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Background The high occurrence of treatment resistance in patients with hormone receptor-positive (HR +) breast cancer is a global health concern. Thus, effective immunotherapy must be developed. The public neoantigens, estrogen receptor 1 ( ESR1 ) and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha ( PIK3CA ), shared by HR + and endocrine-resistant breast cancer, could be ideal targets for immunotherapy; however, their presentation by human leukocyte antigen class II (HLA II) and recognition by CD4 + T cells remain largely unknown. Methods Seven mutations in ESR1 and ten mutations in PIK3CA were subjected to major histocompatibility complex (MHC)-peptide binding analysis and enzyme-linked immunospot (ELISPOT) assays using peripheral blood mononuclear cells (PBMCs) from healthy donors carrying DRB4*01:03, or DRB4*01:03 and DPA1*02:02-DPB1*05:01 (DP5). DRB4*01:03- or DP5-restricted peptides were inferred from binding measurements and ELISPOT assays. Other DRB1 alleles that can also present these mutant peptides were identified using binding measurements. Results Positive IFN-γ responses by CD4 + T cells were detected for most peptides. The peptides that contain ESR1 (E380Q) and PIK3CA (N345K, E542K, E545K/A, E726K, H1047R/L/Y, and G1049R) are presumably restricted by DRB4*01:03, which is frequently found globally (carrier frequency: 35–63%), or by DRB4*01:03 and DRB1*04 alleles. Some PIK3CA (H1047R/L/Y) peptides can also be presented by DRB1*01:01, DRB1*09:01, DRB1*11:01, and DRB1*15:02. ESR1 (Y537S/N, D538G) peptides are potentially restricted by DP5, a frequently found allele in East Asian populations, and DRB1*01:01 and DRB1*15:01. Conclusions Mutations in ESR1 and PIK3CA were recognized by CD4 + T cells from healthy donors through potential restriction by common HLA II alleles. Further studies are warranted to elucidate the landscape of HLA II presentation and validate the clinical applicability of these mutations for the immunotherapy of patients with endocrine-resistant breast cancer.

Neoantigens have attracted attention as biomarkers or therapeutic targets. However, accurate prediction of neoantigens is still challenging, especially in terms of its accuracy and cost. Variant detection using RNA sequencing (RNA‐seq) data has been reported to be a low‐accuracy but cost‐effective tool, but the feasibility of RNA‐seq data for neoantigen prediction has not been fully examined. In the present study, we used whole‐exome sequencing (WES) and RNA‐seq data of tumor and matched normal samples from six breast cancer patients to evaluate the utility of RNA‐seq data instead of WES data in variant calling to detect neoantigen candidates. Somatic variants were called in three protocols using: (i) tumor and normal WES data (DNA method, Dm); (ii) tumor and normal RNA‐seq data (RNA method, Rm); and (iii) combination of tumor RNA‐seq and normal WES data (Combination method, Cm). We found that the Rm had both high false‐positive and high false‐negative rates because this method depended greatly on the expression status of normal transcripts. When we compared the results of Dm with those of Cm, only 14% of the neoantigen candidates detected in Dm were identified in Cm, but the majority of the missed candidates lacked coverage or variant allele reads in the tumor RNA. In contrast, about 70% of the neoepitope candidates with higher expression and rich mutant transcripts could be detected in Cm. Our results showed that Cm could be an efficient and a cost‐effective approach to predict highly expressed neoantigens in tumor samples. We evaluated the utility of RNA‐seq data instead of WES data in variant calling to detect neoantigen candidates. We found that the method combining tumor RNA‐seq data and normal WES data (Combination method) could detect neoantigen candidates that have higher expression and rich variant transcripts, and this method may be an efficient and cost‐effective strategy alternative to the conventional method (DNA method).

The activities of non-haematopoietic cells (NHCs), including mesenchymal stromal cells and endothelial cells, in lymphomas are reported to underlie lymphomagenesis. However, our understanding of lymphoma NHCs has been hampered by unexplained NHC heterogeneity, even in normal human lymph nodes (LNs). Here we constructed a single-cell transcriptome atlas of more than 100,000 NHCs collected from 27 human samples, including LNs and various nodal lymphomas, and it revealed 30 distinct subclusters, including some that were previously unrecognized. Notably, this atlas was useful for comparative analyses with lymphoma NHCs, which revealed an unanticipated landscape of subcluster-specific changes in gene expression and interaction with malignant cells in follicular lymphoma NHCs. This facilitates our understanding of stromal remodelling in lymphoma and highlights potential clinical biomarkers. Our study largely updates NHC taxonomy in human LNs and analysis of disease status, and provides a rich resource and deeper insights into LN and lymphoma biology to advance lymphoma management and therapy. Abe et al. profile, characterize and compare non-haematopoietic cells in normal human lymph nodes versus nodal lymphomas from patients, providing insights into stromal modelling in health and disease.

