Half Dose Pegfilgrastim for Patients With Breast Cancer During Chemotherapy: A Case-series.

BACKGROUND/AIM: This study aimed to show the trend of neutrophil counts and frequency of febrile neutropenia after changing pegfilgrastim from 3.6 mg to 1.8 mg. PATIENTS AND METHODS: This case-series study was performed between April 2016 and December 2021 at Hyogo Prefectural Amagasaki General Medical Center. All patients who reduced their normal dose of 3.6 mg pegfilgrastim to 1.8 mg due to adverse events or markedly elevated neutrophil counts were included. Any type of chemotherapy was acceptable. Patients who dropped out within 1 month of receiving 1.8 mg pegfilgrastim were excluded. The primary outcome was the neutrophil counts after receiving 1.8 mg pegfilgrastim. The secondary outcome was febrile neutropenia, which was evaluated by the Common Terminology Criteria for Adverse Events v5.0. RESULTS: The study included seven patients who used a regimen of dose-dense epirubicin and cyclophosphamide, trastuzumab, pertuzumab, and docetaxel, docetaxel, or docetaxel and cyclophosphamide. After using 1.8 mg pegfilgrastim, neutrophil counts changed from a mean of 18,944 [standard deviation (SD)=-7,768] to only 4,447 (SD=1,224). The patients experienced grades 1 to 3 adverse events during the use of 1.8 mg and 3.6 mg pegfilgrastim doses, including febrile neutropenia, and pain. Four patients (57%) complained of grade 1 or 2 fatigue and anorexia. After switching from 3.6 mg pegfilgrastim to 1.8 mg, three patients (42%) experienced adverse events. CONCLUSION: In patients who experienced adverse events due to markedly elevated neutrophil counts with pegfilgrastim, reducing the dose of pegfilgrastim by half may reduce adverse events.

Promoters of BRCA testing under insurance coverage for non-metastatic breast cancer patients in Japan: a retrospective cohort study.

BACKGROUND: We investigated the barriers to and promoters of taking BRCA testing, after the start of national healthcare insurance coverage for non-metastatic breast cancer patients in Japan. PATIENTS AND METHODS: This was a multi-center, retrospective, cohort study. We included stage 0 to III breast cancer patients who were diagnosed and met the criteria for insurance coverage of BRCA testing between April 2020 and December 2021. We examined the association between BRCA testing and possible exposures: breast cancer diagnosis at 45 years or younger, triple-negative breast cancer (TNBC) diagnosis at the age of 60 or younger, two or more primary breast cancers, family history of breast cancer or ovarian cancer in the third degree of relatives, male breast cancer, medical expense limits, and parity. We used logistic regression analysis. RESULTS: We included 222 patients and 123 (55.4%) of them underwent the test. In univariate analysis, a family history of ovarian cancer (odds ratio (OR) 10.59; 95% CI 1.35-82.96, p = 0.025), diagnosis of breast cancer at the age of 45 or younger (OR 2.78; 95% CI 1.52-5.14, p = 0.0009), and diagnosis of TNBC at the age of 60 or younger (OR 3.95; 95% CI 1.55-10.07, p = 0.004) were associated with taking the test. After multivariate logistic regression analysis, a family history of ovarian cancer (adjusted OR 12.80; 95% CI 1.51-108.80, p = 0.0195), diagnosis of breast cancer at the age of 45 or younger (adjusted OR 4.43; 95% CI 1.98-9.90, p = 0.0003), and TNBC at the age of 60 or younger (adjusted OR 5.28; 95% CI 1.90-14.66, p = 0.0014) were consistently associated. CONCLUSION: For non-metastatic breast cancer patients whose BRCA testing is covered by insurance, costs would no longer be a definite barrier. Physicians should keep in mind that a family history of ovarian cancer, breast cancer diagnosis at 45 years of age or younger and TNBC diagnosis at 60 years of age or younger are strong promoters.

Association Between Treated Periodontal Disease and Febrile Neutropenia in Perioperative Chemotherapy for Breast Cancer: A Retrospective Cohort Study.

