bluuebunny/crossref_metadata_2025 huggingface dataset:
Immune-related adrenal insufficiency: A single center retrospective analysis.
Authors: Polshina Natalya , Filonenko Daria , Volkova Ekaterina , Zhukova Lyudmila
Published: June 2023

2659

Background: Immune checkpoint inhibitors (ICI) became widely used for treatment of various malignancies. They may cause different immune-related adverse events (irAEs), including adrenal insufficiency (irAI). IrAI was reported to be comparatively uncommon but potentially life threatening. We conducted a retrospective single center study to identify and describe the incidence and characteristics of AI associated with ICI. Methods: We reviewed the medical records of patients treated at an oncological department at Loginov Moscow Clinical Scientific Center between Sep’2019 and Jan’2023 with immunotherapy under direct cortisol monitoring every 6-8 weeks. The main criteria for AI was low serum cortisol in the absence of glucocorticoid intake. Results: A total 101 patients (pts) treated by ICI or ICI in combination with chemotherapy or targeted therapy for various malignancies were included in our retrospective analysis. 16 patients (15.8%) were diagnosed with AI: 7 pts with renal cell carcinoma (RCC), 6 pts with melanoma (2 in adjuvant setting), 1 with non-small-cell lung cancer (NSCLC), 1 with small-cell lung cancer (SCLC), 1 with MSI-high colorectal cancer (CRC). Median age was 65 (range 46-79), the majority (10 pts, 62.5%) were male. The median time of irAI onset from ICI start was 5 months (range 2-15). Assessment of serum cortisol was performed every 6-8 weeks routinely and off-schedule in patients who had new onset AI-like symptoms. The most frequent symptoms were unspecific and included fatigue and weakness (100%), loss of appetite/anorexia (69%), hypotension (50%), weight loss (44%), insomnia (38%), chills (31%), nausea/vomiting (31%), muscle pain or cramps (31% and 25% respectively), dizziness (25%), dry mouth (25%), headache (13%), fever (6%). Remarkably, laboratory detected serum cortisol decline preceded any AI symptoms in 7 patients (43.7%). Other 7 patients (43.7%) had concurrent secondary hypothyroidism which suggested panhypopituitarism. Hydrocortisone replacement led to rapid symptoms recovery in 15/16 patients. Additional treatment with fludrocortisone was required for only one patient who had primary/mixed AI due to bilateral metastases of RCC in adrenal glands. All patients resumed immunotherapy after symptoms resolved. Only 1 patient needed treatment modification (ipilimumab cessation). By 12th February 2023 median follow-up from irAI onset is 7 months (range 0.5-37), 12 patients are alive, they all remain on permanent hydrocortisone replacement therapy. Conclusions: Routine cortisol assessment during immunotherapy allowed us to detect irAI in 15.8% of patents that is higher than usually reported. Detection of irAI before clinical presentation let us prevent severe consequences including life threating. We consider that routine cortisol assessment during immunotherapy should be implemented in clinical practice.
Discontinuation of immunotherapy over 2 years for patients with non–small cell lung cancer (NSCLC): A search for predictors.
Authors: Cascetta Priscilla , Reni Anna , Facchinetti Francesco , Meyer May-Lucie , Riudavetz Mariona , Aldea Mihaela , Dall'Olio Filippo Gustavo , Marinello Arianna , Tagliamento Marco , Remon Masip Jordi , Besse Benjamin , Planchard David , Barlesi Fabrice , Derosa Lisa
Published: June 2023

2661

Background: In advanced NSCLC, treatment completion at 24 months emerged in trials evaluating immune checkpoint inhibitors (ICI). Nevertheless, in clinical practice the question of the optimal treatment duration is under debate. Methods: We performed a retrospective study on advanced NSCLC treated with ICI (alone or with chemotherapy) at Gustave Roussy before 2021. Among patients still receiving ICI at 12 months, we analyzed the reasons for ICI discontinuation at 18 and 24 months. Results: Of the 682 patients treated with ICI (first-line for n=230, 33.7%), 159 (23.3%) received ICI for ≥ 12 months and 122 (17.9%) for ≥ 18 months. Between 18-24 months, 20 (57.1%) patients interrupted ICI for progressive disease (PD), 8 (22.8%) for toxicity and 7 (20.0%) after discussion with the patient. Out of the 88 (12.9%) patients who completed 2-years of ICI (median duration of treatment: 31.46 months, first-line for n=51), 22 (25.0%) patients discontinued ICI for PD and 40 (45.5%) without PD: 14 (15.9%) for toxicities, patient request or unknown causes and 26 (29.5%) for clinical decision before (n=16, 61.5%) or after (n=10, 38.5%) 30 months of treatment. Discontinuation according to phase III clinical trial design was supported by complete response (CR) by PET imaging +/- tissue biopsy of metabolically active lesions +/- ctDNA in 17 (65.4%) cases just before therapy discontinuation. After a median follow-up of 45.6 months since treatment discontinuation for these 26 patients, only two experienced PD at 4 and 6 months from ICI interruption, in both cases with no proof of CR at ICI discontinuation (p=0.111). The remaining 26 (29.5%) patients who continued ICI after 2 years, are on treatment based either on absence of CR at PET-CT +/- tissue biopsy of metabolically active lesions (n=20, 76.9%) or after discussion with the patients (n=6, 23.1%). After a median follow-up of 40.17 months from the of 24-months landmark, the median progression-free survival was unreached in both continuation and discontinuation groups. Conclusions: The patients who completed 2-years of ICI treatment usually continue to experience long‐term response after discontinuation. Considering that a subgroup of patients could still benefit from maintained ICI administration, PET imaging was considered to guide ICI cessation or continuation. Prospective studies specifically designed to investigate biomarkers of maintained responses or residual disease (imaging, ctDNA, multi-omics including microbiome) are required to establish the indication for ICI continuation or stop for each patient.
BL-B01D1, a first-in-class EGFRxHER3 bispecific antibody-drug conjugate (ADC), in patients with locally advanced or metastatic solid tumor: Results from a first-in-human phase 1 study.
Authors: Zhang Li , Ma Yuxiang , Zhao Yuanyuan , Fang Wenfeng , Zhao Hongyun , Huang Yan , Yang Yunpeng , Chen Likun , Hou Xue , Zou Wen , Ding Muran , Yu Jing , Zhang Suoyu , Wang Junxian , Xiao Sa , Wang Hongwei , Zhu Hai , Olivo Martin Sebastian , Zhu Yi
Published: June 2023

