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Background: The safety and outcome of breast reconstruction after radiotherapy are controversial, and the aesthetic aspects have not been studied extensively. We compared the results of vascular anastomosis, the incidence of postoperative complications, and aesthetic appearance between patients who had and had not received radiotherapy who then had undergone delayed breast reconstruction with autologous free flaps from the abdomen, thighs, and buttocks., Methods: In total, 257 flaps in 241 patients were investigated; 194 and 63 flaps implanted in patients who did not receive radiotherapy and who received radiotherapy before breast reconstruction, respectively. Of the 257 flaps, 221, 20, 14, and 2 came from the abdomen, thighs, buttocks, and other anatomic locations, respectively. We evaluated aesthetic outcomes in 105 patients who had not received radiotherapy and 35 who had., Results: We found no significant differences between the two groups in the incidence of vascular reanastomosis, the time required for anastomosis, or the incidence of unplanned reoperation. Complications such as flap necrosis were rare in both groups. Aesthetic outcomes were significantly better in the patients who had not received radiotherapy., Conclusions: Breast reconstruction with autologous free flaps can be performed safely in patients who have received radiotherapy, but the aesthetic result is slightly inferior to that in patients who had not received radiotherapy., (© 2024. The Author(s), under exclusive licence to The Japanese Breast Cancer Society.)

Background: Visual assessment of mammographic breast composition remains the most common worldwide, although subjective variability limits its reproducibility. This study aimed to investigate the inter- and intra-observer variability in qualitative visual assessment of mammographic breast composition through a multi-institutional observer performance study for the first time in Japan., Methods: This study enrolled 10 Japanese physicians from five different institutions. They used the new Japanese breast-composition classification system 4th edition to subjectively evaluate the breast composition in 200 pairs of right and left normal mediolateral oblique mammograms (number determined using precise sample size calculations) twice, with a 1-month interval (median patient age: 59 years [range 40-69 years]). The primary endpoint of this study was the inter-observer variability using kappa (κ) value., Results: Inter-observer variability for the four and two classes of breast-composition assessment revealed moderate agreement (Fleiss' κ: first and second reading = 0.553 and 0.587, respectively) and substantial agreement (Fleiss' κ: first and second reading = 0.689 and 0.70, respectively). Intra-observer variability for the four and two classes of breast-composition assessment demonstrated substantial agreement (Cohen's κ, median = 0.758) and almost perfect agreement (Cohen's κ, median = 0.813). Assessments of consensus between the 10 physicians and the automated software Volpara® revealed slight agreement (Cohen's κ; first and second reading: 0.104 and 0.075, respectively)., Conclusions: Qualitative visual assessment of mammographic breast composition using the new Japanese classification revealed excellent intra-observer reproducibility. However, persistent inter-observer variability, presenting a challenge in establishing it as the gold standard in Japan., (© 2024. The Author(s), under exclusive licence to The Japanese Breast Cancer Society.)

Tumor-infiltrating lymphocytes are a general term for lymphocytes or immune cells infiltrating the tumor microenvironment. Numerous studies have demonstrated tumor-infiltrating lymphocytes to be robust prognostic and predictive biomarkers in breast cancer. Recently, immune checkpoint inhibitors, which directly target tumor-infiltrating lymphocytes, have become part of standard of care treatment for triple-negative breast cancer. Surprisingly, tumor-infiltrating lymphocytes quantified by conventional methods do not predict response to immune checkpoint inhibitors, which highlights the heterogeneity of tumor-infiltrating lymphocytes and the complexity of the immune network in the tumor microenvironment. Tumor-infiltrating lymphocytes are composed of diverse immune cell populations, including cytotoxic CD8-positive T lymphocytes, B cells and myeloid cells. Traditionally, tumor-infiltrating lymphocytes in tumor stroma have been evaluated by histology. However, the standardization of this approach is limited, necessitating the use of various novel technologies to elucidate the heterogeneity in the tumor microenvironment. This review outlines the evaluation methods for tumor-infiltrating lymphocytes from conventional pathological approaches that evaluate intratumoral and stromal tumor-infiltrating lymphocytes such as immunohistochemistry, to the more recent advancements in computer tissue imaging using artificial intelligence, flow cytometry sorting and multi-omics analyses using high-throughput assays to estimate tumor-infiltrating lymphocytes from bulk tumor using immune signatures or deconvolution tools. We also discuss higher resolution technologies that enable the analysis of tumor-infiltrating lymphocytes heterogeneity such as single-cell analysis and spatial transcriptomics. As we approach the era of personalized medicine, it is important for clinicians to understand these technologies., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Although endoscopic mastectomy has been associated with good tolerance and enhanced patient satisfaction, limitations such as the implant or flap size for reconstruction with small incisions remain unresolved. Fat grafting (FG) can expand tissue volume with pinhole skin incisions. Herein, we evaluated the safety and efficacy of endoscopic mastectomy followed by immediate FG., Methods: Patients who underwent endoscopic mastectomy with immediate FG reconstruction from 2015 to 2021 were retrospectively evaluated to establish surgical outcomes and prognosis., Results: Twenty-three patients with clinical stage 0 or I breast cancer underwent unilateral endoscopic mastectomy with immediate FG. The median age was 45 years (41-55), and the median body mass index was 19.3 kg/m 2 (15.8-26.6). Endoscopically performed procedures included skin-sparing mastectomies in 18 patients (78%) and nipple-sparing mastectomies in five patients (22%). The median procedure duration was 295 min (242-346). The median specimen weight was 133 g (71-334), and the median grafted fat volume was 200 mL (136-320). No patient required reoperation or additional procedures for complications. One patient experienced recurrence at a median follow-up of 56.1 months and underwent resection; the patient was alive without recurrence 54 months post-resection., Conclusion: To the best of our knowledge, this is the first report of endoscopic mastectomy with immediate FG for reconstruction. When compared with other immediate autologous reconstructions, our strategy could minimize the skin incision and procedure duration, as well as limit complications. Further prospective investigations are needed to evaluate oncological safety, surgical outcomes, and patient satisfaction., (© 2024. The Author(s), under exclusive licence to The Japanese Breast Cancer Society.)

Object: The purpose of this study is to develop an image artifact removal method for radar-based microwave breast imaging and demonstrates the detectability on excised breast tissues of total mastectomy., Methods: A cross-correlation method was proposed and measurements were conducted. A hand-held radar-based breast cancer detector was utilized to measure a breast at different orientations. Images were generated by multiplying the confocal image data from two scans after cross-correlation. The optimum reconstruction permittivity values were extracted by the local maxima of the confocal image intensity as a function of reconstruction permittivity., Results: With the proposed cross-correlation method, the contrast of the imaging result was enhanced and the clutters were removed. The proposed method was applied to 50 cases of excised breast tissues and the detection sensitivity of 72% was achieved. With the limited number of samples, the dependency of detection sensitivity on the breast size, breast density, and tumor size were examined., Conclusion and Significance: The detection sensitivity was strongly influenced by the breast density. The sensitivity was high for fatty breasts, whereas the sensitivity was low for heterogeneously dense breasts. In addition, it was observed that the sensitivity was high for extremely dense breast. This is the first detailed report on the excised breast tissues.

BACKGROUND: Characteristics of taxane-induced peripheral neuropathy (PN) could be different between paclitaxel and nab-paclitaxel. The purpose of this prospective observational multicenter cohort study was to compare tri-weekly nab-paclitaxel to weekly standard paclitaxel regarding the severity, onset and recovery of sensory and motor PN in patients with breast cancer., Methods: Patients with histologically confirmed breast cancer who were scheduled to receive standard weekly paclitaxel (80 mg/m 2 ) or tri-weekly nab-paclitaxel (260 mg/m 2 ) at institutions in our multicenter group were eligible for this study. Sensory and motor PN were evaluated every 3 weeks until PN improved for up to one year using patient-reported outcome., Results: Between February 2011 and April 2013, 115 patients were enrolled, including 57 and 58 in the paclitaxel and nab-paclitaxel groups, respectively. The incidence of moderate or severe sensory PN was not significantly different between the two groups (p = 0.40). The incidence of moderate or higher motor PN was more frequent in the nab-paclitaxel group than in the paclitaxel group (p = 0.048). The median period for demonstrating PN were shorter in the nab-paclitaxel group than in the paclitaxel group (sensory, p = 0.003; motor, p = 0.001). The recovery of motor PN was slower in the nab-paclitaxel group than in the paclitaxel group (p = 0.035), while the recovery period of sensory PN was not statistically different., Conclusion: Nab-paclitaxel induced sensory PN sooner than paclitaxel, and no difference was observed in the severity and recovery duration between the two agents. Motor PN was more severe, started sooner, and improved over a longer period in the nab-paclitaxel-treated patients than in the paclitaxel-treated patients., (© 2024. The Author(s), under exclusive licence to The Japanese Breast Cancer Society.)

