Relationships between pathological factors and long-term outcomes in patients enrolled in two prospective randomized controlled trials comparing the efficacy of oral tegafur-uracil with CMF (N·SAS-BC 01 trial and CUBC trial).

PURPOSE: To evaluate the efficacies of cyclophosphamide, methotrexate, and fluorouracil (CMF) and tegafur-uracil (UFT) as adjuvant therapy in patients with resected stage I-IIIA breast cancer by immunohistochemistry (IHC)-based subtype and to determine the relationships between clinicopathological factors and long-term outcomes. METHODS: A pooled analysis of the randomized controlled N·SAS-BC 01 and CUBC studies was conducted. Expression of hormone receptors (HRs; estrogen and progesterone receptors), human epidermal growth factor receptor 2 (HER2), and Ki67were assessed by IHC. Tumor-infiltrating lymphocytes (TILs) and nuclear/histological grades were determined by hematoxylin and eosin staining. Relapse-free survival (RFS) and overall survival (OS) were estimated by Kaplan-Meier analysis and hazard ratios were determined by Cox model adjusted for baseline tumor size and nodal status. RESULTS: A total of 689 patients (342 CMF and 347 UFT) were included in the analyses with a median follow-up of 11.1 years. There was no significant difference in RFS or OS between the two cohorts (RFS: 0.96 [95% confidence interval: 0.71-1.30], log-rank test p = 0.80; OS: 0.93 [0.64-1.35], p = 0.70). There was no difference in RFS or OS between the two cohorts for HR+/HER2- and HR+/HER2+ subtypes. RFS was significantly longer in patients treated with UFT compared with CMF in patients with HR-/HER2+ subtype (0.30 [0.10-0.88], p = 0.03). A high TILs level was associated with a better OS compared with low TILs level (p = 0.02). CONCLUSIONS: This long-term follow-up study showed that RFS and OS were similar in patients with luminal-type breast cancer treated with CMF and UFT.

Atypical pseudoangiomatous stromal hyperplasia showing rapid growth of the breast: Report of a case.

Pseudoangiomatous stromal hyperplasia (PASH) of the breast is a benign lesion manifesting as myofibroblastic proliferation and anastomosing slit-like spaces. Atypical PASH is an extremely rare lesion characterized by cytological alteration of myofibroblast, presenting as myofibroblastic sarcoma arising from PASH. To our knowledge, only one other case has been reported since the first report of Rosen. We present a case of atypical PASH. A 39-year-old female presented with a round, elastic hard, painless mass in the left breast. Mammography and ultrasonography revealed no definitive sign of malignancy. Core needle biopsy report was suggestive of atypical PASH. Five months later, the mass had grown rapidly with pain. Considering the clinicopathological features, excision was performed. Pathological examination revealed the spindle cells proliferation in collagenous stroma. The spindle cell involved the adipose tissue and lobules and lined peudoangiomatous spaces. These cells exhibited marked cytological atypia and mitotic activity. Immunohistochemically, these spindle cells were positive for SMA, CD10, and bcl-2, and negative for podoplanin, p63, CD31, ERG and cytokeratins. The final diagnosis was atypical PASH. She is tumor-free on 12 months follow-up. The nature of atypical PASH remains unknown. Further studies are required for a clear definition, a new histological entity and diagnostic criteria.

[Evaluation of Pre-Therapeutic Ki-67 as a Predictive Marker for Histological Response to Neoadjuvant Therapy in Breast Cancer].

There is controversy as to whether the proliferative marker Ki-67 is useful as a predictive marker for response to neoadjuvant therapy in breast cancer. We evaluated Ki-67 levels in pre-therapeutic breast cancer core biopsies from 52 breast cancer patients. These patients underwent anthracycline and taxane-based chemotherapy (n=48) or endocrine therapy (n=4) followed by surgery between March 2010 and February 2015. Expression of estrogen receptor (ER), progesterone receptor (PgR), HER2, and Ki-67 were examined by immunohistochemistry in the core-needle biopsy specimens. Ki-67 levels were categorized into 3 groups: low (<20%), intermediate (20-50%), and high (≥50%). Pathological response rates were 29%, 15%, and 48% in the low, intermediate, and high-risk groups, respectively. In univariate analysis, pre-therapeutic high levels of Ki-67, as well as negative ER status were significantly associated with the responder group (p<0.05). However, neither Ki- 67 nor ER status were significantly associated with a response in multivariate analysis. Ki-67 appears to be a promising parameter for histological response to neoadjuvant therapy in breast cancer.

