tbuckley/cabot-search huggingface dataset:
Six-gene model based on expression predicts distinct disease-free survival in early-stage microsatellite stability (MSS) endometrial, colorectal and stomach tumors.
Authors: Tufeng Chen, Jianpei Liu, Xinyi Liu, Mengli Huang
Journal: Journal of Clinical Oncology (2021)

e14578 Background: Microsatellite stability (MSS) tumors hardly benefit from immunotherapies and are more probable to occur postoperative recurrence. However, some studies have revealed that a subset of MSS patients harbor “hot immune microenvironment” tumors, indicating high heterogeneity in such wide range of patient population. On the other hand, researches of mechanism of MSI formation found potential similarities in endometrial and gastrointestinal tumors. We hypothesized the transcriptomic features in these cancers correlated with immune-related signatures and patients’ prognosis. Methods: Early stage (I-III stage) MSS tumors, including endometrial, colorectal, and gastric from TCGA project were analyzed as training cohort (n=170). A combined cohort consisting of 604 colorectal and stomach cancers from GEO datasets (GSE39582，GSE62254) was validation cohort. The RNA-Seq profiling data and disease-free survival (DFS) data of patients were collected. Cibersort tool was used to evaluate twenty-two immune cells’ enrichment. The prediction model was developed by three steps: Univariate cox regression of DFS was conducted to select 9 immune cells. Then the train cohort was divided into two groups based on non-negative matrix factorization (NMF) method using this 9 immune cell features. Differentially expressed genes of these two groups were identified and screened further by lasso regression. Log-rank test was used to evaluate the difference of DFS. Results: A six-gene lasso-cox model was developed. The genes were LYZ, WFDC2, CAPS, RHPN1, TFF2 and TGFBR2. Based on the score evaluated by this model, patients in training cohort were divided into high-risk and low-risk groups. Low-risk population had much longer DFS (HR 0.07, 95%CI 0.03-0.18, p&lt;0.001). In validation cohort, lower risk score was also verified to be associated with a lower likelihood of recurrence (HR 0.66, 95%CI 0.5-0.88, p=0.0047). Conclusions: We developed a model of six-genes predicting disease-free survival based on RNA-Seq data in early stage MSS patients. Further validation was needed to implement in larger clinical cohorts.
Patient outcomes following disease progression with enfortumab-vedotin (EV) in metastatic urothelial carcinoma (mUC).
Authors: Mohammed Ateeb Khan, Bernadett Szabados, Julia Choy, Francesca Jackson-Spence, Thomas Powles, Daniel Castellano, Begoña P. Valderrama
Journal: Journal of Clinical Oncology (2021)

e16516 Background: Enfortumab Vedotin (EV) is an antibody drug conjugate (ADC), licensed for use in metastatic urothelial carcinoma (mUC), following disease progression with platinum-based chemotherapy (ChT) and immune checkpoint inhibitors (ICIs). A patient cohort now exists with disease progression following EV with no guidance for subsequent treatment. This retrospective observational study assessed patient outcomes post EV progression. Methods: Patients were identified from 3 centres in Europe (St Bartholomew’s Hospital, University Hospital Virgen Del Rocio and Hospital Universitario 12 de Octubre). Data was collected regarding treatments prior to and post EV, length of EV treatment and overall survival (OS) post EV progression. Descriptive statistics and survival analyses comparing survival outcomes stratified by treatment post EV progression were performed in SPSS (Version 27). Results: All 24 patients had received both an ICI and ChT prior to receiving EV. 10 patients received further treatment following disease progression on EV. 8 patients received ChT (6 patients platinum based, 1 patient paclitaxel, 1 patient vinflunine), 1 patient received radical radiotherapy and 1 patient received derazantinib. No patient received further ICI therapy post EV progression. 2 patients had achieved complete radiological response with EV and had no evidence of disease progression. Point bi-serial correlation showed no significant association between length of EV treatment and receiving further treatment post disease progression on EV. There was also no significant association between pre EV survival length and further treatment post disease progression on EV. Survival analysis (Kaplain-Meier, Mantel-Cox Log Rank) revealed a statistically significant difference in mean OS. Mean OS was 1 month in patients who received no further treatment vs 7 months in patients who received treatment post progression on EV (Chi-Square 16.569, p = 0.000). Conclusions: Less than half of patients who progressed on EV received subsequent treatment. Patients who did receive treatment had significantly increased OS. There is a clear gap in literature and evidence-based guidance for treatment following EV progression and further studies are required with larger samples accounting for confounding factors to further evaluate best practise post disease progression on EV.
