bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase II basket trial of dual anti–CTLA-4 and anti–PD-1 blockade in rare tumors (DART) SWOG S1609: The vulvar cancers.
Authors: Chae Young Kwang , Othus Megan , Patel Sandip Pravin , Edwards Robert P. , Scalici Jennifer Michelle , Chung Liam Il-Young , McLeod Christine , Chen Helen X. , Sharon Elad , Streicher Howard , Ryan Christopher W. , Blanke Charles David , Kurzrock Razelle
Published: June 2023

5517

Background: Dual checkpoint inhibition with Anti-PD-1 and anti-CTLA4 checkpoint inhibitors have proven to be effective in several malignancies but their potential role in various rare solid cancers is yet to be established. The efficacy of immunotherapy in vulvar cancer patients has not been explored. This study presents the first results of ipilimumab and nivolumab in vulvar cancers (cohort 35) of the SWOG S1609 Dual Anti-CTLA-4 & Anti-PD-1 blockade in Rare Tumors (DART) trial. Methods: DART is a prospective, open-label, multicenter/multi-cohort phase 2 clinical trial of ipilimumab (1mg/kg intravenously every 6 weeks) plus nivolumab (240mg intravenously every 2 weeks). The primary endpoint was objective response rate (ORR) (RECIST v1.1) (confirmed complete (CR) and partial responses (PR)); progression-free survival (PFS), overall survival (OS), stable disease (SD) > 6 months, and toxicity are secondary endpoints. Results: Sixteen evaluable patients (median age, 55.5 years) were analyzed. 14 cases were of squamous cell carcinoma histology and 2 were of poorly differentiated carcinoma. ORR was 18.8% (3/16, 25% when including one unconfirmed PR). There was 1 CR (SCC; PFS of 465 days) and 2 PR (both SCC; one with 57% regression with PFS of 1022 days, another with 53% regression with PFS of 501 days). Of note, there was one SCC patient with unconfirmed PR that showed 69% regression with PFS of 209 days. Overall clinical benefit rate (CBR; no progression > 6months) was 31.3% (5/16). The median PFS was 2.2 months, 6-month PFS 33%, 1-year PFS 20%. The median OS was 7.6 months, 6-month OS 62%, 1-year OS 44%. The most common adverse events were diarrhea, fatigue, pruritus, anorexia, and nausea (25%, n = 4 each). Grade 3-4 adverse events occurred in 25% of patients (n = 4). There was 1 grade 3-4 adverse event (6.7%) that led to discontinuation, and 1 (6.7%) grade 5 death adverse event. Conclusions: Ipilimumab plus nivolumab in vulvar cancers resulted in an ORR of 18.8% and CBR of 31.3%, with durable responses seen. Correlative studies to determine response and resistance markers are ongoing. Expanded prospective studies exploring the role of immunotherapy in vulvar cancers are warranted. Clinical trial information: NCT02834013 .
Neoadjuvant camrelizumab plus chemotherapy for locally advanced cervical cancer (NACI study): A prospective, single-arm, phase II trial.
Authors: Chen Jing , Li Kezhen , Hu Yingjie , Han Yingyan , Shen Yuanming , Wang Yanzhou , Song Kun , Xia Bairong , Chen Xiaojun , Zou Dongling , Wang Yingmei , Sun Chaoyang , Chen Gang , Ma Ding
Published: June 2023

5520

Background: First-line treatments for locally advanced cervical cancer (LACC) have limited efficacy and neoadjuvant chemotherapy (NACT) is an emerging approach, however, two-thirds of patients (pts) respond to it and pts without response benefit little. PD-1 inhibitors have shown promising role in recurrent or metastatic cervical cancer. This study aims to evaluate the efficacy and safety of preoperative PD-1 inhibitor camrelizumab combined neoadjuvant therapy for LACC. Methods: The study is designed as a multicenter, open-label, single-arm, prospective phase II study. Pts are enrolled if they had previously untreated LACC (2018 FIGO staged IB3, IIA2 and IIB/IIIC1r (tumor size > 4cm). Eligible pts will receive neoadjuvant chemo-immunotherapy (NACIT), defined as one cycle of cisplatin (75-80 mg/m2, iv) plus nab-paclitaxel (260 mg/m2, iv) NACT and subsequent two cycles of camrelizumab (200mg, iv) combined NACT. Either surgery or concurrent chemoradiotherapy are conducted according to the response as per the Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1. The primary endpoint was objective response rate (ORR), and the secondary endpoints were pathological complete remission (pCR) rate, rate of postoperative adjuvant treatment, event-free survival, overall survival and safety. Results: From Dec 1, 2020 to Feb 1, 2023, 83 pts were enrolled, and 78 pts were evaluated for response. The ORR was 100% (95%CI, 95.38 to 100), with 14 (17.95%) complete response (CR) and 64 (82.05%) partial response. Regarding the pathological findings of 76 pts who underwent radical surgery, 30 (39.47% (95%CI, 28.44 to 51.35)) pts achieved pCR, while 17 (22.37%) needed postoperative adjuvant treatment as indicated in NCCN guideline, of who 14 had positive pelvic nodes, positive surgical margin, and/or positive parametrium and the other three met Sedlis criteria. RECIST CR was significantly associated with pCR ( P = 0.016). Pre-treatment PD-L1 expression (Combined Positive Score) was a predictive biomarker for RECIST CR ( P = 0.036) but not for pCR ( P = 0.078) in these evaluated patients. Grade 3 or 4 treatment-related adverse events occurred in 35 (44.87%) pts during NACIT; the most common were lymphocytopia (25.64%), neutropenia (12.82%) and leucopenia (8.97%). Conclusions: NACIT for LACC demonstrated extremely high ORR and pCR rate with manageable toxicity profile, and greatly reduced the need of postoperative adjuvant therapy. Clinical trial information: NCT04516616 .
The Normal Risk Ovarian Screening Study (NROSS): Twenty-one year update.
Authors: Han Chae Young , Lu Karen H. , Bedi Deepak , Bedia Enrique , Bevers Therese Bartholomew , Holman Laura L. , Leeds Leroy , Mathews Cara Amanda , McCann Georgia Anne-Lee , Moore Richard G. , Schlumbrecht Matthew , Slomovitz Brian , Tobias Daniel , Williams-Brown Marian Yvette , Liu Jinsong , Handy Beverly Carol , Lu Zhen , Bedia Jacob , Skates Steven J , Bast Robert C. ,   NROSS
Published: June 2023

