bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of low RKIP expression with poor prognosis in non-small cell lung cancer.
Authors: Meng Lingbin , Ji Rui , Laber Damian A. , Yan Xuebo , Xu Xiaochun
Published: June 2021

3068

Background: Raf1 kinase inhibitor protein (RKIP) is able to bind Raf1 to inhibit Ras-Raf-MEK-ERK signaling, a major oncogenic pathway. It has been reported that reduced RKIP expression associates with poor prognosis in many cancers, including gastric adenocarcinoma, gliomas and bladder cancer. However, there are only several studies on its role in non-small cell lung cancer (NSCLC) and the conclusion is still controversial. Hence, we performed this study to assess the prognostic significance of RKIP in our NSCLC population. Methods: Between June 2017 and June 2020, 156 NSCLC patients treated at our hospital were included for the present study. None of the patients had received chemotherapy, radiotherapy or surgery before. Their tumor tissues and surrounding normal lung tissues were collected for immunostain and western blot analysis of RKIP expression and ERK signaling. We collected information about gender, age, histological differentiation, tumor size, TNM stage, and lymph node status. Survival curves were analyzed using the Kaplan-Meier method. Cox proportional hazards model was used to determine the prognostic value of various variables in a univariate and multivariate setting. Results: Immunostain and western blot results showed a lower RKIP expression and a higher p-ERK level in cancer tissues compared with the surrounding normal tissues. A reduced RKIP expression with high level of p-ERK was also observed in TNM stages III and IV as compared with I and II. Pearson's chi-squared test confirmed low RKIP expression associated with poorer TNM stage ( p< 0.001) and N-stage ( p< 0.05). No significant correlation was observed between RKIP expression level and gender, age, histological type or tumor size. Kaplan-Meier survival analysis revealed that patients with low RKIP expression had significantly worse overall survival than patients with high RKIP expression ( p= 0.019, log-rank). This conclusion was consistent in the stage I&II patients ( p= 0.011, log-rank) but not in the stage III&IV patients ( p= 0.711, log-rank). Univariate Cox proportional hazards regression analysis indicated Tumor size, TNM stage and RKIP expression significantly affected overall survival of the NSCLC patients. Multivariate Cox proportional hazards regression analysis confirmed RKIP expression remained a significant predictor of survival after correcting for the effects of Tumor size and TNM stage (hazard ratio = 1.730, 95% confidence interval = 1.017 – 2.942, p = 0.043). Conclusions: In this study, low RKIP expression was a poor prognostic indicator in NSCLC as it significantly correlated with poorer TNM stage, N-status, and overall survival. Our findings suggest that by inhibiting Ras-Raf-MEK-ERK pathway RKIP may play an anti-tumor role in NSCLC.
Preliminary efficacy from an ongoing phase 1 dose escalation study of seclidemstat (SP-2577) in patients (pts) with advanced solid tumors (AST).
Authors: Chawla Sant P. , Chua-Alcala Victoria S. , Sachdev Jasgit C. , Wages David S. , Stenehjem David D. , Santiesteban Daniela Y. , Mirza Nadeem Q. , Gordon Michael S.
Published: June 2021

3073

Background: Lysine-specific demethylase 1 (LSD1) is an epigenetic enzyme that is aberrantly expressed in many solid tumors. High levels of LSD1 expression are often correlated with poor patient prognosis due to LSD1’s role in cancer cell proliferation, metastasis, and chemoresistance. Seclidemstat is a novel, selective, reversible and oral LSD1 inhibitor capable of inhibiting both LSD1’s catalytic and scaffolding functions. We report preliminary efficacy in AST from an ongoing phase 1 trial. Methods: SALA-003-AC19 (NCT03895684) is a phase 1 trial of single agent SP-2577 in pts with AST. All pts had progressive disease (PD) at time of study entry. Pts received oral SP-2577 twice a day under fasting condition, in 28-day cycles (C). The primary objective is safety and tolerability. Secondary objectives are to determine maximum-tolerated dose, preliminary efficacy, pharmacokinetics, and pharmacodynamics. Results: As of December 30, 2020, 19 pts with AST (10 sarcoma, 2 prostate, 2 ovarian, 2 pancreatic, 1 renal, 1 cervical, 1 breast) were enrolled. Pts received escalating doses of SP-2577 from 150 to 600 mg BID and the dose escalation is ongoing. The median age was 63 years (range, 21–79). 42% were male, and pts had received a median of 4 (range, 1–8) prior systemic therapies. The most common (>5%) grade 3 treatment-related adverse events were GI related including diarrhea (5.3%) and abdominal pain (5.3%). No grade 4 events were reported and there were no treatment-related deaths. Safety data will be presented after completion of phase 1. Three pts had at least one dose reduction. Among the 13 pts who were evaluable for response at end of C2, 7 pts (54%) had best response of stable disease (SD) with median time to progression (TTP) of 4.3 months (range, 2.1–11.5). Four of the 7 pts had genetic abnormalities that may demonstrate increased sensitization to SP-2577 according to preclinical studies. Characteristics of 7 pts with SD at C2 and beyond are shown in the table. Conclusions: Seclidemstat has shown activity among advanced sarcoma pts with a manageable safety profile. The dose escalation is ongoing and preliminary clinical data supports further exploration in FET-translocated sarcoma as single agent and in combination therapy. Clinical trial information: NCT03895684. [Table: see text]
High-intensity focused ultrasound ablation for treatment of chemotherapy-induced thrombocytopenia and hypersplenism.
Authors: Yuan Min , Xu Qing , Zhu Zhongzheng , Mao Wei , Guo Xianling , Wang Hui , Qian Hong , Wu Jianguo
Published: June 2021

