bluuebunny/crossref_metadata_2025 huggingface dataset:
Circulating tumor DNA (ctDNA) in HER2 exon 20 insertion mutations and responses in NSCLC HER2 exon 20 insertion treated with poziotinib.
Authors: Thiagalingam Arunthi , Lakshmikanthan Sribalaji , Mak Allysia , Shell Scott A. , Leu Sharon , Sun Sophie , Bertino Erin Marie , Haura Eric B. , Washington Rocky , Bhat Gajanan , Lebel Francois M. , Barrett John A.
Published: June 2022

3051

Background: ctDNA levels in plasma samples permits temporal assessment of tumor mutational status and tumor burden during therapy. Poziotinib is an oral HER2 TKI in development for NSCLC patients harboring HER2 exon 20 insertion mutations. We assessed serial plasma samples for changes in HER2 exon 20 insertion mutations and other driver mutations in first- and second-line patients comparing to clinical response per RECIST1.1. Methods: NSCLC patients harboring HER2 exon 20 insertion mutations were enrolled into the poziotinib ZENITH20 using tumor tissue based NGS. Serial plasma samples were collected at baseline, at C3D1, at Day 1 of every other cycle until disease progression. The Guardant360â 74-gene liquid biopsy assay was used to assess changes in tumor-associated somatic variants including the target variant HER2 exon20 insertion as well as other emergent driver mutations in ctDNA as expressed as percent variant allele frequency (%VAF). Results: 23 first- and second-line NSCLC patients were evaluable with tumor tissue confirmation of HER2 exon 20 insertion mutations. 22 of 23 (96%) had baseline plasma samples with detectable ctDNA. 21 of 22 samples had detectable HER2 exon 20 insertion mutations (mean % VAF 20±5) resulting in a concordance of 95% versus tissue based NGS. 7 patients had serial testing through C7D1 permitting assessment of ctDNA dynamics and comparison to clinical responses. 5 of 7 (71%) serially tested patients treated with poziotinib at 16mg QD had undetectable HER2 exon 20 insertion at C3D1 which was associated with a tumor response PR. Tumor escape (PD) was observed in 2 of the 5 patients which correlated with increases in target HER2 exon 20 insertion VAF in the plasma with the remaining 3 patients ≥PR. Notably, the rise in HER2 exon 20 in ctDNA occurred prior to tumor escape. In one patient treated with poziotinib at 16 mg QD we observed undetectable levels of the HER2 exon 20 insertion in ctDNA at C3D1 which continued through C16. This patient’s responses correlated with patient tumor response of SD at C2 which then became PR through C9 and CR through C17. Conclusions: Poziotinib treatment resulted in reductions in HER2 exon 20 insertion mutations in ctDNA preceded and correlated with the clinical tumor response. Increases in ctDNA HER2 exon 20 insertion mutations were observed prior to confirmation of tumor escape. Serial monitoring of ctDNA is a potential predictive biomarker for treatment response and disease progression. Future evaluation in a larger population is required to confirm the impact of these findings.
The HERPET study: Imaging HER2 expression in breast cancer with the novel PET tracer [18F]GE-226, a first-in-patient study.
Authors: Kenny Laura M. , Gilbert Fiona J , Gopalakrishnan Gosala , Aravind Preetha , Barwick Tara , Patel Neva , Hiscock Duncan ROBERT , Boros Istvan , Kealey Steven , Aigbirhio Franklin I , Lozano-kuehne Jingky , Cleator Susan Jane , Fleming Ben , Riddle Pippa , Ahmad Rizvana , Chua Sue , Johnston Stephen R.D. , Mansi Janine , Cook Gary J. , Aboagye Eric O.
Published: June 2022

3069

Background: Over-expression the human epidermal growth factor receptor-2 (HER2) is seen in 20% of breast cancers; this is an adverse prognostic factor and used to guide therapy selection. At present HER2 expression can only be determined using biopsy material using immunohistochemistry or fluorescence in situ hybridisation. Heterogeneous expression of HER2 is now being recognised as a cause of treatment resistance but is difficult to characterise. A non-invasive method for determining HER2 expression could have several advantages and help select appropriate therapy for patients. GE-226 is a novel radiolabelled GE-Affibody radioligand which binds to the HER2 receptor with high affinity at a different epitope than trastuzumab. Methods: Patients with locally advanced or metastatic breast cancer were recruited and scanned for 65 mins after iv injection of 200MBq of GE-226 (mean activity injected for each patient 202MBq (range 164-223MBq, mean radiochemical purity 94%) of radioligand, over one bed position for dynamic imaging, followed by a half-body scan. Blood sampling was used to measure metabolism of the tracer. Safety was assessed. HER2-extracellular domain (ECD) domain was measured in blood. Tumoural uptake was quantified by semi-quantitative and fquantitative parameters in HER2 positive and HER2 negative tumours. Patients had routine baseline FDG imaging. Results: Twenty patients completed the study. GE-226 scans were well tolerated. There were no serious adverse events. GE-226 was slowly metabolised into a single metabolite in the liver; 97% of parent remained at 60 minutes post injection (range 82-100). There was a significant difference in tumoural radioligand uptake between biopsy proven HER2 positive and HER2 negative tumoural patients as measured by SUVmean and SUVmax (p < 0.001). Comparing HER2 positive to HER2 negative cases, there was also a significant difference between tumour to normal tissue uptake ratios SUVmean. Heterogeneous uptake was observed in three patients, two with interlesional uptake variation and one with intralesional heterogeneity. Tumoural uptake increased over time. Normal physiological uptake in salivary glands and the thyroid gland was noted. GE-226 was able to differentiate between lymphadenopathy due to sarcoidosis and cancer in one patient and was superior to FDG which had shown widespread uptake in the benign and malignant nodes. Conclusions: [18F]GE-226 imaging is well tolerated and shows promise for imaging of HER2 positive breast cancer. Further studies with this agent are now planned. Clinical trial information: NCT03827317.
Image-based detection of FGFR3-fusion in urothelial bladder cancer.
Authors: Peled Nir , Zalach Jonathan , Gazy Inbal , Hayun Ido , Avinoam Assaf , Nataf Daniel , Paz-Yaacov Nurit
Published: June 2022