Emerging evidence suggests that DNAM-1 (CD226) play an important role in the recognition of tumor cells and their lysis by cytotoxic T lymphocytes (CTL) and NK cells. Although the DNAM-1 ligand CD155 is ubiquitously expressed in various tissues, many human tumors significantly upregulate the expression of CD155; DNAM-1 on CTL and NK cells may be involved in tumor immunity. However, unlike those in mice, human tissues also express soluble isoforms of CD155 (sCD155) that lack the transmembrane region. Here, we show that sCD155 levels were significantly higher in the sera of 262 patients with lung, gastrointestinal, breast, and gynecologic cancers than in sera from healthy donors. In addition, the sCD155 levels were significantly higher in patients with early stage (stages 1 and 2) gastric cancer than in healthy donors, and were significantly higher in patients with\\nadvanced stage (stages 3 and 4) disease than in patients in those with early stage disease and healthy donors. Moreover, the sCD155 levels were significantly decreased after surgical resection of cancers. Thus, sCD155 level in serum may be potentially useful as a biomarker\\nfor cancer development and progression.

Stable breast cancer cell (BCC) lines are valuable tools for the identification of breast cancer stem cell (BCSC) phenotypes that develop in response to several stimuli as well as for studying the basic mechanisms associated with the initiation and maintenance of BCSCs. However, the characteristics of individual, BCC‐derived BCSCs varies and these cells show distinct phenotypes depending on the different BCSC markers used for their isolation. Aldehyde dehydrogenase (ALDH) activity is just such a recognized biomarker of BCSCs with a CD44+/CD24− phenotype. We isolated BCSCs with high ALDH activity (CD44+/CD24−/Aldefluorpos) from a primary culture of human breast cancer tissue and observed that the cells had stem cell properties compared to BCSCs with no ALDH activity (CD44+/CD24−/Aldefluorneg). Moreover, we found Aldefluorpos BCSCs had a greater hypoxic response and subsequent induction of HIF‐1α expression compared to the Aldefluorneg BCSCs. We also found that knocking down HIF‐1α, but not HIF‐2α, in Aldefluorpos BCSCs led to a significant reduction of the stem cell properties through a decrease in the mRNA levels of genes associated with the epithelial‐mesenchymal transition. Indeed, HIF‐1α overexpression in Aldefluorneg BCSCs led to Slug and Snail mRNA increase and the associated repression of E‐cadherin and increase in Vimentin. Of note, prolonged hypoxic stimulation promoted the phenotypic changes of Aldefluorneg BCSCs including ALDH activity, tumorigenesis and metastasis, suggesting that hypoxia in the tumor environment may influence BCSC fate and breast cancer clinical outcomes. Aldehyde dehydrogenase (ALDH) activity is just such a recognized biomarker of breast cancer stem cells (BCSC) with a CD44+/CD24− phenotype. We found Aldefluorpos BCSCs had a greater hypoxic response and subsequent induction of HIF‐1α expression compared to the Aldefluorneg BCSCs. Moreover, we identified hypoxic induction of Aldefluorpos cells from Aldefluorneg cells and those altered Aldefluorpos cells expressed angiogenic genes rather than EMT‐related genes.

Background Chemotherapy-induced peripheral neuropathy (CIPN) is a common and debilitating side effect of taxane-based chemotherapy in breast cancer patients. Previous findings suggest that compression therapy may be a safe and effective preventive strategy against CIPN. However, patient-reported comfort and usability aspects of such therapy remain underexplored. This sub-analysis aimed to evaluate patient-reported discomfort and pressure associated with compression therapy and explore potential usability barriers to compliance. Methods This sub-analysis of a Phase I single-arm, open-label trial focused on patient-reported outcomes related to the subjective experience of compression therapy using double-layered surgical gloves and stockings during taxane administration. Parameters such as discomfort, pressure, pain, and itch in hands and feet were collected via questionnaires from 10 patients receiving neoadjuvant or adjuvant chemotherapy. Post hoc univariable analyses were conducted to explore potential factors associated with discomfort scores. Results Most patients reported minimal discomfort (mean hand discomfort score: 1.8; mean foot discomfort score: 2.2) and no pain in hands or feet during therapy. Mean perceived pressure scores were generally rated as “slight” to “mild,” though higher in calves (3.0) than toes (2.6) or fingertips (2.8). No statistically significant associations were identified between discomfort scores and other reported factors, though a positive trend between pain and discomfort was observed. Free-text responses highlighted that application and removal of double-layer compression garments posed greater challenges than physical discomfort itself. Conclusions Compression therapy using standard gloves and stockings appears tolerable and feasible for CIPN prevention. However, ease of application rather than discomfort may be the primary barrier to patient compliance. Future designs should prioritize usability and fit to ensure sustained adherence, especially in clinical settings. Trial registration jRCTs032210221, registered on 4 August 2021.

