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Journal For Immunotherapy of Cancer Nov 2023It is possible to induce immunomodulation in HER2-positive breast cancer (BC) by modifying the route of administration of trastuzumab. (Randomized Controlled Trial)
Randomized Controlled Trial
Randomized, open-label, phase II, biomarker study of immune-mediated mechanism of action of neoadjuvant subcutaneous trastuzumab in patients with locally advanced, inflammatory, or early HER2-positive breast cancer-Immun-HER trial (GOIRC-01-2016).
BACKGROUND
It is possible to induce immunomodulation in HER2-positive breast cancer (BC) by modifying the route of administration of trastuzumab.
METHODS
In this multicenter randomized phase II trial, all enrolled patients (pts) with T2-T4d HER2-positive BC received 3 cycles of neoadjuvant treatment (NAT) with fluorouracil, epirubicin and cyclophosphamide every 3 weeks (q21), followed by docetaxel/pertuzumab plus intravenous trastuzumab (arm A) or, docetaxel/pertuzumab plus subcutaneous (SC) trastuzumab (arm B) q21x4 cycles. After surgical operation, each pt was treated with trastuzumab q21x14 cycles using the same SC or intravenous formulation of NAT. Primary endpoint was the proportion of subjects with high stromal tumor-infiltrating lymphocytes (sTILs) in postneoadjuvant residual disease (RD).
RESULTS
Sixty-three pts (31 (arm A) and 32 (arm B)) were enrolled. Pathological complete response was obtained by 20/31 pts (64.5%; 95% CI 45.4% to 80.1%) in arm A and 19/32 pts (59.4%; 95% CI 40.1% to 76.3%) in arm B. High sTILs were observed in 27% and 46% of postneoadjuvant residual tumors in arms A and B, respectively. CD8+ T cells increased significantly in RDs of both arms (p=0.014 and 0.002 for arm A and B, respectively), whereas a significant decline in the level of CD4+ FoxP3+ regulatory T cells was observed only in arm B (p=0.016). A significant upregulation of PD-1 on sTILs was found in RD of pts enrolled in arm B (p=0.012), while programmed death-ligand 1 (PD-L1) was significantly overexpressed in residual tumors of arm A (p=0.02). A strong negative correlation was reported in arm B between expression of PD-L1 on pretreatment sTILs and CD3 expression on sTILs in RD (τ: -0.73). Grade≥3 AE incidence rates were similar between the two arms.
CONCLUSIONS
SC trastuzumab induced relevant sTILs enrichment, with favorable variations of immune parameters in HER2-positive BC pts with RD after NAT. Novel immunotherapy strategies should be tested to achieve SC-specific, antitumor immune response.
TRIAL REGISTRATION NUMBER
NCT03144947, and EudraCT number: 2016-000435-41.
Topics: Humans; Female; Trastuzumab; Breast Neoplasms; B7-H1 Antigen; Docetaxel; Neoadjuvant Therapy; Neoplasm, Residual; Receptor, ErbB-2; Treatment Outcome; Antineoplastic Combined Chemotherapy Protocols
PubMed: 38016718
DOI: 10.1136/jitc-2023-007667 -
International Journal of Molecular... Sep 2023SUMOylation is an important part of post-translational protein modifications and regulates thousands of proteins in a dynamic manner. The dysregulation of SUMOylation is...
SUMOylation is an important part of post-translational protein modifications and regulates thousands of proteins in a dynamic manner. The dysregulation of SUMOylation is detected in many cancers. However, the comprehensive role of SUMOylation in prostate cancer (PCa) remains unclear. Using 174 SUMOylation-related genes (SRGs) from the MigDSB database and the transcript data of PCa from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), we constructed a SUMOylation-related risk score and correlated it with prognosis, tumor mutation burden (TMB), tumor microenvironment (TME) infiltration, and response to chemotherapy and immunotherapy. Moreover, we validated two vital SRGs by RT-qPCR, western blotting, and immunohistochemistry. Two vital SRGs (DNMT3B and NUP210) were finally selected. The risk score based on these genes exhibited excellent predictive efficacy in predicting the biochemical recurrence (BCR) of PCa. A nomogram involving the risk score and T stage was established to further explore the clinical value of the risk score. We found the high-score group was correlated with worse prognosis, higher TMB, a more suppressive immune microenvironment, and a better response to Docetaxel but worse to PD-1/CTLA-4 blockade. Meanwhile, we validated the significantly higher expression level of NUP210 in PCa at mRNA and protein levels. This study elucidated the comprehensive role of SUMOylation-related genes in PCa. Importantly, we highlighted the role of an important SRG, NUP210, in PCa, which might be a promising target in PCa treatment. A better understanding of SUMOylation and utilizing the SUMOylation risk score could aid in precision medicine and improve the prognosis of PCa.
