bluuebunny/crossref_metadata_2025 huggingface dataset:
Effectiveness and durability of benefit of mTOR inhibitors (mTORi) in a real-world cohort of metastatic prostate cancer (mPCA) patients with PI3K pathway alterations.
Authors: Eule Corbin , Flaig Thomas W. , Wong Katy Ann , Graf Ryon , Lam Elaine T.
Published: June 2022

e17034

Background: Alterations in the PTEN/PI3K/AKT/mTOR pathway are prevalent in prostate cancer, as frequent as 41% by prospective comprehensive genomic profiling (CGP) (PMID: 31218271). The use of mTORi in unselected patients (pts) with metastatic castrate-resistant prostate cancer (mCRPC) has limited efficacy in inducing a PSA response or clinical response. In this retrospective study, we evaluated the clinical effectiveness of mTORi specifically in mPCA pts with tissue assessed PI3K pathway alterations. Methods: This study used the nationwide (US-based) de-identified Flatiron Health-Foundation Medicine mPCA clinico-genomic database (FH-FMI CGDB), originating from approximately 280 US cancer clinics (̃800 sites of care). We evaluated treatment data for pts with mPCA from October 2014 to February 2020 and selected all pts who received mTORi therapy. Unique patients who received mTORi therapy were included if they had PI3K pathway alteration by tissue CGP. Demographic and clinical data were extracted and analyzed for PSA response and time to next treatment (TTNT) on mTORi therapy. Results: In a cohort of 2301 mPCA pts with 7208 evaluable treatment lines in the database, there were 20 pts who underwent mTORi treatment. After excluding 1 pt who had liquid CGP and 2 pts who did not have PI3K pathway alterations, we included 17 mPCA pts with tissue assessed PI3K pathway alterations who received mTORi treatment. Pts had a median age of 72y (IQR 68.0, 76.0) and were heavily pretreated (11 pts, 64.7% on 4th- or later-line therapy). Two pts (11.8%) were treated in first-line metastatic hormone-sensitive prostate cancer (mHSPC) setting and the remaining 15 pts (88.2%) had mCRPC. All 15 mCRPC pts received prior novel hormone therapy (NHT), and 10 pts (58.8%) were previously treated with a taxane. The PI3K pathway alterations included PTENdel (10 pts, 58.8%), AKT1mut (4 pts, 23.5%), PTENmut (2 pts, 11.8%), and dual PTENmut and PIK3CAmut (1 pt, 5.9%). Most (15 pts, 88.2%) were treated with everolimus (EVE) monotherapy; 1 pt received EVE + abiraterone (EVE/ABI); 1 pt had EVE + docetaxel (EVE/DOC). The median pre-treatment PSA (14 pts available) was 148.9 ng/dL (range 1.16, 3430). Among 10 pts with on treatment PSA available, 3 pts had PSA decrease at ̃ week 12 (range -0.1%, -44.0%) and 5 patients had PSA decrease overall. Only 1 pt (with PTEN homozygous deletion) had a PSA response with nadir -95.1% and TTNT of 7.5 months (mo). The median TTNT was 3.62 mo (range 0, 8.52). Interestingly, the ABI/EVE pt had PSA nadir -17.2% and TTNT 2.0 mo; the EVE/DOC pt had nadir of -21.9% and TTNT 7.5 mo. Conclusions: The clinical use of mTORi in patients with prostate cancer is low overall. In this small cohort of mPCA pts with tissue assessed PI3K pathway alterations, mTORi therapy was not effective with few PSA responses and short duration of therapy.
High exosomal PD-L1 expression in relation to lymph node progression in metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone (abi) or enzalutamide (enza).
Authors: Conteduca Vincenza , Del Re Marzia , Scarpi Emanuela , Crucitta Stefania , Gurioli Giorgia , Restante Giuliana , Cucchiara Federico , Lolli Cristian , Brighi Nicole , Schepisi Giuseppe , Casadei Chiara , Ulivi Paola , Beltran Himisha , Danesi Romano , De Giorgi Ugo
Published: June 2022

e17038

Background: Programmed death-ligand 1 (PD-L1) has been recently found in tumor-derived exosomes and associated with progressive disease (PD) ( Poggio, Cell 2019). In localized prostate cancer, PD-L1 tumor expression has been shown to be a biomarker for node-positive patients (pts) ( Petitprez, Eur Urol Focus 2019) but its role in mCRPC is largely unexplored. We aimed to determine the potential of PD-L1 exosomal expression to predict lymph nodal PD in mCRPC receiving abi or enza. Methods: In a biomarker prospective study (REC 2192/2013), exosomes were isolated from plasma samples collected before first-line therapy with abi/enza between December 2014 and October 2018. RNA was extracted for analysis of PD-L1 by digital droplet PCR ( Del Re, Prostate Cancer Prostatic Dis 2021). Results: In our cohort of 55 node-positive mCRPC pts (median age: 76 years, range 47-89), the amount of exosomal PD-L1 expression (pts dichotomized in “high” and “low” as below or above median PD-L1/ACTB ratio = 0.0052) was associated with radiographic response after the first 3 months abi/enza therapy [high PD-L1 vs low PD-L1: 8 (25.8%) vs 0 (0%) PD, 23 (74.2%) vs 18 (75%) stable disease, and 0 vs 6 (25%) partial/complete response] (p = 0.0009). We observed an overall median progression-free survival (PFS) of 14.3 months [95% confidence interval (CI) 8.6-not reached] shorter in high PD-L1 compared to low PD-L1 10.6 (6.5-23.4) vs not reached [hazard ratio (HR) 3.1 (95% CI 1.1-8.5), p = 0.023]. In multivariable analysis including exosomal PD-L1 and androgen receptor (AR) variant 7, AR copy number gain detected in plasma, neutrophil lymphocyte ratio (NLR), lactate dehydrogenase, exosomal PD-L1; AR-V7 and AR gain were independent predictors of nodal PFS (HR 5.8, 95% CI 1.4-24.2, p = 0.01, HR 3.2, 95% CI 1.1-9.2, p = 0.03 and HR 12.9, 95% CI 2.3-73.2, p = 0.004), whereas AR-V7, AR gain, NLR > 3 were independent predictors of OS (HR 4.9, 95% CI 1.8-13.1, p = 0.001, HR 4.4, 95% CI 1.1-17, p = 0.02, and HR 3.2 95% CI 1.1-9.4, p = 0.03, respectively). Moreover, a trend of a worse OS was reported in high PD-L1 compared to low PD-L1 pts (HR 2.6, 95% CI 0.9-7.5, p = 0.07). Conclusions: In mCRPC pts treated with ARSI, exosomal PD-L1 expression may be considered as a predictive biomarker of lymph nodal response, playing a potential role in individualized disease monitoring and treatment combining between ARSI and immunotherapy. Larger evaluation of treatment decisions based on exosomal PD-L1 expression is now required.
Real-world treatment patterns among veterans with nonmetastatic castration-resistant prostate cancer (nmCRPC).
Authors: Halwani Ahmad Sami , Patil Vikas , Morreall Deborah , Li Chunyang , Yong Christina , Appukkutan Sreevalsa , Partridge Jamie , Jhaveri Jay , Rasmussen Kelli Marie
Published: June 2022

