bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase II trial of palbociclib combined to letrozole after progression on second-line chemotherapy for women with ER/PR-positive high-grade serous or endometrioid ovarian, fallopian tube, or peritoneal cancer: LACOG 1018.
Authors: Damian Fernanda Bronzon , Melo Andreia Cristina De , Zibetti Dal Molin Graziela , Rodrigues Angelica Nogueira , Calabrich Aknar Freire de Carvalho , Werutsky Gustavo , Filho Elias Abdo , Rebelatto Taiane Francieli , de Jesus Rafaela Gomes , Jimenez Mirela Foresti
Published: June 2023

5514

Background: Treatment options for patients with high-grade ovarian serous (HGSC) or endometrioid carcinoma (HGEC) who progress after receiving chemotherapy for recurrence are limited. Methods: LACOG 1018, a phase II, single-arm, multicenter trial evaluated the efficacy of letrozole 2.5mg/day po continuously plus palbociclib 125mg/day po for 21 days in 28-day cycles in patients with histologically proven ovarian HGSC or HGEC, fallopian tube or peritoneal cancer who had progressed on prior chemotherapy for locoregional recurrence or metastatic disease (at least one platinum-based regimen). Patients had centrally confirmed ER and/or PR positivity (> 10% by immunohistochemistry) and ECOG PS 0-2. The primary endpoint was progression-free survival (PFS) at 12 weeks by RECIST 1.1. Secondary endpoints were overall survival (OS), overall response rate (ORR), clinical benefit rate (CBR) and safety. Tumor evaluations were performed every 6 weeks until week 24. Sample size was calculated as 31 patients for the primary endpoint (90% power to detect a two-sided significance level of 5%, 45% PFS at 12 weeks) and 39 patients for secondary endpoints considering 10% drop-out. NCT03936270. Results: A total of 41 eligible patients were included in five Brazilian centers between Feb2020-Jan2022 (table). The PFS-week12 rate was 63.4% (95%CI 46.8 – 76.1). At the time of analysis (cut-off date Jan 18th, 2023) median follow-up was 18.1 months (95%CI 12.9 – 24.3), and 37 PFS events had occurred. Median PFS was 4.2 months (95%CI 2.7 – 5.5) and median OS was 13.4 months (95%CI 10.4 – 20.1). The ORR was 7.7% (N=3 PR) and the CBR was 71.8%. Treatment-related adverse event rates of any grade and grade 3-4 were 95.1 % and 51.2 %, respectively. Grade 3-4 neutropenia was reported in 17 (41.5%) patients, and febrile neutropenia in 1 (2.4%). Only one patient (2.4 %) discontinued the treatment due to toxicity. At the cut-off date, three patients remained on treatment. Conclusions: Palbociclib combined to letrozole demonstrated a significant efficacy in terms of PFS rate at 12 weeks (63.4%) and CBR (71.8%), with no new safety concerns in women with recurrent advanced and metastatic hormone receptor-positive ovarian cancer. These results warrant further investigation of palbociclib plus letrozole in high-grade ovarian cancer. Clinical trial information: NCT03936270 . [Table: see text]
Camrelizumab plus apatinib in patients with advanced or recurrent endometrial cancer after failure of at least one prior systemic therapy: A single-arm phase II trial.
Authors: Wang Huaying , Tian Wenjuan , Ren Yulan , Lu Jing , Wang Tingting , Li Haiming , Jing Chuyu , Shan Boer , Yang Huijuan , Cheng Xi
Published: June 2023

5516

Background: The first stage results of a Simon’s two-stage single-arm phase II trial showed promising antitumor activity and manageable safety of camrelizumab (a humanized anti-PD-1 monoclonal antibody) plus apatinib (a highly selective VEGFR2 inhibitor) in patients with advanced or recurrent endometrial cancer after failure of prior systemic therapy. Here, we report the primary results of this trial. Methods: This open-label, single-arm, phase II trial used a minimax Simon’s two-stage design. Patients with advanced or recurrent endometrial cancer that had progressed after at least one prior systemic therapy were treated with camrelizumab (200 mg, intravenously, every two weeks) and apatinib (250 mg, orally, daily) on a four-week cycle until disease progression or intolerable toxicity. The primary endpoint was the objective response rate per Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1. Other assessed endpoints were disease control rate, time to response, duration of response, time to treatment failure, progression-free survival, overall survival, and treatment-related adverse events. Results: Between January 20, 2020 and October 14, 2022, 36 patients (median age: 60 [range: 29, 76] years; 17 [47.2%] had Eastern Cooperative Oncology Group [ECOG] performance status 1; 15 [41.7%] had received at least two prior systemic therapies) were enrolled. At the date of data cutoff (December 31, 2022), the median follow-up time was 13.9 (interquartile range: 5.8-23.2) months. All 36 patients were evaluable for efficacy, the confirmed objective response rate was 44.4% (95% CI: 27.9%, 61.9%) and the conformed disease control rate was 88.9% (95% CI: 73.9%, 96.9%), with two complete response, 14 partial response, and 16 stable disease. The median progression-free survival was 6.4 (95% CI: 5.2, 13.0) months. The treatment-related adverse events of grade 3 or greater occurred in 19 (52.8%) patients, with increased gamma-glutamyltransferase (8 [22.2%]), hyperglycemia (4 [11.1%]), hypertension (4 [11.1%]) and increased direct bilirubin (4 [11.1%]) being most common. Reactive cutaneous capillary endothelial proliferation occurred in 6 (16.7%) patients and all were grade 1 or 2. No treatment-related death occurred. Conclusions: Camrelizumab plus apatinib show promising antitumor activity and manageable toxicity in patients with advanced or recurrent endometrial cancer after failure of prior systemic therapy and warrant further investigation. Clinical trial information: ChiCTR2000031932 .
Beneficial effect of repeated participation in breast cancer screening upon survival.
Authors: Smith Robert A. , Duffy Stephen W , Yen Amy Ming-Fang , Tabár László , Lin Abbie Ting-Yu , Chen Sam Li-Sheng , Hsu Chen-Yang , Dean Peter , Chen Tony Hsiu-Hsi
Published: June 2023