Incidence and heterogeneity of C797S and other EGFR resistance mutations on routine comprehensive genomic profiling (CGP).
Authors: Pasi A. Janne, Jessica Kim Lee, Russell Madison, Jeffrey Michael Venstrom, Alexa Betzig Schrock, Geoffrey R. Oxnard
Journal: Journal of Clinical Oncology (2021)

9101 Background: The emergence of osimertinib (osi) as standard of care therapy for EGFR-mutant NSCLC has led to investigations into understanding and overcoming drug resistance. There are now a number of therapeutic approaches aimed at overcoming EGFR resistance mutations (muts). We sought to understand the biology of EGFR C797S and other EGFR resistance muts through querying our clinico-genomic database (CGDB). Methods: CGP results from tissue (n = 60,889) or circulating tumor DNA (ctDNA; [n = 9,922]) samples from 70,811 NSCLC patients (pts) were queried for known osi resistance muts in EGFR (C797, L792, G796, L718, G724). Clinical outcomes were evaluated for a cohort of NSCLC pts with osi resistance from the Flatiron Health-Foundation Medicine CGDB, a nationwide de-identified EHR-derived database linked to CGP data. Results: Between 12/2014 and 11/2020, 261 osi resistance mutations in EGFR were detected in 228 samples. The most common were C797S (66%), L718X (14%), G724S (11%), and others (9%). 173 C797S muts were detected in 155 samples (123 ex19del, 30 L858R, 2 other EGFR muts); 100 tissue, 55 ctDNA (median VAF = 7.6%). EGFR T790M co-occurred with C797S muts (96% cis, 3.7% trans) in 118 (76%) samples and decreased over time, occurring in 92% (24/26) of C797S samples tested in 2017 vs 56% (20/36) of samples tested in 2020 (p = 0.002). In 19/155 (12%) samples with C797S (14 ctDNA), multiple changes resulting in EGFR resistance muts were present: 16 samples had &gt; 1 nucleotide changes resulting in C797S (100% trans), 3 samples had other resistance muts (L718Q/V, L792H, L792F) and 3 samples had multiple C797S changes with other resistance muts (C797G, L792H/F + G796S, L718Q + G796S+C797G). 29 pts (14 ctDNA) had C797S with potential off-target resistance (17 PIK3CA muts, 4 BRAF muts, 3 CCDC6- RET fusions, 3 KRAS muts, 2 ERBB2 amplifications (amps), 1 ERBB2 ex16 del, 1 STRN- ALK fusion, 1 FGFR3- TACC3 fusion). In the CGDB, 527 EGFR-mut NSCLC pts had documented receipt of osi. Pre and post osi-treated specimens were available for 19 of these pts (12 ex19del, 6 L858R, 1 G719A/S768I). Heterogeneous acquired resistance mechanisms were observed in the post-osi specimen, including 2 CCDC6- RET fusions, 2 MET amps, 2 BRAF fusions, BRAF V600E, and secondary EGFR muts (C797S, L704F, L718V). 161/527 pts had a documented line of therapy after osi discontinuation and most frequently received platinum doublet + immunotherapy (27%) or platinum doublet alone (23%); 17 (11%) pts received another EGFR tyrosine kinase inhibitor. 214/527 had documented osi progression and median post-progression survival was 11.8 months. Conclusions: Osi resistance in EGFR-mutant NSCLC is a poor prognosis condition. EGFR C797S is a recurring resistance mut which, in a minority of cases, can co-occur with alternate on and off target resistance muts detected with tissue and liquid biopsy.