Topics: Male; Humans; Sumoylation; Prostatic Neoplasms; Prostate; Immunotherapy; Precision Medicine; Tumor Microenvironment
PubMed: 37686409
DOI: 10.3390/ijms241713603 -
Cureus Aug 2023Introduction Triple-negative breast cancer (TNBC) comprises a heterogeneous group of tumors with a single trait in common: an evident aggressive nature with higher rates...
Introduction Triple-negative breast cancer (TNBC) comprises a heterogeneous group of tumors with a single trait in common: an evident aggressive nature with higher rates of relapse and lower overall survival in the metastatic context when compared to other subtypes of breast cancer. To date, not a single targeted therapy has been approved for the treatment of TNBC, and cytotoxic chemotherapy remains the standard treatment. In the present experimental study, we examine the effects of the chemotherapeutic docetaxel and the bcr/abl kinase inhibitor dasatinib on TNBC cell lines (in vitro) and on TNBC tumor xenograft mouse models (in vivo). Materials and methods TNBC cell lines were cultivated and treated with various concentrations of docetaxel and dasatinib (5 nM to 100 nM). Cell death and apoptosis were studied by flow cytometry. TNBC cell lines were then injected in BALB/c athymic nude mice to express the tumor in vivo. Four groups of mice were created (group A: control; group B: DOC; group C: DAS; group D: DOC + DAS) and treated, respectively, with the drugs and their combination. Tumors were obtained, maintained in a 10% formaldehyde solution, embedded in paraffin, and sent for further histological evaluation (hematoxylin-eosin staining and immune-histochemical analysis) to assess the tumor growth inhibition. Results The cytotoxic effects of docetaxel seem statistically important, with little effect on apoptosis. The effect of dasatinib in vitro and vivo is statistically important, in terms of apoptosis and tumor reduction, with little adverse effects. Conclusions TNBC is a difficult-to-treat oncologic condition, even in an experimental setting. Promising results concerning the addition of targeted therapies (dasatinib) to the conventional cytotoxic ones (docetaxel) have been shown, awaiting further evaluation.
PubMed: 37719631
DOI: 10.7759/cureus.43534 -
JCO Oncology Practice Jul 2023On the basis of the results from CLEOPATRA, pertuzumab plus trastuzumab and chemotherapy is the first-line standard of care for human epidermal growth factor receptor 2...
Real-World First-Line Use of Pertuzumab With Different Taxanes for Human Epidermal Growth Factor Receptor 2-Positive Metastatic Breast Cancer: A Comparative Effectiveness Study Using US Electronic Health Records.
PURPOSE
On the basis of the results from CLEOPATRA, pertuzumab plus trastuzumab and chemotherapy is the first-line standard of care for human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC). However, discrepancies have been reported between clinical trial and real-world outcomes. We report real-world outcomes for patients with HER2-positive MBC treated with first-line pertuzumab plus trastuzumab and a taxane in routine clinical practice in the United States.
METHODS
A retrospective analysis was conducted using electronic health record-derived deidentified data from the Flatiron Health database. Patients were grouped according to the first taxane received (paclitaxel/nab-paclitaxel or docetaxel). Median real-world progression-free survival (rwPFS) and overall survival (rwOS) was estimated using Kaplan-Meier methodology. Subgroup analyses were conducted in patients treated with docetaxel who met CLEOPATRA's key eligibility criteria.
RESULTS
We included 1,065 patients; 313 patients received paclitaxel/nab-paclitaxel and 752 received docetaxel. Patients who received paclitaxel/nab-paclitaxel were older, had a worse Eastern Cooperative Oncology Group Performance Status, and had more recurrent metastatic disease compared with the docetaxel group. After adjustment for potential confounders, similar median rwPFS (inverse probability of treatment weighted average treatment effect for the treated [IPTW-ATT] hazard ratio [HR], 1.09; 95% CI, 0.9 to 1.3; = .365) and rwOS (IPTW-ATT HR, 1.23; 95% CI, 0.96 to 1.58; = .101) was observed between treatment groups. In the subgroup of CLEOPATRA-eligible patients, median rwPFS and rwOS were 16.9 months and 57.8 months, respectively.
