tbuckley/cabot-search huggingface dataset:
Genomics to select treatment for patients (pts) with metastatic cancer: Final analysis of Molecular Tumor Board (MTB) evaluations in the ROME trial.
Authors: Andrea Botticelli, Simone Scagnoli, Pierfranco Conte, Chiara Cremolini, Paolo Antonio Ascierto, Federico Cappuzzo, Massimo Aglietta, Federica Mazzuca, Ettore Capoluongo, Giovanni Blandino, Umberto Malapelle, Marianna Nuti, Giulia D'Amati, Bruna Cerbelli, Giancarlo Pruneri, Mauro Biffoni, Giuseppe Giannini, Francesco Cognetti, Giuseppe Curigliano, Paolo Marchetti
Journal: Journal of Clinical Oncology (2024)

3157 Background: The ROME trial (NCT04591431) investigates the efficacy of a tailored treatment (TT), driven by extensive genomic tests and Molecular Tumor Board (MTB) evaluation, compared to standard treatment (SoC) in patients (pts) with refractory metastatic cancer. Here we report the prevalence of actionable variants identified and the personalized treatment received by the patients enrolled. Methods: A centralized extensive NGS test (FoundationOne CDx and Liquid CDx) was performed on both tissue and blood samples. Pts with at least one potentially targetable alteration matched to the available drugs were discussed at the MTB. MTB evaluation criteria were: genomic variant type, tumor mutational burden (TMB), VAF, availability of preclinical or clinical data of efficacy and patients’ clinical characteristics. COSMIC, ClinVar, OncoKB and VarSome datasets were used to evaluate the clinical actionability of genomic alterations. MTB indications were: randomization to TT vs SoC, screening failure (SF), or indication to other trial/access to the drug. Results: From November 2020 to August 2023, 1794 pts were screened. A total of 127 weekly MTB meetings were conducted and 899 cases were discussed (7 cases/meeting on average). After MTB discussion, a targetable genomic alteration was identified in 425 pts, who received an indication to be randomized. MTB assigned ICIs to 190 pts (155 to ipilimumab plus nivolumab; 8 to nivolumab) due to high (≥10 mut/mb) TMB. 234 pts had indications to target therapy: 86 pts (37%) to PI3K/AKT/mTOR inhibitors(i), 59 (25%) anti-HER2 agents, 34 (15%) FGFRi, 31 (13%) BRAF/MEKi, 7 (3%) PARPi, 5 (2%) CDK4/6i, 4 (2%) ALKi, 2 (&gt;1%) NTRKi, 2 (&gt;1%) RETi, 2 (&gt;1%) Hedgehog-i, 1 (&gt;1%) JAKi, 1 (&gt;1%) MEKi. 27 pts had indication to ICIs plus target therapy combinations. Additionally, 150 pts with potentially hereditary variants were addressed to genetic counselling and germline testing. Finally, according to the genomic evaluation, 63 pts were referred by MTB to other clinical trial even if considered SF for the ROME trial, 34 patients received from the MTB a modification of the initially proposed standard therapy and 4 had both suggestions. Overall, 652 pts (36%) received an indication following NGS test and MTB evaluation. Conclusions: Our study provides evidence that MTB discussion of comprehensive genomic profiling data identifies a personalized treatment in a large (36%) fraction of patients, thus outperforming the traditional histological approach. Clinical trial information: NCT04591431 .
A phase 1 study of HRS-1167 (M9466), a highly selective PARP1 inhibitor, in patients (pts) with advanced solid tumors.
Authors: Lingying Wu, Jing Wang, Ning Li, Jin Zhang, Danbo Wang, Shusuan Jiang, Liang Chen, Yongsheng Li, Dongling Zou, Jiuwei Cui, Min Yan, Wei Wang, Hongwei Zhao, Ying Wang, Xiaojia Wang, Funan Liu, Youzhong Zhang, Jing Wang, Dapeng Zhang, Qingqing Miao
Journal: Journal of Clinical Oncology (2024)

