bluuebunny/crossref_metadata_2025_split huggingface dataset:
Therapeutic vulnerabilities among KRAS G12C mutant (mut) advanced cancers based on co-alteration (co-alt) patterns.
Authors: Nusrat Maliha , Roszik Jason , Holla Vijaykumar , Cai Tiantian , Hong Meiyue , Coker Oluwadara , Johnson Benny , Rodon Ahnert Jordi , Janku Filip , Kopetz Scott , Shaw Kenna Rael , Meric-Bernstam Funda , Hong David S. 
Published: May 2020

3625 Background: Oncogenic KRAS mut drive cancers and confer therapeutic resistance by activating MAPK signaling. Inhibiting KRAS has been elusive until the recent promising phase I trials with KRAS G12C inhibitors (i). We characterized frequencies of KRAS G12C mut and gene co-alt among advanced cancer patients (pts) to identify therapeutic vulnerabilities for combination development. Methods: We analyzed next generation sequencing datasets from MD Anderson Cancer Center (MDACC, n = 42,316) and AACR GENIE (n = 56,970). Genes and individual alterations were annotated for potential actionability with approved or investigational drugs and grouped into 12 oncogenic pathways. Frequencies of potential drug combinations with KRAS G12Ci were estimated per tumor type based on co-occurrence of potentially actionable alterations. Results: KRAS G12C was present in 850/34,801 (2.4%) advanced solid tumor and 22/7698 (0.3%) hematologic malignancy pts in MDACC dataset; and 1422 (2.5%) pts in AACR GENIE. Among solid tumor pts, 798 had histology data and 640 had ≥46 gene profiling. Most common cancers were non-small cell lung (NSCLC, 67%), colorectal (CRC, 24%), other gastrointestinal (oGI, 4%) and gynecologic (gyn, 2%). KRAS G12C prevalence was 19.5% (441/2265) in NSCLC and 4.2% (146/3469) in CRC. Genes most commonly co-altered were TP53 (42%), STK11 (17%) and MET (11%) in NSCLC; TP53 (58%), APC (54%) and PIK3CA (24%) in CRC; TP53 (42%), APC (21%) and ATM (21%) in oGI; TP53 (56%), PIK3CA (25%), and PTEN (19%) in gyn cancers. These co-alt did not impact overall survival. In both datasets, as compared to KRAS wild, KRAS G12C was significantly co-altered with STK11 in NSCLC; PIK3CA and SMAD4 in CRC (P < 0.05 for all). EGFR mut in NSCLC and BRAF mut in CRC rarely co-occurred with KRAS G12C (P < 0.01). Most frequently co-altered oncogenic pathways in NSCLC, CRC, oGI and gyn cancers respectively included PI3K (27, 32, 33, 44 %), receptor tyrosine kinases (13, 16, 42, 13 %) and DNA damage repair (12, 10, 38, 19 %). Potentially actionable co-alt frequencies suggest that combining KRAS G12Ci with mTORi or PI3Ki would be indicated most frequently, in 24% and 13% of all pts respectively. Conclusions: KRAS G12Ci development is most relevant for NSCLC, gastrointestinal and gyn cancers. The co-alt patterns highlight relevant oncogenic pathways and candidate drugs for future combination therapies. Co-inhibition of PI3K-mTOR and MAPK pathways has shown synergism in prior pre-clinical studies but had poor tolerance in pts. There is opportunity to revisit this approach with the new KRAS G12Ci.
Employing RNA sequencing to enhance treatment options for cancer patients.
