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Surgery Open Science Dec 2023The purpose of this study was to compare the efficacy and safety of utidelone plus capecitabine for advanced first-line versus second-line or above therapy in metastatic...
BACKGROUND
The purpose of this study was to compare the efficacy and safety of utidelone plus capecitabine for advanced first-line versus second-line or above therapy in metastatic breast cancer patients who had previously received anthracycline and taxane. At the same time, we compared the efficacy of utidelone plus capecitabine and vinorelbine plus cisplatin in advanced first-line treatment of metastatic breast cancer.
PATIENTS AND METHODS
A retrospective cohort of 11 patients with metastatic breast cancer previously treated with anthracycline and taxane (including neoadjuvant and adjuvant therapies) for advanced first-line with utidelone plus capecitabine, 32 patients treated with second-line or above, and 60 patients with vinorelbine plus cisplatin between October 2011 and August 2022 was collected. The first and second groups were treated with utidelone plus capecitabine, and the third group was treated with vinorelbine plus cisplatin. The primary endpoint was progression-free survival (PFS), and secondary endpoints were overall survival (OS), objective response rate (ORR), and treatment safety.
RESULTS
By 03/31/2023, median PFS reached 11.70 months (95 % CI 0.093-0.141) in utidelone plus capecitabine group in the advanced first-line therapy, compared to 5.60 months (95 % CI 0.025-0.079) in the second-line or above therapy [HR 0.42, (95 % CI 0.226-0.787), P = 0.0077]. In utidelone plus capecitabine, the median OS was not reached in the advanced first-line therapy, with a mean overall survival of 23.16 months (95 % CI 0.198-0.265); whereas the median OS in the second-line or above therapy was 19.50 months (95 % CI 0.083-0.307), with a mean overall survival of 16.89 months (95 % CI 0.136-0.202) [HR 0.26, (95 % CI 0.098-0.678), P = 0.0495]. The ORR for advanced first-line therapy was 27.27 % (95%CI 0.060, 0.610) compared with 15.63 % (95%CI 0.053, 0.328) for second-line or above. In advanced first-line therapy, utidelone plus capecitabine was superior to vinorelbine plus cisplatin with a median PFS of 6.12 months (95 % CI 0.051-0.072) [HR 0.49, (95 % CI 0.286-0.839), P = 0.0291]. Compared with utidelone plus capecitabine, the median OS in vinorelbine plus cisplatin advanced first-line therapy group was 35.37 months (95 % CI 0.258-0.449), and the mean overall survival was 40.79 months (95 % CI 0.315-0.501) [HR 0.54, (95 % CI 0.188-1.568), P = 0.2587]. The ORR for vinorelbine plus cisplatin was 18.33 % (95 % CI 0.095, 0.304). The most common adverse events in our study were neurological toxicity, hand-foot syndrome, hematological toxicity, gastrointestinal toxicity, and hepatic and renal function abnormalities. There were no deaths due to adverse effects during the utidelone plus capecitabine treatment period.
CONCLUSIONS
In MBC, advanced first-line therapy with utidelone plus capecitabine resulted in more favorable PFS, OS, and ORR than second-line or above therapy. In advanced first-line therapy, utidelone plus capecitabine had superior PFS, and ORR compared with vinorelbine plus cisplatin. This study concludes that utidelone plus capecitabine is a more valuable chemotherapy option in advanced first-line MBC.
PubMed: 38026829
DOI: 10.1016/j.sopen.2023.10.008 -
Molecular Oncology Feb 2024The phase III IMPACT study (UMIN000044738) compared adjuvant gefitinib with cisplatin plus vinorelbine (cis/vin) in completely resected epidermal growth factor receptor...
NOTCH1 and CREBBP co-mutations negatively affect the benefit of adjuvant therapy in completely resected EGFR-mutated NSCLC: translational research of phase III IMPACT study.
