Carboplatin Treatment Research Articles

Metabolic imaging distinguishes ovarian cancer subtypes and detects their early and variable responses to treatment.

High grade serous ovarian cancer displays two metabolic subtypes; a high OXPHOS subtype that shows increased expression of genes encoding electron transport chain components, increased oxygen consumption, and increased chemosensitivity, and a low OXPHOS subtype that exhibits glycolytic metabolism and is more drug resistant. We show here in patient-derived organoids and in the xenografts obtained by their subcutaneous implantation that the low OXPHOS subtype shows higher lactate dehydrogenase activity and monocarboxylate transporter 4 expression than the high OXPHOS subtype and increased lactate labeling in 13C magnetic resonance spectroscopy (MRS) measurements of hyperpolarized [1-13C]pyruvate metabolism. There was no difference between the subtypes in PET measurements of 2-deoxy-2-[fluorine-18]fluoro-D-glucose ([18F]FDG) uptake. Both metabolic imaging techniques could detect the early response to Carboplatin treatment in drug-sensitive high OXPHOS xenografts and no response in drug-resistant in low OXPHOS xenografts. 13C magnetic resonance spectroscopic imaging of hyperpolarized [1-13C]pyruvate metabolism has the potential to be used clinically to distinguish low OXPHOS and high OXPHOS tumor deposits in HGSOC patients and to detect their differential responses to treatment.

A case of karyomegalic interstitial nephritis without FAN1 mutations in the setting of brentuximab, ifosfamide, and carboplatin exposure

BackgroundKaryomegalic interstitial nephritis (KIN) is a rare renal diagnosis associated with both genetic and medication etiologies. The primary gene associated with KIN is the FAN1 gene which encodes a protein responsible for DNA interstrand repair. Common medication triggers of KIN are chemotherapeutic agents, especially those which disrupt DNA structure such as carboplatin. Despite overlap between these mechanisms, it has not clearly been established if medication usage requires an underlying genetic predisposition for triggering KIN or if medications alone are sufficient. This ambiguous pathogenesis can make it difficult to appropriately assess risk of KIN development when starting patients on one of the known KIN-inducing therapies. Additionally, brentuximab vedotin, an antibody–drug conjugate directed against CD30, has not been previously implicated in KIN development.Case presentation.We present a 49-year-old woman previously diagnosed with metastatic Hodgkin’s lymphoma who was treated with doxorubicin, bleomycin, vinblastine, and dacarbazine, then 3 cycles of ifosfamide, carboplatin, etoposide, all of which were discontinued due to side effects. Following an episode of acute kidney injury, the serum creatinine was 1.09 mg/dL. She then received 2 doses of brentuximab, the serum creatinine rose, and the drug was discontinued. Kidney biopsy done 2 months after brentuximab and 5 months following ifosfamide therapies showed karyomegalic interstitial nephritis. Genetic evaluation showed no FAN1 gene mutations. The patient was started on pembrolizumab; no steroids were given due to concerns about interference with lymphoma immunotherapy. She remains with stable disease and stable chronic kidney disease.ConclusionsThis case presents a patient who developed KIN with a progressively rising serum creatinine after ifosfamide, carboplatin and brentuximab treatment. Although ifosfamide and carboplatin have known associations with the development of KIN, this case raises the possibility that brentuximab, which has a different mechanism of action, also may be associated with KIN. Additionally, the genetic findings demonstrate that drug-induced KIN can develop in the absence of FAN1 mutations, a finding not previously reported.

CNSC-04. UNDERSTANDING PEDIATRIC BRAIN TUMOR CHEMOTHERAPY INDUCED LONG-TERM DEFICITS IN HIGH-ORDER NEUROCOGNITIVE AND SENSORIMOTOR FUNCTION

Abstract Because of major advancements in cancer treatment especially chemotherapy, 85% of children with cancer are predicted to survive for 5 years or more. However, chemotherapy can cause long-term health problems when childhood cancer survivors enter adulthood (known as late effects). The neurocognitive features of these late effects (chemobrain) include trouble in concentrating, memorizing, and decreased processing speed, and results in lower IQ and academic achievement, poor hand-eye coordination, and slower development over time. Despite such a negative impact on the quality of life of cancer-surviving children, the mechanism is poorly understood and there is no FDA-approved drug to prevent or cure these side effects. To gain a better understanding of the mechanism underlying chemotherapy-induced cognitive impairments, we developed a pre-clinical model using carboplatin in juvenile mice to study long-term neurological defects. Carboplatin is commonly used chemotherapy drug in pediatric brain tumor patients. We have tested the capacity of different doses of carboplatin and its long-term effect on cognitive and sensorimotor function and performed single nuclear RNA sequencing (snRNAseq) of the hippocampus. Our preliminary data demonstrated dose-dependent deficits in executive and sensorimotor function 7-9 weeks after carboplatin administration in the mice of both sexes. snRNAseq of the hippocampus showed changes in the glial cell number as well as genes associated with oxidative phosphorylation and neurodegeneration at early and late time points. Bioenergetics using Seahorse in the brain synaptosomes revealed mitochondrial dysfunction in the form of decreased maximum respiratory capacity long after carboplatin treatment. This study established a preclinical model that can be leveraged to mechanistically understand the long-term neurocognitive side effects of brain tumor chemotherapy during childhood. Future studies will aim to identify potential targets to prevent and/or treat the neurotoxic effects of cancer treatment in pediatric patients.

