Everolimus-Related Pneumonitis in Patients with Metastatic Breast Cancer: Incidence, Radiographic Patterns, and Relevance to Clinical Outcome.

BACKGROUND: This study investigated the incidence, radiographic patterns, and relevance to clinical outcome of everolimus-related pneumonitis (ERP) in patients with metastatic breast cancer (MBC). MATERIALS AND METHODS: Data of patients with MBC treated with everolimus who had baseline and at least one follow-up chest computed tomography (CT) were obtained from a medical electronic database system. An independent review of the CT scans of these patients was conducted by two radiologists (NCT03730428). Log-rank and Cox proportional hazard regression analyses were used for time-to-event analyses. RESULTS: ERP was radiographically detected in 45 of 86 patients (52.3%). In more than 80% of these patients, ERP occurred during the first 4 months of everolimus treatment. Only 14 of the 45 patients with ERP were symptomatic (31.1%). Symptoms included cough, fever, and shortness of breath. Bilateral and lower distribution of the pneumonitis was most common. In most of the cases, ground-glass opacities and reticular opacities were noticed. Elderly patients were more likely to develop ERP. Patients with ERP had significantly longer progression-free survival (PFS; 6.8 vs. 4.1 months, p = .024) and overall survival (OS; 42.8 vs. 21.3 months, p = .016). ERP was a predictor of OS improvement confirmed by multivariate Cox analysis (hazard ratio, 0.49; 95% confidence interval, 0.25-0.97; p = .040). CONCLUSIONS: ERP was noted in half of the patients with MBC treated with everolimus. Our data suggested that ERP was associated with improved prognosis and may be used as a biomarker for the efficacy of everolimus in MBC. Close monitoring, prompt diagnosis, and proper treatment for ERP are essential to maintain the quality of life of patients and achieve maximum treatment benefits. IMPLICATIONS FOR PRACTICE: Everolimus-related pneumonitis (ERP) is one of the most worrying drug adverse events, especially in Asian patients. However, little has been known about the clinical and radiographic details of ERP in patients with metastatic breast cancers (MBCs) treated with everolimus. The present study investigated the clinical characteristics, radiographic patterns, and its correlation with treatment outcome in patients with MBC. ERP was identified in more than half of patients with MBC during everolimus therapy and was associated with improved outcome. Close monitoring and prompt diagnosis and appropriate treatment for ERP are critical for the preservation of patients' quality of life and achievement of maximal treatment benefits.

Xanthine dehydrogenase as a prognostic biomarker related to tumor immunology in hepatocellular carcinoma.

BACKGROUND: Xanthine dehydrogenase (XDH) is a critical enzyme involved in the oxidative metabolism of purines, pterin and aldehydes and a central component of the innate immune system. However, the prognostic value of XDH in predicting tumor-infiltrating lymphocyte abundance, the immune response, and survival in different cancers, including hepatocellular carcinoma (HCC), is still unclear. METHODS: XDH expression was analyzed in multiple databases, including Oncomine, the Tumor Immune Estimation Resource (TIMER), the Kaplan-Meier plotter database, the Gene Expression Profiling Interactive Analysis (GEPIA) database, and The Cancer Genome Atlas (TCGA). XDH-associated transcriptional profiles were detected with an mRNA array, and the levels of infiltrating immune cells were validated by immunohistochemistry (IHC) of HCC tissues. A predictive signature containing multiple XDH-associated immune genes was established using the Cox regression model. RESULTS: Decreased XDH mRNA expression was detected in human cancers originating from the liver, bladder, breast, colon, bile duct, kidney, and hematolymphoid system. The prognostic potential of XDH mRNA expression was also significant in certain other cancers, including HCC, breast cancer, kidney or bladder carcinoma, gastric cancer, mesothelioma, lung cancer, and ovarian cancer. In HCC, a low XDH mRNA level predicted poorer overall survival, disease-specific survival, disease-free survival, and progression-free survival. The prognostic value of XDH was independent of the clinical features of HCC patients. Indeed, XDH expression in HCC activated several immune-related pathways, including the T cell receptor, PI3K-AKT, and MAPK signaling pathways, which induced a cytotoxic immune response. Importantly, the microenvironment of XDHhigh HCC tumors contained abundant infiltrating CD8 + T cells but not exhausted T cells. A risk prediction signature based on multiple XDH-associated immune genes was revealed as an independent predictor in the TCGA liver cancer cohort. CONCLUSION: These findings suggest that XDH is a valuable prognostic biomarker in HCC and other cancers and indicate that it may function in tumor immunology. Loss of XDH expression may be an immune evasion mechanism for HCC.

Phase II trail of nab-paclitaxel in metastatic breast cancer patients with visceral metastases.