The addition of 10 mg olanzapine to the standard triplet antiemetic therapy has shown superiority in controlling chemotherapy-induced nausea and vomiting compared with triplet therapy alone for highly emetogenic chemotherapy, albeit with sedative side-effects. We aimed to investigate if administering 5 mg of olanzapine at home after anthracycline plus cyclophosphamide chemotherapy, rather than before chemotherapy, can maintain efficacy in controlling chemotherapy-induced nausea and vomiting while minimising sedative side-effects and associated risks. This was a phase 3, double-blind, randomised, placebo-controlled trial, done in 15 hospitals and cancer centres in Japan. Eligible patients were female adults aged 20 years or older with stage I–III breast cancer and an Eastern Cooperative Oncology Group performance status of 0–1, who were scheduled to receive intravenous anthracycline plus cyclophosphamide-based chemotherapy, and were naive to chemotherapy or had never received moderately to highly emetogenic chemotherapy. Eligible patients were randomly assigned 1:1 to oral olanzapine 5 mg or placebo via the central registration system. Randomisation was performed using blocked stratification, with age (≥55 years vs <55 years) and institution as stratification factors and a block size of two. Allocation was concealed and masking was achieved by using tablets with identical appearance. Treatment was administered at home within 5 h after the end of anthracycline plus cyclophosphamide administration and before the patient's evening meal on day 1 to minimise the risk of sedation during hospital visits and transportation, and on the next 3 days after their evening meal, both with pre-chemotherapeutical application of intravenous dexamethasone 9·9 mg, intravenous palonosetron 0·75 mg, and oral aprepitant 125 mg on day 1 followed by an additional dose of aprepitant 80 mg on days 2 and 3 or intravenous fosaprepitant 150 mg as a premedication on day 1. The primary endpoint was the proportion of patients with a complete response, defined as no vomiting and no rescue medication during the overall phase (0–120 h after the initiation of anthracycline plus cyclophosphamide) based on patient diary. The primary analysis was done by modified intention-to-treat, including all patients who received at least one dose of the study treatment and had at least one efficacy evaluation. Safety was analysed in all patients who received any treatment. This trial was registered with the Japan Registry of Clinical Trials, jRCT1031200134, and is complete. Between Oct 26, 2020 and Nov 2, 2022, 500 female patients from 15 medical institutions in Japan were randomly assigned to receive olanzapine (n=251) or placebo (n=249). Median age at enrolment was 52 years (IQR 45–60) in the olanzapine group and 51 years (46–60) in the placebo group. Data on gender and race or ethnicity were not collected. The median follow-up was 168 h (IQR 168–168). 480 participants (246 in the olanzapine group and 234 in the placebo group) received at least one dose of study medication and were eligible for the efficacy analysis. The complete response rate in the olanzapine group (58·1%, n=143) was significantly higher than in the placebo group (35·5%, n=83; difference 22·7%, 95% CI 14·0–31·4%; p<0·0001) during the overall phase. The most frequently reported severe or very severe symptoms based on the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) version 1.0 were anorexia (33 [13%] of 246 patients in the olanzapine group vs 89 [38%] of 235 in the placebo group) and constipation (30 [12%] vs 37 [16%]). Severe or very severe concentration impairment was reported in 25 (10%) of 246 patients in the olanzapine group and 34 (14%) of 235 patients in the placebo group. Experimental drug-related grade 3–4 adverse events according to the Common Terminology Criteria for Adverse Events version 5.0 included somnolence (four [2%] of 246 patients in the olanzapine group vs none of 235 in the placebo group), and concentration impairment (two [1%] vs none). There were no deaths. Post-chemotherapy administration of 5 mg olanzapine in combination with triplet antiemetic therapy before anthracycline plus cyclophosphamide-based chemotherapy significantly improved the complete response rate for chemotherapy-induced nausea and vomiting during the overall phase compared with placebo in female patients with breast cancer receiving outpatient chemotherapy, with an acceptable level of safety. The findings represent a substantial advancement in managing chemotherapy-induced nausea and vomiting and provide assurance that the safe and effective administration of olanzapine can be achieved at a dosage of 5 mg. The Capture of Outstanding Clinical Research and Evolution (CORE) project at Juntendo University.