3154 Background: The use of first-generation dual PARP1/2 inhibitors is limited due to their hematological toxicities and inevitable drug resistance. Given that loss of PARP1 is the primary driver of synthetic lethality in homologous recombination repair (HRR) deficient tumors, and PARP2 is largely associated with hematological toxicities, development of next-generation PARPi with selectivity for PARP1 is warranted. Here, we present results of the dose escalation (D-ESC) and dose expansion (D-EXP) parts of a first-in-human study of HRS-1167 (M9466), a highly selective PARP-1 inhibitor, in pts with advanced solid tumors. Methods: Pts were eligible for the D-ESC part if they had advanced solid tumors that had progressed on standard therapies or for which no standard therapies were available. The D-ESC part began with accelerated titration (30 mg; QD) and then switched to the BOIN design (50, 100, 200, and 300 mg; QD). In the D-EXP part, previously treated pts harboring germline or somatic BRCA1/2, PALB2, or RAD51C/D mutations received HRS-1167 at 50, 100, and 200 mg QD. Prior PARPi was allowed. The primary objectives were to assess the safety and tolerability of HRS-1167. Results: As of Nov 20, 2023, 40 pts were enrolled (median lines of prior treatment, 2 [range, 1–5]; prior PARPi, 15.0%). No dose-limiting toxicities occurred, and the maximum tolerated dose was not reached. Grade ≥3 treatment-related adverse events occurred in 12 (30.0%) pts, with the most common being anemia (6 [15.0%]), decreased neutrophil count (5 [12.5%]), and decreased WBC count (5 [12.5%]). Of the 24 pts with HRR mutations who had at least one post-baseline assessment for tumor response, 10 (41.7%) pts had objective responses (8 ovarian cancer, 1 prostate cancer, and 1 pancreatic cancer). PK exposures were approximately dose-proportional. The median T max was 1.0–1.5 h, and the mean t 1/2 was 10.5–15.0 h following a single dose of HRS-1167 at 30–300 mg. No obvious drug accumulation was observed (Rac, 1.08–1.30 for C max ; 1.29–1.62 for AUC 0-24 ). Conclusions: HRS-1167 was well-tolerated and exhibited favorable safety and PK profiles in pts with advanced solid tumors, and demonstrated promising anti-tumor activity in pretreated pts with HRR mutations. Clinical trial information: NCT05473624 .
Prevalence of recreational and medical cannabis products in Veterans and their interactions with cancer directed pharmacological treatment.
Authors: Tsvetelina V Todorova, Elizabeth John, Srishti Sareen, Vaishnavi Tandra, Jessica Daune Rich Davis, Nicholas A DiLoreto, Alva Bowen Weir
Journal: Journal of Clinical Oncology (2024)

3089 Background: There is proliferation of literature about the medical uses of cannabis products in patients with malignancies. However, research is lacking as to how cannabis use is affecting the efficacy and toxicity of anti-neoplastic regimens It is known that cannabis is metabolized by the cytochrome p450 pathway, the same as many anti-neoplastic agents and thus there are concerns for potential interactions. Methods: We report an observational study to identify cannabis users in veterans receiving anti-neoplastic therapy in the Memphis VA health system, and to then analyzed for potential interactions between cannabis product and the antineoplastic agent/s they were receiving. Data was collected via voluntary surveys. We then reviewed their charts, recorded the anti- neoplastic medications they were receiving, and evaluated for potential interactions with cannabis, based on a literature review of potential interactions. Results: In this study, 132 veterans agreed to participate. 50 of them acknowledged recent use of cannabis products within the last 90 days. Thus, the prevalence of cannabis use amongst those who participated is 37.87%. Demographically, 10% of the cannabis users were female, and 90% were male, with the majority aged 60-65 (range 46-85). Predominantly, patients inhaled cannabis once daily (38%) as opposed to using a different formulation. The patients who admitted cannabis use were primarily on chemotherapy (42%), while 38% were on immunotherapy, 24% were on targeted therapy and 20% were on endocrine therapy. Some were on multiple drugs. Based on this data and a literature search for interactions, we found that a significant number of the patients in our Veteran’s oncology clinic have a potential increase in toxicity or decreased efficacy from their ant-neoplastic therapy due to CYP interactions with cannabis use. Conclusions: In this exploratory study, we discovered a notable prevalence of patients concurrently using cannabis products while on anti-neoplastic treatment. Given that many anti-neoplastic agents undergo metabolism via the CYP450 pathway, our data suggest that a moderate number of patients in our clinic risk less than optimal outcomes due to concurrent cannabis and anti-neoplastic therapy. To delve deeper, we intend to conduct a follow-up study, focusing on specific adverse effects, hospitalizations, and the subsequent need for 2nd and 3rd line treatments in patients using cannabis. A much larger multi-institutional study should be considered to provide statistically relevant data on true outcomes. [Table: see text]
Phase II study of the combination of lenvatinib (L) and eribulin (E) in advanced solid tumors.
Authors: Ranjit Singh Banwait, Heidi Chwan Ko, Joel Michalek, Kate Ida Lathrop, Elizabeth Ann Bowhay-Carnes, Georgios Fotopoulos, Richard M. Elledge, Anand B. Karnad, Virginia G. Kaklamani
Journal: Journal of Clinical Oncology (2024)

