Platinum-resistant Patients Research Articles

CUL4B increases platinum-based drug resistance in colorectal cancer through EMT: A study in its mechanism.

Platinum-based chemotherapy drugs play a very important role in the treatment of patients with advanced colorectal cancer, but the drug resistance of platinum-based chemotherapy drugs is an important topic that puzzles us. If we can find mechanisms of resistance, it will be revolutionary for us. We analysed the differential genes, core genes and their enrichment pathways in platinum-resistant and non-resistant patients through a public database. Platinum-resistant cell lines were cultured in vitro for in vitro colony and Transwell analysis. Tumorigenesis analysis of nude mice in vivo. Verify the function of core genes. Through differential gene and enrichment analysis, we found that CUL4B was the main factor affecting platinum drug resistance and EMT. Our hypothesis was further verified by in vitro drug-resistant and wild-type cell lines and in vivo tumorigenesis analysis of nude mice. CUL4B leads to platinum drug resistance in colorectal cancer by affecting tumour EMT.

BRCA mutation carriers suffering from ovarian cancer as a model for treatment decision in higher lines - Place for platinum reinduction.

Ovarian carcinoma is a malignancy with the highest mortality among gynecological cancers. Mutations in BRCA1/2 genes are believed to be a favorable prognostic factor and that, in general, the biological behavior of ovarian cancer in BRCA-positive individuals differs from others. However, some clinically relevant issues (i.e., prediction of response to chemotherapy and treatment of platinum-resistant BRCA-positive patients) remain unclear. (1) The aim of this study was to examine the prevalence of germline BRCA mutations in unselected recurrent ovarian cancer patient population, (2) analyze whether biological behavior of BRCA-positive tumors differs from others, and (3) analyze the effect of platinum reinduction in platinum-resistant BRCA-positive patients. This was a single-institution retrospective analysis. Consecutive recurrent ovarian cancer patients from years 2012 to 2020 were included; their BRCA1/2 mutational status was analyzed and correlated with progression-free survival (PFS), type of treatment, and response to treatment. Statistical significance of differences between and among patients was tested for continuous variables by the Mann-Whitney U-test or the Kruskal-Wallis test; a maximum likelihood Chi-square test was used for categorical variables. Two hundred and forty-three recurrent ovarian cancer patients were included. The median follow-up was 37 months. Pathogenic mutation in BRCA1 or BRCA2 gene was found in 18.1% of patients. There was no difference in PFS comparing BRCA-positive to BRCA-negative patients (median PFS: 10.2 vs. 10.1 months, P = 0.874); there was a difference in PFS comparing BRCA-negative versus BRCA-positive platinum-sensitive patients (9.4 vs. 14.3 months, P = 0.002). BRCA-positive platinum-resistant patients reinduced with platinum achieved a median PFS of 8 months (compared to those receiving nonplatinum treatment, median PFS: 4 months, P = 0.062). Germline BRCA mutations are not exclusive to platinum-sensitive ovarian cancer patients; even in platinum-resistant patients, mutation can be detected. We found no difference in PFS for platinum-sensitive BRCA-positive and BRCA-negative patients. Platinum reinduction may be considered for BRCA-positive platinum-resistant ovarian cancer patients to prolong PFS. Even these data describe only a small population, it supports the clinical practice of platinum-based chemotherapy use in platinum-resistant BRCA-positive patients.

Potential Targeted Therapies in Ovarian Cancer.

We aimed to identify somatic pathogenic and likely pathogenic mutations using next-generation sequencing (NGS). The mutational findings were held against clinically well-described data to identify potential targeted therapies in Danish patients diagnosed with high-grade serous ovarian cancer (HGSC). We characterized the mutational profile of 128 HGSC patients. Clinical data were obtained from the Danish Gynecological Database and tissue samples were collected through the Danish CancerBiobank. DNA was analyzed using NGS. 47 (37%) patients were platinum-sensitive, 32 (25%) partially platinum-sensitive, 35 (27%) platinum-resistant, and three (2%) platinum-refractory, while 11 (9%) patients did not receive chemotherapy. Overall, 27 (21%) had known druggable targets. Twelve (26%) platinum-sensitive patients had druggable targets for PARP inhibitors: one for tyrosine kinase inhibitors and one for immunotherapy treatment. Eight (25%) partially platinum-sensitive patients had druggable targets: seven were eligible for PARP inhibitors and one was potentially eligible for alpesilib and hormone therapy. Seven (20%) platinum-resistant patients had druggable targets: six (86%) were potentially eligible for PARP inhibitors, one for immunotherapy, and one for erdafitinib. PARP inhibitors are the most frequent potential targeted therapy in HGSC. However, other targeted therapies remain relevant for investigation according to our mutational findings.