Authors: Basu Gargi D. , LoBello Janine , Ozols Audrey 
Published: May 2020

3628 Background: Fusions and translocations account for 20% of cancer mortality globally. Maximizing their detection enhances the utility of precision medicine for various solid and hematologic cancers. Practice guidelines stress the importance of RNA sequencing. Novel assay techniques employing a comprehensive genomic profiling approach, including RNA sequencing, yield information beyond conventional DNA next generation sequencing (NGS) alone. Methods: Tumor samples (N = 1517) were assayed combining whole transcriptome (RNA) sequencing, whole exome (DNA) sequencing, and comparison of tumor sequence vs. paired normal DNA. Results were analyzed to determine the frequency of rare and common RNA fusion and variant detection. Findings were mapped to a knowledge-base of targeted treatment options. Results: Analysis detected 79 (5.2%) actionable fusions and 15 (1%) transcript variants across major solid and heme-based malignancies. Notably, we observed actionable transcript variants that are not detectable at the DNA level including: EGFRvIII, EGFRvIVa and EGFRvIVb in GBM; ARv7 in prostate, and METe14 in TNBC. Many fusion cases (42%, n = 33) had no other actionable molecular abnormalities. Novel fusions included: SLC12A/ROS1 in low-grade spindle cell neoplasm with myogenic differentiation, KANK1/NTRK2 in ganglioneuroblastoma, ETV6/NTRK3 in metastatic mammary analogue secretory carcinoma, FGFR1/SCT in germ cell tumor, ZNF33B/RET fusion in GBM, SH3BP4/ERBB4 and EML4/ALK in RCC, VTCN1/NRG1 in pancreatic cancer, and AGRN/NRG1 in cholangiocarcinoma. More common actionable fusion events included: EML4/ALK in NSCLC, KIAA1549/BRAF in pilocytic astrocytoma, FGFR2 and FGFR3 in cholangiocarcinoma and urothelial cancers and ESR1 in endocrine therapy-resistant breast cancers. The fusion events detected in heme-based malignancies included MLLT10 and MLLT4 in AML, BCR/ABL in leukemias, TCF3/PBX1 in B cell ALL, NPM1/ALK in ALCL, and novel fusion CIITA/CD274 in DLBCL. All RNA fusions and transcript variants found were matched to FDA-approved or investigational treatment options. Conclusions: Maximizing the rate of variant detection for targeted therapy relies on precise identification of common and rare fusion events. Without the addition of RNA sequencing, 15 transcript variants in our cohort would have been missed and 33 of the fusions may have gone undetected by conventional DNA NGS testing, resulting in zero targeted treatment options for this vulnerable population. Further use of comprehensive genomic profiling is vital to optimizing cancer care.
Identifying functional loss of ATM gene in patients with advanced cancer.
Authors: Pilie Patrick Glen , Gheeya Jinesh S. , Kyewalabye Keith , Goswamy Rohit Vivek , Wani Khalida M , Le Hung , Campbell Erick , Sanchez Nora Sylvia , Yang Dong , Garmezy Benjamin , Ileana Dumbrava Ecaterina Elena , Rodon Ahnert Jordi , Heffernan Timothy , Holla Vijaykumar , Shaw Kenna Rael , Meric-Bernstam Funda , Lazar Alexander J. , Wang Wei-Lien , Yap Timothy A 
Published: May 2020

3629 Background: ATM is frequently mutated in cancer, and defects may serve as a putative predictive biomarker. However, the functional impact of most ATM variants is not well known. In this study, we examined the relationship between ATM variants and ATM protein expression to better discern ATM functional defects in patients (pts) with advanced cancer. Methods: We retrospectively identified pts seen at MD Anderson Cancer Center who had ATM variants detected on CLIA-certified next generation sequencing (NGS) assays. ATM immunohistochemistry (IHC) was performed on available tumors. We then prospectively assessed ATM IHC on tumors from pts who were referred for DNA damage repair inhibitor (DDRi) trials. Functional classification of the variants was performed via published in silico tools and/or precision oncology decision support (PODS). An IHC cut-off of 100% loss in tumor cell nuclei defined ATM loss of protein (LOP). Results: Of 1394 ATM-mutant tumors identified retrospectively, ATM alterations were classified as 16% (N = 216) inactivating, 12% (N = 163) potentially inactivating, 71% (N = 993) variant of unknown significance (VUS), and 2% (N = 22) benign. Coding variants were seen across the