Seven-plus hours of daily sedentary time and the subsequent risk of breast cancer: Japan Multi-Institutional Collaborative Cohort Study.

This study aimed to investigate the association between daily sedentary time and the risk of breast cancer (BC) in a large Japanese population. The participants were 36,023 women aged 35-69 years from the Japan Multi-Institutional Collaborative Cohort Study. Cox proportional hazards analysis was used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for BC incidence in relation to time spent sedentarily (categorical variables: <7 and ≥7 hours/day [h/d]). Additionally, the associations of BC incidence to the joint effect of sedentary time with each component of physical activity, such as leisure-time metabolic equivalents (METs), frequency of leisure-time physical activity, and daily walking time, were examined. During 315,189 person-years of follow-up, 554 incident cases of BC were identified. When compared to participants who spent <7 h/d sedentary, those who spent ≥7 h/d sedentary have a significantly higher risk of BC (HR, 1.36; 95% CI, 1.07-1.71). The corresponding HRs among participants who spent ≥7 h/d sedentary with more physical activity, such as ≥1 h/d for leisure-time METs, ≥3 days/week of leisure-time physical activity, and ≥1 h/d of daily walking were 1.58 (95% CI, 1.11-2.25), 1.77 (95% CI, 1.20-2.61), and 1.42 (95% CI, 1.10-1.83), respectively, compared with those who spent <7 h/d sedentary. This study found that spending ≥7 h/d of sedentary time is associated with the risk of BC. Neither leisure-time physical activity nor walking had a BC-preventive effect in those with ≥7 h/d of sedentary time.

Risk Factors for Infusion Reactions in Patients with Breast Cancer Administered Trastuzumab Therapy.

Trastuzumab is a humanized monoclonal antibody targeting human epidermal growth factor receptor 2 (HER2) that is indicated for the treatment of HER2-positive breast cancer. The administration of biologics, such as trastuzumab, frequently causes infusion reactions (IRs) with fever and chills. This study aimed to clarify the risk factors for IRs in trastuzumab therapy. Between March 2013 and July 2022, 227 patients with breast cancer who started trastuzumab therapy were included in this study. The severity of IRs was graded according to the Common Terminology Criteria for Adverse Events, Version 5.0. The incidence of IRs in trastuzumab therapy was 27.3% (62/227). Dexamethasone administration was significantly different between the IR and non-IR groups in patients receiving trastuzumab therapy (univariate analysis, p < 0.001; multivariate analysis, p = 0.0002). Without dexamethasone, the severity of IRs in the pertuzumab combination group (Grade 1, 8/65; Grade 2, 23/65) was significantly higher than that in the non-pertuzumab group (Grade 1, 9/37; Grade 2, 3/37; p < 0.05). Our findings suggest that the risk of IRs is significantly higher in patients not premedicated with dexamethasone in trastuzumab therapy and that the concomitant use of pertuzumab without dexamethasone increases the severity of IRs caused by trastuzumab.

[A Case of Aortitis Caused by Pegfilgrastim Use during Neoadjuvant Chemotherapy for Treating Breast Cancer].

Granulocyte colony-stimulating factor(G-CSF)is useful for preventing febrile neutropenia induced by chemotherapy. Recently, some cases of aortitis have been reported following administration of G-CSF. Here, we present a case of aortitis induced by pegfilgrastim(peg-G)use during neoadjuvant chemotherapy for treating breast cancer. A 61-year-old woman with breast cancer(cT2N1M0, stage ⅡB, triple negative)started neoadjuvant chemotherapy FEC(100). Eleven days after the third course of peg-G administration, the patient developed a fever and general malaise. Blood test results showed an increase in inflammatory markers and severe anemia. The symptoms were not controlled with antibiotics. Blood and urine culture test results were negative. Computed tomography revealed remarkable wall thickening of the aorta. Therefore, we suspected aortitis induced by peg-G. The symptoms rapidly improved with prednisolone therapy. The possibility of aortitis should be considered for those with fever or raised inflammatory markers following the use of G-CSF. Steroids can be used for the treatment of G-CSF-induced aortitis.

