The Clinicopathological and Prognostic Significance of HER2-Low Breast Cancer: A Comparative Analysis Between HER2-Low and HER2-Zero Subtypes.

BACKGROUND: HER2-low breast cancer (BC) is a newly defined subset of HER2-negative BC. However, it is still uncertain whether HER2-low BC can be categorized as a distinct biological/clinical subgroup with any prognostic significance. METHODS: Invasive BC cases (n = 10,215) with Stage I-III were retrospectively analyzed to determine the HER2 status. The HER2 status was then divided into 3 groups: HER2-0, HER2-low, and HER2-positive. RESULTS: The HER2 status was classified as HER2-0 in 1,227 cases (12.0%), HER2-low in 7,209 cases (70.6%), and HER2-positive in 1779 cases (17.4%). HER2-low cases had more positive nodes and were significantly associated with positive ER/PgR, lower nuclear grade, and lower Ki-67 index. HER2-0 had the lowest OS rate in the primary cases and after recurrence. HER2-0 in the node positive group had the lowest OS and was significantly different from HER2-low in the same group. The pathological complete response (pCR) rate for NAC was lowest in the HER2-low group. The DFS after NAC was significantly better in all the pCR cases, regardless of the HER2 status. However, the DFS was significantly lower in the HER2-low non-pCR cases. CONCLUSION: HER2-low accounted for 70% of the cases and correlated with favorable biological markers. The HER2-low group had a significantly better OS than the HER2-0 group. However, the response to NAC was low in the HER2-low group, and this group had the poorest prognosis among all the non-pCR cases. These findings indicate that HER2-low may have a different biology and prognosis and therefore should be classified as a new entity.

Long-term prognostic value of the GenesWell BCT score in Asian women with hormone receptor-positive/HER2-negative early breast cancer.

BACKGROUND: Accurate prediction of the risk of recurrence is crucial for optimal treatment decisions in hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative early breast cancer. The GenesWell BCT is a molecular assay to predict the 10-year risk of distant metastasis. In this study, we evaluated the long-term prognostic value of the GenesWell BCT assay. METHODS: The BCT score was assessed in patients with HR-positive/HER2-negative early breast cancer who did not receive chemotherapy. We compared the 15-year distant metastasis-free survival (DMFS) between risk groups classified based on the BCT score. The risk of early (0-5 years) and late (5-15 years) recurrence was evaluated based on the BCT score classification. RESULTS: According to the BCT score, 366 patients from Japan and Korea were categorized as BCT low risk (83.6%) and high risk (16.4%) for distant metastasis. Median follow-up time was 17.4 years. The 15-year DMFS rate was significantly lower in the BCT high-risk group (63.3%) than in the BCT low-risk group (93.6%) (P < 0.001). The BCT risk group was an independent prognostic factor for 15-year DMFS (hazard ratio, 4.59; 95% confidence interval 2.13-9.88; P < 0.001). Furthermore, the BCT score was a significant predictor of late recurrence (5-15 years) in patients aged ≤ 50 years and those aged > 50 years, and added prognostic information to traditional clinical prognostic factors. CONCLUSION: The BCT score can identify patients at low risk for recurrence who may not require adjuvant chemotherapy or extended endocrine therapy, regardless of age.

Satisfaction of Patients Who Received Breast-Conserving Surgery Using the Suture Scaffold Technique: A Single-Institution, Cross-Sectional Study.