BACKGROUND: Visceral metastases account for 48-67% of metastatic breast cancer (MBC) patients and presage a worse overall survival. Previous study suggested potential effect of nab-paclitaxel on patients with visceral metastases subgroups. This phase II trial was conducted to explore the efficacy and safety of nab-paclitaxel in such a high-risk group of patients. METHODS: In this prospective, single-center, open-label, phase II study, MBC patients with visceral metastases (N = 80) received nab-paclitaxel (Abraxane, 125 mg/m2, D1, D8, D15 every 28 days). RESULTS: The median PFS was 5.1 months (95% CI: 4.2-6.0 months), with an ORR of 33.8% (95% CI 21.3-43.8%) and CBR of 66.2% (95% CI 56.3-75.0%). In univariate analysis, patients with premenopausal status had a trend of better treatment outcome. Multivariate analysis demonstrated non brain metastasis (adjusted HR 0.31, 95% CI 0.12-0.83, P = 0.019) and first line treatment (adjusted HR 0.37, 95% CI 0.17-0.81, P = 0.013) as independent predictors of longer PFS. The overall safety was acceptable with most common treatment-related, grade ≥ 3 toxicities of neutropenia (16.3%) and sensory neuropathy (3.7%). CONCLUSIONS: This phase II trial documented satisfactory efficacy and safety of nab-paclitaxel in MBC patients with visceral metastases, providing evidence for relative clinical practice. Patients in first line therapy had better treatment outcome. For patients with premenopausal status or brain metastasis, further alternatives (for example, combined chemotherapy or targeting therapy) might be required. This study also demonstrated the efficacy and safety of 125 mg/m2 nab-paclitaxel among Asian patients. TRIAL REGISTRATION: This research is registered under clinicaltrials.gov (NCT02687490, February 22, 2016).

Pretreatment 18F-FDG Uptake Heterogeneity Predicts Treatment Outcome of First-Line Chemotherapy in Patients with Metastatic Triple-Negative Breast Cancer.

BACKGROUND: Intratumoral heterogeneity of 18F-fluorodeoxyglucose (18F-FDG) uptake in primary tumor has proven to be a surrogate marker for predicting treatment outcome in various tumors. However, the value of intraindividual heterogeneity in metastatic diseases remains unknown. The aim of this study was to evaluate pretreatment positron emission tomography/computed tomography (PET/CT) 18F-FDG-based heterogeneity for the prediction of first-line treatment outcome in metastatic triple-negative breast cancer (mTNBC). MATERIALS AND METHODS: mTNBC patients from three clinical trials (NCT00601159, NCT01287624, and NCT02341911) with whole-body 18F-FDG PET/CT scan before first-line gemcitabine/platinum were included. Heterogeneity index (HI) and the maximum of FDG uptake (MAX) across total metastatic lesions (-T) on baseline PET/CT scans were assessed. HI was measured by MAX divided by the minimum FDG uptake across metastatic lesions. Optimal cutoffs were determined by time-dependent receiver operator characteristics (ROC) analysis. Progression-free survival (PFS) and overall survival (OS) were estimated by Kaplan-Meier method and compared by log-rank test. RESULTS: A total of 42 mTNBC patients were included in this study. The median PFS of patients with high HI-T (>1.9) and high MAX-T (>10.5) was significantly shorter than patients with low HI-T (<1.9; p = .049) and low MAX-T (<10.5; p = .001). In terms of OS, only high MAX-T was significant for poorer outcome (p = .013). ROC curve analysis confirmed the predictive value of MAX and HI in mTNBC patients. Area under the ROC curve for MAX-T and HI-T was 0.75 and 0.65, indicating a higher predictive accuracy than conventional clinical risk factors. CONCLUSION: HI and MAX measured among metastatic lesions on pretreatment 18F-FDG PET/CT scans could be potential predicators for first-line treatment outcome in patients with mTNBC. IMPLICATIONS FOR PRACTICE: Intratumoral heterogeneity of 18F-fluorodeoxyglucose (FDG) uptake in primary tumor has proven to be a robust surrogate predictive marker. A novel positron emission tomography/computed tomography (PET/CT) parameter-heterogeneity index (HI) to quantify the heterogeneous characteristics of metastatic disease is proposed. Triple-negative breast cancer (TNBC) is a highly heterogeneous disease and remains a clinical challenge. The predictive performance of HI, along with the maximum FDG uptake (MAX), measured on pretreatment PET/CT scans in patients with metastatic TNBC was evaluated. Results indicate that HI and MAX may serve as applicable imaging predicators for treatment outcome of metastatic TNBC in clinical practice.

Clinicopathological characteristics, evolution, treatment pattern and outcomes of hormone-receptor-positive/HER2-low metastatic breast cancer.