5522

Background: The Normal Risk Ovarian Screening Study (NROSS) tested a two-stage screening strategy in post-menopausal women at conventional hereditary risk where significantly rising CA125 prompted transvaginal sonography (TVS) and abnormal TVS prompted surgery to detect ovarian cancer. Methods: A total of 7,856 healthy postmenopausal women were screened annually for a total of 50,596 women-years in a single arm study ( NCT00539162 ). Serum CA125 was analyzed with the Risk of Ovarian Cancer Algorithm (ROCA) each year. If risk was normal ( < 1:2000), women returned in a year. If risk was elevated ( > 1:500), TVS was undertaken immediately and if risk was intermediate, CA125 was repeated in 3 months, risk recalculated, and the participant re-triaged. An average of 2% of participants were referred to TVS annually. Results: Thirty-four patients were referred for operations detecting 15 ovarian cancers and 2 borderline tumors with 12 in early stage (I-II). In addition, 7 endometrial cancers were detected with 6 in early stage. Thus, the positive predictive value (PPV) of the NROSS trial was 50% (17/34) for detecting ovarian cancer and 74% (25/34) for any cancer, far exceeding the minimum acceptable study endpoint of 10% PPV. As 4 ovarian cancers and 2 borderline tumors were diagnosed within a year of each participant’s last normal risk, the sensitivity for detecting ovarian and borderline cancer was 74% (17/23) and 70% of ROCA-detected cases (12/17) were in stage I-II. NROSS screening reduced incidence of late stage (III-IV) disease by 34% compared to the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) control arm and by 30% compared to US SEER values. Results of our NROSS trial contrast dramatically with those of the recently reported UKCTOCS that showed only a modest 14% early-stage shift, underlying a lack of reduction in mortality. Across multiple randomized trials of mammography, those trials that demonstrated at least a 20% late-stage incidence reduction had a significant mortality reduction, whereas those with less of a stage shift did not. Conclusions: An elevated ROCA, characterized by a significantly rising CA125, prompted referral of 2% of participants to TVS each year and required only 2 operations to detect each case of ovarian cancer, indicating that CA125 used in this way is adequately specific for effective screening. While the NROSS trial was not powered to detect reduced mortality, the high specificity, PPV and marked stage shift support further development of this strategy. Clinical trial information: NCT00539162 .
Active bone marrow-sparing to reduce the incidence of grade 3+ acute hematologic toxicity in patients with locally advanced cervical cancer who receive chemoradiotherapy: A single-center prospective randomized controlled trial.
Authors: Wang ShanBing , Liu JiaPei , Lei Kaijian
Published: June 2023

5524

Background: Acute haematologic toxicity is the most common side effect of chemoradiotherapy in patients with locally advanced cervical cancer .We aim to test the efficacy of single-photon emission computed tomography-defined active bone marrow-sparing volumetric-modulated arc therapy in reducing grade 3+ acute hematologic toxicity (HT) in locally advanced cervical cancer patients treated with chemoradiotherapy. Methods: This was a prospective, single-center, open label, randomized clinical trial that enrolled locally advanced cervical cancer patients. Participants were randomized to the 99mTc sulfur colloid SPECT-defined ABMS VMAT (ABMS group) or control group, who received weekly cisplatin concurrently with volumetric-modulated arc therapy followed by high-dose-rate intracavitary brachytherapy. The ABMS group additionally received SPECT-defined ABM dose constraints. The primary endpoint was the incidence of grade 3+ acute hematologic toxicity.Secondary objectives included acute gastrointestinal toxicity, planning Target Volume (PTV) coverage, dosimetric parameters of organs at risk (OARs), progression-free survival (PFS), overall survival (OS). Results: A total of 192 FIGO stage IB-IIIB patients were randomized treated (96 each in the ABMS control groups). The median follow-up was 24.0 months. The incidence of grade 3+ acute hematologic toxicity in the ABMS group was significantly lower than that in the control group (32.3% vs 53.1%, p<0.01). The number of patients completing five cycles of cisplatin was 88.5% in the ABMS group and 75% in the control group, and the difference was significant (p=0.02). There were no significant differences in the mean dose to 95%, 97% and 99%of the PTV between the ABMS group (45.1 Gy, 44.6 Gy, and 43.3 Gy, respectively) and the control group (45.4 Gy, 44.8 Gy, and 43.6 Gy). There were no differences in dosimetric parameters of OARs ,acute gastrointestinal toxicity, 2-year PFS or 2-year OS between the two groups. Patients in the control group had nonsignificantly worse 2-year distant metastasis than patients in the ABMS group (17.8% vs. 11.1%, p=0.19). Conclusions: ABMS VMAT significantly reduced grade 3+ acute HT and improved chemotherapy delivery compared with the control treatment. We found weak evidence of the effect of ABMS VMAT on distant metastasis. Clinical trial information: ChiCTR-IOR-16010214 .
State-of-the-art management of HER2-negative early breast cancer: Treatment patterns among healthcare professionals and concordance with expert recommendations.
Authors: Becker Marie N. , Abraham Jame , Kalinsky Kevin , Spring Laura , Traina Tiffany A. , Quill Timothy A. , Yardley Denise A.
Published: June 2023