552

Background: The benefit of mammography screening in reducing population mortality from breast cancer is well established. However, the effect of repeated participation at scheduled screens on case survival is less well documented. Methods: In this retrospective analysis of breast cancer survival, we analyzed incidence and survival data on 37,079 women ages 40-69 from nine Swedish counties who had between one and five invitations to mammography screening and were diagnosed with breast cancer between 1992 and 2016. Of these, 4,564 subsequently died of breast cancer. For each breast cancer diagnosed in each county’s period of observation, we obtained data on previous screening history, and subsequent death (or not) from breast cancer. Formal comparisons of survival with respect to numbers of screening exams attended prior to a diagnosis of breast cancer were carried out using Cox proportional hazards regression with time-varying covariates, ie, cumulative numbers of screens, yielding hazard ratios and 95% confidence intervals (CI). We corrected for potential self-selection using the method of Duffy et al, which gives a corrected estimate based on the proportion of participants, the uncorrected estimate, and the relative risk of breast cancer death for non-participants compared to an uninvited population. Results: Depending on number of invitations, 58-73% (average 65%) participated in all scheduled screens, and 73-96% (average 91%) participated in at least one examination. There was successively better survival among women with increasing numbers of screening exams. For a woman with five previous screening invitations who participated in all five screening exams, the hazard ratio was 0.28 (95% CI 0.25-0.33, p<0.0001), a 72% risk of dying from breast cancer, compared to a woman attending none. Following a conservative adjustment for potential self-selection factors, the hazard ratio was 0.34 (95% CI 0.26-0.43, p<0.0001). Conclusions: For those women who develop breast cancer, regular prior participation in mammography screening confers significantly better survival. Most women will not develop breast cancer in their lifetime. These results indicate that for those who do, regular participation in screening considerably improves the probability of surviving it. The distinction between the general, population benefit of mammography screening, and the benefit of regular participation in mammography screening should be clearly articulated in breast cancer screening messaging and decision aids. [Table: see text]
The effects of the Covid-19 pandemic on practice patterns and outcomes in patients diagnosed with gynecologic malignancies in the United States.
Authors: Kohut Adrian , Lugo Santiago Nicole , Senguttuvan Rosemary , Han Ernest Soyoung , Cohen Joshua Garrett , Lee Stephen , Dellinger Thanh Hue , Lin Jeff Feng-Hsu , Nelson Rebecca A. , Song Mihae , Tergas Ana Isabel
Published: June 2023

5523

Background: The Covid-19 pandemic caused historic disruptions in the United States healthcare system due to many factors, including a lack of medical equipment and pharmaceutical availability, over-capacitated hospital censuses, and limited essential workers. The short- and long-term effects on patients diagnosed with gynecologic malignancies during this time have yet to be delineated. Methods: The National Cancer Database (NCDB) was queried for patients diagnosed with ovarian, uterine, and cervical malignancies from 2019 (pre-covid) to 2020 (covid). Descriptive statistics of practice patterns and outcomes were performed and compared using IBM SPSS Statistics (version 29.0). Results: Within the NCDB, 10,261 patients were diagnosed with ovarian cancer in 2019 compared to 8,501 in 2020. A significantly higher proportion of ovarian cancer patients were diagnosed with stage IV disease at diagnosis in 2020 (32.7%) compared to 2019 (30.9%), p = 0.007. Patients were less likely to undergo primary debulking surgery during covid (37.7%) compared to pre-covid (40.5%), p < 0.001. There was no significant difference in time from diagnosis to initiation of treatment (median: 9 vs. 9 days), nor was there a difference in the proportion of patients undergoing cytoreductive surgery to no gross residual disease (54.3 vs. 54.3%). 42,828 patients were diagnosed with uterine cancer in 2019 compared to 37,431 in 2020. A significantly higher proportion of uterine cancer patients were diagnosed with stage IV disease at diagnosis in 2020 (8.7%) compared to 2019 (8.2%), p = 0.016. The median time from diagnosis to initiation of treatment was 28 days in 2020 compared to 30 days in 2019, p < 0.001. The proportion of uterine cancer patients receiving primary radiation was higher during covid (1.7% vs. 0.5%), p < 0.001. Additionally, the proportion of uterine cancer patients receiving primary hormonal management was also higher during covid (2.5% vs. 2.1%, p < 0.001). 9,289 patients were diagnosed with cervical cancer in 2019 compared to 7,661 in 2020. A significantly higher proportion of cervical cancer patients were diagnosed with stage IV disease at diagnosis in 2020 (16.6%) compared to 2019 (14.9%), p = 0.0021. The median time from diagnosis to initiation of treatment was 31 days in 2020 compared to 32 days in 2019, p = 0.005. Conclusions: We identified significant variations in practice patterns and outcomes in patients diagnosed with gynecologic malignancies in the United States in 2020 (covid) compared to immediately before covid (2019). Notably, we found a significantly higher proportion of patients presenting with advanced disease stages in all queried ovarian, uterine, and cervical cancer patients. Long-term follow-up and survival outcomes are currently pending.
Association of HRD ovarian cancer by RAD51 with hot immune microenvironment: Translational analyses of MITO 16A/MaNGO-OV2 trial.
Authors: Pellegrino Benedetta , Capoluongo Ettore , Campanini Nicoletta , Musolino Antonino , Sikokis Angelica , Casartelli Chiara , Normanno Nicola , Arenare Laura , Serra Violeta , Llop-Guevara Alba , Nardelli Carmela , Beltrame Luca , Califano Daniela , D'Incalci Maurizio , Roma Cristin , Mezzanzanica Delia , Baldassarre Gustavo , Perrone Francesco , Marchini Sergio , Pignata Sandro
Published: June 2023