3072

Background: Fibroblast growth factor receptor-3 (FGFR3) is a transmembrane protein, somatically altered in a large spectrum of cancer types. Chromosomal rearrangement resulting in FGFR3 gene fusions leads to a constitutively active tyrosine kinase, mediating tumorigenesis. FGFR3-fusion is a prognostic and predictive marker as well as a validated therapeutic target in urothelial bladder cancer. Both FISH and RT-PCR assays can be used for the detection of FGFR3 rearrangements while immunohistochemistry lacks sufficient sensitivity and specificity. In recent years advances in next-generation sequencing improved their ability to detect these alterations in clinical settings. However, systemic screening of these alterations is still expensive, time-consuming, and requires expertise personnel for data analysis and interpretation. In this study, we aimed to develop and validate an alternative machine learning (ML) based method for the detection of FGFR3-fusions directly from routine pathology hematoxylin and eosin (H&E) slides. Methods: A cohort of 388 H&E whole slide images of bladder urothelial carcinoma samples, obtained from the TCGA Research Network ( https://www.cancer.gov/tcga ) was used. Cases were randomly divided into training (n = 238) and testing (n = 150) sets. Advanced Convolutional Neural Network (CNN) was used to generate the FGFR3-fusion classifier on the training set following validation on the testing set. Results: Validation of the FGFR3-fusion classifier was performed on a cohort of 150 cases from 19 different centers, including three positive cases of FGFR3-TACC3 fusions and 147 negative cases. The AI-classifier performance was measured in comparison to the TCGA dataset. The model demonstrated 100% sensitivity and 94% specificity, with an Area Under the Curve (AUC) of 0.96. Conclusions: Herein, we demonstrate a real-time ML-based genomic testing solution for FGFR3-fusion detection in bladder cancer directly from H&E stained slide images. Utilization of such an alternative method can facilitate fast, accurate, and systemic screening of patients if integrated within the routine pathological pipeline supporting targeted therapy treatment for these patients.
Pharmacokinetic and pharmacodynamic activity evaluation of MAK683, a selective oral embryonic ectoderm development (EED) inhibitor, in adults with advanced malignancies in a first-in-human study.
Authors: Ribrag Vincent , Wainberg Zev A. , Iglesias Docampo Lara , Ramkumar Thiruvamoor , Barys Louise , Chen Shuqi , Raccuglia Marc , Wilbaux Mélanie , Beltz Karen , Luyt Amy , Fan Yu Yun , Suenaga Naoko , Luo Fangjun , Dai Xuan , Lai Clinton , Chen Jia
Published: June 2022

3083

Background: Polycomb Repressive Complex 2 (PRC2) regulates transcription via trimethylation of histone H3 at lysine 27 (H3K27me3). Its dysregulation and over-expression are associated with tumorigenesis in several conditions. MAK683 is a potent oral inhibitor of PRC2 activation, allosterically targeting the EED–H3K27me3 binding site. Methods: NCT02900651 is an ongoing first-in-human dose-escalation study of MAK683 in adults with advanced malignancies. MAK683 was administered fasted once (QD) or twice daily (BID) on a continuous schedule in 28-day treatment cycles. The pharmacokinetic (PK) profile of MAK683 was assessed in sequential blood samples on Days 1, 8 and/or 15 of Cycles 1–6. MAK683 pharmacodynamic activity in Cycle 1, measured by change in H3K27me3, was evaluated in peripheral blood monocytes on Days 1, 8, and 15 by flow cytometry and in tumor biopsies at baseline and Day 15 by H-score. Results: As of Aug 30, 2021, 125 patients had received MAK683 at doses of 10–800 mg QD or 60–450 mg BID. MAK683 was well absorbed with a median Tmax of ̃1-4 hours across cohorts. PK exposure (Cmax, AUC) increased generally with dose over the entire dose range with no major deviation from dose proportionality, taking into account the sample size and PK variability. Apparent terminal half-life (geometric mean) was 2.5–6.6 hours across cohorts and constant over time. MAK683 accumulation of ̃0.9-2.2-fold (QD) or ̃1.3-2.0-fold (BID) was seen with repeat dosing. Peripheral monocytes showed substantial on-treatment reductions from baseline in the H3K27me3/H3 ratio across doses. Maximum percentage reduction was proportional to cumulative MAK683 AUC, with a trend towards greater reductions at higher baseline H3K27me3. H3K27me3 H-score reductions from baseline > 40 were observed in 7/10 patients with diffuse large B-cell lymphoma (n = 4) or epithelioid sarcoma (n = 6) and paired baseline–Day 15 biopsies. RNA-seq characterization of biopsy samples is ongoing. Conclusions: MAK683 has a PK profile supportive of QD or BID dosing in patients with advanced malignancies. Analysis of H3K27me3 in blood monocytes and tumor biopsy confirm the in vivo pharmacodynamic activity of MAK683. Clinical trial information: NCT02900651.
Safety, tolerability, pharmacokinetics and preliminary efficacy of MIL93, an anti-Claudin18.2 monoclonal antibody, in patients with advanced solid tumors: A phase 1 clinical study.
Authors: Huang Jing , Zhang Bo , Wang Ying , Wang Feng , Wu Shikai , Zheng Yi , Xu Jianping , Lan Dongmei , Wei Min , Liu Sijun
Published: June 2022

