly patients with early estrogen receptor (ER)-negative breast cancer and diabetes mellitus (DM), the data on 112 patients, ≥70 years of age, with early, operable ER-negative breast cancer who were treated at the Cancer Hospital of Fudan University, Shanghai, China, between 2000 and 2010, were analyzed. The overall survival (OS), disease-free survival (DFS), and breast cancer-specific survival (BCS) were compared. Survival analysis was performed using the Kaplan-Meier method. The Cox proportional hazards model was used to evaluate the prognostic value of DM and chemotherapy for OS, DFS, and BCS. The univariate Cox regression analysis revealed that DM at diagnosis, the number of positive lymph nodes, and radiotherapy were associated with OS, the number of positive lymph nodes, human epidermal growth factor 2 (HER2/neu) status, and radiotherapy were associated with DFS, and the number of positive lymph nodes, tumor size, HER2/neu status, chemotherapy, and radiotherapy were associated with BCS. The subsequent multivariate analysis identified DM at diagnosis (hazard ratio [HR]=3.797; 95% confidence interval [CI], 1.515-9.520; P=0.004) as an independent prognostic factor for OS (with the addition of chemotherapy regimen). Chemotherapy was not an independent prognostic factor for either OS (HR=1.275; 95% CI, 0.614-2.646; P=0.515) or DFS (HR=0.849; 95% CI, 0.445-1.619; P=0.619) when other possible factors that may affect the results were adjusted. In conclusion, chemotherapy was not found to be indispensable for elderly (≥70 years of age) female patients with early ER-negative breast cancer with DM because, particularly in such patients, the treatment of DM may be more important compared with chemotherapy.

Background: Neoadjuvant chemotherapy has become standard treatment for women with locally advanced breast cancer. The aim of this study was to compare the efficacy and safety of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) versus paclitaxel combined with carboplatin., Methods: Thirty patients were treated with neoadjuvant nab-paclitaxel (125 mg/m(2), days 1, 8, and 15) and carboplatin (area under the curve =2; days 1, 8, and 15) every 21 days for four cycles. Ninety matched patients received paclitaxel (80 mg/m(2), days 1, 8, and 15) and carboplatin every 21 days for four cycles. Weekly trastuzumab is recommended for overexpression of human epidermal receptor-2. The primary endpoint was pathologic complete response (defined as ypT0/is ypN0). Matching was conducted according to six variables: body mass index, clinical tumor stage, clinical lymph node status, estrogen receptor status, HER2 status, and trastuzumab receiving rate., Results: Ninety percent of patients in the nab-paclitaxel group and 80% of patients in the paclitaxel group experienced a clinical objective response (complete response or partial response; P=0.450). Eight patients in the nab-paclitaxel group and 23 patients in the paclitaxel group had a pathologic complete response in the breast and axillary nodes (26.7% versus 25.6%; P=0.904). Nab-paclitaxel showed a beneficial effective trend on clinical tumor stage II (36.8% versus 15.8%; P=0.051). When trastuzumab was added to nab-paclitaxel, the pathologic complete response rate was not significantly improved more than with trastuzumab and paclitaxel (43.6% versus 39.6%; P=0.769). Carboplatin plus nab-paclitaxel or paclitaxel had similarly low pathologic complete response rates (7.7% versus 10.5%) for the luminal molecular subtype. One (50%) triple-negative patient achieved a pathologic complete response. The nab-paclitaxel regimen caused more grade 4 neutropenia than the paclitaxel regimen (56.7% versus 21.1%; P<0.001)., Conclusion: Our study shows that weekly nab-paclitaxel and carboplatin with or without trastuzumab resulted in a pathologic complete response rate that was not superior to the matched cohorts. Future, larger trials are needed to validate that nab-paclitaxel is beneficial for clinical tumor stage II and the triple-negative subgroup.