Young-onset colorectal cancer: A call for action.
Authors: Iosune Baraibar, Francesc Salva, Raquel Comas, Javier Ros, Ariadna Garcia, Mireia Sanchis, Jose Luis Cuadra, Nadia Saoudi, Augusto Valdivia, Nuria Mulet, Ana Virgili, Jorge Hernando, Jaume Capdevila, Marc Martí, Stefania Landolfi, Helena Verdaguer, Eloy Espin, Paolo Nuciforo, Josep Tabernero, Elena Elez
Journal: Journal of Clinical Oncology (2021)

10563 Background: Young-onset colorectal cancer (YOCR) is defined as diagnosis below the age of 50. Over the past decades, the incidence of YOCRC has increased at an alarming rate, but causes and pathogenesis still remain unknown. Early detection of colorectal cancer (CRC) has demonstrated to improve survival. Despite these facts, adults &lt; 50 years old are not yet included in screening programs and YOCRC is not well characterized. We aimed to characterize the clinical and molecular characteristics of YOCRC in patients (pts) diagnosed at our institution. Methods: Consecutive pts with a diagnosis of CRC below the age of 50 visited for the first time at Vall d’Hebron University Hospital in Spain between January 2017 and October 2020 were included in the analysis. Data of clinicopathologic features and treatment were collected retrospectively from medical records. Results: 205 pts met the inclusion criteria, 111 (54%) were females, 8 (4%) presented a personal history of cancer at diagnosis and 109 (53%) a family history of cancer. Age at diagnosis was: &lt; 30: 10 (5%), {30 – 40): 52 (25%), {40-45): 51 (25%), {45-50): 92 (45%). Site of primary tumor was: right colon: 50 (24%), left colon: 107 (52%): rectum: 48 (24%). Stage at diagnosis was I: 3 (1%), II: 14 (7%), III: 60 (29%), IV: 128 (63%). 6 of 14 (43%) and 44 of 60 patients (73%) with stage II and III CRC presented disease progression after initial treatment, respectively. Molecular status was: KRAS mutation: 74 (36%), NRAS mutation: 7 (3%), BRAF mutation: 12 (6%), MSI-H: 12 (6%). 43 pts (21%) had documentation of genetic counseling. Median (range) number of lines of treatment for metastatic disease was 3 (1-7), 53 pts (30%) received at least 4 lines of treatment. Median (range) number of metastatic sites was: 2 (1-6). 114 patients (55.6%) had died at the cut-off timepoint. Conclusions: YOCR is usually diagnosed with a more advanced stage than standard-onset CRC, with a poorer course of the disease. Further studies in young adults with CRC should address this phenomenon to understand the underlying causes, and prioritize genetic counseling. Our results support the unmet need of initiating screening programs in adults younger than 50 years, the urgency for a global consensus and a call for action.
Role of GATA2 in the Maintenance of the Bone Marrow Microenvironment
Authors: Shin Hasegawa, Tohru Fujiwara, Yoko Okitsu, Hiroki Kato, Yuki Sato, Noriko Fukuhara, Yasushi Onishi, Kenichi Ishizawa, Ritsuko Shimizu, Masayuki Yamamoto, Hideo Harigae
Journal: Blood (2017)
Improved universal tumor screening program with paired testing: Experience at a large community-based teaching hospital.