553

Background: The management of high-risk HER2-negative early-stage breast cancer (EBC) has recently evolved with the addition of newer agents including abemaciclib, olaparib, and pembrolizumab as (neo)adjuvant therapy options for appropriate patients. To aid healthcare professionals (HCPs) in the recommended implementation of these agents, we developed an online treatment decision support tool providing case-specific treatment guidance from 5 breast cancer experts. Here, we report an analysis of cases entered into the tool by HCPs, comparing their planned treatment with expert recommendations. Methods: Expert therapy recommendations for 10 case scenarios in high-risk HER2-negative EBC based on 3 pivotal clinical trials (KEYNOTE-522, OlympiA, and monarchE) were obtained in March 2022. Patient and disease characteristics included hormone receptor (HR) status, BRCA mutational status, lymph node positivity, presence of residual disease after resection, and additional criteria based on the 3 practice-changing trials. HCPs entered specific patient and disease factors into the tool along with their intended treatment plan and were shown 5 individual expert treatment recommendations for the unique case scenario. Results: From June 2022 to January 2023, 547 HCPs entered 982 patient case scenarios into the tool. A comparison of treatment recommendations by experts and HCPs showed divergence for several case scenarios. For patients with high-risk HR-positive/HER2-negative EBC and no BRCA mutation, all 5 experts recommended adjuvant abemaciclib plus endocrine therapy. By contrast, 64% of HCPs’ therapy choices were discordant with the experts, with 49% choosing chemotherapy followed by endocrine therapy. For patients with triple-negative breast cancer (TNBC) who received neoadjuvant chemotherapy and have no residual disease, all 5 experts recommended observation, whereas 36% of HCPs recommended additional adjuvant therapy. In the setting of BRCA-mutated TNBC with residual disease after neoadjuvant pembrolizumab plus chemotherapy, 4 of 5 experts recommended adjuvant pembrolizumab plus olaparib, but just 33% of HCPs chose this combination. One third of HCPs who initially selected treatment options that diverged from expert recommendations or who were uncertain about treatment choice intend to change their therapy selection to align with the experts. Conclusions: Analysis of data from this tool suggests differences in clinical practice between experts and HCPs for multiple case scenarios of high-risk EBC, including examples of potential overtreatment. Moreover, our data demonstrate that this decision support tool may lead to better alignment of HCP treatment choices with experts, with the potential to improve clinical management of patients.
Patient-reported outcomes during pelvic radiation therapy: A secondary analysis on sexual function from NRG-RTOG 1203.
Authors: Corrigan Kelsey L , Paulus Rebecca , Klopp Ann , Wenzel Lari B. , Yeung Anamaria R , Thompson J Spencer , Doncals Desiree E. , Kundapur Vijayananda , Wiggers Nancy H , Mohan Dasarahally S. , Ghamande Sharad A. , Westin Shannon Neville , Schnarr Kara , Haas Michael , Gaffney David K. , Waggoner Steven E. , Vanderwall Pamela , Jastaniyah Noha , Pugh Stephanie L. , Kachnic Lisa A.
Published: June 2023

5533

Background: NRG-RTOG 1203 reported that intensity-modulated radiation therapy (IMRT) reduced patient-reported GI and GU toxicities in cervical/endometrial cancer patients receiving adjuvant RT, as compared to standard whole field pelvic RT (WPRT). We conducted a secondary analysis of patient-reported sexual function (PR-SF) to compare this endpoint among treatment groups and identify factors associated with sexual dysfunction. Methods: Patients on NRG-RTOG 1203 were randomly assigned to WPRT vs. IMRT and completed the PRO-CTCAE for GI toxicity and the cervical cancer FACT-Cx at baseline, week 5 of RT, and at 4-6 weeks, 1-year, and 3-years post-RT. Patient responses to FACT-Cx sexual function questions were analyzed. The between arm frequency and severity of responses were tested using chi-square. PR-SF was compared with PRO-CTCAE GI toxicity using chi-square. A repeated measures logistic regression model was used to determine the impact of clinical/treatment factors on sexual function by dichotomizing the responses. Results: Of the 279 patients included for primary analysis, 236 (85%) completed PR-SF questions; 125 (53%) in the WPRT arm and 111 (47%) IMRT. There were no significant differences in PR-SF between treatment groups (p>0.05). PR-SF improved for both groups post-RT, except responses to “my vagina feels too narrow or short” worsened (Table). Women without abdominal pain interference at 4-6 weeks post-RT were less likely to fear sex (74.2% vs. 25.8%, P=0.03) and more likely to like their body appearance at 1 year (95.7% vs. 4.3%, P<0.01) compared to women with interference. Women liked the appearance of their body less during RT vs. at baseline (OR 1.95, 95% CI 1.04-3.64, P=0.04). Women were less interested in sex during RT in both arms (WPRT: OR 3.61, 95% CI 1.40-9.34; IMRT: OR 3.96, 95% CI 1.02-15.34) and at 4-6 weeks post-RT for IMRT (OR 3.16, 95% CI 1.14-8.72) vs. at baseline. Conclusions: PR-SF was similar between treatment groups. PR-SF during and post-RT was not significantly reduced compared to baseline with the exception of patients with abdominal pain interference, who had significantly worse PR-SF at 4-6 weeks and 1-year post-RT. Clinical trial information: NCT01672892 . [Table: see text]
Final results of a phase II trial of prolgolimab with platinum-based therapy and bevacizumab in patients with advanced cervical cancer.
Authors: Fogt Sergey , Andabekov Timur , Shamsutdinova Yana , Dvorkin Mikhail , Artamonova Elena , Chistyakov Valerii , Zukov Ruslan , Moiseenko Vladimir , Nechaeva Marina , Odintsova Svetlana , Fadeeva Natalia , Kislov Nikolai , Tantsyrev Denis , Tjulandin Sergei , Fomin Eugeniy , Linkova Iuliia , Zinkina-Orikhan Arina , Shustova Mariia , Zhukova Lyudmila
Published: June 2023