e17042

Background: Prostate cancer (PC) is the most common cancer diagnosed among U.S. Veterans. Non-metastatic castration-resistant prostate cancer (nmCRPC) occurs in patients who, despite having received androgen deprivation therapy, experience a rising prostate-specific antigen (PSA) and castrate testosterone levels, with no evidence of metastatic disease on radiographic imaging. Given the recent approval of novel antiandrogens, the treatment landscape for nmCRPC has rapidly evolved. Although there have been numerous clinical trials examining the safety and efficacy of these treatments, few studies have identified real-world treatment patterns among nmCRPC patients. Methods: We conducted a retrospective observational study using patient information obtained from the Veterans Affairs (VA) Clinical Cancer Registry and the VA Corporate Data Warehouse (CDW) to identify patients who were diagnosed with PC at the VA, and later developed nmCRPC, defined as having: (1) evidence of rising PSA, i.e., 2 consecutive increases in PSA concentration over a baseline value; (2) evidence of ongoing androgen deprivation consisting of a serum testosterone level of ≤50 ng/dL (≤2.0 nmol/L); and (3) no evidence of metastatic disease on radiology reports. Treatments were extracted from CDW pharmacy dispensation records and were indexed at nmCRPC diagnosis. Results: A total of 12,549 patients were diagnosed with nmCRPC and treated in the VA from 2006 to 2020; of these, 7,239 (58%) were white, 3,386 (27%) were black, 784 (6%) were Hispanic, and 1,140 (9%) other. Median age at PC diagnosis was 69 years, with most patients residing in the South 4,817 (38%). Of the 7,659 (61%) patients receiving first-line (1L) nmCRPC therapy, 5,508 (72%) received bicalutamide, 621 (8%) ketoconazole, 563 (7%) abiraterone, 492 (6%) enzalutamide, and 242 (3%) flutamide. Although bicalutamide remained the most frequently used 1L nmCRPC therapy regardless of year, the adoption of abiraterone and enzalutamide beginning in 2012 resulted in a decline of 1L bicalutamide from 80% of patients in 2006 to 43% in 2020. Ketoconazole was the second most common 1L nmCRPC therapy and the most common second-line (2L) and third line (3L) nmCRPC therapy. Of patients receiving 1L therapy, 2,244 (31%) received 2L therapy, and of these, 708 (32%) received 3L therapy. Conclusions: To our knowledge, this is the largest real-world cohort of nmCRPC patients treated in a nationwide equal-access health care system. Despite the recent approval of several nmCRPC treatments (apalutamide, darolutamide, enzalutamide) which have demonstrated improved metastasis-free survival and treatment-related quality of life, our real-world findings suggest that older, first-generation antiandrogens remain the predominant 1L treatment for nmCRPC patients.
Unpacking low-value castration practices using behavior specification to guide de-implementation in prostate cancer care.
Authors: Skolarus Ted A. , Forman Jane , Sparks Jordan B. , Metreger Tabitha , Hawley Sarah T. , Caram Megan Veresh , Dossett Lesly Ann , Larkin Angela , Paniagua Cruz Alan , Makarov Danil V. , Leppert John T. , Shelton Jeremy B. , Stensland Kristian D. , Hollenbeck Brent K. , Shahinian Vahakn , Wittmann Daniela A. , Deolankar Varad , Sriram S.
Published: June 2022

e17055

Background: Many men with prostate cancer will be exposed to ADT at some point during cancer survivorship. Unfortunately, ADT overuse in low-value scenarios is not uncommon (e.g., monotherapy in localized prostate cancer, biochemically-recurrent non-metastatic disease) resulting in more harms than benefits. We conducted an innovative survey study to unpack ADT overuse to inform behavior change and de-implementation strategies. Methods: Our survey used the Theoretical Domains Framework (TDF), and the Capability, Opportunity, Motivation – Behavior (COM-B) Model. The survey was fielded to the Society of Government Service Urologists listserv in December 2020. We stratified respondents based on their likelihood of stopping ADT monotherapy in the case of a localized prostate cancer patient presenting to their office (yes/probably yes, probably no/no), and characterized Likert scale responses to 7 COM-B statements. We used multivariable logistic regression to identify associations between stopping ADT and COM-B responses across a dichotomized Likert scale of “strongly disagree/disagree/neutral” and “agree/strongly agree.”. Results: Our survey was completed by 84 respondents (13% response rate), with 27% indicating ‘probably no’/‘no’ to stopping low-value ADT monotherapy in the case of a localized prostate cancer patient presenting to their office. Our multivariable model identified 2 COM-B statements significantly associated with lower likelihood of stopping low-value ADT. Conclusions: Using an innovative, behavioral theory-informed survey, we identified that providers less likely to stop low-value ADT had greater concern about patient worry and were more interested in providing ADT recommendations consistent with peers, informing de-implementation strategy selection. Clinical trial information: MCT03579680. [Table: see text]
HPV E7 oncogene expression impairs Rb function and confers CDK4/6 inhibitor resistance in cervical cancer.
Authors: Xiong Yudi , Wang Yuan , Ou Haibin , Zhou Yunfeng
Published: June 2022

