Actionable Driver Research Articles

Clinical value of timely targeted therapy (TT) for patients with advanced non-small cell lung cancer (aNSCLC) with actionable driver oncogenes (ADO).

6507 Background: Recent real-world studies observed that some aNSCLC pts with ADO initiated non-targeted therapy (non-TT) before biomarker test results became available. This study assesses the clinical impact of the timing of first line (1L) TT in aNSCLC pts with ADO. Methods: In a retrospective analysis of the nationwide Flatiron Health electronic health record-derived de-identified database, pts aged ≥18 years, diagnosed (Dx) with aNSCLC between 1/1/2015-10/18/2022, had ADO (ALK, BRAF, EGFR, RET, MET, ROS-1, or NTRK) based on biomarker testing ≤ 90 days of advanced Dx, and received 1L treatment (tx) were included. Cohorts were defined by tx patterns after test result: Cohort 1 received 1L TT ≤ 42 days; Cohort 2 initiated 1L non-TT before or after testing but switched to TT ≤ 42 days; Cohort 3 initiated non-TT before or after testing and did not switch to TT ≤ 42 days. Pts were followed from test results + 42 days until 11/30/2022 or death, whichever earliest. Multivariate Cox regression evaluated real-world progression-free survival (rwPFS) and overall survival (OS) between cohorts. Results: A total of 5156 aNSCLC pts with ADO were included: 79% were treated in the community setting and 56% received NGS testing. Most common ADO were EGFR and ALK for both Cohort 1 (78% and 13%) and Cohort 2 (67% and 24%); EGFR (39%) and BRAF (35%) for Cohort 3. Cohort 3 included more rare mutations (MET, NTRK, RET). Statistically significant differences were observed in gender, race/ethnicity, practice type, and area-level socioeconomic status across all cohorts. There was no significant difference in outcomes observed between Cohort 2 and 1, but significantly inferior outcomes in Cohort 3 vs 1. Conclusions: Our findings demonstrated better outcomes with upfront 1L TT vs non-TT in aNSCLC pts with ADO. The comparable outcomes between pts who received 1L TT after test result and pts who switched to TT ≤ 42 days of test result available underscore the importance of timely tx decisions based on ADO detection in lieu of tx-switch at progression. Opportunities remain to improve utilization of NGS to identify all ADO upfront to inform the appropriate 1L TT when indicated. [Table: see text]

Discovery of gene fusions in driver-negative NCI-MATCH screening samples.

3112 Background: NCI-MATCH aimed to determine the treatment efficacy of identifying actionable genetic alterations, irrespective of cancer histology, and to tailor treatment to the putative molecular drivers of tumors. Leveraging next-generation sequencing (NGS) and ThermoFisher’s Oncomine assay, this phase II trial genotyped 5,540 patient samples during active screening. Reviewing the genotyping statistics, we noted that NCI-MATCH identified fusions in 164 tumors, only 2.96%. This result is substantially lower than expected, given that clinical assays used at MGH’s and Yale’s diagnostic laboratories identified fusions in 8.5% of the 7,500 sequenced cases, 2.5% of which were novel. Notably, the Oncomine assay, based on multiplexed PCR, is unable to detect driver fusion events when either of the gene partners are unknown, or a novel breakpoint is involved. Cross-referencing identified fusions from MGH’s cohort with Oncomine’s primers, 5-30% of these fusions were potentially missed, suggesting that we could detect up to 30% more fusions than originally identified. Developed at MGH’s Molecular Diagnostics Laboratory, Anchored Multiplex PCR (AMP) interrogates 138 known fusion partners, enabling unbiased fusion detection when only one partner is known. With a high likelihood of identifying novel fusion drivers using AMP technology, we sequenced 663 cases that had no identified mutations of interest (MOI) from the NCI-MATCH cohort. Methods: A total of 200ng of RNA per sample was shipped from ECOG-ACRIN’s repository at MD Anderson Cancer Center to MGH (n = 319) and Yale (n = 349). Samples were processed with ArcherDX’s FusionPlex Pan Solid Tumor v2 kit and sequenced on the NextSeq500 with 150 base pair (bp) Paired-End (PE) kits. Data analysis was completed with ArcherDX’s analytics platform in conjunction with custom Python and R code. Reported fusions were manually verified on a case-by-case basis. All statistical tests were conducted in R. Results: Of the cases sequenced, most (663/693, 95.7%) were successfully processed with AMP. We identified 142 cases with at least one gene fusion out of 663 MOI-Negative cases (21%; 95% CI [18%, 25%]), with 90 as unique fusions, significantly more than the 8.5% observed at MGH (P < .001). Of the 142 fusion-positive cases, 36 have potentially actionable driver events, 27 contain novel fusions not previously described, and in 63 cases no drugs are available to target either component of the fusion. Additionally, we identified fusions in (12/34, 35%) Cholangiocarcinoma and (38/101, 37.6%) Sarcoma cases, 9 and 3 of which were potentially actionable respectively. Conclusions: As hypothesized, we identified fusions that the NCI-MATCH screening had missed, detailing sequencing technology improvement that could be broadly applicable to many clinical laboratories sequencing tumors. Clinical trial information: NCT02465060 .

Green politics beyond the state: radicalizing the democratic potentials of climate citizens’ assemblies

In recent years, countries like France, UK, Germany, and Denmark have all carried out climate citizens’ assemblies where a group of representatively selected citizens come together to discuss issues around climate politics and provide policy recommendations to decision-makers. The hope is that these deliberative-democratic innovations can circumvent the flaws of representational politics and help break the existing gridlock around climate politics. In this article, relying on the case of the Danish climate citizens’ assembly that began its work in 2020, we argue that to truly realize the democratic potentials of climate citizens’ assemblies, there is a need to think about how citizens’ assemblies might come to multiply and proliferate in political spaces away from, or at least in addition to, those in and around the state, so they can become local drivers of democratic action and community empowerment. The argument is not that citizens’ assemblies should give up on affecting the state and parliamentary politics altogether, but that we must be careful not to put too much faith in state institutions, and also look for spaces outside the state where the conditions for transformative change and democratic capacity-building currently appear more fecund. Drawing together these arguments, we offer what we call a more radical vision of the democratic potentials of climate citizens’ assemblies, and provide some guidelines for what that would look like in practice.

