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British Journal of Cancer Jun 2024This randomized, parallel-controlled, double-blinded, phase III equivalence study evaluated the equivalence of a proposed pertuzumab biosimilar QL1209 to the pertuzumab...
QL1209 (pertuzumab biosimilar) versus reference pertuzumab plus trastuzumab and docetaxel in neoadjuvant treatment for HER2-positive, ER/PR-negative, early or locally advanced breast cancer: A multicenter, randomized, double-blinded, parallel-controlled, phase III equivalence trial.
BACKGROUND
This randomized, parallel-controlled, double-blinded, phase III equivalence study evaluated the equivalence of a proposed pertuzumab biosimilar QL1209 to the pertuzumab (Perjeta®) each with trastuzumab and docetaxel in neoadjuvant treatment of early or locally advanced breast cancer patients with HER2-positive, ER/PR-negative.
METHODS
Eligible patients were randomly (1:1) assigned to receive 4 cycles of neoadjuvant QL1209 or pertuzumab each with trastuzumab and docetaxel, and adjuvant treatment. The primary endpoint was total pathologic complete response (tpCR), with equivalence margins of 0.76 to 1.32.
RESULTS
Among the 585 patients enrolled, 257 and 259 patients were assigned to the QL1209 and pertuzumab groups, respectively. The tpCR rates were comparable in the QL1209 (109/255, 42.75%; 90% CI 37.65 to 47.84) and pertuzumab (117/259, 45.17%; 90% CI 40.09 to 50.26) groups. The tpCR risk ratio was 0.95 (90% CI, 0.80 to 1.11), and the 90% CI fell within the predefined equivalence margin. The most common grade ≥3 treatment-related adverse event was decreased neutrophil count (10. 9% vs. 12.7%) in the QL1209 and pertuzumab groups.
CONCLUSIONS
QL1209 demonstrated equivalent efficacy and comparable safety profile to the reference pertuzumab in neoadjuvant treatment of HER2-positive, ER/PR-negative, early, or locally advanced breast cancer.
TRIAL REGISTRATION
Chinadrugtrials.org CTR20201073; ClinicalTrials.gov NCT04629846.
PubMed: 38906970
DOI: 10.1038/s41416-024-02751-2 -
Nature Communications Jun 2024Chemoresistance is a main reason for treatment failure in patients with nasopharyngeal carcinoma, but the exact regulatory mechanism underlying chemoresistance in...
Chemoresistance is a main reason for treatment failure in patients with nasopharyngeal carcinoma, but the exact regulatory mechanism underlying chemoresistance in nasopharyngeal carcinoma remains to be elucidated. Here, we identify PJA1 as a key E3 ubiquitin ligase involved in nasopharyngeal carcinoma chemoresistance that is highly expressed in nasopharyngeal carcinoma patients with nonresponse to docetaxel-cisplatin-5-fluorouracil induction chemotherapy. We find that PJA1 facilitates docetaxel resistance by inhibiting GSDME-mediated pyroptosis in nasopharyngeal carcinoma cells. Mechanistically, PJA1 promotes the degradation of the mitochondrial protein PGAM5 by increasing its K48-linked ubiquitination at K88, which further facilitates DRP1 phosphorylation at S637 and reduced mitochondrial reactive oxygen species production, resulting in suppression of GSDME-mediated pyroptosis and the antitumour immune response. PGAM5 knockdown fully restores the docetaxel sensitization effect of PJA1 knockdown. Moreover, pharmacological targeting of PJA1 with the small molecule inhibitor RTA402 enhances the docetaxel sensitivity of nasopharyngeal carcinoma in vitro and in vivo. Clinically, high PJA1 expression indicates inferior survival and poor clinical efficacy of TPF IC in nasopharyngeal carcinoma patients. Our study emphasizes the essential role of E3 ligases in regulating chemoresistance and provides therapeutic strategies for nasopharyngeal carcinoma based on targeting the ubiquitin-proteasome system.