e17504

Background: Malignant tumor proliferation is one of the important factors for poor prognosis. CDK4/6 inhibitors can delay tumor progression by inhibiting cell cycle and inducing apoptosis, so they are potentially effective broad-spectrum anti-tumor targeted drugs, but drug resistance limits their clinical applications. Our previous research found that the CDK4/6 inhibitor LEE011 has anti-tumor effects on cervical cancer C33A cells, but no anti-tumor activity against HeLa. The mechanism is not very clear, we speculate that it is related to HPV infection. In this research, our aim is to clarify the correlation between HPV and tumor drug sensitivity and explore the possible mechanisms. Methods: Two HPV positive human cervical cancer cell lines, SiHa and Caski were chosen to verify the sensitivity to LEE011 by cell morphology, cell cycle and apoptosis. The antitumor activity of CDK4/6 inhibitor LEE011 by E7 knockin C33A and E7 knock-down HeLa cell lines was assessed by in vitro clonogenic assay, flow cytometry, and target inhibition verified by immunoblotting. Effects of LEE011 and E7 knock-down combination in vivo were studied by xenograft tumor regrowth delay, and tissue section immunohistochemistry. Results: SiHa and Caski were insensitive to LEE011 antitumor activity. Enhancement of drugsensitivity was lost in cell lines with HPV positive. After down-regulation of E7, LEE011 treatment increased the inhibition cell proliferation and pro-apoptosis of HeLa. Mechanistically, the loss of E7-induced Rb inactivation and LEE011 inhibited Rb phosphorylation, leading to cell-cycle arrest. In vivo, LEE011 inhibited tumor regrowth, with sustained inhibition of cyclin D-CDK4/6-Rb-E2F1 activity in E7 knock-down HeLa. However, up-regulation of E7 can reduce the ability of LEE011 to inhibit cell proliferation and pro-apoptosis of C33A. In summary, our study signifies inhibiting the CDK4/6 pathway by LEE011 in combination with down-regulation of E7 as a promising therapeutic strategy to treat cervical cancer. Conclusions: These findings suggested that HPV can affect Rb function by expressing oncoprotein E7 leading to resistance to targeted drug therapy, which means that HPV may be a biomarkers of drug therapy efficacy.
Prognostic analysis of doublet agent concurrent chemoradiotherapy in locally advanced cervical cancer: A propensity score analysis.
Authors: Wang Jingjing , Shan Minjie , Feng Yeqian , Wang Jinlei , Wu Lin , Liu Xianling , Zou Wen
Published: June 2022

e17514

Background: Platinum-based concurrent chemoradiotherapy (CCRT) is the current standard treatment for patients with locally advanced cervical cancer (LACC). Previous reports showed that doublet agent CCRT can provide better prognosis than single agent CCRT. However, several controversies surround the doublet agent regimen. This retrospective study compared the efficacy and safety of cisplatin and nedaplatin in doublet agent CCRT by propensity score (PS) matching. Methods: Information on patients with stage IIB-IIIC2 cervical cancer who received doublet agent CCRT from January 2015 to December 2020 were collected. The chemotherapy regimen was docetaxel (75mg/m2) combined with carboplatin (AUC = 4-5) / cisplatin (50–70mg/m2) / nedaplatin (50-75mg/m2) once every 3 weeks. All patients underwent external-beam radiotherapy with intensity-modulated radiotherapy at a dose of 45–50 Gy/25fx to the pelvis with or without involving the para-aortic region and 60 Gy/25fx to gross disease in the lymph nodes, and 2-dimensional intracavitary brachytherapy with dose of 30 Gy/5fx to point A. Patients were classified into the cisplatin group and nedaplatin group. Treatment outcomes were compared between the two groups after 1:1 ratio PS matching adjusted for age, BMI, FIGO stage, pathology, tumor diameter, differentiation, complication, and cycles of chemotherapy. Categorical variables were compared using the χ2 test or Fisher's exact test. Clinical outcomes were analyzed using the Kaplan–Meier method with log-rank test. Results: There are 295 patients enrolled, median age 55 years (32–73 years). The median follow-up time was 38 months (5–77 months). The median number of chemotherapy cycle is 4 (1–6 cycles). The 5-year overall survival (OS) and progression-free survival (PFS) rates were 82.5% and 80.4%, respectively. After PS matching, there were 83 patients each in the nedaplatin group and cisplatin group. All background factors between the two groups were well-balanced. There was no significant difference between the cisplatin and nedaplatin groups in terms of objective response rate (97.6% and 98.8%, p = 0.212), 5-year OS rate (96.5 vs.69.8, p = 0.066), and PFS rate (90.8 vs.72.4, p = 0.166). Also, there was no significant difference between the cisplatin and nedaplatin groups in terms of hematological toxicity (36.1% vs. 28.9%, p = 0.408), nausea and vomiting (19.3% vs. 20.4, p = 0.874), radiation proctitis (25.3% vs. 14.5%, p = 0.535), and radiation proctitis (12% vs.9.6%, p = 0.212). Conclusions: Doublet agent concurrent chemoradiotherapy is feasible, safe, and shows high efficacy in LACC patients. Here, the cisplatin group and nedaplatin group have similar prognosis and side effects, suggesting that nedaplatin and cisplatin are equivalent and can be replaced with each other for concurrent doublet agent CCRT.
Genomic characterization of primary cervical cancer and lung metastasis.
Authors: Tang Huarong , Yin Zhuomin , Lou Hanmei , Yu Yangyang , Song Yunjie , Xiao Mingzhe , Qi Chuang
Published: June 2022