P393 EDOXABAN: NEW PERSPECTIVE IN A PATIENT WITH CANCER–ASSOCIATED THROMBOSIS COMPLICATED BY BRAIN METASTASES. A RARE CLINICAL CASE

Abstract Herein, we present the case of a 58 y–o Caucasian man with unremarkable cardiovascular history and a strong family history for cancer. He was diagnosed with lung adenocarcinoma IVb (pleura, pleural effusion, lymph nodes), PDL1: 2% TPS and absence of actionable driver mutations on DNA and RNA NGS (only ERBB2 mutation). Started first–line chemotherapy with cisplatin–pemetrexed regimen and immunotherapy with pembrolizumab. He developed common/superficial femoral and popliteal deep vein thrombosis (DVT) and pulmonary embolism (PE). The patient started low–molecular–weight heparin (LMWH) namely enoxaparin 1 mg/kg x 2/d (weight: 65 Kg). After 1 mo, CT showed PE resolution. Due to DVT persistence and patient’s preference for oral administration, LMWH was replaced with direct oral anticoagulant (DOAC) namely edoxaban 60 mg 1 cp/d. After 2 mo, resolution of common femoral and popliteal vein thrombosis with partial recanalization of superficial femoral DVT were detected. However, he developed brain metastases treated with WB radiotherapy. We decided for edoxaban full dose long–term anticoagulant treatment with monthly cardioncological surveillance. After 6 mo since cancer diagnosis, the patient was still adherent to DOAC therapy, although in a maintenance combined regimen pemetrexed–pembrolizumab based, without both drug–drug interactions and brain bleeding. Conclusions Thromboembolism is the second leading cause of death in malignancy. In this clinical case, a man with advanced lung cancer developed extended cancer–associated thrombosis (CAT). However, the appearance of brain metastases has posed a clinical dilemma: to continue or to withdraw the anticoagulant therapy and, also, which drug to choose between LMWH and DOAC. Literature is limited on the use of DOACs in cancer patients with brain metastases. Besides, current guidelines neither advocate contraindication to DOAC, nor suggest caution as requested for gastrointestinal and genitourinary sites of cancer. We decided to proceed with edoxaban therapy, despite chemotherapy combined to immunotherapy were still ongoing and the concurrent appearance of brain metastases, with good results in efficacy, patient’s adherence and, mostly, safety. In conclusion, in regard to our clinical experience, we point out DOAC as a reliable and manageable therapeutical choice in CAT, also in active cancer patients with brain metastases receiving chemo–immunotherapy.

Establishment of patient-derived tumor organoids to functionally inform treatment decisions in metastatic colorectal cancer

Metastatic colorectal cancer (mCRC) patients tend to have modest benefits from molecularly driven therapeutics. Patient-derived tumor organoids (PDTOs) represent an unmatched model to elucidate tumor resistance to therapy, due to their high capacity to resemble tumor characteristics. We used viable tumor tissue from two cohorts of patients with mCRC, naïve or refractory to treatment, respectively, for generating PDTOs. The derived models were subjected to a 6-day drug screening assay (DSA) with a comprehensive pipeline of chemotherapy and targeted drugs against almost all the actionable mCRC molecular drivers. For the second cohort DSA data were matched with those from PDTO genotyping. A total of 40 PDTOs included in the two cohorts were derived from mCRC primary tumors or metastases. The first cohort included 31 PDTOs derived from patients treated in front line. For this cohort, DSA results were matched with patient responses. Moreover, RAS/BRAF mutational status was matched with DSA cetuximab response. Ten out of 12 (83.3%) RAS wild-type PDTOs responded to cetuximab, while all the mutant PDTOs, 8 out of 8 (100%), were resistant. For the second cohort (chemorefractory patients), we used part of tumor tissue for genotyping. Four out of nine DSA/genotyping data resulted applicable in the clinic. Two RAS-mutant mCRC patients have been treated with FOLFOX-bevacizumab and mitomycin-capecitabine in third line, respectively, based on DSA results, obtaining disease control. One patient was treated with nivolumab-second mitochondrial-derived activator of caspases mimetic (phase I trial) due to high tumor mutational burden at genotyping, experiencing stable disease. In one case, the presence of BRCA2 mutation correlated with DSA sensitivity to olaparib; however, the patient could not receive the therapy. Using CRC as a model, we have designed and validated a clinically applicable methodology to potentially inform clinical decisions with functional data. Undoubtedly, further larger analyses are needed to improve methodology success rates and propose suitable treatment strategies for mCRC patients.

Detection of multiple types of cancer driver mutations using targeted RNA sequencing in non-small cell lung cancer.