Authors: Gnyapti Majmudar, Kristina Ivan, Tara Rangarajan, Dana Zakalik
Journal: Journal of Clinical Oncology (2021)

e22505 Background: Lynch syndrome (LS) is the most common cause of hereditary predisposition to colon, endometrial, and other cancers. The universal tumor screening program for LS at Beaumont Health (BH) utilizes immunohistochemistry (IHC) of the mismatch repair (MMR) proteins to identify patients for genetics evaluation. We present the 8-year experience of the program at a large community-based teaching hospital. Methods: The MMR IHC results for all colorectal cancer (CRC) resection specimens screened from August 2012 to September 2020 were reviewed. Specimens with absent MLH1 and PMS2 were evaluated for MLH1 promoter hypermethylation with reflex to BRAF V600E mutation analysis. All abnormal results were referred for cancer genetics evaluation. The distribution of abnormal MMR and germline genetic testing results was analyzed. Results: Specimens from 2361 CRC resections were screened, and 511 specimens had abnormal MMR IHC (22%). Most cases of absent MLH1 and PMS2 were explained by hypermethylation or BRAF analysis (n = 338, 66% of all abnormal, 89% of MLH1 and PMS2). Of the remaining cases showing MMR deficiency (n = 173), the most common result was absence of MSH2 and MSH6 (n = 67), followed by absence of MLH1 and PMS2 (n=41, see table). Germline genetic testing of 83 individuals with abnormal MMR IHC revealed 49 cases of Lynch syndrome [MLH1 (n=9), MSH2 (n= 25), MSH6 (n=7), PMS2 (n=7), EPCAM (n=1)]. A significant proportion of cases (n=34, 40%) had negative germline testing, and had unexplained MMR deficiency. Paired germline/tumor testing was implemented in 2017, and 14 patients had this analysis. Using this approach, 5 individuals were identified to have somatic mutations explaining their result, and the proportion of unexplained cases was reduced to 29% (n = 4). Conclusions: Recent advances in cancer screening and therapeutics have underscored the importance of analyzing tumors for mismatch repair deficiency (dMMR), with known challenges to implementation and interpretation of results. The BH cancer genetics program has demonstrated successful growth of a universal tumor screening program over 8 years. This has led to the identification of a large number of dMMR tumors (22% of all CRC resections) and LS cases (2% of all CRC resections), which impacts management for patients and their families. Recent implementation of paired germline/tumor testing has improved the testing algorithm, and resulted in more accurate interpretation of a greater proportion of abnormal IHC results. This combined approach allows for focused high-risk screening for LS patients, access to novel therapeutic interventions including immune therapies for patients with dMMR tumors, and future precision oncology approaches.[Table: see text]
Outcomes of stage IV melanoma in the era of immunotherapy (IO): A National Cancer Database (NCDB) analysis.
Authors: Tamara A. Sussman, Wei Wei, Pauline Funchain, Brian Gastman
Journal: Journal of Clinical Oncology (2021)

e21520 Background: The majority of data for IO in melanoma stems from trials that have specific inclusion criteria and often exclude important populations. In this analysis, we present the first real-world evidence of outcomes for stage IV patients (pts) with cutaneous melanoma receiving IO from 2015–2017 (addition of anti-PD-1 therapies) and factors associated with receipt of IO, and compare these outcomes with pts receiving IO (likely interferon and interleukin-2) from 2004–2010, and IO (addition of ipilimumab) from 2011–2014. Methods: The NCDB was analyzed to identify pts with stage IV melanoma from 2004–2017. Pts were categorized into receipt of IO or not during time periods 2004–2010, 2011–2014, and 2015–2017. Overall survival (OS) was analyzed by Kaplan-Meier, log-rank, and Cox proportional hazard models; IO status was analyzed using logistic regression. Results: 24,544 pts were analyzed from 2004–2017. Overall, 5,238 pts (21.3%) that received IO had improved median OS compared to those that did not (20.2 vs. 7.4 mos; p&lt;0.0001). 