Platinum-based Treatment Research Articles

Overall survival using radium-223 (Ra223) in metastatic castrate-resistant prostate cancer (mCRPC) patients with and without DNA damage repair (DDR) defects.

121 Background: Ra223 is a therapeutic option for mCRPC patients (pts) with symptomatic bone metastases. DDR-defective prostate cancers, specifically those with homologous recombination deficiency (HRD), accumulate irreparable DNA damage following genotoxic treatment. This study assessed presence or absence of DDR alterations in mCRPC pts treated with Ra223, investigating the effect on efficacy and overall survival (OS). Methods: All pts included were treated with Ra223 and had genomic results from a comprehensive next-generation sequencing panel of DDR genes that directly or indirectly led to HRD, from primary or metastatic tissue. Exclusion criteria were prior platinum-based chemotherapy or treatment with poly-ADP ribose polymerase inhibitors (PARPi). Pts were grouped by presence (DDR+) or absence (DDR-) of pathogenic somatic and/or germline aberrations in DDR genes. Primary endpoint was OS, and secondary endpoints were time to alkaline phosphatase (ALP) progression, time to next systemic therapy and biochemical responses; comparing DDR+ and DDR– groups. Results: 93 pts were included in this two-centre retrospective study. Median age was 68 years. 56% received prior chemotherapy. Baseline characteristics where comparable between DDR status subgroups. 28 (30%) pts had mutations in DDR genes, most frequently occurring in ATM (8.6%), BRCA2 (6.5%), and CDK12 (4.3%) genes. DDR+ pts showed prolonged OS (median 36.3 vs. 17.0 months; HR 2.29; 95% CI 1.21-4.32; P= 0.01). Median time to alkaline phosphatase progression was 6.9 months for DDR+ pts and 5.8 months for DDR- pts (HR 1.48; 95% CI 0.87-2.50; P =0.15), and median time to next systemic therapy was 8.9 months for DDR+ pts and 7.3 months for DDR- pts (HR 1.58; 95% CI 0.94-2.64; P =0.08). A higher proportion of DDR+ pts completed Ra223 therapy (79% vs 47%; P= 0.05). No differences in biochemical (prostate-specific antigen, ALP) responses were seen. Conclusions: Pts harboring deleterious DDR aberrations more commonly completed Ra223, and derived a greater OS benefit. These findings need prospective confirmation, but support combination of Ra223 with PARPi or ATR inhibitors in DDR-defective mCRPC pts.

Is there a role for conventional-dose chemotherapy in relapsed germ cell tumors?

404 Background: Patients with germ cell tumors (GCT) that relapse after first-line platinum-based chemotherapy can still be successfully rescued with second-line regimens. High-dose chemotherapy has shown favorable outcomes, and is a preferred option in most instances. Herein, we argued if conventional-dose chemotherapy (CDCT) could also be an alternative in selected patients. Methods: We performed a retrospective observational study, analyzing medical data of 57 GCT male patients treated with salvage chemotherapy after relapse to first-line platinum-based treatment from 2000 to 2015 at the Brazilian National Cancer Institute. Results: The median age was 28 years (range 15 to 49). 26 patients (46%) were Afro-Brazilian, 45 (79%) were non-seminoma, and 53 (93%) had primary testis tumors. 14 patients (25%) had bone, liver or brain metastasis at relapse, and in 35 (61%) the progression-free interval (PFI) after first-line was < 3months. The International Prognostic Factors Study Group (IPFSG) risk classification at relapse for very-low/low, intermediate and high/very-high risk were 8 (14%), 25 (44%), 24 (42%), respectively. After a median follow-up of 8 years, the 2-year PFS was 30% (95% IC, 20 % to 45 %) and the 2-year overall survival (OS) was 34% (95% IC, 23% to 49%). PFI < 3m after first-line (HR 2,38; p<0,005) and AFP > 1000 at relapse (HR 2,38, p<0,023) were negative prognostic factors for PFS and OS. The 2-year PFS and OS for IPFSG risk classification very-low/low, intermediate and high/very-high risk were 75% and 73%, 28% and 32%, 18% and 24%, respectively. Conclusions: In patients with relapsed GCT and very-low/low risk disease by the IPFSG classification, CDCT may be a reasonable option, achieving long-term survival rates. However, CDCT was associated with poor outcome in intermediate and high/very-high risk groups. Further studies should be conducted to assess the best treatment in this subset, since even in second-line, many of patients are still potentially curable.

Response to immunotherapy, platinum-based chemotherapy or their combination in metastatic urothelial carcinoma (MUC) with or without FGFR-3 alterations: Single cohort experience.