BACKGROUND: Optimal cosmetic results after breast-conserving surgery (BCS) improve patient satisfaction. The suture scaffold technique (SST) is a breast reconstruction technique that all breast surgeons can perform without any extensive training in plastic surgery. OBJECTIVE: We aimed to investigate patient satisfaction after BCS and compare blood loss and operative duration between the SST, breast glandular flap technique (BGFT), and no oncoplastic technique (NOT). METHODS: This was a prospective, single-center, cross-sectional study. All patients who underwent BCS from August 2017 to September 2019 in our institution were included, with the exception of those with cT3 tumors or those who underwent nipple excision or bilateral breast surgery. The BREAST-Q™ was used to survey the patients, and the raw sum scale scores of the BREAST-Q™ were converted into BREAST-Q scores. RESULTS: Overall, we identified 421 eligible patients. The NOT was used in 47 (11.1%) patients, the BGFT was used in 231 (54.8%) patients, and the SST was used in 143 (33.9%) patients. In the univariable model, the BGFT and the SST had higher BREAST-Q scores than the NOT, while in the multivariable model, the SST had significantly higher BREAST-Q scores than the NOT (ß = +7.7, 95% confidence interval [CI] 0.9-13.7; p = 0.01). Blood loss was significantly less with the SST compared with the BGFT (ß = -4.4, 95% CI -7.3 to -1.4), and there was no difference in operative duration between the methods. CONCLUSIONS: Patient satisfaction with the SST was higher than with the NOT and was similar to the BGFT. The SST is an oncoplastic technique that all breast surgeons can perform and which requires comparable blood loss and operative duration in the NOT.

Combined Use of Texture Features and Morphological Classification Based on Dynamic Contrast-enhanced MR Imaging: Differentiating Benign and Malignant Breast Masses with High Negative Predictive Value.

PURPOSE: We evaluated the diagnostic performance of the texture features of dynamic contrast-enhanced (DCE) MRI for breast cancer diagnosis in which the discriminator was optimized, so that the specificity was maximized via the restriction of the negative predictive value (NPV) to greater than 98%. METHODS: Histologically proven benign and malignant mass lesions of DCE MRI were enrolled retrospectively. Training and testing sets consist of 166 masses (49 benign, 117 malignant) and 50 masses (15 benign, 35 malignant), respectively. Lesions were classified via MRI review by a radiologist into 4 shape types: smooth (S-type, 34 masses in training set and 8 masses in testing set), irregular without rim-enhancement (I-type, 60 in training and 14 in testing), irregular with rim-enhancement (R-type, 56 in training and 22 in testing), and spicula (16 in training and 6 in testing). Spicula were immediately classified as malignant. For the remaining masses, 298 texture features were calculated using a parametric map of DCE MRI in 3D mass regions. Masses were classified into malignant or benign using two thresholds on a feature pair. On the training set, several feature pairs and their thresholds were selected and optimized for each mass shape type to maximize specificity with the restriction of NPV > 98%. NPV and specificity were computed using the testing set by comparison with histopathologic results and averaged on the selected feature pairs. RESULTS: In the training set, 27, 12, and 15 texture feature pairs are selected for S-type, I-type, and R-type masses, respectively, and thresholds are determined. In the testing set, average NPV and specificity using the selected texture features were 99.0% and 45.2%, respectively, compared to the NPV (85.7%) and specificity (40.0%) in visually assessed MRI category-based diagnosis. CONCLUSION: We, therefore, suggest that the NPV of our texture-based features method described performs similarly to or greater than the NPV of the MRI category-based diagnosis.

Anthracycline-containing regimens or taxane versus S-1 as first-line chemotherapy for metastatic breast cancer.

BACKGROUND: We have previously demonstrated S-1 is non-inferior to taxane with respect to overall survival as first-line chemotherapy for HER2-negative metastatic breast cancer. We aimed to confirm whether S-1 is also non-inferior to anthracycline-containing regimens in the same setting. METHODS: We conducted an open-label, non-inferiority, Phase 3 study. Individuals who had HER2-negative metastatic breast cancer, had received no chemotherapy for advanced disease and had endocrine therapy resistance, were randomly assigned to the anthracycline-containing regimens or S-1. The primary endpoint was overall survival. A pre-planned combined analysis of our two Phase 3 studies was also carried out. RESULTS: We enrolled 230 patients (anthracycline, n = 115; S-1, n = 115). Median overall survival was 30.1 months (95% CI 24.9-35.8) with the S-1 group and 33.7 months (95% CI 25.5-36.9) with the anthracycline group. The HR for the anthracycline group was 1.09 (95% CI 0.80-1.48). The combined analysis constituted 814 patients (395 assigned to standard treatment (anthracycline or taxane); 419 assigned to S-1). Median overall survival was 36.3 months in the standard treatment group and 32.7 months in the S-1 group. S-1 was non-inferior to standard treatment in terms of overall survival (HR 1.06 (95% CI 0.90-1.25); P non-inferiority = 0.0062). CONCLUSIONS: S-1 could be considered a new treatment option for first-line chemotherapy for patients with HER2-negative metastatic breast cancer. CLINICAL TRIAL REGISTRATION: The University Hospital Medical Information Network, Japan: UMIN000005449. This trial was registered on 15 April, 2011.