5536

Background: Here we present the final results of single-arm phase II CAESURA (NCT03912402) study of prolgolimab (anti-PD-1 antibody) with platinum doublet and bevacizumab in subjects with advanced cervical cancer (CC). Methods: 58 patients (pts) with metastatic or recurrent/persistent CC with measurable disease received prolgolimab (3 mg/kg) Q3W together with paclitaxel, platinum drug (cis- or carboplatin) and bevacizumab for 6 cycles and then therapy with prolgolimab and bevacizumab until disease progression or toxicity. Objective response rate (ORR) was assessed by central radiology review per RECIST 1.1 (primary endpoint) and iRECIST criteria. CT scans were performed after 9 and 18 weeks of treatment and in case of suspicion on disease progression. Results: Distant metastases at screening had 42 pts, 16 had recurrent or persistent CC. The median age of pts was 48 [38; 58] years old. Squamous cell carcinoma was diagnosed in 50 of 58 subjects. PD-L1 CPS ≥ 1 (22C3) was found in 45 pts, CPS < 1 in 6 cases. ORR per RECIST 1.1 was 63.8% (37 of 58 pts) and included 2 complete, 35 partial responses. ORR per iRECIST was 70.7% (41 of 58 pts) with 2 complete and 39 partial responses. At the cut-off date (12 months) PFS (secondary endpoint) per RECIST 1.1 criteria counted 8.5 (95% CI 5.7; 10.9) months, per iRECIST criteria it reached 13.1 (95% CI 8.1; 13.6) months. Median overall survival was not reached. Any grade adverse events (AEs) occurred in 98% (57/58) of pts, of them in 69% (40/58) they were related to study treatment, including 12 cases of severe events (gr. 3 or higher). Immune-related AEs (irAEs) occurred in 38% (22/58) of pts. The most common irAEs were gr. 1–2 endocrine disorders (26%), including thyroid disorders and one case of gr. 2 adrenal insufficiency. Other important irAEs included 2 cases of enterocolitis (gr. 3 and 4), 1 case of dermatitis (gr. 3), several cases of gr. 2–3 transaminase elevation (9%). In 15 pts at least one component of study treatment was discontinued due to AE, of them 4 events were related to study treatment (including immune-related enterocolitis and adrenal insufficiency). Conclusions: Prolgolimab in combination with chemotherapy and bevacizumab demonstrated promising efficacy, known and acceptable safety profile in pts with advanced CC. Phase III placebo-controlled trial evaluating prolgolimab with chemotherapy and bevacizumab (NCT03912415) as first-line therapy option in subjects with CC is ongoing. Clinical trial information: NCT03912402 .
Association between serum folate and vitamin B12 and cervical high-risk human papillomavirus (HPV) infection.
Authors: Peitz Josephine , Adebamowo Clement Adebayo , Adebamowo Sally Nneoma
Published: June 2023

5541

Background: Serum concentration of folate (vitamin B9) and vitamin B12 were inversely associated with cervical intraepithelial neoplasia and cervical cancer in some studies. The association between folate and vitamin B12, and human papillomavirus (HPV) infection has not been well elucidated. We evaluated whether low serum level of folate and vitamin B12 was associated with high-risk HPV (hrHPV) infection. Methods: The study population was 6,452 women, aged 18-59 years old, enrolled in the National Health and Nutrition Examination Survey (NHANES), from 2003 to 2016, in the United States. In this cross-sectional study, odds ratios (ORs) of hrHPV were calculated, by quintiles of low folate and vitamin B12 combined, using logistic regression models. Results: The mean age (standard deviation) of the women was 36.98 (12.19) years. Women in the lowest quintile had less than 20.6 nmol/L of folate and less than 248 pmol/L of vitamin B12. Some of the women, 23% (1,509/6,452), were hrHPV positive. In age-adjusted models, low folate and vitamin B12 was significantly associated with hrHPV infection. The ORs and 95% confidence intervals (CI) was (OR: 0.704, 95% CI: 0.509 - 0.975, p = 0.034) for the second, (OR: 0.671, 95% CI: 0.479 - 0.940, p = 0.020) third, (OR: 0.534, 95% CI: 0.370 - 0.770, p = 0.0008) fourth and (OR: 0.476, 95% CI: 0.33 - 0.679, p < 0.0001) fifth quintiles, compared to women in the lowest quintile. The association remained statistically significant after the models were further adjusted for smoking status and income level; women in the highest quintile were less likely to have hrHPV infection compared to those in the lowest quintile (OR: 0.541, 95% CI: 0.343 - 0.855, p = 0.008). Conclusions: This study supports an association between low serum levels of folate and vitamin B12, and hrHPV infection, among women in the United States.
The spectrum of homologous recombination deficiency in cervical cancer: Is it also a cervical issue?
Authors: Ahsan Muhammad Danyal , Webster Emily M. , Kahn Ryan M , Levi Sarah R. , Qazi Murtaza , Perez Luiza , Brewer Jesse T. , Keenahan Laura , Cantillo Evelyn , Chapman-Davis Eloise , Holcomb Kevin , Frey Melissa Kristen
Published: June 2023

