tbuckley/cabot-search huggingface dataset:
Rising trends in HPV (+) &amp; HPV (-) vulvar cancers among US non-Hispanic White and Hispanic White females 50 years and older.
Authors: Ana Paola Mata Zetina, Sritha Rajupet, Theodore Strange, Meekoo Dhar, Lohitha Dhulipalla, Asmaa Mokhtar, Mario R Castellanos
Journal: Journal of Clinical Oncology (2024)

5620 Background: Our prior studies show that vulvar cancer in older females is increasing in the US, aligning with lengthened USPSTF cervical cancer screening intervals. Most medical societies do not recommend genital exams post-cervical cancer screening, and data on vulvar cancer is lacking to make comprehensive screening strategies. We utilized the SEER database to examine vulvar cancer, HPV status, and race/ethnicity to better understand the characteristics of patients who develop cancer. Methods: We examined vulvar cancer cases &amp; data from 2000-2020, as reported in the SEER database. Estimations of HPV-positive vulvar cancer rates by age were derived using HPV attribution percentages from the HPV Centre Information United States Full Report, with younger females defined as &lt; 54 years. Correspondingly, cases not within this percentage were classified as HPV-negative. Results: From 2000 to 2020, vulvar cancer incidence in the US increased by 14%, with rates rising from 2.18 to 2.40 per 100,000. This rise was most pronounced in Non-Hispanic White females over 50, whose rates grew from 2.41 in 2000 to 2.87 in 2020, more than any other race and ethnicity. For HPV-positive vulvar cancer, there was a 1.5% decrease in cases among females under 54. In contrast, there were significant increases in the 55-64 and 65+ age groups, with 53% and 14% rises, respectively. Additionally, the 55-64 age group experienced a notable 23% increase in HPV-negative cases, and those 65+ had a 9% rise. Conclusions: This study is the first to show a significant increase in vulvar cancer among non-Hispanic White females, particularly those aged above 50 years. Surprisingly, we observed that HPV (+) cancers, typically associated with younger demographics, are continuing to occur in older females. This is concerning since the HPV vaccine, introduced in 2007, wasn't available for HPV prevention in females now over 50. Concurrently, there is a rise in HPV-negative vulvar cancers within these older age groups. The current guidelines don't recommend routine genital exams for females over 65, indicating that there may be an opportunity to reexamine this recommendation given the US vulvar cancer trends in older females.
Fruquintinib plus sintilimab in treated advanced endometrial cancer (EMC) patients (pts) with PMMR status: Results from a multicenter, single-arm phase 2 study.
Authors: Xiaohua Wu, Jing Wang, Danbo Wang, Guiling Li, Jieqing Zhang, Hongmin Chen, Hongying Yang, Qi Zhou, Ke Wang, Yumei Wu, Tienan Yi, Jihong Liu, Yi Huang, Yuxian Bai, Keming Wang, Kui Jiang, Hanmei Lou, Ruifang An, Xiumin Li, Weiguo Su
Journal: Journal of Clinical Oncology (2024)

5619 Background: Antiangiogenic therapy plus immunotherapy significantly improved PFS and OS as compared to chemotherapy among pts with previously treated advanced EMC per KEYNOTE-775 study. However, no combination immunotherapies are currently approved for EMC in China. Fruquintinib (F, a highly selective VEGFR inhibitor) plus sintilimab (S, an anti-PD-1 monoclonal antibody) showed encouraging antitumor activity in multiple solid tumors. Here, we reported the results of F plus S in treated EMC with pMMR status from an open-label, single-arm registrational phase 2 study (NCT03903705). Methods: Eligible pts had histologically confirmed, previously treated advanced EMC with pMMR status confirmed by central lab. They received F (5 mg QD, 2 weeks on/1 week off, orally) plus S (200 mg, IV, Q3W) in 21-day cycles until disease progression or unacceptable toxicity. The primary endpoint was IRC-assessed ORR per RECIST v1.1. Secondary endpoints included DCR, DoR PFS, and OS. Results: As of data cutoff date (November 15, 2023), a total of 98 pts with pMMR status were enrolled and received the combination treatment. All pts had previously received at least first-line platinum-containing systemic therapy, and 22.4% pts