Circulating microRNA Panel as a Potential Novel Biomarker for Oral Squamous Cell Carcinoma Diagnosis.

A lack of reliable biomarkers for oral squamous cell carcinoma (OSCC) poses a major clinical issue. The sensitivity and specificity of classical serum tumor markers, such as the squamous cell carcinoma antigen (SCC-Ag), are quite poor, especially for early detection. This study aimed to identify specific serum miRNAs potentially serving as OSCC biomarkers. The expression levels of candidate miRNAs in serum samples from 40 OSCC patients and 40 healthy controls were quantitatively analyzed via microarray and reverse transcription PCR (RT-PCR) analyses. To enhance the accuracy of detection, we used Fisher's linear discriminant analysis to establish a diagnostic model that incorporated a combination of selected miRNAs. Consequently, miR-19a and miR-20a were significantly upregulated in the patient group (p = 0.014 and 0.036, respectively), whereas miR-5100 was downregulated (p = 0.001). We found that a combination of six miRNAs (miR-24, miR-20a, miR-122, miR-150, miR-4419a, and miR-5100) could distinguish between OSCC and the control group with a higher degree of accuracy (Area Under the Curve, AUC: 0.844, sensitivity: 55%, and specificity: 92.5%). Furthermore, compared to serum SCC antigen, the 6-miRNA panel could accurately detect the presence of OSCC. The present specific miRNAs panel may serve as a novel candidate biomarker of oral cancer.

Pilot Study of Irinotecan and S-1 (IRIS) for Advanced and Metastatic Breast Cancer.

BACKGROUND/AIM: Irinotecan is rarely used on the metastatic breast cancer (MBC) setting. S-1 is an oral mixture of tegafur, gimeracil and oteracil. We conducted this pilot study to assess efficacy and safty of chemotherapy with combined irinotecan and S-1 (IRIS). PATIENTS AND METHODS: Irinotecan was given intravenously at 80 mg/m2 on days 1 and 8 and S-1 was given orally at 80-120 mg/day depending on body surface area for 2 weeks, repeating the cycle every 3 weeks. RESULTS: Twenty-two patients were enrolled in the study. Median age was 50.5 years (range=26-72). Nineteen patients were evaluable for response. Median overall survival and progression-free survival were 672 days (95% CI=420-967) and 166 days (95% CI=76-814), respectively. CONCLUSION: The IRIS regimen has an acceptable safety profile and modest efficacy against MBC in patients previously heavily treated with chemotherapy. This regimen has potential to treat MBC.

Factors affecting enrollment in randomized controlled trials conducted for patients with metastatic breast cancer.

BACKGROUND: It is critical to obtain informed consent from eligible patients to complete clinical trials. We investigated the factors that affect the participation rates of eligible patients. PATIENTS AND METHODS: Patients with metastatic breast cancer who were eligible for SELECT BC or SELECT BC-CONFIRM trials, randomized controlled trials conducted for patients with chemotherapy-naive metastatic breast cancer were recruited to prospective studies, SELECT BC-FEEL and SELECT BC-FEEL II, respectively. SELECT BC FEEL and SELECT BC-FEEL II were conducted to identify the factors affecting the rates at which informed consent was obtained, using a self-administered questionnaire we developed. RESULTS: In total, 232 patients participated in the studies. The patients who agreed to take part in the randomized trials were more likely than the refusers to answer that they decided to participate because: 'My doctor wanted me to participate in this trial' (P = 0.00000), ' My family or friends wanted me to participate in this trial' (P = 0.00000), 'Both treatment regimens used in the trial are suitable to me' (P = 0.00383), 'I know that the trial is conducted to determine which is a better treatment' (P = 0.01196), and ' I think that my participation in the trial will contribute to the benefit to future patients with the same disease' (P = 0.00756). CONCLUSIONS: To enhance the consent rate in randomized trials of metastatic breast cancer patients, concepts of the trials must be considered important and acceptable not only by patients but also by doctors and their families.