3082

Background: Chemotherapy-induced thrombocytopenia (CIT) contributes to treatment dose delay and/or modification, often resulting in poorer survival and disease progression. Compared with partial splenic embolization (PSE) and drugs, high-intensity focused ultrasound has the advantages as following: (1) it is a noninvasive treatment modality with potentially fewer adverse effects and complications; (2) the hospital stay and recovery time after treatment are short; (3) its cost is relatively low compared to surgery. The purpose of this work was to preliminarily investigate the efficacy and safety of high intensity focused ultrasound treatment of chemotherapy-induced thrombocytopenia (CIT) and hypersplenism. Methods: 26 patients with chemotherapy-induced thrombocytopenia and hypersplenism (15 male and 11 female; median age, 56 years; range, 51-66 years) were treated with ultrasound guided high-intensity focused ultrasound. Complications were recorded. Laboratory examination and magnetic resonance imaging were used to evaluate the efficacy. The spleen volume and ablation volume rate of the spleen were calculated by MRI after treatment. They were followed closely for at least 6 months. Results: After high-intensity focused ultrasound treatment, the MRI showed that the ablation area had turned into a non-perfused volume, the mean percent spleen ablation volume was 18.76% ± 6.1% (range, 11.17%-32.34%). After 6 months of HIFU ablation, the ablated area shrank evidently; the sunken spleen formed a lobulated shape and the splenic volume decreased. The platelet count increased 3-7 days after treatment and remained for 1-2weeks higher than baseline (53.33 ± 15.80 × 109/L). The white blood cell count and platelet count of the patients were substantially improved during the follow-up period. No substantial difference was observed in RBC counts between baseline and after treatment. In addition, symptoms such as epistaxis and gingival bleeding were ameliorated or even eliminated, and the quality of life was improved. Follow-up imaging showed a nonperfused volume in the spleen. Conclusions: For the first time to our knowledge, high-intensity focused ultrasound ablation was used to treat Chemotherapy-induced thrombocytopenia (CIT) and hypersplenism. High-intensity focused ultrasound ablation of the spleen may cause damage to a certain volume of the spleen parenchyma to achieve the purpose of hypersplenism treatment. High intensity focused ultrasound may be an effective and safe alternative for treatment of CIT and hypersplenism.
Partitioning of cancer therapeutics in nuclear condensates.
Authors: Klein Isaac , Boija Ann , Afeyan Lena , Hawken Susana , Fan Mengyang , Taatjes Dylan , Chakraborty Arup , Sharp Phillip , Chang Young Tae , Hyman Anthony , Gray Nathanael , Young Richard
Published: June 2021

3131

Background: The molecules of the cell are compartmentalized into membrane- and non-membrane-bound organelles. Many non-membrane-bound organelles are phase-separated biomolecular condensates with distinct physicochemical properties that can absorb and concentrate specific proteins and nucleic acids involved in discrete biochemical processes. We reasoned that selective condensate partitioning might also occur with small molecule drugs whose targets occur within condensates, and that the therapeutic index and efficacy of such compounds might therefore relate to their ability to partition into condensates. Methods: To study the behavior of drugs within condensates, these were modeled in cells and in vitro with purified proteins and visualized by fluorescent confocal microscopy. The functional outcomes of condensate partitioning were queried in cells. Results: We found that cisplatin, tamoxifen, JQ1, THZ1, and mitoxantrone are concentrated in specific protein condensates in vitro, and that this occurs through physicochemical properties independent of the drug target. A screen of a chemically diverse fluorescent probes and mutant-protein condensates demonstrated that pi-system interactions between aromatic moieties in the protein and small molecule govern concentration in condensates. These results show that clinically important drugs partition into specific protein condensates in vitro by virtue of defined chemical properties, thereby altering their local concentration. In vitro droplet assays revealed that cisplatin is selectively concentrated in transcriptional condensates, and that this ability is required for efficient platination of target DNA. In cell studies revealed that cisplatin preferentially targets DNA contained within MED1 condensates, and disrupts the genetic regulatory elements that compose phase-separated transcriptional condensates. Live cell imaging demonstrated that transcriptional condensates are dissolved by cisplatin, whereas other condensates remain intact. Conclusions: Our results show that antineoplastic drugs partition selectively into biomolecular condensates, that this can occur through physicochemical properties independent of their molecular targets, and that drug activity may occur through condensate-related mechanisms. These results have implications for development of efficacious cancer therapeutics; effective target engagement will depend on factors such as drug partitioning in condensates. Assays of the type described here may thus help optimize condensate partitioning, target engagement, and the therapeutic index of drugs for cancer treatment.
Prevalence of fertility discussions between young adult colorectal cancer survivors and their providers.
Authors: Stal Julia , Yi Serena , Cohen-Cutler Sally , Gallagher Phuong , Barzi Afsaneh , Milam Joel , Freyer David R. , Lenz Heinz-Josef , Miller Kimberly Ann
Published: June 2021

3518

Background: Clinical guidelines indicate that oncologists should discuss potential treatment-induced infertility with patients with reproductive potential. Due to tumor location and use of multimodal therapies, young adults with colorectal cancer (CRC) are at heightened risk for treatment-related infertility. Methods: An online, cross-sectional survey was administered in collaboration with a national patient advocacy organization for young adult CRC survivors (currently under age 50). Survivors were asked to indicate if a doctor had ever talked to them about potential problems with their ability to have children after treatment and if they banked eggs/embryos (females) or sperm (males) prior to their cancer therapy. Those who reported that they did not preserve fertility were asked to indicate why ( not sure; I chose not to; I did not know this was an option; I wanted to, but could not afford it; and I wanted to, but my treatment would not allow it). Results: A total of 234 colon (N=86) or rectal (N=148) cancer survivors were included in the study (male [61.9%] and White [77.9%; table]). Most respondents were diagnosed with stage 2 cancer (55.8% colon, 61.6% rectal). Over half of male and female survivors reported that their doctor did not talk to them about problems with their ability to have children after treatment, and 75% did not bank eggs/embryos or sperm prior to their cancer therapy. Of those, over 20% endorsed ‘I wanted to, but could not afford it’ and over 20% endorsed ‘I did not know this was an option’. Conclusions: Most CRC survivors in this study reported never having a fertility discussion with their provider, suggesting that survivors are not receiving, or cannot recall, comprehensive and guideline-concordant cancer care. In addition, one-fifth were not aware of preservation options, suggesting potential healthcare and/or provider-level barriers to appropriate fertility counseling. Fertility preservation cost is another barrier to the appropriate delivery of care. Providers must ensure that patients receive timely fertility discussions covering options to preserve fertility to mitigate this late effect of cancer treatment to ensure optimal quality of life for CRC patients with reproductive potential.[Table: see text]
Association of HER2 expression with pathologic features and prognosis in stage II and III colon cancer.
Authors: Wu Zehua , Hu Huabin , Deng Yanhong
Published: June 2021