The phase III IMPACT study (UMIN000044738) compared adjuvant gefitinib with cisplatin plus vinorelbine (cis/vin) in completely resected epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC). Although the primary endpoint of disease-free survival (DFS) was not met, we searched for molecular predictors of adjuvant gefitinib efficacy. Of 234 patients enrolled in the IMPACT study, 202 patients were analyzed for 409 cancer-related gene mutations and tumor mutation burden using resected lung cancer specimens. Frequent somatic mutations included tumor protein p53 (TP53; 58.4%), CUB and Sushi multiple domains 3 (CSMD3; 11.8%), and NOTCH1 (9.9%). Multivariate analysis showed that NOTCH1 co-mutation was a significant poor prognostic factor for overall survival (OS) in the gefitinib group and cAMP response element binding protein (CREBBP) co-mutation for DFS and OS in the cis/vin group. In patients with NOTCH1 co-mutations, gefitinib group had a shorter OS than cis/vin group (Hazard ratio 5.49, 95% CI 1.07-28.00), with a significant interaction (P for interaction = 0.039). In patients with CREBBP co-mutations, the gefitinib group had a longer DFS than the cis/vin group, with a significant interaction (P for interaction = 0.058). In completely resected EGFR-mutated NSCLC, NOTCH1 and CREBBP mutations might predict poor outcome in patients treated with gefitinib and cis/vin, respectively.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Gefitinib; Lung Neoplasms; Cyclic AMP Response Element-Binding Protein; Translational Research, Biomedical; ErbB Receptors; Cisplatin; Vinorelbine; Mutation; Protein Kinase Inhibitors; Receptor, Notch1; CREB-Binding Protein
PubMed: 37864465
DOI: 10.1002/1878-0261.13542 -
Cell Death & Disease Jul 2020The use of aspirin has been associated with reduced breast cancer risk, but it is litter known if aspirin overcomes chemoresistance in triple-negative breast cancer...
The use of aspirin has been associated with reduced breast cancer risk, but it is litter known if aspirin overcomes chemoresistance in triple-negative breast cancer (TNBC). Herein, we demonstrated that changes in the expression of Yes-associated protein (YAP) and β-catenin might be a promising predictive biomarker for neoadjuvant chemotherapy sensitivity in TNBC patients. Inhibition of YAP or β-catenin enhanced the cytotoxicity of the anti-microtubule agents docetaxel and vinorelbine against drug-resistant TNBC cells as well as the sensitivity of these cells to the agents in vitro and in vivo. Interestingly, aspirin not only significantly inhibited the growth of TNBC cells, but also attenuated YAP and β-catenin expression by upregulating the E3 ubiquitin ligase β-TrCP to abolished docetaxel and vinorelbine resistance. The combination of aspirin and docetaxel or vinorelbine remarkably inhibited the growth of drug-resistant TNBC cells in vitro and in vivo. Moreover, TNBC patients with high YAP and/or β-catenin expression had a higher risk of relapse or mortality than patients with low YAP and/or β-catenin expression. Collectively, our study discovered a novel role of aspirin based on its anticancer effect, and put forward some possible mechanisms of chemoresistance in TNBC. The combined use of aspirin and anti-microtubule drugs presented several promising therapeutic approaches for TNBC treatment.
Topics: Animals; Aspirin; Cell Cycle Proteins; Disease Models, Animal; Drug Resistance, Neoplasm; Female; Humans; Mice; Mice, Nude; Transcription Factors; Triple Negative Breast Neoplasms; beta Catenin
PubMed: 32661222
DOI: 10.1038/s41419-020-2719-2 -
Strahlentherapie Und Onkologie : Organ... Jan 2022Treatment of muscle-invasive bladder cancer (MIBC) remains challenging, especially for elderly and/or comorbid patients. Patients who are unfit for or refuse surgery...
PURPOSE
Treatment of muscle-invasive bladder cancer (MIBC) remains challenging, especially for elderly and/or comorbid patients. Patients who are unfit for or refuse surgery should receive bladder-preserving multimodality treatment (BPMT), consisting of transurethral resection of the bladder tumor (TURB) followed by combined chemoradiotherapy (CRT). We aimed to investigate the effectiveness of vinorelbine, a chemotherapeutic agent not routinely used for MIBC, in patients referred to CRT who are unfit for standard chemotherapy and would thus rely solely on radiotherapy (RT).
METHODS
We retrospectively analyzed 52 consecutive patients with MIBC who received standard CRT with cisplatin (n = 14), CRT with vinorelbine (n = 26), or RT alone (n = 12). Primary endpoints were median overall survival (OS) and median cancer-specific survival (CSS). Secondary endpoints were median local control (LC), median distant control (DC), and OS, CSS, LC, and DC after 1, 2, and 3 years, respectively.
RESULTS
Median OS and CSS were significantly higher for patients who received vinorelbine as compared to RT alone (OS 8 vs. 22 months, p = 0.003; CSS 11 months vs. not reached, p = 0.001). Median LC and DC did not differ significantly between groups. Vinorelbine was well tolerated with no reported side effects >grade II.