Incisional scarring is a factor of cosmetic appearance evaluated after breast reconstruction, along with the shape, position, and size of the breast. This study aimed to examine the effect of the incision scar location on patient satisfaction after breast reconstruction. Using the Japanese version of the SCAR-Q, we assessed the scar appearance, symptoms and psychosocial effects. Plastic surgeons performed assessments using the Manchester Scar Scale. The patients were divided into two groups: those with scars on the margins of the breast (MB group) and those with scars in the breast area (IB group). The results revealed that patients in the MB group reported significantly higher satisfaction with the scar appearance and psychological impact than those in the IB group. However, assessments using the Manchester Scar Scale did not reveal any significant differences between the two groups. In conclusion, this study underscores the importance of patient-reported outcomes in the evaluation of scar satisfaction after breast reconstruction. Patients tend to prefer and have higher satisfaction with scars along the breast margin, which offers valuable insights into surgical decisions. Further studies with larger and more diverse sample sizes are required for validation., (© 2024 The Authors. International Wound Journal published by Medicalhelplines.com Inc and John Wiley & Sons Ltd.)

Purpose: Breast cancer often metastasizes to the central nervous system. Although the prognosis of brain metastases from breast cancer has been considered poor, and systemic therapy has not contributed to an improved prognosis, newer agents are expected to be more effective. BRCAness is defined as the status of homologous recombination deficiency (HRD) in tumor tissue, regardless of the presence of pathogenic germline BRCA1/2 variants. A study employing next-generation sequencing analysis showed that HRD was found relatively frequently in brain metastases of breast cancer patients. However, there have been no studies evaluating BRCAness in brain metastases of breast cancer with more efficient, rapid, and cost-effective methods., Methods: We retrospectively investigated 17 brain metastases of breast cancer that were surgically resected at our hospital from January 2007 to December 2022. Of these, samples from 15 patients were evaluable for BRCAness by employing multiplex ligation-dependent probe amplification (MLPA) assay., Results: Of the 15 patients, five patients (33%) had tumors with BRCAness. Clinicopathological factors of patients with brain metastases with BRCAness were not statistically different from those of patients who possessed tumors without BRCAness. Patients with brain metastases with BRCAness had shorter overall survival compared to those without BRCAness (BRCAness, median 15 months (95% CI 2-30) vs. non-BRCAness, median 28.5 months (95% CI 10-60); P = 0.013)., Conclusion: In this study, we evaluated BRCAness in brain metastases of breast cancer with the MLPA method, and found that about one-third of patients had BRCAness-positive tumors. The analysis of BRCAness using MLPA has the potential for practical clinical use., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

In cases where there are 2 or more tumors, it is crucial to conduct core needle biopsies on each of them. A 39-year-old woman presented at our hospital with pain in her left breast. Ultrasonography(US)revealed the presence of 2 contiguous tumors: a 35 mm tumor(tumor 1)and a 20 mm tumor(tumor 2)in the AC area of the left breast. US-guided core needle biopsies(CNB)were performed. The histological findings confirmed an invasive ductal carcinoma, characterized by ER(-)/ PR(-)/HER2(3+). Neoadjuvant chemotherapy indicated tumor 1 as PD and tumor 2 as PR, and surgery was subsequently performed(Bt plus SLN). Upon histopathological examination, the findings demonstrated a non-pCR invasive ductal carcinoma, featuring an ER(+)/PR(-)/HER2(-)profile. Depending on the specific subtype identified, post-operative treatment included HER2-targeted therapy or ER/PR-targeting hormone therapy in conjunction with chemotherapy.

Objective: To investigate the clinical relevance of intratumoral tumor infiltrating lymphocytes (TILs) in breast cancer as measured by computational deconvolution of bulk tumor transcriptomes., Summary Background Data: Commonly assessed TILs, located in tumor stroma without direct contact with cancer cells (stromal TILs), correlate with breast cancer treatment response and survival. The clinical relevance of intratumoral TILs has been less studied partly due to their rarity; however, they may have nonnegligible effects given their direct contact with cancer cells., Methods: In all, 5870 breast cancer patients from TCGA, METABRIC, GSE96058, GSE25066, GSE163882, GSE123845, and GSE20271 cohorts were analyzed and validated., Results: The intratumoral TIL score was established by the sum of all types of lymphocytes using the xCell algorithm. This score was the highest in triple-negative breast cancer (TNBC) and the lowest in the ER-positive/HER2-negative subtype. It correlated with cytolytic activity and infiltrations of dendritic cells, macrophages, and monocytes, and uniformly enriched immune-related gene sets regardless of subtype. Intratumoral TIL-high tumors correlated with higher mutation rates and significant cell proliferation on biological, pathological, and molecular analyses only in the ER-positive/HER2-negative subtype. It was significantly associated with pathological complete response after anthracycline- and taxane-based neoadjuvant chemotherapy in about half of the cohorts, regardless of the subtype. Intratumoral TIL-high tumors correlated with better overall survival in HER2-positive and TNBC subtypes consistently in 3 cohorts., Conclusions: Intratumoral TILs estimated by transcriptome computation were associated with increased immune response and cell proliferation in ER-positive/HER2-negative and better survival in HER2-positive and TNBC subtypes, but not always with pathological complete response after neoadjuvant chemotherapy., Competing Interests: T.K. pathology faculty advisor for AstraZeneca. The remaining authors report no conflicts of interest., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: There is increasing interest in the use of liquid biopsies, but data on longitudinal analyses of circulating tumor DNA (ctDNA) remain relatively limited. Here, we report a longitudinal ctDNA analysis of MONALEESASIA, a phase Ib trial evaluating the efficacy and safety of ribociclib plus endocrine therapy (ET) in Asian patients with hormone receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer., Methods: MONALEESASIA enrolled premenopausal and postmenopausal Japanese and postmenopausal non-Japanese Asian patients. All patients received ribociclib with ET (letrozole, fulvestrant, or tamoxifen with goserelin). ctDNA was analyzed using a targeted next-generation sequencing panel of 572 cancer-related genes and correlated by best overall response (BOR)., Results: Five hundred seventy-four cell-free DNA samples from 87 patients were tested. The most frequently altered genes at baseline included PIK3CA (29%) and TP53 (22%). Treatment with ribociclib plus ET decreased ctDNA in most patients at the first on-treatment time point, regardless of dose or ET partner. Patients with partial response and stable disease had lower ctDNA at baseline that remained low until data cutoff if no progressive disease occurred. Most patients with progressive disease as the best response had higher ctDNA at baseline that remained high at the end of treatment. For patients with partial response and stable disease with subsequent progression, ctDNA increased towards the end of treatment in most patients, with a median lead time of 83 days (14-309 days). In some patients with BOR of partial response who experienced disease progression later, specific gene alterations and total ctDNA fraction increased; this was sometimes observed concurrently with the development of new lesions without a change in target lesion size. Patients with alterations in PIK3CA and TP53 at baseline had shorter median progression-free survival compared with patients with wild-type PIK3CA and TP53, 12.7 and 7.3 months vs 19.2 and 19.4 months, respectively (P = .016 and P = .0001, respectively)., Conclusions: Higher ctDNA levels and PIK3CA and TP53 alterations detected at baseline were associated with inferior outcomes. On-treatment ctDNA levels were associated with different patterns based on BOR. Longitudinal tracking of ctDNA may be useful for monitoring tumor status and detection of alterations with treatment implications., Trial Registration: ClinicalTrials.gov NCT02333370 . Registered on January 7, 2015., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: The extended latissimus dorsi (ELD) musculocutaneous flap is one of the surgical techniques used for breast reconstruction. Preoperative preparation to determine the exact amount of flap tissue to be harvested is important to achieve a good outcome with autologous tissue reconstruction. However, few reports exist on objective preoperative volume prediction of ELD flaps. The purpose of this study was to quantify the elevated ELD volume as a preoperative plan., Methods: Patients who underwent immediate or delayed breast reconstruction with ELD flap after mastectomy between March 2015 and January 2022 are included. (1) The ELD flap was designed preoperatively, X-ray contrast thread was applied along the design, and CT imaging was performed in the same lateral supine position as the surgical position. 3D images were constructed, and the volume-rendering method was used to obtain the integrated volume. (2) Intraoperative ELD flap volume was calculated using the water displacement method. The correlation between (1) and (2) was examined., Results: (1) The mean preoperative predicted value was 290.2 mL and (2) the mean intraoperative ELD flap volume was 298.3 mL. The correlation coefficient between the two volumes was 0.93, indicating that they were correlated., Conclusion: We could quantify the ELD flap volume using the volume-rendering method with X-ray contrast threads. This study could be a useful method for preoperative prediction planning of the ELD flap in breast reconstruction., Level of Evidence Iv: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 ., (© 2023. Springer Science+Business Media, LLC, part of Springer Nature and International Society of Aesthetic Plastic Surgery.)