5527

Background: Homologous recombination repair (HRR)-deficient Ovarian Cancer (OvC) is sensitive to PARP inhibitors and platinum salts. Genomic HRR-deficiency (HRD) tests (i.e. Myriad MyChoice) are currently used to guide treatment selection in the maintenance setting. However, they are showing a limited predictive value, they are expensive and static, i.e. unable to capture the restoration of the HRR functionality, as a mechanism of drug resistance. Methods: We performed the functional and dynamic RAD51 test on 164 patients with high-grade serious OvC, enrolled in the MITO16A/MANGO OV2 trial and treated with first-line therapy containing carboplatin, paclitaxel, and bevacizumab. The RAD51 assay included the immunofluorescence of gH2AX (as a marker of Double Strand Breaks DNA damage), BRCA1 and RAD51 nuclear foci. Stromal Tumor Infiltrating Lymphocytes (TIL) by Immunohistochemistry, and gene expression profile were performed on the same samples. Results: RAD51 assay was informative on 70% (115/164) of the samples. On evaluable samples, median gH2AX score was 57%. BRCA1 foci by immunofluorescence were detected on 55% (49/112) of the samples; 45% (63/112) of the tumors did not show BRCA1 foci likely due to germline or somatic BRCA1 mutations, or BRCA1 promoter hypermethylation. RAD51 identified 69% (79/115) of all tumors as HRD, with a median RAD51 score of 8.8%. HRD tumors presented a statistically significantly higher TIL content than HRR-proficient ones (p = 0.03). Conclusions: Our preliminary results confirmed the feasibility of the RAD51 functional assay on primary untreated OvC. The association between HRD by RAD51 and TIL content encouraged to investigate the efficacy, in clinical trials, of the combination of PARPi and immune-checkpoint inhibitors on selected patients (i.e. HRD by RAD51 and TIL high). Gene expression profile and comparison of the HRD status by RAD51 and genomic HRD (both Myriad MyChoice and academic) and correlations with clinical outcomes will be available for the meeting.
Development of cervical cancer patient reported clinical outcome assessment scale (CC-PRO137): A dedicated tool for multidimensional evaluation of treatment outcomes.
Authors: Wu Xin , Qiu Ling , Zhu Shurong , Feng Hao , Wang Hui , Hou Yingchun , Zhang Tao , Luo Shen , Yu Hailin , Zhao Junda , Li Ming , You Yanan , Qiao Danze , Ruan Yuanyuan , Du Yan , Jiang Hua
Published: June 2023

5537

Background: Worldwide, cervical cancer ranks fourth among female malignant tumors in terms of both incidence and mortality. In addition, there is an increasing trend of cervical cancer incidence among younger women. Since the uterus is located at the center of vascular-neural traffic of the pelvic floor, cervical cancer surgery may damage the function of multiple systems such as urinary, digestive, neurological, endocrine, and pelvic floor muscles, and further lead to short- and long-term effects in the psychological domain including sexual status, anxiety, and depression. Therefore, we developed the current scale, Cervical Cancer Patient Reported Clinical Outcome Assessment Scale (CC-PRO137), aimed to construct a functional patient self-report system scale to conveniently and accurately quantify the quality of life of cervical cancer patients from multiple dimensions. Methods: Items included in the scale were proposed by gynecologic oncologist, and were evaluated and modified by experts in various specialties. This scale (CC-PRO137) includes 3 domains and 13 modules, including physiological systems, psychological related symptoms, social life status. A total of 304 participants were tested within 6 and 12 months postoperatively. Subgroup analyses were carried out for different time period, stages, surgical methods and adjuvant treatment plans. Results: The reliability analysis showed that the Cronbach's α in each module of the physiological domain was between 0.602-0.929, the composite reliability was between 0.226-0.946, and the test-retest reliability was between 0.660-0.829; the Cronbach’s α of the psychological domain were between 0.700-0.940, the composite reliability was between 0.584-0.950, and the test-retest reliability was between 0.697-0.807; the Cronbach’s α of the social domain was between 0.836-0.861, the composite reliability was between 0.777-0.886, the test-retest reliability was between 0.732-0.792, and the reliability of each module was optimal. The content validity adopted the expert judgment. Convergent validity (CV) analysis showed that the average variance extraction of each module in the physiological domain was between 0.382-0.706, in the psychological domain was between 0.433-0.801, and in the social domain was 0.440-0.616. The convergent validity of each module was acceptable. Conclusions: Our results showed the effectiveness of CC-PRO137 as a comprehensive assessment tool for cervical cancer patients' quality of life, suggesting that the scale can accurately measure subtle changes postoperatively. CC-PRO137 can be a useful tool to quantitatively assess cervical cancer patients.
SEER analysis of 9-year breast cancer specific mortality (BCSM) in patients (pts) with invasive lobular breast cancer (ILC) assessed by the 21-gene Breast Recurrence Score assay.
Authors: Geyer Charles E. , Bennett John , Tang Gong , Racz Jennifer M. , Russell Christy Ann , Byun Jung S. , Foldi Julia , Baehner Frederick L. , Petkov Valentina I.
Published: June 2023

