tbuckley/cabot-search huggingface dataset:
A phase II study of fulvestrant and abemaciclib in hormone receptor positive advanced or recurrent endometrial cancer.
Authors: Angela Green, Qin Zhou, Alexia Iasonos, William Zammarrelli, Britta Weigelt, Lora H Ellenson, Rashmi Chhetri-Long, Pooja Shah, Vania Hom, Joseph P. Erinjeri, Iva Petkovska, Sarat Chandarlapaty, Seth M. Cohen, Rachel N. Grisham, Jason A. Konner, Maria M Rubinstein, William P. Tew, Tiffany A. Troso-Sandoval, Carol Aghajanian, Vicky Makker
Journal: Journal of Clinical Oncology (2024)

5511 Background: Inhibition of the Cyclin D-Cyclin dependent kinase (CDK)4/6-INK4-retinoblastoma pathway can overcome acquired or de novo treatment resistance to endocrine monotherapy. Elevated CDK4 expression is observed in 34–77% of endometrioid endometrial cancers (ECs) and is an early event of neoplastic transformation. Responses to endocrine monotherapy in advanced or recurrent EC are suboptimal and short-lived. We hypothesized that CDK4/6 inhibition with abemaciclib combined with fulvestrant is a promising strategy to improve outcomes with endocrine therapy in patients (pts) with advanced or recurrent hormone receptor-positive EC. Methods: This was an investigator-initiated, open label, single arm phase II study in pts with advanced or recurrent EC. Eligibility criteria included age ≥18 years, estrogen receptor or progesterone receptor expression ≥ 1% by immunohistochemistry, measurable disease, ≤ 2 prior lines of chemotherapy, and ≤ 1 prior line of hormonal therapy. All histologies were eligible except carcinosarcoma. Mixed histologies required ≥ 95% endometrioid component. Pts received fulvestrant 500 mg intramuscularly monthly with an initial 2-week loading dose and abemaciclib 150 mg orally twice daily until disease progression or prohibitive toxicity. Primary endpoint was objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors v1.1. Results: At data cutoff (October 7, 2023), 27 pts initiated protocol therapy and 25 pts were evaluable for efficacy. 24 pts (89%) had tumors with endometrioid histology. 9 pts (33%) had prior hormonal therapy and 26 pts (96%) had ≥1 prior line of chemotherapy. 11 pts achieved a partial response resulting in an ORR of 44% (90% CI, 27.0% to 62.1%). The median duration of response, among pts that experienced a response, was 15.6 months (90% CI, 7.2 – nonestimable (NE)). All responses were in grade 1 or 2 endometrioid ECs. 10 out of 11 responses (91%) were in pts with copy number low/no specific molecular profile ECs, while 1 response (9%) was in a patient with microsatellite instability-high EC. Median PFS was 9.0 months (90% CI 1.8 to 20.4) and median OS was 37.8 months (90% CI 16.3 to NE). Most common ≥ grade 3 treatment related adverse events were neutropenia (22%) and anemia (19%). Conclusions: The combination of abemaciclib and fulvestrant has promising activity with durable responses observed in pts with advanced or recurrent EC; a phase 3 trial is planned. Clinical trial information: NCT03643510 .
A phase 1/2 study of the TORC1/2 inhibitor onatasertib combined with toripalimab in patients with advanced solid tumors: Cervical cancer cohort.