Breast cancer subtype and distant recurrence after ipsilateral breast tumor recurrence.

BACKGROUND: There is little information about the impact of breast cancer subtype on prognosis after ipsilateral breast tumor recurrence (IBTR). METHODS: One hundred eighty-five patients were classified according to breast cancer subtype, as approximated by estrogen receptor, human epidermal growth factor receptor 2 (HER2), and Ki-67, of IBTR, and we evaluated whether breast cancer subtype was associated with distant recurrence after IBTR. RESULTS: There was a significant difference in distant disease-free survival (DDFS) after IBTR according to breast cancer subtype defined by a cutoff of the Ki-67 index of 20 % (p = 0.0074, log-rank test). The 5-year DDFS rates for patients with luminal A, luminal B, triple-negative, and HER2 types were 86.3, 57.1, 56.6, and 65.9 %, respectively. In addition, breast cancer subtype was significantly associated with distant recurrence after IBTR on adjustment for various clinicopathologic factors (p = 0.0027, Cox proportional hazards model). CONCLUSIONS: Our study suggests that breast cancer subtype based on immunohistochemical staining predicts the outcomes of patients with IBTR. Further analyses are needed (UMIN-CTR number UMIN000008136).

Cell Block-Based Two-Dimensional and Immunocytochemical Analyses Could Reduce Atypical/Indeterminate Case Frequency in Breast Fine-Needle Aspiration Cytology: A Retrospective Analysis.

INTRODUCTION: In fine-needle aspiration of the breast (FNAB), the "atypical" category encompasses both benign and malignant lesions, particularly papillary proliferative lesions, as per the latest WHO classification. We aimed to reduce atypical cases and improve diagnostic accuracy by investigating the utility of cell block (CB) analysis. METHODS: FNAB CB samples (2018-2022) were reviewed using smear only or CBs. CB-based diagnosis was performed with 2D morphological analysis and immunocytochemistry using ER, CK5/6, p63, SMA, and CD56. Samples were reclassified as "benign," "atypical," "suspicious of malignancy," "malignant," or "insufficient/inadequate." Atypical cases were reexamined. Diagnoses were validated histologically. RESULTS: On examining the FNAB samples (n = 149; 32 atypical), 2D CB sectioning achieved a clearer definition of myoepithelial cells and fibrovascular cores than Papanicolaou staining. Immunocytochemistry was evaluated for 36 cases: estrogen receptor (ER)- and CK5/6+ tumors were reclassified as benign; ER+ and CK5/6- tumors as malignant; p63- tumors as invasive; papillary malignant tumors with a smooth muscle actin (SMA)+ fibrovascular core and p63- myoepithelial cells as encapsulated papillary carcinoma; and CD56+ carcinomas as neuroendocrine carcinoma. Diagnostic rates were as follows: benign (44% FNAB, 51% CB), atypical (21% FNAB, 3% CB), suspicious of malignancy and malignant (28% FNAB, 40% CB), and insufficient/inadequate (7% FNAB, 6% CB). CB achieved >85% sensitivity, specificity, and positive and negative predictive values. CONCLUSION: CBs represent 3D FNA cell morphology using 2D sections, enabling adaption of pathology criteria to the cytological material. Immunocytochemical staining of CBs can predict low nuclear grade papillary tumors and reduce atypical case frequency, improving diagnostic accuracy.

A prospective analysis of two studies that used the 5-mm interval slices and 5-mm margin-free method for ipsilateral breast tumor recurrence after breast-conserving surgery without radiotherapy.

