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Cancer Biology & Medicine Mar 2023The choice of chemotherapeutic regimen for triple-negative breast cancer (TNBC) remains controversial. Homologous recombination deficiency (HRD) has attracted increasing...
OBJECTIVE
The choice of chemotherapeutic regimen for triple-negative breast cancer (TNBC) remains controversial. Homologous recombination deficiency (HRD) has attracted increasing attention in informing chemotherapy treatment. This study was aimed at investigating the feasibility of HRD as a clinically actionable biomarker for platinum-containing and platinum-free therapy.
METHODS
Chinese patients with TNBC who received chemotherapy between May 1, 2008 and March 31, 2020 were retrospectively analyzed with a customized 3D-HRD panel. HRD positivity was defined by an HRD score ≥ 30 or deleterious mutation. A total of 386 chemotherapy-treated patients with TNBC were screened from a surgical cohort (NCT01150513) and a metastatic cohort, and 189 patients with available clinical and tumor sequencing data were included.
RESULTS
In the entire cohort, 49.2% (93/189) of patients were identified as HRD positive (40 with deleterious mutations and 53 with intact with an HRD score of ≥ 30). In the first-line metastatic setting, platinum therapy was associated with longer median progression-free survival (mPFS) than platinum-free therapy [9.1 3.0 months; hazard ratio (HR), 0.43; 95% confidence interval 0.22-0.84; = 0.01]. Among HRD-positive patients, the mPFS was significantly longer in those treated with platinum rather than platinum-free therapy (13.6 2.0 months; HR, 0.11; = 0.001). Among patients administered a platinum-free regimen, HRD-negative patients showed a PFS significantly superior to that of HRD-positive patients ( = 0.02; treatment-biomarker -interaction = 0.001). Similar results were observed in the -intact subset. In the adjuvant setting, HRD-positive patients tended to benefit more from platinum chemotherapy than from platinum-free chemotherapy ( = 0.05, -interaction = 0.02).
CONCLUSIONS
HRD characterization may guide decision-making regarding the use of platinum treatment in patients with TNBC in both adjuvant and metastatic settings.
Topics: Humans; Adjuvants, Immunologic; Homologous Recombination; Retrospective Studies; Triple Negative Breast Neoplasms; East Asian People; Platinum; Antineoplastic Agents
PubMed: 36861447
DOI: 10.20892/j.issn.2095-3941.2022.0525 -
Molecules (Basel, Switzerland) Feb 2023Since the accidental discovery of the anticancer properties of cisplatin more than half a century ago, significant efforts by the broad scientific community have been... (Review)
Review
Since the accidental discovery of the anticancer properties of cisplatin more than half a century ago, significant efforts by the broad scientific community have been and are currently being invested into the search for metal complexes with antitumor activity. Coordination compounds of transition metals such as platinum (Pt), ruthenium (Ru) and gold (Au) have proven their effectiveness as diagnostic and/or antiproliferative agents. In recent years, experimental work on the potential applications of elements including lanthanum (La) and the post-transition metal gallium (Ga) in the field of oncology has been gaining traction. The authors of the present review article aim to help the reader "catch up" with some of the latest developments in the vast subject of coordination compounds in oncology. Herewith is offered a review of the published scientific literature on anticancer coordination compounds of Pt, Ru, Au, Ga and La that has been released over the past three years with the hope readers find the following article informative and helpful.
Topics: Antineoplastic Agents; Coordination Complexes; Transition Elements; Ruthenium; Platinum
PubMed: 36838947
DOI: 10.3390/molecules28041959 -
ChemMedChem Nov 2020Platinum drugs are heavily used first-line chemotherapeutic agents for many solid tumours and have stimulated substantial interest in the biological activity of... (Review)
Review
Platinum drugs are heavily used first-line chemotherapeutic agents for many solid tumours and have stimulated substantial interest in the biological activity of DNA-binding metal complexes. These complexes generate DNA lesions which trigger the activation of DNA damage response (DDR) pathways that are essential to maintain genomic integrity. Cancer cells exploit this intrinsic DNA repair network to counteract many types of chemotherapies. Now, advances in the molecular biology of cancer has paved the way for the combination of DDR inhibitors such as poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) and agents that induce high levels of DNA replication stress or single-strand break damage for synergistic cancer cell killing. In this review, we summarise early-stage, preclinical and clinical findings exploring platinum and emerging ruthenium anti-cancer complexes alongside PARPi in combination therapy for cancer and also describe emerging work on the ability of ruthenium and gold complexes to directly inhibit PARP activity.