Authors: Li Yuan, Pei Shu, Xiaoyu Li, Guiling Li, Keqiang Zhang, Lin Lai, Jinsheng Hong, Chu-Ying Huang, Yongsheng Wang, Hui Xie, Li Zheng, Qi Zhou
Journal: Journal of Clinical Oncology (2024)

5509 Background: Preliminary clinical data of oral TORC1/2 inhibitor, onatasertib (ATG-008), demonstrated anti-tumor activity and acceptable tolerability when combined with toripalimab (tori), an anti-PD-1 monoclonal antibody in solid tumors, especially in cervical cancer (CC). Here, we present results from the anti-PD1 naïve CC cohort of the TORCH-2 study who had at least prior 1 line of chemotherapy with the combination of onatasertib and tori. Methods: The TORCH-2 study is a phase 1/2 open-label, dose escalation and expansion trial of Onatasertib in combination with tori in patients (pts) with advanced solid tumours (NCT04337463). Eligibility criteria included at least one measurable lesion, ECOG 0-1 and adequate organ function. Pts with prior PI3K/AKT/mTOR inhibitor therapy were excluded, regardless of PD-L1 expression. Onatasertib was administered 15mg orally once a day (QD) in combination with tori 240 mg, once every 21 days (Q3W), which is the recommended phase 2 dose for the combination based on previous data. Efficacy assessments were reported based on RECIST1.1 criteria. Results: As of Oct 20, 2023, 31 checkpoint inhibitor (CPI) naïve advanced CC pts who had at least prior 1 line of systemic chemotherapy were enrolled. Median age was 54 years. Baseline ECOG scores were 0 (11 pts) and 1 (20 pts); 29 pts had stage IV disease. There were 19 and 12 pts who had received 1 and ≥2 prior lines of systemic therapy, respectively. The median time from last prior systemic therapy was 16.7 months(m). The efficacy-evaluable population (30 CC pts) had an overall response rate (ORR; best response) of 53.3% (16/30, 3 responders unconfirmed), including 4 CR and 12 PR. The disease control rate was 86.7%. The median time to response was 1.4 months. Median progression free survival (PFS) and 24m PFS rate was 8.4 m and 31.0%, respectively. Median overall survival (OS) was not reach and 24m OS rate was 51.6%. The ORRs of PD-L1 positive, PD-L1 negative, and PD-L1 NA populations were 61.5% (8/13), 55.6% (5/9), and 37.5% (3/8), respectively. One CC pt with negative PD-L1 expression achieved CR and remains on treatment for over 3 years. Thirty pts (96.8%) had ≥ 1 TEAEs; 13 (41.9%) pts had grade ≥ 3 TRAEs. The most common grade ≥ 3 TRAEs included rash (12.9%), lymphocyte count decreased (9.7 %), and decreased platelet count (6.5%). Conclusions: Onatasertib in combination with tori is tolerable with encouraging response rate and disease stabilisation in CC pts at the RP2D combination dose, regardless of PD-L1 expression. Enrolment in the expansion cohort for CPI-treated CC is ongoing, and updated data will be presented. Clinical trial information: NCT04337463 .
Specific vaginal and gut microbiome and the anti-tumor effect of butyrate in women with cervical cancer.
Authors: Mengzhen Han, Yun Feng, Yuhang Zhou, Li Han, Xiaolin Liu, Tao Sun, Junnan Xu
Journal: Journal of Clinical Oncology (2024)

5529 Background: To investigate the vaginal and gut microbes changes during the carcinogenesis of cervical and the auxiliary diagnostic value of microbial markers. To investigate the effect of microbiome-specific metabolites butyric on cervical cancer cells. Methods: We studied 416 vaginal 16S rRNA sequencing data and 116 gut data. Reads were processed using VSEARCH. We used Shannon index, Chao1 index, Simpson diversity index, Beta diversity index, LEfSe analysis, co-abundance network analysis and KEGG enrichment analysis to explore microbiome differences between groups. We constructed random forest models based on genus and validated the models to test their diagnostic effectiveness. Finally, we used the cell counting kit-8 (CCK-8) method to detect cell proliferation capacity and flow cytometry to detect apoptosis and induction of cell cycle progression. Results: Compared to the non-cancerous population, patients with cervical cancer had unique microbial community characteristics in both vaginal and gut ecological niches. Our predictive model based on genus in two ecological regions achieved high accuracy in the diagnosis of cervical cancer (vaginal model AUC=91.58%; gut model AUC=99.95%). Potential functional pathways analysis indicated significant differences between the normal women microbiomes and cervical cancer women microbiomes. Butyric inhibited cervical cancer cell proliferation in a concentration-dependent manner and promoted apoptosis of cancer cells. Conclusions: Significant differences were found in vaginal and gut microbes in patients with cervical cancer compared to the non-cancerous population, and the microflora is involved in cervical carcinogenesis. The prediction models constructed at the genus level in both ecological sites have good diagnostic value for cervical cancer. Microorganisms may be involved in cervical cancer progression in a metabolite-dependent way, and targeting butyric may provide therapeutic options for cervical cancer.
Beacon: A phase II study of bevacizumab, atezolizumab, and cobimetinib in patients with recurrent, platinum resistant, high grade serous ovarian cancer.