e17527

Background: Cervical cancer ranks fourth in incidence and mortality among female tumors in the world. Lung metastases are the most common metastatic foci of cervical cancer, which were associated with poor prognosis. Exploring the different genomic landscape between primary tumor and lung metastasis would help to understand the mechanism of cervical cancer lung metastasis. Methods: A total of 52 Chinese cervical cancer patients with lung metastasis were enrolled between 2016 and 2020. Among whom 37 patients had paired samples (primary tumor and lung metastasis), 6 had only primary tumor samples, and 9 had only lung metastasis samples. Lung metastasis samples were confirmed as cervical cancer metastasis via immunohistochemistry. All the formalin-fixed paraffin-embedded (FFPE) tumor samples and matched peripheral blood were collected and underwent whole-exome sequencing (WES). The Illumina NovaSeq 6000 (Illumina, San Diego, CA, USA) sequencing platform was used to perform 150-nt paired-end multiplex sequencing of DNA samples. The average coverage depth was 340× in FFPE samples and 170× in white blood cell controls. Normally distributed data were compared using the t-test and data with abnormal distribution were compared using the Mann–Whitney U test. Results: There were 4,212 and 6,341 somatic mutations in primary tumor and lung metastasis, respectively. The consistencies for SNVs/indels and CNVs were 41.22% (2.86%–76.11%) and 13.65% (3.69%–76.11%). The most frequently altered genes in primary tumor and lung metastasis were PIK3CA (23.26% vs. 36.96%; p = 0.26), TTN (23.26% vs. 39.96%; p = 0.18), MUC4 (16.28% vs. 39.96%; p = 0.03), ARMCX4 (25.58% vs. 26.09%; p = 1), and MUC16 (18.60% vs. 26.09%; p = 0.45). MUC4 had a significantly higher mutation frequency in lung metastasis than in primary tumor. To explore the mutation characteristics, co-mutations in primary tumor and lung metastasis were analyzed. EP300/MUC16 co-mutation (p < 0.01) was identified in primary tumor. KMT2D/MUC16 co-mutation (p < 0.01) was identified in lung metastasis. Among the paired samples, the Cosmic Signature analysis had shown that Signature 2, which was attributed to activity of the AID/APOBEC family of cytidine deaminases, was higher in lung metastasis than primary tumor (p = 0.042). Meanwhile, the amplification of 17q12 was more frequently observed in lung metastasis in contrast to primary tumor (p = 0.035). Furthermore, the GO/KEGG analysis had revealed that the mutant genes which only observed in lung metastasis were significantly enriched in ATPase activity and inositol phosphate metabolism. Conclusions: In summary, comprehensive genomic profiling of primary cervical cancer and lung metastasis can be of help to identify metastasis-specific features and understand the mechanism of cervical cancer lung metastasis.
Clinicopathological analysis of 285 cases of elderly patients with epithelial ovarian cancer.
Authors: Duan Yuanqiong , Zhang Mengpei , Yin Rutie , Han Jinbiao
Published: June 2022

e17539

Background: Elderly patients with epithelial ovarian cancer often cannot receive standard treatment, and their survival time decreases with age, seriously threatening their lives. Elderly patients with epithelial ovarian cancer tend to have many complications and poor tolerance to surgery and chemotherapy, resulting in poor overall prognosis. Methods: The clinicopathological data of EOC patients aged ≥ 60 years old who were diagnosed and treated in our hospital from January 2013 to January 2018, with completed clinical and pathological data were collected for analysis and followed up through outpatient review, telephone, WeChat, QQ group, etc. to analyze the diagnosis and treatment plan and main prognostic factors. The deadline for follow-up was March 1, 2020. Results: Comparison of recurrence and the overall survival in different groups, the results respectively showed that the difference had statistically significant (χ2 = 255.027, p < 0.001) 、(χ2 = 314.443, p < 0.001). Analysis of the factors affecting the recurrence and death of patients showed that the results of single factor analysis showed age, BMI, Combined with cardiovascular and cerebrovascular diseases, pre-treatment CA125 value, thrombus score, FIGO staging, pathological type, residual lesion size are the influencing factors of recurrence. Further multivariate analysis showed that combined cardiovascular and cerebrovascular diseases, pre-treatment CA125 value, FIGO stage, residual lesion size is an independent factor affecting relapse. The median survival time of relapse-free in the neoadjuvant chemotherapy group was 39.00 (30.67̃44.95) months; the median survival time of relapse-free in the directing surgery group was 36.00 (29.47̃42.53) months, statistical comparison showed no significant difference (χ2 = 2.426, p = 0.119). The total median survival time of the neoadjuvant chemotherapy group was 49.57 months; for the directing surgery group, the total median survival time was 47.07 months, and the statistical comparison showed no significant difference (χ2 = 0.166, p = 0.684). Conclusions: For the epithelial ovarian cancer in elderly patients the results showed that the standard treatment group was better than the non-standard treatment group, chemotherapy-only group, surgery-only group, and untreated group. Comparing with primary tumor debulking surgery (PDS),neoadjuvant chemotherapy-Interval debulking surgery (NACT-IDS) group could improve the intraoperative situation，reduce the amount of intraoperative bleeding, shorten the operation time, reduce the wound healing rate and the incidence of surgical complications, but it had no effect on the tumor removal rate, PFS and OS.
Connective tissue growth factor expression maintains the epithelial phenotype of ovarian cancer in early epithelial to mesenchymal transition.
Authors: Ramos Harry , Galoforo Sandra , You Yuan , Winer Ira Seth , Mor Gil , Alvero Ayesha , Gogoi Radhika
Published: June 2022

