Time-series blood cytokine profiles correlate with treatment responses in triple-negative breast cancer patients.

BACKGROUND: Triple-negative breast cancer (TNBC) is the most heterogeneous breast cancer subtype. Partly due to its heterogeneity, it is currently challenging to stratify TNBC patients and predict treatment outcomes. METHODS: In this study, we examined blood cytokine profiles of TNBC patients throughout treatments (pre-treatment, during chemotherapy, pre-surgery, and 1 year after the surgery in a total of 294 samples). We analyzed the obtained cytokine datasets using weighted correlation network analyses, protein-protein interaction analyses, and logistic regression analyses. RESULTS: We identified five cytokines that correlate with good clinical outcomes: interleukin (IL)-1α, TNF-related apoptosis-inducing ligand (TRAIL), Stem Cell Factor (SCF), Chemokine ligand 5 (CCL5 also known as RANTES), and IL-16. The expression of these cytokines was decreased during chemotherapy and then restored after the treatment. Importantly, patients with good clinical outcomes had constitutively high expression of these cytokines during treatments. Protein-protein interaction analyses implicated that these five cytokines promote an immune response. Logistic regression analyses revealed that IL-1α and TRAIL expression levels at pre-treatment could predict treatment outcomes in our cohort. CONCLUSION: We concluded that time-series cytokine profiles in breast cancer patients may be useful for understanding immune cell activity during treatment and for predicting treatment outcomes, supporting precision medicine. TRIAL REGISTRATION: The study has been registered with the University Hospital Medical Information Network Clinical Trials Registry ( http://www.umin.ac.jp/ctr/index-j.htm ) with the unique trial number UMIN000023162. The association Japan Breast Cancer Research Group trial number is JBCRG-22. The clinical outcome of the JBCRG-22 study was published in Breast Cancer Research and Treatment on 25 March 2021. https://doi.org/10.1007/s10549-021-06184-w .

Comparison of cisplatin-based versus standard preoperative chemotherapy in patients with operable triple-negative breast cancer: propensity score matching and inverse probability of treatment weighting analysis.

PURPOSE: The efficacy of carboplatin is non-equivalent to that of cisplatin (CDDP) for various tumor types in curative settings. However, the role of CDDP in operable triple-negative breast cancer (TNBC) patients remains unknown. We conducted a multicenter observational study to examine the effects of CDDP added to preoperative chemotherapy in patients with TNBC. METHODS: This retrospective study consecutively included previously untreated patients with stage I-III TNBC treated with preoperative chemotherapy with or without CDDP. The primary endpoint was distant disease-free survival (DDFS). Propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) were used to minimize confounding biases in comparisons between the two groups. RESULTS: A total of 138 patients were enrolled in the study. Of these, 52 were in the CDDP group and 86 in the non-CDDP group. DDFS was significantly better in the CDDP group than in the non-CDDP group (unadjusted hazard ratio (HR) 0.127 and p < 0.001, PSM HR 0.141 and p < 0.003, IPTW HR 0.123 and p = < 0.001). Furthermore, among the patients with residual cancer burden (RCB) class II/III, DDFS was better in the CDDP group than in the non-CDDP group (unadjusted HR 0.192 and p = 0.013, PSM HR 0.237 and p = 0.051, IPTW HR 0.124 and p = 0.059). CONCLUSION: Our study showed that CDDP-containing regimens achieved favorable prognoses in patients with operable TNBC, especially for the RCB class II/III population. Confirmative studies are warranted to elucidate the role of CDDP in TNBC treatment.

Cellular senescence triggers intracellular acidification and lysosomal pH alkalinized via ATP6AP2 attenuation in breast cancer cells.

Several chemotherapeutic drugs induce senescence in cancer cells; however, the mechanisms underlying intracellular pH dysregulation in senescent cells remain unclear. Adenosine triphosphatase H+ transporting accessory protein 2 (ATP6AP2) plays a critical role in maintaining pH homeostasis in cellular compartments. Herein, we report the regulatory role of ATP6AP2 in senescent breast cancer cells treated with doxorubicin (Doxo) and abemaciclib (Abe). A decline in ATP6AP2 triggers aberrant pH levels that impair lysosomal function and cause immune profile changes in senescent breast cancer cells. Doxo and Abe elicited a stable senescent phenotype and altered the expression of senescence-related genes. Additionally, senescent cells show altered inflammatory and immune transcriptional profiles due to reprogramming of the senescence-associated secretory phenotype. These findings elucidate ATP6AP2-mediated cellular pH regulation and suggest a potential link in immune profile alteration during therapy-induced senescence in breast cancer cells, providing insights into the mechanisms involved in the senescence response to anticancer therapy.

Tumor immune microenvironment and systemic response in breast cancer.

Cancer immunotherapies, particularly immune checkpoint inhibitors (ICIs) that target programmed cell death protein 1 (PD-1) or programmed cell death ligand 1 (PD-L1), have revolutionized cancer treatment. ICIs are effective against breast cancer, and their efficacy against triple-negative breast cancer (TNBC) has been reported. The efficacy of immunotherapy is related to the tumor immune microenvironment. In particular, tumor-infiltrating immune cells, hypoxia, and mitochondria in the tumor microenvironment are closely associated with anti-tumor immunity. Moreover, breast cancer (BC) tumors exhibit high heterogeneity; however, identification of effective biomarkers, via tissue biopsies, is limited owing to the invasiveness of the procedure. Therefore, it is crucial to develop non-invasive protocols (e.g., blood and fecal sampling) to identify components of the tumor immune microenvironment that reflect the systemic immune response, for the characterization of immunotherapy biomarkers. Herein, we review the relationship among systemic immune responses-via liquid biopsy analysis-the microbiome, and the tumor immune microenvironment in BC, while characterizing prospective biomarkers. Relationship between TIME and systemic response in breast cancer.