Topics: Humans; Docetaxel; Drug Resistance, Neoplasm; Nasopharyngeal Carcinoma; Cell Line, Tumor; Nasopharyngeal Neoplasms; Pyroptosis; Ubiquitination; Animals; Ubiquitin-Protein Ligases; Mice; Mice, Nude; Female; Dynamins; Reactive Oxygen Species; Phosphoprotein Phosphatases; Male; Xenograft Model Antitumor Assays; Mice, Inbred BALB C; Antineoplastic Agents; Phosphorylation; Mitochondrial Proteins; Fluorouracil; Gene Expression Regulation, Neoplastic; Mitochondria; Cisplatin; Middle Aged; Gasdermins
PubMed: 38906860
DOI: 10.1038/s41467-024-49675-2 -
Urology Jun 2024To assess if receiving sequential intravesical chemotherapy (Gemcitabine-Docetaxel, Gem-Doce) therapy was associated with similar oncologic efficacy to bacillus...
Sequential Intravesical Chemotherapy for Treatment Naïve, High-Risk Non-Muscle Invasive Bladder Cancer: Oncologic Outcomes, Tolerance, and Comparison to Contemporary Controls.
OBJECTIVES
To assess if receiving sequential intravesical chemotherapy (Gemcitabine-Docetaxel, Gem-Doce) therapy was associated with similar oncologic efficacy to bacillus Calmette-Guérin (BCG) in patients with treatment-naïve, high-risk non-muscle invasive bladder cancer (HR-NMIBC).
METHODS
Single-center, retrospective cohort study of 80 patients with HR-NMIBC initiating first-line Gem-Doce or BCG between August 2020 and August 2023. Surveillance conducted with cystoscopy, urine cytology, and cross-sectional imaging. The primary oncologic outcome was high-grade bladder tumor recurrence during surveillance. Kaplan-Meier method applied to determine 12- and 24-month recurrence free survival (RFS) after initiation of therapy. Tolerance of each intravesical therapies was assessed.
RESULTS
53/80 (66%) received Gem-Doce and 27/80 (34%) received BCG with overall 18-month median follow up. There were 10 recurrences after Gem-Doce and seven after BCG. The RFS at 12- and 24-months for Gem-Doce (12-months: 87%, 24-months: 75%) was not significantly different than BCG (12-months: 85%, 24-months: 81%). Lastly, Gem-Doce had significantly fewer patients with AEs compared to BCG (40% vs 74%). Limitations include retrospective design, small cohort size, and intermediate oncologic follow-up.
CONCLUSIONS
Our data suggest that sequential intravesical Gem-Doce is an oncologically efficacious and, potentially better tolerated, alternative to BCG for treatment-naïve HR-NMIBC.
PubMed: 38906268
DOI: 10.1016/j.urology.2024.06.020 -
Biomedicine & Pharmacotherapy =... Jun 2024Aberration of Notch signaling is one of the key events involved in the development and progression of head and neck squamous cell carcinoma (HNSCC). The Notch pathway...
Aberration of Notch signaling is one of the key events involved in the development and progression of head and neck squamous cell carcinoma (HNSCC). The Notch pathway controls the tissue-specific differentiation of normal squamous epithelial cells and is frequently altered in squamous carcinomas, thus affecting their proliferation, growth, survival, and chemosensitivity or resistance against anti-cancer agents. In this study, we show that the use of novel, small-molecule inhibitors of Notch signaling, such as FLI-06, can have a beneficial effect on increasing the chemosensitivity of HNSCC to taxane-based chemotherapy. Inhibition of Notch signaling by FLI-06 alone virtually blocks the proliferation and growth of HNSCC cells in both 2D and 3D cultures and the zebrafish model, which is accompanied by down-regulation of key Notch target genes and proteins. Mechanistically, FLI-06 treatment causes cell cycle arrest in the G-phase and induction of apoptosis in HNSCC, which is accompanied by increased c-Jun phosphorylation. Combining FLI-06 with Docetaxel shows a synergistic effect and partially blocks the cell growth of aggressive HNSCC cells via enhanced apoptosis and modification of c-Jun phosphorylation via GSK-3β inhibition. In conclusion, inhibition of Notch signaling in HNSCC cells that retain active Notch signaling significantly supports taxane-based anticancer activities via modulation of both the GSK-3β and the c-Jun.
PubMed: 38906029
DOI: 10.1016/j.biopha.2024.116822 -
JCO Precision Oncology Jun 2024Androgen receptor splice variant 7 (ARV-7) is a resistance mechanism to hormonal therapy in metastatic castrate-resistant prostate cancer (mCRPC). It has been associated...