554

Background: Linking of the results of the 21-gene Breast Recurrence Score (RS) commercial assay to SEER registries provides opportunity to assess real world prognostic performance of the assay in important subgroups of early breast cancer (BC). ILC is less common than invasive ductal carcinoma (IDC) and the performance of the RS assay in ILC is of interest. The relationship between RS results and 5-year BCSM in patients with ILC was reported based on a linkage in 2015 at this meeting in 2017. Here we present a comparison of 9-year BCSM of ILC vs IDC from a linkage update in 2019. These results will be updated further based on a new linkage of RS data to be completed in April 2023. Methods: Eligible pts had 0-3 axillary nodes at initial surgery, were hormone receptor positive and HER2-negative with a RS result, had no prior malignancy, and were diagnosed between January 2004 and December 2012. Pts with ICD-O-3 code 8520 were categorized as ILC and those with code 8500 as IDC. 9-year BCSM of both cohorts was estimated using actuarial methods. Multivariable Cox proportional hazards models characterized association between RS results and BCSM. Results: Of 89818 pts, 9835 (11.0%) had ILC and 64669 (72.0%) had IDC. Among pts with ILC, median age was 60 years; 12.5% were N1 and 28.4%, 63.7% and 7.9% were grade 1, 2 and 3. Median follow-up was 84 months. Chemotherapy (CT) use and BCSM increased with increasing RS result in both cohorts. After adjusting for age, race, tumor grade, tumor size, nodal status, and histologic subtype, the RS result was independently associated with BCSM ( p < .001) in both ILC and IDC. Conclusions: In this linked SEER analysis of pts with ILC or IDC, the RS results were prognostic for 9-year BCSM, regardless of nodal status. [Table: see text]
Correlating expression of NaPi2b and FRa in high grade serous ovarian cancer (HGSOC).
Authors: Richardson Debra L. , Barve Minal A. , Hamilton Erika P. , Taylor Sara Kristina , Anderson Charles K , Buscema Joseph , Huang Marilyn , Arend Rebecca Christian , Hays John L. , Thaker Premal H. , Lakhani Nehal J. , Mosher Rebecca , Shaw Pamela , Bradshaw Chelsea , Lu Min
Published: June 2023

5545

Background: Biomarker driven therapies are increasingly being used for gynecologic cancers, with mirvetuximab soravtansine, a Folate Receptor alpha (FRa) targeting antibody drug conjugate (ADC) being a recent FDA approved agent for patients with FRa positive PROC. Uptifitamab rilsodotin (UpRi) is a late-stage, first in class NaPi2b-targeting ADC with a novel scaffold-linker-payload that enables high drug to antibody ratio and a controlled bystander effect. Approximately 29% of HGSOC patients have FRa positive tumors (Roche VENTANA FOLR1 (FOLR-2.1) RxDx Assay. USPI 2022); ~59% have NaPi2b positive tumors (Okeke et al, USCAP 2022). With the high unmet medical need in PROC and the evolving landscape of available treatments, understanding biomarker expression and correlation between FRa and NaPi2b is critical. Here we evaluate NaPi2b and FRa RNA expression correlation in HGSOC. Methods: Tumor samples (N=84) from the Ph1b UpRi expansion (EXP) cohort were analyzed via Nanostring (770 immune-focus genes from IO 360 panel + 30 customized ADC-related genes) to evaluate the association between NaPi2b and FRa expression. The cutoff for NaPi2b RNA positive or negative was based on approximately 60% of HGSOC patients having NaPi2b positive tumors (top 60% of samples based on expression deemed NaPi2b positive; bottom 40% NaPi2b negative) and FRa RNA cutoff assumed that ~30% of samples were FRa positive. To correlate the NaPi2b expression level between RNA and IHC, the N=84 samples with known expression levels via IHC were analyzed via Nanostring. Results: When evaluating NaPi2b and FRa RNA expression correlation, 21% (N=18) of samples had both NaPi2b positive and FRa positive expression. 38% (N=32) samples were NaPi2b positive and FRa negative. No statistically significant association was observed (Chi-squared test, p=0.129). NaPi2b RNA and IHC expression was evaluated; a statistically significant association was observed (Kappa statistic, p=0.001). Results are in the Table below. Conclusions: Based on this analysis of a limited sample size, there does not appear to be an association between FRa and NaPi2b expression, with the majority of NaPi2b positive samples not being FRa positive. Additionally, general NaPi2b prevalence and the correlation of expression between RNA and IHC suggest that NaPi2b may be a rational biomarker to integrate in RNA tumor panel testing. This research underscores the importance of early, comprehensive testing of all relevant biomarkers to guide therapy selection, and suggests that additional research is needed to evaluate the potential association between FRa and NaPi2b expression via IHC. [Table: see text]
The impact of adjuvant platinum-based chemotherapy in early adult granulosa cell tumor of the ovaries: A meta-analysis of comparative studies.
Authors: Keerty Dinesh , Devarashetty Sindhu Priya , Haddad Philip A.
Published: June 2023

5547

Background: Adult granulosa cell tumors (AGCT) are the most common type of malignant ovarian sex chord stromal tumors but only comprise 2 to 5 percent of all malignant ovarian neoplasms. Most granulosa cell tumors have an indolent growth pattern, and prognosis depends on the disease stage at diagnosis and the presence of residual disease after surgery. Though these tumors have metastatic potential, their tendency for late relapses is well documented. Despite the lack of supporting data, the National Cancer Centers Network recommends platinum-based adjuvant chemotherapy (AC) for Stage I with intermediate and high-risk features. Most studies have failed to show any benefit of AC with disease-free or overall survival. However, several of these studies were small, and some had short median follow-ups. Others included advanced stages and the juvenile variant of the disease. Therefore, we conducted this meta-analysis to evaluate the impact of AC on disease recurrence in a stage I enriched AGCT. Methods: A review of the medical literature was conducted using online databases. Inclusion criteria consisted of English language, diagnosis of AGCT, studies with a preponderance of stage I, comparative studies of AC versus none, and studies that reported recurrence rates. Studies that had a preponderance of advanced stages or juvenile variants were excluded. A meta-analysis using the fixed effects and random effects models was conducted. Results: Seven retrospective comparative studies with a total of 500 patients were included. The average median age was 47 years, and the average median follow-up was 58 months. Approximately 79% of the sample were stage I, and 79% of stage I were IC. Most AC regimens used were BEP and EP, though it varied among the regions. Platinum-based AC in early-stage AGCT failed to impact recurrence rates compared to clinical observation (HR=1.39, 95%CI 0.86-2.25, I2=48%, p=0.18). Conclusions: This is the first meta-analysis to show that adding platinum-based adjuvant chemotherapy to surgery does not improve the recurrence rate in early AGCT. Therefore, in the absence of evidence supporting any benefit of AC in this disease, recommendations to use AC should be re-evaluated, especially since the risk of platinum-based AC with or without Bleomycin is well-documented and carry potentially serious side effects.
Venous thromboembolism prophylaxis during neoadjuvant chemotherapy for patients with ovarian cancer.
Authors: McLaughlin Hannah Dysinger , Straubhar Alli M. , Rolston Aimee , McCool Kevin , Brackmann Melissa , Siedel Jean Hansen , McLean Karen , Reynolds R. Kevin , Uppal Shitanshu
Published: June 2023