BACKGROUND: This study aimed to examine whether the incidence of febrile neutropenia (FN) during perioperative chemotherapy for breast cancer increased in patients with periodontal disease who had received prior dental treatment. METHODS: This retrospective cohort study conducted at a single tertiary care center included patients diagnosed with clinical stages I-III of breast cancer and had started neoadjuvant or adjuvant intravenous chemotherapy between July 2015 and November 2021. The exposure was periodontal disease (probing depth ≥6 mm) diagnosed by dentists before the start of chemotherapy. Almost all the patients received dental treatment and oral care before initiating chemotherapy. The primary outcome was FN incidence during chemotherapy. We used a multivariable logistic regression model adjusted for age, diabetes mellitus, chemotherapy regimen, and the mean relative dose intensity. RESULTS: Based on the eligibility criteria of this study, 141 women were included. The incidence of FN in the periodontal group (probing depth ≥6 mm) and control group (probing depth <6 mm) was 36.4% and 25.9%, respectively. The crude odds ratio (OR) for FN incidence was 1.63 (95% confidence interval [CI], 0.71-3.74; P = 0.24), and the adjusted OR was 1.52 (95% CI, 0.62-3.73; P = 0.36).  Conclusions: Occurrence of FN during perioperative chemotherapy for breast cancer is not a concern in patients undergoing dental treatment for periodontal disease before or during chemotherapy.

Phase Ib/II study of nivolumab combined with palliative radiation therapy for bone metastasis in patients with HER2-negative metastatic breast cancer.

Radiation therapy (RT) can enhance the abscopal effect of immune checkpoint blockade. This phase I/II study investigated the efficacy and safety of nivolumab plus RT in HER2-negative metastatic breast cancer requiring palliative RT for bone metastases. Cohort A included luminal-like disease, and cohort B included both luminal-like and triple-negative disease refractory to standard systemic therapy. Patients received 8 Gy single fraction RT for bone metastasis on day 0. Nivolumab was administered on day 1 for each 14-day cycle. In cohort A, endocrine therapy was administered. The primary endpoint was the objective response rate (ORR) of the unirradiated lesions. Cohorts A and B consisted of 18 and 10 patients, respectively. The ORR was 11% (90% CI 4-29%) in cohort A and 0% in cohort B. Disease control rates were 39% (90% CI 23-58%) and 0%. Median progression-free survival was 4.1 months (95% CI 2.1-6.1 months) and 2.0 months (95% CI 1.2-3.7 months). One patient in cohort B experienced a grade 3 adverse event. Palliative RT combined with nivolumab was safe and showed modest anti-tumor activity in cohort A. Further investigations to enhance the anti-tumor effect of endocrine therapy combined with RT plus immune checkpoint blockade are warranted.Trial registration number and date of registration UMIN: UMIN000026046, February 8, 2017; ClinicalTrials.gov: NCT03430479, February 13, 2018; Date of the first registration: June 22, 2017.

Effectiveness of eribulin as first-line or second-line chemotherapy for HER2-negative hormone-resistant advanced or metastatic breast cancer: findings from the multi-institutional, prospective, observational KBCRN A001: E-SPEC study.

BACKGROUND: The optimal positioning of eribulin treatment remains unclear. This study aimed to investigate the effectiveness of eribulin administration as first- and second-line chemotherapy in patients with endocrine-resistant advanced or metastatic breast cancer (AMBC) in the real-world clinical setting. METHODS: This multi-institutional prospective cohort study enrolled patients with triple-negative AMBC or estrogen receptor-positive AMBC refractory to at least one previous endocrine therapy. The overall survival (OS) from the start of first-line (OS1) and second-line chemotherapy (OS2) was assessed. Data analysis included real-world chemotherapy sequences of first- to third-line chemotherapy regimens. The adjusted hazard ratio (HR) with 95% confidence interval (CI) for treatment regimen comparison was calculated using a stratified proportional hazards model. RESULTS: Among 201 patients enrolled, 180 were included in the final analysis. Eribulin was administered as first- and second-line chemotherapy to 46 (26.6%) and 70 (47.9%) patients, respectively. Median OS1 and OS2 were 2.25 (95% CI 1.07-2.68) and 1.75 (95% CI, 1.28-2.45) years for first- and second-line eribulin, respectively. Oral 5-FU followed by eribulin had a numerically longer OS1 (2.84 years) than the other sequences. Among patients who proceeded to second-line or later chemotherapy, the median OS1 for those treated with anthracycline or taxane as first- or second-line (n = 98) was 2.56 years (95% CI 2.27-2.74), while it was 2.87 years (95% CI 2.20-4.32) for those who avoided anthracycline and taxane as first- and second-line (n = 48) (adjusted HR, 1.20; 95% CI 0.70-2.06). In the exploratory analysis, OS1 was 2.55 (95% CI 2.14-2.75) and 2.91 years (95% CI 2.61-4.32) for those aged < 65 and ≥ 65 years, respectively (adjusted HR of ≥ 65, 0.91; 95% CI 0.56-1.46). CONCLUSIONS: Eribulin or oral 5-FU administration in first- and second-line chemotherapy without anthracycline/taxane was acceptable in the real-world setting. TRIAL REGISTRATION: This study is registered with Clinical Trials.gov (NCT 02,551,263).