Topics: Antineoplastic Agents; Coordination Complexes; Gold; Humans; Neoplasms; Platinum; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases; Ruthenium
PubMed: 32812709
DOI: 10.1002/cmdc.202000391 -
BMC Cancer Dec 2023Immunotherapy in combination with platinum-etoposide (EP) chemotherapy has been approved as a first-line treatment for extensive-stage small cell lung cancer (ES-SCLC).... (Comparative Study)
Comparative Study
Comparison of efficacy and safety between PD-1 inhibitors and PD-L1 inhibitors plus platinum-etoposide as first-line treatment for extensive-stage small-cell lung cancer: a multicenter, real-world analysis.
BACKGROUND
Immunotherapy in combination with platinum-etoposide (EP) chemotherapy has been approved as a first-line treatment for extensive-stage small cell lung cancer (ES-SCLC). However, real-world (RW) data regarding the use of immune checkpoint inhibitors (ICIs) in ES-SCLC are lacking. We aimed to assess the differences between programmed death protein 1 (PD-1) inhibitors and programmed death ligand 1 (PD-L1) inhibitors, both in conjunction with EP chemotherapy, as first-line treatment for ES SCLC.
METHODS
We conducted a real-world, multicenter, retrospective cohort, controlled study to compare the prognosis, efficacy, and safety of PD-1 and PD-L1 inhibitors in ES-SCLC patients when used along with chemotherapy. Each patient received up to six cycles of etoposide, carboplatin, or cisplatin combined with ICI drugs, including PD-1 and PD-L1 inhibitors. The primary endpoints were investigator-assessed progression-free survival (PFS) and overall survival (OS). The secondary endpoints were the investigator-assessed objective response rate (ORR) and disease control rate (DCR) according to the Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1).
RESULTS
Between January 2017 and December 2021, 194 patients with ES-SCLC from three clinical centers in a PLA general hospital were included in our study, including 93 patients in the PD-1 group and 101 patients in the PD-L1 group. At the time of data cutoff, progression-free survival in the PD-1 group (median PFS, 6.8 months; 95% CI, 5.3-8.1) was similar to that in the PD-L1 group (median PFS, 6.4 months; 95% CI, 5.5-7.5); the stratified hazard ratio for PFS was 1.12 (95% CI, 0.83-1.53; P = 0.452). The median OS was similar in the PD-1 and PD-L1 groups (15.8 m vs. 17.7 m, P = 0.566); the hazard ratio was 0.90 (95% CI, 0.62-1.30, P = 0.566). The two groups had comparable investigator-assessed confirmed objective response rates (ORR) (76.3% vs. 76.2%). Adverse effect (AE)-related discontinuation occurred in 4 (4.3%) patients in the PD-1 group and 2 (2.0%) patients in the PD-L1 group. Deaths due to AEs of any cause occurred in 2 (2.2%) patients in the PD-1 inhibitor group and 1 (1.0%) patient in the PD-L1 inhibitor group.
CONCLUSIONS
Our research revealed that there were no significant differences in efficacy or prognosis between PD-1 inhibitor + EP chemotherapy and PD-L1 inhibitor + EP chemotherapy. The two groups seemed to have comparable safety profiles, but the number of discontinuation or death events was too small to draw a firm conclusion.
Topics: Humans; B7-H1 Antigen; Etoposide; Immune Checkpoint Inhibitors; Lung Neoplasms; Platinum; Programmed Cell Death 1 Receptor; Retrospective Studies; Small Cell Lung Carcinoma
PubMed: 38057736
DOI: 10.1186/s12885-023-11709-1 -
Philosophical Transactions. Series A,... Mar 2015Platinum compounds are a mainstay of cancer chemotherapy, with over 50% of patients receiving platinum. But there is a great need for improvement. Major features of the... (Review)
Review
Platinum compounds are a mainstay of cancer chemotherapy, with over 50% of patients receiving platinum. But there is a great need for improvement. Major features of the cisplatin mechanism of action involve cancer cell entry, formation mainly of intrastrand cross-links that bend and unwind nuclear DNA, transcription inhibition and induction of cell-death programmes while evading repair. Recently, we discovered that platinum cross-link formation is not essential for activity. Monofunctional Pt compounds such as phenanthriplatin, which make only a single bond to DNA nucleobases, can be far more active and effective against a range of tumour types. Without a cross-link-induced bend, monofunctional complexes can be accommodated in the major groove of DNA. Their biological mechanism of action is similar to that of cisplatin. These discoveries opened the door to a large family of heavy metal-based drug candidates, including those of Os and Re, as will be described.
