bluuebunny/crossref_metadata_2025 huggingface dataset:
Differential genomic and transcriptomic analysis of invasive lobular and ductal carcinomas.
Authors: Mouabbi Jason A , Meric-Bernstam Funda , Khorkova Svetlana , Turova Polina , Kotlov Nikita , Chernyshov Konstantin , Kushnarev Vladimir , Love Anna , Clayton Patrick , Nomie Krystle , Fowler Nathan , Tripathy Debu
Published: June 2023

579

Background: Invasive lobular carcinoma (ILC) is more aggressive than hormone receptor (HR)-positive invasive ductal carcinoma (IDC). However, in practice, ILC and IDC are often treated in a similar fashion with endocrine therapy and chemotherapy. Identifying novel biomarkers, genetic alterations, transcriptomic features, and tumor microenvironment (TME) variations could initiate the development of personalized treatment plans for patients with ILC. Methods: We collected ILC and luminal (non-basal/non-HER2) IDC samples from four datasets (TCGA, METABRIC, RATHER PMC4700448, and UQCCR PMC31263747) and performed differential expression and gene set enrichment analyses, revealing novel genomic, transcriptomic, and TME differences. Using methods from Bagaev et al., we quantified the activity of 29 functional gene expression signatures with single sample gene set enrichment analysis before clustering the samples into five TME subtypes; statistical significance was measured with the Mann-Whitney U test. Differential expression analysis of RNA-Seq data was completed using DESeq2. Further, we analyzed the frequency of specific biomarkers to identify potential therapeutic options. Mutations and biomarker enrichment were assessed using the chi-squared test. Results: We analyzed 1,735 samples (1,442 luminal IDCs and 293 ILCs). CDH1 mutations were more prevalent in ILC samples (56%) compared to IDC samples (6%). Of the 44% of ILC samples with wild-type CDH1, 90% had low CDH1 expression. Inference models showed differences in transcription factors expression between ILC and IDC. ILC had significantly higher expression of TFAP2B, SOCS2, NOSTRIN, THBS4, SCUBE2, and GDF9 and lower expression of CDCA4, PSMG1, LMOD1, and SLC7A5 (adj p < 0.0001 for all genes). Analysis of the TME showed that 44% of ILC samples were immune enriched with high PDL1, CTLA4, and LAG3 expression. In comparison, approximately 30% of ILC samples contained enhanced vascularization and expressed high VEGFA, PDGFRA, and PDGFRB. Finally, compared to luminal IDC, ILC tend to have a statistically significant higher TROP2 expression, similar to that seen in basal subtype. Conclusions: ILC and IDC expressed distinct genomic alterations, gene expression, transcriptomic features, TMEs, and biomarkers. These differences can be used as a blueprint to tailor ILC phenotype-specific interventional clinical trials.
Use of machine learning to predict pathological complete response using multi-modal data from I-SPY2 clinical trials.
Authors: Ahmed Fahad Shabbir
Published: June 2023

592

Background: The objective of the current analysis of the I-SPY 2 data from multiple breast cancer clinical trials for stages II and III cancers was to look at the possibility of developing a machine learning algorithm to predict pathological complete response using multimodal data. Methods: Imagining, clinical and biomarkers data form the I-SPY 2 trial was used in this analysis. Four different experiments were designed for to assess different data pre-processing and machine learning methods mainly deep neural networks (DNN) and random forest (RF) classifiers. Experiment 1 and 3 use DNNs while Experiment 2 and 4 used RFs; more over the first two experiments used data that was continuous in nature from the point of view of pre-performed imaging analysis while in later two experiments we had binarized all the variables using a median cutoff for high vs low values. The variables used were treatment recieved, HER2/neu receptor status, hormone receptor status, age, ethnicity, gynecological history, MRI feature data. All models were evaluated using robust testing methods that included sensitivity, specificity, positive predictive values (PPV), negative predictive values (NPV), accuracies (training and test sets), area-under the receiver-operator curve and F1-Score. Results: From a total of 985 patients with clinical data we used 384 that had multi-feature MRI data. Time series data for the initial scan (T0) and a scan 3 weeks later (T1). The final comparative analysis showed the best model among the 4 experiment the best performing algorithms for this analysis was random forests using median cutoffs with a best F1-score (0.43), specificity (86.4%), PPV (47.8%), accuracies (train sets, 100%; test sets, 75%), and AUROCs (0.78, 0.56-0.73). Conclusions: The use of machine learning to predict pathological complete response using multimodal data shows good potential as a digital biomarker. However, these results need further validation before a clinical tool is available for the clinicians. [Table: see text]
Association of HER2/CEP17 ratio with pCR after HER2-directed neoadjuvant treatments in the phase III NeoALTTO trial.
Authors: Singer Christian F. , König Franz , Kacerovsky-Strobl Stephanie , Danzinger Sabine , Brunner Christine , Suppan Christoph , Deutschmann Christine , Balic Marija , Greil Richard , Egle Daniel , de Azambuja Evandro , Di Cosimo Serena , Gnant Michael
Published: June 2023