Investigation of a Novel S-1 Administration Schedule for Treating Metastatic and Recurrent Breast Cancer (KBCOG13).

BACKGROUND/AIM: S-1, a 5-fluorouracil(5-FU) oral anti-cancer drug, has been traditionally used with a schedule of 4-week oral administration followed by 2-week rest for breast cancer treatment. We, herein, aimed to investigate the clinical efficacy and safety of a schedule of 2-week oral administration followed by 1-week rest for patients with metastatic breast cancer. PATIENTS AND METHODS: We enrolled patients with HER2-negative metastatic breast cancer who had not received prior chemotherapy. S-1 was administered consecutively for 2-weeks followed by a 1-week rest. RESULTS: Between September 1, 2013 and August 31, 2016, 32 patients were enrolled. The median follow-up time was 32.1 months. The median progression-free survival (PFS) was 9.4 months. Overall survival (OS) was 41.0 months, time to treatment failure (TTF) was 7.8 months, response rate (RR) was 31.3%, and disease control rate (DCR) was 78.1%. The incidence of grade 3 side-effects was not high. CONCLUSION: The 3-week schedule of S-1 can be considered useful as a treatment for patients with metastatic breast cancer, helping in maintaining a high quality of life.

Optimization of prediction methods for risk assessment of pathogenic germline variants in the Japanese population.

Predicting pathogenic germline variants (PGVs) in breast cancer patients is important for selecting optimal therapeutics and implementing risk reduction strategies. However, PGV risk factors and the performance of prediction methods in the Japanese population remain unclear. We investigated clinicopathological risk factors using the Tyrer-Cuzick (TC) breast cancer risk evaluation tool to predict BRCA PGVs in unselected Japanese breast cancer patients (n = 1,995). Eleven breast cancer susceptibility genes were analyzed using target-capture sequencing in a previous study; the PGV prevalence in BRCA1, BRCA2, and PALB2 was 0.75%, 3.1%, and 0.45%, respectively. Significant associations were found between the presence of BRCA PGVs and early disease onset, number of familial cancer cases (up to third-degree relatives), triple-negative breast cancer patients under the age of 60, and ovarian cancer history (all P < .0001). In total, 816 patients (40.9%) satisfied the National Comprehensive Cancer Network (NCCN) guidelines for recommending multigene testing. The sensitivity and specificity of the NCCN criteria for discriminating PGV carriers from noncarriers were 71.3% and 60.7%, respectively. The TC model showed good discrimination for predicting BRCA PGVs (area under the curve, 0.75; 95% confidence interval, 0.69-0.81). Furthermore, use of the TC model with an optimized cutoff of TC score ≥0.16% in addition to the NCCN guidelines improved the predictive efficiency for high-risk groups (sensitivity, 77.2%; specificity, 54.8%; about 11 genes). Given the influence of ethnic differences on prediction, we consider that further studies are warranted to elucidate the role of environmental and genetic factors for realizing precise prediction.

Genetic and clinical landscape of breast cancers with germline BRCA1/2 variants.