560 Background: Fibroblast growth factor receptor-3 (FGFR-3) is a promising target therapy in metastatic urothelial carcinoma. Its role in patient’s clinical outcome and treatment response is unclear. We present data for overall survival (OS) and response to platinum-based treatment, immunotherapy and combination (platinum plus immunotherapy) in MUC. Methods: Enrolled patients were diagnosed with muscle-invasive urothelial cancer (MIUC) between 2/2009-6/2019 at Clinic Hospital of Barcelona, Spain. All have been screened for FGFR-3 alterations using next-generation sequencing or qualitative real-time polymerase chain reaction-based assays in tumour or blood. Demographic, pathology, treatments and treatment response were collected retrospectively. Results: 101 patients with MIUC were screened, 99% had progressed to metastatic stage. At diagnosis 32.67% were metastatic. 77% were man and median age was 68y (38-85y). Median follow-up (FU) since metastatic disease was 16.25 months (1.2-89.72m) with 69.31% of patients had died at cut-off. 32% presented FGFR-3 alteration (fusion =1 and mutation=31). FGFR-3 altered more frequently had papillary histology than FGFR-3 wild type tumours (69 vs 26%, p<0.05). No statistical differences were detected between both groups for gender, age, stage at diagnosis, median FU, primary tumour site (upper vs lower tract) or previous history of non-invasive urothelial carcinoma. 58% patients received 1st line platinum-based chemotherapy, 25% immunotherapy and 8% the combination of both (9% with other therapies). FGFR-3 altered tended to present more benefit (complete, partial response or stable disease) with platinum-based chemotherapy than FGFR-3 wild type (81% vs 62%) but without reach statistical significance. No differences were detected for immunotherapy or combination therapies. Moreover, OS was similar for FGFR-3 altered (median 14.6m) and FGFR-3 wild- type (median 17.1 m) (HR 0.76, p=0.3). Conclusions: In our series, no significant differences related to response to first line therapy or survival was observed.

Abstract P4-14-09: Platinum-based chemotherapy in early-stage triple negative breast cancer: A meta-analysis

Abstract Background: The addition of platinum agents to anthracycline and taxane-based chemotherapy in early-stage triple negative breast cancer (TNBC) patients improves pathological complete response (pCR). Long-term outcomes, such as disease-free survival (DFS) and overall survival (OS), have not been well-established. Methods: A systematic literature review identified studies using platinum-based treatment in TNBC patients in the neoadjuvant or adjuvant setting with reportable long-term outcomes. Hazard ratios (HR) from collected data were pooled in a meta-analysis using generic inverse-variance and random effects modeling. Subgroup analyses were conducted based on treatment setting (neoadjuvant vs. adjuvant) and study design (retrospective vs. randomized controlled trials). When available, odds ratios (OR) for commonly reported safety and tolerability measures such as treatment-related death, treatment discontinuation without progression, dose reduction, neuropathy, renal impairment and hematological toxicity were calculated. Results: Seven studies comprising 1699 patients met the inclusion criteria. Median follow up was 54.5 months. All studies reported DFS and 4 studies reported OS. DFS was significantly better in platinum-based treatment (HR 0.71, 95% confidence interval (CI) 0.53-0.96; P = 0.03). However, OS was no different with a higher number of events in the platinum-based treatment arm (HR 1.17, 95% CI 0.81-1.69; P = 0.42). There was no significant difference between treatment settings (p = 0.74) or between study designs (p = 0.74), although a higher HR for OS was observed for studies in the adjuvant (HR 1.34, 95% CI 0.54-3.35) compared to neoadjuvant setting (HR 1.14, 95% CI 0.76-1.70). The reporting of toxicity was suboptimal with most studies not reporting safety and tolerability metrics clearly. Platinum-based treatment was associated with more neutropenia and thrombocytopenia and treatment discontinuation, however, the magnitude of this effect could not be estimated accurately. Conclusions: Platinum-based treatment improves DFS but has no effect on OS and increases toxicity. The discordant effect of platinum-based treatment on DFS and OS suggest the potential development of platinum resistance and worse outcomes after recurrence. The higher magnitude of discordance in adjuvant compared to neoadjuvant studies suggests an effect of platinum-based therapy on loco-regional control prior to surgery rather than prevention of distant metastatic disease. Platinum-based chemotherapy cannot be recommended in unselected patients with TNBC. Citation Format: Ramy Saleh, Michelle B Nadler, Alexandra Desnoyers, Rouhi Fazelzad, Eitan Amir. Platinum-based chemotherapy in early-stage triple negative breast cancer: A meta-analysis [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-14-09.