600

Background: HER2-directed therapies are approved for the treatment of patients with HER2-positive invasive breast cancer as defined by HER2 protein overexpression, or HER2 gene amplification based on HER2/chromosome enumeration probe (CEP17) ratio ≥ 2.2. Above this accepted HER2 status determination, however, it is still unknown whether the efficacy of HER2-directed therapy in early breast cancer increases with increasing HER2/CEP17 ratios. Therefore, the purpose of the presented work is to evaluate whether quantitative assessment of the HER2/CEP17 ratio predicts pathological complete response (pCR) and event-free survival (EFS) of patients treated with neo-adjuvant HER2-based regimen in the prospective phase III NeoALTTO trial. Methods: 455 women with HER2-positive early breast cancer, who had received neo-adjuvant trastuzumab and/or lapatinib for 6 weeks and then together with 12 cycles of weekly paclitaxel were included in this analysis. The HER2/CEP17 ratio in the primary tumor samples was correlated with pCR and survival outcome. Results: The Median HER2/CEP17 ratio in NeoALTTO was 5.1 (range: 1.1 – 100.0), and ratios were not associated with age, hormone receptor status, or any of the other clinicopathological variables analyzed. The log HER2/CEP17 ratio significantly predicted for pCR in both uni-variate (OR: 1.83; 95% CI: 1.11 - 3.01, p = 0.0176) and multivariate analysis (OR: 1.79; 95% CI: 1.07 - 2.99, p = 0.0257). Higher HER2/CEP17 ratios were, however, not associated with improved EFS (adjusted HR = 0.79; p = 0.3537). A pCR prediction model which included HER2/CEP17 ratio, treatment arm, and hormone receptor status improved the predictive strength of treatment arm alone from a ROC AUC value of 0.60 to 0.69. Conclusions: In patients treated with HER2-based neoadjuvant therapy, quantitative analysis of the readily available pre-treatment HER2/CEP17 ratio by FISH is predictive of pCR but not EFS.
Induction chemotherapy plus radiotherapy alone versus cisplatin-based concurrent chemoradiotherapy in locoregionally advanced nasopharyngeal carcinoma: An open-label, non-inferiority, randomized phase 3 trial.
Authors: Chen MingYuan , Huang Peiyu , Chen Xuyin , Ding Xi , Ling Guo , Mo Hao-Yuan , Duan Chongyang , Ling Li , Zou Xiong , Liu You-Ping , You Rui , Xie Yulong , Cao Jingyu , Liu Sihan , Wang Zimeng , Yang Qi , Qiu Fang , Hua Yijun , Cao Kajia , Luo Dong-Hua
Published: June 2023

6001

Background: Cisplatin-based concurrent chemoradiotherapy (CCRT) has long been regarded as standard treatment for locoregionally advanced nasopharyngeal carcinoma (LA-NPC) due to its favorable local control. However, concurrent platinum is associated with intolerable toxicities and ineffective in preventing distant metastasis. Since IMRT enhances the local control and induction chemotherapy (IC) decreases the risk of distant failure, it is worth exploring whether IC plus IMRT alone regimen could replace CCRT for patients with LA-NPC. Methods: This open-label, phase 3, non-inferiority clinical trial was conducted from June 12, 2015 to April 30, 2019. Patients with stage T1-4N2-3 or T3-4N0-1 M0 NPC were randomly assigned (1:1) to receive gemcitabine (1000 mg/m²) and cisplatin (80 mg/m²) IC for 2 cycles followed by IMRT alone or IMRT plus concomitant weekly cisplatin (40 mg/m²) up to 7 cycles. 2-year failure-free survival was set as primary endpoint and non-inferiority margin of 10% was established. Efficacy analysis and safety analysis were dividedly performed in the intention-to-treat and safety population. Results: A total of 249 patients were enrolled, including 124 patients in IC group and 125 patients in CCRT group. Median follow-up time was 60 months (IQR, 48-71). 2-year failure-free survival was 90.2% in IC group versus 86.3% in CCRT group, with an HR of 0.818 (95% CI, 0.479-1.397) and absolute difference of 3.9% (1-sided 95%CI, -4.2 to 11.9). No significant differences were observed between groups in overall survival, locoregional relapse, or distant metastasis. Compared with CCRT group, fewer grade ≥3 AEs occurred in IC group (47.5% vs 61.5%, p = 0.015), including leucopenia, anemia, mucositis, nausea and dysphagia. The IC group had significantly better QoL during and short periods after IMRT, including domains of global health status, physical functioning, fatigue, nausea and vomiting, pain, and appetite loss. Conclusions: For LA-NPC, gemcitabine and cisplatin induction chemotherapy plus IMRT alone was not inferior in 2-year failure-free survival to concurrent chemoradiotherapy. Clinical trial information: NCT02460887 .
A phase Ib/II study of GFH018 in combination with toripalimab in recurrent/metastatic nasopharyngeal carcinoma (R/M NPC).
Authors: Mai Hai-Qiang , Guo Ye , Yang Muh-Hwa , Yang Kunyu , Chen Li-Tzong , Mun Hui , Yang Yan , Wang Shuang , Zhu Huaqiang , Shen Haige , Wang Yu
Published: June 2023