5552

Background: The primary objective was to assess the rate of venous thromboembolism (VTE) in patients with ovarian cancer who received neoadjuvant chemotherapy (NACT) following a quality improvement (QI) intervention of routine pharmacologic VTE prophylaxis compared to patients that did not receive prophylaxis. Methods: This is a retrospective cohort study of patients with pathologically confirmed ovarian cancer that received NACT between January 2009 to December 2021 from a single institution. Patients were excluded if VTE was diagnosed prior to initiating NACT. Routine pharmacologic VTE prophylaxis during NACT started in January 2017 following a QI initiative. VTE events were diagnosed by doppler scan of extremities or computed tomography of the chest ordered for symptomatic patients or diagnosed incidentally on routine treatment imaging. Patient factors and perioperative variates of interest were investigated for their association with VTE events through univariate and multivariate models. Results: A total of 290 patients with ovarian cancer received NACT and were included, with 106 of 290 patients (36.5%) receiving pharmacologic prophylaxis during NACT. Rate of VTE prophylaxis prior to the QI intervention was 3.68% (n=5) compared to 65.58% (n=101) after. The rate of VTE during NACT was 11.41% (n=21) without prophylaxis and 2.83% (n=3) with prophylaxis (p=0.013) (Table). The rate of any VTE event from the start of NACT through adjuvant chemotherapy was 20.11% (n=37) without prophylaxis and 4.72% (n=5) with prophylaxis (p<0.01). There was no difference in adverse bleeding events in those that received prophylaxis to those that did not (0% vs 1.32%, p=0.239). On univariate analysis, VTE prophylaxis was associated with a decreased risk of VTE during NACT (OR 0.23; 95% CI: 0.06-0.78) and any VTE during primary treatment (OR 0.19; 95% CI 0.07-0.52). On multivariate analysis, VTE prophylaxis remained significantly associated with reduced VTE rates during NACT and during primary treatment (p=0.02 and p=0.001, respectively). Conclusions: Routine administration of pharmacologic VTE prophylaxis during NACT for patients with ovarian cancer is associated with reduced risk of VTE during NACT and throughout primary treatment and is not associated with adverse bleeding events. [Table: see text]
Pegylated liposomal doxorubicin and carboplatin versus paclitaxel and carboplatin as first-line treatment for Chinese patients with ovarian cancer: A multi-center, randomized, open-label trial.
Authors: Shen Yuanming , Kong Beihua , Xia Bairong , Wang Fei , Yin Rutie , Li Qingshui , Yue Ying , Kang Shan , He Liping , Wang Ke , Meng Yuanguang , Wang Shixuan , Qu Pengpeng , Huang Xianghua , Guo Ruixia , Yan Ping , Pan Mei , Lou Ge , Cheng Wenjun , Xie Xing
Published: June 2023

5556

Background: Paclitaxel combined with carboplatin is a standard first-line chemotherapy regimen for ovarian cancer. This study was designed to evaluate the efficacy and safety of pegylated liposomal doxorubicin (PLD) plus carboplatin (CD) compared with paclitaxel plus carboplatin (CP) as first-line treatment for epithelial ovarian cancer (EOC). Methods: Patients with stage IC to IV EOC, fallopian tube cancer, or primary peritoneal cancer were eligible for enrolment in this open-label, randomized controlled trial at 20 centers in China. Patients were randomly assigned 1:1 to CD group (carboplatin area under the curve [AUC] 5 plus PLD 30 mg/m2) or CP group (carboplatin AUC 5 plus paclitaxel 175 mg/m2) every 3 weeks for 3-6 cycles. The primary end point was progression free survival (PFS); secondary end points were overall survival (OS), objective response rate (ORR), disease control rate (DCR) and safety. Results: Between March, 2019 to December, 2021, 395 patients were enrolled, of whom 391 patients were analyzed (195 assigned to CD, 196 to CP). Baseline characteristics were balanced between the two treatment groups. The median follow-up was 21.6 months for the CD group and 22.5 months for the CP group. There was no significant difference in PFS between the two arms (P=0.516); the median PFS was 28.1 months and 30.1 months in the CD and CP arms, respectively. OS data were immature at data cutoff, with a total of 26 deaths in the two treatment groups. In patients with at least one measurable lesion at baseline, ORR was 65.5% in the CD arm and 66.2% in the CP arm (P= 0.941); DCR was 74.1% and 73.8% in the CD and CP arms, respectively (P= 0.971). Among patients who were evaluable by GCIG CA125 criteria, CA125 response was obtained in 86.0% and 88.5% of patients in the CD and CP arms, respectively (P=0.560). More frequent grade 1 to 3 alopecia (32.1% vs 12.3%) and neurotoxicity (20.4% vs 0%) were observed in the CP arm; more hand-foot syndrome (grade 1 to 3, 10.8% vs 2.6%), and oral mucositis (grade 1-3, 12.8% vs 5.1%) in the CD arm. Conclusions: The efficacy of CD regimen is comparable to that of CP, with less alopecia and neurotoxicity. CD may be an alternative first-line treatment for EOC. However, survival data are not yet mature, and longer follow-up is needed. Clinical trial information: NCT03794778 .
The role of innate immune system in modulating CHK1 inhibitor (CHK1i) response in BRCA wild-type (BRCAwt), platinum-resistant high-grade serous ovarian cancer (PR-HGSOC): Exploratory analysis from a phase II study of CHK1i prexasertib.
Authors: Giudice Elena , Nair Jayakumar , Huang Tzu-Ting , Lee Min-Jung , Trepel Jane B. , Lee Jung-Min
Published: June 2023