3001

Background: BL-B01D1 is a first-in-class novel ADC consisting of an EGFRxHER3 bispecific antibody linked to a novel TOP-I inhibitor payload via a cleavable linker. We now present safety/efficacy results from a FIH phase I study of BL-B01D1. Methods: This study included patients (pts) with locally advanced or metastatic solid tumors. For dose escalation (D-ESC, i3+3), BL-B01D1 was administered intravenously at doses of 0.27, 1.5, 3.0 mg/kg QW, 2.5, 3.0, 3.5mg/kg D1D8 Q3W or 4.5, 5.0, 6.0 mg/kg D1 Q3W. A subset of pts were enrolled into dose-expansion (D-EXP) at Q3W regimens. Results: As of Dec 31, 2022, 150 pts were enrolled and received at least one dose (D-ESC, n=25; D-EXP, n=125). DLTs were neutropenia, febrile neutropenia and thrombocytopenia at 3.0mg/kg QW and 3.5mg/kg D1D8 Q3W. The MTDs were determined to be 3.0mg/kg D1D8 Q3W and 6.0mg/kg D1 Q3W. D-EXP was carried out at 2.5, 3.0mg/kg D1D8 Q3W and 4.5, 5.0, 6.0 mg/kg D1 Q3W. 144 pts were enrolled across all Q3W dose levels (D-ESC and D-EXP), including 89 NSCLC, 7 SCLC, 27 nasopharyngeal cancer (NPC), 19 HNSCC and 2 others. Most common TRAEs (>10%, all grade / ≥ G3) were leukopenia (60%/30%), neutropenia (51%/34%), anemia (45%/15%), thrombocytopenia (44%/19%), alopecia (30%/0%), nausea (29%/<1%), vomiting (28%/0%), asthenia (21%/<1%), decreased appetite (22%/<1%), asthenia (21%/<1%), hypophagia (16%/0%), diarrhoea (15%/2%), mouth ulceration (15%/<1%), rash (13%/0%). No ILD was observed. 122 pts were evaluable for efficacy (at least 1 tumor assessment). PK and other details will be updated in the meeting. Conclusions: BL-B01D1 demonstrated encouraging efficacy in heavily pretreated metastatic/locally advanced solid tumors, especially in pts with EGFRm NSCLC. The safety profile showed adequate safety and tolerability. Clinical trial information: NCT05194982 . [Table: see text]
FUTURE-SUPER: A randomized, subtyping-based umbrella phase II trial for first-line treatment of metastatic triple-negative breast cancer.
Authors: Zhimin Shao , Fan Lei , Linxiaoxi Ma , Wu Songyang , Chen Li , Liu Xiyu , Zhang Wenjuan , Hu Xin , Jiang Yizhou , Wang Zhonghua , Li Huajun
Published: June 2023

3011

Background: Triple-negative breast cancers (TNBCs) are heterogeneous in molecular drivers and immune traits. Our previous studies classified TNBCs into four subtypes (luminal androgen receptor, LAR; immunomodulatory, IM; basal-like immune-suppressed, BLIS; and mesenchymal-like, MES). The subtyping-based treatment strategy was proved clinically feasible, with promising efficacy (Cell Res 2021, NCT03805399) in patients with heavily pretreated metastatic TNBC (mTNBC). Here, we conducted FUTURE-SUPER, a multi-cohort, randomized trial to further evaluate the efficacy of subtyping-based therapy in the first-line treatment of mTNBC. Methods: Patients with untreated locally recurrent inoperable or mTNBC were enrolled. After categorization into 5 cohorts according to TNBC subtypes and genomic biomarkers, patients were randomly assigned (in a 1:1 ratio) to receive nab-paclitaxel (control group) or nab-paclitaxel plus subtyping-based treatment (subtyping-based group): pyrotinib (LAR-HER2 mut), everolimus (LAR- PI3K/AKTmut), camrelizumab and famitinib (IM), bevacizumab (BLIS/MES- PI3K/AKT WT), everolimus (MES- PI3K/AKT mut). The primary endpoint was progression-free survival (PFS). Secondary endpoints included PFS in each subtyping-based cohort, objective response rate (ORR), overall survival (OS) and safety. Results: Between July 29, 2020, and October 17, 2022, 139 patients were enrolled and randomly assigned. With a median follow-up of 18.5 mo (range, 3.5 to 30.3), 101 (72.7%) events of disease progression or death occurred. Median PFS was significantly longer in the subtyping-based group than in the control (11.3 mo vs 5.8 mo; hazard ratio [HR], 0.38; 95% confidence interval [CI], 0.25 to 0.57; P<0.0001). Greater magnitude of PFS benefits were seen for the IM (median, 15.1 mo vs 6.5 mo; HR 0.37; 95% CI, 0.19 to 0.73), BLIS (median, 9.4 mo vs 3.9 mo; HR 0.41; 95% CI, 0.16 to 0.56) and LAR- PI3K/AKT mut (median, 19.1 mo vs 8.4 mo; HR 0.42; 95% CI, 0.12 to 1.53) subtypes. The ORR (measurable-disease population) was higher in the subtyping-based group than in the control group (80.0% [48/60] vs. 44.8% [26/58]; odds ratio, 0.20; 95% CI, 0.09 to 0.46). OS data were not mature. Most adverse events were of grade 1 or 2. Grade 3 and 4 toxicities were as expected, with neutropenia more frequently reported in the subtyping-based group (56.5% vs 26.1%). No treatment-related deaths were recorded. Further high-throughput biomarker analyses are ongoing. Conclusions: Subtyping-based precision treatment significantly prolonged PFS versus nab-paclitaxel in the first-line treatment of advanced TNBC, with manageable toxicities. Our findings highlight the profound clinical benefits with treatment optimization according to molecular/immunological subtypes in TNBC, outlining a direction for further exploration. Clinical trial information: NCT04395989 .
Tissue-agnostic efficacy of trastuzumab deruxtecan (T-DXd) in advanced solid tumors with HER2 amplification identified by plasma cell-free DNA (cfDNA) testing: Results from a phase 2 basket trial (HERALD/EPOC1806).
Authors: Taniguchi Hiroya , Yagisawa Masataka , Satoh Taroh , Kadowaki Shigenori , Sunakawa Yu , Nishina Tomohiro , Komatsu Yoshito , Esaki Taito , Sakai Daisuke , Doi Ayako , Kajiwara Takeshi , Ono Hiromi , Asano Masatoshi , Hirano Nami , Odegaard Justin Iver , Fujii Satoshi , Nomura Shogo , Sato Akihiro , Yoshino Takayuki , Nakamura Yoshiaki
Published: June 2023