6026

Background: The transformed growth factor beta (TGF-β) signaling pathway is dysregulated in carcinogenesis. In NPC patients, upregulation of TGF-β pathway is correlated with disease stage or phenotype due to Epstein-Barr virus (EBV) infection. GFH018, a novel TGF-βRI inhibitor, can inhibit tumor growth through inhibiting the activity of TGF-βRI kinase to block the signal transduction of TGF-β and modulate the tumor immune microenvironment. Preclinical studies showed that GFH018 in combination with PD-1/PD-L1 monoclonal antibody can significantly inhibit tumor growth synergistically. Here we report the preliminary results of combining GFH018 and Toripalimab treating R/M NPC patients (pts). Methods: This is a phase Ib/II study to evaluate the safety and efficacy of the combination of GFH018 and Toripalimab in pts with advanced solid tumors. Patients with RM NPC were enrolled to receive GFH018 80mg twice a day (BID) 14-day-on/14-day-off in combination with Toripalimab 3mg/kg every two weeks. Tumor assessment was performed every 8 weeks per Response Evaluation Criteria in Solid Tumor (RECIST) 1.1. Results: As of 31 Dec 2022, 32 pts with R/M NPC who had progressed on at least one prior line therapy were enrolled. Sixteen (50%) had received ≥3 lines of prior therapies, and 19 (59.4%) had previously received immune checkpoint inhibitors (ICIs) and platinum-based chemotherapies. The median duration of study drug exposure was 7 weeks. Twenty-five pts (78.1%) experienced treatment-related adverse events (TRAEs) of any grades, and 11 pts (34.4%) had ≥ Grade 3. The most common TRAEs (occurring in ≥ 3 pts) were anaemia (n = 6, 18.8%), hyponatraemia (n = 6, 18.8%), rash (n = 6, 18.8%), fatigue (n = 4, 12.5%), white blood cell count decreased (n = 4, 12.5%), aspartate aminotransferase increased (n = 3, 9.4%), back pain (n = 3, 9.4%), decreased appetite (n = 3, 9.4%), hypokalaemia (n = 3, 9.4%), and hypothyroidism (n = 3, 9.4%). As of 18 Jan 2023, among the 27 pts with post-baseline tumor assessments, 8 achieved partial response (PR), and 5 stable disease (SD); the overall response rate (ORR) was 29.6%, and disease control rate (DCR) was 48.1%. Six PR and 2 SD were observed among the 12 pts without prior treatment of ICIs; the ORR was 50%, and DCR was 66.7%. Four pts discontinued treatment without any post-baseline tumor assessments due to AEs or withdrawal of consent, and 1 patient is premature for tumor assessment. Conclusions: GFH018 combined Toripalimab was well tolerated and demonstrated preliminary efficacy in pts with R/M NPC. Specifically, in pts who had not previously received ICIs, promising antitumor activity was observed supporting further investigation to this group of pts. Clinical trial information: NCT04914286 .
Final results from TACTI-002 Part C: A phase II study of eftilagimod alpha (soluble LAG-3 protein) and pembrolizumab in patients with metastatic 2nd line head and neck squamous cell carcinoma unselected for PD-L1.
Authors: Doger de Spéville Bernard , Felip Enriqueta , Forster Martin , Majem Margarita , Bajaj Pawan , Peguero Julio Antonio , Carcereny Enric , Krebs Matthew G , Mukherjee Uma , Mueller Christian , Triebel Frederic
Published: June 2023

6029

Background: Eftilagimod alpha (E), a soluble LAG-3 protein, acts as an MHC class II agonist triggering activation of antigen-presenting cells (APC) and CD8 T-cells. Using efti to enhance patients’ immunity may lead to stronger anti-tumor responses than observed with pembrolizumab (P) alone. We report final results from Part C of the TACTI-002 trial (NCT03625323) where 2nd line metastatic head and neck squamous cell carcinoma (HNSCC) patients (pts) unselected for PD-L1 were treated with E + P. Methods: Pts with metastatic HNSCC, unselected for PD-L1 expression with disease progression on or after 1st line platinum-based therapy (± cetuximab) were enrolled. Primary endpoint (EP) was objective response rate (ORR) by iRECIST. Other EPs included tolerability, progression free survival (PFS), duration of response (DoR), and overall survival (OS). Pts received E (30 mg SC Q2W for eight 3-week cycles and then Q3W up to 1 yr) with P (200 mg IV Q3W up to 2 yrs). Imaging was performed Q9W. PD-L1 was retrospectively assessed using the IHC 22C3 kit. The study was approved by ethic committees and institutional review boards. Results: 39 pts were enrolled between Mar 2019-Jan 2021 (cut-off Jul 2022) with HNSCC of oropharynx (38%), oral cavity (32%), hypopharynx (19%) and larynx (16%). Median age was 63 yrs (48-84 yrs) and 90% were male. ECOG PS was 0 and 1 in 35% and 65% of pts. Two pts were excluded from efficacy results due to fatal COVID-19 prior to their first post-baseline scan. The primary EP, ORR by iRECIST, was 30% with 14% complete responders (see table). ORR by RECIST 1.1 was comparable (24%). Median PFS by iRECIST was 2.1 mo with 32% of pts progression-free at 6 mo. Median OS was 8.7 mo with 46% alive at 12 mo. Median DoR by iRECIST was not reached with 17 mo min FU. Responses were seen in all PD-L1 subgroups (see table). ORR, 6-mo PFS, 12-mo OS rates for PD-L1 CPS ≥20 were 60%, 53%, 73% with a median OS of 15.5 months. Two pts (5%) discontinued due to adverse events (AE) (fatigue and arthralgia [each grade 2]; pneumonitis [grade 3]) that were related to study treatment (efti and/or pembro). The most common (≥15%) AEs were hypothyroidism (21%), asthenia (21%), cough (18%), anemia (18%), weight decrease (18%), and fatigue (15%). Conclusions: Efti + pembrolizumab is safe, showing encouraging antitumor activity in platinum and partially cetuximab pre-treated, 2nd line HNSCC patients. TACTI-003 (NCT04811027) a randomized study in 1st line HNSCC is currently recruiting. Response by iRECIST: Clinical trial information: NCT03625323 . [Table: see text]
Results from two phase II studies of SI-B001, an EGFR×HER3 bispecific antibody, with/without chemotherapy in patients (pts) with recurrent and metastatic head and neck squamous cell carcinoma (HNSCC).
Authors: Xue Liqiong , Yang Kunyu , Fang Meiyu , Ma Xuelei , Zou Wen , Ding Muran , Wang Zhaoxiang , Peng Yujia , Xiao Sa , Wang Hongwei , Zhu Hai , Olivo Martin Sebastian , Zhu Yi , Guo Ye
Published: June 2023