Hyperthermic intraperitoneal chemotherapy in the treatment of recurrent ovarian cancer: When, and for whom?

The aim of this study is to evaluate the progression-free survival (PFS) of recurrent ovarian cancer (ROC) patients treated with cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy (HIPEC). ROC patients who underwent cytoreductive surgery plus HIPEC between 2015 and 2021 were retrospectively evaluated. Patients' demographic information and clinicopathological characteristics including cancer type, histology, platinum status, presence of ascites, type of surgery, complications, chemotherapy history, and disease progression were documented. PFS was calculated using the Kaplan-Meier method. A total of 104 patients with ROC were included. The median age was 57 years and the median follow-up time was 15 months (range: 5-69 months). In Cox regression multivariate analyses, platinum resistance (hazard ratio[HR]: 3.32, 95% confidence interval [CI]: 1.91-5.76, p = 0.00), more than one relapse prior HIPEC (HR: 2.81, 95% CI: 1.65-4.87, p = 0.024), and presence of ascites (HR: 1.88, 95% CI: 1.08-3.26, p = 0.00) were found to be negative prognostic factors for PFS. In subgroup analyses of patients with the first recurrence, the median PFS was 21 months for platinum-sensitive patients and 6 months for platinum-resistant patients (p = 0.032). HIPEC at the time of first platinum-sensitive relapse may lead to favorable PFS in the treatment ROC. However, HIPECas salvage treatment even with R0 cytoreductive surgery does not seem effective.

Whole-exome sequencing of epithelial ovarian carcinomas differing in resistance to platinum therapy.

Epithelial ovarian carcinoma (EOC) is highly fatal because of the risk of resistance to therapy and recurrence. We performed whole-exome sequencing of blood and tumor tissue pairs of 50 patients with surgically resected EOC. Compared with sensitive patients, platinum-resistant patients had a significantly higher somatic mutational rate in <i>TP53</i> and lower in several genes from the Hippo pathway. We confirmed the pivotal role of somatic mutations in homologous recombination repair genes in platinum sensitivity and favorable prognosis of EOC patients. Implementing the germline homologous recombination repair profile significantly improved the prediction. In addition, distinct mutational signatures, for example, SBS6, and overall mutational load, somatic mutations in <i>PABPC1</i>, <i>PABPC3</i>, and <i>TFAM</i> co-segregated with the resistance status, high-grade serous carcinoma subtype, or overall survival of patients. We generated germline and somatic genetic landscapes of prognostically different subgroups of EOC patients for further follow-up studies focused on utilizing the observed associations in precision oncology.

IDO1 Modulates the Sensitivity of Epithelial Ovarian Cancer Cells to Cisplatin through ROS/p53-Dependent Apoptosis.

Indoleamine 2,3-dioxygenase 1 (IDO1) is a heme-containing dioxygenase that may play a part in chemoresistance in ovarian cancer. However, its role in cisplatin (DDP) resistance is unclear. Here, the expression level of IDO1 in tumors in platinum-resistant (n = 22) and -sensitive (n = 46) ovarian cancer patients was determined, and then how IDO1 modulated DDP resistance was explored in vitro and in vivo. The IDO1 expression level in platinum-resistant patients was higher than that in -sensitive patients, and a higher IDO1 level was correlated with poor prognosis in type II cancer patients. Up-regulating IDO1 decreased DDP-induced apoptosis in SKOV3 cells via inhibiting the ROS/p53 cell-death pathway, thereby attenuating cytotoxicity of DDP. Silencing IDO1 enhanced p53-dependent apoptosis by increasing ROS accumulation, thereby enhancing DDP against SKOV3 cells. Down-knocking IDO1 augmented the action of DDP in vivo. These data demonstrated that silencing IDO1 enhanced the efficacy of DDP by intensifying p53-dependent apoptosis, and that targeting IDO1 can be a strategy to modulate DDP-based chemotherapy for epithelial ovarian cancer.