3014

Background: HER2 ( ERBB2) gene amplification (amp) is a potential therapeutic target beyond breast and gastric cancers. HER2 amp can be detected in plasma cfDNA which may be an alternative to tissue biopsy. HERALD/EPOC1806 was a multicenter, investigator-initiated phase 2 trial of T-DXd for patients with HER2-amplified advanced solid tumors identified by cfDNA testing. Methods: We enrolled adults with advanced solid tumors harboring HER2 amp detected by next-generation sequencing of cfDNA (Guardant360) in the GOZILA study (UMIN000029315). We excluded breast or gastric cancer patients with HER2 overexpression (IHC 3+ or IHC 2+/ISH+). Patients received T-DXd 5.4 mg/kg every 3 weeks until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed objective response rate (ORR). Results: From December 2019 to January 2022, 4,734 patients were screened by cfDNA in the GOZILA study. Among 252 with HER2 amp, 62 with 16 cancer types were enrolled in HERALD. Median baseline plasma HER2 copy number (CN) was 8.55 (range, 2.4–73.9). All patients but 3 (all with salivary gland cancer) received prior anti-cancer therapy (median, 3 lines; range, 0–8). At a median follow-up of 8.9 months (data cut-off: July 17, 2022), the confirmed ORR was 56.5% (95% CI, 43.3–69.0%), statistically higher than the threshold value of 5%. Responses were observed for 13 cancer types, including KRAS-mutant colorectal (1/3), PIK3CA-mutant endometrial (5/6), and tissue HER2-negative gastric cancers (1/2). Plasma HER2 CN above vs. below the baseline median value did not impact response (ORR: 58.1% vs. 54.8%); however, the clearance vs. persistence of HER2 amp in cfDNA on Cycle 2 Day 1 corresponded to higher response (ORR: 88.0% vs. 22.7%). ORR by independent review was 58.1% (95% CI, 44.8–70.5%), and the disease control rate was 90.3% (95% CI, 80.1–96.4%). Median progression-free survival was 7.0 (95% CI, 4.9–9.7) months, and the median duration of response was 8.8 months (95% CI, 5.8–11.2). Most adverse events were mild to moderate. Interstitial lung diseases occurred in 16 patients (25.8%, G1/G2/G3; 14/1/1). Conclusions: T-DXd achieved a high ORR, durable response with a manageable safety profile in patients with advanced solid tumors and HER2 amp detected in cfDNA. Clinical trial information: JapicCTI-194707 .[Table: see text]
A novel genetic marker of fluoropyrimidine-induced cardiovascular toxicity.
Authors: Palles Claire , Lucas Marie , Watts Katie , Galavotti Sara , Chin Ik Shin , Campbell Cameron , Briggs Sarah E W , Jaeger Emma , Church David , Taylor Karen , Bliss Judith , Fisher David , Madi Ayman , Cameron David A. , Maughan Timothy S. , Tomlinson Ian , Iveson Timothy , Kerr David James , Kerr Rachel , Cheadle Jeremy
Published: June 2023

3028

Background: Fluoropyrimidine (FP) based adjuvant chemotherapy (5-Fluorouracil and Capecitabine) increases survival of patients with colorectal and breast cancers. However, 1-5 % of patients experience cardiovascular toxicity, which is not explained by variants in the gene encoding dihydropyrimidine dehydrogenase. Methods: We sought genetic determinants of FP-induced cardiovascular toxicity by performing a genome wide association study of NCI-CTCAE graded cardiovascular toxicity using samples from the QUASAR 2 trial (n=759 patients with colorectal cancer (CRC)). Validation studies (n= 5438 patients with CRC and 1478 patients with breast cancer) were performed in the SCOT, COIN and TACT2 trials. The most commonly reported symptoms were chest pain, angina and arrhythmias with 6 patients experiencing myocardial infarctions. Results: rs4904753, mapping to an intron of D-glutamate cyclase (DGLUCY) was genome wide significant in QUASAR 2 (P =4.38 x 10-16) and validated in SCOT, COIN and TACT2 (P<0.0002 in all studies. rs4904753 was associated with levels of expression of DGLUCY in multiple tissues including the atrial appendage. Under a recessive model, 45.3% (61/137) of patients with cardiac toxicity as compared to 10.2% (691/6786) of controls carried both minor alleles (meta-analysis: OR=7.72, 95% CI 5.31-11.22, P=1.03 x 10-26). Conclusions: The sensitivity, specificity, positive predictive value and negative predictive values of testing for two copies of the toxicity associated allele of rs4904753 were 48%, 90%, 8% and 99% respectively. Clinical implementation of testing for this variant has the potential to identify almost half of those at risk of FP-induced cardiovascular toxicity with high specificity, thereby enabling changes to their clinical management. [Table: see text]
First report of tumor-informed circulating tumor DNA in fibrolamellar carcinoma in adolescents and young adults: 51 patients.
Authors: McKenna Elise , Kent Paul , Tasse Jordan C , Schadde Erik , Fisher Oliver M , Humar Abhinav , Kato Tom , Ellison Jessica , Yamashiro Darrell , Cornelius Albert
Published: June 2023