Artificial intelligence for breast cancer detection in mammography: experience of use of the ScreenPoint Medical Transpara system in 310 Japanese women.

BACKGROUND: To compare the breast cancer detection performance in digital mammograms of a panel of three unaided human readers (HR) versus a stand-alone artificial intelligence (AI)-based Transpara system in a population of Japanese women. METHODS: The subjects were 310 Japanese female outpatients who underwent digital mammographic examinations between January 2018 and October 2018. A panel of three HR provided a Breast Imaging Reporting and Data System (BI-RADS) score, and Transpara system provided an interactive decision support score and an examination-based cancer likelihood score. The area under the receiver operating characteristic curve (AUC), sensitivity, and specificity were compared under each of reading conditions. RESULTS: The AUC was higher for human readers than with stand-alone Transpara system (human readers 0.816; Transpara system 0.706; difference 0.11; P < 0.001). The sensitivity of the unaided HR for diagnosis was 89% and specificity was 86%. The sensitivity of stand-alone Transpara system for cutoff scores of 4 and 7 were 93% and 85%, and specificities were 45% and 67%, respectively. CONCLUSIONS: Although the diagnostic performance of Transpara system was statistically lower than that of HR, the recent advances in AI algorithms are expected to reduce the difference between computers and human experts in detecting breast cancer.

Correlation between 18F-FDG uptake on PET/MRI and the level of tumor-infiltrating lymphocytes (TILs) in triple-negative and HER2-positive breast cancer.

PURPOSE: The tumor microenvironment is related to the metabolism of cancer cells and local immune reactions. Previous studies have established TILs could be a significant prognostic factor, especially for triple-negative breast cancers (TNBC) and human epithelial growth factor receptor 2 (HER2)-positive breast cancers. We explore the association between metabolic information on PET/MRI with TILs in TNBC and HER2-positive breast cancer. METHOD: We retrospectively reviewed the cases of 55 women with triple-negative or HER2-positive invasive ductal carcinomas who had undergone 18F-FDG PET/MRI without neo-adjuvant treatment for pre-operative evaluation. FDG uptake was quantified as standardized uptake value (SUV) max. The existence of peritumoral edema on PET/MRI was also recorded. The TIL score of the breast cancers was defined histologically on the basis of the proportion of the area infiltrated by lymphocytes, and classified as low (<10 %), intermediate (10-50 %), and high (>50 %). The association between PET/MRI findings and TILs was assessed using Kruskal-Wallis test and Wilcoxon signed-rank test. RESULTS: There were 14 high TIL, 20 intermediate TIL and 21 low TIL lesions. Higher values of SUVmax were found in the high and intermediate TIL group as compared to the low TIL group (P = 0.013). On the other hand, the lesions with peritumoral edema in the low TIL group tended to show high SUVmax (P = 0.014). CONCLUSIONS: 18F-FDG uptake on PET/MRI correlated with TIL levels in patients with TNBC and HER2-positive breast cancer. This finding suggests that preoperative PET/MRI may be useful as a non-invasive tool for guiding the treatment plan.

Diffuse distribution of tumor-infiltrating lymphocytes is a marker for better prognosis and chemotherapeutic effect in triple-negative breast cancer.