ATM exonic structure/splice sites, and 20 individual variants were shared in > 10 pts. 263/297 available retrospective tumor samples had interpretable IHC results; 27% (N = 72) had ATM LOP. LOP was most prevalent in tumors with inactivating ATM variants (39/100, 39%); but, importantly, LOP was seen in 20% (N = 33/162) of potentially inactivating/VUS, thus better clarifying their functional impact. In the prospective cohort of 217 pt tumors, 17% (N = 37) had ATM LOP. 29% (N = 62/217) of this cohort also had ATM variants. ATM LOP was seen in 48% of tumors with inactivating variants (N = 14/29), 25% of tumors with potentially/VUS(N = 9/36), and 9% (N = 14/156) of tumors without ATM variants identified. ATM LOP was detected most commonly in colorectal (24%; N = 8/34), cholangiocarcinoma (20%; N = 6/30), prostate (16%; N = 16/104) and pancreatic (9%; N = 1/11) cancers among this cohort of pts referred for DDRi trials. Conclusions: ATM coding variants occurred across the gene, with certain variants shared across tumor types. The functional impact of most ATM variants was VUS, and ATM LOP can help clarify function in up to 25% of these VUS. Also, ATM LOP can be seen even in tumors without ATM variants identified, suggesting epigenetic or post-translational loss. Future prospective studies assessing predictive capability of paired DNA and protein-level profiling of ATM are warranted.
Predictive value of a CLIA-approved organoid based drug sensitivity test.
Authors: Margossian Astrid , Richardson Annie , Churchill Michael , Schaub Franz , Rosati Rachele , Appleyard Lauren , Pollastro Madison , Katabian Carolina , Motamedi Kathleen , Diaz Robert , Pereira Shalini , Kemp Christopher , Gadi Vijayakrishna K. , Grandori Carla 
Published: May 2020

3630 Background: Precision medicine integrates genetic, molecular, and clinical information to optimize therapy selection for cancer patients. Ex vivo drug testing has the potential to match the right drug to the right patient. We developed a CLIA-certified functional drug assay for all solid tumors which provides an actionable report of organoid sensitivity to targeted, endocrine and chemotherapy agents as a tool for therapeutic decisions. Objectives: To establish the predictive power of the test in relation to well-known genomic biomarkers as well as prior treatments to identify drug sensitivity. To demonstrate that functional drug testing increases the actionability of genomic reports. Methods: From 2016 to 2019, 240 organoids from cancer patients were subjected to functional testing at SEngine Precision Medicine. Patients with advanced primary or metastatic cancer (solid tumors) who were treatment naïve or had previous therapies fail. Fresh samples of tumor cells from core biopsies, surgical excisions, or fluids arrived <48 hrs following collection and were cultured as 3D organoids. They were evaluated using a multi-dose response format with a library of up to 130 compounds. Drug sensitivity was quantified using a score that combines sensitivity and personalization of each patient’s response relative to a reference population. Known genomic actionability from levels of evidence 1-2 from MSKCC OncoKB were queried against results for correlation. Results: Organoids were derived from breast (18.7%), ovarian (18.3%), colorectal (17.9%), pancreatic (6.7%), and others solid tumors (38,3%). Median age of patients was 53 (r5-83). 68 drugs on average were tested per patient with a mean turnaround time of 18 days (r9 -37). A mean of 7 drugs per patient were identified as top scoring drugs. In 75 patients with genomic data, we found high concordance of drug sensitivity with known genomic anchors (e.g., inhibitors of BRCA1/ PARP, ERBB2/HER2, FGFR1-2/FGFR, KRAS, PIK3CA/PI3K), measured as sensitivity to drugs among this targeted groups. However, several patient samples demonstrated sensitivity to targeted agents in the absence of known genomic biomarkers. Most important, analysis of previous treatments indicated >90% of retrospective concordance. Conclusions: Organoid based drug testing exhibits strong concordance with genomic and retrospective clinical evidence. In addition, functional testing identifies candidate therapies in patients with no known biomarkers and can identify the significance of variants currently not validated.