DNA-based next-generation sequencing has been widely used in the selection of target therapies for patients with nonsmall cell lung cancer (NSCLC). RNA-based next-generation sequencing has been proven to be valuable in detecting fusion and exon-skipping mutations and is recommended by National Comprehensive Cancer Network guidelines for these mutation types. The authors developed an RNA-based hybridization panel targeting actionable driver oncogenes in solid tumors. Experimental and bioinformatics pipelines were optimized for the detection of fusions, single-nucleotide variants (SNVs), and insertion/deletion (indels). In total, 1253 formalin-fixed, paraffin-embedded samples from patients with NSCLC were analyzed by DNA and RNA panel sequencing in parallel to assess the performance of the RNA panel in detecting multiple types of mutations. In analytical validation, the RNA panel achieved a limit of detection of 1.45-3.15 copies per nanogram for SNVs and 0.21-6.48 copies per nanogram for fusions. In 1253 formalin-fixed, paraffin-embedded NSCLC samples, the RNA panel identified a total of 124 fusion events and 26 MET exon 14-skipping events, in which 14 fusions and six MET exon 14-skipping mutations were missed by DNA panel sequencing. By using the DNA panel as the reference, the positive percent agreement and the positive predictive value of the RNA panel were 98.08% and 98.62%, respectively, for detecting targetable SNVs and 98.15% and 99.38%, respectively, for detecting targetable indels. Parallel DNA and RNA sequencing analyses demonstrated the accuracy and robustness of the RNA sequencing panel in detecting multiple types of clinically actionable mutations. The simplified experimental workflow and low sample consumption will make RNA panel sequencing a potentially effective method in clinical testing.

Overall survival in patients with advanced non-small cell lung cancer with KRAS G12C mutation with or without STK11 and/or KEAP1 mutations in a real-world setting

BackgroundKRAS mutations occur frequently in advanced non-small cell lung cancer (aNSCLC); the G12C mutation is the most prevalent. Alterations in STK11 or KEAP1 commonly co-occur with KRAS mutations in aNSCLC. Using real-world data, we assessed the effect of KRAS G12C mutation with or without STK11 and/or KEAP1 mutations on overall survival (OS) in patients with aNSCLC receiving cancer immunotherapy (CIT), chemotherapy, or both in first line (1L) and second line (2L).MethodsPatients diagnosed with aNSCLC between January 2011 and March 2020 in a clinico-genomic database were included. Cox proportional hazards models adjusted for left truncation, baseline demographics and clinical characteristics were used to analyze the effect of STK11 and/or KEAP1 co-mutational status on OS in patients with KRAS wild-type (WT) or G12C mutation.ResultsOf 2715 patients with aNSCLC without other actionable driver mutations, 1344 (49.5%) had KRAS WT cancer, and 454 (16.7%) had KRAS G12C–positive cancer. At 1L treatment start, significantly more patients with KRAS G12C–positive cancer were female, smokers, and had non-squamous histology, a higher prevalence of metastasis and programmed death-ligand 1 positivity than those with KRAS WT cancer. Median OS was comparable between patients with KRAS G12C–positive and KRAS WT cancer when receiving chemotherapy or combination CIT and chemotherapy in the 1L or 2L. Median OS was numerically longer in patients with KRAS G12C vs KRAS WT cancer treated with 1L CIT (30.2 vs 10.6 months, respectively) or 2L CIT (11.3 vs 7.6 months, respectively). Co-mutation of STK11 and KEAP1 was associated with significantly shorter OS in patients receiving any type of 1L therapy, regardless of KRAS G12C mutational status.ConclusionsThis real-world study showed that patients with KRAS G12C–positive or KRAS WT cancer have similar OS in the 1L or 2L when treated with chemotherapy or combination CIT and chemotherapy. In contrast to aNSCLC patients with EGFR or ALK driver mutations, patients with KRAS G12C–positive cancer may benefit from CIT monotherapy. Co-mutation of STK11 and KEAP1 was associated with significantly shorter survival, independent of KRAS G12C mutational status, reflecting the poor prognosis and high unmet need in this patient population.

Abstract CT213: Biomarker analysis from Phase 1/2 study of tusamitamab ravtansine (SAR408701) in patients with advanced non-small cell lung cancer (NSCLC)

Abstract Background Tusamitamab ravtansine is an antibody-drug conjugate of a humanized carcinoembryonic antigen (CEA)-related cell adhesion molecule 5 (CEACAM5)-specific monoclonal antibody linked to DM4. A Phase 1/2 study (NCT02187848) showed tusamitamab ravtansine antitumor activity in pretreated patients (pts) with advanced nonsquamous NSCLC and high CEACAM5 expression. Here, we explore biomarker associations with tumor CEACAM5 expression by immunohistochemistry (IHC), and whether biomarkers predict objective response rate (ORR). Methods We assessed CEACAM5 expression by IHC, RNA sequencing, and whole exome sequencing (WES) on latest archival tumor samples; and circulating CEACAM5 (cCEACAM5) and CEA (cCEA). We enrolled 2 cohorts of pts with IHC CEACAM5 membrane expression at ≥2+ intensity: in ≥50% of tumor cells (high expressors, HEs, n = 64); and in ≥1% to <50% of tumor cells (moderate expressors, MEs, n = 28). Pts received tusamitamab ravtansine 100 mg/m2 IV every 2 weeks. Results cCEA and cCEACAM5 were strongly associated (Spearman rho, 0.9), with weak associations between IHC CEACAM5 and cCEA or cCEACAM5 (Spearman rho, 0.3 and 0.4, respectively). Higher levels of CEACAM5 mRNA were observed in CEACAM5 HEs vs MEs (P=0.0027). EGFR and KRAS genetic alterations by WES were present in 44.8% and 65.5% of CEACAM5 HEs, respectively, and 21.4% and 78.6% of CEACAM5 MEs, respectively. Confirmed partial responses were seen in 13/64 HEs (ORR 20.3%) and 2/28 MEs (ORR 7.1%). In CEACAM5 HEs with available baseline (BL) cCEA data, 25/62 (40.3%) had a cCEA level ≥100 µg/L, with a median value of 71.6 µg/L (range 1-8809); corresponding values in CEACAM5 MEs were 7/28 (25.0%) and 12.4 µg/L (range 0.5-684). In response evaluable CEACAM5 HEs with available BL cCEA data (n = 61), ORR was 10/24 (41.7%) in pts with high cCEA (≥100 µg/L) and 3/37 (8.1%) in pts with low cCEA (<100 µg/L); corresponding ORRs in CEACAM5 MEs were 0/7 and 2/21 (9.5%). Conclusions In CEACAM5 HEs, high cCEA was associated with numerically greater ORR vs low cCEA (41.7% vs 8.1%). Associations were also observed between: cCEA and cCEACAM5; IHC CEACAM5, cCEA, and cCEACAM5; and IHC CEACAM5 and CEACAM5 tumor mRNA levels, but not between IHC CEACAM5 and actionable oncogenic drivers. Clinical Trials Registration: ClinicalTrials.gov NCT02187848 Citation Format: Anas Gazzah, Joon Sang Lee, Emma Wang, Nils Ternès, Hong Wang, Eric Boitier, Aude Lartigau, Mustapha Chadjaa, Colette Dib, Gaëlle Muzard, Sandrine Valence, Anne Remaury, Cintia C. Palu, Anne-Laure Bauchet. Biomarker analysis from Phase 1/2 study of tusamitamab ravtansine (SAR408701) in patients with advanced non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT213.