Background: This subgroup analysis of the Cancer-VTE Registry, a nationwide, large-scale, multicenter observational study with a 1-year follow-up, assessed real-world data on venous thromboembolism (VTE) among Japanese patients with breast cancer., Methods: Patients with stage II-IV pretreatment breast cancer screened for VTE at enrollment were included. During the 1-year follow-up period, incidences of VTE, bleeding, and all-cause death, and background factors associated with VTE risk were examined., Results: Of 9,630 patients in the Cancer-VTE Registry analysis set, 993 (10.3%) had breast cancer (973 [98.0%] did not have and 20 [2.0%] had VTE at baseline). The mean age was 58.4 years, 73.4% of patients had stage II cancer, and 94.8% had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0. Risk factors for VTE at baseline by univariable analysis were age ≥ 65 years, ECOG PS of 2, VTE history, and D-dimer > 1.2 μg/mL. During follow-up, the incidence of symptomatic VTE was 0.4%; incidental VTE requiring treatment, 0.1%; composite VTE (symptomatic VTE and incidental VTE requiring treatment), 0.5%; bleeding, 0.2%; cerebral infarction/transient ischemic attack/systemic embolic event, 0.2%; and all-cause death, 2.1%. One patient with symptomatic VTE developed pulmonary embolism (PE) and died. Incidences of VTE and all-cause death were higher in patients with VTE vs without VTE at baseline., Conclusions: In Japanese patients with breast cancer, VTE screening before initiating cancer treatment revealed a 2.0% prevalence of VTE. During follow-up, one patient had a fatal outcome due to PE, but the incidences of VTE were low., Clinical Trial Registration: UMIN000024942; UMIN Clinical Trials Registry: https://www.umin.ac.jp/ctr/ ., (© 2023. The Author(s).)

Lysophosphatidic acid receptors (LPARs) are six G-protein-coupled receptors that mediate LPA signaling to promote tumorigenesis and therapy resistance in many cancer subtypes, including breast cancer. Individual-receptor-targeted monotherapies are under investigation, but receptor agonism or antagonism effects within the tumor microenvironment following treatment are minimally understood. In this study, we used three large, independent breast cancer patient cohorts (TCGA, METABRIC, and GSE96058) and single-cell RNA-sequencing data to show that increased tumor LPAR1 , LPAR4 , and LPAR6 expression correlated with a less aggressive phenotype, while high LPAR2 expression was particularly associated with increased tumor grade and mutational burden and decreased survival. Through gene set enrichment analysis, it was determined that cell cycling pathways were enriched in tumors with low LPAR1 , LPAR4 , and LPAR6 expression and high LPAR2 expression. LPAR levels were lower in tumors over normal breast tissue for LPAR1 , LPAR3 , LPAR4 , and LPAR6 , while the opposite was observed for LPAR2 and LPAR5 . LPAR1 and LPAR4 were highest in cancer-associated fibroblasts, while LPAR6 was highest in endothelial cells, and LPAR2 was highest in cancer epithelial cells. Tumors high in LPAR5 and LPAR6 had the highest cytolytic activity scores, indicating decreased immune system evasion. Overall, our findings suggest that potential compensatory signaling via competing receptors must be considered in LPAR inhibitor therapy.

Background: The selection of recipient vessels for free-flap breast reconstruction is important for the success of the surgery and the aesthetics of the breast mound. The thoracodorsal artery and vein (TDA/V) allow reconstruction without noticeable scars from the anterior view, but TDA/V exposure is an invasive and time-consuming process on sentinel node biopsy. This study aimed to determine the effectiveness of the lateral thoracic artery and vein (LTA/V) as recipient vessels by comparing them with the TDA/V., Methods: This study included 270 flaps that underwent immediate free-flap breast reconstruction after nipple/skin-sparing mastectomy by lateral incision. The patients were categorized into two groups (LTA and TDA) based on the recipient vessel selected., Results: The LTA and TDA groups comprised 78 and 192 flaps, respectively. Among the 131 short and small pedicle flaps, such as gluteal artery perforator flap and profunda artery perforator flap, 65 (50%) used the LTA as the recipient vessel. The external diameters of the LTA/LTV (median, 1.2 mm/1.5 mm) were significantly lower than those of the TDA/TDV (median, 1.65 mm/2.0 mm). The LTV was present in 94%, and the second vein was present in 49% of cases with anastomosis. No significant differences in flap-related complications were observed between the two groups., Conclusions: The LTA/V can be used as recipient vessels for immediate free-flap reconstruction. Because of their superficial location and small caliber, they are easily accessible and suitable for short and small pedicle flaps., Clinical Question/level of Evidence: Therapeutic, III., (Copyright © 2023 by the American Society of Plastic Surgeons.)

Background: For women diagnosed with hereditary breast and ovarian cancer, the clinical guidelines recommend risk-reducing salpingo-oophorectomy at age 35-40 years or after completion of childbearing. However, there is limited information regarding the current status of risk-reducing salpingo-oophorectomy in Japan., Methods: To clarify factors influencing decision-making for risk-reducing salpingo-oophorectomy among Japanese women diagnosed with hereditary breast and ovarian cancer and their clinical outcomes, we analyzed the medical records of 157 Japanese women with germline BRCA pathogenic variants (BRCA1 n = 85, BRCA2 n = 71 and both n = 1) at our institution during 2011-21. Specimens obtained from risk-reducing salpingo-oophorectomy were histologically examined according to the sectioning and extensively examining the fimbriated end protocol., Results: The risk-reducing salpingo-oophorectomy uptake rate was 42.7% (67/157). The median age at risk-reducing salpingo-oophorectomy was 47 years. Older age, married state and parity were significantly associated with risk-reducing salpingo-oophorectomy (P < 0.001, P = 0.002 and P = 0.04, respectively). History of breast cancer or family history of ovarian cancer did not reach statistical significance (P = 0.18 and P = 0.14, respectively). Multivariate analyses revealed that older age (≥45 years) and married state may be independent factors associated with risk-reducing salpingo-oophorectomy. Interestingly, the annual number of risk-reducing salpingo-oophorectomy peaked in 2016-17 and has increased again since 2020. The rate of occult cancers at risk-reducing salpingo-oophorectomy was 4.5% (3/67): ovarian cancer (n = 2) and serous tubal intraepithelial carcinoma (n = 1)., Conclusion: Age and marital status significantly affected decision-making for risk-reducing salpingo-oophorectomy. This is the first study to suggest possible effects of Angelina Jolie's risk-reducing salpingo-oophorectomy in 2015 and the National Health Insurance introduced for risk-reducing salpingo-oophorectomy in 2020. The presence of occult cancers at risk-reducing salpingo-oophorectomy supports clinical guidelines recommending risk-reducing salpingo-oophorectomy at younger ages., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Zoledronic acid and denosumab are bone-modifying agents that are clinically important in multiple aspects of bone management for breast cancer patients. These aspects include the prevention of osteoporosis induced by cancer-treatment bone loss, treatment and prevention of bone metastasis, and improvement of survival directly or indirectly by maintaining bone health. Interestingly, zoledronic acid and denosumab have different anticancer activities, and they may be associated with the improvement of survival of breast cancer patients under different mechanisms. Zoledronic acid is the most potent bisphosphonate. It provides significant benefits for improving breast cancer mortality in patients with suppressed estrogen level such as in postmenopausal or ovarian suppression condition. Although denosumab's anticancer activity has not been clearly proven compared with zoledronic acid's anticancer activity, denosumab is promising in preventing BRCA1 mutant breast cancer because RANKL is a targetable pathway in BRCA1-associated tumorigenesis. Further studies and more effective clinical use of these agents are anticipated to contribute to the improvement of the clinical outcome of breast cancer patients., (© 2023. The Japanese Society Bone and Mineral Research.)

In recent years, the treatment of breast cancer has advanced dramatically and neoadjuvant chemotherapy (NAC) has become a common treatment method, especially for locally advanced breast cancer. However, other than the subtype of breast cancer, no clear factor indicating sensitivity to NAC has been identified. In this study, we attempted to use artificial intelligence (AI) to predict the effect of preoperative chemotherapy from hematoxylin and eosin images of pathological tissue obtained from needle biopsies prior to chemotherapy. Application of AI to pathological images typically uses a single machine-learning model such as support vector machines (SVMs) or deep convolutional neural networks (CNNs). However, cancer tissues are extremely diverse and learning with a realistic number of cases limits the prediction accuracy of a single model. In this study, we propose a novel pipeline system that uses three independent models each focusing on different characteristics of cancer atypia. Our system uses a CNN model to learn structural atypia from image patches and SVM and random forest models to learn nuclear atypia from fine-grained nuclear features extracted by image analysis methods. It was able to predict the NAC response with 95.15% accuracy on a test set of 103 unseen cases. We believe that this AI pipeline system will contribute to the adoption of personalized medicine in NAC therapy for breast cancer., (© 2023 The Authors. The Journal of Pathology: Clinical Research published by The Pathological Society of Great Britain and Ireland and John Wiley & Sons Ltd.)