JMJD2C is a candidate oncogene that encodes a histone lysine demethylase with the ability to demethylate the lysine 9 residue of histone H3 (H3K9). The expression levels of JMJD2C are associated with tumor development and clinical outcome. Here we identify JMJD2C as a new substrate for caspase-3. JMJD2C is cleaved by caspase-3 at DEVD396G motif and then loses its demethylase activity. Additionally, we uncover D396N polymorphism (rs2296067) in the cleavage site of JMJD2C and establish its influence on the resistant to the cleavage by caspase-3. Importantly, we determined that D396N polymorphism is significantly associated with the prognosis of human breast cancer. We further found that the basal levels of DSB (double strand DNA break) repair proteins γ-H2AX (gamma-H2AX) increased when cells were treated with tumor necrosis factor-α (TNF-α) which activates caspase-3 activity. We also show that knockdown of JMJD2C expression results in up-regulation of basal γ-H2AX. We propose that D396N polymorphism of JMJD2C affects the prognosis of human breast cancer via altering the cleavage by caspase-3 and the ability of DSB repair which may contribute to therapy resistance.

Although nanoparticle albumin-bound paclitaxel (nab-paclitaxel) is approved to be given every 3 weeks, weekly use of this drug is becoming a new standard of care in patients with metastatic breast cancer (MBC). This prospective Phase II study was conducted to improve the efficacy of weekly nab-paclitaxel with cisplatin in MBC patients. Seventy-three women with recurrent or MBC were eligible for participation. Nab-paclitaxel was administered weekly at a dose of 125 mg/m(2) on day 1, day 8, and day 15, followed by cisplatin 75 mg/m(2) on day 1, repeated every 28 days with a maximum of 6 cycles. The primary objective was investigator-assessed overall response rate (ORR). A high ORR of 67.1% was obtained, with rates of 80.6% for the first-line patients and 80% for patients not pretreated with taxanes. Among those who had objective responses, a large percentage of patients (83.7%) showed quickly remarkable tumor shrinkage during the first two cycles. The median progression-free and overall survival times were 9.8 and 26.9 months, respectively. For the patients receiving first-, second-, and third-line therapy or beyond, median progression-free survival was 11.7, 7.7, and 7.6 months, respectively (P=0.005). Molecular subtype was not significantly associated with ORR or disease progression. Grade 4 neutropenia occurred in 46 patients (63.0%), with febrile neutropenia found in 9 patients (12.3%). Grade 3 peripheral neuropathy was an accumulated dose-limiting toxicity occurring in 19 patients (26.0%). Efficacy of weekly nab-paclitaxel can be improved by adding cisplatin. The doublet is highly effective, with quick response, manageable toxicity, and possible equivalence across molecular subtypes in MBC patients.

Introduction: Investigate the patterns of mammographically detected calcifications before and after neoadjuvant chemotherapy (NACT) to determine their value for efficacy evaluation and surgical decision making., Methods: 187 patients with malignant mammographic calcifications were followed to record the appearances and changes in the calcifications and to analyze their responses to NACT., Results: Patients with calcifications had higher rates of hormonal receptor (HR) positive tumors (74.3% versus 64.6%) and HER2 positive tumors (51.3% versus 33.4%, p = 0.004) and a similar pathologic complete response (pCR) rate compared to patients without calcifications (35.4% versus 29.8%). After NACT, the range of calcification decreased in 40% of patients, increased in 7.5% and remained stable in 52.5%; the calcification density decreased in 15% of patients, increased in 7.5% and remained stable in 77.5%; none of these change patterns were related to tumor response rate. No significant correlation was observed between the calcification appearance (morphology, distribution, range, diameter or density) and tumor subtypes or pCR rates. Among patients with malignant calcifications, 54 showed calcifications alone, 40 occurred with an architectural distortion (AD) and 93 with a mass. Calcifications were observed inside the tumor in 44% of patients and outside in 56%, with similar pCR rates and patterns of change., Conclusions: Calcification appearance did not clearly change after NACT, and calcification patterns were not related to pCR rate, suggesting that mammogram may not accurate to evaluate tumor response changes. Microcalcifications visible after NACT is essential for determining the extent of excision, patients with calcifications that occurred outside of the mass still had the opportunity for breast conservation.