CNSC-07. OLIGODENDROGLIAL IMPAIRMENT IN WHITE MATTER TRACTS FOLLOWING NEUROFIBROMATOSIS TYPE 1 (NF1) GERMLINE MUTATION OR CARBOPLATIN TREATMENT

Abstract Neurofibromatosis type 1 (NF1) is a cancer predisposition syndrome due to mutations in the NF1 gene. The disease affects 1 in 2500-3000 people worldwide and patients are predisposed to neoplasms such as optic pathway glioma, plexiform neurofibroma. In addition, NF1 patients often experience neurological issues such as learning difficulties. Unfortunately, there is no cure for NF1 yet. Chemotherapy (e.g., carboplatin) remains the first-line treatment for NF1-associated low-grade glioma; while effective in reducing tumor burden, it does not reliably restore neuronal function. In this study, we sought to determine how chemotherapy and Nf1 germline mutations influence neurological function, using genetically engineered mice of NF1. Nf1-heterozygous mice received carboplatin (60 mg/kg/day) or vehicle every other day for one week. Their optic nerves were collected and processed for immunofluorescence and transmission electron microscopy (EM). We found that carboplatin treatment reduces the density of oligodendrocytes in Nf1-heterozygous mice and impairs myelination. Moreover, a similar effect of carboplatin was observed in wild-type mice, suggesting that carboplatin impairs oligodendroglia independent of the NF1 status and the effect of carboplatin should also be evaluated in the non-NF1 context. In another set of experiments, we sought to understand how germline Nf1 mutations influences oligodendroglia. Whereas we did not observe a difference in optic nerve oligodendrocyte density in mice with an engineered mutation targeting the GTPase-activating protein-related domain (GRD) domain of the Nf1 gene, a reduction of oligodendrocyte density was observed in mice harboring a patient-derived mutation (R1809C), which localizes outside of the GRD. A similar effect was observed in the corpus callosum of Nf1+/R1809C mice together with myelin impairment, suggesting a RAS-independent mechanism of Nf1 regulation of oligodendrocytes. Together, these findings indicate that both Nf1 germline mutations and chemotherapy could contribute to oligodendrocyte and myelin deficits in white matter tracts.

IMMU-46. CROSS-TALK OF INNATE IMMUNE CELLS IN GLIOBLASTOMA PATHOPHYSIOLOGY: UNDERSTANDING NLRP3 AND NLRP12

Abstract Glioblastoma (GBM) are malignant gliomas with an average survival of less than 14 months after diagnosis, despite surgery, chemotherapy, and radiotherapy. Tumor survival is aided by the heterogeneous cell populations in the tumor microenvironment. Two crucial innate immune cells of the brain, namely microglia and macrophages, favor a tumor-promoting microenvironment IN GBM. The nucleotide-binding domain leucine-rich repeat-containing receptor (NLR) family in astrocytes and microglia cells recognizes pathogen- and damage-associated molecular patterns that induce inflammation. NLRP3, upon activation, leads to cleavage and activation of Caspase-1, causing the proteolytic cleavage-mediated activation and conversion of pro-IL-1ß and pro-IL-18 to IL-1ß and IL-18, leading to pyroptosis. NLRP12 downregulates inflammatory responses in microglia and macrophages by regulating the NF-kB pathway. NLRP3 and NLRP12 have tumor-promoting and anti-tumour functions in various cancers. NLRP12 is a prognostic marker for glioblastoma, and its increased expression correlates with poor survival in GBM patients. However, the cellular and molecular mechanisms of NLRP3 and NLRP12 in GBM pathophysiology are largely unknown. This study aims to understand the effect of NLRP3 and NLRP12 expression in GBM, to interpret the pathophysiology, and to help develop future targeted therapeutic interventions. To understand the baseline expression of NLRP3 and NLRP12 in cell lines and patient-derived GBM cells, PCR, western blotting, and Immunocytochemistry were performed comparing WT and nlrp3-/- and nlrp12-/- cells. Differential expression of NLRP3 and NLRP12 in patient-derived cells can be compared to GBM, astrocyte, and microglia cell lines. This may be the underlying cause for intra and inter-tumor heterogeneity and resultant differential therapy outcomes. To understand cell-to-cell communication in GBM-like tumor microenvironments, heterocellular 3D organoids, and patient-derived tumor organoids were developed. Cell viability in 3D patient-derived tumor organoids decreased by up to 10% with Doxorubicin and 40% with Carboplatin treatment decreases compared to untreated controls. This suggests the scope of developing drugs targeting inflammation regulatory genes.