Pooled safety analysis of single-agent lurbinectedin versus topotecan (Results from a randomized phase III trial CORAIL and a phase II basket trial).
Authors: Leary Alexandra , Gaillard Stephanie , Vergote Ignace , Trigo Jose , Kahatt Carmen Maria , Nieto Antonio , Fernandez Cristian Marcelo , Cullell-Young Martin , Zeaiter Ali Hassan , Subbiah Vivek 
Published: May 2020

3635 Background: Lurbinectedin (L), an inhibitor of active transcription, has shown activity in second-line (2L) small cell lung cancer (SCLC) (ASCO 2019). Topotecan (T) is the only approved drug in 2L SCLC and is also used in platinum resistant ovarian cancer (PROC). Methods: This pooled safety analysis includes data from 554 patients (pts) treated with L at 3.2 mg/m2 Day 1 q3wk 1-h (no primary prophylaxis with G-CSF required): 335 with selected solid tumors (9 indications, including 105 pts with SCLC) from a phase II Basket study and 219 with PROC in the phase III CORAIL study. An indirect exploratory comparison (pooled data from CORAIL + Basket) and a direct comparison (data from CORAIL) of L vs. T are presented. Results: Most common adverse events with L were grade 1/2 fatigue, nausea and vomiting. Treatment-related (L/T): dose reductions: 22.9/48.3%, delays: 25.8/52.9%, grade ≥3 serious adverse events (SAEs): 15.0/32.2%, discontinuations: 3.2/5.7%, deaths: 1.3/1.5%, G-CSF use: 23.8/70.1%, and transfusions: 15.9/52.9%. Conclusions: Lurbinectedin has a predictable and manageable safety profile. A significant safety advantage was observed when lurbinectedin was compared with topotecan in the CORAIL trial in terms of hematological toxicities. With the limitations of indirect comparisons, in the pooled safety analysis, fewer lurbinectedin-treated pts had severe hematological toxicities, SAEs, dose adjustments, treatment discontinuations and use of supportive treatments than topotecan-treated pts. Clinical trial information: NCT02421588 and NCT02454972 . [Table: see text]
Phase I dose-finding study of oral ERK1/2 inhibitor LTT462 in patients (pts) with advanced solid tumors harboring MAPK pathway alterations.
Authors: Janku Filip , Elez Elena , Iyer Gopa , Yamamoto Noboru , Tan Daniel Shao-Weng , Stathis Anastasios , Stammberger Uz M. , Evans Helen , Seroutou Abdelkader , Mais Anna , Schuler Martin H. 
Published: May 2020

3640 Background: LTT462 is an investigational small molecule inhibitor of ERK1/2, which has demonstrated preclinical activity in multiple MAPK activated cancer cells and xenograft models. This first-in-human study was designed to evaluate the safety and tolerability of LTT462 in advanced solid tumors harboring MAPK pathway alterations (NCT02711345). Methods: The dose-escalation part of this Phase I, open-label study, enrolled adult and adolescent pts with advanced solid tumors harboring ≥1 documented MAPK pathway alteration with progressive disease (PD) despite standard therapy, or for whom there is no effective standard treatment. Oral LTT462 was given once daily (QD) at 45–600 mg or twice daily (BID) at 150 mg or 200 mg. Objectives were to determine the maximum tolerated dose (MTD) using a Bayesian hierarchical logistic regression model guided by escalation with overdose control, and characterize safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of LTT462. Results: Sixty-five pts (median age 60 years) including 1 pt aged 15 were enrolled in the dose-escalation; most pts (22%) had 3 prior therapies. Most common primary sites for cancer were in the colon (n = 21; 32%), ovary (n = 9; 14%), and pancreas (n = 7; 11%). All pts discontinued, the majority due to PD (n = 44; 68%). Eleven pts experienced DLTs; 6 pts experienced Grade 3 eye disorder DLTs (4 pts retinopathy, 2 pts chorioretinopathy). Treatment-related adverse events (TRAEs) were reported for 89% of pts, most commonly ( > 30%) diarrhea (n = 25; 38%) and nausea (n = 22; 34%). Grade 3/4 TRAEs were