3524

Background: We examined the frequency, tumor characteristics, and prognostic impact of HER2 protein expression in stage II and III colon cancer after curative resection. Methods: Paraffin-embedded tumors from consecutive primary stage II and III colon cancer patients were analyzed for HER2 protein expression by immunohistochemistry between April, 2013 and May, 2020. HER2 determination of immunohistochemistry scores (0/1+/2+/3+) was according to HERACLES diagnostic criteria. Results: A total of 2088 stage II and III colon cancer patients were included (53.8% stage II, 46.3% stage III). HER2 scored positive (3+) was detected in 48(2.3%) tumors, and was correlated with younger age (P < 0.001), well/moderate differentiation (P = 0.026), proficient mismatch repair (pMMR) (P = 0.045) and KRAS wild-type (P < 0.001). HER2 scored positive (3+) was not significantly associated with disease-free survival (DFS) compared with HER2 scored negative (0/1+), neither in stage III patients (multivariable HR, 0.86; 95CI, 0.38 to 1.94; P = 0.717), nor in stage II patients (multivariable HR, 1.68; 95CI, 0.74 to 3.84; P = 0.218). In a separate analysis involving stage II patients without any high-risk factor (n = 741), those with HER2 scored positive (3+) tumors (n = 16) showed significantly reduced DFS (multivariable HR, 2.91; 95CI, 1.04 to 8.81; P = 0.041) compared with patients with HER2 scored negative (0/1+) tumors, independent of sex, age and MMR status. Conclusions: HER2 scored positive (3+) was independently associated with poor DFS in stage II colon cancer patients without high-risk factors. HER2 expression determination may help to judge the prognosis of those patients and guide adjuvant chemotherapy.
Patient-reported quality of life data from patients with pre-treated metastatic colorectal cancer receiving trifluridine/tipiracil: Interim results of the TALLISUR study.
Authors: Karthaus Meinolf , Kretzschmar Albrecht , Fuxius Stefan , Riera Knorrenschild Jorge , Kaiser Florian , Mahlberg Rolf , Welslau Manfred , Pelz Henning , Heinemann Volker ,   on behalf of the TALLISUR Study Group
Published: June 2021

3526

Background: Compared to placebo, trifluridine/tipiracil (FTD/TPI) significantly improved overall and progression-free survival in patients (pts) with pre-treated metastatic colorectal cancer (mCRC) in the phase III RECOURSE trial. Although time to deterioration of ECOG performance status (PS) from 0/1 to ≥ 2 was significantly longer in pts treated with FTD/TPI, health-related quality of life (HRQoL) was not formally assessed by direct means. Therefore, a two-arm trial with best supportive care (BSC) as appropriate comparative treatment was designed to specifically address the effect of FTD/TPI on HRQoL. Methods: In this prospective, multi-center, German, open-label, phase IV study, pts with pre-treated mCRC could choose between BSC or oral FTD/TPI (35 mg/m2 bid on days 1-5 and 8-12 of each 28-day cycle). EORTC QLQ-C30 and EQ-5D-5L questionnaires were employed to assess HRQoL. Primary endpoint was the rate of responders with stabilized ( > -10 and < 10 scores) or improved (≥ 10 scores) response (RR). Response was calculated as the mean score of the EORTC QLQ-C30 global health status/ QoL scale from the 2nd cycle until the end of treatment/ observation compared to the baseline score. Results: Of 194 eligible pts, 185 pts chose treatment with FTD/TPI (median 3 cycles), while 9 pts decided to receive BSC only. Questionnaires from 109 pts receiving FTD/TPI and from 6 pts with BSC were evaluable for RR. The primary endpoint (RR) was 59.6% (95% CI 49.8 – 68.9) in FTD/TPI-treated pts and 50.0% (95% CI 11.8 – 88.2) in pts receiving BSC. Analysis of the extended follow-up period, demonstrated that RR was 67.0% (95% CI 57.3 – 75.7) in FTD/TPI-treated pts. In the FTD/TPI-group, median time to deterioration of HRQoL was 121 days ( n = 61; 95% CI 87 – 151) according to EORTC QLQ-C30 and 119 days ( n = 63; 95% CI 85 – 138) according to EQ-5D-5L. Conclusions: If pts can choose between treatment and BSC in late-stage CRC, the vast majority opts for treatment. According to the present results, FTD/TPI-treatment induced prolonged stabilization of HRQoL, a highly desired attribute of therapies for pts with late-stage cancer. Clinical trial information: No 2017-000292-83.
A panel of DNA methylation markers for the classification of consensus molecular subtypes 2 and 3 in patients with colorectal cancer.
Authors: van Den Berg Inge , Smid Marcel , Coebergh van den Braak Robert R.J. , van de Wiel Mark A , Van Deurzen Carolien H. M. , de Weerd Vanja , Martens John W.M. , IJzermans Jan N.M. , Wilting Saskia M
Published: June 2021