CONCLUSION
There was no statistically significant difference in real-world outcomes between patients treated with paclitaxel/nab-paclitaxel and those treated with docetaxel. Selecting patients using key CLEOPATRA eligibility criteria resulted in rwPFS and rwOS similar to those observed in CLEOPATRA, highlighting the importance of ensuring similar patient populations when comparing clinical trial and real-world data.
Topics: Humans; Female; Breast Neoplasms; Docetaxel; Electronic Health Records; Retrospective Studies; Trastuzumab; Taxoids; Paclitaxel
PubMed: 37167571
DOI: 10.1200/OP.22.00565 -
Journal of Translational Medicine May 2024The intersection of nanotechnology and pharmacology has revolutionized the delivery and efficacy of chemotherapeutic agents, notably docetaxel, a key drug in cancer... (Review)
Review
The intersection of nanotechnology and pharmacology has revolutionized the delivery and efficacy of chemotherapeutic agents, notably docetaxel, a key drug in cancer treatment. Traditionally limited by poor solubility and significant side effects, docetaxel's therapeutic potential has been significantly enhanced through its incorporation into nanoplatforms, such as nanofibers and nanoparticles. This advancement offers targeted delivery, controlled release, and improved bioavailability, dramatically reducing systemic toxicity and enhancing patient outcomes. Nanofibers provide a versatile scaffold for the controlled release of docetaxel, utilizing techniques like electrospinning to tailor drug release profiles. Nanoparticles, on the other hand, enable precise drug delivery to tumor cells, minimizing damage to healthy tissues through sophisticated encapsulation methods such as nanoprecipitation and emulsion. These nanotechnologies not only improve the pharmacokinetic properties of docetaxel but also open new avenues in regenerative medicine by facilitating targeted therapy and cellular regeneration. This narrative review highlights the transformative impact of docetaxel-loaded nanoplatforms in oncology and beyond, showcasing the potential of nanotechnology to overcome the limitations of traditional chemotherapy and pave the way for future innovations in drug delivery and regenerative therapies. Through these advancements, nanotechnology promises a new era of precision medicine, enhancing the efficacy of cancer treatments while minimizing adverse effects.
Topics: Humans; Docetaxel; Regenerative Medicine; Neoplasms; Animals; Nanoparticles; Antineoplastic Agents; Treatment Outcome; Drug Delivery Systems
PubMed: 38816723
DOI: 10.1186/s12967-024-05347-9 -
ACS Nano Aug 2023Modest tissue penetrance, nonuniform distribution, and suboptimal release of drugs limit the potential of intracranial therapies against glioblastoma. Here, a...
Modest tissue penetrance, nonuniform distribution, and suboptimal release of drugs limit the potential of intracranial therapies against glioblastoma. Here, a conformable polymeric implant, μMESH, is realized by intercalating a micronetwork of 3 × 5 μm poly(lactic--glycolic acid) (PLGA) edges over arrays of 20 × 20 μm polyvinyl alcohol (PVA) pillars for the sustained delivery of potent chemotherapeutic molecules, docetaxel (DTXL) and paclitaxel (PTXL). Four different μMESH configurations were engineered by encapsulating DTXL or PTXL within the PLGA micronetwork and nanoformulated DTXL (nanoDTXL) or PTXL (nanoPTXL) within the PVA microlayer. All four μMESH configurations provided sustained drug release for at least 150 days. However, while a burst release of up to 80% of nanoPTXL/nanoDTXL was documented within the first 4 days, molecular DTXL and PTXL were released more slowly from μMESH. Upon incubation with U87-MG cell spheroids, DTXL-μMESH was associated with the lowest lethal drug dose, followed by nanoDTXL-μMESH, PTXL-μMESH, and nanoPTXL-μMESH. In orthotopic models of glioblastoma, μMESH was peritumorally deposited at 15 days post-cell inoculation and tumor proliferation was monitored via bioluminescence imaging. The overall animal survival increased from ∼30 days of the untreated controls to 75 days for nanoPTXL-μMESH and 90 days for PTXL-μMESH. For the DTXL groups, the overall survival could not be defined as 80% and 60% of the animals treated with DTXL-μMESH and nanoDTXL-μMESH were still alive at 90 days, respectively. These results suggest that the sustained delivery of potent drugs properly encapsulated in conformable polymeric implants could halt the proliferation of aggressive brain tumors.