CONCLUSION
Our results suggest that CRT with vinorelbine is well tolerated and superior to RT alone in terms of OS and CSS. Therefore, this treatment regime might constitute a new treatment option for patients with MIBC who are unfit for or refuse surgery or standard chemotherapy. This study encourages a randomized controlled trial to compare this new regime to current standard therapies.
Topics: Aged; Cisplatin; Humans; Muscles; Neoplasm Invasiveness; Retrospective Studies; Treatment Outcome; Urinary Bladder; Urinary Bladder Neoplasms; Vinorelbine
PubMed: 34414475
DOI: 10.1007/s00066-021-01837-7 -
Thoracic Cancer May 2021To evaluate the long-term outcomes of high-dose (74 GyE) proton beam therapy (PBT) with concurrent chemotherapy for stage III non-small cell lung cancer (NSCLC).
BACKGROUND
To evaluate the long-term outcomes of high-dose (74 GyE) proton beam therapy (PBT) with concurrent chemotherapy for stage III non-small cell lung cancer (NSCLC).
METHODS
Between July 2007 and March 2018, 45 patients with stage III NSCLC were treated with passive-scattering PBT of 74 GyE and concurrent chemotherapy. Among the 45 patients, the median age was 62 years (range 39-79 years) and 32 patients were men. The clinical stages were stage IIIA in 14 patients and stage IIIB in 31 patients. Thirty-six patients received chemotherapy consisting of cisplatin and vinorelbine.
RESULTS
The median follow-up time was 42.1 months (range 6.4-127.0 months) for all patients and 63.5 months (range 9.4-127.0 months) for the 12 survivors. The 3- and 5-year overall survival rates were 63.7% and 38.8%, respectively, and the median overall survival was 49.1 months. Over the follow-up period, disease recurrence was observed in 32 (71%) patients. The 3- and 5-year progression-free survival rates were 22.2% and 17.7%, respectively, with a median progression-free survival of 13.1 months. In-field control improved survival and the in-field control rate was better in patients with T0-3 tumors (p = 0.023) and stage IIIA/IIIB-N3 disease (p = 0.030). Dosimetric parameters of the heart and lung were not associated with survival. No grade 4 or 5 acute or late non-hematologic toxicities were observed.
CONCLUSIONS
Passive-scattering PBT of 74 GyE with chemotherapy showed favorable survival and a low incidence of severe adverse events in patients with stage III NSCLC.
Topics: Adult; Aged; Carcinoma, Non-Small-Cell Lung; Female; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Proton Therapy
PubMed: 33675285
DOI: 10.1111/1759-7714.13896 -
BioRxiv : the Preprint Server For... Jun 2023Type I interferons (IFNs) increase the excitability of dorsal root ganglion (DRG) neurons via activation of MNK-eIF4E translation signaling to promote pain sensitization...
Type I interferons (IFNs) increase the excitability of dorsal root ganglion (DRG) neurons via activation of MNK-eIF4E translation signaling to promote pain sensitization in mice. Activation of STING signaling is a key component of type I IFN induction. Manipulation of STING signaling is an active area of investigation in cancer and other therapeutic areas. Vinorelbine is a chemotherapeutic that activates STING and has been shown to cause pain and neuropathy in oncology clinical trials in patients. There are conflicting reports on whether STING signaling promotes or inhibits pain in mice. We hypothesized that vinorelbine would cause a neuropathic pain-like state in mice via STING and signaling pathways in DRG neurons associated with type I IFN induction. Vinorelbine (10 mg/kg, i.v.) induced tactile allodynia and grimacing in WT male and female mice and increased p-IRF3 and type I IFN protein in peripheral nerves. In support of our hypothesis, vinorelbine-mediated pain was absent in male and female Sting mice. Vinorelbine also failed to induce IRF3 and type I IFN signaling in these mice. Since type I IFNs engage translational control via MNK1-eIF4E in DRG nociceptors, we assessed vinorelbine-mediated p-eIF4E changes. Vinorelbine increased p-eIF4E in DRG in WT animals but not in Sting or (MNK1 KO) mice. Consistent with these biochemical findings, vinorelbine had an attenuated pro-nociceptive effect in male and female MNK1 KO mice. Our findings support the conclusion that activation of STING signaling in the peripheral nervous system causes a neuropathic pain-like state that is mediated by type I IFN signaling to DRG nociceptors.