e17544

Background: Epithelial to Mesenchymal Transition (EMT) is essential to the process of metastasis in ovarian cancer (OC). Early expressions of proteins and pathways during EMT essential for understanding mechanism and potential therapeutic targets in OC. The aim of our study is to evaluate the role and mechanism of Connective Tissue Growth Factor (CTGF) in OC. Methods: R182 and R2615 are well-characterized epithelial OC cell lines. CTGF expression +/- Transforming Growth Factor -b (TGF-b) was determined via Western blot. R182 and R2615 CTGF knock out (KO) were derived utilizing a Cas9/CRISPR-Cas9 lentivirus plasmid vector and confirmed via PCR. Anoikis resistance and invasion assays were performed to characterize phenotypes of R182 and R2615 wild type (WT) and KO cells. For anoikis resistance, cells were plated in triplicate in an ultra-low adhesive (ULA) cell plate Promega CellTiter assay which measured cell viability quantified by absorbance at 450 nm at 0, 24, 48, and 72 hrs. For invasion assay, 3000 cells were suspended in 50% reduced growth factor Basement Membrane Extract. Human recombinant CTGF was added at 50 and 100 ng/mL concentrations. Cells were plated in tissue culture plate and placed in Cytation 5/Biospa and imaged at 4-hour interval for up to 6 days. Western blot evaluated expression of mesenchymal markers. Chemo-sensitivity was measured by half maximal inhibitory concentration (IC50) for Cisplatin between the WT and KO cells. RNA sequence analysis was performed for both R182 WT and KO cells and analyzed utilizing iPathway Guide. Results: CTGF is constitutively expressed in R182 and R2615 OC cells line as early as 6 hrs of culture and after 30 min of TGF-b treatment. Loss of CTGF promoted anoikis resistance. At 72 hr, R182 CTGF WT cells displayed 75% viability while R182 KO only have 10% viability. Further, we demonstrated that loss of CTGF increases invasion. Administration of exogeneous CTGF in KO cells suppresses invasion in a dose dependent manner demonstrated. Along with epithelial markers CK-18 and beta-catenin, the KO cells expressed the mesenchymal marker SNAIL. No difference in chemo-sensitivity to Cisplatin was seen between WT and KO in either cell line. RNA sequence analysis identified 1106 out of 14054 differentially expressed genes between the WT and KO cells. PI3KAkt, cell adhesion molecules and ECM receptor interaction were pathway that were most significantly regulated. Conclusions: CTGF expression maintains the epithelial phenotype of OC cells during EMT. Loss of CTGF allows anoikis resistance and invasion which are vital characteristics in the metastatic nature of OC. We suggest that loss of CTGF expression in OC cells could be a biomarker for more aggressive OC.
The value of a negative genetic result when triaging an adnexal mass.
Authors: Asulin Yitzhack , Dunton Charles J. , Haverbusch Victoria , Done James , Bullock Rowan , Ure Daniel , Debboli-Cop Marisa , Greenwood Jessica , Northrop Lesley
Published: June 2022

e17553

Background: The baseline risk for ovarian cancer in the general population is 1.2%1. However, women with germline variants in ovarian cancer-associated genes can have a much higher baseline risk for ovarian cancer, up to 54%2. Such a difference in baseline risk presents a triaging challenging for physicians when evaluating adnexal masses. It is well known that identifying pathogenic variants in hereditary cancer syndrome genes often leads to changes in care. Less is known about the utility of negative genetic testing results, specifically in the context of adnexal mass assessment. Methods: An observational, prospective study was designed to examine the clinical impact of multivariate index assay (MIA) and germline genetic testing in patients with a known adnexal mass planned for surgery. Inclusion criteria were: female subjects aged 18-65, presence of an adnexal mass, receiving MIA, and consideration of germline genetic testing. Enrolled physicians selected patients under their care that met inclusion criteria and filled out a short survey describing how the results of each test impacted clinical management. This study was considered IRB-exempt as all information was de-identified. Results: 23 patients were enrolled that received both MIA and germline genetic testing. 21 cases had negative genetic testing and two had positive genetic testing. Both patients with positive genetic testing had low-risk MIA results. Both had risk-reduction surgery with benign findings. Three patients had high-risk MIA results with negative genetic results. All patients had a serial monitoring plan of care. Nine patients with low-risk MIA results and negative genetic results proceeded to surgery. No malignancies were reported. Of the 21 patients with negative genetic results, 17 were not immediately planned for surgery. Conclusions: While not reaching statistical significance, there is a strong association between a negative genetic result and non-immediate surgical intervention. While positive genetic testing results may lead to more aggressive, prophylactic surgical management, negative genetic results may support an expectant management approach. Effectively ruling out the most common hereditary cancer predisposition syndromes may provide physicians with useful insight into a patient's baseline risk. [Table: see text]
The correlation of homologous recombination deficiency status with and Olaparib efficacy in Chinese ovarian cancer patients.
Authors: Peng Yongpai , Xie Qingsheng , Xu Guocai , Zhang Bingzhong
Published: June 2022