Topics: Animals; Glioblastoma; Pharmaceutical Preparations; Nanoparticles; Paclitaxel; Docetaxel; Polymers; Polyvinyl Alcohol; Cell Line, Tumor
PubMed: 37379253
DOI: 10.1021/acsnano.3c01574 -
Nature Communications Dec 2023The role of pyrotinib in the treatment of HER2-positive metastatic breast cancer (MBC) has been well-established. This multicenter, single-arm phase II trial...
The role of pyrotinib in the treatment of HER2-positive metastatic breast cancer (MBC) has been well-established. This multicenter, single-arm phase II trial (NCT03876587) aimed to assess the benefit of pyrotinib plus docetaxel as a first-line treatment for HER2-positive MBC. Women with HER2-positive MBC who had not undergone HER2 blockade or chemotherapy for metastatic disease were enrolled in the study and received daily oral pyrotinib 400 mg plus intravenous docetaxel 75 mg/m every 3 weeks. The primary endpoint was the objective response rate (ORR), secondary endpoints included progression-free survival (PFS), duration of response (DoR), clinical benefit rate (CBR), overall survival (OS) and safety. From June 2019 to June 2021, 79 patients were enrolled. The confirmed ORR was 79.7% (95% confidence interval [CI], 70.8-88.6), and the CBR was 87.3% (95%CI, 80.0-94.6) in the intention-to-treat population. The pre-specified primary endpoint was met. The median DoR was 15.9 months (interquartile range, 8.3-19.5); the median PFS was 16.0 months (95% CI, 11.2-20.8), and the median OS was not reached. The most common grade ≥3 treatment-related adverse events observed were leukopenia (29.1%), neutropenia (27.8%), and diarrhea (21.5%). This study demonstrates that pyrotinib plus docetaxel show an acceptable safety profile and promising antitumor activity as a first-line treatment option for patients with HER2-positive MBC.
Topics: Humans; Female; Breast Neoplasms; Docetaxel; Trastuzumab; Receptor, ErbB-2; Antineoplastic Combined Chemotherapy Protocols
PubMed: 38097605
DOI: 10.1038/s41467-023-44140-y -
European Urology Jul 2024The utility of prostate radiotherapy (RT) is unclear in men with metastatic hormone-sensitive prostate cancer (mHSPC) receiving intensified systemic therapy with... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND AND OBJECTIVE
The utility of prostate radiotherapy (RT) is unclear in men with metastatic hormone-sensitive prostate cancer (mHSPC) receiving intensified systemic therapy with androgen deprivation therapy (ADT) and androgen receptor pathway inhibitors (ARPIs). We performed a network meta-analysis of randomized controlled trials (RCTs) to investigate the role of prostate RT in low-volume mHSPC.
METHODS
Bibliographic databases and conference proceedings were searched through July 2023 for RCTs evaluating the addition of ARPIs or prostate RT to standard of care (SOC) systemic therapy, defined as ADT or ADT plus docetaxel, for the initial treatment of mHSPC. We focused exclusively on aggregate data from the low-volume mHSPC subpopulation in these trials. We pooled the treatment arms into four groups: SOC, SOC plus ARPI, SOC plus RT, and SOC plus ARPI plus RT. The primary outcome was overall survival (OS). To compare treatment strategies, a fixed-effects Bayesian network meta-analysis was undertaken, while a Bayesian network meta-regression was performed to account for across-trial differences in docetaxel use as part of SOC and in proportions of patients with de novo presentation.
KEY FINDINGS AND LIMITATIONS
Ten RCTs comprising 4423 patients were eligible. The Surface Under the Cumulative Ranking Curve scores were 0.0006, 0.45, 0.62, and 0.94 for SOC, SOC plus RT, SOC plus ARPI, and SOC plus ARPI plus RT, respectively. On a meta-regression, in a population with de novo mHSPC and no docetaxel use, we did not find sufficient evidence of a difference in OS between SOC plus ARPI plus RT versus SOC plus ARPI (hazard ratio [HR]: 0.76; 95% credible interval: 0.51-1.16) and SOC plus RT versus SOC plus ARPI (HR: 1.10; 95% credible interval: 0.92-1.42).