Carboplatin dosing in obese patients.

The study aimed to: 1) Describe the carboplatin dosing criteria in obese patients in routine clinical practicein a general university hospital. 2) Evaluate toxicity based on the dosing criterion used. 3) Assess effectiveness in major diagnoses according to the dosing criterion employed. An observational, retrospective, descriptive study, including all obese patients (BMI ≥ 30 kg/m2) who started carboplatin treatment between 1st January 2012 and 31st January 2015. Data on patient characteristics, disease and treatment were collected. As a result variables were collected: carboplatin dosing methods, dosage criteria, alternative dosing approaches, treatment delays, dose reductions, relative dose intensity, adverse reactions and severity (CTCAE v. 4.0) as well as overall survival and progressive free survival for major diagnoses. 1) Carboplatin dosing at the centre used Calvert's formula for calculating AUC and Cockcroft-Gault's formula for estimating glomerular filtration rate. 2) Cockcroft-Gault's formula employed actual body weight and ideal adjusted body weight in similar proportions. 3) The ideal adjusted body weight was more commonly used in patients with higher obesity and diabetes. 4) In the general population, the developmental trend of toxicity during treatment was greater in the group dosed by actual body weight, reaching significant differences in thrombopenia, neutropenia, GOT elevation, hyporexia and myalgias. 5) Major diagnoses in the present study were ovarian cancer and non-small cell lung cancer. The effectiveness in terms of overall survival and progression-free survival, comparing the groups dosed by actual body weight and ideal adjusted body weight within each pathology did not show statistically significant differences.

Retrospective analysis of carboplatin-induced cumulative neutropenia in cancer-bearing dogs.

To determine the clinical significance of performing repeated postchemotherapy CBC for cancer-bearing dogs receiving ≥ 4 carboplatin treatments. The secondary aim was to identify risk factors associated with cumulative carboplatin-induced neutropenia in those dogs. 40 client-owned dogs diagnosed with cancer. A retrospective study using medical records from a single academic institution during 2012 to 2023. Dogs that received ≥ 4 doses of carboplatin with pre- and postchemotherapy CBCs available were included. Signalment and possible risk factors were recorded. Veterinary Cooperative Oncology Group-Common Terminology Criteria for Adverse Events was used for neutropenia grading. 40 dogs met the inclusion criteria, with a total of 206 prechemotherapy and 188 postchemotherapy CBC results available. The median carboplatin dosage was 300 mg/m2 (range, 200 to 300 mg/m2). The median interval between carboplatin administration and the postchemotherapy CBC was 10 days (range, 6 to 38 days). Eleven dogs developed a grade 2 or higher neutropenia, with 5 dogs developing multiple neutropenic events, for a total of 18 separate events (18/394). Only 2 of 18 neutropenic events were recorded at the 10- to 14-day postchemotherapy CBC. The yield of detecting neutropenia at a postchemotherapy CBC at any carboplatin chemotherapy after the second dose was < 1% (1/149). Dogs that developed neutropenia at the pre-2nd chemotherapy CBC had a significantly higher risk of developing another neutropenic event at subsequent prechemotherapy CBC (P < .001). The incidence of cumulative neutropenia after 4 to 6 doses of carboplatin is low in cancer-bearing dogs. If a grade 2 or higher neutropenia is observed at or before the second prechemotherapy CBC, the dog is at a higher risk of developing neutropenia following future treatments.

Genomic and transcriptomic profiling of pre- and postneoadjuvant chemotherapy triple negative breast cancer tumors.

Our understanding of neoadjuvant treatment with microtubule inhibitors (MTIs) for triple negative breast cancer (TNBC) remains limited. To advance our understanding of the role of breast cancer driver genes' mutational status with pathological complete response (pCR; ypT0/isypN0) prediction and to identify distinct gene sets for MTIs like eribulin and paclitaxel, we carried out targeted genomic (n = 50) and whole transcriptomic profiling (n = 64) of TNBC tumor samples from the Japan Breast Cancer Research Group 22 (JBCRG-22) clinical trial. Lower PIK3CA, PTEN, and HRAS mutations were found in homologous recombination deficiency (HRD)-high (HRD score ≥ 42) tumors with higher pCR rates. When HRD-high tumors were stratified by tumor BRCA mutation status, the pCR rates in BRCA2-mutated tumors were higher (83% vs. 36%). Transcriptomic profiling of TP53-positive tumors identified downregulation of FGFR2 (false discovery rate p value = 2.07e-7), which was also the only common gene between HRD-high and -low tumors with pCR/quasi-pCR treated with paclitaxel and eribulin combined with carboplatin, respectively. Differential enrichment analysis of the HRD-high group posttreatment tumors revealed significant correlation (p = 0.006) of the glycan degradation pathway. FGFR2 expression and the differentially enriched pathways play a role in the response and resistance to MTIs containing carboplatin treatment in TNBC patients.