Abstract 4678: Characterization of a PDX panel covering molecular diversity of non-small cell lung cancer to accelerate the development of precision therapy

Abstract Lung cancer remains the first cause of cancer-related deaths worldwide, of which Non-Small Cell Lung Cancer (NSCLC) represents more than 80% of patients with advanced disease at the time of diagnosis. NSCLC is a highly heterogenous disease, and the identification of its main actionable oncogenic drivers (i.e. EGFR, ALK, PI3K/AKT/mTOR, RET, MET, BRAF and NTRK/ROS1) and the development of specific inhibitors against these targets has transformed therapeutic care. In addition, immune-checkpoint therapy has emerged as an indispensable treatment modality, especially for patients lacking actionable oncogenic drivers, although biomarkers for predicting response to immune-checkpoint inhibition have remained elusive. Despite these new therapeutic options, NSCLC remains a lethal disease in the majority of patients due to tumor plasticity and selection leading to frequent resistance development and disease progression. Efforts are therefore needed to identify drugs and drug combinations that can prevent or overcome these resistance pathways. Patient-Derived Xenografts (PDX) models developed in immune-compromised mice recapitulate the disease more faithfully than any other in vivo model in terms of histopathologic and genomic features. They have proven their relevance in the study of pathways leading to the development and progression of cancer, to the mechanisms linked to tumor resistance and to the identification of novel effective therapies, facilitating the translation of preclinical results in the clinical setting. We describe a platform of over 35 NSCLC PDX models covering most of the molecular diversity of the disease, that have been fully characterized at the molecular level and for their response to a panel of cytotoxic chemotherapies and targeted therapies. These NSCLC PDX models have been established in immune-deficient mice from tumor biopsies collected in treatment-naïve patients or in patients having acquired resistance following an initial objective response to a variety of targeted inhibitors (EGFRi, ALKi, ROSi, BRAFi,⋯) in the MATCH-R clinical trial. In addition, 4 PDX models were established from circulating tumor cells (CTC) isolated from the blood of advanced NSCLC patients. Finally, some of these NSCLC PDX models were established in highly immunodeficient mice humanized with human PBMCs or CD34+ cells allowing testing of efficacy of bispecific T-Cell engager antibody or immune-checkpoint inhibitors. This panel of NSCLC PDX models provides a powerful preclinical platform to improve our knowledge on the mechanisms underlying resistance to treatment and to rapidly evaluate response to new treatments and translate this knowledge to the clinic. Citation Format: Delphine Nicolle, Laura Brulle-Soumare, Katell Mevel, Ludovic Bigot, Tala Tayoun, Benjamin Besse, Françoise Farace, Luc Friboulet, Didier Decaudin, Erwan Corcuff, Anaïs Joachim, Bernard Malissen, Ana Zarubica, Hervé Luche, Jean-Gabriel Judde, Olivier Deas. Characterization of a PDX panel covering molecular diversity of non-small cell lung cancer to accelerate the development of precision therapy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4678.

Abstract 3217: Risk of thromboembolism in patients with non-small lung cancer (NSCLC) treated with immune check point inhibitors (ICIs) versus chemoimmunotherapy (ChemoIO)

Abstract Background: Immune checkpoint inhibitors with or without chemotherapy form the backbone of treatment for patients with advanced NSCLC without an actionable driver mutation. Emerging literature shows that ICIs increase the risk of venous thromboembolism (VTE), which is a major cause of death in patients with NSCLC. The mechanism is yet to be elucidated but is likely secondary to inflammation. Since chemotherapy is immunosuppressive, we sought to understand if the addition of chemotherapy to ICIs impacted the incidence of VTEs. Methods: We performed a retrospective cohort study to evaluate thromboembolic outcomes in patients diagnosed with advanced NSCLC between 2012 and 2018 and treated with either ICIs or chemo immunotherapy at Cleveland Clinic Foundation. Diagnosis of thrombotic events (TE) (arterial/deep vein thrombosis and/or pulmonary embolism) was confirmed by imaging. Overall survival (OS) was estimated by Kaplan-Meier and compared using log rank test. Odds of developing TE was estimated and compared between ICI and ChemoIO groups, using Fisher's Exact Test. Results: A total of 367 NSCLC patients (242 pts on ICI only and 125 pts on ChemoIO regimen), were identified with a median age 65 years ( range 58-72), 52% were men, 82% white, 85.3% smokers, 91.8% had ECOG ≤2, 73 % had adenocarcinoma and 18% had squamous cell carcinoma, 34% with brain metastasis and the distribution of PDL1expression was as follows- <1 (26.4%), 1-49% (48%) and ≥50% (25.6%). Adjusted response rates to treatment were (N, %): Complete Response (CR) (6/367, 1.9%), Partial Response (PR) (96/367, 30%), Stable Disease (SD) (76/367, 24%) and PD (143/367, 45%). TE was detected in 19% of the cohort (n=70) (8.4% DVT, 4.9% PE, 5.2 % both, and 0.5 % arterial TE. Rate of TE in NSCLC pts on ICI alone was 18% (44/242) Vs. 21% (26/125) for those on ChemoIO (OR 1.5, 95% CI 0.66-2.1, P 0.6). Development of TEs was not associated with survival differences with either regimen (P >0.05). Conclusion: Rates of TE were high in patients with advanced NSCLC who received ICI therapy, but no different if treated with ICIs alone or ChemoIO. Further studies to better understand the pathophysiology of TE in patients treated with ICIs might allow us to identify subgroups of patients that are at the highest risk for TEs. Citation Format: Doaa Attia, Ran Zhao, Alok A. Khorana, Prandya Patil. Risk of thromboembolism in patients with non-small lung cancer (NSCLC) treated with immune check point inhibitors (ICIs) versus chemoimmunotherapy (ChemoIO) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3217.