The genetic and clinical characteristics of breast tumors with germline variants, including their association with biallelic inactivation through loss-of-heterozygosity (LOH) and second somatic mutations, remain elusive. We analyzed germline variants of 11 breast cancer susceptibility genes for 1,995 Japanese breast cancer patients, and identified 101 (5.1%) pathogenic variants, including 62 BRCA2 and 15 BRCA1 mutations. Genetic analysis of 64 BRCA1/2-mutated tumors including TCGA dataset tumors, revealed an association of biallelic inactivation with more extensive deletions, copy neutral LOH, gain with LOH and younger onset. Strikingly, TP53 and RB1 mutations were frequently observed in BRCA1- (94%) and BRCA2- (9.7%) mutated tumors with biallelic inactivation. Inactivation of TP53 and RB1 together with BRCA1 and BRCA2, respectively, involved LOH of chromosomes 17 and 13. Notably, BRCA1/2 tumors without biallelic inactivation were indistinguishable from those without germline variants. Our study highlights the heterogeneity and unique clonal selection pattern in breast cancers with germline variants.

Baseline neutrophil-to-lymphocyte ratio and c-reactive protein predict efficacy of treatment with bevacizumab plus paclitaxel for locally advanced or metastatic breast cancer.

The effect of bevacizumab plus paclitaxel therapy on progression-free survival (PFS) is prominent; however, no overall survival (OS) benefit has been demonstrated. Our aim was to study the predictive efficacy of peripheral immune-related parameters, neutrophil-to-lymphocyte ratio (NLR), absolute lymphocyte count (ALC), and c-reactive protein (CRP) in locally advanced and metastatic breast cancers. A total of 179 patients treated with bevacizumab plus paclitaxel were recruited from three institutes in the test cohort. The cut-off values of NLR, ALC, and CRP were set at 3, 1500/µL, and 1.0 mg/dL, respectively, and baseline values of these factors were measured. The PFS of patients with NLR-low was significantly longer than that of patients with -high (median, 12.6 vs. 7.2 months; hazard ratio (HR), 0.48, 95% confidence interval (95% CI), 0.31-0.73; p = 0.0004). OS of patients with NLR-low was significantly better than those with-high (22.2 vs. 13.5 months; HR, 0.57, 95% CI, 0.39-0.83; p = 0.0032). Similarly, improved PFS and OS were recognized in patients with CRP-low as compared with patients with -high (HR, 0.44, 95% CI, 0.28-0.68; p = 0.0001 and HR, 0.39, 95% CI, 0.26-0.61, p < 0.0001, respectively). In the validation cohort from two institutes (n = 57), similar significant improvements in PFS and OS were confirmed for patients with NLR-low (p = 0.0344 and p = 0.0233, respectively) and CRP-low groups (p < 0.0001 and p = 0.0001, respectively). Low levels of NLR and CRP at baseline were significantly associated with improved prognosis in patients treated with bevacizumab plus paclitaxel.

Real-World Outcomes of Treating Advanced Breast Cancer Patients With Palbociclib: A Multicenter Retrospective Cohort Study in Japan-The KBCOG-14 Study.

BACKGROUND: Clinical studies have shown that palbociclib improves progression-free survival in hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) patients with advanced breast cancer (ABC). However, there are insufficient data on its use in a real-world setting in Japan. The aim of this study was to investigate the effectiveness, predictive factors, and safety of palbociclib among Japanese patients in routine clinical practice. METHODS: Between December 1, 2017, and April 30, 2019, we recruited patients from 9 hospitals and retrospectively evaluated the data on HR+/HER2- patients with ABC who received palbociclib for at least 1 week. The correlation between time-to-treatment discontinuation (TTD) and clinical background was investigated via univariate and multivariate analyses using Cox hazards models. RESULTS: A total of 177 women were available for analysis. Of these patients, 58 (33%) patients were treated with palbociclib with an aromatase inhibitor and 117 (66%) patients were treated with palbociclib and a selective estrogen receptor degrader. Approximately three-fourths of the patients (n = 130, 73%) received palbociclib as third- or later-line therapy. One-third of the patients had 3 or more metastatic sites (n = 59, 33%), and one-third of the patients had liver metastasis (n = 59, 33%). The median follow-up duration at the time of data cutoff was 8.9 months, the median TTD was 6.3 months, and the median overall survival was not reached. Liver metastasis (hazard ratio [HR]: 1.54 [95% confidence interval {CI}: 1.03-2.27]), high serum lactate dehydrogenase (LDH) level (>300 U/L) (HR: 2.58 [95% CI: 1.49-4.26]), and high neutrophil-to-lymphocyte ratio (NLR) (⩾3.0) (HR: 1.76 [95% CI: 1.13-2.69]) were significantly associated with shorter TTD. The most common hematologic adverse event was neutropenia, which occurred in 93% of the patients. CONCLUSION: Based on the results of the pivotal phase 3 trials, the median TTD recorded in this study was shorter than expected. Our results suggest that liver metastasis, serum LDH level, and NLR may be predictive factors for HR+/HER2- ABC treatment outcomes.