3086

Background: Claudin18.2 (CLDN18.2) is specifically expressed in the tight junction of gastric epithelial cells, and has been identified as a promising target in gastric and pancreatic cancer as well as several other malignancies. MIL93 is a humanized IgG1 monoclonal antibody targeting CLDN18.2. From January 2021, we started a multicenter, dose escalation and expansion phase 1 study of MIL93, for the treatment of patients with advanced solid tumors (Protocol number MIL93-CT101, Beijing Mabworks Biotech Co. Ltd.) at 6 clinical study sites in China. Currently the study is still ongoing. Methods: We already enrolled 13 pts aged 18 years or older with advanced solid tumors whose disease had progressed after standard systemic treatments. Pts were required to have measurable lesion as per RECIST v1.1; ECOG PS score of 0-1 and adequate organ functions. In the dose escalation phase, 6 dose levels (0.3mg/kg, 1mg/kg, 3mg/kg, 10mg/kg, 20mg/kg and 30mg/kg, Q3W) of MIL93 were planned for assessment. Accelerated titration was adopted for the first 2 dose levels, and the 3+3 design was used afterwards. In the dose expansion phase, pts with CLDN18.2-positive cancers received the selected RP2D. The primary objectives were the safety and tolerability, dose limiting toxicities (DLTs) and maximum tolerated dose (MTD) of MIL93. Secondary objectives included pharmacokinetics, immunogenicity and preliminary efficacy. Results: At the data cut-off date (February 14, 2022), 13 pts were enrolled between April 23, 2021 and February 9, 2022. MIL93 was well-tolerated for the dosages tested (0.3mg/kg through 20mg/kg Q3W) as no DLTs were observed, and dose escalation was ongoing at 30mg/kg. In particular, Grade 3 nausea and vomiting occurred in 2 cases in the third dose group, so preventive antiemetic treatment was given from the fourth dose group. 9 pts (69.2%) experienced at least one treatment-emergent adverse event (TEAE) with no Grade 4 or Grade 5 AEs. The most common treatment-related adverse events (TRAEs) occurring in ≥10% of pts were nausea (46.2%), vomiting (46.2%), fatigue (15.4%), anemia (15.4%). Serious adverse events (SAEs) were observed in 3 (23.1%) pts, and MIL93-related SAEs occurred in 1 pt (7.7%, Grade 3 nausea). Among the 10 pts who had at least one post-treatment radiological evaluation, 1 pt with CLDN18.2-positive gastric cancer achieved PR and 3 pts had SD, including 1 case of gastric cancer, 1 case of gastroesophageal junction cancer and 1 case of gallbladder cancer. Conclusions: MIL93 had a favorable safety profile with no DLTs observed through 20mg/kg Q3W. Pts with CLDN18.2-positive gastric cancer responded to the treatment. Dose escalation and expansion in selected tumor types is currently underway. Clinical trial information: NCT04671875.
A phase 1 dose-escalation study of the ABN401 (c-MET inhibitor) in patients with solid tumors.
Authors: Lee Dae Ho , Roohullah Aflah , Cho Byoung Chul , Lemech Charlotte Rose , de Souza Paul L. , Millward Michael , Choi Jun Young , Park Kyung Eui , Kim Na Young , Kim EuiYoung , Lee Saehyung , Kim YeongMun , Shin YOUNGKEE , Han Ji-Youn
Published: June 2022

3105

Background: MET is a proto-oncogene encoding a receptor tyrosine kinase c-MET for hepatocyte growth factor (HGF). Dysregulated MET signaling by MET exon14 skipping, MET gene amplification and c-MET overexpression in cancer plays a critical role in the development of primary oncogenesis, acquired drug resistance and metastasis. This is a first-in-human trial, phase 1 dose-escalation study of the highly selective MET kinase inhibitor, ABN401. ABN401was evaluated in subjects with advanced solid tumors in South Korea and Australia. Methods: Patients with advanced solid tumors were enrolled in escalating dose cohorts using an accelerated titration design. ABN401 was orally administered daily with 21-day cycle. The primary objective was to evaluate safety and tolerability to define dose-limiting toxicity (DLT), maximum tolerated dose (MTD) according to CTCAE v5. Secondary objectives included pharmacokinetic, recommended phase II dose (RP2D), and preliminary efficacy assessments. Tumor assessment was determined using Response Evaluation Criteria in Solid Tumors (RECIST 1.1). Results: Out of 28 screened patients, 16 patients with 6 different tumor types were treated with ABN401 at daily dose levels of 50, 100, 200, 400, 800 and 1200 mg, 15 patients were evaluated for DLT and one unevaluable. No DLT was observed in all 6 dose levels and the MTD has not been reached. No drug related grade ≥ 3 AEs were observed: only one drug-related SAE (transient peripheral edema) was reported. For treatment response, 5 patients with stable disease, and 2 with partial response were observed. These two patients with partial response had non-small cell lung cancer (NSCLC) with c-MET overexpression and had been treated with ABN401 for 10 and 18 months, respectively. Conclusions: ABN401 dosed up to 1200 mg QD was well tolerated with an acceptable safety profile and promising preliminary antitumor activity in patients with advanced solid tumors. The extension (pilot expansion) for additional efficacy assessment is under way at 800 mg daily dose with c-MET altered NSCLC patients in South Korea and Australia. In addition, a phase 2 expansion study is to start in the United States and South Korea. Clinical trial information: NCT04052971.
Central nervous system (CNS) outcomes and progression patterns in patients with RET fusion-positive lung cancers treated with selpercatinib.
Authors: Murciano-Goroff Yonina R. , Falcon Christina J. , Lin Sabrina T. , Dhawan Aradhika , Grimaldi Grace , Liu Dazhi , Wilhelm Clare , Thomas Reeja , Iasonos Alexia , Drilon Alexander E.
Published: June 2022

