Search

Purpose:Prior molecular profiling of hepatocellular carcinoma (HCC) has identified actionable findings that may have a role in guiding therapeutic decision-making and clinical trial enrollment. We implemented prospective next-generation sequencing (NGS) in the clinic to determine whether such analyses provide predictive and/or prognostic information for HCC patients treated with contemporary systemic therapies.Experimental Design:Matched tumor/normal DNA from patients with HCC (N = 127) were analyzed using a hybridization capture–based NGS assay designed to target 341 or more cancer-associated genes. Demographic and treatment data were prospectively collected with the goal of correlating treatment outcomes and drug response with molecular profiles.Results:WNT/β-catenin pathway (45%) and TP53 (33%) alterations were frequent and represented mutually exclusive molecular subsets. In sorafenib-treated patients (n = 81), oncogenic PI3K–mTOR pathway alterations were associated with lower disease control rates (DCR, 8.3% vs. 40.2%), shorter median progression-free survival (PFS; 1.9 vs. 5.3 months), and shorter median overall survival (OS; 10.4 vs. 17.9 months). For patients treated with immune checkpoint inhibitors (n = 31), activating alteration WNT/β-catenin signaling were associated with lower DCR (0% vs. 53%), shorter median PFS (2.0 vs. 7.4 months), and shorter median OS (9.1 vs. 15.2 months). Twenty-four percent of patients harbored potentially actionable alterations including TSC1/2 (8.5%) inactivating/truncating mutations, FGF19 (6.3%) and MET (1.5%) amplifications, and IDH1 missense mutations (Conclusions:Linking NGS to routine clinical care has the potential to identify those patients with HCC likely to benefit from standard systemic therapies and can be used in an investigational context to match patients to genome-directed targeted therapies.See related commentary by Pinyol et al., p. 2021

MSK IMPACT Gene Panels

Supplemental Figure 1: Distribution of tumor mutation burden (TMB) across different tumor types, comparing TMB in this HCC cohort (N=127) to the most common other tumor types in the MSK-IMPACT clinical sequencing cohort. The mutation rate was plotted as in (Zehir et al. Nat Med 2017).47

MSK cohort compared to TCGA

Outcomes to treatment based on genomic mutation

TPS6605 Background: Precision medicine represents a new era in oncology and population health. Comprehensive molecular profiling and hereditary cancer testing are increasingly important in the routine management of many malignancies, yet may not be widely adopted in many practices and leads to patients not consistently receiving care recommended by current national guidelines such as NCCN and ASCO. In addition, available targeted DNA sequencing panels may be limited to only defined drivers and lack detection in precancerous conditions. Whole exome sequencing (WES) combined with whole transcriptome sequencing (WTS) represent an expanded testing approach that identifies additional genetic changes beyond standard commercial panel tests. Current evidence suggests that WES/WTS is feasible to carry out in routine clinical practice, with improved detection of somatic alterations compared to smaller panels, and the promise to enhance access to targeted therapies and clinical trials. The primary purpose of the ASAP study is to understand the breadth of molecular characteristics present in participants cared for in a large integrated community-based health system, by linking comprehensive molecular profiles with clinical data extracted and curated from the electronic medical record. Methods: Avera Health is a large, Midwestern, predominantly rural vertically integrated health system with six regional cancer centers and over 40 oncology outreach sites across South Dakota and surrounding states. The ASAP study was initiated in November 2021 in GYN and as of February, the study is enrolling in the Otolaryngology clinic and expected to open in medical oncology and hematology in March/April 2022. The study will expand to include additional cancer centers outside of Sioux Falls later in 2022 and is anticipated to be open for accrual for 5 years. Enrolled participants are expected to receive WES/WTS and proteomics on their primary tumor and metastatic sites were feasible as well as hereditary testing, pharmacogenomics (PGx) and microbiome profiling. Liquid biopsies will be performed every 3 months while on treatment or when treatment is changed, in follow up to coincide with scheduled radiographic testing, and as part of annual routine surveillance. For participants not diagnosed with cancer, each participant will receive hereditary testing, PGx, microbiome, and a liquid biopsy at least annually. Participants also consent to sharing their electronic health information. Future stages of this work will employ natural language processing (NLP) methods to develop algorithms to help identify opportunities to improve patient outcomes. Projected enrollment is 1000 participants in year 1, 1500 participants in year 2, and up to 3000 annually thereafter. Approximately 50 patients have consented as of February 1 2022. Clinical trial information: NCT05142033.