Background: Breast screening services were suspended for several months owing to the coronavirus disease 2019 (COVID-19) pandemic. We estimated the potential impact on breast cancer mortality using long-term global observations. However, the magnitude of the impact may vary across countries; therefore, we conducted an analysis and modeling study of this impact in Japan., Patients and Methods: We compared the clinicopathological features of breast cancers between the nonpandemicgroup (April 1, 2019 to October 31, 2019) and the pandemic group (April 1, 2020 to October 31, 2020). We also compared the estimated 10-year survival rates between the two groups based on the weighted average of the 10-year survival rate by clinical stage and site (2004-2007)., Results: Results...Pandemic-related disruption decreased the number of breast cancer cases from296 to 249 during both 7-month periods. The percentage of patients with stage IIB or higher disease was significantly higher in the pandemic group than in the non-pandemic group (22.0% vs. 31.3%, P = 0.0133). The percentage of cases with a Ki-67 labeling index higher than 20% tended to be higher in the pandemic group than in the non-pandemic group (62.2% vs. 54.4%). The estimated 10-year survival rate was lower in the pandemic group than in the non-pandemic group (83.9% vs. 87.9%, 95% confidence interval of the difference: 0.87-8.8, P > 0.05)., Conclusion: We found more aggressive and advanced disease afterthe suspension of breast cancer screening services owing to the COVID-19 pandemic. This may have affected the long-term clinical outcomes of patients with breast cancer., (Copyright © 2023. Published by Elsevier Inc.)

Objective: Neoadjuvant chemotherapy (NAC) is essential for surgical downstaging of early-stage breast cancer, but taxane administration is associated with neuropathy. We investigated whether eribulin induces less neuropathy than paclitaxel., Methods: In this multicentre, randomised study (UMIN000012817), patients diagnosed with invasive breast cancer between December 2013 and April 2016 were randomly assigned to group E (eribulin followed by fluorouracil, epirubicin, and cyclophosphamide; FEC) or group P (paclitaxel followed by FEC). The primary endpoint was incidence of grade 1 or higher peripheral neuropathy according to the Common Terminology Criteria for Adverse Events (CTCAE). Secondary endpoints were pathological complete response (pCR), clinical response, breast-conserving surgery, adverse events, disease-free survival (DFS), and patient neurotoxicity questionnaire (PNQ) analysis., Results: One hundred and eighteen cases were analyzed for safety and 115 were evaluated for efficacy. Peripheral sensory neuropathy was significantly lower in group E after week 6, while peripheral motor neuropathy in group E was significantly lower at weeks 9, 12, and 15. pCR in groups E and P was 20.7% and 29.8% (P = .289), respectively, and clinical response was 55.2% and 77.2% (P = .017), respectively. Three-year DFS was 89.7% in group E and 86.0% in group P (P = .561). Neutropenia was more frequent and more severe in group E. PNQ was evaluated for 4 years, and item 1 (sensory) was consistently lower in group E., Conclusion: Neuropathy was significantly less frequent and less severe in patients who received eribulin compared with paclitaxel. Thus, eribulin could be a good alternative to paclitaxel in patients suffering severe neuropathy., (Copyright © 2022. Published by Elsevier Inc.)

Introduction: β-ray strontium-89 (Sr-89) intra-irradiation therapy has been approved and clinically used to reduce bone metastasis pain not alleviated by bone-modifying agents, external radiation, and analgesic agents. We examined the efficacy of zoledronic acid (ZOL) and Sr-89 combination therapy compared with ZOL alone in breast cancer patients with bone metastases., Materials and Methods: A randomized controlled trial was conducted on breast cancer patients with bone metastasis to compare the efficacy between ZOL monotherapy and ZOL plus Sr-89 combination therapy. The primary endpoints were changes in urinary NTX levels at 13 weeks and brief pain inventory scores. The secondary endpoints were analgesic drug usages, response rates, changes in bone metabolism markers, quality of life, and adverse event rates., Results: Thirty of the planned 60 cases were randomly assigned to ZOL alone or ZOL + Sr-89. There were no significant differences in the changes in urinary NTX levels between the 2 groups (P = 0.365). There was no consistent difference in the pain score changes between the 2 groups. Sr-89 addition to ZOL slightly reduced the white blood cell and platelet counts. However, all adverse events were Grade 1. Safety and analgesic drug dose reduction were more evident in ZOL + Sr-89., Conclusion: This trial showed the lack of benefits from Sr-89 addition to ZOL for breast cancer patients with painful bone metastases. However, safety and analgesic drug dose reduction were more evident in ZOL + Sr-89, indicating its potential for pain control. Sr-89 therapy is safe, thus more effective radiopharmaceuticals are anticipated., (© 2022. The Japanese Society Bone and Mineral Research.)

Aim: Postmastectomy radiotherapy (PMRT) is the standard treatment for locally advanced breast cancer. However, the effectiveness of PMRT in patients with pT1-2 and N1 tumours remains controversial. Therefore, this study aimed to determine the prognostic impact of PMRT in patients with breast cancer and with pT1-2 and 1-3 lymph node metastases., Methods: Using data from the Japanese National Clinical Database from 2004 to 2012, we evaluated the association of PMRT with locoregional recurrence (LRR), any recurrence, and mortality. We enrolled patients who had undergone mastectomy and axillary node dissection and were diagnosed with pT1-2 and N1. We compared clinicopathological factors and prognosis between patients who received (PMRT group) and those who did not receive (No-PMRT group) PMRT., Results: Among 8914 patients enrolled, 492 patients belonged to the PMRT group and 8422 to the No-PMRT group. The median observation time was 6.3 years. There was no significant difference in the incidences of LRR (4.0% versus 5.0%, P = 0.61), recurrence (13.8% versus 11.8%, P = 0.23) and breast cancer death (6.0% versus 4.3%, P = 0.08) at 5 years between the groups. Multivariable analysis revealed that LRR was significantly associated with tumour size, number of node metastases and triple-negative subtype but not with PMRT., Conclusions: The LRR rate in the No-PMRT group was 5.0% at 5 years among patients with T1-2 and N1. PMRT did not significantly influence LRR in patients with T1-2 and N1. However, PMRT administration should be tailored considering the individual risks of tumour size, 3 node metastases and triple-negative subtype., Competing Interests: Conflict of interest statement A.Y. received honoraria from AstraZeneca, Chugai, Daiichi Sankyo, Eisai, Eli Lily, Kyowa Kirin, Nihon Medi-physics, Nippon Kayaku, Pfizer, and Taiho. N.H. received fees from the speakers' bureaus at Chugai, Novartis, AstraZeneca, Allergan, Pfizer, Taiho, Eisai, Exact science, Eli Lily, and Daiichi Sankyo, outside the submitted work. H.K. received speaker's fees from Pfizer Japan Inc. and Johnson & Johnson KK, Chugai and consultation fees from Mitsubishi Tanabe Pharma Corporation. H.K. received speaker's fees from Pfizer Japan Inc. and Johnson & Johnson KK, and consultation fees from Mitsubishi Tanabe Pharma Corporation. H.K. and H.M. are affiliated with the Department of Health Quality Assessment at the University of Tokyo and the Social Collaboration Department supported by the National Clinical Database, Johnson & Johnson K.K., and Nipro Corporation. M.N. received honoraria from Chugai, AstraZeneca, Eli Lilly, Pfizer, Novartis, Taiho, Daiichi Sankyo, Eisai, Kyowa Kirin, and Denka. K.T. received research funds from Chugai and Eisai. K.N. received honoraria from Eisai, Nippon Kayaku, Kyowa Kirin, Novartis, AstraZeneca, Eli Lilly, Pfizer. T.I. received honoraria from AstraZeneca, Eisai, Daiichi Sankyo, Pfizer, Taiho, Eli Lilly, Nippon Kayaku and Takeda. S.O. received fees from the speakers' bureaus at AstraZeneca, Pfizer, Chugai, Eisai, Eli Lilly. S.I received Taiho, Chugai, Eisai, Daiichi Sankyo, Kyowa Kirin, Nippon Kayaku, Eli Lilly. All remaining authors have declared no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: Platelet-derived growth factor B (PDGFB) is known to play essential roles in angiogenesis and lymphangiogenesis during development, and tumor growth and vessel stabilization in experimental models. However, whether these findings could be translated to breast cancer patients remains unclear. We hypothesized that PDGFB gene expression is associated with angiogenesis, cell proliferation, and clinical outcomes in breast cancer patients., Methods: A total of 7635 primary breast cancer patients with full transcriptome and clinical data available from 13 independent cohorts were analyzed using in silico approach. The median value was used to divide each cohort into high and low PDGFB expression groups., Results: High PDGFB gene expression was associated with increased expression of angiogenesis-related genes, higher amount of vascular cell infiltrations, and with enrichment of angiogenesis gene set, lymphangiogenesis-related gene expressions, lymphangiogenesis-related cell infiltrations, and enrichmentof lymphangiogenesis gene set in GSE96058 and validated by TCGA cohorts; however, not with lymphatic metastasis. PDGFB expression was neither associated with cell proliferation as assessed by Ki67 expression nor with Nottingham histological grade, or response to neoadjuvant chemotherapy. We found that PDGFB was most extensively expressed by endothelial and perivascular-like cells in the tumor microenvironment, and minimally by cancer cells consistently in two single-cell sequence cohorts. High PDGFB expression enriched TGFβ, epithelial-mesenchymal transition, hypoxia, and cancer stem cell-associated pathways. However, no association with distant metastasis was observed. Disease-specific and disease-free survival were worse in the high PDGFB expression group consistently in TCGA and METABRIC cohorts., Conclusion: PDGFB is predominantly expressed in endothelial cells and is associated with angiogenesis and lymphangiogenesis, but not with cellular proliferation or metastasis in breast cancer., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