5543

Background: Tumors deficient in homologous recombination DNA damage repair (HR-DDR) demonstrate sensitivity to therapeutic agents targeting the HR-DDR pathway, such as poly-ADP ribose phosphate (PARP) inhibitors. The landscape of homologous recombination deficiency (HRD) is not well-characterized for cervical cancer; thus, we sought to analyze the prevalence of somatic pathogenic gene variants (PGVs) in HRD genes in cervical cancers. Methods: The American Association for Cancer Research’s (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) database version 13.0 was queried for all cervical cancer tumors via cBioPortal (http://genie.cbioportal.org). This is a publicly available, multi-institutional database of next-generation sequencing (NGS) genomic profiles of multiple tumors. PGV frequencies of 27 genes involved in HR-DDR were descriptively reported for cervical cancer tumors, with histologic stratification: ATM, ARID1A, ATRX, BRCA1, BRCA2, BARD1, BRIP1, BLM, BAP1, CHEK1, CHEK2, FANCA, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCL, MRE11, NBN, PALB2, RAD50, RAD51, RAD51B, RAD51C, RAD51D, WRN. Results: A total of 857 cervical tumors from 817 patients were included for analysis. At least one somatic PGV in an HRD gene was found in 16.5% of all tumors (141/857). When stratified by histological subtypes with at least 25 tumors sequenced, highest frequencies of ≥1 PGV in HRD genes were observed in mucinous cervical cancer (13/66, 19.7%), cervical adenocarcinoma (48/262, 18.3%), squamous cell cervical cancer (53/349, 15.2%), adenosquamous cervical cancer (6/43, 14.0%) and neuroendocrine cervical cancers (5/42, 11.9%). Substantial rates of PGVs in HRD genes were also observed in histological subtypes with fewer than 25 sequenced tumors. Across all tumors, HRD genes with the highest frequencies of PGVs were ARID1A (9%), BAP1 (3%), ATM (1.6%) and BRCA1 (1.6%). Conclusions: NGS data demonstrate a substantial rate of somatic PGVs in HRD genes in cervical cancers, including among HPV related subtypes. These data suggest the need to expand routine functional HRD status assessment to cervical cancers in order to further characterize the landscape of HRD in these tumors. Furthermore, genetically driven clinical trials are warranted to evaluate the efficacy of HRD-targeted therapies such as PARP inhibitors, ataxia telangiectasia, and Rad-3 related kinase (ATR) inhibitors. [Table: see text]
Efficacy of subsequent therapies in patients (pts) with advanced ovarian cancer (AOC) in the phase III PAOLA-1/ENGOT-ov25 trial according to whether disease progression occurred during or after the end of olaparib (ola) maintenance.
Authors: Harter Philipp , Mouret-Reynier Marie-Ange , Lorusso Domenica , Cropet Claire , Guerra Eva M. , Wolfrum-Ristau Pia , Matsumoto Takashi , Vergote Ignace , Colombo Nicoletta , Maenpaa Johanna Unelma , Lebreton Coriolan , de Gregorio Nikolaus , Mosconi Anna Maria , Rubio-Pérez Maria Jesús , Bourgeois Hugues , Fasching Peter A. , Hardy-Bessard Anne-Claire , Denschlag Dominik , Pujade-Lauraine Eric , Ray-Coquard Isabelle Laure
Published: June 2023

5550

Background: In the PAOLA-1/ENGOT-ov25 trial (NCT02477644), maintenance ola (a PARP inhibitor) + bevacizumab (bev) led to prolonged progression-free and overall survival vs placebo (pbo) + bev in AOC pts, specifically those with homologous recombination-deficient (HRD+) tumors (Ray-Coquard et al. ESMO 2022, LBA29). Here, we explore the efficacy of subsequent chemotherapy (CT) in pts after progression on first-line (1L) treatment in PAOLA-1. Methods: The efficacy of subsequent CT was explored by analyzing the median time from first subsequent therapy (FST) to second subsequent therapy (SST). Efficacy was compared by FST type, HRD status, and timing of progression (during/after ola). A multivariate Cox model was used in ola + bev pts to identify prognostic factors influencing time from FST to SST, including HRD status, platinum-free interval (PFI), clinical risk based on disease stage and surgical status, timing of progression, and response to 1L CT. All P values are exploratory. Results: In total, 544/806 (67.5%) pts progressed and received subsequent CT: 338/537 (62.9%) ola + bev pts and 206/269 (76.6%) pbo + bev pts. In the overall population and in the subgroup who received platinum-based combination therapy (PBC), time from FST to SST was shortest in pts who progressed during ola (Table). Pts who progressed after ola had similar outcomes to pbo + bev pts (Table). Efficacy was broadly consistent regardless of HRD status (Table). The multivariate analysis confirmed that progression after (vs during) ola prolonged time from FST to SST (hazard ratio [HR] 0.65, 95% confidence interval [CI] 0.50–0.84; P=0.0011) independently of other known prognostic factors, such as PFI ≥12 vs <12 months (HR 0.38, 95% CI 0.29–0.51; P<0.0001) or lower vs higher clinical risk (0.58, 0.42–0.81; P=0.0015). Conclusions: In this post hoc exploratory analysis of PAOLA-1, the efficacy of subsequent CT at relapse appeared dependent on whether progression occurred during or after the end of ola treatment. Efficacy was reduced when relapse occurred during ola but was comparable between pts who progressed after ola vs pbo + bev pts. Clinical trial information: NCT02477644 . [Table: see text]
BRCA1 and RAD51 methylation impact on outcome in patients with advanced ovarian cancer: A PAOLA-1 ancillary study.
Authors: Blons Helene , Abdelli Justine , Taly Valerie , Mulot Claire , Laurent Puig Pierre , You Benoit , Harter Philipp , Lorusso Domenica , Garcia Yolanda , Schauer Christian , Hietanen Sakari , Colombo Nicoletta , Vergote Ignace , Kobayashi Hiroaki , De La Motte Rouge Thibault , Buderath Paul , Cecere Sabrina Chiara , Bataillon Guillaume , Pujade-Lauraine Eric , Ray-Coquard Isabelle Laure
Published: June 2023