Background As an oncologic emergency related to abnormalities in calcium metabolism, hypercalcemia associated with paraneoplastic syndrome and bone metastases is well known. Meanwhile, the incidence of hypocalcemia is low, except in cases associated with bone-modifying agents used for bone metastases. Hypocalcemia induced by bone-modifying agents typically occurs early after the initial administration, and its incidence can be significantly reduced by preventive administration of calcium and vitamin D3 supplements. Case report We report two cases of recurrent severe hypocalcemia occurring during chemotherapy for metastatic breast cancer with multiple bone metastases. Case 1: A 35-year-old Japanese woman developed metastases in the bone, liver, and ovaries during postoperative endocrine therapy for invasive lobular carcinoma of the breast. She underwent chemotherapy and treatment with denosumab. She experienced recurrent episodes of severe hypocalcemia subsequent to a change in the chemotherapy regimen. Case 2: A 65-year-old Japanese woman encountered multiple bone metastases after postoperative anti-human epidermal growth factor receptor 2 therapy and during endocrine therapy for invasive ductal carcinoma of the breast. She underwent anti-human epidermal growth factor receptor 2 therapy and treatment with denosumab. She experienced recurrent severe hypocalcemia subsequent to a change in the chemotherapy regimen to letrozole + lapatinib, trastuzumab emtansine, and lapatinib + capecitabine. Conclusions We observed two cases of recurrent severe hypocalcemia in patients with advanced breast cancer and bone metastases after modifications to their therapy regimens. These cases differed from the typical hypocalcemia induced by bone-modifying agents. It is possible that antitumor drugs affect calcium and bone metabolism associated with bone metastases. While these cases are rare, it is crucial for oncologists to be aware of hypocalcemia not only at the initiation of bone-modifying agents but also throughout the entire antitumor therapy, as hypocalcemia can lead to fatal outcomes.

Purpose The randomized phase 2 Neo-peaks study examined usefulness of neoadjuvant trastuzumab emtansine + pertuzumab (T-DM1 + P) following docetaxel + carboplatin + trastuzumab + pertuzumab (TCbHP) as compared with the standard TCbHP regimen. We previously reported that pCR rate after neoadjuvant therapy tended to be higher with TCbHP followed by T-DM1 + P. We conducted an exploratory analysis of prognosis 5 years after surgery. Methods Neoadjuvant treatment with TCbHP (6 cycles; group A), TCbHP (4 cycles) followed by T-DM1 + P (4 cycles; group B), and T-DM1 + P (4 cycles; group C, + 2 cycles in responders) were compared. Group C non-responders after 4 cycles were switched to an anthracycline-based regimen. We evaluated 5-year disease-free survival (DFS), distant DFS (DDFS), and overall survival (OS). Results Data from 203 patients (50, 52, and 101 in groups A–C, respectively) were analyzed. No significant intergroup differences were found for DFS, DDFS, or OS. The 5-year DFS rates (95% CI) were 91.8% (79.6–96.8%), 92.3% (80.8–97.0%), and 88.0% (79.9–93.0%) in groups A–C, respectively. TCbHP followed by T-DM1 + P and T-DM1 + P with response-guided addition of anthracycline therapy resulted in similar long-term prognosis to that of TCbHP. Conclusions In patients who achieved pCR after neoadjuvant therapy with T-DM1 + P, omission of adjuvant anthracycline may be considered, whereas treatment should be adjusted for non-pCR patients with residual disease. T-DM1 + P with response-guided treatment adjustment may be useful for minimizing toxicity. Trial registration number and date of registration UMIN-CTR, UMIN000014649, prospectively registered July 25, 2014. Some of the study results were presented as a Mini Oral session at the ESMO Breast Cancer 2023 (Berlin, Germany, 11–13 May 2023).

Background/Aim: This study describes a rare cell sorter (RCS) method to detect circulating tumor cells (CTCs) and CTC clusters in whole blood without pretreatment. Patients and Methods: We collected samples from breast cancer patients at the University of Tsukuba Hospital. A total of 15 whole-blood specimens from patients with breast cancer were collected and analyzed via a microfluidics chip, fluorescence-conjugated antibody staining, and fluorescence microscopy. Of 15 total cases, eight were analyzed by RCS ver3 and seven were analyzed by RCS ver3.5 to reveal potential clinical differences in scanning methods. We then examined the HER2 status on 4 of the 15 patients using our RCS system. Results: RCS efficiently detected all subtypes of CTCs and CTC clusters from the peripheral blood of cancer patients. The concordance rate of HER2 status between tissue and CTCs in 4 tested clinical samples was 100%. Conclusion: RCS is a non-invasive method that allows for simultaneous detection of CTCs, cluster presence, and surface marker (e.g., HER2) status. Frequent sampling is, thus, possible and the large amount of data obtained will be clinically useful to predict response to therapy as well as plan adjunct support therapies in cancer patients.