3545

Background: Consensus molecular subtypes (CMSs) can guide precision treatment of colorectal cancer (CRC). Currently available assays can identify CMS1 and CMS4 cases well, while a dedicated test to distinguish CMS2 and 3 is lacking. This study aimed to identify a panel of methylation markers to distinguish between CMS2 and 3 in patients with CRC. Methods: Fresh-frozen tumor tissue of 239 patients with stage I-III CRC was included. CMS classification was performed on RNA-seq data using the single-sample-prediction parameter from the “CMSclassifier” package. Methylation profiles were obtained using the Infinium HumanMethylation450 BeadChip. We performed adaptive group-regularised logistic ridge-regression with post-hoc group-weighted elastic net marker selection to build prediction models for classification of CMS2 and CMS3 based on 15, 10 or 5 markers. Data from TCGAwas used for validation. Results: Overall methylation profiles differed between CMS2 and CMS3. Group-regularisation of the probes was done based on their location either relative to a CpG island or relative to a gene present in the CMS classifier resulting in two different prediction models and subsequently different marker panels. For both panels, even when using only 5 markers, sensitivity, specificity, and accuracy were > 90%. Validation showed comparable performances. Conclusions: Our highly sensitive and specific methylation marker panel can be used to distinguish CMS2 and 3. This enables development of a qPCR DNA methylation assay in patients with CRC to provide a specific and non-invasive classification tool.
Impact of a metastatic site on circulating tumor DNA (ctDNA) analysis in patients (pts) with metastatic colorectal cancer (mCRC).
Authors: Bando Hideaki , Nakamura Yoshiaki , Taniguchi Hiroya , Shiozawa Manabu , Yasui Hisateru , Esaki Taito , Ohta Takashi , Denda Tadamichi , Satoh Taroh , Yamazaki Kentaro , Sunakawa Yu , Kato Takeshi , Goto Masahiro , Yuki Satoshi , Nishina Tomohiro , Oki Eiji , Shinozaki Eiji , Matsuhashi Nobuhisa , Hata Masayuki , Yoshino Takayuki
Published: June 2021

3554

Background: ctDNA genotyping has been used as an alternative to tissue genotyping for precision oncology. In mCRC, although low plasma RAS variant allelic frequencies (VAFs) and low concordance with tissue RAS tests have been reported in pts with lung-only metastasis (mets) (Kagawa Y. et al., Clin Cancer Res 2021), the association of ctDNA identified using the next-generation sequencing method with metastatic sites is still unknown. Methods: We investigated the association between metastatic site and ctDNA detection by using the Guardant360 (G360), a ctDNA assay which detects 74 gene alterations including mutations with the 95% of limit of detection of 0.2%, in mCRC pts with single organ mets in pts who had not received anti-EGFR therapy in the SCRUM-Japan GOZILA study. We also evaluated the correlations between the size/number of mets by CT and detected VAFs. Results: Of 1187 mCRC pts enrolled in GOZILA, 138 pts (49 with liver-only, 15 with lymph node-only, 27 with peritoneum-only, and 47 with lung-only mets) were eligible for this study. The concordance of RAS/ BRAF status between G360 and tissue in-vitro diagnostic tests were 93.9% in liver-only, 80.0% in lymph node-only, 56.0% in peritoneum-only, and 65.9% in lung-only mets. The median maximum VAF (maxVAF) corresponding to the highest ctDNA fraction and the median numbers of detected variants were 23.1% and 5 in liver-only, 6.0% and 5 in lymph node-only, 0.4% and 3 in peritoneum-only, and 0.4% and 3 in lung-only (all P<0.001, Kruskal-Wallis test). A few pts with liver-only (2.0%) and lymph node-only mets (13.3%) had a maxVAF of <0.2%, but maxVAF was more frequently <0.2% in pts with lung-only (27.7%) or peritoneum-only mets (29.6%), especially in those with lung-only mets <20 mm as the longest diameter and <20 lesions (69.2%) or with peritoneum-only mets <20 mm as the longest diameter (87.5%). Conclusions: Lung-only and peritoneum-only mets had significantly lower maxVAF and lower numbers of detected variants, suggesting lower detections of subclonal variants. To ensure the sufficient clinical performance in G360 assay, inclusion of pts with lung-only mets ≥20 mm of longest diameter and/or ≥20 lesions, and ≥20 mm of the longest diameter in pts with peritoneum-only mets may be required.[Table: see text]
Circulating tumor derived cell-free DNA (ctDNA) to predict recurrence of metastatic colorectal cancer (mCRC) following curative intent surgery or radiation.
Authors: Chee Bryant , Ibrahim Faaiz , Esquivel Mikaela , Van Seventer Emily E. , Jarnagin Joy X. , Zhang Li , Ju Jin Hyun , Price Kristin Sedgwick , Raymond Victoria M. , Corvera Carlos U. , Hirose Kenzo , Nakakura Eric K. , Van Loon Katherine , Corcoran Ryan Bruce , Parikh Aparna Raj , Atreya Chloe Evelyn
Published: June 2021

3565

Background: Over half of patients (pts) with oligometastatic CRC treated with curative intent surgery or radiotherapy experience cancer recurrence with or without adjuvant chemotherapy. ctDNA detection post-definitive treatment could identify high risk pts for additional intervention to eliminate molecular residual disease. Here we report results of a prospective observational study aiming to determine ctDNA detection rates using a sensitive liquid biopsy and to correlate post-procedure ctDNA detection (post-ctDNA (+)) with radiographic mCRC recurrence. Methods: Pts with mCRC intending to undergo a curative intent procedure were prospectively recruited at two US sites. ctDNA was collected pre-procedure, 3 weeks post-procedure, and at multiple structured follow-up timepoints. The presence of ctDNA was evaluated using a plasma-only integrated genomic and epigenomic assay (Guardant Reveal, Guardant Health). A bioinformatic classifier was applied to differentiate tumor derived versus non-tumor derived cell-free DNA. Results: Among 52 enrolled pts, post-ctDNA data is available for 45 pts (87%), with a median of 4 (range 1-10) timepoints per pt. The sample analysis failure rate was 1% (2/217). As of 1/1/2021, the radiographic recurrence rate was 60% with a median follow-up time of 50 (range 4-192) weeks. 23 of 25 pts with post-ctDNA(+) have had recurrence (Positive Predictive Value [PPV], 92%). On average, ctDNA was detected 28 weeks before radiographic recurrence (mean 12 vs. 40 weeks, respectively). The two pts with post-ctDNA(+) but no recurrence have > 3 years follow-up; one pt received adjuvant chemotherapy and cleared ctDNA. With a median event-free follow-up time of 97 (range 4-192) weeks, 4 of 20 pts with no post-ctDNA detection (-) have recurred (Negative Predictive Value, 80%). 3 of 4 pts with recurrence despite post-ctDNA(-) also were pre-ctDNA(-). We observed a sensitivity of 85% and a specificity of 89% for the ctDNA assay. The median time to radiographic recurrence was 36 wks for ctDNA(+) vs. not reached for ctDNA(-) (Hazard Ratio, 7.7; 95% CI, 2.6-22.5; P <.001). Conclusions: In mCRC pts undergoing curative intent surgery or radiotherapy, detection of ctDNA post-procedure had a high PPV for cancer recurrence, with a median lead time of 6 months compared to surveillance imaging. Thus, ctDNA holds promise as a biomarker for pt enrollment on clinical trials and as an endpoint for monitoring of response to experimental therapies in this oligometastatic CRC population.
Final results from the CAVE (cetuximab rechallenge plus avelumab) mCRC phase II trial: Skin toxicity as a predictor of clinical activity.
Authors: Martini Giulia , Napolitano Stefania , Famiglietti Vincenzo , De Braud Filippo G. , Terminiello Marinella , Borrelli Carola , Vitiello Pietro Paolo , Avallone Antonio , Normanno Nicola , Maiello Evaristo , Falcone Alfredo , Santabarbara Giuseppe , Pinto Carmine , Santini Daniele , Di Liello Alessandra , Renato Daniela , Esposito Lucia , Marrone Francesca , Troiani Teresa , Ciardiello Davide
Published: June 2021