5557

Background: Immune checkpoint blockade, e.g., anti-PD-1/PD-L1, demonstrated limited efficacy in HGSOC despite high levels of tumor-infiltrating lymphocytes, suggesting the innate, rather than adaptive, immune system may play a prominent role in anticancer response. Preclinical studies suggest CHK1i modulates the innate immune milieu. We previously showed clinical activity of prexasertib in BRCAwt, PR-HGSOC patients (pts). Here, we investigated the association of innate immunogenic features with CHK1i response. Methods: Prexasertib was given at 105 mg/m2 IV every 14 days in a 28-day cycle. Baseline (BL) fresh core biopsies were collected from pts enrolled in the biopsy (Bi) cohort for RNA sequencing. Computational immunogenomic analysis (CIBERSORT) was used for immune cell fractions quantification. Blood samples (BS) were obtained at BL and cycle 1 day 15 (C1D15) from pts enrolled in both Bi and non-Bi (nBi) cohorts for multiparametric flow cytometry (FC) analysis to evaluate dynamic changes in immune cell subsets. Mann-Whitney and Wilcoxon tests were used to compare unpaired and paired data, respectively. Results: 49 BRCAwt, PR-HGSOC pts were enrolled in the Bi cohort (n=25) and nBi cohort (n=24). 39 were evaluable per RECIST v1.1. 18/39 pts (46.2%) had a clinical benefit (CB), defined as progression-free survival≥6 months. Transcriptomic profiles of BL biopsies (n=15) met the quality control and assurance (Gene Similarity Index, Principal Component Analysis) for further in silico analysis. CIBERSORT analysis did not exhibit any differences in the immune cell fractions between CB and non-CB (NCB) groups at BL. FC analysis on paired BS (BL and C1D15) showed an increase of immunosuppressive monocytic myeloid-derived suppressor cells (M-MDSCs, p<0.001) and classical monocytes (CM, p=0.003) in the NCB group (18 paired BS). In the CB group (19 paired BS), CD141+ and CD1c+ dendritic cells (DCs) express higher rates of CD83, a marker of maturity and functionality (p<0.001 and p<0.001, respectively), despite no increase in the absolute number of DCs. At C1D15, a higher rate of M-MDSCs (median 7.8% vs. 5.52%; p=0.03) and CM (median 40.7% vs. 31.7%; p=0.03) were found in the NCB group (n=18) compared to the CB group (n=19); also, CM showed lower expression of HLA-DR in the NCB group (median 19.25% vs. 27.8%; p=0.02). Conclusions: Collectively, our data suggest the possible involvement of innate immunity in modulating CHK1i response. Increasing peripheral immunosuppressive cells and lower immunocompetence of the innate immune system may contribute to CHK1i resistance, whereas the functionality of DCs may be involved in the response. Enhancing innate immunity may represent a strategy to increase CHK1i response in this hard-to-treat population. Clinical trial information: NCT02203513 .
DNA methylation patterns between tissue and blood samples in ovarian cancer.
Authors: Wen Hao , Feng Zheng , Ge Huijuan , Wang Yanan , Wang Jingshu , Sun Xiaoran , Yang Bo , Quan Chenlian , Zhou Xiaoyan , Wu Xiaohua
Published: June 2023

5558

Background: Altered DNA methylation pattern, with functional consequences in the activity of key carcinogenic pathways, has been shown to be involved in the carcinogenesis of ovarian cancer. Tumor DNA is released into the blood via apoptosis or necrosis. Therefore, cell-free DNA (cfDNA) methylation alteration can also be detected in blood, which has shown promising performance in ovarian cancer early detection and prognostication. However, the difference of DNA methylation patterns between the tissue and blood samples of ovarian cancer is still unclear. Methods: PERCEIVE-I study (NCT04903665) is a prospective study aimed at the early detection of gynecological malignancies. Blood and paired tissue samples from this study were collected at the Fudan University Shanghai Cancer Center. Blood samples from age-matched non-cancer controls were also collected. All the blood and paired tissue samples were sequenced by a target methylation panel covering ~490,000 CpG sites. Finally, The ovarian cancer methylation patterns were analyzed based on 11 paired cancer-adjacent tissue samples and 170 blood samples (cancer, n=48; non-cancer control, n=122). Results: In total, 7,225 differentially methylated blocks (DMBs) were identified by comparing cancer and adjacent tissues, with 5,093 hypomethylated and 2,132 hypermethylated. By contrast, there were 5,853 hypomethylated and 8,685 hypermethylated DMBs in cancer blood samples compared with non-cancer controls. Among the 7,225 DMBs in tissues, 3,962 (54.8%) blocks were also observed to be altered in blood samples, including 2,354 hypomethylated blocks and 1,114 hypermethylated blocks. GO analysis revealed that these hypomethylated blocks were mainly associated with functions such as regulation of synaptic membrane and DNA-binding transcription activator activity, while the hypermethylated blocks were mainly enriched in the pattern specification process, transcription factor complex, and the DNA-binding transcription activator activity. The alteration of the above 3,962 DMBs in tissue were highly correlated with the alteration in blood (correlation coefficient of 0.71, 0.50, 0.73 and 0.73 for stage I-IV, respectively). Furthermore, in patients carrying germline BRCA1/2 mutations (n=11), most of the above DMBs were not significantly different from those without germline BRCA1/2 mutations (n=37). Conclusions: In this study, we demonstrated that blood DNA methylation alteration was highly consistent with tissue DNA methylation alteration in ovarian cancer, indicating the sustained release of DNA methylation signals from the primary cancer sites. These results suggest that cfDNA methylation can be used as reliable biomarkers for the early detection of ovarian cancer. Clinical trial information: NCT04903665 .
Detection of homologous recombination deficiency (HRD) using a novel genomic and epigenomic liquid biopsy assay in patients with breast cancer.
Authors: Barbacioru Catalin , Yen Jennifer , Tolkunov Denis , Safabakhsh Pegah , Wang Hao , Gross Andrew , Overstreet Brooke , Jenkins Colby , Drusbosky Leylah , Kiedrowski Lesli Ann , Eagle Craig , Chuang Han-Yu
Published: June 2023