BRCA Mutational Status is a Promising Predictive Biomarker for Platinum- based Chemotherapy in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) can be distinguished from other breast malignancies by the lack of expression of estrogen receptors (ER), progesterone receptors (PR) as well as human epidermal growth factor receptor 2 (HER2). TNBC is associated with adverse clinical outcomes and high risk of metastasis. Currently, several clinical and translational reports are focusing on developing targeted therapies for this aggressive cancer. In addition to approved targeted drugs such as poly(ADP-ribose) polymerase inhibitors (PARPi) and immune-checkpoint inhibitors, platinum-based chemotherapy is still a cornerstone therapeutic option in TNBC. However, despite the observed improved outcomes with platinum- based chemotherapy in TNBC, there is still a large proportion of patients who do not respond to this treatment, hence, the need for predictive biomarkers to stratify TNBC patients and therefore, avoiding unwanted toxicities of these agents. With the emergence of genetic testing, several recent studies suggested mutations in breast cancer susceptibility gene (BRCA) in TNBC patients as important predictors of outcomes. These mutations alter the homologous recombination repair (HRR) mechanisms leading to genomic instability. Consequently, sensitivity to platinum-based treatments in this subpopulation of TNBC patients may be explained by cell death enhanced by deoxyribonucleic acid (DNA) damage induced by these potent anticancer drugs. Through this paper, we review several recent studies on this topic to better understand the mechanisms and discuss the potential of BRCA mutational status as a predictive biomarker of platinum-based chemotherapy in TNBC.

An Emerging Regulatory Role for the Tumor Microenvironment in the DNA Damage Response to Double-Strand Breaks.

Radiation, alkylating agents, and platinum-based chemotherapy treatments eliminate cancer cells through the induction of excessive DNA damage. The resultant DNA damage challenges the cancer cell's DNA repair capacity. Among the different types of DNA damage induced in cells, double-strand breaks (DSB) are the most lethal if left unrepaired. Unrepaired DSBs in tumor cells exacerbate existing gene deletions, chromosome losses and rearrangements, and aberrant features that characteristically enable tumor progression, metastasis, and drug resistance. Tumor microenvironmental factors like hypoxia, inflammation, cellular metabolism, and the immune system profoundly influence DSB repair mechanisms. Here, we put into context the role of the microenvironment in governing DSB repair mechanisms.

Impact of ERCC1 gene polymorphisms on response to cisplatin based therapy in oral squamous cell carcinoma (OSCC) patients.

Cisplatin is one of the major drugs that used in the treatment of oral cancer.Excision repair cross-complementation group 1 (ERCC1) is a key DNA repair gene in the nucleotide excision repair pathway which is activated in the repair of intra- and interstrand DNA crosslink caused by platinum-based treatment. The aim of this study was to investigate the association between polymorphisms in ERCC1 (C118T & C8092A) genes and the response to cisplatin-based chemotherapy. ERCC1polymorphisms (C118T & C8092A) were studied using PCR-RFLP method from 150 OSCC patients as cases as well as 150 normal tissues from the same patients were collected as controls for this study. Results: Frequencies of ERCC1 C118C, C118T and T118T genotypes were 60%, 28% and 12% in OSCC patients and 78%, 19% and 3% in the controls, respectively. The C118T & T118T genotype had a 1.69 and 4.97 -folds increased risk for OSCC. Frequencies of ERCC1 C8092C, C8092A and A8092A were 78%, 18% and 4% in the OSCC patients and 89%, 10%, amd 1% in the controls, respectively. The C8092A genotype showed a 1.97-fold increased risk for OSCC. In conclusion, this study highlights the DNA repair gene polymorphisms that might play a role in mediating susceptibility to oral squamous cell carcinoma and cisplatin therapy. Our data suggest that the ERCC1 C118T, T118T and ERCC1 C8092A genotypes are genetic risk factors for Oral squamous cell carcinoma and ERCC1 118 C/T and C8092A polymorphisms have significant influence on clinical outcome.

“Real-World” Peripheral T-Cell Lymphomas Experience in Portugal: Is There Reason for Optimism?