A Phase 2 study of prexasertib (LY2606368) in platinum resistant or refractory recurrent ovarian cancer

ObjectiveHigh-grade serous ovarian cancer, the most frequent type of ovarian cancer, has a poor prognosis and novel treatments are needed for patients with platinum resistant/refractory disease. New therapeutic strategies targeting cell cycle checkpoints, including CHK1 inhibition with prexasertib, may help improve clinical response and overcome resistance. MethodsPatients with ovarian cancer (N = 169) were assigned to 4 cohorts as part of the Phase 2 multicenter trial (NCT03414047): Cohort 1: platinum resistant, BRCA-wildtype with ≥3 lines prior therapy; Cohort 2: platinum resistant BRCA-wildtype with <3 lines prior therapy; Cohort 3: platinum resistant, BRCA-mutated with prior PARP inhibitor therapy; Cohort 4: platinum refractory, BRCA-mutated, or BRCA-wildtype with any number of prior therapy lines. The primary endpoint was objective response rate (ORR) and secondary endpoints included disease control rate (DCR), and safety. DNA from tumor biopsies was sequenced to identify biomarkers. ResultsThe ORR in platinum resistant patients (Cohorts 1--3) was 12.1%, and 6.9% in platinum refractory patients. In platinum resistant patients, DCR was 37.1%, and consistent across cohorts. In platinum refractory patients, DCR was 31.0%. Consistent with the prexasertib mechanism of action, the most common treatment related adverse events of all grades included thrombocytopenia, neutropenia, fatigue, nausea, and anemia. ConclusionsPrexasertib demonstrated durable single agent activity in a subset of patients with recurrent ovarian cancer regardless of clinical characteristics, BRCA status, or prior therapies, including PARPi. There was no obvious correlation with genomic alterations in responders vs non-responders, emphasizing the need for alternative biomarker approaches for responder identification.

Using Patient-Derived Xenograft (PDX) Models as a 'Black Box' to Identify More Applicable Patients for ADP-Ribose Polymerase Inhibitor (PARPi) Treatment in Ovarian Cancer: Searching for Novel Molecular and Clinical Biomarkers and Performing a Prospective Preclinical Trial.

Simple SummaryThe clinical application of PARPis in patients with ovarian cancer has unresolved issues, and whether PARPis can have a similar first-line efficacy to that of platinum-based chemotherapy is still undefined. This study used the PDX model to explore the above problems. We demonstrated that the PDX model can reflect PARPi efficacy more accurately than BRCA mutation, homologous recombination deficiency positivity, and platinum sensitivity. Moreover, the novel clinical and molecular biomarkers suggested that KRAS overexpression was associated with PARPi sensitivity. Additionally, ATK1 enrichment could lead to PARPi resistance, and CA125 less than 10 U/mL during chemotherapy can be a potential indicator for the therapeutic use of PARPi. Above all, PARPis cannot replace platinum-based chemotherapy as first-line treatment in our preclinical trial, indicating that chemotherapy-free tests in the unselected population are not recommended.(1) The accuracy of patient-derived xenografts (PDXs) in predicting ADP-ribose polymerase inhibitor (PARPi) efficacy in ovarian cancer was tested, novel biomarkers were investigated, and whether PARPis could replace platinum-based chemotherapy as a first-line therapy was explored. (2) PDXs were reconstructed for 40 patients with ovarian cancer, and niraparib, olaparib and paclitaxel, and carboplatin (TC) sensitivity tests were conducted. Whole exon sequencing and homologous recombination deficiency (HRD) scores were performed, and patient clinical information was collected. The molecular biomarkers were identified by reverse-transcription quantitative PCR and immunoblotting. (3) Niraparib and olaparib sensitivity were tested in 26 patients and showed high consistency. Approximately half of BRCA wild-type, HRD-negative, and platinum-resistant patients may benefit from PARPis. AKT1 enrichment indicated PARPi resistance; high KRAS expression indicated PARPi sensitivity. CA125 below 10 U/mL during chemotherapy has a sensitivity and specificity similar to platinum sensitivity in predicting PARPi efficacy. Niraparib and TC sensitivity tests were performed on 23 patients, and TC showed a better response in this preclinical trial. (4) PDX can indicate individualized PARPi efficacy. Decreased CA125 levels and KRAS and ATK1 expression levels may be novel biomarkers. The preclinical evidence does not support the implementation of PARPis as the first-line treatment in an unselected population.

1744P Camrelizumab plus nab-paclitaxel in platinum-resistant patients with unresectable locally advanced or metastatic urothelial carcinoma: A multicentre, single-arm, phase II study

Several immune checkpoint inhibitors (ICIs) have become the standard of care for patients with advanced urothelial carcinoma (aUC) that progressed after platinum-based chemotherapy. Nab-paclitaxel is increasingly employed in aUC patients. The efficacy and safety of camrelizumab (ICI) plus nab-paclitaxel in platinum-resistant unresectable local advanced/metastatic urothelial carcinoma was investigated in this study.