Objective: Despite the promising efficacy of the novel antibody-drug conjugate trastuzumab deruxtecan in treating Hormone Receptor (HoR)-positive/Human Epidermal Growth Factor Receptor 2 (HER2)-low metastatic breast cancer (MBC), its categorization as a distinct entity remains disputed, as does the divergence in its endocrine and chemotherapy outcomes. This study aimed to elucidate the clinical characteristics, primary/metastatic lesion HER2 expression, and treatment outcomes of HoR-positive/HER2-low patients. Methods: We included HoR-positive/HER2-negative MBC patients who underwent 1st and 2nd line endocrine treatment from July 2010 to October 2022 at the Fudan University Shanghai Cancer Center, comparing the clinical pathological characteristics, HER2 expression in primary/metastatic lesions, treatment, and therapeutic effects of the HER2-low and HER2-zero groups. Results: Among the 458 HoR-positive/HER2-negative MBC patients, 54.37% (249/458) were HER2-low. The HER2-low group and the HER2-zero group had similar clinical pathological characteristics and similar progression-free survival (PFS) of 1st and 2nd line endocrine treatment (median PFS: 8.05 months vs 10.12 months, p=0.114, HR 1.257, 95% CI 0.771 to 1.028). The PFS of the HER2-low and HER2-zero groups was also similar, treated with different endocrine drugs (including aromatase inhibitors, tamoxifen/toremifene, fulvestrant, palbociclib, and everolimus). However, the HER2-low group had significantly shorter PFS during 1st and 2nd line chemotherapy compared to the HER2-zero group (median PFS: 8.64 vs 9.03 months, p=0.027, HR 0.841, 95% CI 0.721-0.980). Additionally, 41.18% (63/153) of patients exhibited a change in HER2 expression between primary and metastatic lesions. Notably, patients whose HER2 status changed from zero to low expression had significantly prolonged PFS during chemotherapy compared to those who maintained low HER2 expression (median PFS: 14.29 vs 11.27 months, p=0.048, HR 0.597, 95% CI 0.358-0.996). Conclusion: In HoR-positive MBC, patients with low and zero HER2 expression have similar clinical characteristics and respond similarly to endocrine treatment, but the chemotherapy effect is worse in the HER2-low patients. Moreover, the transformation of HER2 status from primary to metastatic lesions may have potential influence on chemotherapy outcomes. Therefore, the expression and heterogeneity of HER2 should be considered in clinical decisions.

Comparing pyrotinib with trastuzumab and pertuzumab with trastuzumab for HER2-positive metastatic breast cancer: a retrospective, multicenter analysis.

Objective: Pyrotinib and pertuzumab are effective treatment options for HER2-positive metastatic breast cancer (HER2+ MBC). Our study was to directly compare the efficacy and safety of pyrotinib plus trastuzumab (PyroH) and pertuzumab plus trastuzumab (HP) in patients with HER2+ MBC. Methods: We conducted a retrospective examination of HER2+ MBC patients who received PyroH plus chemotherapy or HP plus chemotherapy between 2017 and 2022 at five institutions in China. Our primary endpoint was progression-free survival (PFS). Results: This study involved 333 patients, among which 161 received PyroH and 172 received HP. The utilization of PyroH as a first-line therapy for MBC was more prevalent among older patients, those with a shorter duration of disease-free interval, or those who had previously been treated with trastuzumab. Although in the first-line advanced treatment HP cohort showed numerically longer PFS (median PFS: 14.46 vs. 22.90 months, p=0.057), in the second-line or later treatments, there was no significant difference in PFS between the PyroH and HP groups (median PFS: 8.67 vs. 7.92 months, p=0.286). Despite HP showing a longer PFS in the overall cohort (median PFS: 9.30 vs. 13.01 months, p=0.005), it did not serve as an independent predictor of PFS in the multivariate analysis (HR 1.134, 95% CI 0.710-1.811, p=0.598). Without taxane, PyroH demonstrated a longer PFS than HP (median PFS: 10.12 vs. 8.15 months, p=0.017). PyroH group displayed a numerically longer median PFS in patients with brain metastases compared to the HP group, though not statistically significant (median PFS: 9.03 vs. 8.15 months, p=0.976). PyroH had higher incidence of grade 3/4 diarrhea (34.3% vs. 3.0%) but similar overall adverse events. Conclusion: In conclusion, PyroH is comparable in second-line or later treatment and during brain metastasis, even having superior efficacy without taxane in real-world setting. Toxicities were tolerable in both groups. (ClinicalTrials.gov: NCT05572645).

Real-world data of triplet combination of pyrotinib, trastuzumab, and chemotherapy in HER2-positive metastatic breast cancer: a multicenter, retrospective study.

Background: Pyrotinib, an irreversible pan-human epidermal growth (HER) inhibitor, has proven its antitumor efficacy as a second-line treatment for HER2-positive metastatic breast cancer (HER2+ MBC) when combined with capecitabine. However, real-world data concerning the pyrotinib, trastuzumab, and chemotherapy (PyroHC) combination remains scarce. Objectives: Our study is to report the treatment patterns, efficacy, and safety of the PyroHC combination in a real-world setting. Design: This study enrolled patients with HER2+ MBC from five institutions in China, treated with PyroHC between June 2017 and January 2023 (ClinicalTrials.gov, identifier: NCT05839288). Methods: We evaluated progression-free survival (PFS), objective response rate (ORR), toxicity profile, and utilized treatment regimens. Results: Of the 135 patients in our cohort, 91.9% had prior trastuzumab exposure and 52.2% underwent at least two systematic therapy lines before receiving PyroHC. The most prevalent chemotherapies paired with PyroH were capecitabine (36.3%). Patients receiving PyroHC achieved a median PFS of 8.67 months [95% confidence interval (CI): 6.84-10.51] and an ORR of 51.3% (95% CI: 42.1-61.5%). The first-line treatment with PyroHC led to a median PFS of 14.46 months (95% CI: 6.35-22.56). Patients with brain metastases showed a median PFS of 9.03 months (95% CI: 6.56-11.50), achieving an ORR of 52.17% (95% CI: 51.74-83.39). Longer previous trastuzumab (⩾6.37 months) or lapatinib (⩾10.05 months) therapies could indicate improved PFS, while prior pyrotinib exposure negatively influenced PFS. Notably, the most common grade 3/4 adverse events were diarrhea (37.8%), which were generally manageable. Conclusion: PyroHC shows promising efficacy and a satisfactory safety profile for treating HER2+ MBC, both as a first-line option and for heavily treated patients, including those with brain metastasis. Our findings suggest the duration and history of anti-HER2 therapy as potential predictors for PyroHC efficacy in advanced settings.

