bluuebunny/crossref_metadata_2025_split huggingface dataset:
Factors associated with receipt of second-line recurrent or metastatic cervical cancer treatment in the United States: A retrospective administrative claims analysis.
Authors: Sonawane Kalyani , Castellano Tara , Washington Christina , Ayer Turgay , Surinach Andy , Kirshner Carol , Ting Jie , Chhatwal Jagpreet , Moore Kathleen N. 
Published: June 2022

5532 Background: There is limited real-world data on the proportion of eligible patients who received second-line (2L) treatment following progression on first-line (1L) systemic therapy for recurrent or metastatic cervical cancer (r/mCC). In addition, factors impacting selection of 2L are not well-understood. The objective of this study was to determine the prevalence and predictors of subsequent therapy among patients with 1L-treated r/mCC. Methods: We conducted a retrospective analysis of the 2015-2020 MarketScan claims database. Women ≥18 years of age with at least one inpatient claim or two outpatient claims with a diagnosis for malignant neoplasm of the cervix followed by 1L therapy codes were identified. The last recorded date of 1L treatment was assigned as the index date for each woman. Continuous enrollment criteria of minimum 3-month pre-index and 12-month post-index were applied. Women with claims for a new therapy after 60 days but no later than 365 days from the end of 1L treatment were identified as those who continued r/mCC treatment. We used descriptive statistics to examine the baseline characteristics of the final analytical cohort. A multivariable logistic regression model examined the factors associated with treatment discontinuation. All analyses were performed using SAS, Cary, NC. P-value was tested at 0.05. Results: A total of 1,080 patients with 1L-treated r/mCC were identified, of whom 384 met the study criteria. Post-1L treatment, 196 (51.0%) patients received a new therapy within a median duration of 122 days. A total 188 (49.0%) patients did not receive subsequent therapy. The geographic location of patient (identified based on census region as Northeast, Midwest, South, or West) and prior bevacizumab exposure were significant predictors of receiving subsequent therapy. Specifically, patients from the Midwest (odds ratio [OR] = 0.43; 95% CI: 0.23-0.84) and Southern (OR = 0.53; 95% CI: 0.29-0.96) regions had lower likelihood of receiving 2L treatment after 1L, compared to those living in the Northeast. Women without prior bevacizumab treatment were also less likely to receive subsequent therapy (OR = 0.65; 95% CI: 0.42-0.99). Age, type of health plan, and comorbidities were not associated with the likelihood of receiving subsequent treatment. Conclusions: Overall, nearly half of the 1L-treated r/mCC patients did not continue to 2L therapy, with findings showing treatment drop-off differing significantly by geographic region and prior treatment. Additional research and targeted outreach efforts are needed to understand geography-, population-, or practice-specific barriers impacting access to therapy among r/mCC patients.
Immunological correlatives of durable responses and survival benefit for patients with cervical cancer in a trial of combined chemotherapy and immune therapy.
Authors: Honan Amanda M , Castillo Rosa P , Castillo Melissa N , Saigh Shannon J , Cai Xiaodong , Chen Zhibin , Huang Marilyn 
Published: June 2022

5537 Background: Recurrent, metastatic, or persistent cervical cancer is largely an incurable disease due to lack of effective therapies. New treatment strategies are needed to provide long-term anti-tumor responses. We sought to gain insight into the immune pathways contributing to treatment response to immunotherapy. Methods: Fourteen patients with recurrent, persistent, or metastatic cervical cancer were enrolled in a single-arm phase II clinical trial (NCT03367871) with the combination of chemotherapy, bevacizumab and pembrolizumab regardless of tumor PD-L1 status. We designed a 40-color full spectrum flow cytometry panel to profile the protein markers of immune cells in peripheral blood mononuclear cells (PBMCs) at the single cell level to assess immunological correlates in blood with patients' anti-tumor responses. Results: In this trial with a cohort of predominantly Black and Hispanic patients (93%), 50% had durable responses to a combination therapy, and no difference was observed in the combined PD-L1 score (CPS) between responders and non-responders. With 40-color flow cytometry multiplex assays, we detected several differences between the non-responders and responders within the B and T cell populations. Within the B cell population, we observed a significant increase in the HLA+CD200hi B cells, a potentially suppressive cell subset, within the non-responders while among the responders we observed an increase in the number of HLA+CD200lo B cells. This HLA+CD200lo subset was mainly composed of IgD-CD27- memory B cells, a population suggested to have effector function. Moreover, the HLA+CD200hi B cell population contained a higher percentage of PD-L1 expressing cells than the HLA+CD200lo population, further supporting the suggestion that the HLA+CD200hi population may be an immunosuppressive subset. Within the T cell compartment, we observed an increase in the number of CD4+CD69+ T cells, which represent an activated CD4 T cell population, in the responder group compared to the non-responder group. The number of activated CD4+ T cells was observed to correlate (r = 0.5) with the HLA+CD200hi B cell subset. Conclusions: This study identified novel immunological correlates in peripheral blood that were associated with durable antitumor responses and survival benefit for cervical cancer patients. These results suggest a role for T-B collaboration in effective antitumor immunity induced by combination of chemotherapy and immune therapy against cervical cancer. Clinical trial information: NCT03367871.