Authors: Sathya Manoharan, Mathias Bressel, Paige James, Yi-An Ko, Anne L. Hamilton, Clare L. Scott, Linda R. Mileshkin, Marisa Grossi, Nikki Burdett, Sumitra Ananda, Jayesh Desai, Danny Rischin, Paul J. Neeson, David Bowtell, George Au-Yeung
Journal: Journal of Clinical Oncology (2024)

5565 Background: Platinum resistant high grade serous ovarian cancer (HGSC) is associated with a poor prognosis and limited treatment options. Immune checkpoint inhibitors have failed to show significant impact in treatment of HGSC to date. Bevacizumab (anti-VEGF) and atezolizumab (anti-PDL1) have shown synergy in multiple cancer types. Cobimetinib (MEK inhibitor) may also potentiate immune responses, particularly by altering the tumour microenvironment. We sought to evaluate the efficacy of cobimetinib, bevacizumab and atezolizumab in women with platinum resistant HGSC. Methods: BEACON is a Phase II single arm study of cobimetinib (60mg oral D1-21 q 28-days), bevacizumab (5mg/kg IV q2w) and atezolizumab (840mg IV q2w from Cycle 2) in patients with platinum-resistant recurrent HGSC. Patients continued therapy until progression or unacceptable toxicity. The primary endpoint was overall response rate (ORR) according to RECIST 1.1 at 24 weeks. Secondary endpoints included best overall response (BOR), safety, progression free survival, and response duration. Correlative studies on paired tumor biopsy and blood samples will explore molecular characteristics/subtypes and potential biomarkers of response as exploratory objectives. This study has now completed accrual and we present the 24-week response data, with a data cut off 21st December 2023. Results: Twenty-nine patients were enrolled between September 2018 and June 2023. Median age was 62 years (range 37 - 79) and 97% had received ≥ 2 prior lines of chemotherapy. The median number of cycles received was 3 cycles of atezolizumab and cobimetinib, and 4 cycles of bevacizumab. The ORR at 24 weeks was 21% [95% CI: 8-40], and a further 28% had stable disease as assessed per RECIST. Five patients (17%) have remained on study treatment for ≥ 52 weeks to date, suggesting that in some patients there was durable disease control. In terms of safety, 22 patients (76%) required a dose reduction in cobimetinib, mainly due to gastrointestinal and skin toxicity. Seventeen patients (59%) experienced a ≥Grade 3 treatment related adverse event, most commonly hypertension (6 patients, 21%). Two patients (7%) discontinued all study treatments due to toxicity. Conclusions: Preliminary results from this study show promising efficacy with the combination of atezolizumab, bevacizumab and cobimetinib in platinum resistant HGSC. Duration of response, progression free survival data and translational data exploring molecular characteristics will be presented as data matures. Clinical trial information: NCT03363867 . [Table: see text]
Phase Ib INEOV neoadjuvant trial of durvalumab +/- tremelimumab with platinum chemotherapy for patients (pts) with unresectable ovarian cancer (OC): Survival outcomes and immune correlates.
Authors: Alexandra Leary, Laure Chardin, Alain Lortholary, Bernard Asselain, Jerome Alexandre, Coriolan Lebreton, Aude-Marie Savoye, Stephane Oudard, Céline Gavoille, Benoit You, Veronique D'hondt, Julien Grenier, Elisa Yaniz-Galende, Cyril Roussel-Simonin, Thibault De La Motte Rouge, Eric Pujade-Lauraine
Journal: Journal of Clinical Oncology (2024)

5569 Background: Ineov was a phase Ib randomized trial of neoadjuvant carboplatin/paclitaxel (NACT) + durvalumab (D) +/- tremelimumab (T) in unresectable OC. We previously reported safety and encouraging complete resection rates (CC0=70%) and complete pathological response rates (pCR=18%) at interval debulking surgery (IDS). However there were no significant differences with the addition of T to D+NACT. Here we report survival outcomes and immune correlates with a focus on long-term responders. Methods: Pts with unresectable stage IIIC/IV OC were randomized to NACT + D (1125mg) alone (arm A) or with T (75mg once at C2) (arm B). IDS was planned after C3, or delayed after C6. Pts in arm A not operable after C3 crossed over to arm B, pts in arm B crossed over to standard of care (SOC) and assessed for delayed IDS after C6. PFS was assessed by Kaplan-Meier and PFS compared between arms A and B by Log-Rank test. Intra-epithalial CD8+ lymphocytes were scored as nb/mm 2 and HLA-I expression was scored by H-score. Results: 70 patients were randomized to Arm A (N=36) or Arm B (N=34). 4 pts were replaced for early toxicity and one early death attributed to COVID. Median PFS in all pts was encouraging at 18mo but not different between arms. CCO at IDS was associated with significantly improved PFS (mPFS 25mo vs 14mo; p 0.0008). NACT+D+/-T significantly increased intra-epithelial CD8+ infiltration (p&lt;0.0001) and HLA-I levels (p=0.007), but the changes were no different in arm A vs B. While high ieCD8 predicted improved pathological response (p=0.0014), neither ieCD8 nor HLA-1 levels at baseline or IDS predicted improved PFS. 8 (12.5%) pts were disease free at &gt;40months. When compared to the other patients in the trial, this subset of long-responders was characterized by higher pCR (38% vs 11%), higher CC0 rates (100% vs 66% ) but showed no differences in immune profile. Among pts with known BRCA status, 43% of long-responders had a BRCAm (vs 20%). Conclusions: NACT combined with immunotherapy resulted in encouraging CC0, pCR and PFS in pts with unresectable OC, however the addition of T to D did not improve immune infiltration or outcomes. Features associated with long response were pCR, CC0 and BRCAm, not immune features. Clinical trial information: NCT03249142 .