had received bevacizumab therapy. Detailed disease histories are summarized in the table. With the median (95% CI) follow-up time of 15.7m (14.6, 17.7), 87/98 pts had at least one post-baseline tumor assessment result (efficacy evaluable pts), among them, IRC-assessed ORR and DCR was 35.6% (CR: 2/87 and PR: 29/87) and 88.5% respectively; DoR was not reached and the 9m-DoR rate was 80.7%. Among 98 pts, the median (95% CI) PFS and OS was 9.5m (5.6, -) and 21.3m (17.3, -) respectively. Based on prior bevacizumab therapy (Yes vs No), ORR was 40.9% vs 30.3%, and median (95%CI) PFS was 13.8m (4.1, -) vs 9.5m (5.5, -). All pts experienced TEAEs, and the most common ≥Grade 3 TEAEs included hypertension (18.4%), hypertriglyceridaemia (11.2%), and palmar-plantar erythrodysaesthesia syndrome (11.2%). Conclusions: F plus S showed meaningful efficacy improvements in advanced EMC pts with pMMR status, regardless of prior bevacizumab treatment. The combination therapy had a manageable toxicity profile. F plus S could offer a new potential treatment option for this patient population. Clinical trial information: NCT03903705 . [Table: see text]
Molecular characterization of cervical cancer histological subtypes: The VENUS study.
Authors: Dina Braik, Husam Alqaisi, Vikas Garg, Pamela Soberanis Pina, Liana Valente Lage, Ana Veneziani, Brooke Grant, Anmol Kaur Pannu, Katherine Lajkosz, Anthony Msan, Anjelica Hodgson, Marjan Rouzbahman, Tracy Stockley, Valerie Bowering, Robert C Grant, Neesha C. Dhani, Stephanie Lheureux, Amit M. Oza
Journal: Journal of Clinical Oncology (2024)

5537 Background: While the landscape of cervical cancer treatment has undergone considerable advances, systemic treatment options following recurrence remain limited. There is paucity of data on predictive and prognostic molecular alterations within distinct histologic subtypes. Methods: In this prospective, translational, single-institution study (NCT03420118), patients diagnosed with cervical cancer were enrolled. Tumor tissue samples (biopsy or archival) were obtained at different time points from initial histological diagnosis to each progression, when feasible. Genomic DNA was extracted and analyzed, using the UHN Hi5 Panel and the Illumina TruSight Oncology 500 assays, to detect molecular alterations. Variant annotations were obtained from OncoKB database. In addition, clinical data for each patient, including histopathologic subtype, stage at diagnosis, and lines of treatment were collected. Results: 124 patients (median age 48 years; range 24-80) with a pathologic diagnosis of cervical cancer were enrolled. Clinical characteristics of patients with available tumor tissue samples (n=112) are detailed in the table. In 99 of the 112 (88.4%) available tumor tissue samples, 243 validated molecular alterations were identified across 88 different genes. Seven tumors had ≥ 5 alterations detected per sample; one squamous cell carcinoma (SCC) and one poorly differentiated adenocarcinoma (AC) had 14 alterations each. PIK3CA, the most frequently detected alteration (41/243; 16.8%), was identified in 22 of 58 (37.9%) SCC samples vs 8 of 38 (21.1%) AC samples (p-value 0.11). Other commonly detected alterations included TP53 (18/243; 7.4%) and KRAS (13/243; 5.3%), both identified more frequently in AC compared to SCC tumor samples (28.9% vs 3.4%; p-value &lt; 0.001, and 23.7% vs 3.4%; p-value 0.006, respectively). KRAS alterations were predominantly G12D or G12V. No G12C variants were detected. All tumors were MSI-stable. Among rare histologic subtypes, unique alterations were detected. Adenosquamous subtypes had alterations of TET2, BARD1, BRAF, in addition to CCND3 and CCNE1amplifications, while neuroendocrine subtypes showed alterations of ATM, MYC, SDHB, TSC1, FANCE, and FGFR1. Overall survival did not show a significant correlation with molecular alterations among different subtypes. Conclusions: Genomic analysis of histologic subtypes of cervical cancer reveals distinctive molecular features which may allow the development of genomic biomarkers of resistance and sensitivity. [Table: see text]
Analysis of healthcare provider treatment of advanced endometrial cancer and concordance with expert recommendations in 2023 vs 2022.