PURPOSE: High-density tumor-infiltrating lymphocytes (TILs) are a prognostic marker for triple-negative breast cancer (TNBC). However, lymphocytic infiltration is heterogeneous in its pattern. We aimed to explore the utility of TIL distribution patterns against TIL density for predicting TNBC prognosis and chemotherapeutic effects. METHODS: Primary invasive TNBC cases were retrieved from a single institutional cohort, and archived samples were reviewed by two board-certificated pathologists. We used 154 consecutive surgical specimens from patients with standard adjuvant therapy, and 80 biopsies taken before primary systemic chemotherapy. The average density of stromal TILs was scored at 10% intervals, while the distribution pattern of TILs was evaluated as diffuse or non-diffuse. The association between TILs and prognosis or pathological complete response (pCR) was statistically analyzed. RESULTS: A diffuse pattern of TILs at primary surgery correlated with better prognosis (relapse-free survival [RFS], hazard ratio [HR] 3.71, 95% confidence interval [CI] 1.60-8.57; overall survival [OS], HR 3.87, 95% CI 1.46-10.27), as well as high TIL density (≥ 50%; RFS, HR 4.51, 95% CI 2.06-9.90; OS, HR 3.28, 95% CI 1.32-8.14). Diffuse TIL pattern and nodal status were independent prognostic factors in multivariate analysis. Diffuse TIL pattern upon biopsy was associated with higher pCR rate (diffuse, 46%; non-diffuse, 21%; P = 0.032). All high TIL cases had diffuse patterns and the best outcome. Interobserver concordance was moderate (k = 0.53-0.55; distribution pattern) to good (weighted k = 0.67-0.69; density), and it was faster to assess the distribution pattern than to assess the density of TIL. CONCLUSIONS: Showing similar clinical impacts to the TIL density, diffuse TILs could be a predictive marker for better prognosis and higher pCR. The assessment of TIL distribution pattern is simple, faster, and practical. Heterogeneous tumor immunity may contribute to further stratification of TNBC treatment.

Does integrated shimming improve lesion detection in whole-body diffusion-weighted examinations of patients with breast cancer?

PURPOSE: To evaluate the feasibility of proposed integrated slice-by-slice shimming (iShim) for whole-body diffusion weighted imaging (WB-DWI) in comparison to conventional 3D shim in patients with breast cancer. MATERIALS AND METHODS: Retrospective analysis of 116 consecutive patients (116 lesions) who underwent whole-body PET/MR using iShim (iShim group) were performed and compared with historical control of 103 patients (105 lesions) using 3D Shim (3D Shim group). RESULTS: As compared with dynamic contrast-enhanced (DCE) breast MRI, the apparent diffusion coefficient (ADC) value could not be determined for 15 (14%) of the 105 lesions of the 3D shim group and for 10 (9%) of the 116 lesions on iShim group. The intergroup difference failed to reach statistical significance (P = 0.1843). On the other hand, there was a significant difference in the frequencies of PET-positive and DWI-negative lesions between the 3D shim and iShim group (8.6% vs. 1.7%, respectively, P = 0.01942). CONCLUSION: In regard to detectability of breast cancers by DWI, iShim may allow improved detectability as compared to conventional 3D shim.

Simultaneous whole-body and breast 18F-FDG PET/MRI examinations in patients with breast cancer: a comparison of apparent diffusion coefficients and maximum standardized uptake values.

PURPOSE: To compare standardized uptake value (SUV) and apparent diffusion coefficient (ADC) values acquired using a PET/MRI scanner in breast cancer patients. MATERIALS AND METHODS: Whole-body PET/MRI and breast PET/MRI were performed in 108 consecutive patients. Ninety-four patients who had a total of 100 breast cancers were analyzed. SUVmax and ADCmean acquired using breast PET/MRI were compared with pathologic prognostic factors. RESULTS: All the lesions were visually detectable using PET and diffusion-weighted imaging (DWI) on breast PET/MRI; however, lesions were visually undetectable on whole-body DWI in 13 patients (13%) or on whole-body PET in 7 patients (7%). An analysis of ADCmean and SUVmax demonstrated a statistically significant correlation between whole-body imaging and breast imaging (rho = 0.613, p < 0.001 and rho = 0.928, p < 0.001, respectively). In a univariate analysis, SUVmax was significantly correlated with HER2 status (p < 0.001), Ki-67 (p = 0.014), tumor size (p = 0.0177), and nuclear grade (p = 0.0448). In multiple regression analysis, only tumor size (p = 0.00701) was shown to independently influence SUVmax. CONCLUSION: Prone breast imaging was more sensitive than whole-body PET/MRI for detection of breast cancers. Both SUVmax and ADCmean showed limited correlation with pathologic prognostic factors.