CONCLUSIONS AND CLINICAL IMPLICATIONS
There was some evidence that SOC plus ARPI plus RT reduced mortality compared with the next best strategy of SOC plus ARPI in patients with low-volume de novo mHSPC. A meta-analysis with individual patient data or an RCT is needed to confirm these findings.
Topics: Humans; Male; Prostatic Neoplasms; Network Meta-Analysis; Androgen Antagonists; Randomized Controlled Trials as Topic; Neoplasm Metastasis
PubMed: 38570246
DOI: 10.1016/j.eururo.2024.03.018 -
Biomedicines Jul 2023Taxanes (paclitaxel and docetaxel) are one of the most useful classes of anticancer drugs. Taxanes are highly hydrophobic; therefore, these drugs must be dissolved in... (Review)
Review
Taxanes (paclitaxel and docetaxel) are one of the most useful classes of anticancer drugs. Taxanes are highly hydrophobic; therefore, these drugs must be dissolved in organic solvents (polysorbate or Cremophor EL), which contribute to their toxicities. To reduce this toxicity and to enhance their efficacy, novel formulations have been developed. Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) is an albumin-stabilized, Cremophor-free, and water-soluble nanoparticle formulation of paclitaxel. Nab-paclitaxel has better solubility and less infusion-associated toxicity compared to solvent-based paclitaxel. Additionally, nab-paclitaxel can be given at higher doses and concentrations compared with solvent-based paclitaxel. Based on its superior clinical efficacy and safety profile, nab-paclitaxel received FDA approval for metastatic breast cancer (2008) and NSCLC (2011). Among gastrointestinal cancers, it is now approved in the USA for treating patients with metastatic adenocarcinoma of the pancreas as first-line therapy in combination with gemcitabine. Furthermore, several clinical trials have suggested the potential efficacy of nab-paclitaxel as a single agent or in combination with other agents for the treatment of metastatic esophageal, gastric, bowel, and biliary tract cancers. Nab-paclitaxel has been demonstrated to have greater overall response rates (ORR) with enhanced progression-free survival (PFS), overall survival (OS) and a superior safety profile with fewer adverse effects in patients with gastrointestinal tract cancers. This review summarizes the advantages associated with nab-paclitaxel-based regimens in terms of improving clinical efficacy and the safety profile in upper gastrointestinal cancer.
PubMed: 37509639
DOI: 10.3390/biomedicines11072000 -
The World Journal of Men's Health Jul 2024This study aimed to compare the short-term outcomes and safety profiles of androgen-deprivation therapy (ADT)+abiraterone/prednisone with those of ADT+docetaxel in...
Comparison of Short-Term Outcomes and Safety Profiles between Androgen Deprivation Therapy+Abiraterone/Prednisone and Androgen Deprivation Therapy+Docetaxel in Patients with Metastatic Hormone-Sensitive Prostate Cancer.
PURPOSE
This study aimed to compare the short-term outcomes and safety profiles of androgen-deprivation therapy (ADT)+abiraterone/prednisone with those of ADT+docetaxel in patients with metastatic hormone-sensitive prostate cancer (mHSPC).
MATERIALS AND METHODS
A web-based database system was established to collect prospective cohort data for patients with mHSPC in Korea. From May 2019 to November 2022, 928 patients with mHSPC from 15 institutions were enrolled. Among these patients, data from 122 patients who received ADT+abiraterone/prednisone or ADT+docetaxel as the primary systemic treatment for mHSPC were collected. The patients were divided into two groups: ADT+abiraterone/prednisone group (n=102) and ADT+docetaxel group (n=20). We compared the demographic characteristics, medical histories, baseline cancer status, initial laboratory tests, metastatic burden, oncological outcomes for mHSPC, progression after mHSPC treatment, adverse effects, follow-up, and survival data between the two groups.
RESULTS
No significant differences in the demographic characteristics, medical histories, metastatic burden, and baseline cancer status were observed between the two groups. The ADT+abiraterone/prednisone group had a lower prostate-specific antigen (PSA) progression rate (7.8% 30.0%; p=0.011) and lower systemic treatment discontinuation rate (22.5% 45.0%; p=0.037). No significant differences in adverse effects, oncological outcomes, and total follow-up period were observed between the two groups.
CONCLUSIONS
ADT+abiraterone/prednisone had lower PSA progression and systemic treatment discontinuation rates than ADT+docetaxel. In conclusion, further studies involving larger, double-blinded randomized trials with extended follow-up periods are necessary.
PubMed: 38164028
DOI: 10.5534/wjmh.230104