KDM1A/LSD1 inhibition enhances chemotherapy response in ovarian cancer.

Ovarian cancer (OCa) is the deadliest of all gynecological cancers. The standard treatment for OCa is platinum-based chemotherapy, such as carboplatin or cisplatin in combination with paclitaxel. Most patients are initially responsive to these treatments; however, nearly 90% will develop recurrence and inevitably succumb to chemotherapy-resistant disease. Recent studies have revealed that the epigenetic modifier lysine-specific histone demethylase 1A (KDM1A/LSD1) is highly overexpressed in OCa. However, the role of KDM1A in chemoresistance and whether its inhibition enhances chemotherapy response in OCa remains uncertain. Analysis of TCGA datasets revealed that KDM1A expression is high in patients who poorly respond to chemotherapy. Western blot analysis show that treatment with chemotherapy drugs cisplatin, carboplatin, and paclitaxel increased KDM1A expression in OCa cells. KDM1A knockdown (KD) or treatment with KDM1A inhibitors NCD38 and SP2509 sensitized established and patient-derived OCa cells to chemotherapy drugs in reducing cell viability and clonogenic survival and inducing apoptosis. Moreover, knockdown of KDM1A sensitized carboplatin-resistant A2780-CP70 cells to carboplatin treatment and paclitaxel-resistant SKOV3-TR cells to paclitaxel. RNA-seq analysis revealed that a combination of KDM1A-KD and cisplatin treatment resulted in the downregulation of genes related to epithelial-mesenchymal transition (EMT). Interestingly, cisplatin treatment increased a subset of NF-κB pathway genes, and KDM1A-KD or KDM1A inhibition reversed this effect. Importantly, KDM1A-KD, in combination with cisplatin, significantly reduced tumor growth compared to a single treatment in an orthotopic intrabursal OCa xenograft model. Collectively, these findings suggest that combination of KDM1A inhibitors with chemotherapy could be a promising therapeutic approach for the treatment of OCa.

Efficacy of intra-arterial carboplatin and bevacizumab in the C6 rat glioma model of glioblastoma multiforme

BackgroundUtilizing an endovascular rat glioma model, this study aimed to analyze the efficacy of intra-arterial (IA) carboplatin and bevacizumab delivery with blood-brain barrier breakdown (BBBB) for glioblastoma treatment.MethodsC6-glioma cells were...

Association between homologous recombination deficiency status and carboplatin treatment response in early triple-negative breast cancer.

The aim of this study was to assess homologous recombination deficiency (HRD) status and its correlation with carboplatin treatment response in early triple-negative breast cancer (TNBC) patients. Tumor tissues from 225 consecutive TNBC patients were evaluated with an HRD panel and homologous recombination-related (HRR) gene expression data. HRD positivity was defined as a high HRD score and/or BRCA1/2 pathogenic or likely pathogenic mutation. Clinicopathological factors, neoadjuvant treatment response, and prognosis were analyzed with respect to HRD status in these TNBC patients. HRD positivity was found in 53.3% of patients and was significantly related to high Ki67 levels (P = 0.001). In patients who received neoadjuvant chemotherapy, HRD positivity (P = 0.005) or a high HRD score (P = 0.003) was significantly associated with a greater pathological complete response (pCR) rate, especially in those treated with carboplatin-containing neoadjuvant regimens (HRD positivity vs. negativity: 50.00% vs. 17.65%, P = 0.040). HRD positivity was associated with favorable distant metastasis-free survival (hazard ratio HR 0.49, 95% confidence interval CI 0.26-0.90, P = 0.022) and overall survival (HR 0.45, 95% CI 0.20-0.99, P = 0.049), irrespective of carboplatin treatment. TNBC patients with high HRDs had high Ki67 levels and BRCA mutations. HRD-positive TNBC patients treated with carboplatin had a higher pCR rate. Patients with HRD positivity had a better prognosis, irrespective of carboplatin treatment, warranting further evaluation.

Methionine Restriction Reduces Lung Cancer Progression and Increases Chemotherapy Response.