Authors: Kristen M. Rosenthal, Megan Cartwright, Jerfiz D. Constanzo, Hye Sook Chon, Linda R. Duska, Ebony R. Hoskins, Ritu Salani
Journal: Journal of Clinical Oncology (2024)

5613 Background: Practice patterns are rapidly evolving for first-line (1L) treatment (tx) of advanced endometrial cancer (aEC). In 2022, we created an online interactive decision support tool [clinicaloptions.com/Endometrialtool] for healthcare professionals (HCPs) with case-specific recommendations from 5 gynecologic oncology experts for treating 1L and second-line (2L) aEC. In 2023, NCCN guidelines included a recommendation of carboplatin/paclitaxel plus an immune checkpoint inhibitor (ICI) for 1L tx of aEC. Working with the experts, we updated the tool to its current 2023 version. Here, we compare planned tx reported by HCPs using the 2023 tool vs expert recommendations and compare practice patterns for the 2023 vs 2022 tools. Methods: To use the 2023 tool, HCPs entered key characteristics, including the tx setting; tumor histology (1L only); actionable biomarker status (dMMR/MSI-H, HER2, ER/PgR); prior tx, response, and response duration (2L only); and planned tx. After HCPs reported their planned tx, the tool showed expert recommendations for that scenario and asked if the recommendations changed the planned tx. Results: From September 2023 to January 2024, 123 HCPs entered 181 cases into the tool, of which 45% were in the 1L setting. HCPs reported a biomarker status of "unknown” in 30% of 1L cases. In 2022, all experts recommended platinum-based chemotherapy (plt CT) ± bevacizumab for 1L HER2-negative cases, whereas all experts in 2023 recommended plt CT + ICI for 1L cases with dMMR/MSI-H (Table). There was less consensus on adding ICI to plt CT when 1L cases had no actionable biomarker. In 2023, the tx planned by HCPs matched ≥1 expert in 29/54 (54%) of 1L cases—a modest improvement from 2022, when matches occurred in 19/42 (45%) of 1L cases. In 2023, match rates were highest for dMMR/MSI-H cases (50%-86%), followed by cases without actionable biomarker (36%-50%) or HER2+ (33%-67%). Overall, 88% of HCPs indicated that the tool recommendations either changed or confirmed their tx plan. Conclusions: HCPs are challenged to optimally manage 1L aEC in concordance with expert recommendations and/or NCCN guidelines. Detailed analyses of HCP tx vs expert recommendations in the 1L and 2L settings and 2023 vs 2022 practice patterns will be presented. [Table: see text]
Using artificial intelligence-powered evidence-based molecular decision-making for improved outcomes in ovarian cancer.
Authors: Brian Christopher Orr, Arlette Harper Uihlein, Robert Montgomery, Mackenzy Radolec, Robert P. Edwards
Journal: Journal of Clinical Oncology (2024)

5555 Background: High grade serous ovarian cancer (HGSC) is a complex deadly disease. Due to the lack of symptoms at early stages, vast majority patients present at stage III/IV. Frontline chemotherapy and surgery is effective with nearly all patients experiencing a remission, though over 80% patients will recur in the first 1-2 years and ultimately die of the disease in the next few years. Approximately 20% will be long-term survivors, but no current clinical data can predict who may be a short- or long-term survivor. Clinical management, monitoring, and systemic treatment decisions could be optimally individualized to patients if able to better define the prognosis. The goal of this study is to employ artificial intelligence multi-omic machine learning models to predict survival