Cost-effectiveness analysis of the introduction of S-1 therapy for first-line metastatic breast cancer treatment in Japan: results from the randomized phase III SELECT BC trial.

BACKGROUND: This study evaluated the cost-effectiveness of replacing standard intravenous therapy (taxane) with oral S-1 therapy for first-line metastatic breast cancer treatment. METHODS: This cost-effectiveness analysis was based on data from a randomized phase III trial (SELECT BC). As cost-effectiveness was a secondary endpoint of the SELECT BC trial, some of the randomized patients participated in an EQ-5D survey (N = 391) and health economic survey (N = 146). The EQ-5D responses, claims, and prescription data were collected for as long as possible until death. The expected quality-adjusted life years (QALY) obtained from each treatment were calculated using patient-level EQ-5D data, and the expected cost was calculated using patient-level claim data. The analysis was performed from the perspective of public healthcare payers. RESULTS: The estimated EQ-5D least-square means and 95% CI up to 48 months were 0.764 (95% CI, 0.741-0.782) and 0.742 (95% CI, 0.720-0.764) in the S-1 and taxane arms, respectively. The expected QALY was 2.11 for the S-1 arm and 2.04 for the taxane arm, with expected costs of JPY 5.13 million (USD 46,600) and JPY 5.56 million (USD 50,500), respectively. These results show that S-1 is cost-saving. According to probabilistic sensitivity analysis, S-1 was dominant with a probability of 63%. When the willingness to pay (WTP) value was JPY 5 million (USD 45,500) per QALY, the probability of being cost-effective was 92%. CONCLUSIONS: Our results show that the introduction of oral S-1 therapy for metastatic breast cancer is highly likely to be cost-effective. TRIAL REGISTRATION: UMIN CTR C000000416 . Registered on May 10, 2006.

Circulating tumor cells as a prognostic marker for efficacy in the randomized phase III JO21095 trial in Japanese patients with HER2-negative metastatic breast cancer.

PURPOSE: Prognostic effects of circulating tumor cells (CTCs) have been reported in metastatic breast cancer (MBC). However, few phase III trials have investigated the potential role of CTCs in treatment selection. We explored potential relationships between CTCs, efficacy, and differential treatment effects. METHODS: Patients with HER2-negative MBC were randomized to receive either concurrent capecitabine plus docetaxel (XT) or sequential single-agent docetaxel followed by single-agent capecitabine at progression (T â†’ X). Blood samples were collected at baseline, on day 1 of cycles 2 and 3, and at progression. CTCs were counted using the CellSearch® System. The relationship between baseline CTC count and outcomes was investigated using a pre-defined threshold of 2 CTCs/7.5 mL. RESULTS: At screening, 44% of the 148 enrolled patients had positive CTC score. In multivariate analyses of pooled treatment arms, positive baseline CTC and triple-negative disease were strongly associated with worse progression-free survival (PFS) and overall survival (OS). Patients with positive CTC score at the baseline had worse OS, irrespective of change in CTC (decreased versus remaining positive) at cycle 2. The prognostic effect of baseline CTC count on OS appeared slightly less pronounced in XT-treated pts. compared with T â†’ X. CONCLUSIONS: A baseline CTC count ≥2 CTCs/7.5 mL was associated with worse prognosis. However, some improvement in PFS and OS was shown with concurrent XT, thus baseline CTC could be a predictive marker. As the current trial was not designed to evaluate a change in chemotherapy according to on-treatment CTC changes, prospective investigation is required.