In a previous study, we showed that cryotherapy and compression therapy have comparable efficacy in preventing nab-paclitaxel-induced peripheral neuropathy. However, even with cryotherapy or compression therapy, there were patients with National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 grade ≥ 2 and/or Patient Neurotoxicity Questionnaire (PNQ) grade ≥ D peripheral neuropathies. Therefore, this post hoc analysis was performed to identify predictors of nab-paclitaxel-induced peripheral neuropathy. The clinical data in this post hoc analysis were the data of 38 breast cancer patients receiving chemotherapy with nanoparticle albumin-bound paclitaxel (nab-PTX) at our outpatient chemotherapy center from August 2017 to March 2019. The number of patients was analyzed assuming that there were data for 76 hands. Variables related to the development of nab-PTX-induced peripheral neuropathy were used for regression analysis. Multivariate-ordered logistic regression analysis was performed to identify predictors for the development of nab-PTX-induced peripheral neuropathy. Significant factors included smoking history [odds ratio (OR) 4.64, 95% confidence interval (CI) 1.60-13.5; P = 0.0048] with neuropathy evaluated by CTCAE, body mass index (BMI) (OR 1.13, 95% CI 1.01-1.26; P = 0.039) with neuropathy evaluated by PNQ (sensory), and smoking history (OR 3.80, 95% CI 1.40-10.30; P = 0.0087) and age (OR 1.06, 95% CI 1.01-1.11; P = 0.012) with neuropathy evaluated by PNQ (motor). In conclusion, smoking history, BMI and age were identified as significant predictors of the development of nab-PTX-induced-peripheral neuropathy., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: In some breast cancer patients with a contralateral unaffected hypertrophic and ptotic breast, autologous small-breast reconstruction with contralateral breast reduction is a good option. The current study is aimed to assess the efficacy of the double-pedicle unaffected split-breast (USB) flap harvested from the central half of the unaffected breast for unilateral breast reconstruction with contralateral transverse scar reduction mammoplasty., Methods: Between February 2003 and May 2020, 14 patients underwent breast reconstruction using the USB flap. The mean patient age was 59.1 (range: 48-76) years, and the mean body mass index was 24.2 (range: 19.5-33.3) kg/m 2 . This flap comprised half of the contralateral breast tissues with the 3rd or 4th internal mammary perforator (IMAP) and the lateral thoracic vessel (LTA/V). After USB flap elevation and LTA/V resection, flap perfusion from the IMAP was evaluated on indocyanine green (ICG) angiography. The medial pedicle USB flap was rotated 180° and was transferred to the affected site via the midline. The LTA/V was anastomosed to the recipient vessel to supercharge the distal part of the USB flap, which was then used for breast reconstruction. Then, the remaining contralateral upper and lower breast poles were used for transverse scar reduction mammoplasty., Results: The mean flap size was 13.3 × 26.9 (range: 9.5 × 22 to 16 × 29) cm. All flaps and reduced breasts survived without serious complications such as flap necrosis, although there was one patient with hematoma and one patient with hypertrophic scar. ICG revealed poor perfusion in the distal, lateral part of the flap, ranging from 22.0% to 48.5% of the overall flap area. Final aesthetic evaluation was high, with 11 cases (78.6%) being "good" or "excellent" and 3 cases (21.4%) that were either poor or fair. The mean follow-up period for the patients was 53.8 (range: 15-84) months, with none of the patients presenting second primary breast cancer or recurrence in both breasts., Conclusion: USB flap breast reconstruction with contralateral reduction mammoplasty is a valuable option in breast cancer patients with a hypertrophic and ptotic breast., (© 2022 Wiley Periodicals LLC.)

Background: The one-step nucleic acid amplification (OSNA) assay can quantify the cytokeratin 19 messenger RNA copy number as a proxy for sentinel lymph node (SN) metastasis in breast cancer. A large-scale, multicenter cohort study was performed to determine the prognostic value of the SN tumor burden based on a molecular readout and to establish a model for the prediction of early systemic recurrence in patients using the OSNA assay., Methods: SN biopsies from 4757 patients with breast cancer were analyzed with the OSNA assay. The patients were randomly assigned to the training or validation cohort at a ratio of 2:1. On the basis of the training cohort, the threshold SN tumor burden value for stratifying distant recurrence was determined with Youden's index; predictors of distant recurrence were investigated via multivariable analyses. Based on the selected predictors, a model for estimating 5-year distant recurrence-free survival was constructed, and predictive performance was measured with the validation cohort., Results: The prognostic cutoff value for the SN tumor burden was 1100 copies/μL. The following variables were significantly associated with distant recurrence and were used to construct the prediction model: SN tumor burden, age, pT classification, grade, progesterone receptor, adjuvant cytotoxic chemotherapy, and adjuvant anti-human epidermal growth factor receptor 2 therapy. The values for the area under the curve, sensitivity, specificity, and accuracy of the prediction model were 0.83, 63.4%, 81.7%, and 81.1%, respectively., Conclusions: Using the OSNA assay, the molecular readout-based SN tumor burden is an independent prognostic factor for early breast cancer. This model accurately predicts early systemic recurrence and may facilitate decision-making related to treatment., (© 2022 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Purpose: Although the DNA repair mechanism is important in preventing carcinogenesis, its activation in established cancer cells may support their proliferation and aggravate cancer progression. RAD51 cooperates with BRCA2 and is essential in the homologous recombination of DNA repair. To this end, we hypothesized that RAD51 gene expression is associated with cancer cell proliferation and poor prognosis of breast cancer (BC) patients., Methods: A total of 8515 primary BC patients with transcriptome and clinical data from 17 independent cohorts were analyzed. The median value was used to divide each cohort into high and low RAD51 expression groups., Results: High RAD51 expression enriched the DNA repair gene set and was correlated with DNA repair-related genes. Nottingham histological grade, Ki67 expression and cell proliferation-related gene sets (E2F Targets, G2M Checkpoint and Myc Targets) were all significantly associated with the high RAD51 BC group. RAD51 expression was positively correlated with Homologous Recombination Deficiency, as well as both mutational burden and neoantigens that accompanied a higher infiltration of immune cells. Primary BC with lymph node metastases was associated with high expression of RAD51 in two cohorts. There was no strong correlation between RAD51 expression and drug sensitivity in cell lines, and RAD51 expression was lower after the neoadjuvant chemotherapy compared to before the treatment. High RAD51 BC was associated with poor prognosis consistently in three independent cohorts., Conclusion: RAD51 gene expression is associated with aggressive cancer biology, cancer cell proliferation, and poor survival in breast cancer., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background and Aim: Capsular contracture is the most common complication with smooth-type silicone implants. We investigated the preventive effect of an active metabolite of tamoxifen, 4-hydroxytamoxifen (4-OH TAM), on capsular contracture., Methods: A silicone sheet was implanted into the back of 28 female ICR mice. Mixtures of gel with 0.2% 4-OH TAM and 0.1% 4-OH TAM were administered transdermally once a day for 4 weeks. Saline was administered to the control. After killing the mice, capsular thickness was measured in H&E-stained specimens. Estrogen receptor (ER), α-smooth muscle actin (α-SMA), and transforming growth factor-β (TGF-β) expressions were immunohistochemically investigated in the capsules., Results: The capsule was thinner in the 0.2% 4-OH TAM gel group than in the control group (control, 0.1% 4-OH TAM gel, 0.2% 4-OH TAM gel: 52.8 ± 3.4 µm, 54.2 ± 6.8 µm, 46.4 ± 3.3 µm, respectively). ER was found in most fibroblasts of all samples. α-SMA expression in the capsule was significantly lower in the 4-OH TAM gel groups than in the control group (control = 70.0 ± 3.4%, 0.1% 4-OH TAM = 57.0 ± 3.4%, 0.2% 4-OH TAM = 49.4 ± 4.9%). TGF-β expression was significantly reduced by the 4-OH TAM gel injections dose-dependently (control = 67.3 ± 2.2%, 0.1% 4-OH TAM = 52.4 ± 3.1%, 0.2% 4-OH TAM = 45.1 ± 2.4%)., Conclusions: The transdermal administration of 0.1% and 0.2% 4-OH TAM gels inhibited capsule development. The inhibition of TGF-β expression is a mechanism by which 4-OH TAM suppresses fibroblast growth, preventing capsular formation., (© 2022. The Author(s), under exclusive licence to The Japanese Breast Cancer Society.)