The effect of denosumab in breast cancer patients receiving adjuvant aromatase inhibitors: 36-month results.

INTRODUCTION: Aromatase inhibitor (AI)-associated bone loss increases the risk of bone fracture and reduces patients' quality of life, making it a critical issue worldwide. We conducted a prospective non-randomized clinical trial (UMIN-CTR, UMIN 000016173) to assess the effect of denosumab on bone loss in patients treated with adjuvant AI and have previously reported the results at 12 and 24 months. This study aimed to present the results at 36 months of treatment with denosumab for osteopenia in breast cancer patients who were undergoing treatment with adjuvant AI; 36 months is the longest denosumab treatment period reported so far. MATERIALS AND METHODS: Patients received 60-mg denosumab subcutaneously every 6 months. Daily supplements containing 500-mg elemental calcium and at least 400 international units of vitamin D were highly recommended throughout the study period. The levels of bone mineral density (BMD) and bone turnover markers, serum tartrate-resistant acid phosphatase isoform 5b, and bone alkaline phosphatase were determined at baseline and 6, 12, 18, 24, and 36 months. RESULTS: At 36 months, the bone mineral density of the lumbar spine, right femoral neck, and left femoral neck were found to increase by 8.8% (95% confidence interval CI 7.6-10.1), 4.3% (95% CI 3.0-5.5), and 3.1% (95% CI 2.1-4.1), respectively. No non-traumatic clinical fractures occurred in patients receiving AI and denosumab. CONCLUSION: Twice-yearly administration of denosumab to the breast cancer patients treated with adjuvant AI, regardless of the skeletal site, resulted in consistent increases in BMD without severe adverse events at 36 months.

[A Case of Synchronous Bilateral Male Breast Cancer].

A 71-year-old man with right and left mammary tumor came to our hospital. Using needle biopsy, we diagnosed both tumors as ER-positive, PgR-positive, and HER2(1+)invasive ductalcarcinoma. We performed radicalmastectomy and axillary dissection. After surgery, the patient received postoperative chemotherapy, radiotherapy, and hormone therapy. The incidence of male breast cancer has been reported to be<1% of all breast cancer cases; only a few cases of simultaneous bilateral male breast cancer has been reported. Here, we report a rare case of synchronous bilateral male breast cancer.

[A Case of Small Cell Carcinoma of the Breast].

A 67-year-old woman with a mass in the right breast was admitted to our hospital. The tumor measured 35mm in diameter in the right breast, and the lymph node measured 30mm in diameter in the right axilla. The mass was diagnosed as malignant based on core needle biopsy. Immunohistochemistry staining for synaptophysin, chromogranin A, and CD56 was positive, suggesting that the tumor was small cell carcinoma. Positron emission tomography-computed tomography imaging excluded any other primary disease. Thus, the patient was diagnosed as having primary small cell carcinoma of the breast. Modified radical mastectomy with axillary lymph node dissection was performed. The pathological diagnosis of the surgical material confirmed small cell carcinoma. The expression of estrogen, progesterone, and human epidermal growth factor receptors was negative. After surgery, chemotherapy- and radiotherapy-based breast cancer treatment were performed. The patient was relapse free 9 months after surgery.

[Experience of Fulvestrant for Hormone Receptor-Positive HER2-Negative Advanced and Metastatic Breast Cancer].

Several cases of hormone receptor-positive HER2-negative advanced and recurrent breast cancer treated with fulvestrant (FUL)were retrospectively investigated to assess the efficacy and safety of the treatment. FUL was administered to a total of 41 patients-33 with recurrent and 8 with Stage IV cancer-from January 2012 to September 2016. The median number of lines that used FUL was 3, the median time to treatment failure(TTF)was 7 months, the overall response rate(RR)was 19.5%, and the clinical benefit rate(CBR)was 53.6%. Our result was similar to those of the FIRST and the FALCON studies, which showed a decrease in RR after the fourth-line. With regard to RR, FUL seemed to provide better results at Cthird-lines of treatment. While a shorter TTF was seen in the cases with liver metastases, a longer TTF was seen in the cases with soft tissue metastases. Therefore, it may be helpful to consider the site of metastasis when predicting the effects of FUL.