Introduction: Peripheral T-cell lymphomas (PTCL) are a heterogeneous group of mature T-cell neoplasms with aggressive behavior and dismal outcomes. Anthracycline-based chemotherapy is commonly used upfront; hematopoietic stem-cell transplantation (HSCT) is employed as consolidation by some groups. Refractory/relapsed cases (R/R) have a median survival of less than 6 months. Our objective was to analyze the outcomes of all consecutive PTCLs diagnosed and treated in a single center during 16 years according to histological subtype, disease phase (first line and R/R) and treatment strategies. Patients and methods: All adult PTCL patients referred to our center between 2003 and 2019 were included. All cases were locally diagnosed based on the current WHO classification by an expert hemato-pathologist. Initial clinical features, treatment and outcomes were analyzed, as well as salvage strategies. Results: A total of 188 patients were included (118 male, 70 female; median age 62 years). Median OS was 22.7 months, with a median follow up of 54 months. Histological subtypes, initial features, response to treatment and survival are detailed in table 1. Briefly, most cases were diagnosed at advanced stages, with extranodal involvement in 69% and elevated beta-2 microglobulin (B2m) in 77%; half had B symptoms. OS according to different subtypes is shown in figure 1. Of note, anaplastic large cell lymphoma (ALCL)-ALK+ patients had a 5-year OS of 88%. Interestingly, fifteen patients had circulating lymphoma cells (12 PTCL not otherwise specified [NOS], 2 hepatosplenic lymphoma and 1 angioimmunoblastic lymphoma [AITL]), with no impact on outcome. PTCL-NOS was the most prevalent subtype (40%) followed by AITL; unexpectedly, the proportion of PTCL-NOS cases increased while AITL cases decreased after 2008. Seven cases belonging to the recently recognized nodal PTCL with T follicular helper (TFH) phenotype were observed, with baseline characteristics and outcome similar to other PTCLs. IPI score index stratified patients into 4 groups with 24-month OS of 71%, 55%, 42% and 16% for low, int-low, int-high and high risk patients, respectively (P=.049). Only B2m and IPI score maintained independent significance for OS (HR= 3.2 and 1.8, respectively, P<.01) in a multivariate analysis that also included histologic subtype and frontline treatment. Most patients were treated with CHOP (75%), although other regimens were increasingly used in recent years, including CHOEP (9%). Young (<65 years) PTCL-NOS patients had a better outcome when treated with CHOEP compared to CHOP (24-month OS of 100% vs. 37%, P=.04); this difference was not noted in ALCL-ALK- and in AITL cases. Twenty-three patients (21% of transplant-eligible cases) underwent HSCT (18 autologous, 5 allogeneic), mostly (16/23) in first remission. As expected, patients not responding to frontline therapy or relapsing after CR showed a dismal outcome (median OS of 4.1 months from R/R date). Intensive platinum-based salvage treatments (26 cases) led to a median OS from relapse of only 6 months. In contrast, single-drug Gemcitabine at first relapse showed a median OS 17.4 months in 5 elderly patients. Of 76 R/R transplant eligible patients, only 7 underwent HSCT(4 allogeneic, 3 autologous), with a 5-year OS of 86%. Eight patients (4 AITL, 4 ALCL) received Brentuximab-Vedotin (BV) at first or later relapse, with improved outcomes compared to other regimes (24-month OS of 63% vs. 22%, P=.03). Conclusion: Initial features, treatments and outcomes for PTCL have not significantly changed in a 16-year period. Only a minority of cases underwent HSCT or received new agents. Ideal salvage regimens are not defined and, in our experience, single agent Gemcitabine or BV performed better than more aggressive combinations. Although promising new drugs have been recently approved for PTCL, their impact on outcome is still not clear. Recent progresses in molecular characterization of the disease may translate into better outcomes through prospective collaborative efforts in the near future. Disclosures Silva: Gilead Sciences: Consultancy, Other: Travel support, Research Funding; Janssen Cilag: Consultancy, Other: Travel support; Abbvie: Consultancy, Other: Travel support; Celgene: Consultancy; Roche: Consultancy, Other: Travel support.

Inhibition of PI3K/AKT/mTOR and MAPK signaling pathways decreases progranulin expression in ovarian clear cell carcinoma (OCCC) cell line: a potential biomarker for therapy response to signaling pathway inhibitors.

Patients with advanced stage ovarian clear cell carcinoma (OCCC) have a poor prognosis due to resistance to conventional platinum chemotherapy. Recent studies have demonstrated that PI3K/AKT/mTOR and ERK1/2 signaling pathways are involved in this chemoresistance. Progranulin (PGRN) overexpression contributes to cisplatin resistance of epithelial ovarian cancer cell lines. Also, PGRN expression is regulated by AKT/mTOR and ERK1/2 signaling pathways in different cell types. Thus, the present study was designed to identify if PGRN expression is regulated by AKT, mTOR, and ERK1/2 signaling pathways in the OCCC cell line TOV-21G. Cultured TOV-21G cells were incubated with different concentrations of pharmacological cell signaling inhibitors. PGRN expression and phosphorylation of ERK1/2, AKT, and mTOR were assessed by Western blotting. Inhibition of AKT, mTOR, and ERK1/2 significantly reduced PGRN expression. Cell viability was not affected, while cell proliferation significantly decreased with all inhibitors used in this study. These observations demonstrated that inhibition of PI3K/AKT/mTOR and ERK1/2 signaling pathways reduces PGRN expression in TOV-21G cells. Thus, PGRN could be considered as a candidate for explaining the high resistance to platinum-based treatment and a potential biomarker for therapy response to cell signaling inhibitors in patients with OCCC.

Triple negative breast cancer and platinum-based systemic treatment: a meta-analysis and systematic review