Unlabelled: Although endocrine therapy is an effective method to treat estrogen receptor (ER)-positive breast cancer, approximately 30%-40% of all hormone receptor-positive tumors display de novo resistance. The aim of our current study was to analyze whether (18)F-labeled fluoromisonidazole (1-(2-nitro-1-imidazolyl)-2-hydroxy-3-fluoropropane [(18)F-FMISO]) PET/CT could predict primary resistance to hormonal therapy in ER-positive breast cancer., Methods: Postmenopausal women who had ER-α-positive breast cancer, stages II-IV, and had never received prior endocrine therapy were prospectively enrolled in this study. Patients underwent both (18)F-FDG and (18)F-FMISO PET/CT scans before and after treatment. The hottest (18)F-FDG standardized uptake value (SUV) in the tumor foci, the SUVs at 2 and 4 h, and the TBR2 h and TBR4 h for the target lesions were calculated (TBR2 h = SUV2 hT/SUV2 hB and TBR4 h = SUV4 hT/SUV4 hB [TBR is the tumor-to-background ratio]). Clinical outcomes of primary endocrine therapy with letrozole were evaluated according to the criteria of the World Health Organization after at least 3 mo of treatment. Immunohistochemistry for markers of proliferation (Ki67) and hypoxia-induced factor 1α was performed on a subset of tumors that had undergone biopsy or surgery. Pearson and Spearman analysis was used to determine the correlation between the parameters of (18)F-FDG and (18)F-FMISO uptake and clinical or immunohistochemistry outcomes with a 0.01 threshold for statistical significance., Results: A total of 45 lesions (13 primary, 32 metastatic) from 20 patients met the inclusion criteria in this study. Baseline (18)F-FDG and (18)F-FMISO PET/CT scans were obtained for 33 lesions from 16 patients. The correlation between baseline (18)F-FDG uptake and clinical outcome was weak and did not reach statistical significance (r = 0.37, P = 0.031). However, there was a significantly positive correlation between baseline (18)F-FMISO uptake (SUV2 hT, TBR2 h, SUV4 hT, and TBR4 h) and clinical outcomes after ≥3 mo of primary endocrine therapy with letrozole (r = 0.77, 0.76, 0.71, and 0.78, respectively; P < 0.0001). The application of a TBR4 h cutoff of ≥1.2 allowed the prediction of 88% of the cases of progressive disease (15/17). Despite poor correlation between (18)F-FMISO uptake and hypoxia-induced factor 1α expression, a marginal positive correlation between TBR4 h and Ki67 expression was measured (r = 0.51, P = 0.011) in a subset of malignant lesions acquired by biopsy or surgery., Conclusion: (18)F-FMISO PET/CT can be used to predict primary endocrine resistance in ER-positive breast cancer.

Purpose: Clinical data suggest that the estrogen receptor (ER) contributes to chemotherapeutic responsiveness. However, ER status alone is not consistently predictive. In this study, we used a microarray approach to find novel ER-related genes that predicted chemotherapy responses, with the hope of providing a robust multi-variable prediction method., Methods: One hundred and ten patients with stages II and III breast cancer were included. They received four preoperative cycles of a weekly PCb (paclitaxel plus carboplatin) regimen. A total of 55 training cases were used for marker discovery and for identification of any ER-related genes that may have been associated with a chemotherapeutic response ("training cases"). The other 55 patients were available as an independent validation set ("validation cases") to test, using immunohistochemistry (IHC)., Results: In the training set, 20 significantly differentially expressed genes were identified. Among these 20 genes, TFF1, ESR1, GATA3 and TFF3 were found to be ER-related. Among 55 independent validation cases, univariate analysis indicated that clinical variables and ER-related genes were all significantly associated with pCR. It was shown that the pCR rate was as high as 80% when these five factors were all negative. In contrast, these five factors were all positive in seven of nine chemo-resistant patients., Conclusion: In conjunction with levels of ER-related genes, expression of ER protein may provide important predictive outcomes for responses to neoadjuvant chemotherapy and may allow for the identification of a subgroup of patients who could significantly benefit from chemotherapy (or who may be resistant to it)., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Due to the small volume and high density of breast tissue in Asian women, particularly younger women, mammographic diagnosis is sometimes non-conclusive, with a Breast Imaging Reporting and Data System (BI-RADS) result of 0. No alternative based on blood biomarkers has yet succeeded in discriminating between patients with breast cancer (BC) and those with benign breast disease (BBD) among BI-RADS 0 patients. In our study, 84 BC and 94 BBD patients with mammographic results and confirmed pathologic information were enrolled and categorized into two groups, namely, 79 BC and 73 BBD patients with BI-RADS 1-5 and 5 BC and 21 BBD patients with BI-RADS 0. RNA extracted from peripheral blood samples collected in PAXgene (TM) tubes was analyzed after NuGEN WT-Ovation (TM) RNA amplification using Affymetrix GeneChip.