PubMed: 37333411
DOI: 10.1101/2023.06.03.543579 -
British Journal of Cancer Dec 2019The continuum of anti-HER2 agents is a standard treatment of HER2 + metastatic breast cancer (MBC). This study evaluated the efficacy of lapatinib plus vinorelbine... (Randomized Controlled Trial)
Randomized Controlled Trial
Randomised Phase 2 study of lapatinib and vinorelbine vs vinorelbine in patients with HER2 + metastatic breast cancer after lapatinib and trastuzumab treatment (KCSG BR11-16).
BACKGROUND
The continuum of anti-HER2 agents is a standard treatment of HER2 + metastatic breast cancer (MBC). This study evaluated the efficacy of lapatinib plus vinorelbine in patients progressed on both trastuzumab and lapatinib treatments.
METHODS
A total of 149 patients were randomly assigned to lapatinib with vinorelbine (LV) (n = 75; lapatinib, 1000 mg daily; vinorelbine 20 mg/m D1, D8 q3w) or vinorelbine (V) (n = 74; 30 mg/m D1, D8 q3w). The primary endpoint was progression-free survival (PFS) rate at 18 weeks.
RESULTS
The median number of previous anti-HER2 therapies was 2 (range 2-5). There was no significant difference in PFS rate at 18 weeks between LV and V arms (45.9% vs 38.9%, p = 0.40). ORR was 19.7% in LV arm, and 16.9% in V arm (p = 0.88). PFS and OS did not differ between two arms (LV vs V; median PFS, 16 vs 12 weeks, HR = 0.86, 95% CI 0.61-1.22; median OS, 15.0 vs 18.9 months, HR = 1.07, 95% CI 0.72-1.58). Toxicity profiles were similar in both arms and all were manageable.
CONCLUSIONS
Lapatinib plus vinorelbine treatment was tolerable; however, it failed to demonstrate the clinical benefits over vinorelbine alone in patients with HER2 + MBC after progression on both trastuzumab and lapatinib.
CLINICAL TRIAL REGISTRATION
ClinicalTrials.gov number NCT01730677.
Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Disease Progression; Disease-Free Survival; Female; Humans; Lapatinib; Middle Aged; Neoplasm Metastasis; Receptor, ErbB-2; Trastuzumab; Vinorelbine
PubMed: 31690831
DOI: 10.1038/s41416-019-0618-z -
Translational Andrology and Urology Dec 2022The 5-year overall survival rate in metastatic prostate adenocarcinoma (PRAD) is extremely low. Genomic studies of PRAD have improved our understanding of disease...
BACKGROUND
The 5-year overall survival rate in metastatic prostate adenocarcinoma (PRAD) is extremely low. Genomic studies of PRAD have improved our understanding of disease biology. However, the role of immune checkpoint genes (ICGs) in PRAD remains unclear.
METHODS
Univariate and multivariate analyses were used to analyze genes associated with metastasis-free survival (MFS) in The Cancer Genome Atlas (TCGA)-PRAD dataset. The expressions of and were detected via immunohistochemical assay and real-time fluorescence quantitative PCR (RT-PCR) assay in our in-house cohort. The expression of long non-coding RNAs (lncRNAs) , , and were detected via RT-PCR assay in our in-house cohort. Stepwise regression, Cox regression, and nomogram analyses were used to evaluate the prognostic role of these genes in both the TCGA dataset and in-house cohort. The "pRRophetic" R package was used to evaluate drug sensitivity in the TCGA cohort according to the gene mRNA expression level.
RESULTS
In our study, univariate and multivariate analyses revealed that the mRNA expressions of two ICGs, and , were independent factors affecting MFS in PRAD patients. A prognostic 2-ICG model predicted the MFS of PRAD patients with medium-to-high accuracy in the TCGA dataset and in-house cohort. The expressions of , , and were correlated with and . A prognostic lncRNA-ICG model predicted the MFS of PRAD patients with medium-to-high accuracy in the TCGA dataset and in-house cohort. In addition, correlation analyses between the sensitivity of doxorubicin, erlotinib, gemcitabine, or vinorelbine and , , , , and were conducted.
CONCLUSIONS
Our results provide new targets for predicting tumor metastasis in PRAD and treating patients with metastatic PRAD.
PubMed: 36632155
DOI: 10.21037/tau-22-711 -
Breast Care (Basel, Switzerland) May 2023Metronomic chemotherapy (MCT) is increasingly used in oncology due to its favorable therapeutic index. There is still a lack of evidence for MCT in metastatic breast...