BACKGROUND: Breast-conserving surgery with radiotherapy is one of standard treatments for early breast cancer. However, it is regarded as an option to treat elderly patients with small hormone receptor-positive breast cancer with breast-conserving surgery and hormone therapy without radiotherapy. We conducted two sequential prospective studies to examine the feasibility of breast-conserving surgery without radiotherapy since 2002 and present the results. PATIENTS AND METHODS: Primary female breast cancer patients who fulfilled the strict eligibility criteria were prospectively enrolled in two sequential studies named WORTH 1 and 2. The surgical materials were sliced in 5-mm intervals and all slices were examined microscopically. Postoperative radiotherapy was not allowed, but tamoxifen or anastrozole was administered for 5 years. Ipsilateral breast tumor recurrence (IBTR)-free survival was the primary outcome. RESULTS: The data of the two studies were combined (N = 321). The median follow-up period for IBTR was 94 months (4-192 months). Only three patients were treated with adjuvant chemotherapy. The 5- and 10-year IBTR-free rates were 97.0% and 90.5%, respectively. The age at operation and PR status affected IBTR rates independently. When we calculated IBTR-free rates of patients who were 65 years of age or older at the time of surgery and had PR-positive tumors, the 5- and 10-year IBTR rates were both 98.4%. CONCLUSIONS:  Our "5-mm-thick slice and 5-mm free-margin" method may be effective to select patients who can be treated by breast-conserving surgery and hormone therapy without radiotherapy.

Preferences Regarding Breast Surgery Omission Among Patients With Breast Cancer Who Receive Neoadjuvant Chemotherapy.

BACKGROUND/AIM: Currently, several ongoing prospective studies are investigating the safety of breast surgery omission in patients with breast cancer who are exceptional responders to neoadjuvant chemotherapy. However, there is little information about the preferences of these patients regarding omission of breast surgery. PATIENTS AND METHODS: We conducted a questionnaire survey to assess preferences regarding omission of breast surgery among patients with breast cancer who had human epidermal growth factor receptor 2-positive or estrogen receptor-negative tumors and good clinical response after neoadjuvant chemotherapy. Patients' estimation of the risk of ipsilateral breast tumor recurrence (IBTR) after definitive surgery or breast surgery omission was also assessed. RESULTS: Of 93 patients, only 22 (23.7%) said they would omit breast surgery. Under the scenario of omitting breast surgery, the 5-year IBTR rate estimated by patients who said they would omit breast surgery was significantly lower (median, 10%) than the rate estimated by patients who preferred undergoing definitive surgery (median, 30%) (p=0.017). CONCLUSION: The proportion of our surveyed patients who were willing to omit breast surgery was low. Patients who said they preferred to omit breast surgery overestimated the 5-year IBTR risk.

A strategy for large-scale phosphoproteomics and SRM-based validation of human breast cancer tissue samples.

Protein phosphorylation is a key mechanism of cellular signaling pathways and aberrant phosphorylation has been implicated in a number of human diseases. Thus, approaches in phosphoproteomics can contribute to the identification of key biomarkers to assess disease pathogenesis and drug targets. Moreover, careful validation of large-scale phosphoproteome analysis, which is lacking in the current protein-based biomarker discovery, significantly increases the value of identified biomarkers. Here, we performed large-scale differential phosphoproteome analysis using IMAC coupled with the isobaric tag for relative quantification (iTRAQ) technique and subsequent validation by selected/multiple reaction monitoring (SRM/MRM) of human breast cancer tissues in high- and low-risk recurrence groups. We identified 8309 phosphorylation sites on 3401 proteins, of which 3766 phosphopeptides (1927 phosphoproteins) were able to be quantified and 133 phosphopeptides (117 phosphoproteins) were differentially expressed between the two groups. Among them, 19 phosphopeptides were selected for further verification and 15 were successfully quantified by SRM using stable isotope peptides as a reference. The ratio of phosphopeptides between high- and low-risk groups quantified by SRM was well correlated with iTRAQ-based quantification with a few exceptions. These results suggest that large-scale phosphoproteome quantification coupled with SRM-based validation is a powerful tool for biomarker discovery using clinical samples.

Strategy for SRM-based verification of biomarker candidates discovered by iTRAQ method in limited breast cancer tissue samples.

Since LC-MS-based quantitative proteomics has become increasingly applied to a wide range of biological applications over the past decade, numerous studies have performed relative and/or absolute abundance determinations across large sets of proteins. In this study, we discovered prognostic biomarker candidates from limited breast cancer tissue samples using discovery-through-verification strategy combining iTRAQ method followed by selected reaction monitoring/multiple reaction monitoring analysis (SRM/MRM). We identified and quantified 5122 proteins with high confidence in 18 patient tissue samples (pooled high-risk (n=9) or low-risk (n=9)). A total of 2480 proteins (48.4%) of them were annotated as membrane proteins, 16.1% were plasma membrane and 6.6% were extracellular space proteins by Gene Ontology analysis. Forty-nine proteins with >2-fold differences in two groups were chosen for further analysis and verified in 16 individual tissue samples (high-risk (n=9) or low-risk (n=7)) using SRM/MRM. Twenty-three proteins were differentially expressed among two groups of which MFAP4 and GP2 were further confirmed by Western blotting in 17 tissue samples (high-risk (n=9) or low-risk (n=8)) and Immunohistochemistry (IHC) in 24 tissue samples (high-risk (n=12) or low-risk (n=12)). These results indicate that the combination of iTRAQ and SRM/MRM proteomics will be a powerful tool for identification and verification of candidate protein biomarkers.