Targeting tumor metabolism through dietary interventions is an area of growing interest, and may help to improve the significant mortality of aggressive cancers, including non-small cell lung cancer (NSCLC). Here we show that the restriction of methionine in the aggressive KRAS /Lkb1- mutant NSCLC autochthonous mouse model drives decreased tumor progression and increased carboplatin treatment efficacy. Importantly, methionine restriction during early stages of tumorigenesis prevents the lineage switching known to occur in the model, and alters the tumor immune microenvironment (TIME) to have fewer tumor-infiltrating neutrophils. Mechanistically, mutations in LKB1 are linked to anti-oxidant production through changes to cystathionine-β-synthase (CBS) expression. Human cell lines with rescued LKB1 show increased CBS levels and resistance to carboplatin, which can be partially rescued by methionine restriction. Furthermore, LKB1 rescued cells, but not mutant cells, show less G2- M arrest and apoptosis in high methionine conditions. Knock-down of CBS sensitized both LKB1 mutant and non-mutated lines to carboplatin, again rescuing the carboplatin resistance of the LKB1 rescued lines. Given that immunotherapy is commonly combined with chemotherapy for NSCLC, we next wanted to understand if T cells are impaired by MR. Therefore, we examined the ability of T cells from MR and control tumor bearing mice to proliferate in culture and found that T cells from MR treated mice had no defects in proliferation, even though we continued the MR conditions ex vivo . We also identified that CBS is most highly correlated with smoking, adenocarcinomas with alveolar and bronchiolar features, and adenosquamous cell carcinomas, implicating its roles in oxidative stress response and lineage fate in human tumors. Taken together, we have shown the importance of MR as a dietary intervention to slow tumor growth and improve treatment outcomes for NSCLC.

Sarcopenia as a Predictive Factor for Carboplatin Toxicity in Patients with Advanced Non-Small Cell Lung Cancer

Sarcopenia in cancer patients often negatively impacts various outcomes. Carboplatin, a first-line chemotherapy for non-small cell lung cancer (NSCLC), is dosed based on body weight, which doesn’t account for sarcopenia. This study evaluated the association between sarcopenia and carboplatin-related toxicity in NSCLC patients. Patients with locally advanced or metastatic NSCLC treated with carboplatin were included. Toxicity events during the first two cycles of treatment were recorded. Sarcopenia was assessed using pretreatment computed tomography scans analyzed with Slice-O-Matic V4.2 software, defining sarcopenia as a skeletal muscle index (SMI) of <52.4 cm2/m2 for men and <38.5 cm2/m2 for women. Among 146 patients, 52% had sarcopenia. Hematological toxicity occurred in 71.2% of all patients and 77.6% of those with sarcopenia. The fat-free mass index (FFMI) was independently associated with hematological toxicity and dose-limiting toxicity (DLT), which was observed in 55.5% of patients. Sarcopenia significantly correlates with hematological toxicity and DLT during carboplatin treatment in NSCLC patients. Given its prevalence and noninvasive detection, further research is needed to understand its impact on treatment outcomes.

Tumor mutational burden adjusted by neutrophil-to-lymphocyte ratio serves as a potential biomarker for atezolizumab-treated patients with extensive stage small cell lung cancer

BackgroundThere is a desperate for the identification of more accurate and efficient biomarkers for ICI responses in patients with SCLC.MethodsThe data of our study was obtained from IMpower133 study. A total of 202 patients with SCLC received the treatment of placebo plus carboplatin plus etoposide (EC) while a total of 201 patients with SCLC received the treatment of atezolizumab plus EC. Overall survival (OS) was compared using Kaplan Meier analyses. Univariate and multivariate Cox regression analysis were used to determine independent prognostic variables affecting OS in patients with SCLC.ResultsWe have demonstrated that a higher TMB adjusted by a lower neutrophil-to-lymphocyte ratio (NLR) is significantly correlated with improved OS, in patients with SCLC subject to either atezolizumab or placebo (P = 0.001 for atezolizumab and P = 0.034 for placebo). Moreover, Cox model showed that TMB < 10 mut/Mb adjusted by NLR ≥ median was an independent factor of OS for atezolizumab-treated SCLC patients (hazard ratio [HR], 2.82; 95% confidence interval; 1.52–5.24; P = 0.001). Both univariate and multivariate cox regression analysis showed that for patients with SCLC harboring low NLR and high TMB, survival is significantly longer in those treated with atezolizumab than those treated with placebo. Survival benefit is significantly higher in atezolizumab-treated patients with SCLC than those treated with placebo (P = 0.018 for TMB cutoff = 10 mut/Mb, P = 0.034 for TMB cutoff = 16 mut/Mb).ConclusionOur findings provide a promising insight into the utility of NLR-adjusted TMB in the prognosis and immune responses in patients with SCLC.

Unraveling the role of ubiquitin C-terminal hydrolase L1 in high grade serous ovarian cancer pathogenesis.