3034

Background: Fibrolamellar Carcinoma (FLC) is an extremely rare form of primary liver cancer (50-200 cases/year), unrelated to hepatocellular carcinoma. The only established standard of care is surgery. However, recurrence is at least 80%, even with R0 surgery, suggesting that FLC is best thought of as a systemic disease instead of a surgical disease. Systemic therapies in retrospective studies of more than 25 show immunotherapy and chemotherapy combinations have promise. Circulating “tumor-informed” tumor DNA (ctDNA) is a tool for tracking microscopic systemic disease, serving as a marker of systemic involvement, has shown success in management of other cancers. FLC has never been studied using this technology. Our retrospective study of 51 patients over a 2.5-year period is the first attempt to understand if ctDNA can be helpful in the management of FLC. Methods: All patients consented to blood draws on a 1-3 monthly basis, according to the company (Signatera) protocol. All patients had regular imaging reviewed by the FibroFighters Foundation National Tumor Board. Complete response (CR), Partial response (PR) (> 30% decrease), Progressive Disease (PD) (> 20% increase), and Stable Disease (SD) (neither PD/PR/CR) were recorded according RECIST 1.1. The imaging closest in time to the blood draw was used for correlation purposes. “Negative” is defined as a value = 0.00. “Positive” is defined as a value > 0.00. Results: Fifty-one FLC patients (26M, 25F, median age 23, range 10-56), 92% stage (III/IV), consented to ctDNA “blood biopsies,” (n=226 samples, mean 4.4/patient, range 1-11). Negative values correlated with no evidence of disease (NED) on imaging 78% of the time, positive values with disease 94% [PPV/NPV/sens/spec of 0.78/0.94/0.93/0.81]. NPV and sens increased to almost 100% with a ctDNA threshold of > 1.0 at the expense of a lower PPV and spec. However, consecutive negative ctDNA values correlated with radiologic NED 86% [PPV/NPV/sens/spec = 0.86/0.84/0.77/0.91] without a single PD in this cohort (n=64). A “downward trend or slope” on consecutive values predicted Objective Response (CR+PR) and Disease Control (CR+PR+SD) at 68% and 96% [PPV/NPV/sens/spec of 0.68/0.49/0.36/0.78 and 0.96/0.26/0.36/0.94, respectively], while an “upward trend” performed less well to predict relapse [PPV/NPV/sens/spec = 0.54/0.98/0.94/0.81]. Conclusions: In this first exploration of 51 young FLC patients, and 226 tissue-informed cell free ctDNA data points, “Positive” and “Negative” values overall performed well for predicting RECIST 1.1 “disease” or “NED” respectively, especially for consecutive values of zero, where no progressions were observed in 64 distinct FLC scenarios. A downward trend or “slope” performed better than an upward trend to predict objective response (PR+CR) versus relapse (PD).
Early detection of lung cancer using small RNAs.
Authors: Sharma Amita , Sikosek Tobias , Horos Rastislav , Rajakumar Timothy , Tikk Kaja , Schumann Christian , Walterspacher Stephan , Christopoulos Petros , Schuler Martin H. , Darwiche Kaid , Taube Christian , Hegedus Balazs , Rabe Klaus , Rieger-Christ Kimberly M. , Jacobnson Francine , Aigner Clemens , Bankier Alexander A. , Reck Martin , Steinkraus Bruno
Published: June 2023

3035

Background: Low-dose computed tomography (LDCT) screening can significantly reduce lung cancer mortality. However, annual screening is limited by low adherence in the USA and still not broadly implemented in Europe. As a result, <10% of lung cancers are detected through existing programs. Thus, there is great need for additional diagnostic modalities, such as a blood test that could be deployed in the primary care setting. Methods: We prospectively recruited 1,189 patients meeting the 2013 USPSTF screening criteria for lung cancer and collected stabilized whole blood. Ultra-deep small RNA sequencing was performed with a method to remove highly abundant erythroid RNAs, opening bandwidth for the detection of less abundant species originating from plasma or the immune cellular compartment. We utilized 100 random data splits to train and evaluate logistic regression classifiers using small RNA expression, discovered an 18-small RNA feature consensus signature (miLung), and validated this in an independent cohort (246 patients). Blood cell sorting and tumor tissue sequencing were performed to deconvolve small RNAs into their source of origin. Results: We generated diagnostic models and report a median ROC AUC of 0.86 (95% CI 0.84-0.86) in the discovery cohort, and generalized performance of 0.84 in the validation cohort. Diagnostic performance increased stage-dependently from 0.73 (95% CI 0.71-0.76) for Stage I to 0.90 (95% CI 0.89-0.90) for Stage IV. We identified a tumor-shed, plasma-bound ribosomal RNA fragment of the L1 stalk as a dominant predictor of lung cancer. The fragment is decreased following surgery with curative intent. In additional experiments, dried blood spot collection and sequencing revealed that small RNA analysis could potentially be conducted via home-sampling. Conclusions: These data suggest the potential of a small RNA-based blood test as a viable alternative to LDCT screening for early detection of smoking-associated lung cancer. Clinical trial information: NCT03452514 . [Table: see text]
Outcomes in participants with a false positive multi-cancer early detection (MCED) test: Results from >4 years follow-up from DETECT-A, the first large, prospective, interventional MCED study.
Authors: Lennon Anne Marie , Buchanan Adam H , Rego Seema P , Choudhry Omair A , Elias Paul Z , Sadler Jennifer R , Cohen Joshua D , Douville Christopher B , Honushefsky Ashley M , Klein Alison , Salvati Zachary M , Sheridan Kathleen , Tomasetti Cristian , Wagner Eric S , Walter Carroll N , Fishman Elliot K. , Kinzler Kenneth W. , Vogelstein Bert , Beer Tomasz M. , Papadopoulos Nickolas
Published: June 2023