INTRODUCTION
Metronomic chemotherapy (MCT) is increasingly used in oncology due to its favorable therapeutic index. There is still a lack of evidence for MCT in metastatic breast cancer (MBC). In this retrospective unicenter study, we demonstrated real-word data on MCT in MBC.
METHODS
MBC patients who received metronomic oral cyclophosphamide (CTX) (50 mg daily) and methotrexate (MTX) (2.5 mg every other day), CTX and capecitabine (CAPE) (500 mg thrice daily), CTX, or vinorelbine (VRL) (30 mg daily) alone for at least 4 weeks between 2009 and 2021 were included. The primary endpoint was disease control rate (DCR) ≥24 weeks. Secondary endpoints were progression-free survival (PFS) and overall survival (OS). Patient characteristics and therapy response were analyzed using χ test. For survival analyses, Kaplan-Meier estimator and log-rank test were used.
RESULTS
Seventy-two patients were identified. Sixty-two patients received CTX/MTX, three CTX/CAPE, two CTX, and five VRL. Median age at diagnosis MBC and at start of MCT was 59.0 years and 64.5 years, respectively. 72.2% tumors were hormone receptor positive and 27.8% were triple-negative. 54.2% patients had more than two different metastases. 80.6% patients showed visceral involvement. 31.9% patients achieved DCR ≥24 weeks. Median PFS was 17.0 weeks (95% CI 14.5-19.5) and median OS was 58.0 weeks (95% CI 29.0-87.0). MCT showed similar DCR ≥24 weeks and clinically meaningful but not statistically significant shorter median PFS compared to prior therapy (31.9% versus 32.8% [ = 0.570] and 17.0 weeks versus 20.0 weeks [ = 0.093], respectively) and statistically significant higher DCR ≥24 weeks and longer median PFS compared to subsequent therapy (31.9% versus 17.4% [ = 0.038] and 17.0 weeks versus 12.0 weeks [ = 0.006], respectively). Three (4.2%) patients terminated MCT because of toxicity.
CONCLUSION
In this real-world retrospective study, MCT was effective and well tolerated and may thus represent a valuable treatment option in selected MBC patients.
PubMed: 37261128
DOI: 10.1159/000528042 -
Journal of Clinical Laboratory Analysis Sep 2020Chemoresistance posed a barrier to successful treatment of breast cancer (BC), and lncRNA MEG3 has been documented to implicate in BC development. However, whether MEG3...
BACKGROUND
Chemoresistance posed a barrier to successful treatment of breast cancer (BC), and lncRNA MEG3 has been documented to implicate in BC development. However, whether MEG3 methylation, which led to low MEG3 expression, was relevant to BC progression and chemoresistance remained uncertain.
METHODS
In the aggregate, 374 pairs of tumor tissues and adjacent normal tissues were collected from pathologically confirmed BC patients, and four BC cell lines, including MDA-MB-231, Bcap-37, MCF-7, and SK-BR-3, were purchased. Moreover, methylation-specific polymerase chain reaction (PCR) was adopted to evaluate the methylation status of BC tissues and cell lines, and chemo-tolerance of BC cell lines was assessed by performing MTT assay. Concurrently, transwell assay and scratch assay were carried out to estimate the migratory and invasive capability of BC cell lines.
RESULTS
Methylated MEG3, lowly expressed MEG3, large tumor size (≥2 cm), advanced TNM grade and lymphatic metastasis were potentially symbolic of poor prognosis among BC patients (P < .05). Besides, MDA-MB-231 cell line exhibited the strongest resistance against paclitaxel, adriamycin, and vinorelbine (P < .05), while MCF-7 cell line seemed more sensitive against these drugs than any other BC cell line (P < .05). Furthermore, pcDNA3.1-MEG3 and 5-Aza-dC markedly sensitized MDA-MB-231 and MCF-7 cell lines against the drug treatments (P < .05). Simultaneously, proliferation and metastasis of the BC cell lines were slowed down under the force of pcDNA3.1-MEG3 and 5-Aza-dC (P < .05).
CONCLUSION
Preventing methylation of MEG3 might matter in lessening BC chemoresistance, owing to its hindering proliferation and metastasis of BC cells.
Topics: Antimetabolites, Antineoplastic; Apoptosis; Biomarkers, Tumor; Breast Neoplasms; Cell Proliferation; DNA Methylation; Decitabine; Drug Resistance, Neoplasm; Female; Gene Expression Regulation, Neoplastic; Humans; Middle Aged; Prognosis; RNA, Long Noncoding; Tumor Cells, Cultured
PubMed: 32618397
DOI: 10.1002/jcla.23369