Outcomes of Japanese breast cancer patients treated with pre-operative and post-operative anastrozole or tamoxifen.

The present study examined long-term efficacy outcomes in a subgroup of postmenopausal, estrogen receptor-positive Japanese breast cancer patients from the Pre-Operative "Arimidex" Compared with Tamoxifen trial, following pre-operative (3 months) and post-operative (5 years) adjuvant treatment with either anastrozole or tamoxifen. Patients with large, potentially operable, locally-advanced breast cancer were randomized to receive anastrozole (1 mg/day) plus tamoxifen placebo or tamoxifen (20 mg/day) plus anastrozole placebo pre-operatively. After surgery at 3 months, patients continued on the same study medication as adjuvant therapy for up to 5 years or until recurrence, intolerable toxicity or withdrawal of patient consent. Recurrence-free survival and overall survival were measured from the date of randomization to the date of recurrence or death, whichever occurred first. Patients were monitored for adverse events throughout the study period and up to 30 days following administration of the last study medication. During post-operative adjuvant therapy, 4/48 (8%) anastrozole and 25/49 (51%) tamoxifen patients experienced recurrence. There was a significant difference in recurrence-free survival between the two groups (hazard ratio 0.14; 95% confidence interval 0.05-0.41; P = 0.0003). There was a significant increase in overall survival with anastrozole (0.21; 0.05-0.96; P = 0.0436) and there were 2/48 (4%) and 10/49 (20%) deaths with anastrozole and tamoxifen, respectively. Most patients responding to pre-operative therapy remained recurrence-free. Sequential pre-operative/post-operative treatment with anastrozole resulted in lower recurrence and death rates, compared with tamoxifen.

Randomized phase II study of three doses of oral TAS-108 in postmenopausal patients with metastatic breast cancer.

This randomized phase II study was intended to identify the optimal dose of TAS-108, a novel steroidal antiestrogen, for the treatment of breast cancer in postmenopausal Japanese women. The potential clinical effects of TAS-108 on the uterus, bone, serum lipids, and hormones were also investigated. Postmenopausal women with hormone receptor-positive metastatic breast cancer who had previously received one or two endocrine therapies were randomly assigned to one of the three possible dose levels of TAS-108 (40, 80 or 120 mg/day). Oral TAS-108 was given daily, and the efficacy and safety of the three doses were evaluated. A total of 97 patients (33, 32, and 32 in the 40-, 80-, and 120-mg groups, respectively) were treated with TAS-108. The clinical benefit rate was 30.3% for the 40-mg, 25.0% for the 80-mg, and 25.0% for the 120-mg group. The 40-mg group achieved the prespecified target threshold. TAS-108 at all dose levels was well tolerated and appeared to have no harmful effects in terms of the variables examined in this study. We conclude that the optimal dose of TAS-108 among the three doses is 40 mg, once daily, for further studies. JAPIC Clinical Trials Information number: Japic CTI - 121754.

Ipsilateral breast tumor recurrence (IBTR) in patients with operable breast cancer who undergo breast-conserving treatment after receiving neoadjuvant chemotherapy: risk factors of IBTR and validation of the MD Anderson Prognostic Index.