BackgroundTriple negative breast cancer (TNBC) represents 15–20% of breast cancers. Due to its heterogeneity and high rates of relapse, there is a need to optimize treatment efficacy. Platinum chemotherapy is still controversial and currently not recommended as first-line treatment for TNBC. Recent studies have shown promising activity of this regimen. This study was done to evaluate the effect of platinum chemotherapy on pathologic complete response (pCR) after neoadjuvant treatment for early TNBC and progression-free survival (PFS) in metastatic TNBC.MethodsA systematic search of Pubmed, Embase, Cochrane, Clinical trials databases and hand search were done to identify randomized controlled trials (RCTs) investigating the use of platinum-based chemotherapy in adults with TNBC. Studies were appraised using the Cochrane Collaboration tool. Using the random effects model, pooled Odds ratios (ORs) with 95% confidence intervals (CI) for pCR, and Hazard Ratios (HRs) with 95%CI for PFS were analyzed.ResultsEleven RCTs were included (N = 2946). Platinum-based chemotherapy showed pCR benefit of 40%vs27% (OR1.75,95% CI 1.46–2.62,p < 0.0001) in the neo-adjuvant setting. Subgroup analysis showed increased pCR rates (44.6%vs27.8%) with platinum plus taxane regimen (p < 0.0001). In metastatic TNBC, three RCTs were analyzed (N = 531), platinum treatment did not show PFS advantage (HR1.16,95%CI 0.90–1.49,p = 0.24).ConclusionPlatinum chemotherapy is associated with increased pCR rates in TNBC, hence it is a viable option for patients in the neoadjuvant setting. Subgroup analysis showed that the combination of platinum and taxanes (Carboplatin/Paclitaxel) improved pCR. However, no PFS advantage was seen in metastatic TNBC. Given the current conflicting data in metastatic TNBC, further exploration with additional powered studies is needed.

Identification of modules and hub genes associated with platinum-based chemotherapy resistance and treatment response in ovarian cancer by weighted gene co-expression network analysis.

High-grade serous ovarian carcinoma (HGSOC) is the most prevalent and malignant ovarian tumor.To identify co-expression modules and hub genes correlated with platinum-based chemotherapy resistant and sensitive HGSOC, we performed weighted gene co-expression network analysis (WGCNA) on microarray data of HGSOC with 12 resistant samples and 16 sensitive samples of GSE51373 dataset.A total of 5122 genes were included in WGCNA, and 16 modules were identified. Module-trait analysis identified that the module salmon (cor = 0.50), magenta (cor = 0.49), and black (cor = 0.45) were discovered associated with chemotherapy resistant, and the significance for these platinum-resistant modules were validated in the GSE63885 dataset. Given that the black module was validated to be the most related one, hub genes of this module, alcohol dehydrogenase 1B, cadherin 11, and vestigial like family member 3were revealed to be expressional related with platinum resistance, and could serve as prognostic markers for ovarian cancer.Our analysis might provide insight for molecular mechanisms of platinum-based chemotherapy resistance and treatment response in ovarian cancer.

Intensive Induction Therapy Compared With CHOP for Hepatosplenic T-cell Lymphoma

IntroductionHepatosplenic T-cell lymphoma (HSTCL) is a rare peripheral T-cell lymphoma that disproportionately affects individuals with a clinical history of immunosuppression. It carries a poor prognosis, and, owing to its rarity, there is no single or well-established treatment. Patients and MethodsWe conducted the largest-to-date individual-level meta-analysis based on literature searches to determine the best induction therapy for HSTCL. We compared response rates and survival among patients who received “non–CHOP-based” induction with regimens containing cytarabine, etoposide, and/or platinum-based treatment to those receiving treatment with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) or CHOP-like therapy. We also review additional regimens including alemtuzumab and pentostatin, and assessed the role of consolidation with hematopoietic stem-cell transplantation (HSCT). ResultsWe identified 166 patients with HSTCL, 118 of whom had sufficient information on induction treatment and survival. Eighty-four patients received non-CHOP-based (N = 34) or CHOP/CHOP-like (N = 50) induction treatment. Non-CHOP-based induction was associated with a complete/partial response rate of 82% compared with 52% (P = .006) with CHOP/CHOP-like and increased median overall survival (P = .00014). Our data showed that maximum survival among patients with HSTCL was achieved with non-CHOP-based induction followed by consolidation with HSCT. ConclusionsNon-CHOP-based induction appears superior to CHOP/CHOP-like induction in both achieving complete/partial response and durable survival. Induction therapy of HSTCL should be intensified with non-CHOP-based regimens and followed by consolidation with HSCT in eligible patients.

Exploring the Clinical Impact of Predictive Biomarkers in Serous Ovarian Carcinomas.

Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy. Although initial response rates to standard platinum-based treatment are at 70-80%, long-term response in advanced EOC disease is rarely achieved with the development of chemoresistance and recurrence, contributing to overall survival rates below 45%. Additional challenges stem from EOC heterogeneity, reflecting at least five histological subtypes, each with different underlying molecular characteristics and clinicopathology that have significant implications in treatment effectiveness and management. Since the last decade, technologies in genomics, proteomics and pathology have been deployed to find reliable clinical markers that can identify patients sensitive to standard chemotherapy treatments and stratify patients for more suitable targeted therapies. These efforts have identified several molecular markers of prognostic value that have been validated as biomarkers, such as BRCA and KRAS mutations, or are currently under investigation in clinical trials, such as CD8 T cells, immune checkpoint inhibitors and progesterone receptor. Recent advancements in biomarker research have also revealed new targets that have expanded treatment options, introducing poly (ADP-ribose) polymerase (PARP) inhibitors, anti-angiogenic agents, inhibitors targeting signaling pathways, and immunotherapy to improve maintenance therapies or enhance first-line therapy. This review presents a summary of current biomarkers, in clinical use or under evaluation, demonstrating a potential to inform on patient selection for treatment efficacy and predict response to EOC therapies, with particular focus on the serous subtypes, including high-grade and low-grade serous carcinomas.