3109

Background: Selpercatinib, a potent/selective RET inhibitor, is approved for the treatment of RET fusion-positive non-small cell lung cancers. While the drug is known to have substantial intracranial activity (intracranial ORR 82%) in patients with existing brain metastases, (1) central nervous system (CNS) outcomes in patients without brain metastases and (2) CNS progression patterns in patients with brain metastases have not been explored. Methods: Patients with advanced RET fusion-positive lung cancers were prospectively treated with selpercatinib on the registrational LIBRETTO-001 trial (NCT03157128) or the LIBRETTO-201 multi-center expanded access program (EAP, NCT03906331). Key overall and CNS eligibility criteria were previously presented. Patients with and without pre-selpercatinib brain metastases who underwent serial CNS and extracranial imaging were eligible for analysis. The data cutoff was November 24, 2020. Cumulative incidence rates (CIRs) were calculated using a competing risk model with systemic progression of disease (PD) or death as competing risks; patients with simultaneous CNS and systemic PD were treated as having had CNS PD. Results: Sixty-two patients (48 LIBRETTO-001, 14 EAP) were identified. Median age was 64. Thirty-two (52%) were female and 47 (76%) were never smokers. The most common 5’ fusion partner was KIF5B (68%). The median number of prior therapies was 2 (range 1-11); 34% received prior multikinase inhibitor therapy. The median time on treatment was 21.8 months. Thirty-one (50%) patients had no baseline brain metastases. In these patients, the CIR of CNS metastasis was 0% at 6 months and 12 months; none of these patients developed CNS metastasis during selpercatinib treatment. The 9 patients that progressed did so extracranially. Of the 31 patients with baseline brain metastases, 12 (39%) had prior CNS radiation and 3 (10%) had prior CNS surgery. At the time of data cut-off, 23 patients had some evidence of progression, including 8 in both the CNS and systemically, 6 only in the CNS, and 9 only systemically. Overall, 17 of the 31 patients with baseline brain metastasis did not develop evidence of CNS progression as of the data cut. Among patients with baseline brain metastasis, the CIR for evidence of CNS PD was 6.7% at 6 months and 27.4% at 12 months. Conclusions: In patients with RET fusion-positive lung cancers without baseline brain metastases, new CNS metastases were not observed during selpercatinib therapy. Among patients with baseline brain metastasis, a substantial number did not experience progression in the CNS on treatment.
Pan-cancer analysis of exogenous (microbial) sequences in tumor transcriptome data from the ORIEN consortium and their association with cancer and tumor microenvironment.
Authors: Spakowicz Daniel , Hoyd Rebecca , Wheeler Caroline E. , Zakharia Yousef , Dodd Rebecca D. , Ose Jennifer , Hardikar Sheetal , Tarhini Ahmad A. , Robinson Lary A. , Singer Eric A. , Carpten John D. , Chan Carlos Hou Fai , Ikeguchi Alexandra , Ulrich Cornelia M , McCarter Martin ,   The exORIEN Consortium
Published: June 2022

3113

Background: The tumor microbiome holds great potential for its ability to characterize various aspects of cancer biology and as a target for rational manipulation. For many cancer types, little is known about the role of microbes and in what contexts they affect clinical outcomes. Non-human (i.e. exogenous) sequences can be observed in low abundance within high throughput sequencing data of tumors. Here, we describe a collaboration among members of The Oncology Research Information Exchange Network (ORIEN) to leverage tumor biopsy RNAseq data collected under a shared protocol and generated at a single site to better understand the tumor microbiome, its association with prognostic features of the tumor microenvironment (TME) such as hypoxia, and how it may be used to improve clinical outcomes. Methods: Tumor RNAseq samples from 10 primary source locations including the tissues colon, lung, pancreas, and skin from ORIEN and similar cancers from The Cancer Genome Atlas (TCGA) were processed through the exoTIC (exogenous sequencing in tumors and immune cells) pipeline to identify and count exogenous sequences, filter contaminants, and normalize across datasets. Gene expression signatures of the TME, such as hypoxia, were calculated using ‘tmesig’. Microbe relative abundances were modeled with primary tumor location and hypoxia score using a gamma-distributed generalized linear regression via the stats package in R. Results: We analyzed RNAseq data of 2892 and 2720 tumors from ORIEN and TCGA, respectively. Patients’ ages were significantly greater in the ORIEN than the TCGA dataset (62 vs 58 yo, t-test p<0.001). The ORIEN data contained more sarcoma samples than TCGA (n = 691 vs 259) with roughly equivalent numbers in other cancer types. Fewer microbes were significantly associated with the hypoxia score than with cancer type (n = 32 vs 210). This trend was observed in both the ORIEN and TCGA datasets. The largest effect sizes were observed between microbes and small cell lung cancer. Conclusions: We found microbial sequences in all ORIEN and TCGA tumor RNAseq samples tested. Cancer type showed more significant associations with microbes than a hypoxia signature. These observations merit further investigation into the interaction between microbes and the TME. [Table: see text]
Variable detection of actionable alterations across racial groups and association with testing patterns.
Authors: Sturgill Emma , Correia Jessica , Schumacher Cooper , Luckett Daniel , Jones Suzanne Fields , Burris III Howard A. , Spigel David R. , McKenzie Andrew Jacob
Published: June 2022