3578

Background: Promising antitumor activity of so called rechallenge treatment with anti-epidermal growth factor receptor (EGFR) drugs in patients with RAS wild type (RAS WT) metastatic colorectal cancer (mCRC) has been recently reported. Beside the absence of resistance mutations at plasma circulating tumor DNA (ctDNA) analysis, no biomarkers of response to anti-EGFR rechallenge strategy have been identified. Methods: We conducted the single arm phase II CAVE mCRC trial to evaluate the combination of cetuximab as rechallenge plus avelumab treatment in 77 RAS WT mCRC patients, with complete (CR) or partial response (PR) to first line chemotherapy plus anti-EGFR drugs, who developed acquired resistance and received a subsequent line of therapy. A post-hoc baseline analysis of circulating tumor DNA (ctDNA) for KRAS, NRAS, BRAF and EGFR-S492R mutations was performed for 67/77 (87%) patients. The correlation of skin toxicity (ST) and other clinical variables with OS, PFS and response rate (RR) was assessed. Results: Cetuximab plus avelumab provided in the intention to treat population (ITT) median overall survival (mOS) of 11.6 months [95% Confidence Interval (CI), 8.4-14.8] and median PFS (mPFS) of 3.6 months (95% CI, 3.2-4.1) with a manageable toxicity profile. Thirty-three (42.9%) patients experienced grade 2-3 ST with mOS of 17.8 months (CI 95% 14.9-20.7), whereas 44 (57.1%) patients with grade 0-1 ST exhibited mOS of 8.2 months (CI 95% 5.6-11), (HR 0.51, CI 95% 0.29-0.89, P = 0.019). mPFS was 4.6 months (CI 95% 3.5-5.8) in patients with grade 2-3 ST, compared to 3.4 months (CI 95% 2.8-4.1) in patients with grade 0-1 ST (HR 0.49, CI 95% 0.3-0.8, P = 0.004). Grade 2-3 ST and baseline RAS/BRAF/EGFR WT ctDNA were the only variables with statistically significant effect on OS both at univariate and multivariate analyses. ST, number of metastatic sites ≤2, surgery of primary tumor and RAS/BRAF/EGFR WT ctDNA were associated with an improvement in PFS only at univariate analysis. In the 33 patients with grade 2-3 ST, 1 (3%) CR, 2 (6.1%) PR and 24 (72.7%) stable disease (SD) were observed, with disease control rate (DCR) of 81.8%. In the 44 patients with grade 0-1 ST 0 CR, 3 (6.8%) PR, 20 (45.5%) SD, with 52.3% DCR were reported. Conclusions: Cetuximab plus avelumab is effective and well tolerated as rechallenge treatment in mCRC. ST is a clinical biomarker for the identification of RAS/BRAF mCRC patients that could benefit from anti-EGFR rechallenge. Clinical trial information: NCT04561336.
Circulating tumor DNA and circumferential resection margin as key prognostic indicators for survival in rectal cancer.
Authors: Shepherdson Mia , Symonds Erin L. , Byrne Susan , Gormly Kirsten , Karapetis Christos Stelios , Vatandoust Sina , Young Graeme P. , Roy Amitesh Chandra
Published: June 2021