574P Myriad MyChoice plus intermediate performance to discriminate platinum-resistant high-grade ovarian cancer patients

PARPi are indicated as maintenance therapy after 1st line chemotherapy, for patients (pts) with high-grade ovarian cancer (HGOC) in case of BRCA mutation, high genomic instability score (GIS), or objective response to platinum. Herein, GIS is required straight away, for all pts with HGOC to select the best maintenance strategy between bevacizumab, PARPi or both combined. Around 10% of HGOC are platinum-refractory with progressive disease during or within 4 weeks of last platinum, and additional 10% present no objective response (OR-) to platinum, and both are not eligible for PARPi.

GLS1 is a protective factor in patients with ovarian clear cell carcinoma and its expression does not correlate with ARID1A-mutated tumors.

Targeting glutamine metabolism has emerged as a novel therapeutic strategy for several human cancers, including ovarian cancer. The primary target of this approach is the kidney isoform of glutaminase, glutaminase 1 (GLS1), a key enzyme in glutamine metabolism that is overexpressed in several human cancers. A first-in-class inhibitor of GLS1, called CB839 (Telaglenastat), has been investigated in several clinical trials, with promising results. The first clinical trial of CB839 in platinum-resistant ovarian cancer patients is forthcoming. ARID1A-mutated ovarian clear cell carcinoma (OCCC) is a relatively indolent and chemoresistant ovarian cancer histotype. In OCCC-derived cells ARID1A simultaneously drives GLS1 expression and metabolism reprograming. In ARID1A-mutated OCCC-derived mouse models, loss of ARID1A corresponds to GLS1 upregulation and increases sensitivity to GLS1 inhibition. Thus, targeting of GLS1 with CB839 has been suggested as a targeted approach for OCCC patients with tumors harboring ARID1A-mutations. Here, we investigated whether GLS1 is differentially expressed between OCCC patients whose tumors are ARID1A positive and patients whose tumors are ARID1A negative. In clinical specimens of OCCC, we found that GLS1 overexpression was not correlated with ARID1A loss. In addition, GLS1 overexpression was associated with better clinical outcomes. Our findings have implications for human trials using experimental therapeutics targeting GLS1.

Cediranib in Combination with Olaparib in Patients without a Germline BRCA1/2 Mutation and with Recurrent Platinum-Resistant Ovarian Cancer: Phase IIb CONCERTO Trial.

The efficacy, safety, and tolerability of cediranib plus olaparib (cedi/ola) were investigated in patients with nongermline-BRCA-mutated (non-gBRCAm) platinum-resistant recurrent ovarian cancer. PARP inhibitor-naïve women aged ≥18 years with platinum-resistant non-gBRCAm ovarian cancer, ECOG performance status of 0-2, and ≥3 prior lines of therapy received cediranib 30 mg once daily plus olaparib 200 mg twice daily in this single-arm, multicenter, phase IIb trial. The primary endpoint was objective response rate (ORR) by independent central review (ICR) using RECIST 1.1. Progression-free survival (PFS), overall survival (OS), and safety and tolerability were also examined. Sixty patients received cedi/ola, all of whom had confirmed non-gBRCAm status. Patients had received a median of four lines of chemotherapy; most (88.3%) had received prior bevacizumab. ORR by ICR was 15.3%, median PFS was 5.1 months, and median OS was 13.2 months. Forty-four (73.3%) patients reported a grade ≥3 adverse event (AE), with one patient experiencing a grade 5 AE (sepsis), considered unrelated to the study treatment. Dose interruptions, reductions, and discontinuations due to AEs occurred in 55.0%, 18.3%, and 18.3% of patients, respectively. Patients with high global loss of heterozygosity (gLOH) had ORR of 26.7% [4/15; 95% confidence interval (CI), 7.8-55.1], while ORR was 12.5% (4/32; 95% CI, 3.5-29.0) in the low gLOH group. Clinical activity was shown for the cedi/ola combination in heavily pretreated, non-gBRCAm, platinum-resistant patients with ovarian cancer despite failing to meet the target ORR of 20%, highlighting a need for further biomarker studies.