Unveiling the unique identity of clear-cell endometrial cancer (CCEC): A comprehensive comparative analysis with ovarian counterpart and other endometrial subtypes.
Authors: Felix Blanc-Durand, Natalie Ngoi, Etienne Rouleau, Patricia Pautier, Judith Michels, Kaïssa Ouali, Catherine Genestie, Yi Wan Lim, Diana Lim, Silvana Talisa Wijaya, Alexandra Leary, David Shao Peng Tan
Journal: Journal of Clinical Oncology (2024)

5521 Background: Clear cell endometrial cancer (CCEC) is a rare and poorly understood entity, comprising less than 10% of endometrial cancer cases. In contrast, clear-cell ovarian cancer (CCOC) ranks as the second most prevalent subtype among epithelial ovarian cancers. CCOC is distinguished by specific phenotypic and molecular features, coupled with an overall aggressive behavior. CCEC and CCEC both share clinical and pathologic characteristics, suggesting common pathogenesis. This study aims to elucidate the molecular landscape of CCEC, in comparison with CCOC and other EC subtypes (nEC). Methods: We conducted a multicenter, retrospective analysis of CCOC, CCEC and nEC patients from Institut Gustave Roussy in France and National University Cancer Institute in Singapore. All patients underwent comprehensive molecular profiling using the tumor-based FoundationOneCDX panel. Results: This study analyzed 19 patients with CCEC, 81 patients with CCOC and 91 patients with nEC. CCEC exhibited distinct clinical and molecular features compared to CCOC or nEC. CCEC patients were significantly older (mean age 64.6 years) compared to CCOC (53.0 years, p&lt;0.001) and nEC (59.9 years, p&lt;0.001) cohorts. They also presented more frequently with FIGO IV disease (63.2%) versus 16.7% in CCOC patients (p&lt;0.001) and 28.9% in nEC patients (p=0.007). Compared to CCOC, CCEC harbored significantly fewer ARID1A mutations (15.8% vs 54.3%, p=0.004), fewer KRAS mutations (0% vs 19.8%, p=0.035), significantly more TP53 mutations (42.1% vs 13.6%, p=0.008), and higher loss-of-heterozygosity (LOH) scores (10.5% vs 4.5%, p=0.004). Compared to nEC, CCEC exhibited significantly fewer CTNNB1 mutations (0% vs 18.7%, p=0.04), fewer PTEN mutations (5.3% vs 57.1%, p&lt;0.001) and fewer KRAS mutations (0% vs 22.0%, p=0.021). Additionally, CCEC had higher LOH scores (10.5% vs 3.7%, p=0.019), and tended be less frequently associated with microsatellite instability (0% vs 19.3%, p=0.07) compared to nEC. Conclusions: CCEC significantly differs from CCOC and nEC in both clinical and molecular aspects. These findings support the consideration of CCEC as a distinct entity, advocating for a personalized approach that takes into account both the clear-cell aspect and the endometrial cancer molecular stratification.
Artificial intelligence to predict homologous recombination deficiency in ovarian cancer from whole-slide histopathological images.