Topics: Antineoplastic Agents; Cross-Linking Reagents; DNA; DNA Repair; Drug Design; Humans; Models, Chemical; Neoplasms; Platinum; Transition Elements
PubMed: 25666060
DOI: 10.1098/rsta.2014.0185 -
Life Sciences Nov 2020Defective DNA repair is one of the most important features of tumors. BRCA1/2 participates in homologous recombination repair as a key tumor suppressor gene. BRCA1/2... (Review)
Review
Defective DNA repair is one of the most important features of tumors. BRCA1/2 participates in homologous recombination repair as a key tumor suppressor gene. BRCA1/2 mutation is an important biomarker for predicting the sensitivity of platinum salts and Poly (ADP-ribose) polymerase (PARP) inhibitors in breast cancer, ovarian cancer, and other cancers. However, epigenetic modifications and other mutations in homologous recombination repair (HRR) genes can also cause homologous recombination deficiency (HRD). Patients with no BRCA1/2 mutations, but bearing similar molecular phenotypes (BRCAness) can still obtain clinical benefits from treatment with platinum salts or PARP inhibitors. Therefore, an accurate assessment of HRD is essential for the formulation of personalized treatments. However, methods to identify HRD in tumors vary and are controversial. Currently, genomic scar assays have been used in multiple clinical trials to assess patient clinical benefit. This review summarizes the therapeutic effects of platinum salts and PARP inhibitors in breast and ovarian cancer, clarifies the predictive value of genomic scar assays in evaluating the clinical benefit of different patient groups and treatment options, and proposes the limitations and optimization of current HRD scoring methods. Using and optimizing genomic scar assays can help to accurately screen the population with the most benefit, expand the scope of drug application, and make the most suitable clinical decision based on individual differences.
Topics: Animals; Antineoplastic Agents; Epigenesis, Genetic; Genomics; Humans; Mutation; Neoplasms; Platinum; Poly(ADP-ribose) Polymerase Inhibitors; Recombinational DNA Repair
PubMed: 32941897
DOI: 10.1016/j.lfs.2020.118434 -
British Journal of Cancer Jul 2021Although unresectable or recurrent gastric cancers (GC) are frequently treated with platinum-based chemotherapy, response to treatment remains unpredictable. Because...
BACKGROUND
Although unresectable or recurrent gastric cancers (GC) are frequently treated with platinum-based chemotherapy, response to treatment remains unpredictable. Because Schlafen 11 (SLFN11) is recently identified as a critical determinant of platinum sensitivity, we investigated the potential clinical utility of SLFN11 in the treatment of GC.
METHODS
We analysed the correlation between SLFN11 expression and overall survival in 169 GC patients by our established immunohistochemical approach. The impact of SLFN11 expression on the response to platinum and transition of SLFN11 expression upon long-term treatment with platinum were examined using GC cell lines and organoids.
RESULTS
GC patients with high-SLFN11 expression exhibited significantly better survival than those with low-SLFN11 expression, and the significance increased when we selected patients treated with platinum-based chemotherapy. Knockout of SLFN11 and reactivation of SLFN11 in GC cells conferred resistance and sensitivity to platinum, respectively. In GC cells and organoids, long-term treatment with oxaliplatin suppressed SLFN11 expression while imparting drug resistance. The acquired resistance to oxaliplatin was reversed by reactivation of SLFN11 with epigenetic modifying drugs.
CONCLUSIONS
This is the first report revealing definitive clinical implications of SLFN11 in the treatment of GC patients and providing novel strategies for the drug selection based on SLFN11 expression.
Topics: Cell Line, Tumor; Cell Proliferation; Cell Survival; Down-Regulation; Drug Resistance, Neoplasm; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Gene Knockout Techniques; Humans; Nuclear Proteins; Platinum; Prognosis; Stomach Neoplasms; Survival Analysis; Treatment Outcome
PubMed: 33785877
DOI: 10.1038/s41416-021-01364-3 -
Computer Methods and Programs in... Jun 2022Platinum-induced nephrotoxicity is a severe and unexpected adverse drug reaction that could lead to treatment failure in non-small cell lung cancer patients. Better...
BACKGROUND AND OBJECTIVE
Platinum-induced nephrotoxicity is a severe and unexpected adverse drug reaction that could lead to treatment failure in non-small cell lung cancer patients. Better prediction and management of this nephrotoxicity can increase patient survival. Our study aimed to build up and compare the best machine learning models with clinical and genomic features to predict platinum-induced nephrotoxicity in non-small cell lung cancer patients.
METHODS
Clinical and genomic data of patients undergoing platinum chemotherapy at Wan Fang Hospital were collected after they were recruited. Twelve models were established by artificial neural network, logistic regression, random forest, and support vector machine with integrated, clinical, and genomic modes. Grid search and genetic algorithm were applied to construct the fine-tuned model with the best combination of predictive hyperparameters and features. Accuracy, precision, recall, F1 score, and area under the receiver operating characteristic curve were calculated to compare the performance of the 12 models.