Abstract 3387: ctDNA dynamics in early stage node negative lung cancers

Abstract Introduction: Patients with early-stage lung cancers have a high risk of relapse and death even after curative surgery. Detection of circulating tumour DNA (ctDNA) in plasma perioperatively is associated with shorter recurrence free survival (RFS). ctDNA-Lung-Detect is an investigator-initiated prospective study of ctDNA detection and association with RFS in patients with early stage non-small cell lung cancer (NSCLC). Methods: Patients with clinically staged T<4cm N0 NSCLC planned for surgical resection at the Princess Margaret/University Health Network underwent ctDNA assessment before and after surgery (~1 month and 1 year). ctDNA minimal residual disease (MRD) was detected using the highly sensitive and specific tumor-informed Residual Disease and Recurrence (RaDaR®, Inivata, Cambridge, UK) assay, which can track up to 48 tumor-specific variants in plasma. Results: Since August 2021, 64 eligible patients were enrolled (Table 1). One had isolated metastasis from a remote non-lung primary and subsequently excluded; another had their preoperative sample missed but was included. Preoperative ctDNA was detected in 15/62 (23.8%) patients and 1/63 (1.6%) post-operatively at the 1-month landmark timepoint (occult N2 disease found at surgery). All but one (93.3%) had ctDNA clearance with surgical resection. Two patients have recurred radiographically and in plasma at 1 year post-operatively, 1/15 with preoperative ctDNA detected (6.7%) and 1/47 without preoperative ctDNA detected (2.1%). Patients with higher T stage, tumor size, squamous histology, and without actionable driver alterations were more likely to have ctDNA detected at any timepoint. Conclusions: In patients with early stage NSCLC (small node negative tumors), 24% have detectable ctDNA pre-operatively. Surgical resection led to ctDNA clearance in 93% of cases. Our results support ongoing testing beyond the initial MRD landmark. Assessment of the impact on RFS post resection is ongoing. Citation Format: Jamie Feng, Tom Waddell, Kazuhiro Yasufuku, Andrew Pierre, Shaf Keshavjee, Jonathan Yeung, Marcelo Cypel, Laura Donahoe, Elliot Wakeam, Marc de Perrot, Jennifer Law, Alexandra Salvarrey, Lisa W. Le, Jennifer Lister, Michael Cabanero, Ming Tsao, Christodoulos Pipinikas, Karen Howarth, Natasha Leighl. ctDNA dynamics in early stage node negative lung cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3387.

MP33-17 EXAMINING SURVIVAL OUTCOMES BY RACE AND ETHNICITY IN TESTIS CANCER: A REVERSE HISPANIC PARADOX?

You have accessJournal of UrologyCME1 Apr 2023MP33-17 EXAMINING SURVIVAL OUTCOMES BY RACE AND ETHNICITY IN TESTIS CANCER: A REVERSE HISPANIC PARADOX? Michael Rezaee, Maximilian Pallauf, Pranjal Agrawal, Roy Elias, Sean Fletcher, Yasser Ged, and Nirmish Singla Michael RezaeeMichael Rezaee More articles by this author , Maximilian PallaufMaximilian Pallauf More articles by this author , Pranjal AgrawalPranjal Agrawal More articles by this author , Roy EliasRoy Elias More articles by this author , Sean FletcherSean Fletcher More articles by this author , Yasser GedYasser Ged More articles by this author , and Nirmish SinglaNirmish Singla More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003266.17AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: The incidence of testis cancer among Hispanic men in the United States is increasing. Prior research has demonstrated that Hispanic patients exhibit a survival benefit for many medical conditions, a phenomenon known as the “Hispanic Paradox.” However, this paradox may not extend to testis cancer. We sought to examine survival outcomes in testis cancer by race using a large national sample. METHODS: A population-based retrospective cohort study of testis cancer patients was performed using Surveillance, Epidemiology, and End Results (SEER) data for the years 2000 through 2019. Cox proportional hazards models were used to examine the relationship between race/ethnicity and testis cancer-specific survival, both overall and by histologic type (seminoma vs. nonseminomatous germ cell tumors [NSGCT]). All models were adjusted for age, stage, receipt of postoperative radiation or chemotherapy, year of diagnosis, income, marital status, and rural status. RESULTS: The final analytic cohort consisted of 18,600 patients, of whom 66.8% were Non-Hispanic White (NHW), 2.2% Non-Hispanic Black (NHB), 24.9% Hispanic (all races), and 6.1% Non-Hispanic Asian or Pacific Islander (API). Median follow up was 92 months. Death from testis cancer occurred in 2.7% of patients. A greater proportion of Hispanics were diagnosed at an age less than 30 years (54.4%) and with initial metastatic disease (15.2%) compared to other groups. Hispanics experienced significantly worse cancer-specific survival (hazard ratio [HR] = 1.8, 95% CI: 1.5-2.2) compared to NHW patients overall (Figure 1). When stratified by tumor type, cancer-specific survival was significantly worse for Hispanics (HR = 1.8, 95% CI: 1.4-2.2) and API’s (HR = 1.6, 95% CI: 1.1-2.5) with NSGCTs. No difference was observed in cancer-specific survival by race/ethnicity for seminoma patients, however. CONCLUSIONS: Contrary to the Hispanic paradox reported across many medical conditions, cancer-specific survival is significantly worse for Hispanic men with testis cancer, particularly among those with NSGCT tumors. Future investigation of both public health and biological factors is needed to identify actionable drivers for this observed difference. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e457 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Michael Rezaee More articles by this author Maximilian Pallauf More articles by this author Pranjal Agrawal More articles by this author Roy Elias More articles by this author Sean Fletcher More articles by this author Yasser Ged More articles by this author Nirmish Singla More articles by this author Expand All Advertisement PDF downloadLoading ...