6037

Background: SI-B001 is an EGFR×HER3 bispecific antibody. We present the efficacy and safety results from two ongoing studies of SI-B001, S209 and S206, in recurrent and metastatic HNSCC. Methods: S209 included pts with recurrent and metastatic HNSCC progressed on prior anti-PD-1/L1 plus platinum-based chemotherapy (PBC). Pts were treated with SI-B001 16mg/kg IV QW. S206 included pts with recurrent and metastatic HNSCC progressed on prior anti-PD-1/L1 with or without PBC and received no more than two lines of treatment. Pts enrolled in S206 were divided into two groups: Group A, pts without prior exposure to paclitaxel were treated with SI-B001 (12mg/kg IV QW) plus paclitaxel (80mg/m2 IV QW); Group B, pts with prior exposure to paclitaxel were treated with SI-B001 (12mg/kg IV QW) plus docetaxel (35mg/m2 IV D1D8D15 Q4W). The study endpoints of the two studies were identical. The primary endpoint was objective response rate (ORR) by investigator per RECIST v1.1. Secondary endpoints were ORR by independent central review, progression-free survival (PFS), disease control rate (DCR), duration of response (DOR), overall Survival (OS), and safety. Results: As of Dec 31, 2022, 11 pts in S209 received SI-B001. Pts had a median of 4 prior lines of therapy. In 9 out of 11 pts who have at least 1 post baseline tumor assessment in S209, ORR (n/N) was 22.2% (2/9), mPFS [95%CI] was 2.7 [1.8-7.9] mo. 29 pts in S206 received SI-B001 plus chemotherapy, including 19 pts in Group A and 10 pts in Group B. In 22 pts who had at least 1 post baseline tumor assessment, ORR was 45.5% (10/22), mPFS was 5.1 [3.7-5.6] mo. 1 nasal sinus cancer pt enrolled had stable disease (SD). 14 out of the 18 pts who have at least 1 post baseline tumor assessment in Group A, ORR was 64.3% (9/14) mPFS was 5.6 [5.1-6.3] mo. 8 out of 10 pts who have at least 1 post baseline tumor assessment in Group B, ORR was 12.5% (1/8), mPFS was 1.9 [1.2-3.7] mo. The most common grade 3 and above treatment-related adverse events (TRAEs) in S209 was Hypomagnesaemia (9%). The most common grade 3+ TRAEs in S206 were rash (16%), anaemia (8%) and white blood cell count decreased (8%). No SI-B001 drug-related deaths occurred in either study. Conclusions: SI-B001 plus paclitaxel demonstrated potential improvements in ORR and DCR compared with SI-B001 monotherapy in recurrent and metastatic HNSCC. The toxicity of SI-B001 plus chemotherapy in HNSCC is manageable and tolerable. Clinical trial information: NCT05044897 ; NCT05054439 . [Table: see text]
TCR-T cells armored with immune checkpoint blockade in EBV-positive nasopharyngeal carcinoma: The first-in-human phase 1/2 trial.
Authors: Jia Qingzhu , Peng Ling , Chen Gang , Wu Haiyang , Zeng Dong , Liu Tao , Zhan Yunpeng , Li Si , Su Frank , Zhu Bo , Li Qi-Jing
Published: June 2023

6047

Background: Nasopharyngeal carcinoma (NPC) refraction and metastasis is common, but therapeutics are limited. As adoptive immunotherapy has emerged as effective against other cancers, engineered T cells bearing a transgenic Epstein-Barr virus (EBV)-specific TCR (TCR-T) represent a viable approach to treat EBV-associated NPC. Given PD-1/PD-L1 induced T cell hypofunction, we herein report preliminary findings of a phase I trial of EBV-targeting TCR-T cells armored with secreted PD-1 blockade for patients who failed in two or more lines of standard therapies. Methods: Patients with advanced NPCs were consented and screened for EBV serotype and HLA haplotype. EBV+/HLA-A*02+ patients were enrolled in a rapid titration setting to escalate the single infusion dose from 5x106 to 1.0x107 and 5.0x107 /kg TCR-T cells. After safety evaluation, the 5.0X107 /kg cohort was expanded for further investigation of combining with IL-2 administration. Fludarabine/cyclophosphamide were administered prior to TCR-T cell transfer as pre-conditioning. Patient monitoring and peripheral blood analysis occurred weekly over the first month and then monthly until disease progression or patient withdrawal. The primary objective was to determine safety and a recommended phase 2 dose (RP2D), while the secondary objective was investigator assessed ORR (RECIST v1.1). Results: One patient per TCR-T dose was treated, and, as no dose-limiting toxicity (DLT) has been observed, dose level 3 (5.0x107 /kg) was expanded with IL-2 administration upon TCR-T cell infusion. As of January 2023, six patients have been treated. One patient (16.7%) exhibited grade 1 CRS (n=6). No grade 4 treatment-related adverse events (TRAEs) have been observed, with leukopenia and fever being the most common AEs. Two patients (33.3%) were assessed as partial response (PR), with one reaching a response duration of 9 months to date. Three patients (50%) were assessed as stable disease (SD). For all patients, pharmacokinetic analysis revealed that levels of TCR-T cells in peripheral blood peak between 3- and 14-days post-infusion, with a maximum duration of 180 days. Conclusions: EBV-targeting TCR-T cells armored with PD-1 blockade are well tolerated. Initial results from this ongoing study indicate that EBV proteins may be safe and effective TCR-T targets to achieve superior outcomes in advanced EBV-positive NPC patients. Clinical trial information: NCT04139057 . [Table: see text]
Induction therapy of toripalimab combined with docetaxel and cisplatin in locally advanced hypopharyngeal squamous cell carcinoma (HPSCC): A single-arm, phase II clinical trial.
Authors: Bai Chunmei , Wang Chenyu , Jia Ning , Chen Xingming , Zhu Xiaoli , Sun Shuai , Shi Xiaohua , Chen Yu , Luo Yaping
Published: June 2023