reported in 29% of pts; most common was retinopathy (n = 4; 6%). MTD of LTT462 was 400 mg QD and 150 mg BID. Overall, 8 pts (12%) had stable disease (SD) and 35 pts (54%) had PD. An unconfirmed partial response was reported in a pt with cholangiocarcinoma with BRAF mutation; best change in sum of target lesions per RECIST 1.1 was -33.9%. LTT462 increased plasma peak drug concentration and drug exposure at increasing doses between 45–450 mg QD. Exposure at LTT462 600 mg QD was lower than anticipated, indicating potential saturation of absorption at this dose. LTT462 inhibited ERK1/2 and reduced DUSP6 expression relative to baseline in most pts evaluated. Conclusions: LTT462 is well tolerated. Limited clinical activity was reported with single agent LTT462; best overall response was SD. An ongoing study is investigating LTT462 in combination with the RAF inhibitor, LXH254, in NSCLC and melanoma. Clinical trial information: NCT02711345 .
A phase II, multicenter, open-label study of trastuzumab deruxtecan (T-DXd; DS-8201) in patients (pts) with HER2-expressing metastatic colorectal cancer (mCRC): DESTINY-CRC01.
Authors: Siena Salvatore , Di Bartolomeo Maria , Raghav Kanwal Pratap Singh , Masuishi Toshiki , Loupakis Fotios , Kawakami Hisato , Yamaguchi Kensei , Nishina Tomohiro , Fakih Marwan , Elez Elena , Rodriguez Javier , Ciardiello Fortunato , Saxena Kapil , Yamamoto Eriko , Bako Emarjola , Okuda Yasuyuki , Shahidi Javad , Grothey Axel , Yoshino Takayuki 
Published: May 2020

4000 Background: T-DXd is an antibody-drug conjugate composed of an anti-HER2 antibody, cleavable tetrapeptide-based linker, and topoisomerase I inhibitor payload. Early studies have shown promising activity in advanced HER2-expressing tumors. DESTINY-CRC01 (DS8201-A-J203; NCT03384940) is a phase 2, open-label, multicenter study of T-DXd in pts with HER2-expressing mCRC. Methods: Pts with centrally confirmed HER2-expressing, RAS–wild type mCRC that progressed on ≥ 2 prior regimens received T-DXd 6.4 mg/kg every 3 weeks (q3w) in 3 cohorts (A: HER2 IHC 3+ or IHC 2+/ISH+; B: IHC 2+/ISH−; C: IHC 1+). The primary endpoint was confirmed objective response rate (ORR) by independent central review in cohort A; secondary endpoints included, disease control rate (DCR; CR + PR + SD), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and ORR in cohorts B and C. Results: At data cutoff (Aug 9, 2019), 78 pts (A, 53; B, 7; C, 18) had received T-DXd. Median age was 58.5 y (range, 27-79 y), 52.6% of pts were male, and 89.7% had left colon or rectum cancer; median number of prior regimens was 4 (range, 2-11); all pts had prior irinotecan. Median treatment duration was 3.5 mo (95% CI, 2.1-4.3 mo; cohort A, 4.8 mo [95% CI, 3.9-5.8 mo]); 38.5% of pts remained on T-DXd treatment. The confirmed ORR was 45.3% (24/53 pts; 95% CI, 31.6%-59.6%) in cohort A, including 1 CR and 23 PRs; median DOR was not reached (95% CI, 4.2 mo-NE). The ORR in pts with prior anti-HER2 treatment was 43.8% (7/16 pts; 95% CI, 19.8%-70.1%). The DCR was 83.0% (44/53 pts; 95% CI, 70.2%-91.9%); median PFS was 6.9 mo (95% CI, 4.1 mo-NE); median OS was not reached. No responses were observed in cohorts B or C. Grade ≥ 3 treatment-emergent adverse events (TEAEs) occurred in 61.5% of pts (48/78); the most common (≥10%) were decreased neutrophil count (21.8%) and anemia (14.1%). Seven pts (9.0%) had TEAEs leading to drug discontinuation. Five pts (6.4%) had interstitial lung disease (ILD) adjudicated by an independent committee as related to T-DXd (2 grade 2; 1 grade 3; 2 grade 5 [the only drug-related deaths]). Conclusions: Overall, T-DXd 6.4 mg/kg q3w demonstrated remarkable activity in pts with HER2-expressing mCRC refractory to standard therapies, with a safety profile consistent with previous results. ILD is an important risk and requires careful recognition and intervention. Clinical trial information: NCT03384940 .