Objective: Conventional cytological diagnosis including duct-washing cytology (DWC) is sometimes performed using ductal epithelial cells collected during mammary ductoscopy; it is useful for detection of early-stage breast cancer such as ductal carcinoma in situ (DCIS). However, conventional cytological diagnosis focuses exclusively on cellular morphology; false negatives and false positives may be caused by inadequate specimen preparation (triggering cell degeneration) or poor examiner diagnostic skills. Molecular diagnosis using RNA biomarkers is expected to compensate for the weaknesses of cytological diagnosis. We previously employed microarray analysis to identify highly expressed genes in DCIS, suggesting that they may be useful for DCIS diagnosis. Here, we explored whether DWC samples yielded RNA of sufficient quantity and quality for RNA biomarker-based diagnosis., Results: We extracted RNAs from 37 DWC samples. RNA from 12 samples exhibited RNA integrities of  ≥ 6, indicative of moderate-to-high quality. We then showed that cocaine and amphetamine regulated transcript prepropeptide (CARTPT) and breast cancer-associated transcript 54 (BRCAT54) mRNA-previously shown by microarray analysis to be highly expressed in DCIS-were detectable in these samples. Therefore, DWC samples may be useful for molecular diagnosis involving RNA biomarkers., (© 2022. The Author(s).)

Background and objectives: In the treatment of the special type of breast cancer (STBC), the choice of chemotherapeutic agents is often based on the characteristic features of the histological type. On the other hand, the surgical strategy is usually determined by the tumor size and presence of lymph node metastasis, and the indication for immediate reconstruction is rarely discussed based on the histological type. The prognoses of STBC and invasive ductal carcinoma of the breast (IDC) patients who underwent subcutaneous mastectomy (SCM) with immediate reconstruction at our institution were compared. Materials and Methods: A total of 254 patients with SCM with immediate reconstruction from 1998 to 2018 were included; their tumor diameter or induration was less than 25 mm, and it was not in close proximity to the skin. Preoperative chemotherapy and non-invasive cancer cases were excluded. Results: The number of patients was 166 for skin-sparing mastectomy (SSM) and 88 for nipple-sparing mastectomy (NSM). The reconstructive techniques were deep inferior epigastric artery perforator flap (DIEP) reconstruction in 43 cases, latissimus dorsi flap reconstruction (LDflap) in 63 cases, tissue expander (TE) in 117 cases, and transverse rectus abdominis myocutaneous flap/vertical rectus abdominis myocutaneous flap (TRAM/VRAM) reconstruction in 31 cases. The histological types of breast cancer were 211 IDC and 43 STBC; 17 were mucinous carcinoma (MUC), 17 were invasive lobular carcinoma (ILC), 6 were apocrine carcinoma, 1 was tubular carcinoma, and 2 were invasive micropapillary carcinoma. There was no difference in local recurrence or disease-free survival (LRFS, DFS) between IDC and STBC, and overall survival (OS) was significantly longer in STBC. OS was better in the STBC group because SCM with immediate reconstruction was performed for STBC, which is a histological type with a relatively good prognosis. Highly malignant histological types, such as squamous cell carcinoma or metaplastic carcinoma, were totally absent in this study. Conclusions: The indications for SCM with immediate reconstruction for relatively common STBCs such as MUC and ILC can be the same as for IDC.

Background: PF-05280014 was compared with trastuzumab sourced from the European Union (trastuzumab-EU), each plus paclitaxel, as first-line treatment for human epidermal growth factor receptor 2-positive metastatic breast cancer in a phase III study. Equivalence between treatment groups was demonstrated., Objective: The aim of this study was to report long-term safety and overall survival (OS) over 6 years after the first patient was screened., Patients and Methods: Randomized patients received intravenous PF-05280014 or trastuzumab-EU, each plus paclitaxel, until objective disease progression. OS, long-term safety, subgroup safety (patients ongoing after day 378), and time-to-treatment discontinuation (TTD) were assessed based on the final statistical analysis plan amended for the ad-hoc analyses., Results: Of 707 randomized patients (n = 352, PF-05280014; n = 355, trastuzumab-EU), 252 (71.6%) in the PF-05280014 and 251 (70.7%) in the trastuzumab-EU group discontinued treatment due to objective progression. Overall, 451 (63.8%) patients completed the study. Between groups (PF-05280014; trastuzumab-EU), estimated median TTDs were 12.25 and 12.06 months (p = 0.692); 61 (17.3%) and 67 (18.9%) patients died; stratified hazard ratio for OS was 0.929 (95% confidence interval 0.656-1.316; p = 0.339); estimated survival rates were 82.3 and 77.4% at 2 years and 77.2 and 75.3% at 3 years. The incidences of treatment-emergent adverse events (TEAEs) overall (98.6%; 96.6%) and for grades ≥3 (41.0%; 43.1%) were comparable between groups. In patients (n = 265; n = 264) ongoing after day 378, the incidences of any TEAEs, grade ≥3 TEAEs, and serious TEAEs were comparable between the treatment groups., Conclusion: Long-term safety and OS were consistent with previous results and demonstrated no clinically meaningful differences between treatment groups., Trial Registration: ClinicalTrials.gov: NCT01989676 (21 November 2013); and EudraCT: 2013-001352-34 (18 December 2013)., (© 2022. Pfizer Inc.)

Background: Evaluation of the cosmetic outcome after breast-conserving surgery (BCS) differs depending on the evaluator. We performed a clinical trial to examine the differences between assessments of cosmetic outcomes performed by a surgeon, patients, and a nurse as a third party after BCS; the evaluation was performed two times (at 3 months and 9 months after surgery). Similarly, we identified factors most significantly affecting the overall cosmetic outcomes., Methods: Sixty-eight patients with primary breast cancer who had undergone BCS between September 2017 and December 2018 were consecutively enrolled in the study. Breast shape, symmetry, hardness, scarring, and overall outcomes were evaluated by a surgeon, patients, and a nurse via a questionnaire., Results: Intraclass correlation coefficients (ICCs) for the 3- to 9-month comparisons of the surgeon, patients, and nurse were 0.73, 0.64, and 0.29, respectively. The ICCs for the surgeon-patient, nurse-patient, and surgeon-nurse comparisons (3 months/9 months) were 0.49/0.44, 0.34/0.10, and 0.41/0.51, respectively. The partial regression coefficient for shape was 0.45 (p = 0.003)/0.61 (p = 0.001), 0.37 (p = 0.005)/0.50 (p < 0.001), and -0.08 (p = 0.48)/0.58 (p < 0.001) for evaluations performed by the surgeon, patients, and nurse, 3 months and 9 months, respectively., Conclusion: With reproducibility, only moderate agreement was observed between the surgeon and the patients. Breast shape was identified as the most important factor affecting cosmetic outcomes., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interests regarding the publication of this article., (Copyright © 2021. Published by Elsevier Taiwan LLC.)

A 70-year-old female with liver metastases from gastrointestinal stromal tumor(GIST)that were found 3 months after partial gastrectomy for the primary GIST underwent Auchincloss operation for left breast cancer with ipsilateral axillary lymph node metastases. The diagnosis was microinvasive ductal cancer that was pT1miN1M0, pStage ⅡA, hormone receptor negative, and HER2 positive. Given the impact of this cancer on the prognosis of liver metastases of GIST, imatinib therapy, but not adjuvant chemotherapy, was started promptly for breast cancer after surgery. Four months after the surgery, left subclavian lymph node recurrence of breast cancer was found. Since the liver metastases of GIST had been stable, imatinib was discontinued, and paclitaxel and anti-HER2 therapy were administered. After confirming tolerability, imatinib was carefully added in combination. Because the lymph nodes shrank and liver metastases of GIST were stable, both anti-HER2 therapy and imatinib were continued. There are few reports of combined chemotherapy for synchronous double cancer, and we report our experience in which careful treatment was required.

The patient is a 67-year-old woman who underwent surgery for left breast cancer in 1990 and right breast cancer in 2003. In 2013, local recurrence of right breast cancer was detected. Then she underwent removal of the local recurrence, axillary lymph node dissection, and post mastectomy irradiation. In 2017 lung metastasis appeared, and she underwent endocrine therapy and chemotherapy. BRCA1/2 analysis showed BRCA1 mutation, so olaparib was started in 2020. The metastatic lesions were reduced markedly, and the skin metastases were crusted over. Although it is necessary to decide when to use olaparib in each case, there is a possibility that olaparib may be effective even in the terminal stage, and it may be considered as one of the treatment options.