3039

Background: Recommended standard of care (SOC) early detection tests are solely available for four cancer types and fewer than 20% of incident cancers in the US are being diagnosed as a result of screening. Advances in detection of tumor-derived analytes in the blood are enabling the development of MCED tests that may expand early cancer detection. While MCED tests are being designed with high specificity, false positive (FP) results remain a concern for clinicians and patients alike, as no long-term outcomes of individuals with a FP MCED test have been reported. DETECT-A was the first prospective interventional clinical trial to evaluate an MCED blood test. The test used was an early version of CancerSEEK, evaluated in 9,911 women without history of cancer ( Science, 369:6499, 2020). This prospectively planned analysis evaluates cancer incidence among DETECT-A participants with FP results, with the intention of providing key long-term data on test effectiveness. Methods: This analysis included 98 DETECT-A participants with FP results, where a FP was defined as a positive CancerSEEK result with subsequent PET-CT and clinical evaluation with no evidence of cancer within 1 year of the initial CancerSEEK test. Sixty-three of 98 participants had no follow-up procedure performed after imaging, and 35 subjects had noninvasive/minimally invasive follow-up procedures performed. Electronic medical records were analyzed from January 2020 through November 2022 for cancer diagnosis, treatment, remission, recurrence, and mortality. Results: Ninety-six of 98 participants with a FP result remained free of cancer with a median follow-up of 4.3 years (IQR: 3.9-4.9) from the initial CancerSEEK test. One stage I breast cancer and one stage III ovarian cancer were diagnosed 2.7 and 2.9 years respectively from the initial CancerSEEK test. Conclusions: Patients with a negative PET-CT and initial clinical evaluation after a positive CancerSEEK test had low (<1% per year) risk for cancer in the ensuing four years after the initial CancerSEEK test. If confirmed, this result should prove reassuring to clinicians and to patients who have no evidence of cancer on comprehensive imaging following a positive MCED test. Further, these results provide preliminary support for the recommendation that patients who participate in MCED testing and receive a FP result can safely return to routine care after comprehensive anatomic and functional imaging and clinical evaluation reveal no suspicion of cancer.
Longitudinal circulating tumor DNA monitoring in patients with esophageal squamous cell carcinoma.
Authors: Takei Shogo , Kotani Daisuke , Sato Kazuma , Fujiwara Naoto , Kawazoe Akihito , Sharma Shruti , Spickard Erik , Dutta Punashi , Liu Minetta C. , Jurdi Adham A , Shitara Kohei , Kojima Takashi , Fujita Takeo
Published: June 2023

3041

Background: The clinical utility of longitudinal monitoring with circulating tumor DNA (ctDNA) as a prognostic and a predictive biomarker was recently reported in patients with resectable colorectal cancer (Kotani D, et al. Nature Medicine 2023). Here we report a prospective, observational study of longitudinal ctDNA monitoring in patients with esophageal squamous cell carcinoma (ESCC) receiving neoadjuvant chemotherapy (NAC) followed by surgery. Methods: Patients with ESCC planned for NAC followed by curative surgery, were prospectively enrolled in this study. As per the protocol, plasma samples were collected at 7 timepoints: pre-NAC, post-NAC, and 4,12, 24, 36, and 48-weeks after surgery. CT scans were conducted every 3 months. Longitudinal ctDNA testing was performed using a personalized, tumor-informed ctDNA assay (Signatera, bespoke mPCR, NGS assay). In this initial report, ctDNA results at 3 time points (pre-NAC, post-NAC, and 4 weeks post-surgery) were analyzed and their association with clinical outcomes and tumor regression grade (TRG) scores were assessed. Results: So far, a total of 83 blood samples from 28 patients with ESCC were collected serially at pre-NAC (N=28), post-NAC (N=27), and post-surgical (N=28) time points. Pre-NAC ctDNA was detectable in 96.4% patients (27/28), and detection rates decreased at the post-NAC (37%; 10/27) and post-surgical (11%; 3/28) timepoints. ctDNA-positivity post-NAC and post-surgery was associated with a significantly shorter recurrence free survival (RFS) with HR of 7.0 (95% CI: 1.4-35.0; p = 0.02) and HR of 14 (95% Cl 3.0-62; p <0.001), respectively. Notably, patients who achieved ctDNA clearance with NAC had favorable RFS as compared to the patients who did not (HR=0.15, 95% CI: 0.03 – 0.75; p = 0.02). Post-NAC ctDNA was also associated with tumor regression grade (TRG) score. None of the patients with TRG3 score (N=3) were ctDNA positive, whereas 7.7% (1/13) patients in the TRG2 category and 81.8% (9/11) in the TRG1 category were ctDNA-positive. Conclusions: Our study demonstrates a strong correlation between ctDNA status and clinical outcomes in ESCC patients. Assessment of ctDNA may be useful monitoring in patients with ESCC post NAC/surgery and may be used in the future to direct post-surgical management in this patient population. Clinical trial information: UMIN000042003 .
A 5-hydroxymethylcytosine-based noninvasive model for ultrasensitive early detection of colorectal advanced adenoma and adenocarcinoma: The METHOD-2 study.
Authors: Xu Jianmin , Chang Wenju , Jia Baoqing , Ding Kefeng , Pan Zhizhong , Zhang Wei , Su Guoqiang , Zhang Wei , Ren Li , He Chuan
Published: June 2023