Climate, Communities, and Capitalism: Critically Imagining and Co-Creating Pathways for a Sustainable Ireland

Climate, Communities, and Capitalism: Critically Imagining and Co-Creating Pathways for a Sustainable Ireland Amanda Slevin (bio) Wildfires, droughts, floods, beloved species facing extinction – a selection of stark indicators of the accelerating climate and ecological emergency. Underpinned by human patterns of production, consumption, and associated environmental degradation, the ‘triple planetary crises’1 of climate change, biodiversity loss, and pollution pose an existential threat to human and non-human species. Consequently, socio-ecological and scientific imperatives for urgent, transformative action have become firmly established, yet with only a few years to 2030 (a landmark year for climate commitments) our shared island, encompassing people on both sides of Ireland’s politically constructed border, is woefully unprepared to tackle the massive difficulties we collectively face. To move towards a genuinely sustainable future profound socioeconomic, ideological, political, and environmental transformations across all levels of every society are essential. Unsurprisingly, major challenges abound, not least the deeply embedded structures, ideologies, and practices fundamental to capitalism, which lie at the core of destructive society– environment interactions. Against this backdrop, it is useful to reflect upon conditions that influence why, how, and when a populace embarks on pathways for transformative change. Prospects for socio-ecological change encompass myriad dimensions and reinvigorate age-old debates around ‘agency’ and ‘structure’, prompting questions of who and/or what shapes human behaviour, as a central feature of transformative, multi-level action. Such deliberations are particularly apt in an era when many people across our island feel disempowered and are struggling, following wave after wave of turmoil, such as the costs of living, energy, and housing crises; consequences of the Covid-19 pandemic; war in Ukraine; ongoing legacies of Northern Ireland’s ethno-nationalist conflict; and Brexit. [End Page 61] Therefore, in this article, I contemplate how we might better respond to socio-ecological threats to enable our collective transition move towards a healthier and fairer future for all that share our island. As a critical interface between structure and agency, I posit ‘community’ as a vital element of societal transformations towards a more sustainable Ireland by 2030, and I explore how diverse communities affect bottom-up and top-down change. To set the scene, I examine mandates for climate action by enunciating pressing socioecological crises in the Anthropocene, the current geological epoch in which humans have become the primary drivers of changes to our planet. While I identify evolving top-down legal and policy frameworks that currently shape climate action, I argue that bottom-up grassroots approaches by communities are core for a sustainable world. Alongside empirical examples of community climate action, I explore diverse understandings of ‘community’, spanning psychological, philosophical, and physical dimensions of human interactions, and recognise the multiplicity of interpretations and forms of community that exist, not all of which are conducive to positive social change, as evident in Northern Ireland. Key questions arise within this inquiry: in the midst of a planetary emergency can ‘community’ act as an impetus to reimagine our shared future? Furthermore, can ‘community’ serve as a locus to regain human agency while acting as a driver for collective climate action across all levels of society? Offering a hopeful perspective, I articulate mechanisms to aid development of a ‘community of communities’ for climate action, including socio-eco-logical imagination, transformative teaching and learning, and sustainability praxis, all of which can be fostered within communities, universities, and wider society. These, in turn, can inform socio-eco-logical awareness, agency, and activism within and beyond diverse communities, enabling critical collective imagining and co-creation of pathways for a sustainable Ireland. I. Socio-ecological emergencies: ‘Code Red’ for Planet Earth Irrefutable scientific evidence by the Intergovernmental Panel on Climate Change (IPCC) and the World Meteorological Organization (WMO), among others, makes clear the ways in which our planet is experiencing an unprecedented climate catastrophe, driven by human activities.2 Anthropogenic (human-caused) climate change is defined as ‘a large-scale, long-term shift in the planet’s weather patterns and average temperatures’3 and is caused by burning fossil fuels like oil, gas, and coal; land-use change [End Page 62] such as cutting down forests; and farming livestock.4 Climate breakdown is part of the escalating planetary...

Abstract P4-07-51: Impact of the Theralink CLIA protein/phosphoprotein assay on treatment selection in routine clinical practice: a prospective observational study in advanced breast cancer