e15078 Background: High grade serous ovarian cancer (HGSOC) is the most lethal of all gynecologic malignancies, due to the fact that the majority of patients are diagnosed at an advanced stage and eventually develop chemoresistant disease 12-18 months following completion of frontline therapy. Therefore, novel targeted therapies are urgently needed to combat chemoresistance and improve patient clinical outcomes. Ubiquitin C-terminal hydrolase L1 (UCHL1) is a deubiquitinating enzyme that plays a vital role in protein homeostasis and is highly overexpressed in HGSOC. It was previously uncovered that targeting UCHL1 with small molecule inhibition reduced cell viability in a chemoresistant ovarian cancer cell line. Methods: Comparative-label free proteomic analysis was used to uncover significant changes in HGSOC cell line OVCAR8WT following treatment with UCHL1 small molecule inhibitor, LDN-5744 or corresponding DMSO control. Significant pathway changes were determined by KEGG analysis. Matched chemosensitive and resistant HGSOC cells PEA1 and PEA2 were treated in combination with LDN-5744 and carboplatin, with cell viability was determined by an MTS assay. Furthermore, western blot analysis was employed to compare common cell growth pathway changes as a result of UCHL1 inhibition in HGSOC cells. Results: Proteomic analysis revealed a significant (p&lt;0.05) upregulation in methyl phosphate capping enzyme (MEPCE) (4.9-fold), asparagine synthetase (ASNS) (2.5-fold), Phosphoserine aminotransferase 1 (PSAT1) (1.7-fold), and downregulation in centrosomal protein 55 (CEP55) (-7.2-fold), These identified proteomic changes were confirmed by western blot. KEGG pathways analysis using all significantly (p&lt;0.05) differentially expressed proteins showcased significant (p&lt;0.05) enrichment in amino acid biosynthesis, and metabolism, and chemical carcinogenesis-reactive oxygen species. Chemoresistant PEA2 cells treated in combination with LDN-5744 and carboplatin demonstrated a 59% reduction in cell viability, significantly (p&lt;0.001) lower than the 13% and 22%, that was observed from UCHL1 and carboplatin treatment alone, respectively. Conversely, PEA1, the chemosensitive counterpart to PEA2 demonstrated a significant (p&lt;0.001) 37% increase in cell viability upon combinatorial treatment compared with carboplatin alone, indicating that UCHL1 inhibition rescues the cells from chemotherapy induced cell death. Finally, LDN-5744 treatment in PEA2 led to a reduction in levels of phospho-(p-)AKT, p-STAT3, and p-ERK, while conversely in PEA1 cells levels of these proteins were increase or unchanged. Conclusions: Our findings demonstrate that targeting UCHL1 results in prominent metabolic changes in HGSOC cells and that the efficacy of UCHL1 inhibition is heavily dependent upon platinum status. Overall, this study highlights UCHL1’s novel therapeutic role in the recurrent HGSOC.

Association between GPRC5A expression and carboplatin efficacy in triple-negative breast cancer patients.

e13142 Background: Triple-negative breast cancer (TNBC) patients often face a grim prognosis, primarily due to their resistance to chemotherapy. Carboplatin is a common treatment for TNBC, particularly effective in BRCA1/2 mutations, but its efficacy varies in BRCA1/2 wild-type patients. A previous study identified GPRC5A expression as a biomarker for carboplatin chemotherapy in ovarian cancer, yet its association with carboplatin efficacy in TNBC remains unknown. This study aims to investigate whether GPRC5A can serve as a biomarker for predicting carboplatin efficacy in TNBC and to elucidate the underlying mechanisms. Methods: Analyzing clinical data from the past 5 years in Division of Breast &amp; Thyroid Surgery in Jiangsu Province Hospital, we identified 199 TNBC patients treated with carboplatin. GPRC5A expression in TNBC tumors was assessed via immunohistochemistry (IHC) and evaluated by three individual pathologists. Expression levels were categorized as low (low), low (mild), high (moderate), and high (high). The Chi-square test was employed to assess the correlation between GPRC5A expression and carboplatin efficacy. TNBC-derived organoids were used to validate the relationship between GPRC5A expression and carboplatin sensitivity. Results: Among the 199 TNBC patients, 31 (17.2%) had BRCA1/2 mutations. The pathologic complete response (pCR) rate in BRCA1/2 mutation patients receiving carboplatin was 83.9%, compared to 61.3% in BRCA1/2 wild-type patients (p=0.016). Analyzing the relationship between GPRC5A expression and BRCA1/2 gene mutations in 145 patient samples revealed no significant association (p=0.37). Irrespective of BRCA1/2 mutation status, patients with low/mild GPRC5A expression had a higher pCR rate (74.1%) compared to those with moderate/high GPRC5A expression (45%, p&lt;0.001). TNBC-derived organoids treated with carboplatin showed a cell survival rate of 31.25% (±8.5%) in low GPRC5A expression organoids and 56.25% (±12.6%) in high GPRC5A expression organoids (p=0.017). Conclusions: Our study demonstrates a correlation between GPRC5A expression and BRCA1/2 mutation status in TNBC. Furthermore, TNBC patients with low GPRC5A expression exhibited a more favorable response to carboplatin treatment, suggesting GPRC5A could be a potential biomarker for predicting carboplatin efficacy in TNBC patients.