556

Background: Homologous recombination and repair (HRR) deficiency (HRD) is characterized by genomic instability associated with dysfunction in BRCA1/2 or other HRR genes. Patients with breast cancer harboring an HRD phenotype with or without HRR mutations have derived clinical benefit from PARPi therapy. We have previously shown that GuardantINFINITY, a novel genomic and epigenomic liquid biopsy assay, can identify HRR SNVs, indels, rearrangements, copy number loss, reversions, and BRCA1 promoter methylation for patient selection and resistance monitoring, a major challenge for PARPi treatment. Here, we present a method of predicting HRD status by cfDNA using GuardantINFINITY in patients with advanced breast cancer. Methods: We developed a probabilistic genomic model to predict HRD status, inferred from genome-wide somatic SNV, indel, and CNV signatures indicative of BRCA1/2 deficiency, including large-scale state transitions (LST), whole-genome tumor loss of heterozygosity (LOH), telomeric allelic imbalance (TAI). A second probabilistic model, based on targeted measurements of genomic and epigenetic changes was learned from a subset of clinical samples to enhance the genomic model. The model was trained and tested on a cohort of over 12,000 GuardantOMNI and GuardantINFINITY clinical breast cancer samples to assess the sensitivity of accurately detecting deficiency in select HRR-genes ( BRCA1/2, PALB2, RAD51D). The aggregated predictive model was validated on an independent cohort of breast cancer samples. Results: The model based on genomic and epigenetic signals identified HRR-gene deficiency in a breast cancer cohort with a estimated 95% LoD of 22.5% tumor fraction and an AUC of 0.75 across all tumor fractions, an improvement in sensitivity over when only the genomic model is used (AUC of 0.7, 95% LoD of 28%). Specificity remained high for both models (100%, n = 83) in cancer free samples. Application of this model in a cohort of 1,101 patients with unselected breast cancer identified 390 patients with an HRD phenotype, of whom 192 patients had a known HRR-gene mutation. Of the 201 patients with a known pathogenic mutation in an HRR gene, 49 also had co-occurring LoH in the same gene, indicating biallelic loss. Conclusions: In this analysis, we demonstrate that a probabilistic model of genomic and methylation predictors can detect HRD status in patients with breast cancer from cfDNA using GuardantINFINITY. Additional analytical and clinical studies to further evaluate this model are ongoing. With HRD prediction, GuardantINFINITY provides a comprehensive minimally-invasive solution for PARPi and DNA damage treatment selection, longitudinal monitoring, and an exploratory platform for investigating epigenetic signals that may underpin resistance.
Efficacy and safety of niraparib maintenance therapy in patients with newly diagnosed advanced ovarian cancer who had measurable residual disease: A post-hoc subgroup analysis of the PRIME study.
Authors: Kong Beihua , Wu Lingying , Zhu Jianqing , Yin Rutie , Wang Jing , Pan Lingya , Zheng Hong , Liu Jihong , Wu Xiaohua , Wang Li , Huang Yi , Wang Ke , Zou Dongling , Zhao Hongqin , Wang Chunyan , Lu Weiguo , Lin An , Zhen Xiaoa , Hang Wenzhao , Hou Jianmei
Published: June 2023

5562

Background: Niraparib maintenance therapy significantly prolonged progression-free survival (PFS) versus placebo in patients with newly diagnosed advanced ovarian cancer (aOC), but its antitumor activity remains unclear in those with measurable residual disease (MRD) after first-line platinum-based chemotherapy (1LCT). This study aims to report the efficacy, including antitumor activity, and safety of niraparib maintenance therapy in patients with MRD after 1LCT from the phase 3 PRIME trial (NCT03709316). Methods: In PRIME, adults with newly diagnosed aOC who had received cytoreductive surgery and responded to 1LCT were randomized 2:1 to receive niraparib or placebo with stratification by receipt of neoadjuvant chemotherapy, response to 1LCT, status of germline BRCA mutations, and tumor homologous recombination deficiency status. Tumor assessment was conducted at baseline and every 12 weeks thereafter by blinded independent central review (BICR) according to RECIST, version 1.1. Between 29 June 2018 and 11 November 2019, 384 patients were randomized (255 niraparib, 129 placebo). The data cut-off date was 30 September 2021. This post-hoc analysis reports BICR-assessed objective response rate (ORR) and PFS in patients with MRD at baseline. An initial response was confirmed ≥4 weeks later. Results: In total, 73 (19.0%) patients (47 niraparib, 26 placebo) had MRD at baseline. Baseline characteristics were well balanced between the two MRD groups. Complete and partial responses, both confirmed, were observed in 12 (25.5%) and 15 (31.9%) niraparib-treated patients and 3 (11.5%) and 5 (19.2%) placebo-treated patients, respectively, leading to a confirmed ORR of 57.4% with niraparib and 30.8% with placebo (odds ratio, 3.20; 95% confidence interval [CI], 1.11–9.11). ORRs by biomarker status are provided in the table. Median PFS (95% CI) was 22.3 (8.7–not estimable) months with niraparib versus 8.3 (5.6–11.0) months with placebo (hazard ratio, 0.36; 95% CI, 0.19–0.71). Treatment-emergent adverse events (TEAEs) of grade ≥3 occurred in 28 (59.6%) niraparib-treated patients and 7 (26.9%) placebo-treated patients. TEAEs led to treatment discontinuation in three (6.4%) niraparib-treated patients and one (3.8%) placebo-treated patient. Conclusions: In patients with newly diagnosed aOC who had MRD after 1LCT, niraparib maintenance therapy tended to induce additional antitumor activity and led to a clinically meaningful increase in PFS versus placebo. Clinical trial information: NCT03709316 .[Table: see text]
The effect of maintenance hormone therapy on overall survival in advanced-stage low-grade serous ovarian carcinoma: A risk-set matched retrospective study.
Authors: Barakzai Syem , Bregar Amy , del Carmen Marcela G. , Eisenhauer Eric L , Goodman Annekathryn , Rauh-Hain Jose Alejandro , Gockley Allison Ann , Melamed Alexander
Published: June 2023