RESULTS
In total, 118 patients were recruited for this study, among which 28 (23.73%) were experiencing nephrotoxicity. Machine learning models with clinical and genomic features achieved better prediction performances than clinical or genomic features alone. Artificial neural network with clinical and genomic features demonstrated the best predictive outcomes among all 12 models. The average accuracy, precision, recall, F1 score and area under the receiver operating characteristic curve of the artificial neural network with integrated mode were 0.923, 0.950, 0.713, 0.808 and 0.900, respectively.
CONCLUSIONS
Machine learning models with clinical and genomic features can be a preliminary tool for oncologists to predict platinum-induced nephrotoxicity and provide preventive strategies in advance.
Topics: Carcinoma, Non-Small-Cell Lung; Drug-Related Side Effects and Adverse Reactions; Humans; Lung Neoplasms; Machine Learning; Platinum
PubMed: 35550456
DOI: 10.1016/j.cmpb.2022.106839 -
ESMO Open 2020The aim of our study was to determine the effect of homologous recombination deficiency (HRD) on prognosis and efficacy of platinum-based chemotherapy in patients with... (Meta-Analysis)
Meta-Analysis Review
Efficacy of platinum-based chemotherapy and prognosis of patients with pancreatic cancer with homologous recombination deficiency: comparative analysis of published clinical studies.
The aim of our study was to determine the effect of homologous recombination deficiency (HRD) on prognosis and efficacy of platinum-based chemotherapy in patients with pancreatic cancer (PC). We performed PubMed and Embase database queries. We included 4 studies into the meta-analysis and 16 studies in the systematic review. Our systematic analysis showed that the average weighted median overall survival (OS) in patients with HRD with advanced PC was 19.8 and 15.6 months in patients without HRD. With platinum-based chemotherapy, the average weighted median OS in patients with HRD was 23.8 and 17.1 months in patients without HRD. Without platinum-based chemotherapy, the average weighted median OS in patients with HRD was 8.3 and 12.0 months in patients without HRD. For resected PC, our meta-analysis demonstrated that HRD status did not affect the prognosis (HR 1.03, 95% CI 0.46 to 2.33), but results were rather heterogeneous (I=83%, p=0.003). Our systematic analysis showed that the average weighted median OS in patients with HRD was 34.6 and 27.0 months in patients without HRD. With platinum-based chemotherapy, the average weighted median OS in patients with HRD was 46.1 and 36.3 months in patients without HRD. Without platinum-based chemotherapy, the average weighted median OS in patients with HRD was 24.2 and 42.9 months in patients without HRD. Results of our meta-analysis and systematic review support the idea of platinum use in patients with HRD both in resected and metastatic PCs, although a randomised trial is warranted to make a more reliable conclusion. PROSPERO REGISTRATION NUMBER: CRD42019121914.
Topics: Homologous Recombination; Humans; Mutation; Pancreatic Neoplasms; Platinum; Prognosis
PubMed: 33551067
DOI: 10.1136/esmoopen-2019-000578 -
Proceedings of the National Academy of... Jul 2022The development of more effective tumor therapy remains challenging and has received widespread attention. In the past decade, there has been growing interest in...
The development of more effective tumor therapy remains challenging and has received widespread attention. In the past decade, there has been growing interest in synergistic tumor therapy based on supramolecular coordination complexes. Herein, we describe two triangular metallacycles (1 and 2) constructed by the formation of pyridyl boron dipyrromethene (BODIPY)-platinum coordination. Metallacycle 2 had considerable tumor penetration, as evidenced by the phenylthiol-BODIPY ligand imparting red fluorescent emission at ∼660 nm, enabling bioimaging, and transport visualization within the tumor. Based on the therapeutic efficacy of the platinum(II) acceptor and high singlet oxygen (O) generation ability of BODIPY, 2 was successfully incorporated into nanoparticles and applied in chemo-photodynamic tumor therapy against malignant human glioma U87 cells, showing excellent synergistic therapeutic efficacy. A half-maximal inhibitory concentration of 0.35 μM was measured for 2 against U87 cancer cells in vitro. In vivo experiments indicated that 2 displayed precise tumor targeting ability and good biocompatibility, along with strong antitumor effects. This work provides a promising approach for treating solid tumors by synergistic chemo-photodynamic therapy of supramolecular coordination complexes.
Topics: Boron Compounds; Cell Line, Tumor; Coordination Complexes; Drug Synergism; Humans; Neoplasms; Photochemotherapy; Platinum; Porphobilinogen
PubMed: 35858319
DOI: 10.1073/pnas.2203994119