3116

Background: Molecular landscape studies are critical to biomarker discovery and precision oncology research. However, non-White patients (pts) have historically been under-represented. In this study, we examine clinico-genomic data from a network of community oncology clinics to evaluate real-world mutational frequencies in Black, White, and Asian pts with cancer. Methods: We utilize Genospace, a precision medicine software, to harmonize clinical data from the Sarah Cannon research network of U.S. community oncology practices with genomic data from commercial NGS vendors. Pts with known race and NGS test results from September 2015 to November 2021 are assessed. Variants of uncertain significance (called by NGS vendor) are excluded. Asian pts are not evaluable in all instances because of low pt number. Statistical analyses include Chi squared and two sample test of proportions with Benjamini-Hochberg false discovery rate correction. Results: A total of 18,399 pts are assessed, with 7% Black (n = 1,319), 92% White (n = 16,903), and 1% Asian (n = 177) pt representation. The most common tumor types include non-small-cell lung (NSCLC; 27% of Black pts, 30% of White pts, 33% of Asian pts), colorectal (15% of Black pts, 12% of White pts, 14% of Asian pts), breast (14% of Black pts, 11% of White pts, 9% of Asian pts), and prostate (6% of Black pts, 5% of White pts, 3% of Asian pts) at roughly equal proportions across racial groups. In NSCLC, EGFR mutations and ALK fusions significantly enrich in Asian pts while KRAS G12C is detected more frequently in Black patients (see table for details; Black: n = 353, White: n = 5,127, Asian: n = 58). In both prostate and breast cancers, plasma-based NGS is less common in Black pts than White pts (plasma-to-tissue ratio = 1.1 (Black prostate: n = 82); 1.5 (White prostate: n = 863); 0.6 (Black breast: n = 178); 0.9 (White breast: n = 1,918)). In prostate, AR mutations are detected less frequently in Black pts. However, when considering plasma-NGS results alone the detection frequency is roughly equal. Similarly, the gap in ESR1 detection frequencies in breast decreases when considering plasma-NGS results alone. Conclusions: Actionable alterations are detected across racial groups at variable frequencies with potential biological and technical underpinnings. In scenarios where plasma-NGS is commonly used to monitor for resistance mutations, discrepancies in NGS ordering patterns likely affect detection frequencies. [Table: see text]
Stress keratin 17 as a novel biomarker of response in immune checkpoint blockade–treated head and neck squamous cell carcinoma.
Authors: Lozar Taja , Fitzpatrick Megan , Wang Wei , Bailey Howard Harry , Yang Bruce Justine Yang , Harari Paul M. , Lambert Paul
Published: June 2022

3117

Background: Low response rates in immune checkpoint blockade (ICB) treated head and neck squamous cell carcinoma (HNSCC)drive a critical need for robust clinically validated biomarkers that can predict response to ICB. Stress keratin 17 (K17) is a known prognostic marker in various types of cancer, including HNSCC; however, its predictive value for ICB response has not been investigated. Preclinical studies suggest K17 suppresses macrophage-mediated CXCL9/CXCL10 chemokine signaling involved in attracting activated CD8+ T cells into tumors. Furthermore, knocking out K17 results in restored response to ICB in a HNSCC mouse model. Here, we evaluated if K17 protein expression predicts response to ICB in human HNSCC patients. Methods: We conducted a retrospective analysis of 26 HNSCC patients that received at least one cycle of pembrolizumab at the University of Wisconsin-Madison Carbone Cancer Center. Pretreatment, archival, formalin-fixed, paraffin-embeded samples were stained by immunohistochemistry using a K17 monoclonal antibody. Clinical outcomes were investigator-assessed for all patients with at least one post-treatment scan or evidence of clinical progression after treatment initiation. Based on independent pathology review, cases were categorized into K17 high vs K17 low based on a cut-off of > 5% strong cytoplasmic staining intensity of tumor cells in the invasive carcinoma component. Correlation between K17 expression and clinical outcomes was assesed using Fischer's exact test and log rank test. Results: The 26 patients included in this study were 85% male, median age 60.5 years, 74% ECOG performance status < 2, with 80% having received prior chemotherapy. Primary site included oral cavity (54%), oropharynx (23%), larynx (4%), or other (19%). Seventeen tumors (65%) showed high K17 expression, and 9 tumors (35%) showed low K17 expression. Eleven patients (42%) had programmed death ligand 1 (PD-L1)+ tumors as determined by combined positive score. Six patients (23%, all K17 low) achieved clinical benefit, while 20 patients (77%, 17 K17 high and 2 K17 low) had progressive disease. High K17 expression was associated with lack of clinical benefit (p < 0.001), shorter time to treatment failure (p < 0.001), progression-free (p = 0.004) and overall survival (p = 0.02). PD-L1 expression by immunohistochemistry (clone 22C3) did not correlate with K17 expression or clinical outcome. Conclusions: Our findings suggest that K17 expression may predict clinical benefit from ICB in HNSCC patients, thus supporting further validation studies. [Table: see text]
Clinical utility of tumor next-generational sequencing (NGS) panel testing to inform treatment decisions for patients with advanced solid tumors.
Authors: Bogdan Lucia , Saleh Ramy R. , Avery Lisa , Del Rossi Samanta , Yu Celeste , Bedard Philippe L.
Published: June 2022