Pretreatment 18F-FDG uptake heterogeneity may predict treatment outcome of combined Trastuzumab and Pertuzumab therapy in patients with metastatic HER2 positive breast cancer.

OBJECTIVE: Intra-tumoral heterogeneity of 18F-fluorodeoxyglucose (18F-FDG) uptake has been proven to be a surrogate marker for predicting treatment outcome in various tumors. However, the value of intra-tumoral heterogeneity in metastatic Human epidermal growth factor receptor 2(HER2) positive breast cancer (MHBC) remains unknown. The aim of this study was to evaluate 18F-FDG uptake heterogeneity to predict the treatment outcome of the dual target therapy with Trastuzumab and Pertuzumab(TP) in MHBC. METHODS: Thirty-two patients with MHBC who underwent 18F-FDG positron emission tomography/computed tomography (PET/CT) scan before TP were enrolled retrospectively. The region of interesting (ROI) of the lesions were drawn, and maximum standard uptake value (SUVmax), mean standard uptake value (SUVmean), total lesion glycolysis (TLG), metabolic tumor volume (MTV) and heterogeneity index (HI) were recorded. Correlation between PET/CT parameters and the treatment outcome was analyzed by Spearman Rank Test. The ability to predict prognosis were determined by time-dependent survival receiver operating characteristic (ROC) analysis. And the survival analyses were then estimated by Kaplan-Meier method and compared by log-rank test. RESULTS: The survival analysis showed that HI50% calculated by delineating the lesion with 50%SUVmax as threshold was a significant predictor of patients with MHBC treated by the treatment with TP. Patients with HI50% (≥ 1.571) had a significantly worse prognosis of progression free survival (PFS) (6.87 vs. Not Reach, p = 0.001). The area under curve (AUC), the sensitivity and the specificity were 0.88, 100% and 63.6% for PFS, respectively. CONCLUSION: 18F-FDG uptake heterogeneity may be useful for predicting the prognosis of MHBC patients treated by TP.

Chromatin Remodelling Molecule ARID1A Determines Metastatic Heterogeneity in Triple-Negative Breast Cancer by Competitively Binding to YAP.

Heterogeneity represents a pivotal factor in the therapeutic failure of triple-negative breast cancer (TNBC). In this study, we retrospectively collected and analysed clinical and pathological data from 258 patients diagnosed with TNBC at the Fudan University Cancer Hospital. Our findings show that low ARID1A expression is an independent prognostic indicator for poor overall survival (OS) and recurrence-free survival (RFS) in TNBC patients. Mechanistically, both nuclear and cytoplasmic protein analyses and immunofluorescent localisation assays confirm that ARID1A recruits the Hippo pathway effector YAP into the nucleus in human triple-negative breast cancer cells. Subsequently, we designed a YAP truncator plasmid and confirmed through co-immunoprecipitation that ARID1A can competitively bind to the WW domain of YAP, forming an ARID1A/YAP complex. Moreover, the downregulation of ARID1A promoted migration and invasion in both human triple-negative breast cancer cells and xenograft models through the Hippo/YAP signalling axis. Collectively, these findings demonstrate that ARID1A orchestrates the molecular network of YAP/EMT pathways to affect the heterogeneity in TNBC.

Cuproptosis-related risk score predicts prognosis and characterizes the tumor microenvironment in colon adenocarcinoma.

Introduction: Cuproptosis is a novel copper-dependent regulatory cell death (RCD), which is closely related to the occurrence and development of multiple cancers. However, the potential role of cuproptosis-related genes (CRGs) in the tumor microenvironment (TME) of colon adenocarcinoma (COAD) remains unclear. Methods: Transcriptome, somatic mutation, somatic copy number alteration and the corresponding clinicopathological data of COAD were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus database (GEO). Difference, survival and correlation analyses were conducted to evaluate the characteristics of CRGs in COAD patients. Consensus unsupervised clustering analysis of CRGs expression profile was used to classify patients into different cuproptosis molecular and gene subtypes. TME characteristics of different molecular subtypes were investigated by using Gene set variation analysis (GSVA) and single sample gene set enrichment analysis (ssGSEA). Next, CRG Risk scoring system was constructed by applying logistic least absolute shrinkage and selection operator (LASSO) cox regression analysis and multivariate cox analysis. Real-time quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry (IHC) were used to exam the expression of key Risk scoring genes. Results: Our study indicated that CRGs had relatively common genetic and transcriptional variations in COAD tissues. We identified three cuproptosis molecular subtypes and three gene subtypes based on CRGs expression profile and prognostic differentially expressed genes (DEGs) expression profile, and found that changes in multilayer CRGs were closely related to the clinical characteristics, overall survival (OS), different signaling pathways, and immune cell infiltration of TME. CRG Risk scoring system was constructed according to the expression of 7 key cuproptosis-related risk genes (GLS, NOX1, HOXC6, TNNT1, GLS, HOXC6 and PLA2G12B). RT-qPCR and IHC indicated that the expression of GLS, NOX1, HOXC6, TNNT1 and PLA2G12B were up-regulated in tumor tissues, compared with those in normal tissues, and all of GLS, HOXC6, NOX1 and PLA2G12B were closely related with patient survival. In addition, high CRG risk scores were significantly associated with high microsatellite instability (MSI-H), tumor mutation burden (TMB), cancer stem cell (CSC) indices, stromal and immune scores in TME, drug susceptibility, as well as patient survival. Finally, a highly accurate nomogram was constructed to promote the clinical application of the CRG Risk scoring system. Discussion: Our comprehensive analysis showed that CRGs were greatly associated with TME, clinicopathological characteristics, and prognosis of patient with COAD. These findings may promote our understanding of CRGs in COAD, providing new insights for physicians to predict prognosis and develop more precise and individualized therapy strategies.