e17556

Background: Homologous recombination and DNA repair are important for genome maintenance. Genetic variations in essential homologous recombination genes, including BRCA1 and BRCA2, results in homologous recombination deficiency (HRD) can be a target for therapeutic strategies of ovarian cancer (OC) including poly (ADP-ribose) polymerase inhibitors (PARPi). Here, we proposed an emerging method based on ADx-GSS algorithm to predict HRD status and explore the correlation between HRD status and first-line maintenance therapy of Olaparib in OC patients or Olaparib maintenance therapy in platinum-sensitive relapsed (PSR) OC patients. Methods: Formalin-fixed, paraffin-embedded tissues of 38 consented OC patients between January 2016 and March 2021 were retrospectively collected. Genomic DNA was extracted and subjected to AmoyDx HRD Focus Panel (Amoy Diagnostics Co., Ltd) covering HRD score and BRCA1/2. The HRD score was calculated as the weighted sum of different types of copy number variation (CNV) trained through BRCAness events. Tumors were defined as genomic instability with an HRD score of ≥ 50 (i.e. HRD-positive). The primary endpoint was progression-free survival (PFS), and was assessed by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). Results: Histology of collected samples were mostly serous OC (84.2%). All samples were at stage III-IV (80.84%). The fractions of HRD-positive (n = 26) and HRD-negative (n = 12) group were 68.4%, and 31.6%, respectively. 65.8% (n = 25) of the OC patients had received Olaparib first-line maintenance therapy and 34.2% (n = 13) of PSR patients had received Olaparib maintenance therapy. In December 2021, 34.2% (n = 13) of the whole patients had relapsed. A significant PFS benefit was seen in HRD-positive patients compared with HRD-negative ones (P = 0.0017) or in the first-line maintenance treated population (P = 0.0068). In patients with HRD-positive tumors that did not have BRCA mutations, the PFS benefit was improved versus HRD-negative patients without BRCA mutations. However, Olaparib showed no efficacy difference between HRD-positive and HRD-negative tumor in PSR OC patients. Conclusions: HRD status tested by AmoyDx HRD Focus Panel is significantly correlated with the efficacy of Olaparib, and our results demonstrated a significant PFS benefit for HRD-positive patients compared with HRD-negative patients, especially for patients received Olaparib first-line maintenance therapy.
Relationship between BRCA mutation status and adverse effects of PARP inhibitors.
Authors: Gao Yuewen , Li Hongqi , Li Changzhong , Wang Fei , Li Chunyan , Zou Yonghui , Zhang Tiange , Gai Minxue , Zhang Hongyang
Published: June 2022

e17566

Background: PARP inhibitors exert their anti-tumor effects by targeting BRCA-deficient cancer cells through a mechanism of synthetic lethality and PARP trapping. However, as a drug in the systemic route of administration, it has the same killing effect on BRCA-deficient normal cells in vivo, especially those with faster proliferation, such as those in the bone marrow hematopoietic cells and cells in the digestive tract. We, therefore, hypothesize that BRCA mutant patients are more likely than BRCA wild-type patients to have severe adverse effects that result in dose reduction, interruption, or discontinuation of the drug, thus affecting the patient's prognosis. Methods: Information was retrospectively collected on 46 patients diagnosed with ovarian cancer who had been treated with PARP inhibitors between August 2018 and October 2021. The patients were divided into BRCA mutation group (n = 24), BRCA wild-type group (n = 16), and BRCA unknown group (n = 6) according to the genetic test results. Results: The most common adverse effects in all three groups were gastrointestinal reactions, mostly grade 1 and 2. Hematologic reactions were the next common adverse effects, the most common of which was anemia. No extremely serious adverse effects such as myelodysplastic syndrome occurred in our patients. The most serious adverse effects in our patients were grade 3, 75% of which were anemia. In BRCA mutant patients, the incidence of gastrointestinal reactions and hematologic effects was 75% and 50%, respectively, while these two rates were 50% and 25% in BRCA wild-type patients. The incidence of adverse effects was significantly higher in BRCA mutant patients than in BRCA wild-type patients. The incidence of grade 3 adverse events was 37.5% in BRCA mutant patients and 12.5% in BRCA wild-type patients. The incidence of grade 3 adverse events was significantly higher in BRCA mutant patients than in BRCA wild-type patients. Overall, adverse events were higher and more severe in the BRCA mutant than in the BRCA wild type (P＜0.05). Conclusions: Patients with BRCA mutations are more likely than patients with BRCA wild-type to have serious adverse effects that result in dose reduction, interruption, or discontinuation of the drug. Therefore, we should pay more attention to the monitoring of BRCA mutant patients and take more measures to prevent or mitigate their adverse effects, so that they can always take PARP inhibitors according to the recommended dose as much as possible, which may lead to a better prognosis for more patients.[Table: see text]
Cancer stem cell assay for identification of effective treatments for platinum-resistant recurrent ovarian cancer.
Authors: Claudio Pier Paolo , Howard Candace M. , Valluri Anisha P , Lawrence Logan , Bush Stephen , Bou Zgheib Nadim , Lirette Seth T. , Denning Krista L , Valluri Jagan
Published: June 2022

e17584

Background: Disease recurrence and progression of ovarian cancer is a common event, which is accompanied by the development of platinum-resistant or refractory disease. The presence of chemo-resistant cancer stem cells (CSCs) contributes to tumor propagation, maintenance, and treatment resistance of this difficult to treat disease. The choice of appropriate chemotherapy is critical to the management of advanced epithelial ovarian cancer. We developed a CSCs assay (ChemoID) that identifies the most effective chemotherapy for individual patients from a panel of FDA-approved chemotherapies. Methods: Ascites or interventional radiology biopsies were collected under physician order from 85 consecutive patients affected by 3rd relapsed ovarian cancer. Test results from the assay were used to treat patients with the highest cell kill drugs, taking into consideration their health status and using dose reductions, if needed. Our study assessed the correlation of the ChemoID test results to treatment outcomes independently of other biomarkers. A retrospective chart analysis and review of CT and PET scans were performed to determine patients’ outcomes for tumor response, progression-free survival (PFS), and overall survival (OS). Results: We observed that recurrent ovarian cancer patients treated with high-cell kill chemotherapy agents guided by the ChemoID drug response assay had an improvement in their median PFS and OS when compared to historical median PFS and OS and/or when compared to patients who could not receive high cell kill chemotherapies (PFS low cell kill 3.5 months vs. high cell kill 12.0 months; OS low cell kill 6.0 months vs. high cell kill 15.0 months). Conclusions: The current evidence strongly suggests that the ChemoID assay predicted the effectiveness of specific therapies, as well as improved outcomes for patients treated with assay-sensitive therapies.
Therapeutic implications of mutations in high grade serous ovarian carcinoma when evaluated by race.
Authors: Garg Ruchi , Schink Julian C. , Buttin Barbara , Elvin Julia Andrea , Godbee Natalie , Moran Amber , Doctor Vicki , Tan Bradford A. , Sequeria Judy , Farley John H. , Markman Maurie
Published: June 2022