5559

Background: The PAOLA-1/ENGOT-ov25 trial showed that adding olaparib (ola) to maintenance bevacizumab (bev) after first-line therapy led to a progression-free and overall survival benefit in advanced ovarian high-grade carcinoma (AOC) patients with homologous recombination deficiency (HRD) (Myriad MyChoiceR Genomic Instability Score) or BRCA1/2 mutations (BRCAmut). Here, we address the impact of BRCA1 and RAD51C epimutations to improve our understanding of GIS beyond BRCAmut. Methods: BRCA1 and RAD51C methylation analysis was assessed and quantified in pre-treatment biopsies (66%), after neoadjuvant chemotherapy (NACT) (20%) or unknown (14%) from bisulfite converted DNAs using fluorescent methylation specific PCR and methylation specific droplet digital PCR (ddPCR). Methylation status was correlated to clinical data, BRCA1/2 mutations, GIS and HRD scores, PFS (PFS1, PFS2) and OS. R (r-project.org) was used for statistical analysis. Results: Among the 537 patients randomized to maintenance ola + bev and 269 to placebo (pbo) + bev, 348 and 171 were available for methylation analysis. Their baseline molecular and clinical characteristics were well balanced with those of the entire cohort. Promoter methylation was identified in 67 (12.9%) samples for BRCA1 and 25 (4.8%) for RAD51C (4 were methylated on both genes). Methylation and BRCAmut were mutually exclusive except for 3 samples. Mean GIS scores were 62.5 [59.6-65.5]; 59.4 [57.2-61.5]; 54.2 [50.5-57.8]; 23.4 [21.6-25.2] for BRCA1 or RAD51C methylated ( met-tumors), BRCAmut, non-mut/non-met HRD+ ( b-/m-HRD+) and HRP (proficient) tumors respectively. Among met-tumors 92% (66/72) were GIS positive (>42). The mean GIS score of Met-tumors were significantly higher than that of b-/m- HRD+ samples (p=0,009). Benefit of adding ola maintenance to bev was in a similar between patients with met AOC and those with b-/m- HRD+ tumors ( table). Conclusions: Methylated BRCA1/RAD51 tumors are HRD+ and provide to ovarian cancer patients a similar clinical benefit of ola+bev as patients with b-/m- HRD+ tumors. Methylation assessment represents a rapid and cost effective tool; which coupled with BRCA1-2 somatic testing allows the identification of the majority (81%) of HRD+ AOC. Clinical trial information: NCT02477644 . [Table: see text]
Trends in ovarian cancer incidence and incidence-based mortality: A 15-year population-based analysis.
Authors: Somasegar Sahana , Reddy Ravali A. , Karam Amer
Published: June 2023

5570

Background: The predicted incidence and incidence-based mortality (IBM) of ovarian cancer (OC) in 2023 is lower than prior years. OC encompasses a range of heterogeneous cancers with subtypes categorized on histology and site of origin. Given differences in survival and treatment paradigms, we aim to characterize trends in OC incidence and IBM based on histology and site of origin to determine what factors are responsible for the decline. Methods: Patients with OC from 2000-2019 were identified from the US Surveillance, Epidemiology, and End Results 17 registry database. Using ICD-O-3 codes, patients with epithelial, stromal, and germ cell cancers of the ovary, fallopian tube, and peritoneum were included. Incidence and IBM were reported as age-adjusted rates and stratified by cancer subtype. Using Joinpoint 4.9.1.0, we characterized piecewise log-linear time trends to identify inflection points in the rates’ annual percentage change (APC). Results: The incidence of epithelial OC decreased significantly from 2004-2019 (APC -1.24%). When stratified by disease stage, this trend was seen in distant disease (APC -2.11%) and unknown/unstaged disease (APC -3.40%); however, there was a significant increase in incidence of local disease (APC +0.83%). There was no significant change in the incidence of germ cell and stromal OC from 2004-2019 in all stages. (APC -0.30% and +0.33%). Among all OC subtypes, there was a significant decline in incidence from 2000-2019 (APC -1.57%) with a sharper decline from 2015-2019 (APC -3.41%). Among all cancer subtypes, the incidence trended down from 2000-2019, with a significant decline from 2015-2019 (APC -2.37%). Similar trends are observed in IBM. Among all stages of epithelial OC, there was a significant decrease in IBM from 2006-2019 (APC -2.02%). When stratified by disease stage, there was a decline in IBM in local disease (APC -7.19%, 2014-2019) and distant disease (APC -2.44%, 2010-2019). There were no changes in IBM of germ cell and stromal OC from 2004-2019 (APC +0.78% and -0.20%). Among all cancers, IBM significantly decreased from 2006-2019 (APC -2.28%). When stratified by disease stage, there was no change among local disease and an increase in regional disease from 2006-2019 with the increase from 2006-2010 (APC +14.35%) compared to 2010-2019 (APC +1.45%). Conversely, there was a significant decrease in IBM for distant disease (APC -2.51% from 2010-2019) and unknown/unstaged disease (APC -3.27% from 2006-2019). Conclusions: There has been an overall decline in incidence and IBM of OC over a 15-year period, primarily driven by the epithelial histology. Over the past 20 years, OC has been increasingly diagnosed at earlier stages with a corresponding improvement in survival. While stage migration and improved survival may contribute to these trends, they do not entirely explain them. As new treatments become available, the incidence and IBM of OC may further decline.
Anlotinib combined with carboplatin/paclitaxel and maintenance anlotinib as front-line treatment for newly diagnosed advanced ovarian cancer: A phase II, single-arm, multicenter study (ALTER-GO-010).
Authors: Jiang Yi , Gao Yingchun , Zhou Huaijun , Cai Yulang , Yu Jinjin , Chen Youguo , Xue Jinling , Cheng Wenjun
Published: June 2023

5575

Background: Several studies have shown that antiangiogenic drug combined with chemotherapy as first-line treatment, followed by antiangiogenic drug maintenance therapy significantly improve outcomes for patients with ovarian cancer. Anlotinib, a highly effective VEGFRs, FGFRs, PDGFRs and c-kit multi-target tyrosine kinase inhibitor, has been approved for multiple tumor types in China. The aim of this single arm, multicentric, phase II study is to investigate the efficacy and safety of using anlotinib combined with carboplatin/paclitaxel as front-line treatment for advanced ovarian cancer patients. Methods: Eligible patients with FIGO stage III–IV primary epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer and ECOG PS 0-1 undergo primary cytoreductive surgery or interval debulking surgery, will receive 6-8 cycles of chemotherapy (paclitaxel 175 mg/m2 + carboplatin area under the curve [AUC] 5 q3w) and anlotinib (12 mg po qd, days 1-14, 21 days per cycle, anlotinib will be omitted from the first treatment cycle to prevent delayed wound healing). After chemotherapy finished, anlotinib continues as maintenance monotherapy until disease progression, unacceptable toxicity, or death. Patients with prior anti-angiogenic therapy or major surgical procedure within 28 days before starting anlotinib therapy will be excluded. The primary endpoint is progression free survival (PFS). Key secondary endpoints include overall response rate, disease control rate per RECIST1.1, overall survival, safety. Results: From 9 Sep 2021 to 30 Jan 2023, 30 pts were enrolled, including 96.7% (29/30) high-grade serous carcinoma (HGSC) and 3.33% (1/30) endometrioid carcinoma (EC). The median age was 56 years old, with 96.7% (29/30) patients in FIGO stage III and 3.33% (1/30) in stage IV Median follow-up was 5.36 (95% CI: 3.68, - 7.98) months. PFS rates at 6 months and 9 months were both 100%. Twenty-nine patients (96.7%) experienced adverse events (AE) of any level. The most common AEs include white blood cell decreased, neutrophil count decreased, anemia, platelet count decreased, lymphocyte count decreased and hypertension. There was no treatment-related death during the study. Conclusions: Preliminary results of anlotinib combined with carboplatin/paclitaxel have shown favorable efficacy and tolerated safety profile in newly diagnosed advanced ovarian cancer patients. Clinical trial information: NCT04807166 .
Understanding differences in the rates of BRCA/HRD testing and treatment in 1st line maintenance in patients with ovarian cancer treated by gynecologic oncologists compared to other providers: A quality initiative by Integra Connect (IC) PrecisionQ.
Authors: Kudrik Fred J. , Gart Mike , Blanc Simon , English Sandy , Alwon Erin
Published: June 2023