This retrospective study aimed to identify predictors for the development of palbociclib-induced neutropenia. This study retrospectively analysed 78 breast cancer patients who had received palbociclib at our hospital between January 2018 and May 2020. For the regression analysis of factors associated with palbociclib-induced neutropenia, variables were extracted manually from medical charts. The level of palbociclib-induced neutropenia was evaluated using the National Cancer Institute's Common Terminology Criteria for Adverse Events (version 5). Multivariate ordered logistic regression analysis was performed to identify predictors for the development of neutropenia. Optimal cut-off thresholds were determined using receiver operating characteristic (ROC) analysis. Values of P < 0.05 (2-tailed) were considered significant. Significant factors identified included concomitant use of statin (odds ratio [OR] = 0.104, 95% confidence interval [CI] = 0.018-0.598; P = 0.011) and body mass index (BMI) (OR = 1.118, 95% CI = 1.007-1.241; P = 0.037). ROC analysis revealed that neutropenia (grade 4) was more likely to occur with a BMI ≥ 22.3 kg/m 2 . In conclusion, no concomitant use of statins and high BMI were identified as significant predictors for the development of palbociclib-induced neutropenia., (© 2021. The Author(s).)

Background/aim: In our previous study, first-line eribulin (ERI) showed 25 weeks of progression-free survival (PFS). This study investigated the efficacy and safety of ERI re-administration in metastatic breast cancer (MBC) patients., Patients and Methods: HER2-negative MBC patients who had never received chemotherapy for MBC received first-line ERI for 18 weeks if they did not have disease progression, and then one cycle of S-1 before ERI re-administration., Results: Twelve patients received ERI re-administration. The PFS of re-administered ERI was 13 weeks. Total duration of ERI use was 30 weeks. The incidence and severity of adverse events were consistent with previous reports., Conclusion: In the first-line setting, the total PFS of eribulin was extended by S-1 administration before disease progression, compared with that of our previous report., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background and objectives : Our department has been performing primary breast reconstruction for breast cancer surgery, incorporating a transverse rectus abdominis myocutaneous flap (TRAM)/vertical rectus abdominis myocutaneous flap (VRAM) since 1998 and a deep inferior epigastric artery perforator flap (DIEP) since 2008. Currently, most gastrointestinal operations in abdominal surgery are performed laparoscopically or are robot-assisted. Cases in which abdominal surgery was performed after breast reconstruction using an abdominal flap were reviewed. Method: A total of 119 cases of primary breast reconstruction using an abdominal flap performed in our department were reviewed. Result: The reconstructive techniques were DIEP in 69 cases and TRAM/VRAM in 50 cases. After breast surgery, seven abdominal operations were performed in six cases. In DIEP cases, one robotic surgery was performed for uterine cancer, and one laparoscopic surgery was performed for ovarian tumor. In TRAM/VRAM cases, two laparoscopic cholecystectomies, one laparoscopic total gastrectomy, one laparoscopic ileus reduction, and one open total hysterectomy oophorectomy were performed. Six surgeries were completed by laparoscopy or robotic assistance. Conclusion: The survival rate after breast cancer surgery is improving, and the choice of breast reconstruction procedure should take into account the possibility of performing a prophylactic resection of the ovaries due to the genetic background and possibly postoperative abdominal surgery due to other diseases. However, in cases in which laparoscopic surgery was attempted after breast reconstruction using an abdominal flap, the laparoscopic surgery could be completed in all cases.

Objective: The incidence of ductal carcinoma in situ (DCIS) is increasing due to more widespread mammographic screening. DCIS, the earliest form of breast cancer, is non-invasive at the time of detection. If DCIS tissues are left undetected or untreated, it can spread to the surrounding breast tissue. Thus, surgical resection is the standard treatment. Understanding the mechanism underlying the non-invasive property of DCIS could lead to more appropriate medical treatments, including nonsurgical options., Data Description: We conducted a microarray-based genome-wide transcriptome analysis using DCIS specimens obtained by puncture from surgical specimens immediately after surgery., (© 2021. The Author(s).)

Background: Nipple reconstruction using local skin flap leaves no morbidity in the healthy nipple. However, one disadvantage of this procedure is that the projection is not often maintained. There are few reports on the rate of long-term maintenance of nipple projection. This study aimed to analyze the 5-year results of clover flap (C-F) nipple reconstruction to determine whether it can be used to maintain nipple projection for long periods and to investigate the factors involved in maintenance of nipple projection., Methods: Patients that underwent nipple-areola reconstruction using C-F after undergoing a two-stage implant-based breast reconstruction with skin-sparing mastectomy between January 2012 and December 2019 were included. The projection of the reconstructed nipple was measured annually for 5 years postoperatively, and the nipple projection maintenance rate (%) was calculated. The influence of eight factors, namely smoking, irradiation, scarred skin, flap pedicle relative to the mastectomy scar, location of the mastectomy scar, flap suturing, and flap necrosis, on nipple height were evaluated., Results: Overall, 275 patients were enrolled. The average maintenance rates (%) at 1-5 years after surgery were 47.1, 39.8, 36.4, 34.6, and 33.5. Creating a well-vascularized skin flap, designing the pedicle farther away from the mastectomy scar, choosing a surgical technique involving an oblique scar on the side of the nipple by wrapping the skin flaps, and including an appropriate amount of fat tissue inside the reconstructed nipple are important for nipple projection maintenance., Conclusion: Nipples reconstructed using the C-F technique on the artificial mound achieve excellent long-term result., Level of Evidence Iv: This journal requires that authors assign a level of evidence to each submission to which evidence-based medicine rankings are applicable. This excludes review articles, book reviews, and manuscripts that concern basic science, animal studies, cadaver studies, and experimental studies. For a full description of these evidence-based medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 ., (© 2021. Springer Science+Business Media, LLC, part of Springer Nature and International Society of Aesthetic Plastic Surgery.)

Background: Sentinel lymph node (SLN) biopsy has been the standard modality for breast cancer patients with clinically node negative disease. In patients who undergo axillary lymph node dissection (ALND) due to SLN metastasis, the harvested nodes (non-SLNs) often contain no metastasis. Here, we evaluated the predictive factors associated with non-SLN metastasis in breast cancer patients., Materials and Methods: This was a retrospective study of patients with operable cT1-3, cN0 invasive breast cancer who underwent SLN biopsy followed by ALND due to SLN metastasis. The clinicopathologic factors and predictive factors of non-SLN metastasis were analyzed. The optimal cutoff for the Ki67 index and the number of positive and negative SLNs that were predictive of non-SLN metastasis were evaluated using receiver operating characteristic curves., Results: The median number of SLN and non-SLN was 3 and 11, respectively. Of the 150 patients, 52 (35.0%) had metastases in non-SLNs. The optimal cutoffs for the Ki67 index and the number of positive and negative SLNs were of 12%, 2, and 1, respectively. In the univariate analysis, the Ki67 index and the number of positive SLNs≥2 and negative SLNs≤1 were higher in the non-SLN + group than that in the non-SLN - group. The number of negative SLNs was as a predictive factor for non-SLNs metastasis in the multivariate analysis., Conclusions: The number of negative SLNs predicts the risk of non-SLN metastasis in breast cancer. When deciding on whether to omit ALND, the number of positive and negative SLNs should be considered., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Aim: To evaluate the association between bromodomain-containing protein 4 (BRD4) expression and clinicopathological factors and prognosis in human breast cancer specimens., Patients and Methods: We used tissue microarrays constructed from samples of patients (n=183) who underwent surgery. We validated the association between BRD4 expression and prognosis in solid tumours, including breast cancer, using The Cancer Genome Atlas (TCGA) database., Results: Immunohistochemical staining showed that BRD4 was widely distributed in breast cancer tissues. BRD4 was strongly expressed in 19.7% of patients but BRD4 staining intensity was not correlated with other clinicopathological factors. Most importantly, patients with a strong BRD4 expression had a significantly longer disease-specific survival than those with a weak BRD4 expression (100.0% vs. 91.3% at 5 years, p=0.027). mRNA expression analysis showed similar results (91.2% vs. 80.2% at 6 years, p=0.047)., Conclusion: Strong BRD4 expression was associated with a significantly better prognosis in breast cancer tumours., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Oncotype DX recurrence score (RS) for breast cancer is a useful tool for determining chemotherapy indication but it is expensive and time-consuming. We determined whether four immuno-histochemical markers, namely human epidermal growth factor 2 (HER2), estrogen receptor (ER), progesterone receptor (PgR), and Ki-67, are predictive of an RS ≥26 in Japanese patients., Patients and Methods: The study included 95 Japanese patients evaluated for RS. A predictive model was created using logistic regression analysis., Results: The discriminant function was calculated as follows: p=1/{1+exp [-(4.611+1.2342×HER2-0.0813×ER- 0.0489 ×PgR+0.0857×Ki67)]}. Using a probability of 0.5 as the cutoff, the accuracy, sensitivity, specificity, positive predictive and negative predictive values were 90.5%, 72.2%, 94.8%, 76.4% and 93.5%, respectively., Conclusion: The model had a high negative predictive value in predicting RS ≥26 in Japanese patients, indicating that Oncotype DX testing may be omitted in patients with a negative result according to the predictive model., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Aim: To describe real-world breast cancer medications among reproductive-age women. Patients & methods: Using data from a Japanese claims database, anticancer prescriptions were classified into seven categories of amenorrhea risk based on fertility preservation guidelines. Results: We identified 2999 women with records of breast cancer and anticancer prescription from 2005 to 2018. The proportions of prescriptions were as follows: high, 4.1-12.9%; intermediate: 6.0-16.3%; low: 0.4-2.3%; very low/no: 0.3-12.2%; unknown: 33.9-45.5%; unlisted combination: 12.2-23.4%; and unlisted drug: 12.5-26.7%. The common drugs in the unknown category were trastuzumab (n = 1527), docetaxel (n = 1014), and paclitaxel (n = 995). For medications unlisted in the guidelines, various drugs and drug combinations were observed. Conclusion: Numerous anticancer drugs are currently being prescribed with insufficient evidence regarding amenorrhea risk.