3158 Background: Tumor angiogenesis remains a focal point in cancer therapeutics, necessitating innovative strategies to counter resistance mechanisms. Lenvatinib, a multitargeted tyrosine kinase inhibitor, and eribulin, a microtubule inhibitor, exhibit promise in disrupting tumor vasculature. Understanding their efficacy and safety in combination therapy is crucial, especially in heavily pretreated patients with advanced solid tumors. Methods: A single-center phase II study (NCT02640508) enrolled patients with stage IV breast carcinoma, lung carcinoma, and sarcoma, evaluating the safety and efficacy of lenvatinib and eribulin combination therapy. Eribulin was given on day 1 and day 8 at 1.4 mg/m 2 and lenvatinib at a dose of 20 mg starting on day 2 of a 21-day cycle. Immunohistochemistry assessed biomarkers CD31, e-cadherin, CA-9, and vimentin. Statistical analyses included multivariate modeling and Kaplan-Meier curves. The primary endpoint of the study was the overall response rate (ORR), defined per RECIST 1.1 as assessed by investigator imaging review. Secondary endpoints included safety, progression free survival (PFS) and overall survival (OS). Results: Among 29 patients enrolled, median age was 58 years, majority were female and had at least ≥3 prior lines of chemotherapy. Treatment with lenvatinib and eribulin resulted in an ORR of 24%, as seen in the table. Median PFS was 7.4 months and OS was 8.2 months. Toxicities were manageable with grade ≥3 neutropenia seen in 34.5%, febrile neutropenia in 17.2%, and hypertension in 13.8% of patients. Treatment-related adverse events leading to study-drug discontinuation occurred in 6.8% of patients. Vimentin-negative patients exhibited significantly increased OS (fold change 4.374, p&lt;0.001) and PFS (fold change 3.395, p&lt;0.001) after adjusting for age, CD31, and CA9. Conclusions: Lenvatinib combined with eribulin showcased promising anti-tumor activity in heavily pretreated patients with metastatic breast carcinoma, lung carcinoma, and sarcoma. Although manageable, neutropenia emerged as a notable adverse effect. These findings underscore the potential of this combination as a therapeutic strategy for advanced solid tumors, warranting further clinical investigation. The observed significant survival benefits in Vimentin-negative patients align with the biological role of Vimentin in tumor invasiveness and metastatic potential, supporting the plausibility of these results biologically. Acknowledgement: This clinical trial was supported by Eisai. Clinical trial information: NCT02640508 . [Table: see text]
Stage‐adapted treatment of HIV‐associated Hodgkin lymphoma: Long‐term results of a prospective, multicenter study
Authors: Marcus Hentrich, Markus Müller, Christoph Wyen, Anna Pferschy, Vindi Jurinovic, Jan Siehl, Jürgen K. Rockstroh, Dirk Schürmann, Christian Hoffmann
Journal: HemaSphere (2024)

Abstract Results of a prospective study of stage‐adapted treatment of human immunodeficiency virus (HIV)‐associated Hodgkin lymphoma (HIV‐HL) showed a 2‐year overall survival (OS) of 90.7% with no significant difference between early favorable (EF), early unfavorable (EU), and advanced HL. Patients with EF HIV‐HL received two to four cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) + 30 Gy involved field (IF) radiation, those with EU HIV‐HL received four cycles of ABVD or BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) baseline + 30 Gy IF, and six to eight cycles of BEACOPP baseline were administered in advanced disease. The objective of the present analysis is to determine long‐term outcomes of HIV‐HL. Of 108 patients, 23 (21%) had EF HL, 14 (13%) had EU HL, and 71 (66%) had advanced‐stage HL. After a median follow‐up of 9.14 (range, 0–12.9) years, there were five primary refractory HL patients (5%) and 11 relapses (10%), of which seven were late relapses (&gt;2 years). A second primary malignancy (SPM) occurred in 10 patients after a median of 7.3 years (range, 1.5–10.7) from HL diagnosis. The 10‐year OS for patients with EF, EU, and advanced HL was 95.7%, 84.6%, and 76.1%, respectively. By multivariate analysis, Center for Disease Control and Prevention category C (hazard ratio [HR] 3.00, 95% confidence interval [CI]: 1.16–7.74, p = 0.023) and achievement of complete remission were significant for OS (HR 0.03, 95% CI: 0.01–0.08, p = 2.45 × 10 −9 ). In conclusion, a stage‐adapted treatment approach for HIV‐HL is highly effective with long‐term survival rates similar to those reported in HIV‐uninfected HL. However, the risk for late relapse and SPM is significant.
Results of IMPACT 2, a randomized study evaluating molecular profiling and targeted agents in metastatic cancer at MD Anderson Cancer Center.
Authors: Apostolia Maria Tsimberidou, Siqing Fu, David S. Hong, Sarina A. Piha-Paul, Aung Naing, Jordi Rodon Ahnert, Timothy A. Yap, Daniel D. Karp, Ecaterina Elena Dumbrava, John Heymach, Jaffer A. Ajani, Carrie Cartwright, Jennifer Beck, Clark R. Andersen, Michael Kahle, David J. Vining, Jeffrey S. Ross, Calvin Y. Chao, Donald A. Berry, Funda Meric-Bernstam
Journal: Journal of Clinical Oncology (2024)