Summary Background RET rearrangements are found in 1–2% of non-small-cell lung cancers. Cabozantinib is a multikinase inhibitor with activity against RET that produced a 10% overall response in unselected patients with lung cancers. To assess the activity of cabozantinib in patients with RET -rearranged lung cancers, we did a prospective phase 2 trial in this molecular subgroup. Methods We enrolled patients in this open-label, Simon two-stage, single-centre, phase 2, single-arm trial in the USA if they met the following criteria: metastatic or unresectable lung cancer harbouring a RET rearrangement, Karnofsky performance status higher than 70, and measurable disease. Patients were given 60 mg of cabozantinib orally per day. The primary objective was to determine the overall response (Response Criteria Evaluation in Solid Tumors version 1.1) in assessable patients; those who received at least one dose of cabozantinib, and had been given CT imaging at baseline and at least one protocol-specified follow-up timepoint. We did safety analyses in the modified intention-to-treat population who received at least one dose of cabozantinib. The accrual of patients with RET -rearranged lung cancer to this protocol has been completed but the trial is still ongoing because several patients remain on active treatment. This study was registered with ClinicalTrials.gov, number NCT01639508. Findings Between July 13, 2012, and April 30, 2016, 26 patients with RET -rearranged lung adenocarcinomas were enrolled and given cabozantinib; 25 patients were assessable for a response. KIF5B-RET was the predominant fusion type identified in 16 (62%) patients. The study met its primary endpoint, with confirmed partial responses seen in seven of 25 response-assessable patients (overall response 28%, 95% CI 12–49). Of the 26 patients given cabozantinib, the most common grade 3 treatment-related adverse events were lipase elevation in four (15%) patients, increased alanine aminotransferase in two (8%) patients, increased aspartate aminotransferase in two (8%) patients, decreased platelet count in two (8%) patients, and hypophosphataemia in two (8%) patients. No drug-related deaths were recorded but 16 (62%) patients died during the course of follow-up. 19 (73%) patients required dose reductions due to drug-related adverse events. Interpretation The reported activity of cabozantinib in patients with RET -rearranged lung cancers defines RET rearrangements as actionable drivers in patients with lung cancers. An improved understanding of tumour biology and novel therapeutic approaches will be needed to improve outcomes with RET-directed targeted treatment. Funding Exelixis, National Institutes of Health and National Cancer Institute Cancer Center Support Grant P30 CA008748.

Purpose: Prior molecular profiling of hepatocellular carcinoma (HCC) has identified actionable findings that may have a role in guiding therapeutic decision-making and clinical trial enrollment. We implemented prospective next-generation sequencing (NGS) in the clinic to determine whether such analyses provide predictive and/or prognostic information for HCC patients treated with contemporary systemic therapies. Experimental Design: Matched tumor/normal DNA from patients with HCC (N = 127) were analyzed using a hybridization capture–based NGS assay designed to target 341 or more cancer-associated genes. Demographic and treatment data were prospectively collected with the goal of correlating treatment outcomes and drug response with molecular profiles. Results: WNT/β-catenin pathway (45%) and TP53 (33%) alterations were frequent and represented mutually exclusive molecular subsets. In sorafenib-treated patients (n = 81), oncogenic PI3K–mTOR pathway alterations were associated with lower disease control rates (DCR, 8.3% vs. 40.2%), shorter median progression-free survival (PFS; 1.9 vs. 5.3 months), and shorter median overall survival (OS; 10.4 vs. 17.9 months). For patients treated with immune checkpoint inhibitors (n = 31), activating alteration WNT/β-catenin signaling were associated with lower DCR (0% vs. 53%), shorter median PFS (2.0 vs. 7.4 months), and shorter median OS (9.1 vs. 15.2 months). Twenty-four percent of patients harbored potentially actionable alterations including TSC1/2 (8.5%) inactivating/truncating mutations, FGF19 (6.3%) and MET (1.5%) amplifications, and IDH1 missense mutations ( Conclusions: Linking NGS to routine clinical care has the potential to identify those patients with HCC likely to benefit from standard systemic therapies and can be used in an investigational context to match patients to genome-directed targeted therapies. See related commentary by Pinyol et al., p. 2021