Detection of early-stage breast cancer in women by plasma lipidomic profiling.
Authors: Kehelpannala Cheka , Pascovici Dana , Li Desmond , Heffernan Kerry , Lamoury Gillian , Batarseh Amani M. 
Published: June 2022

554 Background: Early detection of breast cancer provides the best opportunity for cure. Mammography is the benchmark for screening, but suffers technical, logistic, and diagnostic limitations. An effective and accurate blood test to detect early stages of the disease should increase the screening detection rate for breast cancer. We conducted a series of lipidomic studies in early-stage breast cancer patients and combined the datasets via a machine learning driven analysis to test if plasma lipidomic profiles can detect breast cancer. Methods: Blood samples were collected from women with stage 0-IV breast cancer (4 separate cohorts) with age and BMI matched breast cancer-free controls. Lipids from plasma enriched extracellular vesicles were extracted and analysed by high resolution accurate mass LC-MS. A commercially available software was used to annotate and quantify >400 manually curated lipid species. Following variable selection, a lipid signature was identified capable of distinguishing breast cancer samples from control. Results: Plasma samples from women with breast cancer were distinguished from controls with an average cross-validated accuracy of 0.81, and average AUC of 0.84 across 4 cohorts (Table 1). An optimised cross-cohort subset of early-stage IDC, DCIS and ILC were differentiated from controls with a cross-validated AUC of 0.90, sensitivity of 0.88 and specificity of 0.82 (201 early-stage breast cancer, 199 controls) (Table 1). For this optimised cohort our test achieved a sensitivity of 0.71 at a prescribed specificity of 0.90, or equivalently a sensitivity of 0.89 at a prescribed specificity of 0.80. Conclusions: Our study demonstrates the high sensitivity and specificity of a lipid biomarker signature with potential for early detection of breast cancer. Ongoing studies will prospectively compare the lipid-biomarker based test against mammographic and pathological diagnosis. [Table: see text]
Efficacy and safety of pembrolizumab in combination with anlotinib in the treatment of refractory or recurrent high-grade serous ovarian cancer: A phase 2 nonrandomized clinical trial.