6070

Background: PD-1 (programmed cell death protein-1) inhibitors combination with chemotherapy has a significant efficacy and approved indications in the first-line treatment of head and neck squamous cell carcinoma (HNSCC), but the efficacy of these combination therapies in locally advanced hypopharyngeal squamous cell carcinoma (HPSCC) remains unexplored. We conducted a single-arm, phase II trial to assess the efficacy and safety of toripalimab (a novel PD-1 inhibitor) combined with chemotherapy as induction treatment in locally advanced HPSCC. Methods: Patients with locally advanced HPSCC (cT1N+M0 or T2-4NanyM0, AJCC 8.0) were eligible. All patients received 2 cycles of intravenous docetaxel (75mg/m2), cisplatin (75mg/m2) and toripalimab (240mg) on day 1 every 21 days, followed by radical surgery or concurrent chemoradiotherapy (CCRT) with cisplatin (100mg/m2, q21d). The primary endpoint was objective response rate (ORR) assessed by investigators per RECIST v1.1. Secondary endpoints were major pathologic response (MPR), 2 year disease-free survival (DFS) rate in patients received surgery, 2 year progression-free survival (PFS) rate in patients received CCRT and 2 year overall survival (OS) rate in all patients. Results: From July 2020 to January 2023, 34 patients (median age: 59, range: 46-72, male: 100%, stag IV: 100%) were enrolled. Patients with stage IVA an IVB disease were 19 (19/34, 55.9%) and 15 (15/34, 44.1%), respectively. 33 patients completed 2 cycles induction treatment and efficacy evaluation (1 patient dropped out). The evaluated ORR was 54.5%, including 3 pts achieving complete response and 15 achieving partial response. PD-L1 status (combined positive score, CPS) were known in 8 patients, ORR were 80% (4/5) and 66.7% (4/6) in patients with CPS≥20 and CPS≥1, respectively, 2 patients with CPS＜1 had stable disease. Treatment-related grade 3-4 adverse events occurred in 45.5% (15/33) of patients, leukopenia (42.4%) and neutropenia (3.1%). Immune-related AEs were acceptable, 1 patient (1/33, 3.0%) experienced grade 2 interstitial pneumonia and 2 patients (2/33, 6.1%) experienced grade 1 rash. In the following treatment, 27 patients (27/33, 81.8%) performed CCRT. 4 patients (4/33, 12.1%) underwent surgery followed by CCRT and 2 patients (2/33, 6.1%) refused further treatment. Among these 17 patients finished CCRT and radiological assessment, 9 patients (9/17, 52.9%) had complete response, 7 patients (7/17, 41.2%) had partial response and 1 patient (1/17, 5.9%) had progressive disease. Survival data are not mature by cut-off date. Conclusions: Induction therapy of toripalimab combined with docetaxel and cisplatin was well tolerated and highly efficient for locally advanced HPSCC. Clinical trial information: NCT04296747 .
Impact of acute kidney injury on overall survival in postoperative patients with head and neck cancer who received chemoradiotherapy with cisplatin: A supplementary analysis of a phase II/III trial of JCOG1008.
Authors: Imamura Yoshinori , Kiyota Naomi , Tahara Makoto , Kodaira Takeshi , Hayashi Ryuichi , Nishino Hiroshi , Asada Yukinori , Mitani Hiroki , Iwae Shigemichi , Nishio Naoki , Onozawa Yusuke , Hanai Nobuhiro , Ohkoshi Akira , Hara Hiroki , Monden Nobuya , Nagaoka Masato , Minami Shujiro , Kitabayashi Ryo , Sasaki Keita , Homma Akihiro ,   The Head and Neck Cancer Study Group of the Japan Clinical Oncology Group (JCOG-HNCSG)
Published: June 2023

6079

Background: A randomized phase II/III trial of JCOG1008 demonstrated that chemoradiotherapy (CRT) with weekly cisplatin at 40 mg/m2 (Weekly arm) was noninferior to 3-weekly cisplatin at 100 mg/m2 (3-weekly arm) in terms of overall survival (OS) for postoperative high-risk head and neck cancer (hazard ratio [HR], 0.69 [99.1% CI, 0.37 to 1.27 < 1.32]; J Clin Oncol 2022; 40: 1980-90). Acute kidney injury (AKI) is a major dose-limiting toxicity of cisplatin. Here, we investigated the impact of AKI on OS in patients treated with CRT in JCOG1008. Methods: A total of 251 patients who were treated with CRT in JCOG1008 were analyzed. AKI was defined as an increase in serum creatinine of ≥0.3 mg/dL or a 1.5-fold or more increase from baseline (≥stage I) within 30 days after completion of CRT, based on the AKI Network classification/staging system. OS in the two arms was compared by the development of AKI using the log-rank test. Results: The total incidence of AKI in the weekly arm was lower than that in the 3-weekly arm (38 of 122 [31.1%] vs. 56 of 129 [43.4%]). The incidence of stage II/III AKI was also lower in the weekly arm (8 of 122 [6.6%] vs. 19 of 129 [14.7%]). Total cisplatin dose was similar in patients who did and did not develop AKI in the weekly arm, but was lower in patients who developed AKI in the 3-weekly arm (Table). Moreover, no difference in OS was observed between patients who did and did not develop AKI in the weekly arm (HR, 1.06 [95% CI, 0.53 to 2.10]), whereas patients who developed AKI in the 3-weekly arm had poorer OS than those who did not (HR, 1.83 [95% CI, 1.04 to 3.21]). Conclusions: In this supplementary analysis of JCOG1008, development of AKI impacted OS in the 3-weekly arm, but not in the weekly arm. Consistent exposure to cisplatin through weekly fractionated administration appears of greater clinical significance than cumulative dose, providing maintenance of treatment intensity and better kidney safety, and likely also improving outcomes. Clinical trial information: jRCTs031180135 . [Table: see text]
Use of machine learning derived features from CT and H&E whole-slide images to predict overall survival in head and neck squamous cell carcinoma.
Authors: Song Bolin , Leroy Amaury , Yang Kailin , Viswanathan Vidya Sankar , Li Xiao , Lee Jonathan , Stock Sarah , Fu Pingfu , Saba Nabil F. , Koyfman Shlomo A. , Lewis James S. , Deutsch Eric , Madabhushi Anant
Published: June 2023