4.1% received IO from 2004-2010, 7.8% from 2011-2014, and 9.4% from 2015-2017. Three-year OS significantly improved in pts treated with IO across treatment years; p&lt;0.0001 (Table). Similarly, median time to IO initiation improved over time: 62 days in 2011-2014 vs. 49 days in 2015-2017 (p&lt;0.0001). In the overall cohort, age&lt;65 years, female gender, private insurance, no comorbidities, residence in metropolitan area, and treatment at academic centers were associated with better OS (p&lt;0.0001 for all). Race was not associated with differences in OS (p=0.07). Multivariate analysis for 2015-2017 demonstrated that lack of treatment with IO [HR 1.98, 95%CI 1.81-2.17], radiation therapy [HR 1.20, 95%CI 1.09-1.32], presence of liver metastases [HR 1.87, 95%CI 1.63-2.13], and lack of surgery [HR 1.68, 95%CI 1.45-1.93] were independently associated with worse OS (p&lt;0.0001 for all). In multivariate analysis, receipt of IO from 2015-2017, was associated with age&lt;65 years [OR 1.27, 95%CI 1.08-1.50], African American race [OR 5.88, 95%CI 1.60-28.58], lack of comorbidities [OR 1.43, 95%CI 1.23-1.66], and treatment at academic centers [OR 1.44, 95%CI 1.26-1.65] (p&lt;0.05 for all). Conclusions: OS was improved in stage IV melanoma pts receiving IO, with the highest OS rate in 2015-2017. Our findings that represent a real-world population are consistent with recent trials, like KEYNOTE 006 and CheckMate 067 where 3-year OS for anti-PD-1 therapy was 50% and 52%, respectively. In our study, African Americans demonstrate a 5-fold increase in likelihood of receiving IO, a population underrepresented in clinical trials. Significant socioeconomic factors may impact receipt of IO and survival.[Table: see text]
Choosing optimal therapy for relapsed refractory multiple myeloma: A systematic review and network meta-analysis.
Authors: Mahum Nadeem, Samiksha Gupta, Syed Arsalan Ahmed Naqvi, Irbaz Bin Riaz, Rajshekhar Chakraborty, Mohammed A. Aljama, Muhammad Husnain
Journal: Journal of Clinical Oncology (2021)

e20037 Background: Several treatment options are available for relapsed refractory multiple myeloma(RRMM). However, in the absence of direct-comparative trials, it is unclear how to choose optimal therapy in RRMM. We conducted a network meta-analysis (NMA) to assess the comparative efficacy of different treatment options in RRMM. Methods: Standard electronic databases were searched for abstract and full-text publications of phase 2/3 randomized controlled trials (RCTs) assessing treatment regimens in RRMM. Progression free survival (PFS) , overall survival (OS), complete response (CR), and very good partial response (VGPR) were analyzed. Mixed treatment comparisons were made using fixed-effect network meta-analysis (NMA) within the frequentist framework due to sparse direct evidence. Sensitivity analyses were conducted using the Bayesian approach. Publication bias was assessed by visual inspection of comparison-adjusted funnel plots. P-score plots were used to assess relative rankings of the treatments. R statistical software v 4.0.3 was used to conduct the analyses. Results: After a review of 1137 citations, A total of 37 relevant studies were included in systematic review and 30 studies were analyzed in the network meta-analysis (29 contributed for PFS; 18 for OS; 23 for CR; 25 for VGPR). Mixed treatment comparisons showed high likelihood of PFS benefit with triplet regimens; Isatuximab-Carfilzomib-Dexamethasone (Isa-Kd; P-score: 0.98), followed by Daratumumab-Carfilzomib-Dexamethasone (DKd; P-score: 0.93), Daratumumab-Bortezomib-Dexamethasone (DVd P-score: 0.92), Elotuzumab-Pomalidomide-Dexamethasone (EPd); P-score: 0.84), and Isatuximab-Pomalidomide-Dexamethasone (Isa-Pd; P-score: 0.80) when compared to monotherapy and different doublet regimens. Isa-Kd and DKd continued to show significant PFS advantage when compared to Kd doublet. High likelihood of OS benefit was observed with Carfilzomib-Lenalidomide-Dexamethasone (KRd); P-score: 0.86) followed by Kd (P-score: 0.83), and DVd (P-score: 0.82). However, trials did not consistently report data for OS and most of the mixed treatment comparisons were statistically insignificant. Similar results were observed for CR and VGPR with triplet regimens showing better likelihood for achieving CR and VGPR. Conclusions: This NMA provide most updated evidence on different treatment options in RRMM and can serve as a contemporary guidance in the absence of head-to-head trials. The weight of current evidence favors the use of triplet regimens. Isa-Kd, DKd, DVd, EPd and Isa-Pd showed no statistically significant difference in terms of PFS in RRMM.