3579

Background: Recurrence of colorectal cancer has been linked to the presence of epigenetic circulating tumour DNA (ctDNA) in patient plasma after surgery. The prognostic significance of ctDNA prior to treatment remains unknown. This study investigated the correlation between pre-treatment ctDNA and current radiological (MRI) prognostic markers in patients with rectal cancer. Methods: Forty-two patients with rectal cancer were enrolled, with all having staging MRI prior to treatment. Plasma was taken for ctDNA at diagnosis. The presence of either methylated branched-chain amino acid transaminase 1 (BCAT1) or Ikaros family zinc finger (IKZF1) in cell-free DNA from plasma was deemed a positive ctDNA result. Correlation of MRI prognostic indicators and ctDNA results was assessed with chi-square tests. Univariable and multivariable cox regression analyses were performed to determine variables associated with overall survival (OS). Results: Mean age was 64.4 years (SD 12.5) and majority were male (30/42, 71.4%). 11, 13, 9 & 9 patients had stages I, II, III, IV respectively. Patients had a minimum follow-up of 36 months. Thirty-three (78.6%) patients received neoadjuvant chemoradiotherapy. 29 (69.0%) patients underwent surgical resection. 3-year survival rate was 64% in the overall group. 67% (n=28/42) of patients were positive for the methylated ctDNA at diagnosis. 11 out of 12 patients with a positive circumferential resection margin (CRM +) were ctDNA positive (p=0.03). Univariable analysis showed that prognostic indicators for OS were presence of extramural venous invasion (EMVI) (HR 3.0, 95% CI 1.1-8.4), CRM+ (HR 12.2, 95%CI 3.9-37.6), metastatic disease (HR 7.32, 95% CI 2.63-20.37) and ctDNA% methylation (HR 1.1, 95% CI 1.04-1.13) (Table 1). The presence of CRM+ and a positive ctDNA had a HR of 20.5 (95% CI 5.1-82.3). With multivariable analysis, including adjustment for age and EMVI, only CRM+/ctDNA+ variable was an independent predictor for poor survival (HR 20.2, 95% CI 4.5-90.9). Conclusions: In rectal cancer, almost all patients with CRM involvement have ctDNA, and these patients had the worst prognosis. Future studies with longitudinal ctDNA assessment pre and post treatment could potentially inform prognosis and help tailor patients’ treatment.[Table: see text]
Parameters associated with outcomes in pretreated MSI/dMMR metastatic colorectal cancer (mCRC) treated with immune checkpoint inhibitors (ICI): Subgroup analysis of a prospective cohort.
Authors: Colle Raphael , Cachanado Marine , Rousseau Alexandra , Svrcek Magali , Menu Yves , Cohen Romain , Andre Thierry
Published: June 2021

3580

Background: Immune checkpoint inhibitors (ICI) have demonstrated efficacy in patients (pts) with MSI/dMMR mCRC. We aimed to evaluate clinical, pathological and molecular factors associated with progression-free survival (PFS) and overall survival (OS) in ICI-treated pretreated mCRC patients (pts). Methods: Pts are drawn from a prospective cohort of all patients treated with ICI for MSI/dMMR mCRC at Saint-Antoine Hospital, Paris, France. All MSI/dMMR mCRC pts with disease progression after ≥ 1 prior systemic treatment (fluoropyrimidine and oxaliplatin or irinotecan ± targeted therapy) were included. MSI/dMMR status was centrally reviewed. Lynch syndrome or sporadic status was determined according to MMR gene germline mutational testing, MLH1 methylation status and BRAFV600E mutation. PFS and objective response rate (ORR) were assessed using iRECIST criteria. The impact of Lynch syndrome on PFS was analyzed apart from the multivariate analysis due to the interaction with the BRAFV600E mutation status. Results: Of 130 included pts, 66 received anti-PD1 alone, 1 anti-PDL1 alone and 63 anti-PD1 plus anti-CTLA4. 71% have had at least 2 prior lines of treatment. 33 patients (25%) have BRAFV600Emutation (mt) and 49 (38%) RASmt. The ORR for the whole population was 62.8 % IC95% [53.8; 71.1]. Median follow-up was 21.0 months, median PFS and OS were not reached. Results of PFS unadjusted and adjusted analysis are displayed in the table. BRAFV600E and RAS mutation were not associated with PFS and OS in multivariate analyses. After adjustment for the treatment type, Hazard Ratio (HR) for PFS between patients with proven Lynch syndrome (N=44) and patients with proven sporadic tumors (n= 44) was 0.57 (95%IC 0.26 -1.26). Conclusions: In this cohort, main known clinical, pathological and molecular factors do not influence the efficacy of ICI in pre-treated MSI/dMMR mCRC.[Table: see text]
Minimal residual disease by circulating tumor DNA analysis for colorectal cancer patients receiving radical surgery: An initial report from CIRCULATE-Japan.
Authors: Yukami Hiroki , Nakamura Yoshiaki , Watanabe Jun , Kotaka Masahito , Yamazaki Kentaro , Hirata Keiji , Emi Yasunori , Yokota Mitsuru , Kato Kentaro , Yamaguchi Tatsuro , Ikeda Masataka , Aleshin Alexey , Kotani Daisuke , Mishima Saori , Shirasu Hiromichi , Oki Eiji , Takemasa Ichiro , Kato Takeshi , Taniguchi Hiroya , Yoshino Takayuki
Published: June 2021

3608

Background: Circulating tumor DNA (ctDNA) analysis can be used to predict the risk of recurrence by detecting molecular residual disease (MRD) in patients with colorectal cancer (CRC). We are conducting a prospective observational study to monitor MRD status in patients with clinical stage II–IV or relapsed CRC amenable to radical surgical resection (GALAXY study), as part of the CIRCULATE-Japan, a nationwide ctDNA-guided precision adjuvant therapy project. Methods: Analysis of ctDNA is being performed at pre- and post-surgery timepoints and will continue periodically for up to 2 years using Signatera, a personalized, tumor-informed ctDNA assay that is designed to track 16 patient-specific somatic variants based on whole-exome sequencing of tumor tissue. The association of peri-operative ctDNA status with clinicopathological characteristics was investigated. Results: As of January 13, 2021, 941 patients have been enrolled in the GALAXY study, of which 400 patients had their pre-operative ctDNA status evaluated. Of the 400 patients, baseline ctDNA was detected in 92% (367/400) of the patients: consisting of 35 patients with pathological stage (pStage) I, 135 with pStage II, 152 with pStage III, and 78 with pStage IV or relapsed disease (pStage IV/R). Patient-specific Signatera assays targeting 16 variants were designed for 100% of the patients. Out of the 6400 designed variants 99.3% passed quality control in the plasma analysis and produced the final results. Among 4425 genes selected for 400 patients, 3330 genes were selected for only one patient, while TP53 was the most commonly selected in 113 patients (28%). Median ctDNA levels, measured in mean tumor molecules per mL of plasma and ctDNA detection rate, stratified by stage are presented in table. Positive ctDNA status post-surgery was significantly associated with advanced pStage, pT and pN, and lymphovascular invasion. Of the 13 patients with recurrence, 10 were detected with a positive ctDNA at 4-weeks post-surgery, before confirmation of recurrence by the radiological imaging. Conclusions: Preoperative ctDNA detection rates were observed to be in >90% in patients with pStage II–III by personalized ctDNA assay based on unique somatic variants, specific to each patient. ctDNA- based MRD detected post-surgery (4W) was significantly associated with certain known clinicopathological factors for recurrence with ctDNA positivity associated with a very short-term of recurrence. Clinical trial information: 000039205. [Table: see text]
hENT1 gene expression as a predictor of response to gemcitabine and nab-paclitaxel in advanced pancreatic cancer.
Authors: Perera Sheron , Jang Gun Ho , Zhang Amy , Denroche Robert Edward , Dodd Anna , Ramotar Stephanie , Hutchinson Shawn , Wang Yifan , Tehfe Mustapha , Ramjeesingh Ravi , Biagi James Joseph , Lam Bernard , Wilson Julie , Notta Faiyaz , Fischer Sandra , Zogopoulos George , Gallinger Steven , Grant Robert C , Knox Jennifer J. , O'Kane Grainne M.
Published: June 2021