5576

Background: The role of PARPi in the treatment of advanced ovarian cancer (aOC) has expanded in recent years. In this context, South Carolina Oncology Associates (SCOA) partnered with Integra Connect (IC) on a quality initiative (QI) to evaluate the rate of BRCA and HRD testing in newly diagnosed OC patients and the use of maintenance therapy in the 1st line (1L) setting in aOC. Patients with aOC at SCOA are typically managed by gynecologic oncologists. Methods: Using the IC Precision Q real-world database of over 1 million cancer patients across 275 sites of care, we assessed newly diagnosed OC patients evaluated via medical chart curation from 1/1/2020 to 6/30/2022 for BRCA and HRD testing at SCOA (N = 81) and other oncology practices (N = 1,045). We also studied the use of maintenance therapy in patients with stage II-IV OC who completed platinum-based chemotherapy from 1/1/2020 to 6/30/2022 at SCOA (N = 75) and other oncology practices (N =899). SCOA was compared to other oncology practices in terms of provider specialty treating the patient, rates of HRD and BRCA testing, and use of 1L maintenance treatment in patients with or without BRCA or HRD mutations. Descriptive analyses were used. Proportions were compared using a two tailed two sample z-test. Results: Among newly diagnosed patients at SCOA, 95% of patients with OC were primarily managed by a gynecologic oncologist compared to 5% at other practices. The rate of BRCA testing at SCOA was 81% (66 of 81) compared to 75% (788 of 1045) and HRD testing was 60% (49 of 81) compared to 39% (403 of 1045) at other oncology practices in the IC database. The difference in HRD testing was significant (p < 0.01). The use of 1L maintenance regardless of biomarker status was 64% (48 of 75) at SCOA compared to 50% (449 of 899) at other practices. The difference in 1L maintenance use was significant (p<0.05). PARPi were used at SCOA for maintenance therapy in 82% (38 of 46) of patients compared to 74% (314 of 427) at other practices. The use of maintenance in BRCA or HRD positive patients was 84% (21 of 25) at SCOA compared to 75% (151 of 201) for other practices. Conclusions: In this real-world study, treatment by gynecologic oncologists was associated with higher rates of BRCA and HRD testing and higher use of 1L maintenance treatment in patients with aOC compared to other practices. These findings underscore the importance of gynecologic oncologists in the management of aOC to ensure optimal testing and adherence to treatment guidelines.
Decision value of the circulating tumor DNA on the adjuvant anti-Her2 regimens in patients with Her2-positive breast cancer treated with neoadjuvant therapy.
Authors: Lin Po-Han , Tsai Li-Wei , Lo Chiao , Kuo Sung-Hsin , Huang Chiun-Sheng
Published: June 2023

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Background: A significant proportion of patients with early-stage Her2-positive breast cancer are treated with neoadjuvant therapy (NAT). Previous studies suggested the presence of circulating tumor DNA (ctDNA(+)) after NAT was a significant predictor for recurrence in early-stage Her2-positive breast cancer. However, it is unknown whether the ctDNA(+) was able to guide adjuvant anti-Her2 regimen for patients with early-stage Her2-positive breast cancer? Methods: We enrolled 117 patients who had Her2-positive breast cancer and received NAT. CtDNA was collected before and after NAT as well as detected by Oncomine breast cell-free DNA assay. Adjuvant anti-Her2 regimens were classified as T-DM1 and non-T-DM1. Recurrence-free survival (RFS) was estimated by Kaplan-Meier method and hazard ratio (HR) with 95% confidence interval (CI) was analyzed by Cox proportional hazards regression model. Results: Of the 117 patients enrolled, there were 18 patients receiving adjuvant T-DM1 and 99 receiving trastuzumab (N = 70) or trastuzumab plus pertuzumab (N = 29). CtDNA(+) was observed in 79 patients before NAT while 32 patients remained ctDNA(+) after NAT. Multivariate Cox regression model showed that ctDNA(+) after NAT (HR 3.497 95% CI 1.364-8.964, p = 0.009) was an independently poor factor that predicted recurrence, after adjustment with clinical and pathologic parameters. Non-pCR was associated with an inferior trend of survival but not a statistically significant factor of recurrence. Patients who received adjuvant T-DM1 had a reduced risk of recurrence (HR 0.118, 95% CI 0.015-0.931, p = 0.043) in the multivariate analysis. Further analysis of the prognostic value of adjuvant T-DM1 therapy in context with and without ctDNA, we divided patients into 4 subgroups: ctDNA(-)/non-T-DM1, ctDNA(-)/T-DM1, ctDNA(+)/non-T-DM1 and ctDNA(+)/T-DM1. Our data revealed that patients with ctDNA(+)/T-DM1 had a significantly better RFS than those with ctDNA(+)/non-T-DM1 (p = 0.019). The 5-year RFS was similar between patients with ctDNA (+)/T-DM1 and those with ctDNA(-) after NAT. Conclusions: The presence of ctDNA in patients with early-stage Her2-positive breast cancer after NAT was independently associated with disease recurrence; however, ctDNA(+) after NAT became inconsiderable when patients were treated with adjuvant T-DM1 therapy, which represented ctDNA(+) as an important factor determining adjuvant anti-Her2 regimen.
Triplet maintenance (olaparib, pembrolizumab, and bevacizumab) in BRCA non-mutated patients with platinum-sensitive recurrent ovarian cancer: A multi-center, single-arm phase II study (OPEB-01).
Authors: Kim Yoo Na , Park Boram , Joung Je-Gun , Kim Jae-Weon , Kim Byoung-Gie , Kim Sang Wun , Kim Hee Seung , Choi Chel Hun , Lim Myong Cheol , Ngoi Natalie Yl , Tan David Shao Peng , Lee Jung-Yun
Published: June 2023