3042

Background: Detection of colorectal tumors at a time when there are more treatment options is associated with better outcomes. This prospective case-control study (NCT03676075) assessed the performance of 5-hydroxymethycytosine (5hmC) biomarkers in circulating cell-free DNA (cfDNA) to detect advanced colorectal adenomas (ADA) or adenocarcinomas (CRC). Methods: This multi-center study enrolled 2,576 participants, including patients with newly diagnosed CRC (n=1,074), ADA (n=356), other solid tumors (n=80), and healthy individuals (HEA) (n=1,066), followed by genome-wide 5hmC profiling using the 5hmC-Seal, a highly sensitive chemical labeling approach. A weighted diagnostic model for CRC (stage I-III) and ADA was developed using the elastic net regularization in a training set of age-, sex-, region-matched samples and validated in independent samples. Results: Distribution of 5hmC in cfDNA reflected gene regulatory relevance and tissue of origin. In an independent validation set of 482 samples, a 96-gene model trained in stage I-III CRC, ADA, and HEA achieved an AUC (area under the curve) of 92.6% (95% CI [confidence interval], 90.7-94.5%) for distinguishing CRC from HEA, regardless of primary location or mutation. This model also showed high capacity for distinguishing ADA from HEA with an AUC of 87.9% as well as cancer-type specificity. Model performance was further confirmed in samples from multiple centers. Functionally, differential 5hmC features associated with CRC and ADA demonstrated relevance to CRC biology, including pathways such as calcium and MAPK signaling. Conclusions: Genome-wide mapping of 5hmC in cfDNA shows promise as a highly sensitive and specific approach to be integrated in a screening program for improving early detection of CRC and high-risk ADA. Clinical trial information: NCT03676075 .
Distinguishing between cancer-related mutations and clonal hematopoiesis using cell-free RNA (cfRNA) expression levels in a machine learning model.
Authors: Albitar Maher , Zhang Hong , Ip Andrew , Estella Jeffrey , Charifa Ahmad , Ma Wanlong , Mohtashamian Arash , Gutierrez Martin , Pecora Andrew L , Goy Andre
Published: June 2023

3043

Background: Liquid biopsy is currently considered an important part of the clinical practice of oncology. However, proper interpretation of somatic mutations detected in liquid biopsy remains a challenge. Distinguishing cancer-related mutations from mutations resulting from clonal hematopoiesis of indeterminate potential (CHIP) can be difficult and a source of misinterpretation of liquid biopsy findings. We explored using cell-free RNA (cfRNA) profiling as a means for distinguishing between mutations detected as CHIP vs mutations detected as cancer. Methods: cfDNA and cfRNA from 102 patients with confirmed solid tumors, 93 patients with hematologic neoplasms and 40 patients with CHIP abnormalities were sequenced using a panel of 1501 gene for RNA and 284 genes for DNA. The solid tumors included lung, breast, ovarian, and colorectal. The hematologic neoplasms included lymphoid and myeloid neoplasms. Using a machine learning algorithm, we first selected the relative genes that distinguish between two classes using K-fold cross-validation (K=12). The selected genes were used to predict one class from the other using naïve Bayesian classifier, but we applied geometric mean naïve Bayesian (GMNB) to compensate for the expected underflow. Results: Using machine learning with cfRNA, we were able to distinguish between cases with confirmed cancer-related mutations and CHIP mutations with area under the curve (AUC) of 0.808 (95% CI: 0.720-0.895). Precision, recall and f1-score were 0.86, 0.422 and 0.566 for CHIP and 0.359, 0.825 and 0.500 for solid tumor, respectively. The machine learning required 70 genes for this classification. Leave-one-out (LOO) validation showed AUC of 0.766 (95% CI: 0.671-0.859). Distinguishing between hematologic neoplasms and CHIP was achievable using the expression of 30 genes. The AUC for this model was 0.787 (95% CI: 0.696-0.879). Precision, recall and f1-score were 0.906, 0.516, and 0.658 for CHIP and 0.438, 0.875, and 0.583 for hematologic neoplasms, respectively. Validation using LOO showed AUC of 0.736 (95% CI : 0.638-0.835). The top 10 genes that their expression was critical for distinguishing between CHIP and solid tumors were EIF4E, HNF1A, HOOK3, HIPK2, IL1RAP, BRAF, DNAJB1, GADD45B, H2AX, and HDAC6. The top 10 genes for distinguishing hematologic cancers from CHIP were PBX1, CAMTA1, PFDN5, PCBP1, SDC4, PRKACA, NT5C2, NBR1, RPS21, and AHCYL1. Conclusions: Analyzing cfRNA expression levels when used with machine learning may add another level of confidence to the ability of interpreting mutations detected in liquid biopsy testing, especially when these mutations are at low levels. This is particularly important in liquid biopsy testing for minimal residual disease (MRD) when a tissue baseline sample is not tested (tumor-agnostic).
Pan-cancer detection and tissue-of-origin identification by whole-genome sequencing of plasma cell-free DNA.
Authors: Guo Wei , Wang Wei , Zhou Yanqing , An Heng , Lv Yanhua , Yang Zuoquan , Lu Chao , Zhang Xiaoni , Xu Mingyan , Chen Shifu
Published: June 2023