Validation of late recurrence prediction by gene expression profiles and clinicopathological factors in estrogen receptor-positive breast cancer.

BACKGROUND: The mechanism of late recurrence (LR) of estrogen receptor (ER)-positive breast cancer remains unclear, as previous studies have separately investigated "gene expression profiles" and "clinicopathological factors." Thus, this study aimed to evaluate the predictive capability of LR by combining the two independent factors of gene expression profiles (42-gene classifier: 42GC) and clinicopathological factors (Clinical Treatment Score post-5 years: CTS5) in multiple large cohorts. METHODS: We analyzed microarray CEL file data downloaded from public databases of 28 global cohorts. A total of 2,454 patients with ER-positive breast cancer were analyzed for 42GC, and 1,263 of these, with complete clinicopathological data were analyzed for CTS5. RESULTS: In the analysis of recurrent patients, the 42GC LR and CTS5 low-risk group tended to have LR. Notably, in the analysis of patients with and without recurrence, the highest LR rate beyond 5 years was observed in the CTS5 high-risk group. The combination of the 42GC and CTS5 high-risk groups showed the highest LR rate (16.9%), significantly exceeding that of the 42GC non-LR (NLR) and CTS5 low-risk combination (5.41%) (p = 0.038, odds ratio = 3.53). Furthermore, incorporating a third factor, 95GC, potentially reduced the number of patients prioritized for extended hormonal therapy for approximately one-quarter of patients. CONCLUSIONS: Results confirmed that the two factors, gene expression profiles and clinicopathological factors, affect the time of recurrence. It also showed that the biological predisposition for LR (CTS5 low-risk) differed from the high LR rate (CTS5 high-risk). In clinical practice, patients with the 42GC LR and CTS5 high-risk combination should be prioritized for extended hormonal therapy. The addition of CTS5 and 95GC to 42GC allows for better risk classification of LR.

Investigation of recurrence prediction ability of EndoPredict® using microarray data from fresh frozen tissues in ER-positive, HER2-negative breast cancer and indication expansion of EndoPredict® from microarray data from fresh-frozen to FFPE tissues.

BACKGROUND: EndoPredict® (EP) is a multigene assay to predict distant recurrence risk in luminal breast cancer. EP measures the expression of 12 genes in primary tumor by qRT-PCR from formalin-fixed paraffin-embedded (FFPE) tissues and calculates EP risk score that indicates the risk of distant recurrence. We evaluated the performance of EP in predicting distant recurrence risk using microarray data from fresh frozen (FF) tissues. We also examined the applicability of EP to microarray data from FFPE tissues. METHODS: We analyzed the publicly available data of 431 node-negative and 270 node-positive patients with luminal breast cancer who received endocrine therapy alone. We evaluated the prognostic value of EP using microarray data from FF tissues. Next, we created an algorithm to calculate EP risk score using microarray data from FFPE tissues. We examined the correlation coefficient of EP risk score and concordance rate of EP risk high/low using microarray data from FFPE/FF tissue pairs in a validation set of 39 patients. RESULTS: In 431 node-negative patients, the distant recurrence-free survival (DRFS) rate was significantly worse in those with high EP risk scores (P = 3.68 × 10-6, log-rank). The 5-year DRFS was 95.2% in those with low EP risk score. In the validation set, the correlation coefficient of EP risk score was 0.93 and the concordance rate of EP risk high/low was 91.7%. CONCLUSIONS: EP using microarray data from FF tissues was useful in predicting distant recurrence risk in luminal breast cancer, and EP might be utilized in microarray data from FFPE tissues.

Additional statin treatment enhances the efficacy of HER2 blockade and improves prognosis in Rac1-high/HER2-positive breast cancer.