Abstract Background: The Theralink Reverse Phase Protein Array-based (RPPA) CLIA assay is a novel molecular assay developed to assist physicians in therapy selection for patients diagnosed with advanced/recurrent breast cancer. The assay was specifically designed to quantitatively measure protein activation/phosphorylation of 32 FDA-approved and Phase III drug targets and pathway-linked downstream substrates, providing functional information on actionable oncogenic drivers in individual tumors. Given the recent commercialization of the Theralink assay (TLA), knowledge gaps exist regarding its use in routine clinical practice and the impact of the test on clinical decision-making in real world practice. The primary objective of this analysis was to assess how the TLA has been integrated in therapy selection for breast cancer patients with a focus on understanding its target population, the rationale for patient selection by the treating physician, and the utilization of the molecule information generated by the assay as part of the therapeutic decision-making process. Findings from this study will help optimize patient selection and maximize the clinical impact of the test as a tool for advancing precision oncology. Methods: We prospectively collected data from 124 women with advanced breast cancer whose tumors were profiled using the Breast Cancer TLA from February, 2021 to May, 2022. All patients were confirmed as actively managed for advanced/recurrent breast cancer. Eight μm FFPE sections (n=5) from a recently collected tissue biopsy were used to isolate tumor epithelia via Laser Capture Microdissection and to generate RPPA-based molecular profiles. Clinical management and therapy selection information for 68 patients was gathered via surveys completed by treating physicians. Results: Median age of the 124 participants was 53 years (range 26-82) and 111 (89.5%) patients had stage IV disease. The cohort included 66 hormone receptors positive (of which 5 were HER2+), 51 triple negative, and 7 HR-/HER2+ breast cancers. The TLA yielded molecular information for all specimens and profiles were generated on average in 11 days. One or more targets were highly activated (highly actionable) in 91 patients (73.4%) and moderately activated (partially actionable) in 29 patents; only 4 patients had no actionable target (3.2%). Previous treatment information was available for 118 (95.2%) patients. The TLA was requested to assist with the selection of first-line treatment in 36 patients (of which 24 had previously received neoadjuvant treatment), second-line treatment in 35 patients and third- or subsequential-lines of treatment in 47 patients. Clinicians provided feedback on the use of the assay for 68 patients included in the study. The survey revealed that the TLA impacted treatment selection in 50 (73.5%) cases and was used to either expand options beyond standard of care (30 cases), refine/re-prioritize available treatments (11 cases), narrow treatment from a plethora of options (2 cases) or a combination of the three (7 cases). When TLA data were used for treatment selection, physicians defined the assay highly and moderately beneficial for patient management in 15 and 27 cases, respectively. Conclusion: Our study suggests the TLA yields useful information for selecting treatment for breast cancer patients with advanced/recurrent disease. In this prospective analysis, the assay identified actionable targets in more than 90% of patients, which is significantly higher than what has previously been reported for genomic profiling alone. Overall, physicians found the information yielded by the assay useful for selecting treatment. The inclusion of the TLA in oncology may offer important insights for advancing precision medicine for breast cancer patients. Citation Format: Kris Weinberg, Mariaelena Pierobon, Edik Blais, Justin Davis, Joyce O’Shaughnessy, Emanuel F. Petricoin. Impact of the Theralink CLIA protein/phosphoprotein assay on treatment selection in routine clinical practice: a prospective observational study in advanced breast cancer. [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-07-51.

Abstract OT1-22-01: Liquid biopsy and Ado-trastuzumab emtansine (T-DM1): drug-resistance traits in the blood of HER2-positive metastatic breast cancer patients

Abstract Background: A previous study on 22 metastatic breast cancer (mBC) patients (Allegretti et al. Mol Cancer 2021) has associated drug resistance to Ado-trastuzumab emtansine (T-DM1) with two sets of genomic events: a) reversal of HER2 amplification, b) ‘oncogenic replacement’ of HER2 by alternative cancer drivers. To expand on this, we designed GIM21 (Gruppo Italiano Mammella) study. Materials and Methods: GIM21 is a multicentre, prospective study; tumor and circulating total nucleic acids (tTNA and ctTNA) were obtained from primary and metastatic lesions (n=36 altogether), as well as plasma samples (n=501), the latter serially collected coincident with medical imaging re-evaluations. tCNAs/ctTNAs were sequenced by ultra-deep, largely overlapping 50-gene panels on Ion Torrent Gene Studio S5. Ortogonal dPCR validation was by dPCR (Quant Studio 3D). ctTNAs were correlated with clinical readouts and patient outcomes. Results: from September 2018 to January 2022, 50 HER2+ mBC patients receiving T-DM1 as second-line treatment. Median time to progression was 6.5 months (range 2.0-27.2). As previously shown, only a minority of patients (9/50 – 18%) retained residual HER2 amplification in blood at baseline, likely due to HER2 counterselection during previous therapy lines; all of them (9/9) underwent further neutralization during T-DM1 treatment, but an HER2-neutral blood status was reached in only 5 patients. In contrast, 2 HER2-neutral patients acquired HER2 amplification, suggesting either insufficient T-DM1 pressure or an unprecedented clonal escape mechanism. Overall, the circulating HER2 status did not correlate with progression free survival (PFS), further highlighting a loss of clinically relevant HER2 oncogenic dependence. At baseline, 24 circulating mutations were detected in 29/50 (58%) patients, 9 of which did not overlap with tissue mutations. Of note, carrying a given aberration in either blood or tissue resulted in outcome trends (p=0.16), but no clear association with therapeutic response. Rather, it was serial monitoring (appearance of any aberration in the blood) that predicted a dismal clinical outcome in 16/41 (39%) patients, with a median time to progression of 2.8 months (2.2-3.9). Unfortunately, liquid biopsy (LB) was confirmed to miss most patients developing brain (3/3 patients) or skin (2/3 patients) metastases. Most circulating alterations present at progression (40/60) were actionable (OncoKB level < 3B) in 34/41 (82.9%) patients, suggesting that LB may guide therapeutic strategies in post-T-DM1 settings. Conclusions: GIM21 trial showed that LB accurately predicts clinical outcome and reveals actionable drivers of T-DM1 escape. The final analysis are ongoing. Citation Format: Alessandra Fabi, Matteo Allegretti, Elena Giordani, Gianluigi Ferretti, Grazia Arpino, Alberto Zambelli, Claudia Omarini, Ida Paris, Andrea Botticelli, Emilio Bria, Antonella Palazzo, Stefania Gori, Francesco Cognetti, Patrizio Giacomini. Liquid biopsy and Ado-trastuzumab emtansine (T-DM1): drug-resistance traits in the blood of HER2-positive metastatic breast cancer patients [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT1-22-01.

Overcoming CEP85L-ROS1, MKRN1-BRAF and MET amplification as rare, acquired resistance mutations to Osimertinib.