Mobocertinib (TAK-788) in <i>EGFR</i> exon 20 insertion (ex20ins)+ metastatic NSCLC (mNSCLC): Additional results from platinum-pretreated patients (pts) and EXCLAIM cohort of phase 1/2 study.
Authors: Suresh S. Ramalingam, Caicun Zhou, Tae Min Kim, Sang-We Kim, James Chih-Hsin Yang, Gregory J. Riely, Tarek Mekhail, Danny Nguyen, Maria Rosario García Campelo, Enriqueta Felip, Sylvie Vincent, Shu Jin, Veronica Bunn, Jianchang Lin, Huamao Mark Lin, Minal Mehta, Pasi A. Janne
Journal: Journal of Clinical Oncology (2021)

9014 Background: No approved targeted therapies are available for EGFR ex20ins+ mNSCLC. Mobocertinib, a first-in-class, potent, oral TKI targeting EGFR ex20ins mutations, has Breakthrough Therapy Designation in the US and China for post-platinum-based chemotherapy pts with EGFR ex20ins+ mNSCLC. Methods: This 3-part, open-label, multicenter study (NCT02716116) has dose-escalation/expansion and extension (EXCLAIM) cohorts. Pts with EGFR ex20ins+ mNSCLC, ECOG status 0–1, and ≥1 prior line of therapy for locally advanced/metastatic disease received mobocertinib 160 mg QD. Primary endpoint was confirmed objective response rate (ORR; RECIST v1.1) assessed by independent review committee (IRC). We present additional efficacy and safety data for 114 platinum-pretreated pts (PPP) and 96 pts from EXCLAIM safety cohort. Results: Results are from Nov 1, 2020, data cutoff. Among PPP pts (n=114; median age 60 y [27–84 y]), 66% were female, 60% were Asian, and 59% had ≥2 prior systemic anticancer lines. Confirmed ORR per IRC was 28%, including 1 complete response (CR); disease control rate (DCR) was 78% [95% CI: 69–85]; median duration of response (DOR) was 17.5 mo (Table). In EXCLAIM (n=96; median age 59 y [27–80 y]), 65% were female, 69% were Asian, and 49% had ≥2 prior lines. Confirmed ORR per IRC was 25%, with 1 CR; DCR was 76% [95% CI: 66–84]; median DOR was not reached (Table). In EXCLAIM, baseline brain metastases were present in 33/96 pts (34%); the first site of disease progression by IRC was the brain in 40% of all pts and 73% of pts with baseline brain metastases. Confirmed responses were seen in all prespecified subgroups in PPP and EXCLAIM. Efficacy by EGFR ex20ins mutation variant will be presented. Treatment-related adverse events (TRAEs; &gt;20%) in PPP were diarrhea (91%), rash (45%), paronychia (38%), decreased appetite (35%), nausea (34%), dry skin (31%), vomiting (30%), increased blood creatinine (25%), stomatitis (24%), and pruritus (21%); the only grade ≥3 TRAE in ≥5% was diarrhea (22%). AEs leading to discontinuation in &gt;2% were diarrhea (4%) and nausea (4%). A similar safety profile was observed in EXCLAIM. Conclusions: Mobocertinib demonstrated clinically meaningful benefit for pts with EGFR ex20ins+ mNSCLC in PPP and EXCLAIM cohorts, with a manageable safety profile. Clinical trial information: NCT02716116. [Table: see text]