5568

Background: Low-grade serous ovarian carcinoma (LGSOC) is a rare malignancy often treated similarly to high-grade serous ovarian carcinoma (HGSOC) despite differences in clinical behavior and carcinogenesis. Observational studies suggest that, among patient with advanced-stage LGSOC, maintenance hormonal therapy (HT) following primary treatment is associated with improved progression free survival. We conducted a multi-institutional observational study to investigate whether HT is associated with an overall survival advantage in this setting. Methods: We included patients with histologically confirmed stage III or IV LGSOC diagnosed between Jan 1, 2004, and Dec 31, 2019, treated in Commission on Cancer accredited cancer programs in the US. Patients who received HT within 6 months of diagnosis were matched to controls who did not initiate HT during this timeframe. The primary outcome was risk of death from any cause, within five-years of initiation of HT or observation. For each treated patient, we employed risk-set propensity score matching to identify a control in a manner that avoided the introduction of immortal-time-bias, and balanced groups with respect to year of diagnosis, upfront treatment strategy, age, stage, race/ethnicity, comorbidity index, insurance status, zip-code median income, and cancer program type. Results: There were 296 patients who initiated HT within 6 months of diagnosis, and 2,805 potential controls. Patients who received HT were more often treated in academic medical centers (55% vs 44%), diagnosed later in the study period (62% vs 23% diagnosed in 2018-2019), and received upfront chemotherapy less frequently (55% vs 83%). After risk set and propensity score matching, we identified 204 patients treated with HT and 204 untreated controls, who were otherwise similar with respect to measured covariates. In the matched cohort, maintenance HT was associated with a reduction in the risk of death (hazard ratio 0.61; 95% CI 0.37-0.99), corresponding to a 60-month survival of 71% compared with 61%, and an improvement in 5-year life expectancy of 3.6 months (95% CI 0.004-7.2). Conclusions: Maintenance hormone therapy following primary management of LGSOC is associated with an overall survival benefit compared with observation.
Trends and outcomes of systemic therapy in hormone receptor-positive early-stage male breast cancer: A propensity score analysis.
Authors: Yu Liuwen , Zeng Bangwei , Chen Minyan , Huang Meng , Guo Wenhui , Chen Lili , Lin Yuxiang , Li Jing , Li Yan , Fu Fangmeng , Jacobs Lisa K. , Wang Chuan
Published: June 2023

557

Background: Male breast cancer (MBC) is a rare disease. Research on trends and survival outcomes in systemic treatment for MBC is limited. This study aims to describe trends and survival outcomes of different systemic treatments in hormone receptor-positive (HR+) early MBC and to assess the factors related to treatment selection. Methods: We identified stage I-III HR+ invasive MBC patients who have undergone surgery and systemic therapy diagnosed during 2004-2014 from the National Cancer Database (NCDB). Treatment groups include: endocrine therapy (ET), chemotherapy (ET), combination therapy (ET+CT), and None. Using Cochran-Armitage trend tests to describe the temporal trends of different treatments. Performing propensity score models to evaluate overall survival. Conducting a logistic regression to analyze factors associated with ET+CT. Results: Among 6217 patients included (median follow-up 50.1months), 1290 (20.7%) patients received no systemic therapy (None), 705 (11.3%) patients only received CT, 2358 (37.9%) patients only received ET, and 1864 (30.0%) patients received ET+CT. From 2004 to 2013, there was a significant increase in the use of ET ( P(trend) < .001), which was accompanied by a decrease in CT and no treatment (all P(trend) < .001). And the use of ET+CT showed no significant change. After using overlap weighting (OW) to control confounders, multivariable cox regression analysis showed that ET+CT was associated with improved survival compared with ET (hazard ratio [HR], 0.46; P< .001). Sensitivity analyses (including the inverse probability of treatment weighting (IPTW) (HR,0.49; P < .001), IPTW with stabilized weight (HR,0.49; P< .001), propensity score matching (PSM) (HR,0.51; P < .001), PS regression adjustment (HR,0.47; P < .001), and PS stratification (HR 0.44; P < .001)) and exploratory subgroup analyses (except for well-differentiated, stage I, and breast conservation + radiotherapy subgroups) indicated similar outcome. Factors associated with receiving ET+CT include younger age, private insurance, Charlson Comorbidity Index was 0, poorer differentiation, higher stage, mastectomy and radiotherapy, estrogen receptor-positive and progesterone receptor-negative, and HER2-positive. Conclusions: ET+CT was associated with improved survival compared with ET in HR+ early MBC patients, except for some low-risk subgroups.