Clinical and molecular characteristics of AMBITION patients who received olaparib plus cediranib or olaparib plus durvalumab for homologous recombination repair mutated, platinum-resistant ovarian cancer (KGOG 3045) (032)

Objectives: AMBITION is a multi-center, open-label, five-arm, uncontrolled, umbrella trial in platinum-resistant ovarian cancer patients (NCT03699449). Here, we present an exploratory analysis of clinical and molecular characteristics associated with the benefit of two olaparib-based regimens in the homologous recombination repair (HRR) gene mutation cohort. Methods: Between December 2018 and October 2020, 30 patients who had mutations in HRR genes were randomized, and received either olaparib 200mg bid + cediranib 30mg QD (arm 1; n=16) or olaparib 300mg bid + durvalumab 1500mg q4w (arm 2; n=14). From the pre-treatment biopsy (n=22) and archival (n=8) tumor samples, next-generation whole-exome and whole-transcriptomic sequencing were conducted. We also evaluated tumor immunologic signatures, including the PD-L1 (SP263) assay and tumor-infiltrating lymphocytes (TILs). Clinical and molecular features were compared between responders and non-responders. Results: Arms 1 and 2 showed an acceptable objective response rate at 50.0% and 42.9%, respectively. The responders (n=14) had 12.4 months of a median duration of response. Overall, no differences in serum CA-125 levels, ECOG performance status, histologic subtype, prior lines of therapy, and last treatment-free interval were observed between the responders and non-responders. Intratumoral TILs and stromal TILs were also similar between the responders and non-responders. While all responders had BRCA1/2 mutations, 54.5% of non-responders had BRCA1/2 mutations. DNA damage repair pathways were enriched in the responders. Especially, enrichment of DNA mismatch repair and nucleotide excision repair pathways were associated with prolonged progression-free survival (PFS). In arm 1, cell cycle pathway enrichment significantly improved PFS (p=0.006), but PD-L1 expression did not. In arm 2, patients with PD-L1 ≥1% of tumor cells showed significantly better PFS than those with PD-L1 <1% (p=0.027), and the responders had a significantly higher level of myeloid-derived suppressor cell recruiting score than the non-responders (p=0.041). Objectives: AMBITION is a multi-center, open-label, five-arm, uncontrolled, umbrella trial in platinum-resistant ovarian cancer patients (NCT03699449). Here, we present an exploratory analysis of clinical and molecular characteristics associated with the benefit of two olaparib-based regimens in the homologous recombination repair (HRR) gene mutation cohort. Methods: Between December 2018 and October 2020, 30 patients who had mutations in HRR genes were randomized, and received either olaparib 200mg bid + cediranib 30mg QD (arm 1; n=16) or olaparib 300mg bid + durvalumab 1500mg q4w (arm 2; n=14). From the pre-treatment biopsy (n=22) and archival (n=8) tumor samples, next-generation whole-exome and whole-transcriptomic sequencing were conducted. We also evaluated tumor immunologic signatures, including the PD-L1 (SP263) assay and tumor-infiltrating lymphocytes (TILs). Clinical and molecular features were compared between responders and non-responders. Results: Arms 1 and 2 showed an acceptable objective response rate at 50.0% and 42.9%, respectively. The responders (n=14) had 12.4 months of a median duration of response. Overall, no differences in serum CA-125 levels, ECOG performance status, histologic subtype, prior lines of therapy, and last treatment-free interval were observed between the responders and non-responders. Intratumoral TILs and stromal TILs were also similar between the responders and non-responders. While all responders had BRCA1/2 mutations, 54.5% of non-responders had BRCA1/2 mutations. DNA damage repair pathways were enriched in the responders. Especially, enrichment of DNA mismatch repair and nucleotide excision repair pathways were associated with prolonged progression-free survival (PFS). In arm 1, cell cycle pathway enrichment significantly improved PFS (p=0.006), but PD-L1 expression did not. In arm 2, patients with PD-L1 ≥1% of tumor cells showed significantly better PFS than those with PD-L1 <1% (p=0.027), and the responders had a significantly higher level of myeloid-derived suppressor cell recruiting score than the non-responders (p=0.041).