outcomes. Methods: Clinical data and tumor specimens from University of Pittsburgh Center from 2010-2016 were analyzed. Patient data, whole exome sequencing (WES), whole transcriptome sequencing (WTS), drug response profile, and digital pathology profile were used as input feature sets for training the multi-omic machine learning (ML) models. Hypothesis-free training of the ML models was utilized to classify patient survival at 2yr and 5yr threshold. Model performance was estimated using AUROC (area under the receiver operating characteristic curve) metric, scores &gt;0.5 having higher prediction potential. Validation of the prediction results of each ML model with top performing models meeting statistical significance threshold of α=0.01. Results: 160 HGSC model builds were completed. ML models achieved high prediction accuracy for both short-term (2y) and long-term (5y) patient cohorts, identifying 7 models with ≥ 0.7 AUROC model performance for 2yr OS threshold and 13 models with ≥ 0.7 AUROC model performance for 5yr OS threshold. Addition of multi-omic feature sets to clinical profile improved the model’s ability to predict OS for both short-term and long-term thresholds. Multi-omic feature set inputs led to superior prediction and improved performance over clinical profile information alone, and top performing multi-omic models predicted better than any feature set in isolation. Comparison of top features identified by 2y and 5y OS threshold models, we found that molecular features (WTS followed by WES feature sets) predominantly drove 2y cohort while digital pathology imaging features were the driver the 5y cohort top performing models. Conclusions: Current clinical data does not accurately predict prognosis. Utilizing multi-omic machine learning models, superior prediction of short- and long-term survivors was achieved. The specific drivers of the top performing models were different for the short- and long-term cohorts, identifying future research opportunities as well as development potential of a clinical decision tool.
Telisotuzumab Vedotin Monotherapy in Patients With Previously Treated c-Met Protein–Overexpressing Advanced Nonsquamous <i>EGFR</i>-Wildtype Non–Small Cell Lung Cancer in the Phase II LUMINOSITY Trial
Authors: D. Ross Camidge, Jair Bar, Hidehito Horinouchi, Jonathan Goldman, Fedor Moiseenko, Elena Filippova, Irfan Cicin, Tudor Ciuleanu, Nathalie Daaboul, Chunling Liu, Penelope Bradbury, Mor Moskovitz, Nuran Katgi, Pascale Tomasini, Alona Zer, Nicolas Girard, Kristof Cuppens, Ji-Youn Han, Shang-Yin Wu, Shobhit Baijal, Aaron S. Mansfield, Chih-Hsi Kuo, Kazumi Nishino, Se-Hoon Lee, David Planchard, Christina Baik, Martha Li, Peter Ansell, Summer Xia, Ellen Bolotin, Jim Looman, Christine Ratajczak, Shun Lu
Journal: Journal of Clinical Oncology (2024)

Telisotuzumab vedotin (Teliso-V) is a c-Met-directed antibody-drug conjugate with a monomethyl auristatin E cytotoxic payload. The phase II LUMINOSITY trial (ClinicalTrials.gov identifier: NCT03539536) aimed to identify the optimal c-Met protein-overexpressing non-small cell lung cancer (NSCLC) population for treatment with Teliso-V (stage I) and expand the selected group for efficacy evaluation (stage II). Stage II enrolled patients with nonsquamous epidermal growth factor receptor (
Durvalumab + carboplatin/paclitaxel (CP) followed by durvalumab ± olaparib as first-line treatment for newly diagnosed advanced or recurrent endometrial cancer (EC) in DUO-E: Results by <i>BRCA1</i>/<i>BRCA2</i> mutation (BRCAm) status.