Prognostic and predictive impacts of tumor-infiltrating lymphocytes differ between Triple-negative and HER2-positive breast cancers treated with standard systemic therapies.

Tumor-infiltrating lymphocytes (TILs) have potential value for stratifying the treatment of breast cancer (BC), though their precise use remains unclear. We aimed to investigate the utility of TILs using an alternative approach in different settings. We reviewed patients with triple-negative (TN) or human epithelial growth factor receptor 2 (HER2)-positive invasive ductal carcinomas from a single institutional cohort and classified archived hematoxylin-eosin-stained samples in terms of TIL score as low (<10 %), intermediate, and high (>50 %). The prognostic and predictive values of TILs were analyzed retrospectively in both adjuvant and neo-adjuvant settings. In the adjuvant setting, the presence of TILs at primary surgery was a significant favorable prognostic factor among 154 TNBCs [relapse-free survival (RFS): p = 0.015], but not among 183 HER2+ BCs (RFS: p = 0.097). The TNBC low-TIL group tended to relapse earlier. In the neo-adjuvant setting, detection of TILs on biopsy before primary systemic therapy was associated with the ratio of patients achieving pathological complete response among 48 TNBCs (p = 0.024), but not among 58 HER2+ BCs (p = 0.30). The presence of TILs in surgical specimens after systemic therapy had prognostic value in HER2+ BC (RFS: p = 0.007). The impact of TILs differs between patients with TN and HER2+ BC treated with standard therapies. Our three-grade scale for TILs may contribute to our understanding of the importance of the tumor microenvironment in routine practice. TILs after primary systemic therapy may be useful for the further stratification of treatment of HER2+ BC.

Taxanes versus S-1 as the first-line chemotherapy for metastatic breast cancer (SELECT BC): an open-label, non-inferiority, randomised phase 3 trial.

BACKGROUND: Oral fluoropyrimidines are used for the first-line treatment of metastatic breast cancer to avoid severe adverse effects, although firm supporting evidence is lacking. We aimed to establish whether S-1 is non-inferior to taxanes in this setting. METHODS: We did an open-label, non-inferiority, phase 3 trial at 154 hospitals in Japan. We enrolled individuals who had HER2-negative metastatic breast cancer who had received no chemotherapy for advanced disease, and who were resistant to endocrine treatment. Patients were randomly assigned (1:1) either to taxane (docetaxel 60-75 mg/m(2) at intervals of 3-4 weeks; paclitaxel 80-100 mg/m(2) weekly for 3 of 4 weeks; or paclitaxel 175 mg/m(2) at intervals of 3-4 weeks) or to S-1 (40-60 mg twice daily for 28 consecutive days, followed by a 14-day break). Randomisation was done centrally with the minimisation method, with stratification by institution, liver metastasis, oestrogen and progesterone receptor status, previous treatment with taxanes or oral fluorouracil, and time from surgery to recurrence. The primary endpoint was overall survival, with a prespecified non-inferiority margin of 1·333 for the hazard ratio (HR). The primary efficacy analysis was done in the full analysis set, which consisted of all patients who took at least one study treatment and who had all data after randomisation. This trial is registered with the University Hospital Medical Information Network, Japan (protocol ID C000000416). FINDINGS: Between Oct 27, 2006, and July 30, 2010, we enrolled 618 patients (309 assigned to taxane; 309 assigned to S-1). The full analysis set consisted of 286 patients in the taxane group and 306 in the S-1 group. Median follow-up was 34·6 months (IQR 17·9-44·4). Median overall survival was 35·0 months (95% CI 31·1-39·0) in the S-1 group and 37·2 months (33·0-40·1) in the taxane group (HR 1·05 [95% CI 0·86-1·27]; pnon-inferiority=0·015). The most common grade 3 or worse adverse events were neutropenia (20 [7%] of 307 patients in the S-1 group vs nine [3%] of 290 patients in the taxane group), fatigue (ten [3%] vs 12 [4%]), and oedema (one [<1%] vs 12 [4%]). Treatment-related deaths were reported in two patients in the taxane group. INTERPRETATION: S-1 is non-inferior to taxane with respect to overall survival as a first-line treatment for metastatic breast cancer. S-1 should be considered a new option for first-line chemotherapy for patients with HER2-negative metastatic breast cancer. FUNDING: Comprehensive Support Project for Oncology Research of the Public Health Research Foundation, Japan; Taiho.