4011

Background: Human equilibrative nucleoside transporter 1 (hENT1) belongs to a family of nucleoside transporters critical to entry of gemcitabine into cells. The prognostic and predictive characteristics of this biomarker in pancreatic ductal adenocarcinoma (PDAC) have primarily been evaluated by immunohistochemistry, with conflicting results. We explored the impact of hENT1 gene expression in the Comprehensive Molecular Characterization of Advanced Ductal Pancreas Adenocarcinoma for Better Treatment Selection (COMPASS) trial. Methods: Patients were enrolled on COMPASS from December 2015 to June 2020 and underwent a biopsy for whole genome sequencing (WGS) and RNA sequencing prior to first chemotherapy in the advanced setting. Biopsies underwent laser capture microdissection to enrich for tumour epithelium. Chemotherapy regimen was determined based on clinician preference. The cut-off thresholds for hENT1 expression were determined using the maximal chi-squared statistic. Response rates and overall survival (OS) were computed based on hENT1 expression and chemotherapy regimen. Results: 254 patients were included in the analyses with a median follow-up time of 18 months. 146 patients were treated with modified FOLFIRINOX (FFX), 104 with gemcitabine and nab-paclitaxel (GnP), and 16 received no systemic therapy. Based on gene expression levels, 133 patients were classified as hENT1 high and 121 as hENT1 low. hENT1 expression was significantly associated with the modified Moffitt classifier with higher expression seen in classical tumours (p < 0.001). In the entire cohort, median OS was 10.0 months in hENT1 high vs. 8.3 months in hENT1 low (adjusted HR 0.78, 95% confidence interval 0.59 - 1.03, p = 0.08). In patients receiving modified FFX, there was no difference in response rates (32% vs. 31%, p = 1.00) or OS (10.6 vs. 10.6 months, p = 0.94) between the hENT1 high and hENT1 low groups, respectively. However, in patient treated with GnP, response rates were significantly higher in hENT1 high patients compared to those with hENT1 low tumors (45% vs. 21%, p = 0.035). Median OS in this GnP treated cohort was 9.8 months in hENT1 high vs. 6.1 months hENT1 low (p = 0.003). In an interaction analysis, hENT was predictive of treatment response to GnP (p = 0.0002). Conclusions: Biomarkers predictive of response to GnP and FFX are urgently needed. Here we demonstrate that hENT1 gene expression is a predictor of response to GnP in advanced PDAC.
Gemcitabine (Gem) and nab-paclitaxel (NP) ± nivolumab (nivo) ± CD40 agonistic monoclonal antibody APX005M (sotigalimab), in patients (Pts) with untreated metastatic pancreatic adenocarcinoma (mPDAC): Phase (Ph) 2 final results.
Authors: O'Hara Mark H. , O'Reilly Eileen Mary , Wolff Robert A. , Wainberg Zev A. , Ko Andrew H. , Rahma Osama E. , Fisher George A. , Lyman Jaclyn Paige , Cabanski Christopher R. , Karakunnel Joyson Joseph , Gherardini Pier Federico , Kitch Lacey J. , Bucktrout Samantha , Christopher Elizabeth , Mick Rosemarie , Chen Richard , Trifan Ovidiu C. , Salvador Lisa , O'Donnell-Tormey Jill , Vonderheide Robert H.
Published: June 2021

4019

Background: Results from a ph1b trial evaluating gem/NP with CD40 agonistic monoclonal antibody APX005M ± nivo demonstrated promising clinical activity in pts with untreated mPDAC (O’Hara 2021). Herein, we report results from the follow-on, randomized (rand) ph2 trial evaluating gem/NP ± nivo ± APX005M. Methods: Pts with untreated mPDAC were rand to 1 of 3 open-label arms: gem/NP/nivo (A), gem/NP/APX005M (B), gem/NP/nivo/APX005M (C). All pts were treated with 1000 mg/m2 gem and 125 mg/m2 NP. Patients received 240 mg nivo in arms A and C and 0.3 mg/kg APX005M (RP2D) IV in arms B and C. Ph1b pts were included in ph2 analyses. 1° endpoint: 1-year OS rate of each arm, compared to a 35% historical OS rate for gem/NP (Von Hoff 2013). Key 2° endpoints: ORR, DCR, DOR, PFS and safety. Tumor and blood were collected for biomarker analysis. Planned enrollment of 35 pts/arm provided 81% power for testing the alternative of 58% OS rate vs 35%, using a 1-sided, 1-sample Z test with 5% type I error. Trial was not powered for cross-arm comparison. Results: 93 pts were rand in ph2 (N = 34, 30, 29 to A, B, C); when ph1b pts included, a total of 105 pts (34, 36, 35) were analyzed for efficacy and 108 pts (36, 37, 35) for safety. Min follow-up was 14 months (mos). Baseline characteristics were balanced across arms, inclusive of tumor burden, presence of liver metastases and stage at initial diagnosis (stage 1-3 vs 4). 1-year OS rate was 57% (1-sided p = 0.007 vs 35% historical rate, 95% lower CI bound = 41%) for A, 51% (p = 0.029, 95% bound = 36%) for B and 41% (p = 0.236, 95% bound = 27%) for C. Median OS and secondary endpoints are listed in Table. TRAE rates were similar across arms and to ph1b. 8 (7%) pts experienced an AE leading to tx discontinuation (6, 1, 1 in A, B, C), 40 (37%) pts experienced a serious TRAE (14, 15, 11 in A, B, C) and 2 pts died due to TRAEs; 1 each in B (acute hepatic failure) and C (intracranial hemorrhage). Conclusions: In this ongoing, seamless ph1b/2 trial of gem/NP ± nivo ± APX005M in pts with mPDAC, antitumor activity was observed in all arms. 1° endpoint of 1-year OS > 35% was met when combining gem/NP with either nivo or APX005M; however, not the combination. Safety was manageable; consistent with ph1b. Detailed multiomic immune and tumor biomarker analyses are underway to elucidate mechanisms of action and inform pt subsets that benefit most from these combinations. Clinical trial information: NCT03214250. [Table: see text]
Efficacy and safety of KN046 plus paclitaxel/cisplatin as first-line treatment for unresectable locally advanced, recurrent or metastatic esophageal squamous cell carcinoma (ESCC).
Authors: Xu Jianming , Liu Rongrui , Zhang Yanqiao , Xu Nong , Fan Qingxia , Gao Shegan , Pan Hongming , Cai Mingquan , Yan Dong , Liang Qianqian , Wu Qiong , Guo Baohong , Qi Yakun , Xu Ting
Published: June 2021