BACKGROUND: There is limited information about the risk factors for ipsilateral breast tumor recurrence (IBTR) after patients undergo breast-conserving surgery plus radiotherapy (breast-conserving treatment [BCT]) subsequent to neoadjuvant chemotherapy (NAC). The objective of the current study was to analyze these risk factors. METHODS: The authors collected data from 375 patients who underwent BCT and received NAC and analyzed the risk of IBTR associated with undergoing BCT after NAC. The usefulness of the MD Anderson Prognostic Index (MDAPI) for IBTR also was validated using the current data set. RESULTS: The median follow-up was 47.8 months, and the 4-year IBTR-free survival rate was 95.6%. Multivariate analysis demonstrated that estrogen receptor (ER) status and multifocality of the residual tumor were associated significantly with IBTR-free survival. In addition, patients who had ER-positive and human epidermal growth factor 2 (HER2)-negative tumors did not develop IBTR during the observation period. Although prognostic stratification according to MDAPI was relatively good for the prediction of IBTR in the study patients, the IBTR rate in the high-risk group was not very high and was lower than that in the intermediate-risk group. Multivariate analyses demonstrated that IBTR was an independent predictive factor for overall survival. CONCLUSIONS: ER status and multifocality of the residual tumor after NAC were independent predictors of IBTR after BCT. The MDAPI was barely adaptable to the study patients in terms of predicting IBTR. Patients with ER-positive and HER2-negative tumors had a favorable prognosis, whereas patients who developed IBTR after NAC had significantly worse overall survival. The authors propose a new IBTR prognostic index using the 2 factors that were identified as predictive of IBTR: ER status and multifocality of the residual tumor.

Evaluation of the usefulness of breast CT imaging in delineating tumor extent and guiding surgical management: a prospective multi-institutional study.

OBJECTIVE: The aim of the present study was to evaluate the usefulness of computed tomographic (CT) imaging in delineating tumor extent and guiding surgical management. BACKGROUND: The routine use of preoperative magnetic resonance imaging (MRI) is a controversial issue in breast cancer management. Negative studies with regard to the utility of MRI might be due to differences in positioning during imaging and subsequent surgery. METHODS: Candidates for breast-conserving surgery were eligible for the study. The surgeons marked the line of planned excision on the skin, which was also recorded on the CT image. Contrast-enhanced breast CT was performed in the supine surgical position. The CT results were used to help determine the extent of resection. The pathological findings were then compared with the CT-guided surgical plans. RESULTS: A total of 297 patients were involved. The surgeons widened the extent of resection in 42 (14.1%, 95% confidence interval 10.1%-18.1%) patients on the basis of the CT findings. Among the 6 patients whose procedures were changed to mastectomy, 4 had pathologically multicentric tumors and 2 had widely spread intraductal components. The remaining 36 patients underwent quadrantectomy instead of wide excision on the basis of the CT images. There were 3 patients in whom conversion from wide excision to quadrantectomy resulted in overexcision. Preoperative breast CT may have reduced the positive margin rate and also correctly changed the extent of surgery in 13.1% of patients. CONCLUSIONS: This prospective study suggests that breast CT, carried out in the supine position, is useful in the preoperative determination of the optimal surgical procedure.

Validation of a nuclear grading system for resected stage I-IIIA, high-risk, node-negative invasive breast carcinoma in the N·SAS-BC 01 trial.

BACKGROUND: This retrospective observational study validated nuclear grading criteria developed to identify a high-risk group with recurrence rate ≥20-30% and local pathology diagnosis used in a previous multi-institutional randomized N·SAS-BC 01 trial, where the efficacy of adjuvant chemotherapy regimens was evaluated in 733 high-risk node-negative invasive breast cancer patients. METHODS: Of 545 patients with long-term follow-up data (median 12.1 years), pathology slides, and local pathology diagnosis, 530 eligible patients were subjected to central pathology review (CPR) for histological type and nuclear grade (NG). Concordance in NGs was compared with local diagnosis. The 10/15-year recurrence-free survival (RFS) and overall survival (OS) rates stratified by NG and histological type were calculated. RESULTS: Local diagnoses were invasive ductal carcinoma (IDC)-NG2, IDC-NG3, invasive lobular carcinoma (ILC), and metaplastic carcinoma (MC) in 158/327/38/7 patients, respectively. The 10/15-year RFS rates were 87.2/82.6% for IDC-NG2 and 81.8/75.0% for IDC-NG3 (p = 0.061), and OS rates were 95.0/92.8% for IDC-NG2 and 90.8/85.7% for IDC-NG3 (p = 0.042). CPR graded 485 locally diagnosed IDCs as IDC-NG1/NG2/NG3/unknown in 98/116/267/4 patients, respectively. No significant difference was found among survival curves for the three NG groups. Although the agreement level between local and CPR diagnoses was low (κ = 0.311), both diagnoses identified a patient group with a 15-year recurrence rate ≥ 20%. The 10/15-year RFS rates were 79.4/63.5% for ILC and 68.6%/unknown for MC. CONCLUSIONS: The N·SAS grading system identified a patient group with high-risk node-negative invasive breast cancer, suggesting that local diagnosis was performed efficiently in the N·SAS-BC 01 trial. TRIAL REGISTRATION NUMBER: UMIN000022571. Date of registration: June 1, 2016.