e17590

Background: Individualizing oncologic treatment by using precision oncology techniques that allow for detection of genomic alterations (GA) has become critical. We present an analysis of comprehensive genomic profiling (CGP) of a large series of high grade serous ovarian carcinoma (HGSOC) patients assayed in a nationwide cancer network. Racial disparities in genomic alterations may assist in better targeting therapies, predicting drug resistance, and potential germline mutations. Methods: 312 patients with HGSOC underwent CGP with hybrid capture on tumor tissue for treatment decision-making between 01-2013 to 06-2021. Clinically relevant genomic alterations (CRGA) were reported as targetable marker. Statistical analysis performed with Fisher Exact test. Results: Median age was 55 years (range, 23-81), 71.2% were White, 16.4% were Black, 3.9% were Hispanic, and 1.3% were Asian. GA were identified in 98.7% (308/312) of these patients. TP53 mutations were present in 286 of 312 patients (91.7%) and interestingly, while not statistically significant (p = 0.06) was present in 98% of black women and 89.2% of white women. BRCA1 mutation was present in 14.4% of white women and in 17.6% of black women. BRCA2 mutation was present in 9.9% of white women and 9.8% of black women. Several interesting mutations were identified, see table below. Conclusions: In this 312-patient series of women with HGSOC, we note several prominent mutations in the tumors. While not statistically significant, there is a trend of larger number of poorer prognostic mutations in black women including p53, KRAS and CCNE1. Some studies have found the amplification of CCNE1 and mutation of homologous recombination repair genes to be mutually exclusive in HGSOC which may compel us to find other therapeutic interventions than the PARP inhibitors for these patients.[Table: see text]
Efficacy and safety of apatinib in the treatment of advanced platinum-resistant recurrent epithelial ovarian cancer: A retrospective study.
Authors: Pan Zhongmian , Luo Zhongbin , He Hongying , Chen Yujie , Zhao Bingbing , Yang Zhijun , Li Li
Published: June 2022

e17594

Background: Apatinib is an oral anti-angiogenic drug that mainly targets vascular endothelial growth factor receptor 2 (VEGFR-2) and is widely used in a variety of solid tumours. The purpose of this study is to evaluate the clinical efficacy and safety of apatinib in patients with advanced platinum-resistant relapsed epithelial ovarian cancer (EOC). Methods: This study retrospectively analyzed the clinical data of patients with stage IIIC-IV platinum-resistant relapsed EOC between January 2014 and May 2018. The objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) were reviewed and evaluated. The propensity score matching (PSM) method was used to determine the data included in this study of the final case. Results: This study included 36 patients in the apatinib group and 72 patients in the control group, according to the 1:2 propensity matching. The follow-up ended in January 2019, and the median follow-up time was 28 months. The ORR was 30.56% in the apatinib group and 16.67% in the control group. The DCR in both cohorts was 66.67% and 44.44%, respectively. The median PFS (6.0 vs. 3.3 months) and OS (15.8 vs. 9.2 months) in the apatinib group were significantly longer than that in the control group. In addition, apatinib was more effective than conventional chemotherapy in reducing the risk of PFS [HR 0.40 (95% CI 0.22-0.76), P = 0.0017] and OS [HR 0.40 (95% CI 0.21-0.73), P = 0.002]. Multivariate Cox analysis showed that the course of treatment and decrease in serum CA125 levels are independent risk factors for PFS in patients, while for apatinib, the length of treatment course and the location of the lesion are independent risk factors for recurrence that affects the OS of patients. The most common grade 3/4 toxicities in the apatinib group were hypertension, hand-foot syndrome, and oral mucosal ulcers. Conclusions: Apatinib therapy was an effective treatment for patients with advanced platinum-resistant relapsed EOC. The toxicities were tolerable and manageable.
Associations between genomic instability score (GIS), molecular characterization, and clinical outcomes in high grade serous ovarian cancers (HGSOC).
Authors: Watson Catherine , Paradis Jessie , Thomas Samantha M. , Timms Kirsten , Perry Michael , Perry TC , Secord Angeles Alvarez
Published: June 2022