Background: This study is a retrospective evaluation of the efficacy of neoadjuvant chemotherapy (NC) with a vinorelbine (V) and epirubicin (E) intravenous combination regimen and is aimed at identification of predictive markers for the long-term outcome in noninflammatory locally advanced breast cancer (NLABC)., Methods: One-hundred-and-nineteen patients with NLABC were identified from September 2001 to May 2006. Analysis was performed in March 2008, with a median follow-up of 63.4 months (range, 9-76 months). All patients were diagnosed with invasive breast cancer using 14 G core needle biopsy and treated with three cycles of VE before surgery. Local-regional radiotherapy was offered to all patients after the completion of chemotherapy followed by hormonal therapy according to hormone receptor status. Tissue sections cut from formalin-fixed paraffin-embedded blocks from biopsy specimens and postoperative tumor tissues were stained for the presence of estrogen receptor (ER), progesterone receptor (PgR), HER-2 (human epidermal growth factor receptor-2), and MIB-1(Ki-67)., Results: Patients characteristics were median age 52 years (range: 25-70 years); clinical TNM stage, stage IIB (n = 32), stage IIIA (n = 56), stage IIIB (n = 22) and stage IIIC (n = 9). All patients were evaluable for response: clinically complete response was documented in 27 patients (22.7%); 78 (65.6%) obtained partial response; stable disease was observed in 13 (10.9%); 1 patient (0.8%) had progressive disease. Pathological complete response was found in 22 cases (18.5%). Seventy-five patients were alive with no recurrence after a median follow-up of 63.4 months, the 5-year rates for disease-free survival and overall survival were 58.7% and 71.3%, respectively, after the start of NC. On multivariate analysis, the independent variables associated with increased risk of relapse and death were high pre-Ki-67(p = 0.012, p = 0.017, respectively), high post-Ki-67 expression (p = 0.045, p = 0.001, respectively), and non-pCR (p = 0.034, p = 0.027, respectively). A significantly increased risk of death was associated with lack of pre-ER expression (p = 0.002). Among patients with non-pCR, those with a pathological response at the tumor site with special involvement (i.e. skin, vessel and more than one quadrant) were at a higher risk of disease relapse and death (p < 0.001, p = 0.001, respectively)., Conclusion: This study suggests the promising use of a VE regimen as NC for Chinese NLABC after a median follow-up of 63.4 months. Pathological response in the tumor site, pre-Ki-67 and post-Ki-67 expression, and pre-ER expression were the important variables that predicted long-term outcome. Patients with pathological special involvement at the primary site after NC had the lowest survival rates.

Purpose: To analyze the rule of recurrence risk for breast cancer patients after surgery in order to get characteristics for Chinese breast cancer., Methods: We performed a retrospective study of 2,213 female unilateral breast cancer patients undergoing surgery in Cancer hospital of Fudan University, Shanghai, China. Survival curves were performed with Kaplan-Meier method and annual recurrence hazard was estimated by hazard function., Results: Annual recurrence hazard curve for entire population showed a double-peaked pattern, with a first major recurrence surge reaching the maximum at the second year after surgery and a second recurrence peak near the 9.5th year. The analysis according to tumor size, axillary lymph node (ALN) status (T1 + T2 versus T3, node-positive versus node-negative) and menopausal status as well as hormone receptor (HR) status proved that the double-peaked pattern was present in each subgroup. Compared with ER-positive tumors, ER-negative breast cancers were more likely to recur early. As far as Her-2/neu status was concerned, Her-2/neu-positive patients exhibited a relatively pronounced and variable pattern and tended to have more relapse across all time periods (P<0.05)., Conclusions: The double-peaked pattern observed in our patients gives further support to tumor dormancy hypothesis. It contributes to different treatment strategies (e.g. the type and timing of adjuvant therapy) for different patients, which provide the possibility to improve survival.