6086

Background: Computed tomography (CT) and H&E whole-slide images (WSI) have been found to carry rich prognostic information for patients diagnosed with head and neck squamous cell carcinoma (HNSCC). However, most machine learning models aimed for outcome prediction only took advantage of single image modality. In this work, we developed and validated a prognostic machine learning method incorporating both CT and WSI to predict overall survival in HNSCC patients. Methods: Matched radiographic CT scans and digitized WSI were acquired from the Cleveland Clinic for 167 HNSCC patients, including 120 HPV-associated oropharyngeal cancer and 47 laryngeal cancer. Both primary tumor and the largest suspicious lymph node were annotated on CT scans and primary tumor was delineated on H&E WSI. We split the dataset into training and validation set using a 7:3 ratio, which resulted in 119 patients in the training set and 48 for hold-out validation. We applied a machine learning model (M_ML) using both CT and WSI as input to perform end-to-end predictions of overall survival. We used the harrell’s concordance index (C-index) to evaluate the prognostic performance. Finally, we performed the multivariable cox proportional hazard analysis adjusting for clinicopathological variables (i.e. age, gender, smoking pack-year [PY], AJCC 7th edition overall stage, and treatment modality) to validate the independent prognostic significance of the model. Results: The combined machine learning model M_ML (C-index = 0.81) outperformed the model using CT images alone (C-index = 0.63) and WSI alone (C-index = 0.64) on the validation set. In multivariable analysis, M_ML is still statistically significant accounting for clinicopathologic factors (p = 0.0007). Conclusions: This pilot study shows that a multi-omic machine learning model utilizing both radiographic CT and digitized WSI can predict HNSCC overall survival and outperforms models using only a single modality. [Table: see text]
Whole-genome sequencing based assessment of HER2 focal amplification for precision oncology of breast cancers.
Authors: Kim Ryul , Lim Joonoh , Park Hansol , Park Seongyeol , Oh Baek-Lok , Lee Sangmoon , Kim Ji-Yeon , Nam Seok Jin , Kim Seok Won , Lee Jeong Eon , Yu Jonghan , Ryu Ji In , Lee Jeong Seok , Kwon Minsuk , Lee Jeongmin , Park Yeon Hee , Ju Young Seok
Published: June 2023

609

Background: Focal oncogene amplification confers a growth advantage to tumor cells and drives cancer evolution. Herein, we aimed to explore focally amplified HER2 in breast carcinomas. Methods: We performed whole genome sequencing (WGS) and whole-transcriptome sequencing (WTS) in 787 breast cancer samples. HER2 focal amplification was defined as having a segment length less than 3Mbp and ≥4 higher copy number than the surrounding region. Results: Most of the patients were premenopausal women (n = 574, 72.9%) with a median age of 37 (range 21-76) years. We identified 57 (58.8%) and 27 (5.0%) samples with HER2 focal amplification in HER2-positive (n = 97) and even HER2-negative (n = 536) by immunohistochemistry (IHC) and in-situ hybridization (ISH) according to ASCO guideline for breast cancer, respectively. Regardless of HER2-positivity, HER2 focal amplification was significantly associated with higher HER2 RNA expression. Among 28 patients who received six cycles of docetaxel/carboplatin/trastuzumab/pertuzumab neoadjuvant therapy followed by curative surgery, 21 patients had HER2 focal amplification and 14 (66.7%) achieved pathologic complete remission (pCR). Intriguingly, all patients without HER2 focal amplification (n = 7) failed to achieve pCR. HER2 focal amplification showed enrichment of TP53 mutations (OR 0.245, q < 0.001), but was mutually exclusive with GATA3 mutations (OR 2.82, q = 0.055). The mutational spectrums suggested that the activity in APOBEC family of cytidine deaminases were responsible for the somatic single-nucleotide variants of breast cancer with HER2 focal amplification. Compared to samples without HER2 focal amplification, samples with HER2 focal amplification were less likely to have defective homologous recombination DNA repair pathway. HER focal amplifications were closely associated with various types of structural variations. Translocation partners of HER2 were widespread across the entire genome with notable exceptions on chromosome 2, and most of them were close to super-enhancers implying enhancer hijacking as one of mechanisms of HER2 overexpression. Breast cancers with or without HER2 focal amplification showed distinct RNA expression patterns. Notably, activity of genes involved in doxorubicin-resistance and AKT1 signaling were significantly associated with HER2 focal amplification. Conclusions: Our analysis demonstrates that WGS enables better classification of the HER2 amplification status in breast cancer than IHC with ISH, suggesting WGS as a sensitive tool for screening breast cancers for anti-HER2-targeted therapies.
Darolutamide for patients with androgen receptor positive salivary gland cancers (DISCOVARY): The results of phase 2 study of darolutamide monotherapy.
Authors: Okano Susumu , Tahara Makoto , Imamura Yoshinori , Uryu Hideoki , Otsuka Tomoyuki , Ohkoshi Akira , Sano Daisuke , Tsukahara Kiyoaki , Ono Kazuchika , Hanazawa Toyoyuki , Kano Satoshi , Nishio Naoki , Nagaoka Masato , Kiyota Naomi
Published: June 2023