SPIO-enhanced magnetic resonance imaging for the detection of metastases in sentinel nodes localized by computed tomography lymphography in patients with breast cancer.

BACKGROUND: Superparamagnetic nanoparticle-enhanced magnetic resonance (MR) imaging has been reported to be a promising improvement for diagnostic imaging of lymph node metastases from various tumors. Moreover, sentinel nodes have been reported to be well identified using computed tomography (CT) lymphography (CT-LG) in patients with breast cancer. The aim of this study was to evaluate MR imaging with superparamagnetic iron oxide (SPIO) enhancement for the detection of metastases in sentinel nodes localized by CT-LG in patients with breast cancer. METHODS: This study included 102 patients with breast cancer and clinically negative nodes. Sentinel nodes were identified by CT-LG, and SPIO-enhanced MR imaging of the axilla was performed to detect metastases in the sentinel nodes. A node was considered nonmetastatic if it showed a homogenous low signal intensity and metastatic if the entire node or a focal area did not show low signal intensity on MR imaging. Sentinel node biopsy was performed, and imaging results were correlated with histopathologic findings. RESULTS: The mean number of sentinel nodes identified by CT-LG was 1.1 (range, 1-3). The sensitivity, specificity, and accuracy of MR imaging for the diagnosis of sentinel node metastases were 84.0%, 90.9%, and 89.2%, respectively. In 4 of 10 patients with micrometastases, metastases were not detected, but all 15 patients with macrometastases were successfully identified. CONCLUSIONS: SPIO-enhanced MR imaging is a useful method of detecting metastases in sentinel nodes localized by CT-LG in patients with breast cancer and may avoid sentinel node biopsy when the sentinel node is diagnosed as disease-free.

Repeat lumpectomy for ipsilateral breast tumor recurrence after breast-conserving treatment.

OBJECTIVES: There are limited data on the outcomes of patients treated with repeat lumpectomy at the time of ipsilateral breast tumor recurrence (IBTR). METHODS: We retrospectively analyzed 78 patients who underwent repeat lumpectomy after IBTR. The risk factors for second IBTR were assessed. RESULTS: The median follow-up period was 40 months. The 5-year second IBTR-free survival rate was 78.8%. Patients with estrogen receptor (ER)-positive or unknown tumors at IBTR had a significantly better second IBTR-free survival rate than those with ER-negative tumors at IBTR (88.3 vs. 55.4%, respectively; p = 0.0022). Multivariate analysis revealed that the ER status of IBTR was a significantly independent predictive factor for second IBTR-free survival (p = 0.0177). The low-risk group for second IBTR was detected using the ER status, disease-free interval, margin status of IBTR, and age at diagnosis (5-year cumulative incidence, 7.0%). CONCLUSION: The ER status of IBTR was a significantly independent predictive factor for second IBTR-free survival. Some patients could safely undergo repeat lumpectomy for IBTR.

Efficacy of oral tegafur-uracil (UFT) as adjuvant therapy as compared with classical cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) in early breast cancer: a pooled analysis of two randomized controlled trials (N.SAS-BC 01 trial and CUBC trial).

Two randomized clinical studies comparing the efficacy of oral UFT (2 years) with that of classical cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) (six courses) have been conducted in patients with resected early breast cancer. We have performed a pooled analysis of these two randomized studies. A pooled analysis was performed using individual patient data from the two trials. Hazard ratios (HRs) were determined with a Cox model stratified by study and adjusted for clinical characteristics. We preplanned to verify the following two hypotheses: UFT is non-inferior to CMF in all patients (hypothesis 1) or in ER-positive patients (hypothesis 2) with respect to relapse-free survival (RFS). Non-inferiority of UFT versus CMF was established if the upper limit of the two-sided confidence interval (CI) of the HR for RFS did not exceed 1.30. Hochberg multiplicity adjustment for the significance level was performed. A total of 1,057 patients were analyzed (CMF, n = 528; UFT, n = 529). Median follow-up time was 5.6 years. The HR for RFS was 1.04 (95% CI, 0.78-1.40) in all patients and 0.79 (97.5% CI, 0.49-1.27) in ER-positive patients. UFT was shown to be non-inferior to CMF in ER-positive patients. An exploratory subgroup analysis showed that RFS was better with UFT than with CMF in ER-positive patients who were 50 years or older (HR, 0.58; 95% CI, 0.34-1.01). UFT is non-inferior to CMF in terms of inhibiting recurrence of ER-positive, early breast cancer.