The prognosis of HER2-positive breast cancer (BC) has improved with the development of anti-HER2 therapies; however, the problem remains that there are still cases where anti-HER2 therapies do not respond well. We found that the expression of SREBF2, a master transcriptional factor in the mevalonate pathway, was correlated with ERBB2 (HER2) expression and a poor prognosis in HER2-positive BC. The target gene expressions of SREBF2 were associated with higher expression of ERBB2 in HER2-positive BC cells. Statins, anti-hypercholesterolemia drugs that inhibit the mevalonate pathway, enhanced the efficacy of HER2-targeting agents with inducing apoptosis in a geranylgeranylation-dependent manner. Mechanistically, statins specifically inhibited membrane localization of Rac1, a target protein of geranylgeranylation, and suppressed the activation of HER2 downstreams AKT and ERK pathways. Consistently, retrospective analysis showed a longer recurrence-free survival in Rac1-high/HER2-positive BC patients treated with HER2-targeting agents with statins than without statins. Our findings thus suggest that Rac1 expression could be used as a biomarker to stratify HER2-positive BC patients that could benefit from dual blockade, i.e., targeting HER2 with inhibition of geranylgeranylation of Rac1 using statins, thereby opening avenues for precision medicine in a new subset of Rac1-high/HER2-positive BC.

Eribulin versus S-1 as first or second-line chemotherapy to assess health-related quality of life and overall survival in HER2-negative metastatic breast cancer (RESQ study): a non-inferiority, randomised, controlled, open-label, phase 3 trial.

Background: Eribulin prolongs overall survival (OS) of patients with human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC), particularly in later chemotherapy (ChT) treatment. However, the health-related quality of life (HRQoL) and efficacy of first or second-line therapy in eribulin-treated patients remain unknown. Using eribulin in the first- or second-line may demonstrate the non-inferiority of HRQoL compared to S-1, an oral 5-fluorouracil derivative, while maintaining OS. Methods: This randomised, controlled, open-label, phase III trial was conducted at 50 hospitals in Japan. Patients were enrolled from June 2016 and October 2019. Patients with HER2-negative MBC once under or no previous ChT were randomly assigned (1:1) to receive eribulin or S-1. HRQoL was assessed using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) every six weeks until week 24 and every nine weeks until week 42. The primary endpoint was the deterioration defined as more than 10 points worsening of the general health score of QLQ-C30 or death within one year after randomisation. The secondary endpoints included OS. (Trial ID: UMIN000021398). Findings: Three hundred and two patients were enrolled, with 152 and 148 assigned to the eribulin and S-1 groups, respectively. The questionnaire compliance rate was 85.6%. Risk difference of global health status deterioration through one year was -0.66% (95% CI: -12.47-11.16; non-inferiority P = 0.077) for eribulin compared to S-1 groups. Median time to first deterioration for global health status score was 5.64 (95% CI: 3.51-8.00) and 5.28 months (95% CI: 3.28-7.80) in the eribulin and S-1 groups, respectively. The median OS was 34.7 and 27.8 months, (HR: 0.72, 95% CI: 0.54-0.96; P = 0.026); the median progression-free survival was 7.57 and 6.75 months in the eribulin and S-1 groups, (HR: 0.88, 95% CI: 0.67-1.16; P = 0.35), respectively. No new adverse events occurred. Interpretation: The time of the first clinical deterioration was similar between the two groups and OS significantly increased in eribulin-treated patients. Funding: This study was funded by CSPOR-BC and Eisai CO., Ltd.

Concise synthesis of heterocycle-fused naphthoquinones by employing sonogashira coupling and tandem addition-elimination/intramolecular cyclization.

A concise method for the synthesis of heterocycle-fused naphthoquinones such as naphtho[2,3-b]-furan-4,9-dione, 1H-benz[f]indole-4,9-dione, and naphtho[2,3-b]thiophene-4,9-dione was developed. This method employed Sonogashira coupling and tandem addition-elimination/intramolecular cyclization, and it enabled the preparation of versatile heterocycle-fused naphthoquinones from one substrate.

Incidence and risk factors of infusion reactions in patients with breast cancer administered trastuzumab plus pertuzumab-based regimen.