3055

Background: Despite notable advances in cancer therapeutics, much of the mortality of human cancers results from late diagnosis. The early detection of cancer remains an unmet need that can benefit the effective treatments and better prognosis. Cell-free DNA (cfDNA) in the circulation provides an emerging diagnostic method for non-invasive cancer screening. The fragmentation signatures of cfDNA originating from different cell types or malignancies display distinct patterns, suggesting the potential as cancer biomarkers. This study aims to investigate the fragmentation profiles of cfDNA in several cancer types, and to develop a new approach for pan-cancer detection and tissue-of-origin identification. Methods: Plasma samples from 739 patients with lung (N=577), colorectal (N=98), breast (N=51) and liver (N=13) cancers, as well as 716 healthy individuals were collected in this study. Cell-free DNA was isolated and used to generate the whole-genome sequencing data. We developed an approach called PatternWGS (Pan-cancer detection and tissue-of-origin identification by whole-genome sequencing) to analyze the DNA fragmentation patterns comprehensively. Fragmentation features integrating cfDNA fragment size distribution, frequency of end motif sequence, and copy number variation were utilized to construct the optimal prediction model. We presented a multi-cancer detection model for distinguishing individuals with and without cancer using Generalized Linear Models (glmnet), and further built a cancer-origin model to predict cancer types using Random Forest algorithm. Training and testing occurred on randomly selected sampling splits of 60% and 40% of the data, respectively. Features selection and model construction were performed by only training cohort, and the test set was solely used for performance evaluation. Results: A larger proportion of shorter cfDNA fragments in cancers was observed. We proposed a fragment score indicating the degree of short fragmentation, and this fragment score was significantly higher in cancers (p<0.001). Several end motifs were identified to be specifically enriched in cancer patients. The multi-cancer detection model reached an area under the curve (AUC) of 0.98, with the sensitivity of 93% at 95% specificity. The sensitivity of detecting lung, colorectal, breast, and liver cancers reached 94.2%, 87%, 100% and 100% respectively, at 95% specificity. The cancer-origin model demonstrated an overall accuracy of 81.7% for the identification of tissue of origin. Conclusions: Our prediction model demonstrated a superior performance for multi-cancer detection and cancer origin prediction, suggesting the potential of plasma cfDNA fragmentation signatures as non-invasive biomarkers for early cancer detection in clinical. The distinct fragmentation patterns in cancer provide new insight to understand the mechanism of tumorigenesis.
Clonal hematopoiesis (CH) associated mutations in patients with advanced solid tumors enrolled in phase I clinical trials.
Authors: Rodriguez Julieta , Bayle Arnaud , Pages Arnaud , Danlos Francois-Xavier , Vasseur Damien , Rouleau Etienne , Lacroix Ludovic , Alonso de Castro Beatriz , Goldschmidt Vincent , Seknazi Lauren , Hollebecque Antoine , Michot Jean-Marie , Champiat Stephane , Marabelle Aurelien , Ouali Kaissa , Marzac Christophe , Ponce Aix Santiago , Italiano Antoine , Micol Jean Baptiste , Baldini Capucine
Published: June 2023

3056

Background: An increased number of CH associated mutations has been identified in patients (pts) with solid tumors. Their impact on pts outcomes remains unclear. This study aims to integrate molecular data and clinical characteristics of CH in pts enrolled phase I clinical trials. Methods: Data was collected retrospectively from medical records and molecular profile reports (Foundation One Liquid CDx Assay – 309 genes) performed before first study drug administration at the Drug Development department in Gustave Roussy (Villejuif, France) within the STING trial (NCT04932525). CH prevalence was assessed according to a variant allele frequency (VAF) threshold of 1% in epigenetic modifiers ( DNMT3A, TET2 and ASXL1). Results: From January 2021 to December 2022, 255 pts were enrolled in a phase I clinical trial and had a liquid biopsy. In total, 55% of patients were male with a median age of 62 years [24-86]. Most common tumor locations were gastrointestinal (27%), genitourinary (21%) and thorax (18%). Patients received a median of 2 prior lines of treatment before investigational study drug and CH assessment. At the end of the data cut off, 81% of pts discontinued phase I treatment mostly due to progression disease. Overall, 104 pts (41%) had at least 1 CH mutation in liquid biopsy at baseline with 55 pts (22%) at a VAF of ³ 1%. Mutation frequency was DNMT3A in 42% (n= 23), ASXL1 in 38% (n=21) and TET2 in 31% (n=17). Co-mutations were present in 26 patients, with the most frequent being DNMT3A + ASXL1. Median PFS and OS were 3.7 months (m) for CH group vs 3.5m for no-CH (p=0.3) and 24m CH vs 15m no-CH (p=0.5), respectively. Conclusions: CH is commonly found in pts with solid tumors treated in phase I trials, with a prevalence in our cohort of 22%. Most frequent mutated gene was DNMT3A. Prognostic implications of the impact of these mutations in patient´s outcomes remain to be elucidated and will be presented at the meeting.
68Ga-FAPI-46 PET for cancer imaging: A prospective single-arm clinical trial.
Authors: Fendler Wolfgang P. , Bartel Timo , Pabst Kim M. , Hamacher Rainer , Hirmas Nader , Seifert Robert , Kasper Stefan , Nader Michael , Kesch Claudia , von Tresckow Bastian , Berliner Christoph , Kuemmel Sherko , Harter Philipp , Reinacher-Schick Anke C. , Lugnier Celine , Uhl Waldemar , Hadaschik Boris A. , Siveke Jens T. , Grünwald Viktor , Herrmann Ken
Published: June 2023