Authors: Jiang Man , Li Tianjun , Wang Guanqun , Zhang Xiaochun 
Published: June 2022

5543 Background: Anlotinib, an oral multi-targeted receptor tyrosine kinase inhibitor (TKI), exhibits good safety and efficacy in many advanced refractory solid tumors. Previous studies have indicated that anlotinib has synergistic effects with anti–programmed death-1 antibodies via modulation of the tumor microenvironment. Our study aims to examine the efficacy and safety of anlotinib-pembrolizumab combination therapy as a treatment for refractory or recurrent High-Grade Serous Ovarian Cancer. Methods: Patients with refractory or recurrent High-Grade Serous Ovarian Cancer received pembrolizumab (200 mg, intravenously over 60 minutes, once every 3 weeks) plus anlotinib (12 mg/day, orally, 2 weeks on and 1 week off, every 3 weeks) therapy or pembrolizumab (200 mg, intravenously over 60 minutes, once every 3 weeks) monotherapy, respectively. Primary end points were progression-free survival (PFS) and overall survival (OS). The relationships of potential biomarkers with clinical efficacy were also evaluated. Results: A total of 33 patients were enrolled, with 15 participants received the anlotinib-pembrolizumab combination regime and 18 with pembrolizumab monotherapy, respectively. Grade 3 treatment-related adverse events (TRAEs) were recorded in 3 participants (20%) receive the combination treatment and 3 (16.7%) in the pembrolizumab monotherpay group, respectively. The PFS were 13.0 months and 8.0 months to anlotinib-pembrolizumab combination regime and pembrolizumab mono-treatment, respectively. And the OS of the two groups were equal as 31 months. In the anlotinib-pembrolizumab combination treatment group, patients with ARID1A mutation indicated a significantly survival benefit compared patient with the wide type (PFS: 12.5 VS. 7.0, P = 0.004 ). Conclusions: The anlotinib-pembrolizumab combination showed promising efficacy and favorable safety as treatment for refractory or recurrent High-Grade Serous Ovarian Cancer. The ARID1A are potential biomarkers for predicting the efficacy of this novel regimen.
OReO/ENGOT Ov-38 trial: Impact of maintenance olaparib rechallenge according to ovarian cancer patient prognosis—An exploratory joint analysis of the BRCA and non-BRCA cohorts.
Authors: Selle Frederic , Asselain Bernard , Montestruc François , Bazan Fernando , Pardo Beatriz , Salutari Vanda , Marmé Frederik , Ør Knudsen Anja , Bologna Alessandra , Madry Radoslaw , Glasspool Rosalind , Henry Stéphanie , Korach Jacob , Lheureux Stephanie , Shaw Bob , Santaballa Ana , Cioffi Raffaella , Canzler Ulrich , Lortholary Alain , Pujade-Lauraine Eric 
Published: June 2022

5558 Background: In the Phase IIIb OReO/ENGOT Ov-38 trial (NCT03106987), maintenance olaparib (O) rechallenge significantly improved progression-free survival (PFS) vs placebo in patients (pts) with platinum-sensitive relapsed ovarian cancer (PSROC) regardless of their BRCA status (Pujade-Lauraine, ESMO 2021). The impact of prognostic factors on this PFS benefit were unknown. Methods: Pts had PSROC, one prior line of PARP inhibitor (PARPi) maintenance and were in response to platinum-based chemotherapy (Cx). Pts were enrolled into two cohorts – BRCA mutated (BRCAm) and non-BRCAm – and randomized to receive maintenance O (300 mg bid) or placebo. Primary endpoint was PFS. Post-hoc individual patient data meta-analysis was used to combine both cohorts using fixed and random effect models, interaction, and stratified tests in the Cox model. Stepwise Cox multivariate model for PFS and logistic regression models were used for late relapse, defined as disease progression occurring >24 weeks after randomization. Randomization stratification criteria and cohort effect were included in all models. Results: This study included 220 pts from the BRCAm (n=112) and non-BRCAm (n=108) cohorts recruited between October 3, 2017 and February 10, 2021. No heterogeneity was detected between cohorts: Cochran’s Q test P=0.53 (fixed and random); interaction test P=0.63. The O effect was consistent, and no significant interactions were observed between subgroups. In the multivariate PFS analyses, the main independent factors for prognosis were CA-125 level, visceral disease (liver, lung, pleura, brain), and treatment arm. These factors were independent predictive factors for late relapse among the 181 evaluable pts with the opportunity of at least 6 months of follow-up (Table). Conclusions: In the OReO/ENGOT Ov-38 trial, CA-125 level and presence of visceral disease at baseline were the best predictors of patient outcome. Maintenance olaparib rechallenge was effective overall regardless of prognostic subgroup. Clinical trial information: NCT03106987. [Table: see text]
Whole transcriptome analysis of tumors with discordant oncotype and MammaPrint results in the FLEX trial.