Lung cancer is the most common cancer-related cause of death worldwide, most of which are non-small cell lung cancers (NSCLC). Epidermal growth factor receptor (EGFR) mutations are common drivers of NSCLC. Treatment plans for NSCLC, specifically adenocarcinomas, rely heavily on the presence or absence of specific actionable driver mutations. Liquid biopsy can guide the treatment protocol to detect the presence of various mechanisms of resistance to treatment. We report three NSCLC EGFR mutated cases, each treated with Osimertinib in a combination therapy regimen to combat resistance mechanisms. The first patient presented with EGFR L858R/L833V compound mutation with MET amplification alongside CEP85L-ROS1 fusion gene, the second with EGFR exon 19del and MKRN1-BRAF fusion, and the last EGFR L858R/V834L compound mutation with MET amplification. Each regimen utilized a tyrosine kinase inhibitor or monoclonal antibody in addition to osimertinib and allowed for a prompt and relatively durable treatment response.

The role of targeted therapy and immune therapy in the management of non-small cell lung cancer brain metastases.

Brain metastases are a significant source of morbidity and mortality in patients with non-small cell lung cancer. Historically, surgery and radiation therapy have been essential to maintaining disease control within the central nervous system due to poorly penetrant conventional chemotherapy. With the advent of targeted therapy against actionable driver mutations, there is potential to control limited and asymptomatic intracranial disease and delay local therapy until progression. In this review paper, intracranial response rates and clinical outcomes to biological and immune therapies are summarized from the literature and appraised to assist clinical decision making and identify areas for further research. Future clinical trials ought to prioritize patient-centered quality of life and neurocognitive measures as major outcomes and specifically stratify patients based on mutational marker status, disease burden, and symptom acuity.

Identification of IGF2 as Genomic Driver and Actionable Therapeutic Target in Hepatoblastoma.

Management of hepatoblastoma (HB), the most frequent pediatric liver cancer, is based on surgical resection and perioperative chemotherapy regimens. In this study, we aimed to identify actionable targets in HB and assess the efficacy of molecular therapies in preclinical models of HB. Paired tumor and adjacent tissues from 31 HBs and a validation set of 50 HBs were analyzed using RNA-seq, SNP and methylation arrays. IGF2 overexpression was identified as the top targetable HB driver, present in 71% of HBs (22/31). IGF2high tumors displayed progenitor cell features and shorter recurrence-free survival. IGF2 overexpression was associated in 91% of cases with fetal promoter hypomethylation, ICR1 deregulation, 11p15.5 loss of heterozygosity or miR483-5p overexpression. The antitumor effect of xentuzumab (a monoclonal antibody targeting IGF1/2) alone or in combination with the conventional therapeutic agent cisplatin was assessed in HB cell lines, in PDX-derived HB organoids and in a xenograft HB murine model. The combination of xentuzumab with cisplatin showed strong synergistic antitumor effects in organoids and in IGF2high cell lines. In mice (n=55), the combination induced a significant decrease in tumor volume and improved survival compared to cisplatin alone. These results suggest that IGF2 is an HB actionable driver and that, in preclinical models of HB, the combination of IGF1/2 inhibition with cisplatin induces superior antitumor effects than cisplatin monotherapy. Overall, our study provides a rationale for testing IGF2 inhibitors in combination with cisplatin in HB patients with IGF2 overexpression.

Guidance for clinicians and patients with non-small cell lung cancer in the time of precision medicine.

Major advances in the diagnosis and treatment of non-small cell lung cancer (NSCLC) have resulted in a sharp decline in associated mortality rates, thereby propelling NSCLC to the forefront of precision medicine. Current guidelines recommend upfront comprehensive molecular testing for all known and actionable driver alterations/biomarkers (EGFR, ALK, ROS1, BRAF, KRAS, NTRK, MET, RET, HER2 [ERBB2], and PD-L1), especially in advanced disease stages, as they significantly influence response to therapy. In particular, hybrid capture-based next-generation sequencing (HC-NGS) with an RNA fusion panel to detect gene fusions is a veritable requirement at both diagnosis and progression (resistance) of any-stage non-squamous adenocarcinoma NSCLCs. This testing modality ensures selection of the most timely, appropriate, and personalized treatment, maximization of therapeutic efficacy, and prevention of use of suboptimal/contraindicated therapy. As a complement to clinical testing and treatment, patient, family, and caregiver education is also key to early screening and diagnosis, access to care, coping strategies, positive outcomes, and survival. The advent of social media and increased internet access has amplified the volume of educational and support resources, consequently changing the dynamics of patient care. This review provides guidance on integration of comprehensive genomic testing with an RNA fusion panel as a global diagnostic standard for all adenocarcinoma NSCLC disease stages and provides key information on patient and caregiver education and resources.

The WHO European framework for action to achieve the highest attainable standard of health for persons with disabilities 2022-2030.

There are approximately 135 million persons with disabilities in the WHO European Region. In order to address health inequities experienced by this population, Member States and WHO/Europe developed the 'WHO European framework for action to achieve the highest attainable standard of health for persons with disabilities 2022-2030', in close cooperation with organisations of persons with disabilities. The Framework, with its accompanying Resolution, was adopted by all 53 Member States in September 2022. The Framework is aligned with the core priorities of the WHO European Programme of Work 2020-2025, that is, achieving universal health coverage, protecting against health emergencies, and promoting health and well-being. It consists of four objectives, 13 targets, and 20 indicators that act as measures of progress and success, and as drivers for policy action and a roadmap for Member States towards a disability-inclusive health sector. The Framework is expected to have a significant impact on the health and well-being of all in the Region, and especially persons with disabilities, as it will advance inclusive health systems across the Region. Inclusive health sectors will aid towards the achievement of the Sustainable Development Goals, the protection of the human rights of persons with disabilities, and the promotion of their health.