ER status conversion and subsequent treatment: an assessment of negative ER expression detected by 18F-FES PET in metastatic breast cancer patients with ER-positive primary tumors.

Background: The 18F-fluoroestradiol positron emission tomography/computed tomography (18F-FES PET/CT) technique provides a convenient method to evaluate the overall estrogen receptor (ER) expression in metastatic breast cancer (MBC) patients. There are long debates on the characteristics and treatment strategy of patients with positive primary ER lesions but negative ER expression in metastatic disease. 18F-FES PET offers an opportunity to answer this question. Objectives: This study aimed to characterize the primary ER-positive patients with advanced-stage FES negativity and investigate the real-world treatment decisions made by physicians subsequently, and compare the efficacy between different regimens. Design: This observational cohort study was conducted at Fudan University Shanghai Cancer Center, enrolling breast cancer patients with ER-positive primary tumors who showed advanced-stage FES negativity. Methods: Descriptive statistics were used in clinicopathologic characteristics and compared with a chi-square test or t-test. In addition, progression-free survival (PFS) was estimated by the Kaplan-Meier method and compared by log-rank test. Results: 16.6% (52/314) of patients with an ER-positive primary tumor had negative ER expression assessed by 18F-FES for MBC prior to receiving first-line systemic therapy, among whom adjuvant endocrine therapy was prevalently utilized (86.5%, 45/52). The rate of FES negativity in the advanced stage was negatively correlated with levels of ER expression of primary tumors. Chemotherapy (83.3%, 40/48) was the most common treatment strategy afterward, among which capecitabine monotherapy (62.5%, 25/40) was a dominant alternative. PFS was significantly prolonged with capecitabine alone versus other chemotherapy (median PFS: 13.14 versus 6.21 months, p = 0.029). Conclusion: Negative conversion of ER in MBC detected by 18F-FES occurred frequently. Patients with lower ER expression in the primary lesion were more likely to have negative ER expression in the metastasis. In real-world clinical practice, most physicians primarily opted for chemotherapy, with capecitabine monotherapy being a commonly selected regimen. Trial registration: ClinicalTrials.gov identifier: NCT05797987.

CXCL12, a potential modulator of tumor immune microenvironment (TIME) of bladder cancer: From a comprehensive analysis of TCGA database.

Background: Tumor immune microenvironment (TIME) plays a significant role in the initiation and progression of bladder urothelial carcinoma (BLCA). However, there are only a few researches regarding the association between immune-related genes and tumor-infiltrating immune cells (TICs) in TIME of BLCA. Methods: We calculated the proportion of immune/stromal component and TICs of 414 BLCA samples and 19 normal samples downloaded from TCGA database with the help of ESTIMATE and CIBERSORT algorithms. Differentially expressed genes (DEGs) were obtained from the comparison between Stromal and Immune Score and further analyzed by GO and KEGG enrichment analysis, as well as PPI network and COX regression analysis. CXCL12 was overlapping among the above analyses. Single gene analysis of CXCL12 was carried out through difference analysis, paired analysis and GSEA. The association between CXCL12 and TICs was assessed by difference analysis and correlation analysis. Results: Immune and stromal component in TIME of BLCA were associated with patients' clinicopathological characteristics. 284 DEGs were primarily enriched in immune-associated activities, among which CXCL12 was the most significant gene sharing the leading nodes in PPI network and being closely related with patients' survival. Single gene analysis and immunohistochemistry revealed that CXCL12 was down-regulated in BLCA samples and significantly related with the clinicopathological characteristics of patients. Further analysis suggested that CXCL12 was involved in the immune-associated activities probably through its close cross-talk with TICs. Conclusions: CXCL12 down-regulation could be a potential biomarker to predict the unbalanced immune status of TIME of BLCA, which might provide an extra insight for the immunotherapy of BLCA.

Mammary adipocytes protect triple-negative breast cancer cells from ferroptosis.

Ferroptosis, a novel non-apoptotic form of cell death, can induce tumor cell death and treatment resistance. Lipid metabolism is closely related to ferroptosis; however, the effect of mammary adipocytes on breast cancer ferroptosis remains to be elucidated. Here, we established the co-culture system of adipocyte-breast cancer cells and revealed the protection of triple-negative breast cancer from ferroptosis by adipocytes. Then, we performed the lipidomics analysis comparing lipid metabolites of co-cultured and normal-cultured cells. Mechanistically, oleic acid secreted from adipocytes inhibited lipid peroxidation and ferroptosis of triple-negative breast cancer cells in the presence of ACSL3. Taken together, mammary adipocytes can protect breast cancer cells from ferroptosis through oleic acid in the presence of ACSL3. These findings could provide new ideas and targets for tumor treatment.