Authors: Socoteanu Matei P. , O'Shaughnessy Joyce , Hoskins Kent , Brufsky Adam , Graham Cathy Lynne , Vukelja Svetislava J. , Misleh Jamal Ghazi , Tedesco Karen L. , Layeequr Rahman Rakhshanda , Lee June , Berrocal Julian , Sharma Kamal , Begas Albert , Crozier Jennifer , Grady Ian , D'Abreo Nina , Kuilman Midas M. , Nguyen Holly , Blumencranz Lisa Eileen , Audeh M. William ,   FLEX Investigators Group
Published: June 2022

556 Background: Genomic tests, such as MammaPrint (MP) and Oncotype DX Breast Recurrence Score (RS), assess risk of recurrence in patients with early breast cancer (EBC). Using both assays may yield discordant results which leads to uncertainty in treatment recommendations. The assays differ in technology and genes analyzed. RS relies on RT-PCR to query 16 cancer-related genes and 5 controls. MP uses a microarray to query 70 cancer-related genes and 465 normalization controls. Here we explore the genetic basis for discordance by using the FLEX whole transcriptome database to examine differentially expressed genes among patients who received discordant RS and MP results. Methods: Patients with EBC enrolled in the FLEX study (NCT03053193) undergo standard of care MP and BluePrint (BP) tests, and consent to clinically annotated whole transcriptome data collection. MP stratifies risk of recurrence as Low risk and High. RS classifies patients as Low Risk (RS 0-10), Intermediate (RS 11-25), and High Risk (RS 26-100). Due to low representation of BP Basal and BP HER2-type tumors in this data set, we only examined BP Luminal-type tumors (N = 705). We used full genome transcriptomes to compare gene expression among discordant cases. Gene expression data were quantile normalized and analyzed using R package ‘limma’. Genes were considered differentially expressed at a fold change of at least 1.7 and an adjusted p-value of lower than 0.05. To keep the analysis as unbiased as possible, comparisons between RS categories only included tumors within the same MP score range and similarly comparisons of MP categories only contained tumors within the same RS score range. Results: The comparisons between discordant cases, their numbers and the amount of differentially expressed genes (DEGs) are shown below. Sample sizes are shown in parentheses. Of the 49 DEGs found in the RS Intermediate group, several are associated with increased proliferation or increased metastatic potential. SCUBE2 and MMP9 were among the 49 genes and are among the 70-genes assayed by MP. Conclusions: The comparisons highlight the genomic diversity of the RS Intermediate (RS11-25) group, as seen with the high number of DEGs. MP separates cases into more genomically distinct categories, as reflected by fewer DEGs. Clinical trial information: NCT03053193. [Table: see text]
Potential indicators in circulating cell-free DNA for monitoring PARP inhibitor resistance in high-grade serous ovarian cancer.
Authors: Chen Gang , Hu Dianxing , Guo Ensong , Yang Bin , Qin Xu , Fu Yu , Fan Junpeng , Zang Rongyu , Zhou Qi , Zhao Weidong , Sun Chaoyang 
Published: June 2022

5564 Background: Although the clinical application of PARP inhibitors (PARPis) has brought great survival benefits to patients with high-grade serous ovarian carcinoma (HGSOC), its resistance has gradually become a major challenge for clinicians with the widespread use of PARPis. Unfortunately, there are no effective, non-invasive means for monitoring PARPis resistance in time during maintain therapy. Methods: We collected peripheral blood samples (n = 37) from 37 healthy subjects and a series of longitudinal peripheral blood samples (n = 61) of 25 platinum-sensitive HGSOC patients undergoing Olaparib maintenance therapy. The genome of white blood cell and cfDNA in plasma was extracted for germline and somatic mutation detection by Circular Ligation Amplification and sequencing (CLAmp-seq) based on a targeted 42-gene panel, respectively. Before cfDNA mutation analysis, background noise introduced by random NGS error was removed and clonal hematopoietic mutations were filtered. Variant-supporting reads > 2 and without germline mutations were defined as the criterion for somatic mutations. Progression-free survival (PFS) was collected through regular follow-up. We analyzed the dynamic changes of cfDNA mutation profiles, the correlation between cfDNA mutations and the prognosis of patients, and screened specific mutation sites that closely associated with Olaparib resistance. Results: The elevation of maximum mutant allele frequency (Max MAF) in cfDNA during Olaparib maintenance therapy predicted a poor prognosis of patients ( P = 0.0043). Pathogenic germline mutations in BRCA1/2 or RAD51 were strongly associated with longer PFS ( P = 0.0229) and acquired new MRE11A mutations significantly shortened the PFS in patients ( P = 0.0005). Dynamic fluctuations of somatic mutation sites in CHEK2:p.K373E ( P = 0.0091) and CHEK2:p.R406H ( P = 0.0002) can be used to evaluate the therapeutic efficacy of patients. Remarkably, MRE11A:p.K464R may be a vital driving factor of Olaparib resistance and all patients who acquired new MRE11A:p.K464R in post-treatment cfDNA developed resistance to Olaparib and had significantly shorter PFS than those without it ( P = 0.0005). Besides, the combination of CHEK2:p.R406H and acquired new MRE11A:p.K464R in post-treatment improved the predictive efficiency of patients’ prognosis compared with them alone ( P < 0.0001). Conclusions: Olaparib resistance was robustly associated with the mutation load of tumor cells, and analysis of mutation profiles in cfDNA can be accurately monitor the status of Olaparib resistance in patients with HGSOC. Acquired new MRE11A:p.K464R may be a vital driver of Olaparib resistance and is expected to be a target for anti-tumor drug development.