Authors: Els Van Nieuwenhuysen, Jean-Francois Baurain, Hye Sook Chon, Jessica Thomes Pepin, Michael J. Sundborg, Michael A. Gold, Byoung-Gie Kim, Stephanie V. Blank, Ji-Hong Liu, Michael McCollum, Masahiko Mori, Goda Jonuškienė, Kathleen N. Moore, Zoltán Novák, Pedro Ramos, Charles Andreé Joseph de Padua, Marta Gil-Martin, Matthew Kowgier, Paula Michelle del Rosario, Shannon Neville Westin
Journal: Journal of Clinical Oncology (2024)

5595 Background: DUO-E (NCT04269200) showed statistically significant, clinically meaningful improvement in progression-free survival (PFS) with addition of durvalumab to CP, followed by durvalumab ± the PARP inhibitor olaparib, vs CP alone for patients (pts) with EC (Westin SN et al. J Clin Oncol 2024;42:283–99). PARP inhibitors are an established approach to targeting tumors with homologous recombination deficiency, so we performed post hoc exploratory analyses of PFS by BRCAm status. Methods: Pts with newly diagnosed FIGO Stage III/IV or recurrent EC and naïve to first-line systemic treatment were randomized 1:1:1 to CP (CP + durvalumab placebo [pbo; 6 cycles] followed by durvalumab pbo + olaparib pbo), CP+D (CP + durvalumab [1120 mg q3w; 6 cycles] followed by durvalumab [1500 mg q4w] + olaparib pbo) or CP+D+O (CP + durvalumab [6 cycles] followed by durvalumab + olaparib [300 mg bid]). Tissue BRCAm status was determined retrospectively (FoundationOneCDx assay, Foundation Medicine). Results: Of 718 pts randomized, 19.9% were mismatch repair deficient (dMMR) and 80.1% MMR proficient (pMMR). At primary analysis (April 12, 2023), PFS improvement was observed for CP+D and CP+D+O vs CP irrespective of BRCAm status (Table). BRCAm prevalence was low overall (dMMR: 12.6% BRCAm, 61.5% non-BRCAm, 25.9% unknown; pMMR: 4.0% BRCAm, 65.9% non-BRCAm, 30.1% unknown). PFS outcomes for CP+D+O vs CP in pMMR non-BRCAm pts (HR 0.57, 95% CI 0.42–0.78) were consistent with the overall pMMR subgroup (HR 0.57, 95% CI 0.44–0.73); BRCAm subgroup analyses were descriptive due to small sample size. Conclusions: Clinical benefit with addition of durvalumab to CP, followed by durvalumab + olaparib, vs CP alone was observed in the ITT and pMMR populations irrespective of BRCAm status. Clinical trial information: NCT04269200 . [Table: see text]
Efficacy and safety of cadonilimab plus anti-EGFR monoclonal antibody as de-chemotherapy regimen in persistent, recurrent, or metastatic gynecologic cancer.
Authors: Qiying Zhang, Zi Liu, Jing Zhang, Fei Wang, Shi Fan, Juan Wang, Tao Wang, Jin Su
Journal: Journal of Clinical Oncology (2024)

5538 Background: Cadonilimab, an anti-PD-1/CTLA4 bi-specific antibody, and Nimotuzumab, an anti-EGFR monoclonal antibody, have demonstrated effectiveness in treating persistent, recurrent, or metastatic (P/R/M) cervical cancer individually. However, the exploration of combined bi-specific immunotherapy and anti-EGFR target therapy remains unexplored in P/R/M gynecological cancer. Methods: This open-label, prospective single-arm phase II study (NCT05606263). Eligible participants were P/R/M gynecological cancer patients who declined or couldn’t tolerate chemotherapy, or had failed first-line or subsequent treatments, irrespective of PD-L1 status. Patients received Cadonilimab at 6 mg/kg plus Nimotuzumab at a dose of 400 mg every two weeks. The primary endpoint included safety and objective response rate (ORR), with secondary endpoints comprising progression-free survival (PFS) and overall survival (OS). Results: From July 2022 to February 2024, twenty-nine P/R/M gynecological cancer patients received at least one dose of cadonilimab plus Nimotuzumab, including 22 (75.9%) with cervical cancer, 4 (13.8%) with endometrial carcinoma, and 3 (10.3%) with vulva cancer. The median age was 60 years (range: 39–80 years). Reasons for participating in this clinical trial included refusal of chemotherapy (7/29), inability to tolerate chemotherapy (7/29), and failure of first-line or subsequent lines of systemic therapy (15/29). Among them, 5 patients progressed after PD-1/PD-L1 treatment. After a median follow-up of 6 months (range: 1–18), the best response was observed in 17 patients, with 3 achieving complete response (CR) and 14 partial response (PR). Notably 2 patients relapsed after PD-1 treatment. The ORR was 58.6% (95% CI, 39.7–77.7). Additionally 6 patients achieved stable disease (SD), while 6 patients experienced disease progression. The median PFS and OS were not reached, but the 6-month PFS rate was 58.1% (95% CI, 35.5–75.2), and the 6-month OS rate was 76.5% (95% CI, 54.6–88.8). Adverse events (AEs) were generally manageable and tolerable (Grade 1-2), including hypothyroidism (13.8%), immune-mediated hepatitis (13.8%), rash maculo-papular (6.9%), thrombocytopenia (6.9%) and nephritis (3.4%). Conclusions: To the best of our knowledge, this represents the inaugural clinical report on the de-chemotherapy regimen of Cadonilimab plus Nimotuzumab for P/R/M gynecological cancer. The combination exhibited a promising tumor response rate (58.6%), surpassing the 32.3% observed with Cadonilimab alone, and demonstrated a manageable safety profile. These findings suggest the potential of bi-specific immunotherapy coupled with anti-EGFR target therapy especially in patients who are resistant to chemotherapy or intolerant to it, even in cases where single- specific immunotherapy has previously failed. Clinical trial information: NCT05606263 .