Background Previous models of support for premature sheep fetuses have consisted of cesarean delivery followed by catheterization of umbilical or central vessels and support with extracorporeal membrane oxygenation (ECMO). The limitations of these models have been insufficient blood flow, significant fetal edema, and hemorrhage related to anticoagulation. Methods We performed a gravid hysterectomy on 13 ewes between 135 and 145days gestational age. The uterine vessels were cannulated bilaterally and circulatory support was provided via ECMO. Successful transition was defined as maintenance of fetal heart rate for 30minutes after establishing full extracorporeal support. Circuit flow was titrated to maintain mixed venous oxygen saturation (SvO 2 ) of 70–75%. Results Seven experiments were successfully transitioned to ECMO, with an average survival time of 2hours 9minutes. The longest recorded time from cannulation to death was 6hours 14minutes. By delivering a circuit flow of up to 2120ml/min, all but one of the transitioned uteri were maintained within the desired SvO 2 range. Conclusion We report a novel animal model of fetal ECMO support that preserves the placenta, mitigates the effects of heparin, and allows for increased circuit flow compared to prior techniques. This approach may provide insight into a technique for future studies of fetal physiology.

Purpose Pneumonitis is an uncommon but potentially fatal toxicity of anti–programmed death-1 (PD-1)/programmed death ligand 1 (PD-L1) monoclonal antibodies (mAbs). Clinical, radiologic, and pathologic features are poorly described. Methods Patients who received anti–PD-1/PD-L1 monotherapy or in combination with anti–cytotoxic T-cell lymphocyte associated antigen-4 mAb were identified at two institutions (Memorial Sloan Kettering Cancer Center: advanced solid cancers, 2009 to 2014, and Melanoma Institute of Australia: melanomas only, 2013 to 2015). Pneumonitis was diagnosed by the treating investigator; cases with confirmed malignant lung infiltration or infection were excluded. Clinical, radiologic, and pathologic features of pneumonitis were collected. Associations among pneumonitis incidence, therapy received, and underlying malignancy were examined with Fisher’s exact test as were associations between pneumonitis features and outcomes. Results Of 915 patients who received anti–PD-1/PD-L1 mAbs, pneumonitis developed in 43 (5%; 95% CI, 3% to 6%; Memorial Sloan Kettering Cancer Center, 27 of 578 [5%]; Melanoma Institute of Australia, 16 of 337 [5%]). Time to onset of pneumonitis ranged from 9 days to 19.2 months. The incidence of pneumonitis was higher with combination immunotherapy versus monotherapy (19 of 199 [10%] v 24 of 716 [3%]; P < .01). Incidence was similar in patients with melanoma and non–small-cell lung cancer (overall, 26 of 532 [5%] v nine of 209 [4%]; monotherapy, 15 of 417 v five of 152 [ P = 1.0]; combination, 11 of 115 v four of 57 [ P = .78]). Seventy-two percent (31 of 43) of cases were grade 1 to 2, and 86% (37 of 43) improved/resolved with drug holding/immunosuppression. Five patients worsened clinically and died during the course of pneumonitis treatment; proximal cause of death was pneumonitis (n = 1), infection related to immunosuppression (n = 3), or progressive cancer (n = 1). Radiologic and pathologic features of pneumonitis were diverse. Conclusion Pneumonitis associated with anti–PD-1/PD-L1 mAbs is a toxicity of variable onset and clinical, radiologic, and pathologic appearances. It is more common when anti–PD-1/PD-L1 mAbs are combined with anti–cytotoxic T-cell lymphocyte associated antigen-4 mAb. Most events are low grade and improve/resolve with drug holding/immunosuppression. Rarely, pneumonitis worsens despite immunosuppression, and may result in infection and/or death.

7602 Background: SCLC relies on the Hh developmental pathway for tumor initiation and progression. Pharmacologic blockade with Hh inhibitors blocks these processes. We performed a phase I study to ...