Assessment of axillary node status by ultrasound after neoadjuvant chemotherapy in patients with clinically node-positive breast cancer according to breast cancer subtype.

The use of sentinel node biopsy (SNB) following neoadjuvant chemotherapy (NAC) for patients with cN1 breast cancer is controversial. Improvements of negative predictive value (NPV) by axillary ultrasound (AUS), which corresponds to the accurate prediction rate of node-negative status after NAC, would lead to decreased FNR of SNB following NAC. In this study, we retrospectively investigated the accurate prediction rate of NPV by AUS after NAC in patients with cytologically node-positive breast cancer treated between January 2012 and December 2016. Of 279 eligible patients, the NPV was 49.2% in all patients, but varied significantly by tumor subtype (p < 0.001) and tumor response determined by magnetic resonance imaging (MRI) (p = 0.0003). Of the 23 patients with clinically node negative (ycN0) by AUS and clinical complete response in primary lesion by MRI, the NPV was 100% in patients with HR±/HER2+ or HR-/HER2- breast cancer. In conclusion, regarding FNR reduction post-NAC, it will be of clinical value to take tumor subtype and primary tumor response using MRI into account to identify patients for SNB after NAC.

Metastatic ovarian cancer spreading into mammary ducts mimicking an in situ component of primary breast cancer: a case report.

BACKGROUND: Accurate diagnosis of metastatic tumors in the breast is crucial because the therapeutic approach is essentially different from primary tumors. A key morphological feature of metastatic tumors is their lack of an in situ carcinoma component. Here, we present a unique case of metastatic ovarian carcinoma spreading into mammary ducts and mimicked an in situ component of primary carcinoma. To our knowledge, this is the second case (and the first adult case) confirming the in situ-mimicking growth pattern of a metastatic tumor using immunohistochemistry. CASE PRESENTATION: A 69-year-old Japanese woman was found to have a breast mass with microcalcifications. She had a known history of ovarian mixed serous and endocervical-type mucinous (seromucinous) carcinoma. Needle biopsy specimen of the breast tumor revealed adenocarcinoma displaying an in situ-looking tubular architecture in addition to invasive micropapillary and papillary architectures with psammoma bodies. From these morphological features, metastatic serous carcinoma and invasive micropapillary carcinoma of breast origin were both suspected. In immunohistochemistry, the cancer cells were immunoreactive for WT1, PAX8, and CA125, and negative for GATA3, mammaglobin, and gross cystic disease fluid protein-15. Therefore, the breast tumor was diagnosed to be metastatic ovarian serous carcinoma. The in situ-looking architecture showed the same immunophenotype, but was surrounded by myoepithelium confirmed by immunohistochemistry (e.g. p63, cytokeratin 14, CD10). Thus, the histogenesis of the in situ-like tubular foci was could be explained by the spread of metastatic ovarian cancer cells into existing mammary ducts. CONCLUSION: Metastatic tumors may spread into mammary duct units and mimic an in situ carcinoma component of primary breast cancer. This in situ-mimicking growth pattern can be a potential pitfall in establishing a correct diagnosis of metastasis to the breast. A panel of breast-related and extramammary organ/tumor-specific immunohistochemical markers may be helpful in distinguishing metastatic tumors from primary tumors.

Sequential adjuvant chemoradiotherapy-induced diffuse alveolar haemorrhage in a patient with breast cancer successfully treated with corticosteroid plus recombinant human soluble thrombomodulin.

The effective treatment for corticosteroid (CS)-refractory sequential chemoradiotherapy (CRT)-induced lung injury has not been established. We report a case of sequential CRT-induced diffuse alveolar haemorrhage (DAH) successfully treated with CS therapy plus recombinant human soluble thrombomodulin (rhTM). A 69-year-old woman was treated with sequential adjuvant CRT for early-stage breast cancer. After sequential CRT, she suffered from progressive dyspnoea. Chest CT scan showed consolidations in the irradiation field and diffuse ground-glass attenuations in the non-irradiation regions. We suspected sequential CRT-induced DAH because of increased haemosiderin-laden macrophages in bronchoalveolar lavage fluid. Her clinical conditions did not improve with high-dose CS therapy. Therefore, rhTM was added, and her disease and serum high-mobility group box-1 levels improved rapidly. Therefore, rhTM plus CS might be a safe and effective treatment for sequential CRT-induced lung injury, although further study is necessary to validate these findings.

Experience with Bilateral Risk-Reducing Mastectomy for an Unaffected BRCA Mutation Carrier.

Women with BRCA1/2 mutations have a high risk of breast cancer and may opt for risk-reducing mastectomy (RRM). We report a 38-year-old Japanese woman who was diagnosed as a BRCA2 mutation carrier. She underwent prophylactic bilateral skin-sparing mastectomy (SSM) with excision of the nipple and preservation of the areola skin. It is unclear whether a bilateral RRM leads to better survival compared with intensive surveillance. The oncological risk associated with the presence of remnant breast glandular tissue after SSM or nipple-sparing mastectomy has been obscure. We report the first case of RRM for a Japanese BRCA mutation carrier and provide a literature review on risk management for BRCA mutation carriers with a focus on the concepts and procedures of RRM.