Abstract PO1-15-05: Gene expression signature as a predictor of pathological complete response to neoadjuvant docetaxel, carboplatin, trastuzumab, and pertuzumab treatment in locally advanced HER2-positive breast cancer

Abstract Background: Neoadjuvant pertuzumab and trastuzumab in combination with chemotherapy can achieve pathological complete response (pCR, defined as ypT0/is ypN0) in approximately 40–60% of patients with human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC). Patients who achieve pCR have significantly improved survival. Therefore, the prediction of pCR is crucial for optimizing neoadjuvant therapy. Methods: To identify a gene expression signature that could predict pCR in patients with HER2+ BC, we used the nCounter Breast Cancer 360TM V2 panel to quantify the expression of 758 genes in 104 HER2+ BC samples from patients who received neoadjuvant docetaxel, carboplatin, trastuzumab, and pertuzumab (TCHP) chemotherapy and subsequent curative breast surgery. Data normalization, differentially expressed gene (DEG) analysis, and gene set enrichment analysis (GSEA) were performed using the NanoTube Bioconductor package. Using the elastic net logistic regression model with optimal hyperparameters determined by 5-fold cross-validation (5-CV), we developed a chemosensitivity score based on the expression of significant DEGs (genes with absolute log2-fold-change ≥0.5 and q-value &amp;lt; 0.1). We tested its predictive value for pCR using multivariable logistic regression analysis. Results: The median age at diagnosis was 49.5 years. The clinical stage was II in 53 (51%) patients and III in 51 (49%) patients at diagnosis. Ninety (86.5%) patients had a HER2 immunohistochemistry (IHC) score of 3+, while the remaining 14 (13.5%) patients had HER2 IHC 2+ but HER2 amplification detected by in situ hybridization. Pathological evaluation of surgical specimens revealed that 55 (52.9%) patients achieved pCR. Menopausal status (p = 0.01), PAM50 intrinsic subtype (p = 0.002), hormone receptor (HR) status (p &amp;lt; 0.001), and HER2 IHC score (p = 0.019) were significantly correlated with the pCR rate. DEG analysis using the PAM50 intrinsic subtype, HR status, and HER2 IHC score as covariates revealed 6 downregulated DEGs and 33 upregulated DEGs in patients who achieved pCR compared to patients who did not (Table 1). The 39 DEGs were significantly enriched in nine preselected MSigDB hallmark gene sets representing immunological processes (p &amp;lt; 0.001). The optimal elastic net logistic regression model containing 39 DEGs achieved the mean 5-CV area under the receiver operating characteristic curve of 0.81. The chemosensitivity score calculated using the optimal model parameters was significantly correlated with pCR after adjustment for the PAM50 intrinsic subtype, HR status, and HER2 IHC score (p &amp;lt; 0.001). GSEA revealed eight hallmark gene sets that were significantly up- or downregulated in samples with pCR, including epithelial-mesenchymal transition (normalized enrichment score [NES] = -2.16; q &amp;lt; 0.001), late estrogen response (NES = -2.01; q = 0.004), early estrogen response (NES = -1.972; q = 0.005), and inflammatory response (NES = 1.53; q = 0.06). Conclusion: Our findings demonstrate that gene expression patterns can predict the response to neoadjuvant TCHP chemotherapy in HER2+ BC. The functional characterization of 39 DEGs suggests that the tumor microenvironment, including adjacent immune cells, plays a significant role in modulating the response to neoadjuvant chemotherapy in HER2+ BC. Table 1. Significant DEGs Citation Format: Junghoon Shin, Ji-Yeon Kim, Eun Yoon Cho, Seok Won Kim, Jeong Eon Lee, Hyunwoo Lee, Yeon Hee Park, Jin Seok Ahn, Young-Hyuck Im. Gene expression signature as a predictor of pathological complete response to neoadjuvant docetaxel, carboplatin, trastuzumab, and pertuzumab treatment in locally advanced HER2-positive breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-15-05.

Comparison of Efficacy and Safety of Different Second-line Therapies for Patients With Advanced Thymic Carcinoma

AimsThymic carcinoma (TC) is a rare form of highly invasive tumors. Currently, the standard first-line therapy involves paclitaxel plus carboplatin treatment, while the recommended regimen for second-line therapy remains uncertain. The purpose of this study is to explore the second-line mode of TC patients. Materials and methodsWe evaluated the outcome of subjects with advanced TC between 2009 and 2023 in three medical centers, retrospectively. Tumor response was evaluated according to the Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1). Kaplan-Meier was used for calculating Progression-free survival (PFS) and overall survival (OS). The factors affecting survival in the real world were evaluated by Cox analysis. ResultsTotally 136 patients were included in this study, the median PFS (mPFS) for all subjects was 5.97 months, and the median OS (mOS) was 25.03 months. According to patient's treatment modes, they are divided into monotherapy (n = 95) and combination therapy (n = 41), PFS manifested the difference between two groups (5.17 vs. 9.00 months, P = 0.043). OS also indicated a significant distinction (22.50 vs. 38.00 months, P = 0.017). Furthermore, there was a significant difference in PFS between patients using immunotherapy combined with chemotherapy and those with antivascular therapy (8.57 vs. 13.10 months, P = 0.047). ConclusionIn the second-line therapy for advanced TC, the efficacy of combination therapy was better than monotherapy, especially for immunotherapy combined with antivascular therapy.