Circulating exosomal TMEM205 protein expression for early prediction of platinum-resistance in high grade serous ovarian cancer (255)

Circulating exosomal TMEM205 protein expression for early prediction of platinum-resistance in high grade serous ovarian cancer (255)

Homologous recombination deficiency (HRD) score predicts response to platinum-based chemotherapies in Chinese high grade serous ovarian cancer patients (188)

<b>Objectives:</b> Homologous recombination repair deficiency (HRD), as a major feature of high-grade serous ovarian, is associated with the efficacy of PARP inhibitor (PARPi) therapy. Tumors present with HRD are characterized by a defect in DNA double-strand break repair, which is thought to render particularly sensitive to inter-strand cross-linking agents, including platinum analogs. However, whether HRD status confers sensitivity to platinum-based chemotherapies in high-grade serous ovarian patients remains poorly defined. <b>Methods:</b> In this study, we used the machine learning method to build a genomic scar (GS) model to predict HRD, which takes different types of chromosomal copy numbers into consideration for the calculation of genomic instability. GS score ≥50 was defined as HRD positive, accounting for 94.5% of <i>BRCA</i>-deficient events. HRD score, consisting of heterozygous (LOH), telomeric allelic imbalance (TAI), and Large-scale transition (LST), was also determined (HRD-positive [score ≥42] versus HRD-negative [score <42]), and both GS score and HRD score impacts on clinical efficacy were explored. <b>Results:</b> A total of 94 high-grade serous ovarian patients who received first-line platinum-based chemotherapy but no further PARPi maintenance therapy was picked out and analyzed for the predictive value of GS score and HRD score in platinum-based chemotherapy efficacy. GSS-positive was observed in 78/94 (82.9%) patients, and HRD-positive was observed in 74/94 (78.7%) patients, concordance between GS score and HRD score was 91%. Progression-free survival (PFS) (GSS: HR: 0.604; p=0.00082; HRD: HR: 0.64; p=0.00134), overall survival (OS) (GSS: HR: 0.482; p=0.00155; HRD: HR: 0.496; p=0.00231), and platinum-free interval (PFI) (GSS: HR: 0.621; p=0.00204; HRD: HR: 0.664; p=0.00482) were significantly longer in both GS-positive and HRD-positive groups (Figure 1). In <i>BRCA</i>-wildtype patients, survival differences were also seen in GSS-positive versus GSS-negative (p=0.007674) and HRD-positive versus HRD-negative (p=0.017588) populations (Figure 2). Platinum-resistant patients with a PFI of less than six months show a significantly lower GSS-positive rate and HRD-positive rate than platinum-sensitive patients (PFI>6 months) (Figure 2).Fig. 1 <b>Conclusions:</b> HRD status identifies high-grade serous ovarian patients and remains a significant predictor of response to platinum-based chemotherapy. GSS showed high concordance with the HRD score, which implied the high robustness of the GS model.

PLK3 amplification and tumor immune microenvironment of metastatic tumors are linked to adjuvant treatment outcomes in uterine serous cancer.

Uterine serous carcinoma (USC), an aggressive variant of endometrial cancer representing approximately 10% of endometrial cancer diagnoses, accounts for ∼39% of endometrial cancer-related deaths. We examined the role of genomic alterations in advanced-stage USC associated with outcome using paired primary-metastatic tumors (n = 29) treated with adjuvant platinum and taxane chemotherapy. Comparative genomic analysis of paired primary-metastatic patient tumors included whole exome sequencing and targeted gene expression. Both PLK3 amplification and the tumor immune microenvironment (TIME) in metastatic tumors were linked to time-to-recurrence (TTR) risk without any such association observed with primary tumors. TP53 loss was significantly more frequent in metastatic tumors of platinum-resistant versus platinum-sensitive patients and was also associated with increased recurrence and mortality risk. Increased levels of chr1 breakpoints in USC metastatic versus primary tumors co-occur with PLK3 amplification. PLK3 and the TIME are potential targets for improving outcomes in USC adjuvant therapy.

Safety and efficacy of mitoxantrone hydrochloride liposome in patients with platinum-refractory or platinum-resistant ovarian cancer: A prospective, multicenter, open-label, single-arm, phase Ib clinical trial.