Exploring the tumor microenvironment (TME) in patients with mismatch repair-deficient (MMRd) endometrial cancer (EC) undergoing immune checkpoint inhibitor (ICI) therapy: Proteomic insights into immune resistance mechanisms.
Authors: Juan Francisco Grau Béjar, Qinghe Zeng, Martin Mehnert, Emeline Colomba, Catherine Genestie, Audrey Le Formal, Elodie Edmond, Antoine Amaury Lachaud, Patricia Pautier, Judith Michels, Sebastien Gouy, Amandine Maulard, Elisa Yaniz, Alexandra Leary
Journal: Journal of Clinical Oncology (2024)

5609 Background: MMRd status is a robust predictive biomarker for ICI in EC, however half of these pts do not respond. Most studies exploring biomarkers of response to ICI have focused on tumor or immune cell factors. We aimed to explore the tumor microenvironment (TME) in ICI-Responder (R) versus Non-Responder (NR) MMRd EC pts to identify new predictive biomarkers of response. Methods: Clinical data and outcomes of metastatic MMRd EC pts, treated with ICI at Gustave Roussy Institute (2016-2023), were retrospectively collected. Pts were classified as Rs (CR, PR, or SD ≥12 months) or NRs (PD or SD &lt;12 months). Pre-ICI FFPE tumor samples were subjected to Biognosys UltraDeep TrueDiscovery™ Mass Spectrometry (MS) for the identification of differentially regulated protein expression between R and NR. Criteria for protein candidates’ selection were p-value &lt; 0.01 and average absolute log2 fold change (absolute average Log ratio) &gt; 0.58. CD8+ T cells were quantified in the intratumoral area and expressed as number of cells per mm 2 . Spearman correlation test (r) was used for lineal correlation calculations. Functional enrichment analysis was conducted to elucidate differentially expressed molecular signatures (Odds ratio; adjusted p-value) in Rs vs NRs, utilizing GO_Biological Process database. Results: Twenty-three tumor samples were included in the analysis: 15 from Rs and 8 from NRs. Overall, 11,187 proteins were quantified. Only 72 were found to be differentially abundant between Rs and NRs. Protein candidates present within the tumor microenvironment that were significantly UP-regulated in NRs related to: non-specific inflammation (CRP), arachidonic acid metabolism (LOX15, PTGR3), extracellular matrix synthesis (COL5A2, COL22A1, PXDN), and TGF-b (TFBR1). CRP, LOX15, PXDN and COL5A2, were negatively correlated with CD8 + T cell infiltration (r -0.23, r -0.33, r -0.51, r -0.21). Based on functional enrichment analysis, collagen fibril organization (OR 21.4; p 1.1 e -6 ), extracellular structure organization (OR 10.2; p 1.2 e -6 ), extracellular matrix (ECM) organization (OR 7.5; p 1.1e -6 ), supramolecular fiber organization (OR 3.4; p 0.03), and TGFBR signaling pathway (OR 6.4; p 0.08) were among the top 30 biological process upregulated in NRs. Conclusions: Our preliminary data on high throughput proteomic analysis identified the arachidonic acid pathway, ECM structural organization and TGF-b signaling as potential mediators of ICI resistance in MMRd EC, all of which may be actionable in an effort to enhance sensitivity to ICI.