[Analysis of Five Days of Administration of S-1 Followed by a Two-Day Rest in Patients with Metastatic Breast Cancer].

Although S-1 is an effective oral anticancer drug in patients with metastatic breast cancer, it is difficult for some patients to continue taking S-1 because of its side effects in the approved regimen of 4 weeks of administration followed by a 2-week rest. When S-1 is administered for 5 days followed by a 2-day rest(5-day on/2-day off), the drug concentration is almost equal to that of the approved regimen, and it can be administered for longer without deterioration of its clinical effect. We retrospectively analyzed the effect and safety in 25 cases in which S-1 was administered using the "5-day on/2-day off" regimen in patients with metastatic breast cancer between November 2006 and August 2014 in our hospital. Patients were all female, and their median age was 68 years(44-87). ER was positive/negative in 15/10 cases, and PS 0/1/2were found in 8/ 10/7 cases. They had no prior chemotherapy and had measurable lesions. S-1 was administered at a dose of 80mg/m2 twice a day on a "5-day on/2-day off" schedule and was reduced when its side effects were appeared. The median treatment duration was 25(3-214)weeks, and CR/PR/long SD/SD/PD as clinical responses were observed in 0/8/5/5/7 cases. The overall response rate was 32% and clinical benefit rate was 52%. There was no difference in response rates whether visceral metastases were present or not. In terms of hematologic toxicity, anemia was seen in one case, and there were no cases of neutropenia. In non-hematologic toxicity, no more than Grade 3 side effects were shown. Discontinuance was observed in only one case because of diarrhea. A "5-day on/2-day off" regimen of S-1 in metastatic breast cancer is well tolerated, and we can continue administering it to elderly patients or those with poor PS without reducing QOL; thus, it can be considered as one of the effective metronomic treatments. In the future, a prospective study is warranted to ascertain these results.

Predictive impact of absolute lymphocyte counts for progression-free survival in human epidermal growth factor receptor 2-positive advanced breast cancer treated with pertuzumab and trastuzumab plus eribulin or nab-paclitaxel.

BACKGROUND: Although peripheral blood-based parameters (PBBPs) are reported as prognostic indicators in patients with breast cancers, their utility has not been studied in human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer (ABC). Tumor-infiltrating lymphocytes (TILs) might be a predictive factor in patients with HER2-positive ABC treated with pertuzumab and trastuzumab (PT) plus docetaxel. We aimed to evaluate whether PBBPs could have predictive value in HER2-positive ABC treated with pertuzumab and trastuzumab (PT) combined with eribulin (ERI) or nab-paclitaxel (Nab-PTX). METHODS: Data from 51 patients included in two single-arm, phase II trials were included in this retrospective-prospective study; the ERI + PT (N = 30) and Nab-PTX + PT (N = 21) combinations were registered under clinical trials number UMIN000012375 and UMIN000006838, respectively. We assessed PBBPs using prospectively collected data and investigated the association with progression-free survival (PFS); we evaluated absolute lymphocyte count (ALC), neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR). The cutoff values for ALC, NLR, and PLR were set at 1000 or 1500 cells/µL, 2, and 250, respectively. RESULTS: PFS was significantly improved in patients with ALC ≥1500/µL compared to those with ALC 1000-, <1500/µL or ALC < 1000/µL (P = 0.0106). High baseline ALC was significantly associated with improved PFS (≥1500/µL; hazard ratio [HR]: 0.3715; 95% confidence interval [CI]: 0.1735-0.7955; P = 0.0108). In contrast, improved PFS was not significantly associated with NLR or PLR. Improved PFS in patients with ALC ≥1500/µL was observed irrespective of visceral metastasis or chemotherapy regimen. CONCLUSIONS: Our results showed that baseline ALC was a predictive factor for PFS in HER2-positive ABC treated with PT irrespective of combined chemotherapy regimen. Anti-tumor effects might be mediated not only by the tumor microenvironment, but also by systemic peripheral circulating lymphocytes. Baseline systemic parameters such as peripheral lymphocyte count might be beneficial in addition to disease extent for predicting the efficacy of PT treatment. TRIAL REGISTRATION: UMIN000012375 , registration date: 21NOV2013, and UMIN000006838 , registration date: 6DEC2011.