Chemotherapy Shows a Better Efficacy Than Endocrine Therapy in Metastatic Breast Cancer Patients with a Heterogeneous Estrogen Receptor Expression Assessed by 18F-FES PET.

Background: The heterogeneity of estrogen receptor (ER) expression has long been a challenge for the diagnosis and treatment strategy of metastatic breast cancer (MBC). A novel convenient method of ER detection using 18F-fluoroestradiol positron emission tomography/computed tomography (18F-FES PET/CT) offers a chance to screen and analyze MBC patients with ER uncertainty. Methods: MBC patients who received 18F-FES PET/CT were screened and patients with both FES positive (FES+) and negative (FES-) lesions were enrolled in this study. Progression-free survival (PFS) was estimated using the Kaplan−Meier method and was compared using the log-rank test. Results: A total of 635 patients were screened and 75 of 635 (11.8%) patients showed ER uncertainty; 51 patients received further treatment and were enrolled in this study. Among them, 20 (39.2%) patients received chemotherapy (CT), 21 (41.2%) patients received endocrine-based therapy (ET), and 10 (19.6%) patients received combined therapy (CT + ET). CT showed a better progression-free survival (PFS) compared with ET (mPFS 7.1 vs. 4.6 months, HR 0.44, 95% CI 0.20−0.93, p = 0.03). CT + ET did not improve PFS compared with either CT or ET alone (mPFS 4.4 months, p > 0.2). All three treatment options were well tolerated. Conclusions: 18F-FES PET/CT could identify patients with ER heterogeneity. Patients with bone metastasis are more likely to have ER heterogeneity. Patients with ER heterogeneity showed better sensitivity to CT rather than ET. Combined therapy of CT + ET did not improve the treatment outcome.

Heterogeneity derived from 18 F-FDG PET/CT predicts immunotherapy outcome for metastatic triple-negative breast cancer patients.

BACKGROUND: Recently, immunotherapy has been used to treat metastatic triple-negative breast cancer (mTNBC). Basic research has indicated a relation between tumor heterogeneity and the immune response. Tumor heterogeneity derived from 18 F-FDG PET/CT is a potential predictor of chemotherapy results; however, few studies have focused on immunotherapy. This study aims to develop a convenient and efficient measurement of tumor heterogeneity for the prediction of immunotherapy in mTNBC patients. METHODS: We enrolled mTNBC patients who received immunotherapy (PD-1/PD-L1 antibody) plus chemotherapy as first-line treatment and underwent 18 F-FDG PET/CT scans before treatment. We defined a novel index representing tumor heterogeneity calculated from the standard uptake value (SUV) as IATH and IETH. Optimal cutoffs were determined using time-dependent receiver operator characteristics (ROC) analysis. RESULTS: A total of 32 patients were enrolled and analyzed in this trial. A significantly longer median PFS was observed in the low SUVmax group than in the high SUVmax group (9.4 vs. 5.8 months, HR = 0.3, 95% CI 0.1-0.9, p = 0.025). The median PFS of low-IATH patients was significantly longer than that of high-IATH patients (HR = 0.3, 95% CI 0.1-0.8, p = 0.022). Similarly, patients with low IETH had significantly longer PFS than patients with high IETH (9.4 vs. 4.9 months, HR = 0.3, 95% CI 0.1-0.7, p = 0.01). Multivariate analysis demonstrated IETH as an independent predictor of PFS. CONCLUSIONS: This study proposed a novel method to assess intratumor and intertumor heterogeneity among metastatic breast cancer patients and determined that baseline IETH derived from 18 F-FDG PET/CT could represent a simple and promising predictor for first-line immunotherapy among mTNBC patients.

Temporal Heterogeneity of HER2 Expression and Spatial Heterogeneity of 18F-FDG Uptake Predicts Treatment Outcome of Pyrotinib in Patients with HER2-Positive Metastatic Breast Cancer.

Background: This study aimed to evaluate tumor heterogeneity of metastatic breast cancer (MBC) and investigate its impact on the efficacy of pyrotinib in patients with HER2-positive MBC. Methods: MBC patients who underwent 18F-FDG PET/CT before pyrotinib treatment were included. Temporal and spatial tumor heterogeneity was evaluated by the discordance between primary and metastatic immunohistochemistry (IHC) results and baseline 18F-FDG uptake heterogeneity (intertumoral and intratumoral heterogeneity indexes: HI-inter and HI-intra), respectively. Progression-free survival (PFS) was estimated by the Kaplan−Meier method and compared by a log-rank test. Results: A total of 572 patients were screened and 51 patients were included. In 36 patients with matched IHC results, 25% of them had HER2 status conversion. Patients with homogenous HER2 positivity had the longest PFS, followed by patients with gained HER2 positivity, while patients with HER2 negative conversion could not benefit from pyrotinib (16.8 vs. 13.7 vs. 3.6 months, p < 0.0001). In terms of spatial heterogeneity, patients with high HI-intra and HI-inter had significantly worse PFS compared to those with low heterogeneity (10.6 vs. 25.3 months, p = 0.023; 11.2 vs. 25.3 months, p = 0.040). Conclusions: Temporal heterogeneity of HER2 status and spatial heterogeneity of 18F-FDG uptake could predict the treatment outcome of pyrotinib in patients with HER2-positive MBC, which provide practically applicable methods to assess tumor heterogeneity and guidance for treatment decisions.