Efficacy and safety of an amino acid jelly containing coenzyme Q10 and L-carnitine in controlling fatigue in breast cancer patients receiving chemotherapy: a multi-institutional, randomized, exploratory trial (JORTC-CAM01).

PURPOSE: Cancer-related fatigue (CRF) is one of the most common symptoms reported by cancer patients. This randomized trial investigated the efficacy of the amino acid jelly Inner Power(®) (IP), a semi-solid, orally administrable dietary supplement containing coenzyme Q10 and L-carnitine, in controlling CRF in breast cancer patients in Japan. METHODS: Breast cancer patients with CRF undergoing chemotherapy were randomly assigned to receive IP once daily or regular care for 21 days. The primary endpoint was the change in the worst level of fatigue during the past 24 h (Brief Fatigue Inventory [BFI] item 3 score) from day 1 (baseline) to day 22. Secondary endpoints were change in global fatigue score (GFS; the average of all BFI items), anxiety and depression assessed by the Hospital Anxiety and Depression Scale (HADS), quality of life assessed by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and EORTC Breast Cancer-Specific QLQ (EORTC QLQ-BR23), and adverse events. RESULTS: Fifty-nine patients were enrolled in the study, of whom 57 were included in the efficacy analysis. Median patient age was 50 years. Changes in the worst level of fatigue, GFS, and current feeling of fatigue were significantly different between the intervention and control groups, whereas the change in the average feeling of fatigue was not significantly different between groups. HADS, EORTC QLQ-C30, and EORTC QLQ-BR23 scores were not significantly different between the two groups. No severe adverse events were observed. CONCLUSION: IP may control moderate-severe CRF in breast cancer patients. TRIAL REGISTRATION: The registration number of this study in the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) is UMIN000008646.

The efficacy and safety of FSK0808, filgrastim biosimilar: a multicenter, non-randomized study in Japanese patients with breast cancer.

OBJECTIVE: FSK0808 is a filgrastim biosimilar. This study assessed the efficacy and safety of FSK0808 in patients with breast cancer. METHODS: One hundred and four breast cancer patients undergoing chemotherapy were enrolled in the study. FSK0808 was used to treat the neutropenia experienced by the patients in the course of their chemotherapy. Efficacy was evaluated by the recovery of absolute neutrophil count following FSK0808 administration based on the duration of neutropenia in patients who received pre- or postoperative chemotherapy containing fluorouracil, epirubicin and cyclophosphamide. Adverse events were evaluated in accordance with the Common Terminology Criteria for Adverse Events version 3.0. The incidence of febrile neutropenia and generation of an anti-granulocyte colony-stimulating factor antibody were also evaluated. RESULTS: The average duration of neutropenia in Cycle 2 was 2.2 days with a standard deviation of 1.5 days. The upper limit of the 97.5% one-sided confidence interval was 2.5 days and was confirmed not to exceed 3.0 days, which was defined as the threshold value of absolute neutrophil count recovery. The incidence of febrile neutropenia across all treatment cycles was 34.6%. Observed adverse drug reactions with an incidence of > 5% were back pain (60.6%), bone pain (9.6%), alanine aminotransferase increase (8.7%), aspartate aminotransferase increase (5.8%) and arthralgia (5.8%). Production of the anti-granulocyte colony-stimulating factor antibody was not observed in any patient during the study. CONCLUSIONS: FSK0808 was safe and well tolerated in breast cancer patients undergoing chemotherapy and effectively stimulated neutrophil recovery.