PURPOSE
Androgen receptor splice variant 7 (ARV-7) is a resistance mechanism to hormonal therapy in metastatic castrate-resistant prostate cancer (mCRPC). It has been associated with poor outcomes. On progression to castrate resistance, ARV-7 positivity has been identified in global populations at an incidence of 17.8%-28.8%. Here, we characterize the incidence of ARV-7 positivity in Asian patients with mCRPC in a prospective fashion and evaluate its implications on treatment outcomes.
METHODS
Patients with mCRPC from multiple centers in Southeast and East Asia were enrolled in a prospective manner before initiation of androgen receptor signaling inhibitors or docetaxel. ARV-7 status was evaluated at baseline with three commercially available assays: AdnaTest Prostate Cancer platform, Clearbridge method, and IBN method. Clinical outcomes at progression were assessed. The primary end point of this study was prevalence of ARV-7 positivity; secondary end points were incidence of ARV-7 positivity, prostate specific antigen (PSA) response rate, PSA progression-free survival (PFS), and overall survival (OS).
RESULTS
A total of 102 patients with a median age of 72 years at enrollment participated. Overall, an incidence of ARV-7 positivity of between 14.3% and 33.7% in Asian patients with mCRPC was demonstrated depending on the assay used. Patients found to have ARV-7 positivity at enrollment had a numerically worse PSA PFS compared with ARV-7 negative patients.
CONCLUSION
In this study, the incidence of ARV-7 positivity in Asian patients with mCRPC was shown to be similar to the global population. Patients with ARV-7 positivity appear to have more aggressive disease with numerically worse PSA PFS and OS. Further prospective studies are needed to fully characterize the relationship that ARV-7 positivity has on prognosis of Asian patients with mCRPC.
Topics: Humans; Male; Prostatic Neoplasms, Castration-Resistant; Aged; Receptors, Androgen; Middle Aged; Prospective Studies; Aged, 80 and over; Asian People; Neoplasm Metastasis; Protein Isoforms
PubMed: 38905583
DOI: 10.1200/PO.23.00694 -
Cureus May 2024Prostate cancer (PC) is one of the leading causes of cancer death among men worldwide. Brain metastases from PC are very rare, often presenting in advanced stages of the...
Prostate cancer (PC) is one of the leading causes of cancer death among men worldwide. Brain metastases from PC are very rare, often presenting in advanced stages of the disease, and are associated with a poor prognosis. Treatment is complex and may involve surgery or radiotherapy. We present the case of a 64-year-old male diagnosed with localized prostate adenocarcinoma, initially treated with pelvic radiotherapy associated with long-term hormonal treatment. While on this hormonal treatment, around one year after radical treatment initiation, he developed bilateral pulmonary metastases, histologically proven to be related to PC, defining a state of metastatic castration-resistant PC. He was asymptomatic and therefore treatment with enzalutamide was initiated. A partial response to the lung lesions was obtained and maintained for more than a year, at which time new mediastinal lymph node metastases were identified. An endobronchial ultrasound biopsy revealed metastases from carcinoma with neuroendocrine differentiation, favoring lung small-cell carcinoma. The patient started chemotherapy with carboplatin and etoposide, with a response. Due to the progression of the mediastinal lymph nodes after eight months, the patient had to undergo chemotherapy again, this time in combination with atezolizumab, with once again partial response. Given the possibility of drug interactions, enzalutamide was suspended during both cycles of chemotherapy and successfully reintroduced afterward. Three months after restarting enzalutamide, he began complaining of headaches. Brain imaging revealed a single frontobasal lesion, without evidence of simultaneous extracerebral progression. Considering the epileptogenic potential of enzalutamide, it was again suspended. The patient underwent surgery and histology revealed metastases of prostate adenocarcinoma, a very rare finding. Systemic re-staging after surgery revealed the progression of cerebral and extra-cerebral disease. The patient is currently proposed for treatment with whole brain radiotherapy and chemotherapy with docetaxel. This case demonstrates the difficulties associated with the diagnosis and treatment of a patient with two distinct neoplasms. Therapy choices were necessarily adjusted because of significant drug interactions. The diagnosis of brain lesions was the last complication, and it proved to be a challenge as it is a rare entity, with optimal management options not being well established.
PubMed: 38903358
DOI: 10.7759/cureus.60728 -
Chemical Biology & Drug Design Jun 2024Docetaxel (DTX) resistance poses a significant challenge in the treatment of prostate cancer (PCa), often leading to chemotherapy failure. This study investigates the...