PURPOSE: Pertuzumab (Per) is a humanized monoclonal antibody used in combination with trastuzumab (Tra) in the treatment of human epidermal growth factor receptor-2 (HER2)-positive breast cancer. The administration of biologics, such as Tra and Per, frequently causes infusion reactions (IRs) with fever and chills. This study aimed to clarify the characteristics of and risk factors for IRs in Tra + Per combination therapy. METHODS: Between March 2013 and December 2019, 64 patients with breast cancer who started Tra + Per combination therapy were included in the study. The severity of IRs was graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. RESULTS: The incidence of IRs in the Tra + Per combination therapy was 48.4% (31/64). The severity of IRs in the Tra + Per combination therapy was Grade 1 (9 patients) and Grade 2 (22 patients). Lymphocyte counts were significantly different between the IR and non-IR groups in patients receiving Tra + Per combination therapy (univariate analysis, p = 0.006; multivariate analysis, p = 0.050). ROC curve analysis found the cutoff value of lymphocyte counts were 1.60 (× 103/µL). The incidence of IRs in the lymphocyte counts ≥ 1.60 group was significantly higher than that in the lymphocyte counts < 1.60 group (p < 0.001). CONCLUSION: Our study indicates that the severity of IRs in most patients is moderate or less and the risk of IRs is higher in patients with higher lymphocyte counts (≥ 1.60 × 103/µL).

Multi-gene assay 95- and 155-gene classifiers for prognosis prediction and chemotherapy omission in lymphnode positive luminal-type breast cancer.

BACKGROUND: The prognosis of lymphnode positive breast cancer is worse than that of lymph node negative breast cancer but some cases may not require chemotherapy. We investigated the ability of the new multi-gene assays, 95GC and 155GC, to identify patients with lymphnode positive Luminal-type breast cancer whose chemotherapy can be omitted relatively safely. PATIENTS AND METHODS: We extracted 1721 cases of lymphnode positive Luminal-type breast cancer from 22 public database Caucasoid cohorts and 3 Asian cohorts, and performed recurrence prognosis analysis with 95GC and 155GC. RESULTS: Using 95GC, the cases were stratified as the high (n = 917) and low (n = 202) groups according to the prognosis of lymphnode positive Luminal-type endocrine only breast cancer. The 5 years DRFS in the low risk group was relatively good at 90%, and no additional effect of chemotherapy was observed, suggesting omission of chemotherapy. The recurrence prognosis was also significantly dichotomized into the high and low risks by 95GC in 21GC RS 0-25 cases. Here, we found a group with poor prognosis even in post-menopause RS 0-25 and requiring chemotherapy. Additionally, a group in which the prognosis was good in pre-menopause RS 0-25, and the omission of chemotherapy could be considered. Patients in the high-risk group at 155GC had poor prognosis after chemotherapy. 155GC also showed a group that chemotherapy alone was not sufficient. CONCLUSION: In this study, we demonstrated the possibility of accurately selecting patient groups for which chemotherapy can be omitted from lymphnode positive Luminal-type breast cancer.

Optimal Treatment of Hormone Receptor-positive Advanced Breast Cancer Patients With Palbociclib.

BACKGROUND/AIM: Palbociclib was the first cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor approved worldwide. Currently, CDK4/6 inhibitors are strongly recommended for endocrine therapy in the first or second line with hormone receptor-positive advanced breast cancer. It is expected the use of CDK4/6 inhibitor will further increase. Therefore, the aim was to investigate and better understand the use of palbociclib. PATIENTS AND METHODS: We retrospectively analyzed the data of patients with advanced breast cancer who were treated with palbociclib in three hospitals between 2018 and 2022. Clinical data were obtained from the patients' medical electronic records. RESULTS: A total of 143 patients were enrolled. The median age was 66 years (range=33-89), and the majority (90.9%) were postmenopausal patients. In total, median time-to-treatment discontinuation (TTD) (95% confidence interval, CI) was 7 (6-10) months. Median TTD (95% CI) was 13 (7-20) months for the first or second line, and significantly prolonged compared to TTD for the third or later lines with palbociclib (p<0.0001). The importance of front-line use was indicated. Multivariate analyses showed that no visceral metastasis or first or second line therapy influenced the longer TTD. Between patients above or below 70 years of age, older age did not negatively affect TTD, though there were significantly more cases of dose reduction or withdrawal in patients over 70 years old. The variation of adverse events (AEs) among hospitals was very large (9.0%, 31.3%, 4.5%). We found that understanding of AE management was important. CONCLUSION: This study showed that dose reduction or withdrawal of palbociclib had no harmful effects in Japanese patients. Efficacy was also high in older patients. It is important to manage palbociclib administration more safely and appropriately. A combination of dose reduction and withdrawal is key to this therapeutic strategy.