Overall survival (OS) and long-term disease-free survival (DFS) of three versus six months of adjuvant (adj) oxaliplatin and fluoropyrimidine-based therapy for patients (pts) with stage III colon cancer (CC): Final results from the IDEA (International Duration Evaluation of Adj chemotherapy) collaboration.
Authors: Sobrero Alberto F. , Andre Thierry , Meyerhardt Jeffrey A , Grothey Axel , Iveson Timothy , Yoshino Takayuki , Sougklakos Ioannis , Meyers Jeffrey P. , Labianca Roberto , Saunders Mark P. , Vernerey Dewi , Yamanaka Takeharu , Boukovinas Ioannis , Oki Eiji , Georgoulias Vassilis , Torri Valter , Harkin Andrea , Taieb Julien , Shields Anthony Frank , Shi Qian 
Published: May 2020

4004 Background: In overall population, IDEA pooled analysis did not demonstrate non-inferiority (NI) regarding 3y DFS in pts with stage III CC receiving 3m vs. 6m of adj FOLFOX/CAPOX. However, in pts treated with CAPOX (especially in low-risk pts), 3m of therapy was as effective as 6m. Results of OS and 5y DFS are reported. Methods: OS was defined as time from enrollment to death due to all causes. OS NI margin was conservatively set to be Hazard Ratio (HR) = 1.11, which is equivalent to: the maximum acceptable loss of OS efficacy, by shortening treatment to 3m, was half of the OS efficacy gained in MOSAIC trial (i.e., 2.26% absolute reduction in 5y OS rate). Pre-planned sub-group analyses included by regimen and risk group for both OS and 5y DFS. NI was to be declared if the one-sided false discovery rate adjusted (FDRa) NI p-value < 0.025. Results: With an overall median survival follow-up of 72 m (range per study, 62 to 84 m), 2584 deaths and 3777 DFS events among 12,835 pts from six trials were observed. Across 6 studies, 39.5% of pts received CAPOX (rate by study, 0% to 75.1%). Overall, the 5y OS rate was 82.4% (3m) and 82.8% (6m), with estimated OS HR of 1.02 (95% confidence interval [CI], 0.95-1.11; FDRa NI p, 0.058) and absolute 5-y OS rate difference of -0.4% (95% CI, -2.1 to 1.3%). Overall, the 5y DFS rate was 69.1% (3m) and 70.8% (6m), with estimated DFS HR of 1.08 (95%CI, 1.01-1.15, FDRa NI p, 0.22). HRs (95% CI) within subgroups see table. Conclusions: 5y OS rate reported in IDEA trials was higher than historical rates, regardless of duration of therapy. While overall survival in IDEA did not meet prior statistical assumptions for NI in overall population, the 0.4% difference in 5y OS should be placed in clinical context. OS and 5y DFS results continue to support the use of 3m adjuvant CAPOX for the vast majority of stage III colon cancer pts. This conclusion is strengthened by the substantial reduction of toxicities, inconveniencies and cost associated with shorter treatment duration. Clinical trial information: NCT01150045; 2009-010384-16; NCT00749450; ISRCTN59757862; 2007-003957-10; UMIN000008543; 2007-000354 . [Table: see text]