Docetaxel (DTX) resistance poses a significant challenge in the treatment of prostate cancer (PCa), often leading to chemotherapy failure. This study investigates the ability of piperine, a compound derived from black pepper, to enhance the sensitivity of PCa cells to DTX and elucidates its underlying mechanism. We established a DTX-resistant PCa cell line, DU145/DTX, to conduct our experiments. Through a series of assays, including MTT for cell viability, flow cytometry for apoptosis, Transwell for cell migration and invasion, and western blot for protein expression analysis, we assessed the effects of piperine on these cellular functions and on the Notch signaling pathway components. Our results demonstrated that we successfully established the DTX-resistant PCa cell line DU145/DTX. Piperine effectively decreased the viability of both DU145 and its DTX-resistant counterpart, DU145/DTX, in a concentration and time-dependent manner when used alone and in combination with DTX. Notably, piperine also induced apoptosis and reduced the migration and invasion capabilities of these cells. At the molecular level, piperine down-regulated the Notch pathway by inhibiting Notch1 and Jagged1 signaling, as well as reducing the expression of downstream effectors Hey1 and hes family bHLH transcription factor 1. The study concludes that piperine's ability to modulate the Notch signaling pathway and induce apoptosis highlights its potential as a complementary treatment for DTX-resistant PCa, paving the way for the use of traditional Chinese medicinal compounds in modern oncology treatment strategies.
Topics: Polyunsaturated Alkamides; Humans; Benzodioxoles; Alkaloids; Piperidines; Docetaxel; Male; Cell Line, Tumor; Signal Transduction; Drug Resistance, Neoplasm; Prostatic Neoplasms; Apoptosis; Cell Movement; Receptors, Notch; Antineoplastic Agents; Cell Survival; Receptor, Notch1
PubMed: 38898371
DOI: 10.1111/cbdd.14562 -
Nature Communications Jun 2024This phase II trial aimed to determine the efficacy and safety of induction chemoimmunotherapy of camrelizumab plus modified TPF in locally advanced hypopharyngeal...
This phase II trial aimed to determine the efficacy and safety of induction chemoimmunotherapy of camrelizumab plus modified TPF in locally advanced hypopharyngeal squamous cell carcinoma (LA HSCC) (NCT04156698). The primary endpoint was objective response rate (ORR), and secondary endpoints were 3-year overall survival (OS), progression-free survival (PFS), larynx preservation rate (LPR), and metastasis-free survival (MFS). Patients (cT3-4aN0-2M0), regardless of sex, received induction chemoimmunotherapy for three cycles: camrelizumab 200 mg d1, docetaxel 75 mg/m d1, cisplatin 25 mg/m d1-3, and capecitabine 800 mg/m bid d1-14, q21d. Patients were assigned to radioimmunotherapy if they had a complete or partial response, those with stable or progressive disease underwent surgery and adjuvant (chemo)radiotherapy. Camrelizumab was maintained post-radioimmunotherapy. Fifty-one patients were enrolled with a median follow-up duration of 23.7 months. After induction therapy, the ORR was 82.4% (42/51), meeting the prespecified endpoint. Grade 3/4 adverse events occurred in 26 patients, and no treatment-related death occurred. As three-year outcomes were immature, two-year OS, PFS and LPR were reported. As no distant metastatic event had occurred, MFS was not reported here. The two-year OS, PFS, and LPR rates were 83.0%, 77.1%, and 70.0%, respectively. The induction chemoimmunotherapy of camrelizumab plus TPF showed a high ORR rate with an acceptable safety profile in LA HSCC.
Topics: Humans; Male; Female; Middle Aged; Antibodies, Monoclonal, Humanized; Aged; Hypopharyngeal Neoplasms; Antineoplastic Combined Chemotherapy Protocols; Adult; Immunotherapy; Neoplasm Staging; Cisplatin; Progression-Free Survival; Induction Chemotherapy; Treatment Outcome
PubMed: 38898018
DOI: 10.1038/s41467-024-49121-3 -
European Urology Jun 2024Intensification of therapy may improve outcomes for patients with high-risk localized prostate cancer.