3119

Background: There is limited information about the clinical utility of targeted NGS panel testing to inform decision-making for patients with advanced solid tumors. The Ontario-wide Cancer Targeted Nucleic Acid Evaluation (OCTANE) is an ongoing prospective study that enrolled over 4,500 solid tumor patients for NGS panel testing. We performed a retrospective survey of 21 medical oncologists enrolling OCTANE patients at a single academic institution to evaluate the impact of NGS testing on treatment decisions. Methods: Patients and treating oncologists were identified at the Princess Margaret Cancer Centre between 2016-2021. Tumor-only sequencing was performed using a custom hybridization capture panel of 555 cancer genes (Hi5) or a commercial 161-gene amplicon DNA/RNA panel (Oncomine Comprehensive v3). Oncologists were asked to review testing results for individual patients and complete a survey indicating whether NGS testing impacted treatment decisions. Mutations were defined as actionable based on clinical judgment and compared to classifications provided by OncoKB, an FDA-recognized precision medicine knowledgebase. The primary outcome of this study was rate of treatment change based on mutation results. Patient, test, and physician factors were evaluated for association with treatment changes using univariate analyses and a mixed effects model. Results: Two cohorts were surveyed, the first between 2017-2019 and the second in 2021. Of the 582 surveys sent, 394 (67.7%) were completed. Each physician completed a median of 19 surveys (range, 9-48). We found that 188 (47.7%) patients had a mutation classified as actionable by the oncologist, of whom 134 (71.3%) had ≥1 OncoKB-defined actionable mutation(s). 62/394 (15.7%) patients were matched to a treatment, of whom 37 were enrolled in a clinical trial, 13 received an approved drug, 4 were prescribed off-label therapy and 8 avoided ineffective treatment. 127/188 (67.5%) patients with actionable mutations did not receive treatment due to lack of available therapy, stability on current regimen, clinical deterioration or patient decision. Rate of treatment change was highest for bowel (15/37, 40.5%), breast (14/52, 27.5%), biliary tract (6/22, 27.3%) and lung (4/17, 23.5%) cancers. Treatment decisions were not associated with patient age, gender, physician clinical experience, physician gender, testing experience, OncoKB mutation level or time from biopsy to sequencing. There was no difference in overall survival between patients with matched vs. no matched treatment ( p = 0.55, median survival not reached). Conclusions: OCTANE testing led to a change in drug treatment in 15.7% of patients, supporting the clinical utility of NGS panel testing for patients with advanced solid tumors. Patient, test, and physician characteristics were not significantly associated with treatment change.
De novo EGFR T790M mutations in a community-based oncology practice.
Authors: Holt Marilyn Elaine , Misch Amanda , Rao Smita K. , Sturgill Emma , Jones Carissa , Schlauch Daniel , Luckett Daniel , Spigel David R. , Jones Suzanne Fields , McKenzie Andrew Jacob
Published: June 2022

3146

Background: With the 2018 FDA approval of osimertinib for first-line treatment in EGFR-mutated lung cancers, the prevalence of acquired EGFR T790M mutations is expected to decrease, heightening the significance of de novo T790M mutations. Previous studies have reported a wide range of de novo T790M prevalence, and smaller retrospective studies have indicated that germline T790M may comprise the majority of de novo T790M mutations. Here, we assess the frequency of de novo T790M mutations in a community-based setting and report on germline T790M mutations occurring within this population. Methods: Patients with T790M-positive lung cancer were identified using Sarah Cannon’s clinicogenomics database containing information for patients treated within the Sarah Cannon research network. All T790M mutations were detected on tissue- and plasma-based NGS tests delivered as part of routine care. De novo and germline EGFR T790M status was determined via manual electronic health record chart review. When available, allele fraction and %cfDNA values were extracted from the structured NGS report and analyzed separately. Results: Of T790M-positive lung cancers with available pretreatment testing results, 36% (16/44) were confirmed to be T790M+ prior to EGFR TKI exposure; five of these patients received germline testing, and all five were confirmed to have originated in the germline. Two patients with germline T790M mutations detected on testing ordered by external providers were added to our de novo T790M+ patient analysis after chart review. Co-occurring EGFR mutations, including L858R, were detected in pre-TKI samples for 78% (14/18) of de novo T790M+ patients (Table). Co-occurring mutations in TP53, KRAS, PTEN, or RB1 were detected in pre-TKI samples of all patients without co-occurring EGFR mutations. EGFR C797S was observed after osimertinib treatment in one of four patients with post-TKI testing results. Of confirmed germline T790M+ cases with available allele frequencies, 100% (4/4) had allele fractions >0.5 (tissue) and/or %cfDNA values >50% (plasma). Average allele fraction and %cfDNA values were higher for de novo T790M mutations (allele fraction: 0.5 ± 0.2; %cfDNA: 40% ± 20%) than for acquired T790M mutations (allele fraction: 0.3 ± 0.2; %cfDNA: 2% ± 2%). Conclusions: Roughly one-third of T790M mutations detected in real-world settings occur before EGFR TKI exposure and may be associated with germline inheritance. Allele frequency may be a potential indicator of de novo T790M mutations in scenarios where pre-treatment data is not available. Future studies will investigate the impact of de novo T790M mutations on treatment response and evolution of resistance mechanisms in osimertinib-treated patients. [Table: see text]
STAR-TREC phase II: Can we save the rectum by watchful waiting or transanal surgery following (chemo)radiotherapy versus total mesorectal excision for early rectal cancer?
Authors: Bach Simon Parkinson , de Wilt Johannes H.W. , Peters Femke , Spindler Karen-Lise Garm , Appelt Ane L , Teo Mark , Homer Victoria , Abbott Natalie Louise , Geh Ian , Korsgen Stephan , Al-Najami Issam , Rombouts Anouk J.M. , Christensen Peter , Gilbert Alexandra , Navarro-Nuñez Leyre , Quirke Philip , West Nicholas , Baatrup Gunnar , Marijnen Corrie , Sebag-Montefiore David ,   STAR-TREC Collaborative Group
Published: June 2022