5550 Background: Platinum-refractory or platinum-resistant ovarian cancer remains unmet medical need with an unfavorable prognosis. Its treatment options are limited and sequentially with multiple single-agent regimens or bevacizumab plus single-agent regimens are recommended. Mitoxantrone hydrochloride liposome (PLM60) is the first approved mitoxantrone nano-drug, which has shown favorable pharmacokinetic characteristics with long circulation and high cumulation in tumor tissue, thus has a promising anti-tumor activity. This trial aimed to explore the efficacy and safety of PLM60 in patients with platinum-refractory or platinum-resistant ovarian cancer. Methods: In this multi-center, open-label, single arm study, patients with histologically confirmed, epithelial ovarian, fallopian tube, or primary peritoneal carcinoma, either platinum-refractory or platinum-resistant, with at least one measurable lesion were recruited. PLM60 20 mg/m2 was administered on day 1 of each 21-day cycle for up to 8 cycles treatment or until disease progression or intolerable toxicities. The primary endpoint was safety, adverse events were graded according to CTCAE 5.0. Second endpoint included overall response rate (ORR), duration of response (DoR), disease control rate (DCR), progression free survival (PFS) and overall survival (OS) as per RECIST 1.1. Results: 47 eligible patients with a median age of 54 years (range, 35-67) were treated in 7 institutions in China, including 15 platinum-refractory patients and 32 platinum-resistant patients. 32 (68.1%) of 47 patients received at least 3 prior lines of therapy. Treatment related adverse events (TRAEs) of any grade occurred in 45 (95.7%) of 47 patients, in which 31 (66.0%) were ≥ grade 3. The most common ≥ grade 3 TRAEs (incidence ≥10%) were leucopenia (51.1%), neutropenia (40.4%), anemia (19.1%), lymphocytopenia (17.0%) and thrombocytopenia (17.0%). At the cut-off data of October 31 2021, 39 patients were evaluable for response. ORR was 17.9% (7/39, 95% CI:7.5-33.5%, 7 PRs) and DCR was 56.4% (22/39, 95% CI:39.6-72.2%, 15 SDs). Among 21 platinum-resistant patients with ≥3 prior lines, the median DoR was 4.6 month, 2 responders had a DoR of &gt; 6 months. The ORR and DCR of this cohort were 28.6% (6/21, 95% CI: 11.3-52.2%, 6 PRs) and 61.9% (13/21, 95% CI: 38.4-81.9%, 7 SDs), respectively. Median PFS was 3.6 month (95% CI 1.4-4.6), OS data was not mature. Objective response was not observed in platinum-refractory patients. Conclusions: PLM60 had an encouraging efficacy especially in platinum-resistant patients who had received at least 3 prior lines with tolerable safety profiles. Clinical trial information: NCT04718376.

Long-term survival in newly-diagnosed ovarian cancer patients.

e17543 Background: A proportion of women with ovarian cancer, even those with advanced-stage disease, will experience long-term survival post diagnosis. Mixture cure modeling provides insight into factors related to both short-term recurrence and death as well as long-term survival. The goals of this study were to estimate the long-term survival rate, and to evaluate associations between patient characteristics and the long-term survival rate and landmark 5- and 10- year survival, in a sample of newly-diagnosed ovarian cancer patients. Methods: The Tempus EMR dataset contains patients from academic &amp; community oncology centers in the U.S. This study included adult women with a new primary diagnosis of ovarian, fallopian tube, or peritoneal cancer between 2000 and 2020. Women treated with a poly-ADP ribose polymerase inhibitor (PARPi), pembrolizumab, or nivolumab were excluded (n = 947; final sample size = 6,598). Mixture cure models were used to estimate the long-term survival rate (probability of living as long as an age- and gender-matched person without ovarian cancer), overall and stratified by patient demographic &amp; clinical characteristics. Relative importance of variables associated with long-term survival was evaluated using logistic regression models with 5- and 10-year landmark outcomes. Results: Younger age, earlier stage, lower grade, favorable ECOG score, and platinum sensitivity were associated with better overall survival (OS). The long-term survival rate in our model was 25.0% (95% CI: 21.5-28.9). The long-term survival rate was higher for age &lt; 65 vs. age 75+ [29.0% (24.8-33.6) vs. 10.5% (2.9-31.6)], early vs. advanced stage disease [62.0% (41.4-78.9) vs. 17.8% (14.1-22.2)], grade 1-2 vs. 3-4 [31.4% (12.1-60.3) vs. 20.4% (14.6-27.8)], ECOG 0-2 vs. 3-4 [26.1% (21.4-31.3) vs. 2.6% (0.05- 56.5)], and platinum sensitive vs. platinum resistant patients [47.5% (43.1-51.9) vs. 9.4% (7.0-12.5)]. Analyzing 5- and 10-year landmarks [n = 3,944 (59.8%), n = 3,107 (47.1%), respectively] in multivariable logistic regression models, platinum sensitivity had the strongest association, followed by cancer stage. Conclusions: Understanding differences in long-term survival based on patient characteristics is important for clinical decision-making and personalizing treatment. Overall, one quarter of ovarian cancer patients were long-term survivors; long-term survivors were more likely to be younger and have earlier stage disease, low grade disease, better performance status, or sensitivity to platinum-based therapy. These results also provide a baseline to evaluate long-term survival in patients on newer therapies such as PARPi when sufficient follow-up data are available.