Prognostic significance of neutropenia on day one of anthracycline-based neoadjuvant chemotherapy in operable breast cancer.

OBJECTIVES: It is currently unknown whether neutropenia during neoadjuvant chemotherapy for early breast cancer is associated with prognosis. METHODS: We retrospectively analyzed 103 breast cancer patients who were treated with neoadjuvant chemotherapy including epirubicin-based chemotherapy followed by docetaxel. The association between neutropenia due to epirubicin-based chemotherapy and distant disease-free survival (DDFS) was assessed. RESULTS: Thirty-one patients (30%) demonstrated neutropenia during the epirubicin-based regimen. Patients without neutropenia showed a significantly (p = 0.004) lower 5-year DDFS rate (64%) than those with neutropenia (97%). In addition, multivariate analysis showed that neutropenia is an independent prognostic factor for DDFS (p = 0.02). CONCLUSION: Neutropenia occurring in early breast cancer patients during the initial neoadjuvant treatment is strongly associated with a better prognosis.

Expression of estrogen receptor beta and phosphorylation of estrogen receptor alpha serine 167 correlate with progression-free survival in patients with metastatic breast cancer treated with aromatase inhibitors.

Aromatase inhibitor (AI) is widely used as an endocrine treatment in postmenopausal patients with hormone receptor-positive breast cancer. To identify useful prognostic factors for patients with metastatic breast cancer treated with AI therapy, we investigated the association between several hormone receptor-related factors and prognosis. The expressions of estrogen receptor-α (ERα), ERß, progesterone receptor, the phosphorylation of ERα serine 118 (Ser118) and ERα Ser167 were examined using immunohistochemical techniques for the primary tumors of 41 patients with metastatic breast cancer who received first-line AI therapy after relapse. To assess the associations of protein expression and phosphorylation levels with progression-free survival (PFS), the levels of each factor were categorized into low and high values at optimal cutoff points. In univariate analysis, high ERα expression and high ERα Ser167 phosphorylation correlated with longer PFS (p = 0.016 and 0.013, respectively). In multivariate analysis, low ERß expression and high ERα Ser167 phosphorylation correlated with longer PFS (p = 0.031 and 0.004, respectively). Patients with both low ERß expression and high ERα Ser167 phosphorylation had longer PFS than the others (p = 0.0107). These data suggest that the expression of ERß and phosphorylation of ERα Ser167 may be useful prognostic factors in patients with metastatic breast cancer who received first-line AI therapy.

Phase II trial in Japan of sequential administration of weekly paclitaxel followed by FEC as neoadjuvant chemotherapy for locally advanced breast cancer [KBCSG0206 trial: Kinki Breast Cancer Study Group (KBCSG)].

OBJECTIVE: We conducted a phase II trial in Japan to evaluate the efficacy and tolerability of weekly paclitaxel followed by fluorouracil, epirubicin, and cyclophosphamide (FEC) as neoadjuvant chemotherapy (NAC) for locally advanced breast cancer (LABC). METHODS: Patients with clinical stage IIIA-IIIB breast cancer received NAC consisting of 12 once-a-week cycles of paclitaxel followed by 4 once-every-third-week cycles of FEC. RESULTS: Fifty patients with LABC were enrolled, 47 of whom were administered paclitaxel followed by FEC as NAC. The clinical response rate for all chemotherapies was 85.1%, and the pathological complete response rate was 27.7%. Regarding toxicity, grade 3-4 neutropenia was observed in 10% of patients. No serious toxicities requiring the discontinuation of treatment were encountered. The rate of breast conservation surgery was 31.9%, median survival had not been reached at the time of conclusion of this study, and the 3-year survival rate was 85.1%. Median disease-free survival was 40.2 months, and the 3-year disease-free survival rate was 62.1%. CONCLUSIONS: Weekly paclitaxel followed by FEC demonstrated efficacy and tolerable toxicity in a neoadjuvant setting for LABC.