Background: Tumor-associated tissue eosinophilia (TATE) has been associated with outcomes in a variety of solid tumors; however, its role in breast cancer is not well defined. We hypothesized that tumor-associated tissue eosinophilia is associated with a high mutation and neoantigen load, and we assessed its correlation with cancer outcomes., Methods: The Cancer Genome Atlas was analyzed for eosinophil signatures in breast cancer specimens. Descriptive analyses were performed, including the tumor-infiltrating cell composition using CIBERSORT, cytolytic activity score, and gene set enrichment analysis. Overall survival and disease-free survival were calculated using the Kaplan-Meier method., Results: Out of 1069 cases analyzed, 40 (3.7%) had tissue eosinophils (the tumor-associated tissue eosinophilia group). Tumor-associated tissue eosinophilia was noted in 32.5% luminal, 5% HER2-positive, and 15% triple-negative breast cancer subtypes. The single nucleotide variant-neoantigen load was significantly higher in the tumor-associated tissue eosinophilia group (P = .005), with a higher nonsilent mutation rate (P = .01). The tumor-associated tissue eosinophilia group had lower cytolytic activity (P = .02) but had enriched MYC-targeted (P = .002), E2F-targeted (P = .04), deoxyribonucleic acid repair (P = .03), and unfolded protein response gene sets (P = .05). Tumor-associated tissue eosinophilia was associated with a trend toward improved disease-free survival (P = .06) but presented no differences in overall survival (P = .56)., Conclusion: Tumor-associated tissue eosinophilia was noted in 3.7% of breast cancers and was associated with a higher single nucleotide variant-neoantigen load and nonsilent mutation rate, similar to that of tumor-infiltrating lymphocytes in the triple-negative subtype. However, a lower cytolytic activity score and enriched cell proliferation-related gene sets implicate different roles for tumor-associated tissue eosinophilia than for tumor-infiltrating lymphocytes., (Copyright © 2020 Elsevier Inc. All rights reserved.)

BRCA1 is a well-studied tumor suppressor involved in the homologous repair of DNA damage, whereas PINK1, a mitochondrial serine/threonine kinase, is known to be involved in mitochondrial quality control. Genetic mutations of PINK1 and Parkin cause autosomal recessive early-onset Parkinson's disease. We found that in breast cancer cells, the mitochondrial targeting reagents, which all induce mitochondrial depolarization along with PINK1 upregulation, induced proteasomal BRCA1 degradation. This BRCA1 degradation was dependent on PINK1, and BRCA1 downregulation upon mitochondrial damage caused DNA double-strand breaks. BRCA1 degradation was mediated through the direct interaction with the E3 ligase Parkin. Strikingly, BRCA1 and PINK1/Parkin expression were inversely correlated in cancerous mammary glands from breast cancer patients. BRCA1 knockdown repressed cancer cell growth, and high BRCA1 expression predicted poor relapse-free survival in breast cancer patients. These observations indicate a novel mechanism by which mitochondrial damage is transmitted to the nucleus, leading to BRCA1 degradation.

Background: As Asians are more vulnerable to febrile neutropenia (FN) than Caucasians, evaluations of FN incidence and risk factors in Asians are important for the appropriate use of primary pegfilgrastim (PEG-G)., Patients and Methods: Japanese breast cancer patients receiving standard adjuvant chemotherapies were prospectively enrolled in multicenter institutions from August 2015 to July 2017. FN was evaluated from 2 treatment policies: true FN (T-FN): ≥37.5 °C, grade 4 neutropenia, mandatory hospital visit (visiting); surrogate FN (S-FN): ≥37.5 °C, oral antibiotic, no mandatory visit (non-visiting). PEG-G was used at the physicians' discretion. The primary endpoint was FN incidence during all cycles. Multivariate logistic regression analysis was performed to identify T-FN risk factors., Results: Of 1005 enrolled patients, 980 women treated with FEC, E(A)C, and TC were analyzed. The FN incidence proportions in all patients were 22.5%, 27.5%, and 33.9% for FEC, E(A)C, and TC, respectively. Those of T-FN were 27.7%, 22.4%, and 36.6%; those of S-FN were 17.3%, 32.4%, and 31.5% with more frequent primary PEG-G usage. The relative dose intensity (RDI) of the 3 regimens was ≥0.85 in both groups. In the analysis of risk factors, TC (odds ratio = 2.67), age ≥ 65 years (2.24), and pretreatment absolute neutrophil count (ANC)/1000 μl (0.8) remained significant., Conclusions: FN incidences were above 20% in the 3 regimens, with TC showing the highest. RDI was maintained at a high level in both visiting and non-visiting groups. Patient-related risk factors were age and pretreatment ANC., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: TI has received honoraria from AstraZeneca, Eisai, Daiichi Sankyo, Pfizer, Taiho, Lilly, Nippon Kayaku and Takeda. His institution has received research grants from Taiho, Eisai, Daiichi Sankyo, Nippon Kayaku, and Takeda. KT has received honoraria from AstraZeneca, Eisai, Daiichi Sankyo, Pfizer, Taiho, Lilly, Nippon Kayaku, Chugai, and Takeda. His institution has received research grants from AstraZeneca, Chugai, Taiho, Eisai, Nippon Kayaku, MSD, and Takeda. HM has received honoraria from AstraZeneca, Eisai, Daiichi Sankyo, Pfizer, Taiho, and Takeda. His institution has received research grants from the Japanese government, Eisai, Daiichi Sankyo, Nippon Kayaku, and Pfizer. All remaining authors have declared no conflicts of interest associated with this study., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background/aim: This study aimed to investigate the efficacy of first-line gemcitabine monotherapy for metastatic breast cancer (MBC) and its effect on health-related quality of life (HRQoL) compared with treatment of physician's choice (TPC)., Patients and Methods: We enrolled 96 patients into the first-line gemcitabine group (n=47) or other treatment of physician's choice (TPC) group (n=49) from May 2010 to April 2013. HRQoL was evaluated every 4 weeks., Results: There was no significant difference in the median time to treatment failure (5.3 vs. 4.6 months, hazard ratio=0.87, p=0.546) and the incidence rates of grade 3/4 haematological toxicity (10.6% vs. 8.1%, p=0.677) and grade 3/4 non-haematological toxicity (4.2% vs. 8.1%, p=0.429) between the gemcitabine and TPC groups. Changes in HRQoL from baseline to 12 weeks were not significantly different., Conclusion: Gemcitabine achieves similar efficacy and HRQoL benefit to other chemotherapy and can be used as first-line treatment for MBC., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Sirtuin 1 (SIRT1), an NAD + -dependent deacetylase, is a crucial regulator that produces multiple physiological benefits, such as the prevention of cancer and age-related diseases. SIRT1 is activated by sirtuin-activating compounds (STACs). Here, we report that quercetin 3,5,7,3',4'-pentamethyl ether (KPMF-8), a natural STAC from Thai black ginger Kaempferia parviflora, interacts with SIRT1 directly and stimulates SIRT1 activity by enhancing the binding affinity of SIRT1 with Ac-p53 peptide, a native substrate peptide without a fluorogenic moiety. The binding affinity between SIRT1 and Ac-p53 peptide was enhanced 8.2-fold by KPMF-8 but only 1.4-fold by resveratrol. The specific binding sites of KPMF-8 to SIRT1 were mainly localized to the helix2-turn-helix3 motif in the N-terminal domain of SIRT1. Intracellular deacetylase activity in MCF-7 cells was promoted 1.7-fold by KPMF-8 supplemented in the cell medium but only 1.2-fold by resveratrol. This work reveals that KPMF-8 activates SIRT1 more effectively than resveratrol does.