Survival Outcomes of Retreatment with Trastuzumab and Cytotoxic Chemotherapy for HER2-Positive Recurrent Patients With Breast Cancer Who Had Been Treated with Neo/adjuvant Trastuzumab Plus Multidrug Chemotherapy: A Japanese Multicenter Observational Study.

BACKGROUND: There are little data on the usefulness of trastuzumab (TZM) retreatment as the first-line treatment for patients with HER2 (human epidermal growth factor receptor 2)-positive breast cancer recurrence after perioperative treatment with TZM. AIM: To clarify the outcome and safety of TZM retreatment in patients with recurrent HER2-positive breast cancer. METHOD: An observational study was conducted on patients who relapsed after primary systemic therapy with TZM using the central registration system. The primary end point was progression-free survival (PFS). Secondary end points consisted of the response rate, overall survival (OS), and safety. RESULT: In total, 34 patients were registered between July 2009 and June 2012. The median follow-up time was 23.7 months (2-24 months). The 1- and 2-year PFS rates were 46.9% (95% confidence interval (95% CI): 29.2%-62.9%) and 29.8% (95% CI: 15.0%-46.3%), respectively (median 10.6 months). The median PFS time for patients receiving TZM combined with CTx was 13.9 months. The 1-and 2-year OR rates were 93.9 (95% CI: 77.9%-98.4%) and 84.8% (95% CI: 67.4%-93.4%). Trastuzumab-induced grade 3/4 adverse events were not observed. CONCLUSIONS: This study suggests that the PFS and OS in Japanese patients who relapsed after perioperative TZM therapy improved or were similar to those in previous reports. Differences in patient backgrounds and treatments must be considered when interpreting the results. Trastuzumab should be used combination with CTx and/or HTx for retreatment. Retreatment with TZM is safe.Trial registration: UMIN000002738.

Body mass index and menopausal disorders during menopause affect vasomotor symptoms of postmenopausal Japanese breast cancer patients treated with anastrozole: a prospective multicenter cohort study of patient-reported outcomes.

BACKGROUND: Adverse events related to endocrine therapies have a major impact not only on patients' quality of life but also on treatment discontinuation. Although vasomotor symptoms induced by aromatase inhibitors are frequently recognized, risk factors, especially for Japanese women, are not well reported. To identify risk factors for vasomotor symptoms of Japanese breast cancer patients treated with adjuvant anastrozole, we conducted a prospective cohort study based on patient-reported outcomes (PROs). PATIENTS AND METHODS: For this prospective cohort study (SAVS-JP, UMIN000002455), 391 postmenopausal Japanese estrogen receptor-positive breast cancer patients who were treated with adjuvant anastrozole were recruited from 28 centers. The PRO assessment was obtained from a self-reported questionnaire at baseline, 3, 6, 9 and 12 months between August 2009 and April 2012. Vasomotor symptoms, comprising hot flashes, night sweats, and cold sweats, were categorized into four grades (none, Grade 1: mild, Grade 2: moderate, Grade 3: severe). Pre-existing symptoms were only included if they had become worse than at baseline. RESULTS: Hot flashes, night sweats, and cold sweats at baseline were reported by 20.5, 15.1, and 8.2 % of the patients, respectively, and new appearance or worsening of symptoms in comparison with baseline by 38.4, 29.3, and 28.7 %, respectively. About 80 % of newly occurring symptoms were Grade 1, and less than 5 % were Grade 3. Vasomotor symptoms were reported by 201 out of 362 patients (55.5 %) during the first year and the mean time to onset was 5.6 months. Patients with vasomotor symptoms were significantly younger (mean 62.8 years, range 38-86 vs 64.7 years, range 37-84; p = 0.02), had higher body mass index (BMI) (23.4 kg/m2, range 15.8-39.9 vs 22.4 kg/m2, range 15.8-34.9; p = 0.01), had vasomotor symptoms sooner after menopause (12.4 years, range 0-51 vs 15.1 years, range 1-37; p = 0.002), and had more menopausal disorders during menopause (63.3 vs 36.7 %; p = 0.002). Multivariate analysis showed that BMI [odds ratio (OR) 1.09 per unit of increase, 95 % confidence interval (CI) 1.02-1.16; p = 0.009] and experiencing menopausal disorders (OR 2.11, 95 % CI 1.35-3.30; p = 0.001) were significantly associated with vasomotor symptoms. CONCLUSION: High BMI and experiencing menopausal disorders at menopause were found to be significantly associated with the occurrence of vasomotor symptoms. These findings are expected to prove useful for the management of postmenopausal Japanese women treated with aromatase inhibitors.