Purpose: The selective treatment of internal mammary lymph nodes (IMNs) in breast cancer is controversial. The purpose of this research was to determine the subpopulation patients with high risk of internal mammary lymph nodes metastasis who received extended radical mastectomy without any preoperative treatment from 1956 to 2003 in China., Patients and Methods: 1,679 Chinese patients were underwent extended radical mastectomy (ERM) between 1956 and 2003. Four individual variables were selected (tumor site, tumor size, the number of ALNs involvement, patient age),then classified by following standards: tumor site(lateral, central, medial),tumor size(T1:5 cm), ALNs(0,1-3,4-6, >or=7), age(50 y). Chi-square and binary logistic regression were used to analysis relationship of these variable and IMMs., Results: The four individual variables were significantly associated with IMNs metastasis using univariate analysis. However, three individual variables except for tumor size independently impact the IMNs metastasis using multivariate analysis. The incidence of IMNs metastasis in patients with 4-6 and >or=7 positive ALNs was 28.1%, 41.5%. Within subgroup patients with medial tumor and positive ALNs, the incidence of IMNs metastasis was 23.6% for patients with 1-3 positive ALNs, and 47.5% for 4-6 positive ALNs, 38.7% for patients with >or=7 positive ALNs. The incidence of IMNs metastasis was 25.4% for patients with T3 tumor and younger than 35 y., Conclusion: Patients with following conditions had high risk of IMNS metastasis: (1) patients with 4 or more positive ALNs. (2) patients with medial tumor and positive ALNs.(3) patients with T3 tumor and younger than 35 y. (4) patients with T2 tumor and positive ALNs.(5) patients with T2 tumor and medial tumor .The incidences of IMNS metastasis for those patients were more than 20%.

Objective: To evaluate the feasibility of lymphoscintigraphy in sentinel lymph node biopsy of breast cancer., Method: Lymphoscintigraphy was performed after peritumoral or subdermal injection of radioactive colloid. Then, sentinel lymph node (SLN) biopsy guided by gamma detector probe was performed. Factors correlated with identification-detection rate were assessed., Results: Lymphatic drainage was present in preoperative lymphoscintigraphy in 88(93%) out of 95 patients, with 39 (44.3%) positive for lymphatic drainage other than in the axilla. A total of 91 (95.8%) patients had their SLN identified in the intraoperative procedure. The quality of lymphoscintigraphic image was closely related to SLN identification-detection rate in the intraoperative procedure (P = 0.025)., Conclusion: Sentinel lymph node outside the axilla can be detected by lymphoscintigraphy. The combination of lymphoscintigraphy and gamma detector probe for sentinel lymph node biopsy of breast cancer not only is acceptable but promising.

Objective: To evaluate the accuracy of sentinel lymph node biopsy (SLNB) to predict the axillary lymph node status in breast cancer patients and its clinical significance., Methods: Seventy patients with clinical TNM status T(1 - 2)N(0)M(0) underwent sentinel lymph node biopsy using Tc-99m sulfur colloid radiotracer and gamma probe, which was followed by standard axillary dissection. SLNB was compared with standard axillary dissection for its ability to reflect the final pathological status of the axillary nodes. The SLNs that were tumor negative in conventional HE staining were further evaluated using immunohistochemical stains for CK8, CK19 and KP-1 antibodies., Results: The sentinel lymph node (SLN) was successfully identified in 67 (95.7%) out of 70 patients. The number of sentinel nodes harvested ranged from 1 to 5 (average 1.6). The nonsentinel nodes ranged from 5 to 20 (average 12.3). Of the 67 patients, 29 (43.3%) had histologically positive axillary lymph nodes. SLN was positive in 24 patients with metastasis (35.8%), and in 7 patients without metastasis (10.4%). In 5 patients, SLN was negative for tumor with positive nodes. The accuracy of sentinel lymph node biopsy to predict the axillary lymph node status was 92.5% and the false negative rate was 7.5%. For tumors with diameter less than or equal to 2 cm, the accuracy was 100%. 65 SLNs that were negative for HE stain were also non-reactive to immunostain for CK8 and CK19 antibody., Conclusions: SLNB can accurately predict the axillary lymph node status in most of breast cancer patients. The accuracy is about 100% in patients with T(1) lesions. Immunohistochemical staining at the same level of HE stain can not increase the detection of lymph node micrometastasis.