Tracking longitudinal genetic changes of circulating tumor DNA (ctDNA) in advanced Lung adenocarcinoma treated with chemotherapy

IntroductionPemetrexed combined with platinum complexes can be used as first-line treatment for advanced non-squamous non-small cell lung cancer (NSCLC), however, the efficacy and safety is varying from individuals. There is a need to better understand the genetic variations associated with platinum response.Materials and MethodsWe performed next-generation sequencing (NGS) based on BGI Oseq-ctDNA panel to analyze 98 longitudinal plasma samples from 32 lung adenocarcinoma patients during platinum-based chemotherapy, and a bioinformatic pipeline was developed to detect point mutations.ResultsWe found that mutation burden was decreased after chemotherapy, which reflected chemotherapy sensitivity, especially the frequency of C>G and C>A substitutions. Moreover, neoplastic cells carrying a specific set of somatic mutations, such as EGFR(L858R), KRAS (p.G12C) were obviously correlated with platinum treatment. In addition, the MAPK pathway was found to have a pivotal role in NSCLC and platinum based response. Finally, we found that smokers benefit less from platinum-based chemotherapy.ConclusionsCollectively, this work described the dynamic changes of ctDNA mutation status during platinum-based treatment, which may contribute to advanced lung adenocarcinoma patients stratification and precision treatment.

1923P - Prognostic value of CTCs in advanced NSCLC patients treated with platinum-based chemotherapy

BackgroundLung cancer is the leading cause of cancer-related mortality worldwide. At diagnosis, 70% of patients present advanced disease being chemotherapy the standard of care. Although, specific tumour biomarkers that allow a better treatment selection and monitoring is absent at the moment. Enumeration and characterization of circulating tumor cells (CTCs) have the potential to perform as a prognostic biomarker for a precision medicine approach to lung cancer care. The present study was conducted to validate the characterization CTCs from patients with advanced Non-small cell lung cancer (NSCLC) as a valuable tool for anticipating the disease evolution and the therapy response. Methods78 patients with advanced NSCLC were enrolled in the study at HGUV and CHUS. EpCAM positive CTCs from these patients were isolated and analysed using both CellSearch technology and a qRT-PCR based approach at different times: at baseline and before the 2nd and 5th cycle treatment. A panel of genes with a relevant role for NSCLC aggressiveness and the resistance to platinum-based treatments were analysed. ResultsFrom all patients included in the study 46% were positive for CTCs using CellSearch system at baseline, showing only 12% of patients ≥5 CTCs. Additionally, patients with ≥5 CTCs showed poor PFS (4.66 vs 7.12 months, p=0.040) and OS (3,9 vs 13.43 months, p<0.001) rates compared with those patients with <5CTCs. In addition, patients with high CTCs levels during treatment also had a more aggressive disease evolution in terms of PFS and OS (p=0.007 and p=0.001, respectively). From the analyzed gene panel, patients with lower CHOKα expression at baseline had increased PFS (7.03 vs. 3.9 months, p=0.009) and OS (11.4 vs. 4.07 months, p=0.001). Furthermore, we found low CHOK α levels as a powerful marker to discriminate patients with a good response to chemotherapy from those that progressed during treatment administration (14.35 vs 5.07 months, respectively, p=0.011). ConclusionsWe demonstrated that quantification and gene expression characterization of CTCs represents an adequate strategy to identify prognostic biomarkers in NSCLC patients Supported by RTC-2014-1532-1 from MINECO and CB16/12/00350-CB16/12/00328 from CIBERONC. Legal entity responsible for the studyFIHGUV. FundingSupported from RTC-2014-1532-1 (Spanish Ministry of Economy, Industry and Competitiveness) and CB16/12/00350 and CB16/12/00328 from CIBERONC. DisclosureAll authors have declared no conflicts of interest.