3502

Background: No randomised trials have compared non-operative organ preservation (OP) therapy for early-stage rectal cancer versus standard of care (SoC) using total mesorectal excision (TME) alone. STAR-TREC evaluated the feasibility of recruiting to a study comparing contrasting OP therapies, optimised for treatment of early tumours, versus SoC. Methods: STAR-TREC was a prospective, randomised, open-label, feasibility study in the UK, Netherlands and Denmark. Patients with biopsy proven adenocarcinoma of the rectum, staged ≤mrT3b N0 M0, ≤40mm diameter, ECOG 0-1 were randomised in a 1:1:1 ratio to TME, OP via mesorectal short-course radiotherapy (5x5 Gy), or OP via mesorectal chemo-radiotherapy (25x2 Gy + capecitabine) (Peters FP et al. Mesorectal radiotherapy for early stage rectal cancer: A novel target volume. Clin Transl Radiat Oncol 2020; 21: 104-11). Standardised response assessment classified OP cases as complete response for no further treatment, partial response for transanal endoscopic microsurgery or poor response for TME by 20 weeks. Surveillance following OP consisted of 3-monthly endoscopy/MRI. All cases had CT thorax/abdomen/pelvis at 24 months (m). The primary outcome was recruitment rate over 2 years, with randomisation of 120 international cases calculated as sufficient to support a phase III trial. Secondary outcomes included acute toxicity, stoma and OP rates at 12m, disease free survival (DFS) and non-regrowth DFS (NRDFS) at 24m and EORTC QLQ-C30 summary score at 12 and 24m. Phase II analysis was pre-specified, approved by the data monitoring committee conditional upon grouping of OP arms to inform phase III design, without prejudicing the outcome (STAR-TREC Phase III protocol. Colorectal Disease 2022). Results: Recruitment endpoints were met on 28 Oct 2019. Key secondary outcomes are tabulated by intention to treat. No 6-month mortality occurred. Conclusions: OP pathways optimised for early tumours reduce acute surgical morbidity without introducing substantial radiation toxicity to achieve OP in 60% with no increase in NRDFS at 24m compared to SoC. Overall quality of life was evenly matched. STAR-TREC phase III will determine the optimal strategy for achieving OP (STAR-TREC Phase III protocol. Colorectal Disease 2022). Clinical trial information: NCT02945566. [Table: see text]
Clinical impact of DNA methylation status on first-line antiepidermal growth factor receptor treatment in patients with metastatic colorectal cancer.
Authors: Osumi Hiroki , Ouchi Kota , Shinozaki Eiji , Takahashi Shin , Ooki Akira , Shimozaki Keitaro , Nakayama Izuma , Wakatsuki Takeru , Ogura Mariko , Takahari Daisuke , Chin Keisho , Yamaguchi Kensei , Ishioka Chikashi
Published: June 2022

3528

Background: The CpG island methylator phenotype (CIMP), important for carcinogenesis, is a predictor of prognosis and chemotherapy sensitivity in colorectal cancer. However, there is a lack of consensus of CIMP markers, and thus, more comprehensive methylation markers are required to reliably predict the clinical outcomes. Previously, we reported that genome-wide DNAmethylation statuscould predict the effect of epidermal growth factor receptor (EGFR) inhibitors more accurately than previously reported methylation classifications (Ouchi et al. Cancer Sci 2015). Moreover, we had developed a DNA methylation assay based on MethyLight to reflect genome-wide DNA methylation status and reported its usefulness in predicting prognosis in patients with metastatic colorectal cancer (mCRC) treated with EGFR inhibitors as a third-line chemotherapy (Ouchi et al. Cancer Sci 2022). This study aimed to clarify the effects of genome-wide DNA methylation status on clinical outcomes in patients with mCRC treated with first-line EGFR inhibitors. Methods: We enrolled 241 patients with mCRC, who received chemotherapy plus EGFR inhibitors as a first-line treatment, and analyzed the associations between genome-wide DNA methylation status using a novel comprehensive methylation marker panel and clinical outcomes and evaluated the predictive power and value of the methylation status. Results: Total 169 patients were included in the final analyses. The frequency of highly methylated CRC (HMCC) was 8.9% (15/169). The characteristics of patients with HMCC included right-sided primary tumor location (P = 0.042), undifferentiated histology (P = 0.047), and BRAFV600E mutation (P < 0.001). Patients with HMCC showed worse clinical outcomes than those with low methylated CRC in terms of response rate (P = 0.017), progression-free survival (PFS; P = 0.004), and overall survival (P = 0.019). In the multivariate analysis, peritoneal metastasis (Hazard ratio (HR): 2.24, P = 0.017), methylation status (HR: 3.04, P = 0.037), and BRAFV600E mutations (HR: 5.83, P = 0.0001) were independent factors for shorter PFS. Conclusions: Genome-wide DNA methylation status may be an independent predictor of first-line EGFR inhibitors in patients with mCRC.
Patient-reported outcomes from the GARNET trial in patients with advanced or recurrent mismatch repair deficient (dMMR) colorectal cancer (CRC): A post hoc subgroup analysis.
Authors: Hanlon Jennifer , Veneris Jennifer Taylor , Boklage Susan
Published: June 2022

3558

Background: Dostarlimab is a programmed death 1 (PD-1) inhibitor approved in the US as a monotherapy in patients (pts) with dMMR advanced/recurrent endometrial cancer that has progressed on or after prior treatment with a platinum-containing regimen or in pts with dMMR solid tumors that have progressed on or after prior treatment, with no satisfactory alternative treatment options. Here we report on patient-reported outcomes (PROs) in pts with dMMR CRC, a post hoc subgroup analysis. Methods: GARNET is a multicenter, open-label, single-arm phase 1 study. Cohort F enrolled pts with dMMR/microsatellite instabilityhigh or POLε-mutated non-endometrial solid tumors. Pts with CRC must have received prior fluoropyrimidine, oxaliplatin, and irinotecan. Pts received 500 mg of IV dostarlimab Q3W for 4 cycles, then 1000 mg Q6W until discontinuation. PRO assessment, an exploratory endpoint, was measured using the EORTC-QLQ-C30. PROs were collected at baseline, at each dose cycle, and after discontinuation. Multi-item and item-level analyses were collected and scored; improvement was defined as mean change from baseline (directional change dependent on item). A 10-pt change in mean from baseline was considered clinically significant for the analysis. Results: PRO data at baseline were available for 96 pts with CRC who received ≥1 dose of dostarlimab. Improvements from baseline for quality of life (QOL) and most gastrointestinal symptom scales were observed and maintained from cycle 2 through 7 (Table). Stability in diarrhea was seen from cycles 2 through 7. Conclusions: PROs from the GARNET trial in pts with dMMR CRC show that QOL and disease-related gastrointestinal symptoms were improved or maintained while on dostarlimab treatment. These data, with the previously reported efficacy and safety profile, support the use of dostarlimab in pts with dMMR CRC. Clinical trial information: NCT02715284. [Table: see text]
Preoperative chemoradiotherapy with capecitabine with or without temozolomide in patients with locally advanced rectal cancer: A prospective, randomized phase 2 study stratified by MGMT (O6-methylguanine DNA methyltransferase) status: KCSG-CO17-02.
Authors: Oh Chung Ryul , Jeong Jae Ho , Lee Ji Sung , Kim Jeong Eun , Kim Sun Young , Kim Tae Won , Choi Jene , Kim Jihun , Park In Ja , Lim Seok-Byung , Park Jin-hong , Kim Jong Hoon , Choi Moon Ki , Cha Yongjun , Baek Ji Yeon , Beom Seung-Hoon , Hong Yong Sang
Published: June 2022