5584

Background: The optimal treatment of BRCA 1/2 non-mutated patients with platinum-sensitive recurrent ovarian cancer remains unknown. In this study, we evaluated the efficacy and safety of triplet maintenance therapy in BRCA non-mutated patients with platinum-sensitive recurrent ovarian cancer. Methods: BRCA 1/2 non-mutated patients with platinum-sensitive recurrent epithelial ovarian cancer, showing a complete/partial response after second-line platinum-based chemotherapy, were eligible. Triplet maintenance therapy (olaparib, bevacizumab, and pembrolizumab) was administered until disease progression or unacceptable toxicity. The primary endpoint was the progression-free survival (PFS) rate at six months after therapy initiation. The secondary endpoints were PFS, overall survival, and safety. The translational objectives included biomarker evaluation with respect to survival outcomes. Results: Forty-four patients were enrolled (median age 61 years), majority with high-grade serous carcinoma (93.2%) and partial response (75.0%) to second-line chemotherapy. Overall, 54.6% were homologous recombination deficiency (HRD)-positive (genomic instability score ≥ 42) and 63.6% had PD-L1 positive tumors (combined positive score [CPS] ≥ 1). At 6 months, the PFS rate was 88.6% (95% confidence interval [CI] 75.4–96.2). The median PFS has not been reached. The most common ≥ grade 3 treatment-related adverse events (AEs) were anemia (20.5%) and neutropenia (6.8%), but there were no grade 4 AEs. Exploratory analysis demonstrated remarkable survival outcomes regardless of HRD status, whereas patients with PD-L1 CPS ≥ 1 showed improved PFS compared to those with PD-L1 CPS < 1 ( P = 0·032). Analysis of molecular consensus subtype of the pre-treatment tissue samples showed that patients with mesenchymal subtype demonstrated poor PFS, compared to non-mesenchymal subtypes (p = 0.0023). Conclusions: This is the first report on triplet maintenance therapy in BRCA non-mutated platinum-sensitive recurrent ovarian cancer. The results show that the triplet maintenance therapy is efficacious with manageable toxicity, showing a particular promise for patients with molecular consensus subtype other than mesenchymal. Clinical trial information: NCT04361370 .
Immune features of ovarian tumors with a good response to neo-adjuvant chemotherapy in combination with an anti-PD-L1 alone or with an anti-CTLA4: Data from the randomized IneOV trial (a GINECO study).
Authors: Leary Alexandra , Chardin Laure , Genestie Catherine , Lortholary Alain , Alexandre Jerome , De La Motte Rouge Thibault , D'hondt Veronique , Floquet Anne , Savoye Aude-Marie , Delanoy Nicolas , Gavoille Céline , You Benoit , Grenier Julien , Yaniz-Galende Elisa
Published: June 2023

5586

Background: We have shown that chemotherapy may have immunomodulatory properties and prime the tumor microenvironment (TME) by recruiting cytotoxic immune cells. We previously reported that neoadjuvant chemotherapy (NACT) associated with Durvalumab (D) +/- Tremelimumab (T) resulted in encouraging complete resection (70%) and complete pathological response (18%) rates in patients with unresectable ovarian cancer. Here, we aimed to 1) characterize the immune TME at baseline of responders compared to non-responders and 2) describe changes in immune TME in paired tumor samples at diagnosis and after 3 cycles of NACT with D +/- T in the randomized IneOV trial. Methods: Tumor samples from IneOV trial (55 at diagnosis, 40 after treatment) were analyzed for CD3+, CD68+ and CD20+ by multiplexed immunohistochemistry. Stromal and intra-epithelial TILs were scored as percentage of positive surface. Patients were classified as good pathological responders (pR) (CRS3) or pathological non-responders (pNR) (CRS1 or 2). Intra-tumoral T cell infiltration was described as High or Low (intraepithelial (ie)CD3+ > median vs < , respectively). Non parametric statistical tests were used. We evaluated the correlation of the markers with each others (Spearman test) and with pathological response rate (Mann-Withney test). Results: At diagnosis, in the intra-epithelial compartment of the TME, the most abundant cells were macrophages (median ieCD68+ = 3,4) compared to T (ieCD3+ = 1.1), B (ieCD20+ ND) ANOVA p-value = 0.002 and < 0.0001 respectively . In individual tumors, infiltration by the 3 different immune subsets was poorly correlated suggesting immune TME heterogeneity in OC. Pathological response was evaluable in 64 patients: 19 pR and 45 pNR. At diagnosis, CD3+ (p = 0.02) and CD68+ (p = 0.006) infiltration was significantly higher in pR tumors compared to pNR. Most of pR (76%) had high intra-tumoral CD3+ infiltration versus 39% in pNR (p = 0.011). After treatment, tumors with pR showed significantly greater CD3+ intra-epithelial infiltration compared to pNR (p = 0.047). Conclusions: Our results suggest that good pathological response to NACT +D+/-T is associated with high levels of both T cells and macrophages in iTME at baseline, and increased intratumoral T cell infiltration post-treatment. Work is ongoing to further characterize the iTME, especially in pNR to identify other strategies to enhance the anti-tumor immune response. Clinical trial information: NCT03249142 .