Clinicopathologic and molecular features associated with response to anti-HER2 therapy in endometrial cancer.
Authors: Shen Sherry , Ma Weining , Zhou Qin , Iasonos Alexia , Zhang Yanming , Ross Dara S. , Makker Vicky , Chui Michael Herman 
Published: June 2022

5584 Background: Endometrial cancer (EC) is the most common gynecologic malignancy in the United States. Human epidermal growth factor 2 (HER2) overexpression or gene amplification occurs in 10-60% of EC. The addition of trastuzumab to carboplatin-paclitaxel chemotherapy improves survival in women with HER2-positive serous EC. However, criteria for assessment of HER2 status in EC are not standardized, and furthermore, intratumor heterogeneity may impact therapeutic efficacy. We aimed to identify factors associated with treatment response and survival outcomes in a retrospective cohort of ECs treated with anti-HER2 therapy. Methods: Patients with advanced/recurrent EC treated with trastuzumab or trastuzumab emtansine alone or in combination with chemotherapy from 2013-2021 at our institution were identified. Clinical and treatment information were retrieved from medical records. Central pathology review, HER2 immunohistochemistry (IHC) and fluorescence in-situ hybridization (FISH) were performed. HER2 IHC was scored using modified ASCO/CAP 2007 guidelines for breast cancer. HER2 expression heterogeneity was defined as a 2-degree difference in staining intensity in ≥5% of tumor cells or discordant IHC score on different specimens. HER2 amplification (tumor/normal fold change) was also estimated from targeted next-generation sequencing (NGS). Best response was assessed by RECIST v1.1 as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD), with clinical benefit defined as CR/PR/SD. Results: Among 39 patients included, median age was 69. Histologic subtypes included serous (n = 18, 46%), carcinosarcoma (n = 7, 18%), high-grade EC with ambiguous features (n = 13, 33%) and low-grade endometrioid carcinoma (n = 1, 3%). HER2 IHC results were 0 or 1+ (n = 2, 5%), 2+ (n = 17, 46%), 3+ (n = 18, 49%), with HER2 heterogeneity in 15 cases. By FISH, the HER2/CEP17 ratio was ≥2.0 in 34 (92%) and < 2.0 in 3 (8%); HER2 copy number (CN) was ≥6.0 in 25 (68%) and < 6.0 in 12 (32%). HER2 copy number ≥6.0 was significantly correlated with HER2 amplification by NGS ( p< 0.001). 18 (49%) patients had a co-existing somatic PIK3CA mutation. Amongst parameters assessed, only higher level of HER2 amplification by NGS was significantly associated with clinical benefit ( p= 0.036). None of these features were associated with progression-free survival. Notably, 2 patients with IHC 0/1+ had PD and 1 patient with IHC 3+, but non-amplified by FISH, achieved PR. Conclusions: In our cohort of EC patients treated with anti-HER2 therapy, higher level of HER2 amplification was associated with clinical benefit. Further studies with larger sample sizes are needed to determine whether any additional characteristics are associated with treatment response and survival.