3605

Background: We aimed to evaluate the clinical efficacy of adding temozolomide (TMZ) to preoperative capecitabine (CAP)-based chemoradiotherapy (CRT) in patients with locally advanced rectal cancer (LARC) and validate O6-methylguanine DNA methyltransferase (MGMT) methylation status as a predictive marker for TMZ combined regimens. Methods: : LARC patients with clinical stage II (cT3-4N0) or III (cTanyN+) disease were enrolled. They were stratified into MGMT unmethylated (uMGMT) and MGMT methylated (mMGMT) groups by methylation-specific PCR before randomization, and then were randomly assigned (1:1) to one of four treatment arms: uMGMT/CAP (arm A), uMGMT/TMZ+CAP (arm B), mMGMT/CAP (arm C), and mMGMT/TMZ+CAP (arm D). The primary endpoint was the pathologic complete response (pCR) rate. Results: Between November 2017 and July 2020, 64 patients were randomized. Slow accrual caused early study termination. After excluding 4 ineligible patients, 60 were included in the full analysis set. The pCR rate was 15.0% (9/60), 0%, 14.3%, 18.8%, and 26.7% for arms A, B, C, and D, respectively ( p= 0.0498 between arms A and D). The pCR rate was 9.7% in the CAP group (arms A+C), 20.7% in the TMZ+CAP group (arms B+D), 6.9% in the uMGMT group (arms A+B), and 22.6% in the mMGMT group (arms C+D). Grade 1–2 nausea or vomiting was significantly more frequent in the TMZ+CAP treatment groups (arms B+D) than in the CAP treatment groups (arms A+C, p< 0.001) with no difference in grade 3 adverse events (AEs). There were no grade 4 or 5 AEs. Conclusions: The addition of TMZ to CAP-based CRT tended to improve pCR rates, particularly in those with mMGMT LARC. MGMT status may warrant further investigation as a predictive biomarker for chemotherapeutic agents and radiotherapy. Clinical trial information: NCT03156036.
Label-free and automated approach to rapidly classify microsatellite instability (MSI) in early colon cancer (CC) analyzing the AIO ColoPredictPlus 2.0 (CPP) registry trial.
Authors: Schörner Stephanie , Großerueschkamp Frederik , Kraeft Anna-Lena , Schuhmacher David , Sternemann Carlo Willy , Feder Inke Sabine , Wisser Sarah , Lugnier Celine , Christmann Jens , Heuer Vera , Teschendorf Christian , Mueller Lothar , Mosig Axel , Arnold Dirk , Tannapfel Andrea , Gerwert Klaus , Reinacher-Schick Anke C.
Published: June 2022

3616

Background: MSI due to mismatch repair defects accounts for 15-20% of all CC, has high prognostic and predictive value and is broadly utilized in treatment decisions. Artificial intelligence (AI) integrated, label-free quantum cascade laser (QCL) based infrared (IR) imaging resolves spatial and molecular alterations such as MSI in unstained cancer tissue sections. We aimed to evaluate the method for microsatellite instability/stability (MSI/MSS) classification in samples from the prospective multicenter AIO CPP registry trial. Methods: Paraffin-embedded unstained cancer tissue slides from patients (pts.) participating in CPP were measured (avg. 30 min/slide) and analyzed. The cohort was split into training (train), test (test), and validation (vali) sets. Cancer regions were first preselected based on a self-developed convolutional neural network (CNN) CompSegNet (Schuhmacher, medrxiv 2021). A VGG-16 CNN then classified MSI/MSS in these regions. Endpoints were area under receiver operating characteristic (AUROC) and area under precision recall curve (AUPRC). Results: 547 pts. (train n=331, test n=69, vali n=147) were analyzed. The baseline characteristics for the sub-cohorts are illustrated in the table. Mutation (MT) status: RAS MT: train 30% / test 30% / vali 37%; BRAF MT: train 27% / test 23% / vali 14%. The preselection of cancer regions reached a validation AUROC of 1.0. The subsequent MSI/MSS classifier reached a validation AUROC of 0.9 and AUPRC of 0.74 (sensitivity 85%, specificity 84%). Conclusions: Our multicenter approach using AI integrated label-free IR imaging provides an automated, fast, and reliable classification for MSI/MSS with an AUROC of 0.9 (sensitivity 85%, specificity 84%) almost comparable to the present gold standard immunohistochemistry. The method described here requires less samples for training when compared to other AI approaches which could facilitate the development of prognostic/predictive classifiers in the setting of randomized controlled trials. This novel technique may support further understanding of the increasingly important MSI CC cohort and support treatment decisions e.g. in specific subgroups such as targetable fusions. We expect our approach to be a broadly applicable diagnostic tool in the future.[Table: see text]