3153 Background: To address the limitations of exploratory studies, we conducted IMPACT2. The primary endpoint was to compare the progression-free survival (PFS) between patients treated with matched targeted therapies (MTT) selected on the basis of tumor molecular alterations and those whose treatment was not selected on the basis of alteration analysis (non-targeted therapy, NTT). Methods: Patients with metastatic cancer and targetable alterations were randomized between the 2 arms when eligibility criteria were met (Part A, 5/2014-4/2017; sponsor, Foundation Medicine). In Part B (3/2019-9/2023; sponsor, Tempus), patients who declined randomization selected the treatment arm ( NCT02152254 ). PFS/OS analysis (Kaplan Meier, Cox model; reference group, comparison, NTT). All cases were presented at weekly Molecular Tumor Board meetings; initial plan, to randomize 300 of 1,362 enrolled patients. Results: Overall, 829 patients (Parts A, 391; B, 438); were enrolled (med. age 59.5 yrs, range 18-84; men 50%; med. No. of prior therapies 3, range 0-17; most common cancers: gastrointestinal 34%, head/neck 13.5%, gynecologic 10%, sarcoma 9.53%; most common genomic alterations RAS 38%, PI3K 31%, FGFR 28%). In Part A, 69 were randomized (MTT, n=35; NTT, n=34); Part B (MTT, n=11, NTT=13; Selected arm: n=16: MTT, n=13; NTT, n=3). Results are shown (Table). MTT group: median PFS by therapy type: FDA approved/off-label, 4.7 months (95% CI, 2.93, 7.1); investigational, 2.6 months (95% CI, 2.27,4.87), combined FDA approved/investigational, 1.7 months (1.7, NR) (p=0.22). Conclusions: Considering the challenges to randomize patients (doi: 10.1038/s41698-022-00317-0), and that the study was underpowered for its original goal, no differences in response, PFS (primary endpoint), or OS was noted between the 2 arms, possibly because of the advanced stage disease and the complexity of tumor biology that cannot be addressed by randomization. Clinical trial information: NCT02152254 . [Table: see text]
A phase I study of TAK-659 and paclitaxel in patients with taxane-refractory advanced solid tumors.
Authors: Mohamed Alaa Gouda, Jenny Shunyakova, Aung Naing, Ecaterina Elena Dumbrava, David S. Hong, Ying Yuan, Peiying Yang, Alan Myers, Yulong Liang, Jing Ping, Daniel D. Karp, Apostolia Maria Tsimberidou, Jordi Rodon Ahnert, Timothy A. Yap, Sarina A. Piha-Paul, Funda Meric-Bernstam, Siqing Fu
Journal: Journal of Clinical Oncology (2024)