Corrigendum to "Androgen Deprivation and Radiotherapy with or Without Docetaxel for Localized High-risk Prostat Cancer: Long-term Follow-up from the Randomized NRG Oncology RTOG 0521 Trial" [Eur. Eurol. 84(2) (2023) 156-163].
BACKGROUND
Intensification of therapy may improve outcomes for patients with high-risk localized prostate cancer.
OBJECTIVE
To provide long-term follow-up data from phase III RTOG 0521, which compared a combination of androgen deprivation therapy (ADT) + external beam radiation therapy (EBRT) + docetaxel with ADT + EBRT.
DESIGN, SETTING, AND PARTICIPANTS
High-risk localized prostate cancer patients (>50% of patients had Gleason 9-10 disease) were prospectively randomized to 2 yr of ADT + EBRT or ADT + EBRT + six cycles of docetaxel. A total of 612 patients were accrued, and 563 were eligible and included in the modified intent-to-treat analysis.
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS
The primary endpoint was overall survival (OS). Analyses with Cox proportional hazards were performed as prespecified in the protocol; however, there was evidence of nonproportional hazards. Thus, a post hoc analysis was performed using the restricted mean survival time (RMST). The secondary endpoints included biochemical failure, distant metastasis (DM) as detected by conventional imaging, and disease-free survival (DFS).
RESULTS AND LIMITATIONS
After 10.4 yr of median follow-up among survivors, the hazard ratio (HR) for OS was 0.89 (90% confidence interval [CI] 0.70-1.14; one-sided log-rank p = 0.22). Survival at 10 yr was 64% for ADT + EBRT and 69% for ADT + EBRT + docetaxel. The RMST at 12 yr was 0.45 yr and not statistically significant (one-sided p = 0.053). No differences were detected in the incidence of DFS (HR = 0.92, 95% CI 0.73-1.14), DM (HR = 0.84, 95% CI 0.73-1.14), or prostate-specific antigen recurrence risk (HR = 0.97, 95% CI 0.74-1.29). Two patients had grade 5 toxicity in the chemotherapy arm and zero patients in the control arm.
CONCLUSIONS
After a median follow-up of 10.4 yr among surviving patients, no significant differences are observed in clinical outcomes between the experimental and control arms. These data suggest that docetaxel should not be used for high-risk localized prostate cancer. Additional research may be warranted using novel predictive biomarkers.
PATIENT SUMMARY
No significant differences in survival were noted after long-term follow-up for high-risk localized prostate cancer patients in a large prospective trial where patients were treated with androgen deprivation therapy + radiation to the prostate ± docetaxel.
PubMed: 38897867
DOI: 10.1016/j.eururo.2024.06.009 -
Molecules (Basel, Switzerland) May 2024Breast cancer is a major health concern and the leading cause of death among women worldwide. Standard treatment often involves surgery, radiotherapy, and chemotherapy,...
Breast cancer is a major health concern and the leading cause of death among women worldwide. Standard treatment often involves surgery, radiotherapy, and chemotherapy, but these come with side effects and limitations. Researchers are exploring natural compounds like baicalin and baicalein, derived from the plant, as potential complementary therapies. This study investigated the effects of baicalin and baicalein on the cytotoxic, proapoptotic, and genotoxic activity of doxorubicin and docetaxel, commonly used chemotherapeutic drugs for breast cancer. The analysis included breast cancer cells (MCF-7) and human endothelial cells (HUVEC-ST), to assess potential effects on healthy tissues. We have found that baicalin and baicalein demonstrated cytotoxicity towards both cell lines, with more potent effects observed in baicalein. Both flavonoids, baicalin (167 µmol/L) and baicalein (95 µmol/L), synergistically enhanced the cytotoxic, proapoptotic, and genotoxic activity of doxorubicin and docetaxel in breast cancer cells. In comparison, their effects on endothelial cells were mixed and depended on concentration and time. The results suggest that baicalin and baicalein might be promising complementary agents to improve the efficacy of doxorubicin and docetaxel anticancer activity. However, further research is needed to validate their safety and efficacy in clinical trials.
Topics: Humans; Flavonoids; Flavanones; Docetaxel; Doxorubicin; MCF-7 Cells; Apoptosis; Breast Neoplasms; Female; DNA Damage; Drug Synergism; Antineoplastic Agents; Cell Survival; Human Umbilical Vein Endothelial Cells
PubMed: 38893380
DOI: 10.3390/molecules29112503