Risk factors for joint symptoms in postmenopausal Japanese breast cancer patients treated with anastrozole: a prospective multicenter cohort study of patient-reported outcomes.

BACKGROUND: Endocrine treatment-related adverse events have a strong impact on patients' quality of life and sometimes result in treatment discontinuation. Since joint symptoms are the most frequently recognized side effect of aromatase inhibitors, evaluation of associated risk factors may yield significant findings. PATIENTS AND METHODS: A total of 391 postmenopausal Japanese women with estrogen receptor-positive breast cancer and treated with adjuvant anastrozole were enrolled from 28 centers for assessment of patient-reported outcomes (PROs) in this prospective cohort study (SAVS-JP, UMIN000002455). Patients completed the self-report questionnaire at baseline and after 3, 6, 9, and 12 months of treatment for evaluation of frequency of treatment-related joint symptoms (arthralgia, decrease in range of joint motion, and joint stiffness). RESULTS: We obtained PROs from 362 patients (92.6 %) at baseline and at one or more subsequent points. New or worsening from baseline of joint symptoms were reported by 260 patients (71.8 %). More than 90 % of the symptoms were mild or moderate and nearly 80 % had occurred by 6 months. Multivariate analysis showed that a short time span after menopause [odds ratio (OR) 0.95, 95 % confidence interval (CI) 0.90-0.99; P = 0.02] and adjuvant chemotherapy (OR 2.29, 95 % CI 1.06-4.95; P = 0.03) were significant independent risk factors for joint symptoms. No significant relationships between body mass index (BMI) and joint symptoms were identified. Eighteen patients discontinued treatment during the 1st year and eight of them reported joint symptoms. CONCLUSION: Taking into consideration that PROs may yield higher prevalence rates than physician ratings for symptoms published in pivotal clinical trials, we found that a short time span after menopause and use of adjuvant chemotherapy, but not high BMI, were significantly associated with joint symptoms. These findings might prove useful for counseling before initiating treatment with adjuvant aromatase inhibitors in postmenopausal Japanese women.

Prevalence and risk factors of bone metastasis and skeletal related events in patients with primary breast cancer in Japan.

BACKGROUND: Bone metastasis (BM) is important for studying systemic spread of breast cancer. It often causes skeletal-related events (SREs) that worsen quality of life. We investigated the prevalence and risk factors for BM and SRE using a dataset from the Breast Oncology Research Network (BORN) in Japan. PATIENTS AND METHODS: We collected data on primary breast cancer patients with node-positive or node-negative disease at intermediate to high risk of recurrence. The risk factors affecting the BM-free rate, SRE-free rate and overall survival were analyzed by using the Cox proportional hazard model. RESULTS: Data of 1,779 patients who were diagnosed with breast cancer during 2003-2005 were collected from the BORN and 1,708 cases were used for analysis. The median follow-up duration was 5.71 years. BM developed in 193 cases (11.3 %) and the BM-free rate at 5 years was 89.2 %. The annual hazard ratio of BM development differs remarkably according to the tumor subtype. SREs occurred in 133 (68.9 %) out of 193 patients and the SRE-free rate at 5 years was 92.6 %. In the multivariate analysis, clinical stage (P < 0.0001), number of lymph node (LN) metastases (P = 0.0029), tumor subtype (P = 0.034) and progesterone receptor status (P = 0.038) were independently significant risk factors for BM-free rate, but only clinical stage (P < 0.0001) and number of LN metastases (P = 0.0004) significantly correlated with SRE-free rate. CONCLUSIONS: This retrospective study clarifies the prevalence and risk factors for BM and SRE in Japanese breast cancer patients. Our results show the importance of considering subtype in the care of BM and SRE.