4062

Background: The prognosis of pts with advanced esophageal squamous cell carcinoma (ESCC) remains dismal clinically. Paclitaxel and cisplatin were used as the standard first-line regimen in ESCC for almost two decades. Recently, the combination of PD-1/PD-L1 pathway blockades with chemotherapy has shown synergistic efficacy in a few clinical trials. KN046 is the world's first dual immune checkpoint inhibitor, which can block PD-1/PD-L1 and CTLA-4 pathways at the same time. The purpose of this ongoing phase II trial (NCT03925870) in China was to evaluate the efficacy and safety of KN046 monotherapy or combined with chemotherapy for unresectable locally advanced, recurrent or metastatic ESCC. Methods: This trial included 3 cohorts, one of which enrolled systemic treatment naïve pts with histologically or cytologically confirmed unresectable locally advanced, recurrent or metastatic ESCC who have ECOG PS of 0-1. Eligible subjects were given paclitaxel (135-175mg/m2, iv, d1, q3w) and cisplatin (75mg/m2, iv, d2-4, q3w) plus KN046 (5mpk, iv, d1, q3w) for 4̃6 cycles during initial therapy. For those without progressive disease, maintenance treatment was administrated with KN046 monotherapy (5mpk, iv, q2w) until progression or unacceptable toxicity. Tumour response was assessed according to RECIST 1.1 every 6 weeks. The primary endpoint was investigator-assessed ORR. Secondary endpoints included DCR, safety, PK profile, and immunogenicity. Results: As of December 14, 2020, 15 pts were enrolled, all of them were male, 52.3% ≥60 years, 64% ECOG 1, 80% with distant metastasis. Median exposure time to KN046 was 11.4 wks and average KN046 treatment was 2.4 cycles. 12 pts were included in the efficacy analysis and 15 pts in the safety analysis. The overall response rate (ORR) and disease control rate (DCR) were 58.3% and 91.6%, respectively. 7 pts (58.3%) had partial response (PR) including one complete response of target lesion. 4 pts (33.3%) had stable disease (SD) with 3 pts showing more than 20% of tumor burden reduction. The overall incidence of KN046 related adverse events was 80.0%, with 13.3% Gr 3 or above TRAE. Infusion-related adverse events occurred during 7.8% and most were mild. Immune related adverse events（irAE）were seen in 53.3% and the most common Gr 3 irAE were nausea (n＝1, 6.7%) and rash (n＝1, 6.7%). Conclusions: KN046 plus paclitaxel/cisplatin demonstrated clinical efficacy and acceptable safety as first-line treatment, and might be a favorable option for pts with advanced ESCC. Clinical trial information: NCT03925870. Research Sponsor: Jiangsu Alphamab Biopharmaceuticals Co., Ltd. Clinical trial information: NCT03925870.
Update on overall survival (OS) of RESCUE: An open-label, phase 2 trial of camrelizumab (C) in combination with apatinib (A) in patients with advanced hepatocellular carcinoma (HCC).
Authors: Zhang Yun , Xu Jianming , Shen Jie , Gu Shanzhi , Wu Lihua , Wu Jian , Shao Guoliang , Zhang Yanqiao , Xu Li , Yin Tao , Liu Jingfeng , Ren Zhenggang , Xiong Jianping , Mao Xianhai , Zhang Ling , Yang Jiayin , Li Lequn , Chen Xiaoming , Wang Zhiming , Wang Quanren
Published: June 2021

4076

Background: C+A combination therapy displayed high objective response rate, disease control rate, and durable response with a manageable safety profile in patients (pts) with advanced HCC. Here we performed an updated analysis of OS to characterize the OS benefit of C+A in HCC pts. Methods: 70 pts in first-line cohort and 120 pts in second-line cohort were enrolled. Median OS and 2-year OS rate were evaluated via updated data (data cutoff, 3 January, 2021). Median time from enrollment to data cutoff of the total population (N = 190) was 29.1 months (range, 24.0-33.7). Results: OS events had occurred in 58.6% pts in first-line cohort and 60.0% pts in second-line cohort. The median OS was 20.1 months (95% CI, 14.9-NR) and 2-year OS rate was 43.3% (95% CI, 31.3-54.7) in first-line cohort. The median OS was 21.8 months (95% CI, 17.3-26.8) and 2-year OS rate was 44.6% (95% CI, 35.5-53.3) in second-line cohort. Conclusions: Long-term follow-up of C+A demonstrated remarkable survival benefit in advanced HCC pts, which further suggested that C+A is a promising combination therapy in advanced HCC pts. Clinical trial information: NCT03463876.