e17596

Background: To describe the molecular profiles of tumors with a positive GIS status (GI+) in patients with newly diagnosed BRCA wild-type HGSOC and to examine possible associations between genomic mutations and survival outcomes in these patients. Methods: Genetic testing results of patients who underwent both somatic BRCA1/BRCA2 and germline multigene panel testing between 1/1/2015 and 12/1/2020 were prospectively collected. Patients had multigene panel germline testing in tandem with Myriad somatic BRCA1/2 testing and GIS assay. Expanded somatic NGS testing (108 gene panel) was then performed on GIS+ (GIS ≥42) tumor samples from women without somatic or germline BRCA mutations. The primary outcomes were the type and frequency of genomic mutations, which were grouped according to the following pathways: DNA-repair related (separated into homologous recombination (HR), Fanconi anemia (FA), other DNA repair related pathway) or non-DNA repair related. GIS and molecular profiles of tumors from patients who recurred versus those who did not recur were compared. Results: 143 women with HGSOC underwent both germline and somatic testing. 18/143 (12.5%) tumors with negative germline multigene panel and negative somatic BRCA1/2 testing were GIS+. 17/18 (94.4%) GIS+ tumors had pathogenic TP53 mutations. While all samples had at least one DNA repair related variant, only 22.2% had an HR-associated variant, and 16.7% had an FA variant. At time of analysis, 10 patients had recurred and 8 patients had not recurred. Median PFS of those who recurred was 15.8 months (range 4.8-30.1 months). Patients who recurred had lower GIS (median 47.5 vs. 69.5, p = 0.04), but they had no appreciable differences in gene or pathway alterations when compared to those who did not recur. Conclusions: Known pathogenic alterations in DNA repair pathways commonly associated with HR were rare in this cohort of BRCA negative HGSOC patients with GIS+ tumors. However, there was a high frequency of other DNA repair pathway alterations. Further investigation of the molecular signatures associated with recurrence are needed to identify potential novel targets. Lower GIS in this cohort were associated with higher risk of recurrence, although this finding must be validated in the setting of larger studies. [Table: see text]
A deep learning solution for detection of homologous recombination deficiency in ovarian cancer using low pass whole-genome sequencing: Evaluation of the analytical performance.
Authors: Buisson Adrien , Saintigny Pierre , Pujade-Lauraine Eric , Montoto-Grillot Christine , Vacirca Davide , Barberis Massimo , Colombo Nicoletta , Harle Alexandre , Gilson Pauline , Roma Cristin , Bergantino Francesca , Harter Philipp , Pignata Sandro , Gonzalez Martin Antonio , Schauer Christian , Fujiwara Keiichi , Vergote Ignace , Nøttrup Trine Jakobi , Just Pierre-Alexandre , Ray-Coquard Isabelle Laure
Published: June 2022

e17599

Background: Poly (ADP-ribose) polymerase inhibitors (PARPi) induce synthetic lethality in cells with homologous recombination deficiency (HRD). PARPi treatment revolutionized management of patients with cancer, particularly in types where HRD is common, such as ovarian and breast cancer. However, challenges in the implementation of available methods currently limit adoption of HRD testing in the clinics. Here we present the analytical performance evaluation of the Genomic Integrity Index (GII) (SOPHiA GENETICs SA). Methods: GII is a deep-learning based solution for identification of HRD positive tumors from low-pass whole genome sequencing (lpWGS) data (X1 fold coverage). The analytical performance of the GII was evaluated as positive (PPA), negative (NPA) and overall (OPA) percentage of agreement with the HRD status determined by Myriad myChoice CDx (Myriad Genetic Laboratories, Inc.; US FDA-approved). We generated whole genome sequencing libraries for DNA extracted from 139 ovarian cancer Formalin-Fixed Paraffin- Embedded samples, in 4 independent clinical laboratories. We sequenced to the equivalent of 1X coverage (̃10 million reads, 150 base paired end reads, Illumina) and performed HRD classification data using GII using manufacturer’s recommended thresholds. Results: The GII demonstrated high analytical concordance with Myriad myChoice CDx with 91.7% PPA, 95.5% NPA and 94.5% OPA (Table). The HRD status obtained by GII from a subset of positive and negative samples was 100% reproducible (n = 4) between runs. Conclusions: The HRD status obtained by GII is highly concordant with that obtained from standard method, supporting that GII allows accurate and reproducible detection of HRD from lpWGS data. LpWGS is amongst the most cost-effective and easy to implement genome profiling methods, making it uniquely suited for clinical applications. [Table: see text]
Liquid-biopsy-derived glycoproteomic profiling as a novel means for noninvasive diagnosis of ovarian cancer.
Authors: Serie Danie , Moser Kaitlynn , Pickering Chad , Aiyetan Paul , Xu Gege , Rice Rachel , Ramachandran Prasanna , Lindpaintner Klaus
Published: June 2022

e17604

Background: Ovarian cancer (OC) is the fifth- leading cause of cancer-related deaths among women, and the most lethal gynecological cancer. Currently available biomarkers, including CA-125 and HE4, show suboptimal diagnostic performance for differentiating among benign and malignant pelvic tumors, and the early recognition of OC. Differentiation of benign and malignant pelvic tumors is required for proper patient triaging and management, yet non-invasive methods remain a largely unmet medical need. Methods: We applied a novel platform for characterizing peripheral blood glycoproteomic biomarkers, combining liquid-chromatography/mass spectrometry (LC-MS) with artificial intelligence/neural networks (AI-NN) for the targeted quantification of serum protein glycosylation at intact glycopeptide level to analyze serum samples from 296 treatment-naïve women with histopathology-confirmed diagnosis of either benign (n = 151) or malignant (n = 145) tumors, and from 55 healthy control subjects, procured from a commercial biobank. Using data-dependent acquisition, a panel of 683 serum glycosylated and non-glycosylated peptides, representing 71 serum proteins, was interrogated. Samples were randomly divided into a training and a testing set for multivariable analysis. Data processing was performed using PB-Net, an in-house-developed high-throughput peak integration software. Raw data were normalized, processed by statistical analysis, and applied to machine learning models. Results: Comparison of glycopeptide abundances among patients with OC and benign pelvic tumors yielded 428 statistically significantly differentially expressed glycopeptides/peptides (at FDR < 0.05). A subpanel of these markers used to generate a score for predicting OC yielded areas under the receiver-operating-characteristic of 0.955 and 0.894 in the training and testing sets, respectively. The predicted probability of malignancy increased with cancer stage, and probability distributions were similar across training and test sets. Applying the model to healthy subjects, not utilized in training, resulted in few misclassifications and a spread nearly equivalent to that of the benign tumor cases. This indicates the signature robustly predicts malignancy and severity of disease. Conclusions: Our novel approach exhibited impressive levels of accuracy for the noninvasive differentiation of benign and malignant pelvic masses, compared with existing biomarkers and algorithms, thereby demonstrating the utility of glycoprotein profiles as a powerful, noninvasive new diagnostic modality.