Authors: Jean-Sebastien Frenel, Céline Bossard, Joseph Rynkiewicz, Florian Thomas, Yahia Salhi, Sanae Salhi, Jérôme Chetritt
Journal: Journal of Clinical Oncology (2024)

5578 Background: In the field of ovarian cancer diagnosis, predicting Homologous Recombination Deficiency (HRD) holds paramount importance for personalized treatment strategies. Histopathology tissue analysis is considered as the gold standard in cancer diagnosis, prognosis, and theranostic. Whole Slide Imaging, i.e the scanning and digitization of entire histology slide, is now being adopted in numerous pathology labs, allowing development of deep-learning analysis of the large amount of morphological features contained in these WSI. The aim of this study is the development of a cutting-edge deep learning model designed to predict HRD status directly from WSIs of ovarian cancer tissue samples. Methods: We introduce a DNN designed to predict the HRD status for patients with ovarian cancer from whole slide images (WSI), using a fusion-like model using both cellular information and tissue-level morphological features. The algorithm has been trained and evaluated using a cross-testing and cross-validation technique on 151 patients with at least one WSI from a discovery dataset using a 5-fold stratified framework. We then externally validated the model onto The Cancer Genome Atlas (TCGA) from which the HRD status is available (n=93). Results: The performance of HRD status prediction was assessed on the basis of area under curve (AUC).The proposed architecture achieved an AUC of 0.74 on the discovery cohort and 0.67 on the TCGA. Results to the pathologist could be provided immediately and integrated into the pathologist report. External validation on the PAOLA cohort dataset is ongoing. Conclusions: By harnessing the power of deep neural networks (DNN), we provide a rapid and scalable solution for HRD prediction, circumventing the limitations of traditional molecular assays. Successful integration of this deep learning model into routine pathology workflows could significantly enhance diagnostic efficiency, reduce the turnaround time and financial cost compared with molecular assay. It could finally inform clinicians in tailoring targeted therapeutic interventions for ovarian cancer patients, thereby advancing precision medicine in the context of HRD-associated ovarian cancers.
Consistent data about the predictive factors of the success of interval debulking surgery (CC0-IDS) in patients with advanced ovarian cancers in two large independent datasets.
Authors: Benoit You, Anna Fagotti, Olivier Colomban, Diana Giannarelli, Felix Blanc-Durand, Giovanni Scambia, Aurore Carrot, Domenica Lorusso, Eric Pujade-Lauraine, Raffaella Ergasti, Gaetan De Rauglaudre, Carolina Maria Sassu, Isabelle Laure Ray-Coquard, Filippo Maria Capomacchia, Pierre Combe, Adriana Ionela Apostol, Gwenael Ferron, Umberto Malapelle, Alexandra Leary, Claudia Marchetti
Journal: Journal of Clinical Oncology (2024)

5560 Background: More than 50% of patients with FIGO stage III-IV epithelial ovarian cancers are treated with neoadjuvant chemotherapy (NACT) to achieve a complete interval debulking surgery (IDS), in the case of tumor response. Therefore, understanding the determinants of IDS success is crucial. The French GINECO and the Gemelli (Italy) groups analyzed 2 independent datasets to identify the predictive factors associated with low peritoneal carcinomatosis index (PCI) after 3or4 NACT cycles; complete IDS with no macroscopic residual lesion (CC0); high pathological chemotherapy response score (CRS3). Methods: The French dataset was built with the CHIVA (C) randomized phase II trial in 133 patients (NCT01583322). The Italian dataset was built with the Policlinico GEMELLI (G) real-life registry with 357 patients (ID5936–ProtN45). Univariate/multivariate logistic regression models were used to identify the clinical and biological covariates associated with: 1) low PCI after NACT (Sugarbaker PCI ≤ 10, or Fagotti score at IDS ≤ 2); 2) CC0 IDS; and 3) pathological CRS3. The tested predictors were the modeled CA-125 longitudinal kinetics parameter KELIM; the best radiological response according to RECIST 1.1; and BRCA mutation/ homologous recombination deficiency (HRD) status (C: ShallowHRD; G: Myriad&amp;AmoyDx). The analyses were led independently in the 2 datasets. Results: Odds-ratios (OR) outcomes [95%CI] are presented in Table (*significant variables at multivariate). In both datasets, higher KELIM was the only predictor reproducibly associated with lower PCI after NACT (OR 4.08-4.44); higher probability of complete IDS (OR 4.66-7.29); and higher probability of pathology CRS3 (OR 2.97-12.43). The radiological response was inconsistently significant. The BRCA/HRD status was not predictive of IDS success elements. Conclusions: In 2 independent international datasets, the tumor primary chemosensitivity (assessed by CA-125 KELIM) was the only consistent predictor of IDS success after NACT in both datasets. Clinical trial information: NCT01583322 . [Table: see text]