3152 Background: Paclitaxel resistance in patients is a clinical challenge that limits the durability of clinical benefit in patients with taxane-responsive advanced solid tumors. One proposed mechanism for this resistance is overexpression of spleen tyrosine kinase (SYK); which can be inhibited with new molecules including TAK-659. In this phase I study, we have investigated the combination of TAK-659 and paclitaxel in patients with taxane-refractory advanced solid tumors; hypothesizing that use of TAK-659 would help to overcome resistance to prior taxane-based therapy. Methods: We included patients with advanced solid tumors who received and progressed on prior taxane-based therapy. Patients received treatment with intravenous paclitaxel on day 1,8, and 15 in addition of daily TAK-659 in 28-day cycles. Six cohorts were treated during dose escalation at different dose levels followed by a dose expansion phase in patients with advanced ovarian cancer. We used the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 for evaluation of toxicity and Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 for assessment of preliminary efficacy. Results: We included 49 patients with advanced solid tumors. The maximum tolerated dose was not reached in this study; and no patients experienced treatment-related deaths. Most adverse events were either grade 1 or 2. Grade 3 or more adverse events were reported in 47% of patients (n=23). The most common grade ≥3 adverse events were decreased neutrophil count (n=7; 14%), elevated lipase (n=6; 12%), anemia (n=5; 10%), increased amylase (n=4; 8%), and decreased white blood cell counts (n=4; 8%). In 44 patients with taxane-refractory tumors who were evaluable for efficacy, 9% (n=4) had RECIST partial response and 27% (n=12) had RECIST stable disease, including 3 patients with prolonged stable disease for at least 6 months. Conclusions: The combination of paclitaxel and TAK-659 was well tolerated and showed preliminary modest efficacy which could be possibly overcoming resistance to taxane-based therapy in patients with advanced solid tumors. Clinical trial information: NCT03756818 .
E-cadherin Induces Serine Synthesis to Support Progression and Metastasis of Breast Cancer
Authors: Geonhui Lee, Claudia Wong, Anna Cho, Junior J. West, Ashleigh J. Crawford, Gabriella C. Russo, Bishwa R. Si, Jungwoo Kim, Lauren Hoffner, Cholsoon Jang, Moonjung Jung, Robert D. Leone, Konstantinos Konstantopoulos, Andrew J. Ewald, Denis Wirtz, Sangmoo Jeong
Journal: Cancer Research (2024)

Abstract The loss of E-cadherin, an epithelial cell adhesion molecule, has been implicated in metastasis by mediating the epithelial–mesenchymal transition, which promotes invasion and migration of cancer cells. However, recent studies have demonstrated that E-cadherin supports the survival and proliferation of metastatic cancer cells. Here, we identified a metabolic role for E-cadherin in breast cancer by upregulating the de novo serine synthesis pathway (SSP). The upregulated SSP provided metabolic precursors for biosynthesis and resistance to oxidative stress, enabling E-cadherin+ breast cancer cells to achieve faster tumor growth and enhanced metastases. Inhibition of phosphoglycerate dehydrogenase, a rate-limiting enzyme in the SSP, significantly and specifically hampered proliferation of E-cadherin+ breast cancer cells and rendered them vulnerable to oxidative stress, inhibiting their metastatic potential. These findings reveal that E-cadherin reprograms cellular metabolism, promoting tumor growth and metastasis of breast cancers. Significance: E-Cadherin promotes the progression and metastasis of breast cancer by upregulating the de novo serine synthesis pathway, offering promising targets for inhibiting tumor growth and metastasis in E-cadherin–expressing tumors.
Integrative multi-omics analyses identify molecular subtypes of head and neck squamous cell carcinoma with distinct therapeutic vulnerabilities
Authors: Pengfei Diao, Yibin Dai, An Wang, Xiaoxuan Bu, Ziyu Wang, Jin Li, Yaping Wu, Hongbing Jiang, Yanling Wang, Jie Cheng
Journal: Cancer Research (2024)

Substantial heterogeneity in molecular features, patient prognoses, and therapeutic responses in head and neck squamous cell carcinomas (HNSCC) highlights the urgent need to develop molecular classifications that reliably and accurately reflect tumor behavior and inform personalized therapy. Here, we leveraged the similarity network fusion bioinformatics approach to jointly analyze multiomics datasets spanning copy number variations, somatic mutations, DNA methylation, and transcriptomic profiling and derived a prognostic classification system for HNSCC. The integrative model consistently identified three subgroups (IMC1-3) with specific genomic features, biological characteristics, and clinical outcomes across multiple independent cohorts. The IMC1 subgroup included proliferative, immune-activated tumors and exhibited a more favorable prognosis. The IMC2 subtype harbored activated EGFR signaling and an inflamed tumor microenvironment with cancer-associated fibroblast/vascular infiltrations. Alternatively, the IMC3 group featured highly aberrant metabolic activities and impaired immune infiltration and recruiting. Pharmacogenomics analyses from in silico predictions and from patient-derived xenograft model data unveiled subtype-specific therapeutic vulnerabilities including sensitivity to cisplatin and immunotherapy in IMC1 and EGFR inhibitors (EGFRi) in IMC2, which was experimentally validated in patient-derived organoid models. Two signatures for prognosis and EGFRi sensitivity were developed via machine learning. Together, this integrative multiomics clustering for HNSCC improves current understanding of tumor heterogeneity and facilitates patient stratification and therapeutic development tailored to molecular vulnerabilities. Significance: Head and neck squamous cell carcinoma classification using integrative multiomics analyses reveals subtypes with distinct genetics, biological features, clinicopathological traits, and therapeutic vulnerabilities, providing insights into tumor heterogeneity and personalized treatment strategies.