3064

Background: Fibroblast activation protein (FAP) is expressed at high levels on tumor associated fibroblasts. FAP-directed radioligand positron-emission-tomography (FAP-PET) is a novel diagnostic tool for cancer. However, we currently do not understand the diagnostic performance of FAP-PET as compared to standard FDG-PET. Here we aim to compare tumor detection by FDG- vs. FAP-PET with independent validation of discrepant findings. Methods: Patients with (a) proven or suspected malignancy, (b) longest tumor diameter >1 cm, (c) intended surgery or biopsy, and (d) no prior external beam radiation or systemic tumor therapy within 3 months underwent FDG- and FAP-PET for tumor localization on subsequent days. Clinical reads were analyzed prospectively on a per-patient and per-region basis (local, locoregional nodal, distant organ or soft tissue, bone). Discrepant findings were validated as true vs. false positive by histopathology or image follow-up. Tracer uptake in tumor tissue was assessed by SUVmax. Results: In total n=100 patients (median 62 years, male/female n=68/32) underwent FDG- and FAP-PET. Five most frequent tumor entities and respective median FDG vs FAP uptake were RCC (n=19; SUVmax 8.4 vs. 7.1), sarcoma (n=18; 10.3 vs. 10.9), NSCLC (n=10; 12.4 vs. 13.7), lymphoma (n=9; 18.3 vs. 10.9), and PDAC (n=8; 4.1 vs. 7.3). On a per-patient basis, FDG- vs FAP-PET localized malignancy in n=93/94 patients. FDG- vs FAP-PET was concordant for the assessment of 362/400 (91%) regions. n=16/400 (4%) regions were negative on FDG- and positive on FAP-PET (88% true, 12% false positive). n=22/400 (6%) regions were negative on FAP- and positive on FDG-PET (57% true, 43% false positive). Two false positive FDG-PET findings were due to tracer uptake in reactive lymph nodes. There were no PET-related adverse events. Conclusions: In patients with various tumor entities, standard FDG- and novel FAP-PET localized tumor equally well. Additionally, FAP-PET was associated with a lower rate of false positive findings, especially in lymph node assessments. Clinical trial information: NCT05160051 . [Table: see text]
Utility of artificial intelligence-based genomic classification of occult malignancies in clinical practice.
Authors: Darabi Sourat , Zuazo Carlos E , Brodie Taylor , Demeure Michael J. , Braxton David R.
Published: June 2023

3065

Background: Occult primary malignancies (OPM) are a significant clinical problem, representing 3 to 5% of advanced cancers. Patients with OPM have a worse prognosis and fewer treatment options than when the primary site of origin of cancer can be confidently identified. Novel artificial intelligence-based genomic classification of occult malignancies has been validated for clinical use by previous studies, but reports of clinical utility have not yet been published. We report our experience of consecutive cases where a commercial AI-based genomic classifier was used in routine practice at a high-volume community cancer center. Methods: Malignancies with uncertain pathological classification or site of origin were subjected to molecular profiling and AI-based genomic classification (GPSai) capable of recognizing a set of 115 distinct primary tumor sites and histology classes. Molecular profiling consisted of whole exome and whole transcriptome sequencing of FFPE tumor samples along with other predictive biomarkers assays performed by a commercial laboratory (Caris Life Sciences). The identification of targetable mutations was reported, but variants of unknown significance were excluded when reporting genomic alterations. Results: From 1,316 patients between October 2021-November 2022, we analyzed 70 (5.3%) patients with OPM, including 44 (62.9%) females and 26 (37.1%) males, with 34 (48.6%) being 65 or older. GPSai classification was ordered for 73 samples from 70 patients, which resulted in the classification of 33 (45.2%) tumors, inconclusive results in 36 (49.3%), and insufficient tissue quantity in 4 (5.5%). Of the 33 cases with a GPSai classification, the putative pathology diagnosis was concordant in 26 (78.8%) and discordant in 7 (21.2%) cases. We investigated discordance between the GPSai and pathological diagnoses in discordant cases . The pathological classification was favored over GPSai in all 7 discordant cases. Of the 36 cases that could not be confidently assigned a classification, 14 (38.9%) possessed potentially actionable alterations . 23 of the 36 had no presumptive site of origin. Of these, 10 of 23 (43.5%) were PD-L1 positive, 4 of 23 (17.4%) had a high TMB, and 1 of 23 (4.4%) had MMR deficiency. Additionally, based on molecular profile and examination of RNA expression levels, 2 cases were able to be classified with subsequent IHC confirmation. Based on the results from genomic testing, 55.7% of patients (39 of 70) had FDA-approved treatment options. Conclusions: Over a third of patients with OPM were able to be assigned a cancer diagnosis concordant with diagnoses by pathologists. Of those which could not be classified, targetable biomarkers were commonly found. AI-based genomic classification of occult primaries is useful in clinical practice to help discern the site of origin and identify treatment options.
Systematic review and meta-analysis of the accuracy and applicability of blood-based multi-cancer early detection (MCED) in the general population.
Authors: Park Joo Hee , Oh Youjin , Chung Liam Il-Young , Duan Richard , Djunadi Trie Arni , Yoon Sung Mi , Shah Zunairah , Jung Chan Mi , Hong Ilene , Kim Leeseul , Chae Young Kwang
Published: June 2023

3069

Background: Globally, cancer results in 10.08 million deaths per year. A single blood-based screening tool that detects multiple cancer types could significantly reduce cancer burden. We systematically reviewed and statistically examined both the accuracy and applicability of blood-based MCED tests to strategize their utilization in improving cancer detection. Methods: Original articles were searched from PubMed, Cochrane, and Embase for blood-based screening tests analyzing multiple cancer types and asymptomatic human subjects. We excluded studies with small sample sizes (n<30), hypothesis-generating/diagnostic tests, and non-blood-based tests. For cfDNA-based assays, measurements of diagnostic accuracy were pooled for meta-analysis. Results: Of 1,074 records identified and screened, 15 case-control and 4 cohort studies were analyzed, most of which utilized cfDNA-based diagnostic tests. Twelve cfDNA studies selected for meta-analysis had pooled sensitivity of 0.623 (95%CI 0.517 - 0.719) and specificity of 0.975 (0.942 - 0.990). Summary ROC curve shows variability in sensitivity and specificity between studies. However, sensitivity and specificity were not affected by study type, gender, or assay type. Sensitivity was higher for advanced staged cancers (III/IV 0.774 (0.697 - 0.837)) than early-stage cancers (I/II 0.503 (0.366 - 0.639)). Among cancer types, no significant differences were detected. Lastly, false positive and false negative rates were 0.025 (0.010 - 0.058) and 0.447 (0.438 - 0.456), respectively. Conclusions: Given high sensitivities and specificities, MCED tests show promise as additional screening tools. However, in the general population, misdiagnosis burden from false positive and negative rates is anticipated. Although multiple barriers exist to their application in the clinic, MCED tests may improve patient outcomes for cancers with no conventional screening tools and provide additional credibility when combined with existing tools. Future prospective studies with large and diverse populations are warranted. [Table: see text]