171TiP - Phase II study of olaparib in previously treated advanced solid tumours with homologous recombination repair mutation (HRRm) or homologous recombination repair deficiency (HRD): LYNK-002

BackgroundPoly(ADP-ribose) polymerases (PARPs) play a key role in DNA damage repair (DDR). DDR defects due to HRRm (eg BRCA mutation [BRCAm]) or resulting in HRD (eg global loss of heterozygosity) may sensitize tumors to PARP inhibitors, eg olaparib. Olaparib monotherapy has activity in BRCAm ovarian, breast, pancreatic, and prostate cancer, and in prostate cancer with DDR defects beyond BRCAm (TOPARP). Olaparib improved efficacy outcomes vs placebo/chemotherapy as treatment in≤3rd-line (3L) HER2-negative BRCAm breast cancer (OlympiAD) and ≥2L BRCAm ovarian cancer (SOLO3), and maintenance therapy in≥1L ovarian cancer irrespective of BRCAm (SOLO1, Study 19). LYNK-002 (NCT03742895) evaluates HRRm/HRD positivity (HRD+; per Lynparza HRR-HRD assay, Foundation Medicine, Inc., Cambridge, MA) as biomarkers of tumor-agnostic response to olaparib. Trial designThis open-label, phase 2 study will enroll ∼370 patients (pts) ≥18 y with previously treated, histologically/cytologically confirmed HRRm/HRD+(per Lynparza HRR-HRD assay) advanced solid tumors who failed/are intolerant to/ineligible for available SOC and have no PD during prior platinum-based treatment (any number of prior regimens), measurable disease per RECIST v1.1/Prostate Cancer Working Group (PCWG)-modified RECIST v1.1, no CNS metastases, ECOG PS 0–1, and no persistent toxicity from prior therapy. Newly obtained/archival tumor samples will be centrally evaluated using the Lynparza HRR-HRD assay to confirm eligibility. Pts will be grouped into 2 cohorts: 1) solid tumors with BRCAm (n∼84; excluding breast and ovarian), 2) solid tumors with HRRm (BRCA non-mutated; n∼174)/HRD (n∼112) per Lynparza HRR-HRD assay. Pts will receive olaparib 300mg BID until documented PD/unacceptable toxicity/study withdrawal. Tumor imaging will occur at baseline, Q8W for 1 y, and then Q12W per RECIST v1.1 by BICR/PCWG-modified RECIST v1.1 (modified for ≤5 target lesions/organ; 10 total). Primary endpoint is ORR. Key secondary endpoints are DOR, PFS, and OS. AEs will be graded using NCI CTCAE v4.0. Enrollment is ongoing at 51 sites in 15 countries. As of Apr 18, 2019, 23 patients have been enrolled. Clinical trial identificationNCT03742895. Editorial acknowledgementCindy Taylor, PhD, of C4 MedSolutions, LLC (Yardley, PA, USA), a CHC Group company, funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and AstraZeneca. Legal entity responsible for the studyMerck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and AstraZeneca. FundingMerck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and AstraZeneca. DisclosureD. Hyman: Travel / Accommodation / Expenses, Personal fees: Atara Biotherapeutics; Travel / Accommodation / Expenses, Personal fees: Chugai Pharma; Travel / Accommodation / Expenses, Personal fees: CytomX Therapeutics; Travel / Accommodation / Expenses, Personal fees: Boehringer Ingelheim; Travel / Accommodation / Expenses, Personal fees: AstraZeneca; Research grant / Funding (institution), Research funding: Puma Biotechnology; Research grant / Funding (institution), Research funding: AstraZeneca; Research grant / Funding (institution), Research funding: Loxo Oncology. A. Hendifar: Advisory / Consultancy: Novartis; Advisory / Consultancy: Ipsen; Advisory / Consultancy: Perthera. H. Cheol Chung: Research grant / Funding (institution): Lilly; Research grant / Funding (institution): GSK; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Merck-Serono; Research grant / Funding (institution): BMS/Ono; Research grant / Funding (institution): Taiho; Honoraria (institution): Merck-Sorono; Honoraria (institution): Lilly/Foundation Medicine; Advisory / Consultancy: Taiho; Advisory / Consultancy: Celltrion; Advisory / Consultancy: MSD; Advisory / Consultancy: Lilly; Advisory / Consultancy: Quintiles; Advisory / Consultancy: BMS; Advisory / Consultancy: Merck-Serono. M. Maio: Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Merck Sharp & Dohme; Advisory / Consultancy: Incyte; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Glaxo SmithKline; Advisory / Consultancy: Merck Serono; Advisory / Consultancy: Roche. A. Leary: Advisory / Consultancy, Advisory board: Tesaro; Advisory / Consultancy, Advisory board: AstraZeneca; Advisory / Consultancy, Advisory board: Clovis; Advisory / Consultancy, Advisory board: GamaMabs; Advisory / Consultancy, Advisory board: Gridstone; Advisory / Consultancy, Advisory board: Seattle Genetics; Research grant / Funding (institution), Research funding from the lab: Merus; Research grant / Funding (institution), Research funding from the lab: Inivata; Research grant / Funding (institution), Research funding from the lab: GamaMabs. J. Rhee: Full / Part-time employment: AstraZeneca Pharmaceuticals LP. M. Marton: Full / Part-time employment: employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. M. Chen: Full / Part-time employment: employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. S. Krishnan: Full / Part-time employment: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. R. Shapira: Speaker Bureau / Expert testimony, Speaker honoraria: MSD; Speaker Bureau / Expert testimony, Speaker honoraria: BMS; Speaker Bureau / Expert testimony, Speaker honoraria: Roche; Speaker Bureau / Expert testimony, Speaker honoraria: Novartis; Speaker Bureau / Expert testimony, Speaker honoraria: AstraZeneca. All other authors have declared no conflicts of interest.