6093

Background: There is no standard first-line treatment for recurrent/metastatic (R/M) or unresectable locally advanced (LA) salivary gland cancer (SGC). Androgen receptor (AR) overexpression is known to be particularly high (43-92%) in SDC, depending on histology, and has been identified as a potential molecular target for SGC treatment. However, the clinical utility of this approach has not been well investigated. Here, we evaluated the efficacy and safety of darolutamide for patients with AR-positive SGC. Methods: Eligibility included LA or R/M, SGC histologically confirmed positive for AR by the central laboratory; PS 0-1; adequate organ function; and no suitable local therapy. The study consists of two sequential components: a monotherapy part with darolutamide alone (monotherapy part) and a combination part with darolutamide and goserelin (combination part). Darolutamide was given orally at 1,200 mg daily until disease progression or unacceptable toxicity. Primary endpoint for the monotherapy part was overall response rate (ORR) as determined by the investigator. Secondary endpoints were ORR by independent central review (ICR), clinical benefit rate (CBR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. (ClinicalTrials.gov NCT05694819). Results: From Mar 2020 to Jan 2021, 24 patients were enrolled in the monotherapy component. Median age was 64.6 years and 23 were male. ECOG PS was 0/1 in 18/6 cases. Pathological diagnosis was salivary duct carcinoma, adenocarcinoma NOS, and carcinoma ex pleomorphic adenoma in 16, 4 and 4 patients, respectively. ORR by investigator was 8.3% (90% CI 1.5–24.0) and ORR by ICR was 20.8% (95% CI 7.1–42.2). CBR and DCR were 41.7% (95% CI 22.1–63.4) and 58.3% (95% CI 36.6–77.9), respectably. Median PFS and OS were 5.7 months (95% CI, 1.9–15.2) and not reached (95% CI, 15.5–not estimable [NE]), respectively, with a median follow-up period of 19.1 months. Nine patients (37.5%) had grade 3 or 4 treatment-related adverse events. There were no treatment-related fatal adverse events. Conclusions: This is the first prospective trial of darolutamide for AR-positive SGC. The response rate by ICR and other secondary endpoints confirmed clinically meaningful activity and a well-tolerated safety profile. Patient enrollment to the combination component is now ongoing to evaluate additional benefits. Clinical trial information: NCT05694819 .
Monitoring epithelial, epithelial-mesenchymal, and mesenchymal circulating tumor cells on papillary thyroid cancer following thyroidectomy: A prospective cohort study.
Authors: Park Eunju , Yu Hyeong Won , Lee Seon Kyoung , Kong Ju Hyun , Sunoo Joseph , Hong Soon-Cheol , Choi June Young
Published: June 2023

6097

Background: Monitoring the effectiveness of cancer-removal surgery is challenging in most cases. Therefore, robust and non-invasive techniques have been developed, and liquid biopsy is an apparent method for that purpose. In this prospective cohort study, we examined whether one type of liquid biopsy, an enumeration of circulating tumor cells (CTCs), can monitor the effectiveness of thyroidectomy in patients with papillary thyroid cancer (PTC). Methods: From January 2021 to January 2022, we recruited 62 PTC patients who had operated on isthmectomy, lobectomy, and total thyroidectomy for this study at Seoul National University Bundang Hospital. The blood samples from the recruited patients were collected before surgery and two weeks and three months after the surgery for CTC detection. We collected peripheral blood samples by venipuncture from each patient in EDTA tubes and stored them at 4°C until isolation and characterization of CTCs (within 6 hours). Results: We found the CTCs in 87% (54/62) of PTC patients, with an average number of 8.0. This number significantly decreased after thyroidectomy, with an average of 5.3 and 4.3 post-operation of two weeks and three months, respectively. In the peripheral blood of PTC patients, the CTCs with epithelial-mesenchymal and mesenchymal phenotypes were significantly more frequent than the epithelial phenotype of CTCs. Furthermore, PTC patients with lymphatic invasion, lymph node metastasis, or BRAF V600E mutation showed significantly decreased CTC count after surgery. Conclusions: PTC patients had a significantly higher number of CTCs undergoing epithelial-mesenchymal transition and showed a significant decrease in CTC count after surgery. This indicates that liquid biopsy using CTC enumeration can satisfy the purpose of monitoring the effectiveness of cancer-removal surgery. Clinical trial information: KCT0008179.
Social determinants of health and utilization of neoadjuvant chemotherapy in patients with triple negative breast cancer (TNBC) in the community oncology setting.
Authors: Danso Michael A. , Dye Joseph , Leong Traci , Reid Robert Lawrence , Kidd Angel , Espirito Janet L. , Robert Nicholas J.
Published: June 2023