A retrospective study of combination therapy with glucocorticoids and pirfenidone for PD-1 inhibitor-related immune pneumonitis.

Immune checkpoint inhibitor pneumonitis (ICIP) is thought to be a self-limiting disease; however, an effective treatment option does not currently exist. This study aimed to determine the clinical efficacy of combination therapy with glucocorticoids and pirfenidone for ICIP related to programmed cell death protein-1 (PD-1) inhibitors. We conducted a retrospective analysis of 45 patients with advanced non-small cell lung cancer who developed ICIP following PD-1 inhibitor and albumin-bound paclitaxel or carboplatin treatment at our hospital. The PD-1 inhibitor was discontinued, and glucocorticoids were used alone or in combination with pirfenidone to treat ICIP. The relevant clinical data of these patients were collected and analyzed. Compared with the glucocorticoid alone group, the glucocorticoid-pirfenidone group showed significant improvement in forced vital capacity (FVC), carbon monoxide diffusing capacity [%], peripheral capillary oxygen saturation, and 6-minute walk distance (P < .05). There were benefits with respect to the St. George's Respiratory Questionnaire score and the recurrence rate of ICIP, but there was no significant difference between the 2 groups (P > .05). Adding pirfenidone to glucocorticoid treatment was shown to be safe and may be more beneficial than glucocorticoids alone for improving pulmonary interstitial lesions, reversing ICIP, and preventing its recurrence.

Abstract 2168: Intermittent fasting in combination with carboplatin in a pre-clinical model of obesity-driven endometrial cancer

Abstract Objectives: Endometrial cancer (EC) incidence and mortality continue to rise, with obesity a well-known driver of this disease. Obesity is associated with excess estrogen, hyperinsulinemia, activation of the Akt/mTOR pathway, chronic inflammation, and a heightened capacity to harvest dietary energy, all of which contribute to the development and progression of EC. Intermittent energy restriction (IER) is thought to have anti-tumorigenic benefits and has been shown to have synergistic effects with chemotherapy and hormonal therapy in various cancer types. Thus, we evaluated the anti-tumorigenic effects of a switch from high fat diet (HFD) to either IER or low fat diet (LFD) with carboplatin treatment in a mouse model of obesity-driven endometrioid EC. Methods: Lkb1fl/flp53fl/fl mice were fed either HFD or LFD starting at 4 weeks of age. At 12 weeks of age, the HFD-fed mice were randomized to three treatment groups: continuous HFD, HFD-LFD switch, and HFD-IER switch. The LFD-fed mice were continuously maintained on LFD. At 16 weeks of age, all mice were injected with AdCre into the left uterine horn to induce EC development. At 26 weeks of age, mice were treated with placebo or carboplatin (50 mg/kg intraperitoneally weekly) for 4 weeks (n=8-10 mice per group). EC incidence, tumor weight, and body weight were evaluated. EC gene expression was assessed by microarray analysis. Results: EC incidence was lowest in the HFD-IER group (~60%) and highest in the HFD group (~80%); rates were similar in the other diet groups (~75%). The continuous HFD-fed mice demonstrated a 76% increase in tumor size relative to continuous LFD-fed mice (p&amp;lt;0.001). At sacrifice and after carboplatin treatment, mean body weights were significantly higher (p&amp;lt;0.05) in the HFD group (38g) than groups receiving continuous LFD (26g), HFD-LFD switch (28g), or HFD-IER switch (21g), although mean body weights were not significantly different within diet groups between placebo and carboplatin-treated mice. In placebo-treated groups, mean tumor weights were significantly lower in mice fed continuous LFD (0.62g), HFD-LFD switch (0.60g) and HFD-IER switch (0.26g) relative to continuous HFD-fed mice (1.10 g; p&amp;lt;0.001). When comparing gene expression between the HFD-LFD and the HFD-IER placebo groups, genes related to cholesterol metabolism, estrogen response, and inflammation were preferentially up-regulated in the HFD-IER group. Carboplatin treatment reduced EC tumor size 42-69% across all diet groups (p&amp;lt;0.05); tumor size was the smallest in the HFD-IER group (0.15g) relative to mice receiving continuous HFD (0.34g), HFD-LFD (0.29g) or continuous LFD (0.34g). Conclusion: IER with carboplatin treatment may be an innovative combination treatment strategy in the management of EC, a highly obesity-driven cancer. Citation Format: Jennifer Haag, Olivia Lara, Chunxiao Zhou, Stephen D. Hursting, Victoria Bae-Jump. Intermittent fasting in combination with carboplatin in a pre-clinical model of obesity-driven endometrial cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2168.