Myoid hamartoma of the breast that proved difficult to diagnose: a case report.

Myoid hamartomas of the breast are extremely rare breast lesions, with a poorly understood pathogenesis. We describe the case of a 38-year-old premenopausal woman who presenting with a mass in the left breast. Mammography revealed an oval mass that was partly indistinct, and ultrasonography showed a hypoechoic mass with a slightly irregular margin. Bilateral breast dynamic magnetic resonance imaging was performed for a more detailed evaluation. The images showed rapid initial enhancement and a microlobulated margin. Because the suspicion of malignancy was strong at that time, core needle biopsy was performed. Histologically, the tumor was identified as fibroadenoma. A case of myoid hamartoma of the breast that proved difficult to diagnose is reported, and discussed with reference to the literature.

Low-cost high-speed imaging system for observing vocal fold vibration in voice disorders.

PURPOSE: The aim of this study was to establish a method to observe vocal fold vibration using a low-cost high-speed laryngeal imaging system. PROCEDURES: We assembled a high-speed imaging system with a consumer digital camera and a rigid laryngeal endoscope. The camera can shoot digital images at a rate of 1,200 frames per second and be purchased for about USD 1,000 in Japan. RESULTS: We examined the normal and pathological vocal folds of 215 subjects with our new system and analyzed the vocal fold vibration in these subjects by playback of a video and kymograph images. CONCLUSIONS: Our high-speed laryngeal imaging system is highly cost-effective and can be a useful tool for examining the vocal folds of patients with voice disorders.

[A case of breast cancer with brain metastases responding to paclitaxel and capecitabine therapy].

A 31-year-old woman was referred to our hospital for back pain. After a close investigation, she was diagnosed with multiple bone, liver and brain metastases of breast cancer. She was administered a combination therapy of paclitaxel and capecitabine. Capecitabine was administered orally at 628mg/m / 2 twice daily on days 1-21, and paclitaxel 80 mg/m2 was injected on days 1, 8, and 15. Both drug courses were repeated every 28 days. After 5 courses of treatment, the level of tumor markers and all metastases were reduced. The combination treatment of paclitaxel and capecitabine is considered to be effective for metastatic breast cancer with brain metastases.

[Administration of nab-paclitaxel for 9 metastatic breast cancer patients].

Nab-paclitaxel was administered to 9 patients with refractory advanced or recurrent breast cancer from 1 to 8 times(median 4)triweekly. The median cumulative dose was 775mg/m2(range 260-2, 000), and the median delivered dose intensity was 66. 7mg/m2/week(range 58. 3-86. 7). The response to treatment was CR in one patient, PR in 2 patients, SD in one patient, and PD in 4 patients. In one patient, treatment had to be suspended because of grade 3 peripheral neuropathy. The clinical benefit was 33%. All 4 PD patients were administered other salvage treatments and are alive. Adverse events included 6 case of neutropenia(grade 3-4 in 4 cases), grade 3 AST/ALT elevations in one patient, grade 3 myalgia in one patient. No case of febrile neutropenia was seen. All reactions were under control except for one patient with grade 3 peripheral neuropathy. Concurrent trastuzumab administration was safe also. In conclusion, nab-paclitaxel could be administered safely, and may contribute to the treatment of refractory advanced or recurrent breast cancer.