Comparison of two regimens of weekly paclitaxel plus gemcitabine in patients with metastatic breast cancer: propensity score-matched analysis of real-world data.

Purpose: Weekly gemcitabine + paclitaxel (wGT) administration is widely applied in real-world clinical practice. The 28-day and 21-day regimens of wGT are the most widely accepted regimens. We evaluated the efficacy and safety of wGT administration in patients with metastatic breast cancer (MBC) and compared the two regimens. Methods: Patients with human epidermal growth factor receptor 2 (HER-2)-negative MBC who received wGT between October 2013 and October 2016 were identified using an electronic database. The outcome variables included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and safety profile. Propensity score matching was performed to minimize potential confounders. Results: A total of 140 patients were included. The median PFS and OS was 7.8 [95% confidence interval (CI) = 7.0-8.7] months and 22.5 (95% CI = 18.8-26.1) months, respectively. The toxicity of wGT was manageable. Among the patients, 90 (64.3%) received the 21-day regimen and 50 (35.7%) received the 28-day regimen. A higher number of younger patients and patients receiving later-line therapy received the 28-day regimen. There was no significant difference between the two groups in PFS after propensity score matching, though subgroup analysis showed that patients with early relapse benefited more from the 28-day regimen. The ORR was numerically higher in 28-day regimen (37.8% versus 28.0%, p = 0.310). However, the 21-day regimen was better tolerated than the 28-day regimen. Conclusion: wGT administration showed efficacy and safety in patients with MBC. The efficacy was comparable between the two regimens after adjustment for confounding factors while the 21-day regimen was better tolerated. Plain Language Summary: 21-day regimen of wGT was well tolerated in patients with metastatic breast cancer Weekly gemcitabine + paclitaxel (wGT) administration is widely applied in real-world clinical practice. The 28-day and 21-day regimens of wGT are the most widely accepted regimens. We evaluated the efficacy and safety of wGT administration in patients with metastatic breast cancer (MBC) and compared the two regimens. Patients with human epidermal growth factor receptor 2 (HER-2)-negative MBC who received wGT between October 2013 and October 2016 were identified using an electronic database. The outcome variables included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and safety profile. Propensity score matching was performed to minimize potential confounders. We found that the efficacy was comparable between the two regimens after adjustment for confounding factors while the 21-day regimen was better tolerated.

Identification of cuproptosis-related subtypes, construction of a prognosis model, and tumor microenvironment landscape in gastric cancer.

Introduction: Cuproptosis is a novel identified regulated cell death (RCD), which is correlated with the development, treatment response and prognosis of cancer. However, the potential role of cuproptosis-related genes (CRGs) in the tumor microenvironment (TME) of gastric cancer (GC) remains unknown. Methods: Transcriptome profiling, somatic mutation, somatic copy number alteration and clinical data of GC samples were downloaded from the Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) database to describe the alterations of CRGs from genetic and transcriptional fields. Differential, survival and univariate cox regression analyses of CRGs were carried out to investigate the role of CRGs in GC. Cuproptosis molecular subtypes were identified by using consensus unsupervised clustering analysis based on the expression profiles of CRGs, and further analyzed by GO and KEGG gene set variation analyses (GSVA). Genes in distinct molecular subtypes were also analyzed by GO and KEGG gene enrichment analyses (GSEA). Differentially expressed genes (DEGs) were screened out from distinct molecular subtypes and further analyzed by GO enrichment analysis and univariate cox regression analysis. Consensus clustering analysis of prognostic DEGs was performed to identify genomic subtypes. Next, patients were randomly categorized into the training and testing group at a ratio of 1:1. CRG Risk scoring system was constructed through logistic least absolute shrinkage and selection operator (LASSO) cox regression analysis, univariate and multivariate cox analyses in the training group and validated in the testing and combined groups. Real-time quantitative polymerase chain reaction (RT-qPCR) was used to evaluate the expression of key Risk scoring genes. Sensitivity and specificity of Risk scoring system were examined by using receiver operating characteristic (ROC) curves. pRRophetic package in R was used to investigate the therapeutic effects of drugs in high- and low- risk score group. Finally, the nomogram scoring system was developed to predict patients' survival through incorporating the clinicopathological features and CRG Risk score. Results: Most CRGs were up-regulated in tumor tissues and showed a relatively high mutation frequency. Survival and univariate cox regression analysis revealed that LIAS and FDX1 were significantly associated with GC patients' survival. After consensus unsupervised clustering analysis, GC patients were classified into two cuproptosis molecular subtypes, which were significantly associated with clinical features (gender, age, grade and TNM stage), prognosis, metabolic related pathways and immune cell infiltration in TME of GC. GO enrichment analyses of 84 DEGs, obtained from distinct molecular subtypes, revealed that DEGs primarily enriched in the regulation of metabolism and intracellular/extracellular structure in GC. Univariate cox regression analysis of 84 DEGs further screened out 32 prognostic DEGs. According to the expression profiles of 32 prognostic DEGs, patients were re-classified into two gene subtypes, which were significantly associated with patients' age, grade, T and N stage, and survival of patients. Nest, the Risk score system was constructed with moderate sensitivity and specificity. A high CRG Risk score, characterized by decreased microsatellite instability-high (MSI-H), tumor mutation burden (TMB) and cancer stem cell (CSC) index, and high stromal and immune score in TME, indicated poor survival. Four of five key Risk scoring genes expression were dysregulated in tumor compared with normal samples. Moreover, CRG Risk score was greatly related with sensitivity of multiple drugs. Finally, we established a highly accurate nomogram for promoting the clinical applicability of the CRG Risk scoring system. Discussion: Our comprehensive analysis of CRGs in GC demonstrated their potential roles in TME, clinicopathological features, and prognosis. These findings may improve our understanding of CRGs in GC and provide new perceptions for doctors to predict prognosis and develop more effective and personalized therapy strategies.