[A case of long remission for about 5 years as an outpatient with second-line chemotherapy of weekly PTX after palliative distal gastrectomy for pStage IV advanced gastric cancer].

A 59-year-old man underwent palliative distal gastrectomy for Stage IV advanced gastric cancer with cytological and histopathological peritoneal dissemination. After surgery, he began to receive chemotherapy by S-1 oral administration as an outpatient. About one year and 9 months after surgery, cartinomatous peritonitis grew, and severe obstruction of gastrojejunostomy and dilatation of residual stomach were detected by CT tomography. Then, second-line chemotherapy by weekly paclitaxel(PTX)was started. After one course of weekly PTX was completed, he was feeling better gradually with obvious improvement of carcinomatous peritonitis, which was revealed by sequential CT tomography examinations. Weekly PTX chemotherapy has been continued successfully for 43 courses, and he remains alive today with a good QOL, about 5 years after surgery. He is an outpatient with only a grade 2 or less complication of peripheral neuropathy.

Comparison of the indocyanine green fluorescence and blue dye methods in detection of sentinel lymph nodes in early-stage breast cancer.

PURPOSE: To assess the diagnostic performance of sentinel lymph node (SLN) biopsy using the indocyanine green (ICG) fluorescence method compared with that using the blue dye method, a prospective multicenter study was performed. METHODS: Patients with T1-3 primary breast cancer without clinical lymph node involvement were included in this study. ICG as a fluorescence-emitting source and indigo carmine as blue dye were injected into the subareolar area. Extracted lymph nodes were examined to identify the first, second, and other SLNs. The identified nodes were classified according to the ICG fluorescence signal and blue dye uptake. RESULTS: Ninety-nine eligible patients were included in this study. The ICG fluorescence method identified an average of 3.4 SLNs (range, 1-8) in 98 of 99 patients (detection rate, 99 %). The number of lymph nodes identified by the fluorescence method was significantly higher than that identified by the blue dye method (p < 0.001). SLN involvement was identified in 20 % (20 of 99) of patients, all of whom tested positive for the first SLN. In 16 patients, complete axillary lymph node dissection (ALND) was performed. In 25 % (4 of 16) of these patients, axillary metastases were identified; however, no axillary involvement was found in 8 patients with only one involved node, which was isolated as the first SLN. CONCLUSIONS: High rate of SLN detection was achieved using the ICG fluorescence method. The first SLN identified by fluorescence imaging provides an exact indication of the axillary status. Therefore, the ICG fluorescence method provides precise information required to avoid unnecessary ALND.

Bi-weekly docetaxel in the adjuvant treatment of node-positive or high-risk breast cancer patients: phase I study of the Shiga Breast Cancer Study Group.

BACKGROUND: A phase I study of bi-weekly docetaxel was performed to determine the maximum tolerated dose (MTD) as well as the incidence and severity of toxicities in patients with high-risk node-negative and node-positive breast cancer. METHODS: Docetaxel was administered every 14 days to postoperative breast cancer patients who were axillary lymph node-positive or considered at high-risk. After the completion of six cycles of docetaxel, all patients received epirubicin + cyclophosphamide every 21 days for four cycles. The docetaxel dose was escalated in a stepwise fashion as follows: 45, 50, 55, 60, 65, and 70 mg/m(2) in levels 1, 2, 3, 4, 5, and 6, respectively. Patients were treated in cohorts of three to six per group using a standard phase I study design. The MTD was considered the dose level at which three of three patients or more than three of six patients experienced dose-limiting toxicity (DLT) in the first cycle. RESULTS: Twenty patients were enrolled and received a total of 110 cycles of chemotherapy. The MTD was not reached until level 5. Since three DLTs (grade 3 diarrhea, n = 2; grade 3 constipation, n = 1), were observed in five patients at level 6, level 6 was judged as the MTD. The recommended dose of bi-weekly docetaxel for a phase II trial is 65 mg/m(2). CONCLUSIONS: The MTD of bi-weekly docetaxel was 70 mg/m(2). Further evaluation is warranted to confirm the safety and efficacy in the treatment of early-stage breast cancer.