1140P - A single-arm, open-label, multicenter, phase IIIb clinical trial with nivolumab in subjects with recurrent or metastatic platinum-refractory squamous cell carcinoma of the head and neck

1140P - A single-arm, open-label, multicenter, phase IIIb clinical trial with nivolumab in subjects with recurrent or metastatic platinum-refractory squamous cell carcinoma of the head and neck

ARAP1 is an independent prognostic biomarker in older women with ovarian high-grade serous adenocarcinoma receiving first-line platinum-based antineoplastic therapy

Background: Little is known about the biological factors influencing ovarian cancer (OC) patient outcome, especially in older patients who are often underrepresented in clinical trials. We examined alterations in the transcriptomic profile of primary high-grade serous carcinoma (HGSC) samples from older OC patients (>70 years) receiving first-line platinum-based treatment to identify potential biomarkers for prediction of response to this therapy.Material and methods: Tumor samples from 50 HGSC patients were identified from a retrospective cohort, analyzed by gene expression array. The protein expression of selected biomarkers was examined using immunohistochemistry (IHC).Results: Gene expression profiling revealed 81 genes with significantly altered expression in patients experiencing progression after first-line platinum-based treatment within 6 months versus those who progressed later than 12 months. Expression of ankyrin repeat and PH domain 1 (ARAP1) was significantly lower in the group with early versus late progression (p ≤ .01). Correlation between ARAP1 expression and outcome was further confirmed by IHC staining in the discovery cohort (χ2-test, p = .004) and in independent validation cohorts. The sensitivity of ARAP1 allowed identification of 64.7% of patients with early progression in the discovery population, with a specificity of 78.6% and a negative predictive value of 78.6%. Multivariate regression analysis identified ARAP1 as an independent prognostic factor.Conclusions: This hypothesis generating study suggests that low expression of ARAP1 is an independent prognostic biomarker of shorter RFS in older patients with HGSC receiving first-line platinum-based antineoplastic therapy, which could be used to identify patients who should receive more intensive treatment and closer surveillance.

SIRT2 Prevents Cisplatin-Induced Neuron Injury By Promoting Nucleotide Excision Repair

Radiation and chemotherapy-induced neuropathy are some of the most common causes of dose reduction and discontinuation of cancer treatment, and often cause a major permanent impairment of quality of life in cancer patients. Furthermore, chemotherapy-induced neuropathy acts as a risk factor for development of radiation-induced neuropathy in patients receiving concomitant or adjuvant radiotherapy. The lack of effective treatments for or prevention of this debilitating neuronal toxicity not only compromises optimal treatment, but also leaves cancer survivors with significant disability. Here, we sought to investigate the biological role and underline molecular mechanisms of sirtuin 2 (SIRT2) in cisplatin neurotoxicity. Genetic murine models were utilized to compare the development of cisplatin-induced peripheral neuropathy in transgenic Sirt2 knock-in (Sirt2-KI) mice versus wild-type (WT) mice. The hyperalgesia seen in neuropathy was measured in terms of mechanical and thermal thresholds. Immunostaining and western blot were used to monitor SIRT2 expression in dorsal root ganglion (DRG) sensory neurons. The efficiency of DNA damage repair via nucleotide excision repair (NER) was examined using a dual-luciferase reporter assay, while neuronal cytotoxicity was determined using a trypan blue staining assay. In addition to the genetic approach, the function of SIRT2, an NAD+deacetylase, was pharmacologically modified to validate its role in prevention and treatment of cisplatin-induced neuropathy. High expression of SIRT2 in Sirt2-KI mice produces significant resistance to cisplatin-induced neuropathy compared to WT mice. Cisplatin provoked a nuclear translocation of SIRT2 in DRG sensory neurons, protecting mice against neuropathy. Overexpression of SIRT2 resulted in significantly improved cultured neuronal cell survival through the promotion of nucleotide excision repair of cisplatin-induced DNA crosslinks. In vivo inhibition of NER abolished SIRT2-mediated neuroprotection as evidenced by reductions in mechanical and thermal hyperalgesia thresholds. Finally, administration of nicotinamide riboside activated SIRT2 and prevented cisplatin-induced neuropathy. SIRT2 prevents cisplatin-induced neuron injury by regulating the NER pathway. Identification of this novel function warrants future investigation of nicotinamide riboside-mediated neuroprotection during platinum-based cancer treatment.

Genetic polymorphisms in hMSH2 and hMLH1 genes are associated with prognosis in epithelial ovarian cancer patients

ObjectiveDNA mismatch repair deficiency is not only thought to promote tumorigenesis but is also suggested to be associated with platinum-based chemotherapy treatment. In this study, we investigated the effects of...