Pyrotinib Plus Vinorelbine Versus Lapatinib Plus Capecitabine in Patients With Previously Treated HER2-Positive Metastatic Breast Cancer: A Multicenter, Retrospective Study.

BACKGROUND: Pyrotinib is a newly-developed irreversible pan-ErbB (erythroblastic leukemia viral oncogene homolog) receptor oral tyrosine kinase inhibitor (TKI) with promising efficacy in the human epidermal growth factor receptor-2 (HER2) positive breast cancer. The phase III PHOEBE study proved that pyrotinib plus capecitabine exceeded lapatinib plus capecitabine (LX) in PFS (p < 0.001). Oral vinorelbine is commonly used in combination with anti-HER2 treatment. However, no evidence was reported in terms of the real-world pattern, safety, and efficacy of pyrotinib plus vinorelbine (NP) compared with LX. METHODS: Medical records were retrospectively evaluated for all HER2-positive metastatic breast cancer (MBC) patients who experienced progression on prior trastuzumab-containing regimens (advanced setting) and taxane (any setting) and received NP or LX therapy from 2015 to 2021 in five institutions. RESULTS: A total of 224 patients were enrolled and evaluated, of which 132 (58.9%) patients received LX and 92 (41.1%) patients received NP. The median progression-free survival (mPFS) of NP group was significantly longer than that in LX group (8.3 vs 5.0 months, HR = 0.47 95% CI 0.34-0.65, p < 0.001). The advantage of NP over LX was seen both in patients with trastuzumab resistance (p < 0.001) and refractoriness (p = 0.004). The NP group had more diarrhea cases (23.9%) compared to the LX group (8.3%). Discontinuation rates in the two groups were similar. CONCLUSIONS: This trial revealed the clinical practice of NP and LX treatment among HER2+ MBC patients pretreated with trastuzumab in China. More patients received LX than NP in real-world while the efficacy of NP exceeded LX in terms of PFS regardless of resistant status of trastuzumab. Although the NP group had more diarrhea cases, toxicities in both groups were acceptable.

Prediction of Pretreatment 18F-FDG-PET/CT Parameters on the Outcome of First-Line Therapy in Patients with Metastatic Breast Cancer.

OBJECTIVE: 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) can provide prognostic information, especially 18F-FDG uptake has been proven to be a predictor for the prognosis of various tumors. Nevertheless, the prognosis of other PET parameters in the metastatic setting remains unclear. This study was aimed at investigating pretreatment parameters based on 18F-FDG-PET/CT so as to estimate the progression-free survival (PFS) of metastatic breast cancer (MBC) patients receiving first-line treatment. METHODS: MBC patients who underwent a whole-body 18F-FDG-PET/CT prior to first-line therapy were enrolled. The heterogeneity parameter of PET/CT was analyzed, including heterogeneity index (HI) and general parameters (metabolic tumor volume (MTV), total lesion glycolysis (TLG), maximum standardized uptake value (SUVmax) and mean SUV (SUVmean). PFS was used to evaluate the treatment outcome. Kaplan-Meier method was adopted to carry out survival analysis and Log rank test was conducted to make a comparison. RESULTS: A total of 177 MBC patients were selected, in which 68 were in De novo stage IV. Thirty patients were human epidermal growth factor receptor 2 (HER2)-positive, 60 patients were triple-negative, and 87 patients were hormone receptor (HR)-positive and HER2-negative. In the whole population, patients with high baseline SUVmax, SUVmean, MTV, TLG or HI were associated with lower PFS (P=0.028, 0.005, 0.017, 0.026 and 0.035, respectively). Among the patients in De novo stage IV, those with high HI at baseline had significantly shorter PFS (P=0.001). In HR+/HER2- and HER2+ subgroups, only baseline HI showed the predictive value of PFS (P=0.023 and 0.049, respectively). In the triple-negative subgroup, high baseline SUVmax, MTV or TLG showed the predictive value of worse PFS (P=0.030, 0.011 and 0.023, respectively). CONCLUSION: Pretreatment 18F-FDG-PET/CT parameters show the predictive value of PFS in MBC patients receiving first-line treatment. However, predictive PET/CT parameters might be different in patients with different molecular subtypes and De novo stage IV.