A phase Ia/Ib study of CBP-1008, a bispecific ligand drug conjugate, in patients with advanced solid tumors.

3000 Background: Folate receptor α (FRα) and vanilloid subfamily member 6 of transient receptor potential channels (TRPV6) are overexpressed in many solid tumors hence could be promising therapeutic targets. CBP-1008 is a first-in-class bi-specific ligand drug targeting FRα and TRPV6 carrying monomethyl auristatin E (MMAE) as payload. Here we report the first-in-human, multicenter, phase Ia/Ib study designed to explore the safety, pharmacokinetics and efficacy of CBP-1008 in advanced solid tumors. Methods: CBP-1008 was administered by intravenous infusion. Phase Ia study included a dose-escalation period initiated by accelerated titration (0.015, 0.03mg/kg d1,15; q28d) and then switched to 3+3 scheme (0.12, 0.15, 0.17, 0.18mg/kg d1,15; q28d) and a dose expansion period. Phase Ib clinical expansion study included 3 cohorts, platinum-resistant ovarian cancer (OC), metastatic triple negative breast cancer (TNBC) and other solid tumors. The primary objective was to assess the safety and preliminary efficacy. Results: As of January 13, 2022, 106 patients received at least one dose of study drug were enrolled (phase Ia: n = 30; phase Ib: n = 76) and received median 3 prior regimens. Included tumor species were OC (n = 52), TNBC (n = 20), ER+/Her2+ breast cancer (BC) (n = 16), lung cancer (n = 3), pancreatic cancer (n = 2) and others (n = 13). In phase Ia study, DLTs were observed in 3 patients (0.12, 0.15, 0.18mg/kg, n = 1 each), including grade 4 hypophosphatemia, neutropenia, febrile neutropenia, and grade 3 hyperglycemia, alanine aminotransferase (ALT). MTD was not yet reached. Majority of adverse events were mild to moderate. The most common grade 3/4 treatment-emerging adverse events (TEAEs) were neutropenia (37.7%), AST elevation (6.6%), ALT elevation (5.7%), hyperglycemia (2.8%), hypohemoglobinemia (2.8%) and nausea (1.9%). Drug-related death was not observed. A total of 69 patients at dose of 0.15mg/kg or above were evaluable for efficacy assessment. There were 11 patients achieved partial response (PR) (OC n = 8, ER+/Her2+ BC n = 2, TNBC n = 1) and 30 patients achieved stable disease (SD). In 32 advanced platinum-resistant OC patients with FRα and/or TRPV6-positive expression, 6 PR and 16 SD were observed. Moreover, 6/18 PR (33.3%) and 8/18 SD (44.4%) were observed in enriched OC patients who showed high score of FRα/TRPV6 receptor. Conclusions: The preliminary results showed that CBP-1008 has manageable safety profile. Antitumor activity was observed in patients with FRα/TRPV6 receptor expression, especially in platinum-resistant OC cohort with high score of the two receptors. Clinical trial information: NCT04740398.

MiR-320b and miR-320d as Biomarkers to Predict and Participate in the Formation of Platinum Resistance in Ovarian Cancer Patients.

Patients with ovarian cancer who receive platinum-based chemotherapy typically develop platinum resistance, which leads to tumor recurrence and mortality. Therefore, finding the underlying mechanisms and biomarkers is critical. A total of 51 platinum-resistant and 70 platinum-sensitive ovarian cancer patients were enrolled in this study. We examined the GSE131978 dataset in the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus database for differentially expressed long non-coding RNAs and messenger RNAs (mRNAs) between platinum-resistant and platinum-sensitive patients and completed a microRNA chip analysis. After filtering by Pearson correlation analysis, the competitive endogenous RNA (ceRNA) networks were subsequently constructed. Then, the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology enrichment analyses about mRNAs in ceRNA networks were accomplished. More crucially, we demonstrated the differentially expressed microRNAs using quantitative real-time PCR and fluorescence in situ hybridization. The feasibility of microRNAs as biomarkers to predict platinum resistance and tumor recurrence was assessed using the receiver operating characteristic curve and survival analysis. MiR-320b and miR-320d exhibited high area under the curve values of 0.757 and 0.702, respectively. In our study, ceRNA networks including miR-320b and miR-320d probably provided novel insights for platinum resistance in ovarian cancer patients.