610

Background: TNBC has a higher incidence in African American women compared to European American, often presents at a younger age or more advanced stage, and is associated with worse outcomes. The use of multi-agent neoadjuvant chemotherapy (NC) improves event-free survival and overall survival in patients with early-stage TNBC and is considered standard of care. Race and other social determinants of health (SDOH) have been shown to affect outcomes in patients with TNBC. Differences in use of NC associated with SDOH may be a contributing factor to inferior outcomes. The aim of this study is to determine if SDOH measures affect utilization of NC in patients with early-stage TNBC. Methods: This retrospective observational cross-sectional study examined patient profiles, treatment patterns and SDOH indicators among patients newly diagnosed with early-stage breast cancer in The US Oncology Network. Using iKnowMed EHR data, patients diagnosed with TNBC between 03/31/2017 and 09/30/2021 with stages II-IIIB disease or tumor size ≥2cm (T2 or higher) were included. The initial TNBC diagnosis date was used as the index date for each patient and records were assessed from 6 months pre- to 6 months post-diagnosis for NC initiation, baseline characteristics, and social determinants, including Area Deprivation Index (ADI), a validated measure of socioeconomic status. Results: 3321 patients with TNBC were identified, with a mean age of 58 years; 59% were White, 15% Black, 3% Asian, and 23% other/unknown; and 2139 (64%) received NC. Patients who received NC relative to those who did not were younger (mean 55.9 vs 61.8; p=0.001), had higher BMIs (70% with BMI>25 vs ≤25, p=0.045), and had commercial or Medicaid insurance (67.5% with commercial insurance or Medicaid vs. 52.5% with Medicare; p=0.001). Regional differences were observed, with proportionally fewer patients receiving neoadjuvant chemotherapy in the south US census regions and more in the west. There was no difference in NC use in Black vs White patients (66% vs 64%). No significant differences in receipt of NC were found for race, ethnicity, or ADI. Conclusions: In the community oncology setting, we did not observe inequities in the use of NC based on social determinants analyzed in this study, such as race, ethnicity, and ADI. Poorer outcomes observed in Black patients with TNBC may not be a result of underutilization of NC.
How patient-clinician education can strengthen partnerships and promote tangible actions to improve clinical trial diversity in breast and lung cancer trials.
Authors: Ackbarali Tariqa , Fairley Ricki , Vadaparampil Susan Thomas , Lisberg Aaron Elliott , Osarogiagbon Raymond U. , Gary Monique
Published: June 2023

6510

Background: Some of the greatest disparities in cancer care are related to clinical trial access for our patients. To address the racial/ethnic disparities in breast and lung cancer clinical trials, a tethered educational initiative was designed to empower patients, assess current clinician perceptions/practices, and improve awareness of real-world perspectives of clinical trials. Methods: Two, one-hour online, interactive, video-based programs were designed for patients, caregivers, and providers. This patient/caregiver program was hosted on CancerCoachLive and MedLive in November, 2022, while the provider program was hosted on ClinicalSeriesLive in December, 2022 and will remain on-demand until December 2023. This initiative was conducted in collaboration with TOUCH, the Black Breast Cancer Alliance, BlackDoctors.org, Moffitt Cancer Center, CancerCare, and the Lung Cancer Research Foundation. Herein, we report on an analysis from patients and providers regarding clinical trial diversity, behavioral impact, and qualitative insights. Results: As of data cut-off (02/10/23), 1,425 participants have engaged across both educational programs. Of participating patients, 46% were non-White (non-Hispanic), 36% were in remission, 36% were not on active treatment, and 29% were newly diagnosed. Following the program 81% were motivated to take one or more actions over the next two months: the most common actions being to research clinical trials (38%) or discuss clinical trials with a clinician (19%). Post-activity, 79% were confident to very confident discussing clinical trials with a clinician. Critical data related to clinician preferences was assessed and demonstrated a 23% increase in confidence from pre- to post-activity in improving diversity in clinical trial participation with preferences observed in both breast and lung cancers to offer clinical trials for newly diagnosed and second recurrence settings. Of those who are being offered clinical trials in the community setting, there was a higher likelihood for patients to be offered a clinical trial if their subtype was HER2+ breast cancer subtype or NSCLC with an actionable mutation. Data collection continues as this initiative is ongoing. Qualitative data including clinician write-in examples of behavioral impact and patient perspectives from the interviews will be shared. Conclusions: The outcomes discussed herein reveal a willingness from patients/caregivers to engage in clinical trial discussions and participate in clinical trials, if eligible. These educational programs positively impacted clinician motivation to address barriers to enrollment and clinical trial eligibility with their patients. Real-world accounts of patient experiences provide different perspectives that can help improve approaches to improve clinical trial diversity.
A multi-level system quality improvement project to reduce disparities in lung cancer screening: The Sylvester Lung Screening Project.
Authors: Gay Nicole Ann , Da Silva Melanhy T , Vega Vanessa Patricia , Thomassen Amber , MacIntyre Jessica , Valls-Delgado Georgette , Olazagasti Coral , Rodriguez Estelamari
Published: June 2023

6518

Background: Racial disparities in lung cancer mortality and screening have been well documented in the USA. Annual screening with low dose Computed Tomography (CT) scans is completed in fewer than 6% of the eligible population. Research suggests that many factors contribute to low screening uptake, including barriers to care at patient, clinician, healthcare system, and community levels. In collaboration with the American Cancer Society, the University of Miami/ Sylvester Cancer Center underwent a multi-level system quality improvement (QI) project with the goal to decrease lung cancer screening disparities and improve guideline concordant lung cancer screening across the health care system. Methods: During the one-year multi-level QI project, interventions were put into place to increase lung cancer screening exams via improvements in EMR- identification of eligible patients, patient navigation and expanded provider education services in primary care clinics. Patient level interventions included a marketing campaign, patient navigation, and interpreters to address language barriers. The Patient-interface of the EMR ‘Health Maintenance Gap’ was optimized to alert eligible patients about screening. In addition, a full-time lung cancer screening navigator provided culturally competent, patient-centered counseling, while allowing for an increased capability to manage a higher volume of patients. Provider level interventions included teaching sessions about lung cancer screening and motivational communication skills, and BPA alerts. The primary outcome was the change in the number of screened patients. Results: With the implementation of these multi-level interventions, there was a twenty five percent improvement in the number of lung cancer screening exams completed during the project period January 2022- December 2022 compared to 2021 baseline, from 20 to 25%. The screening rate was highest among Hispanics (12%), followed by Blacks (8%), and Non- Hispanic Whites (NHW) (6%). The majority of LDCT results were Lung RADS Category 1 or 2 (93%). Conclusions: Multi-level interventions that target patients, clinicians, and the health care system can improve lung cancer screening rates in a short-term period. Developing patient-centered, culturally competent interventions is key to reducing disparities in lung cancer screening. This QI intervention was strengthened by tailoring intervention components to the educational primary care physicians and simplifying the referral process. [Table: see text]