bluuebunny/crossref_metadata_2025 huggingface dataset:
In-depth immune and molecular profiling of melanoma patients receiving adoptive T-cell therapy reveals biomarkers of efficacy in ATATIL study.
Authors: Orcurto Angela , Chiffelle Johanna , Ghisoni Eleonora , Barras David , Crespo Isaac , Navarro Rodrigo Blanca , Ochoa de Olza María , Imbimbo Martina , Rusakiewicz Sylvie , Tissot Stephanie , Gannon Philippe O , Dafni Urania , Zimmermann Stefan , Kandalaft Lana E. , Michielin Olivier , Bassani-Sternberg Michal , Dangaj Denarda , Trueb Lionel , Harari Alexander , Coukos George
Published: June 2021

2533

Background: Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TIL) has demonstrated a curative potential for patients with metastatic melanoma (MM). Nevertheless, activity remains unsatisfactory in many patients, requiring development of biomarkers that predict therapeutic efficacy. We report results of a single-center phase I study to assess feasibility, safety and efficacy of TIL-ACT in MM patients (NCT03475134). Methods: Patients with MM refractory to at least one prior line of therapy received TIL therapy with lymphodepleting chemotherapy before T-cell infusion, followed by high-dose interleukin-2. RDG- and FDG-PET imaging was performed before and after TIL infusion. Multispectral immuno-fluorescence (mIF) imaging and bulk-RNA sequencing (Seq) were performed on tumor samples pre-ACT and post-ACT (day+30 and upon progression). Single-cell RNA-Seq and TCR-Seq were performed on pre-ACT tumor and ACT product, as well as on tumor-reactive and neoantigen-specific TILs and on longitudinal blood samples. Results: As of 02/02/2021, thirteen patients (enrolled between March 2018 and December 2020) have successfully completed TIL-ACT therapy, with a median follow-up of 9.5 months (IQR 3.0 -24.6). Median age was 53 years (range 20-69) and all were previously treated with PD-1 based blockade. Median number of TILs infused was 55.0 x109 cells (range 12.8-84.7). The best overall response rate by RECIST 1.1 and disease control rate in evaluable patients was 41.7% (5/12) and 50% (6/12) respectively at 3 months. Two patients have an ongoing near-complete response at 3 years. Up to data cut-off, 10 patients have progressed by RECIST v1.1, with median PFS of 4.8 months (95% CI 1.5 - 9.6), while median OS is not reached. mIF revealed biomarkers of response, which may allow proper identification of patients in subsequent studies. In addition, deep sequencing of bulk and neoepitope-specific TIL clonotypes highlighted transcriptomic signatures revealing cell programs regulating in vitro expansion, in vivo blood persistence as well as tumor infiltration post-ACT. RGD-PET data will also be presented. Conclusions: We demonstrate reproducibility of TIL-ACT in our center, consistently with previous reports. Comprehensive translational studies reveal immune correlates of clinical responses that contribute to the understanding of mechanisms of TIL potency and will guide the development of next-generation cell products. Clinical trial information: NCT03475134.
Progression prediction model for solid tumors with clinical and immunological parameters.
Authors: Novik Aleksei Viktorovich , Girdyuk Dmitrii Viktorovich , Nekhaeva Tatyana Leonidovna , Emelyanova Natalia Viktorovna , Semenova Anna , Teletaeva Gulfiya Midhatovna , Latipova Dilorom Khamidovna , Protsenko Svetlana , Baldueva Irina Alexandrovna
Published: June 2021

2539

Background: The immune system has well-known relation to tumor progression. Numerous immune-related parameters exist, but only a minor part could be used as biomarkers, especially dynamic ones. We trained a progression prediction model based on clinical features and peripheral immune system assessments. Methods: Patients with immunogenic (melanoma, 295, kidney cancer, 81), non-immunogenic (soft tissue sarcoma, 47, colorectal cancer, 26) and multiple primary tumors (29) with immunologic assessments before treatment (23.5%), on therapy (58.3), and in follow-up after the treatment (18.2%) were randomly divided in 7:3 ratio to the training and test groups. Counts of lymphocytes, T-, B, NK cells, cytotoxic lymphocytes, T-helpers were used as immunologic parameters. Age, sex, disease, stage, therapy, mutational status, last response on treatment, disease and therapy duration, previous treatments were used as clinical ones. The model was trained to predict disease progression in the next three months using “Catboost” gradient boosting. We used ROC AUC to test model performance and Yoden’s index for optimal cutoff calculation. We also studied the influence of model prediction on overall survival (OS) and time to progression (TTP) on the test dataset using the Kaplan-Meyer method and Cox regression. Results: We used 1682 assessments of immune parameters (immune status, IS) done in 354 patients (average 5 per patient) to train the model and 616 IS in 124 patients for validation. All IS of one patient were in the same group. The ROC AUC value of the model was 0.801. The model prediction of progression increased the probability of progressive disease from 37.5 to 62% and decreased the response rate from 37,5% to 8.4% (p = 0.016). The model prediction did not add information over known prognostic factors for OS in the multifactorial model but was an independent prognostic factor for TTP (HR 2.204, p = 0.011). False-positive results separate the group of patients with poor prognosis (OS 16 months, TTP 6 months) among patients with clinical benefit from patients with favorable prognosis (OS 61 months, TTP 18 months, p < 0.001), who had a truly negative model prediction. The possibility of prognosis improvement with therapy change was an essential factor for OS and TTP prediction (р < 0.001). The model was useful in predicting higher OS in patients with disease progression (p = 0.033) and shorter response duration in patients with clinical benefit (р = 0.03). Conclusions: Our progression prediction model provides clinically useful information and can be used for decision making in several clinical situations. Its utility should be tested in a prospective trial.
First-in-human dose escalation of ALPN-202, a conditional CD28 costimulator and dual checkpoint inhibitor, in advanced malignancies.
Authors: Moser Justin C , Voskoboynik Mark , Lakhani Nehal J. , Millward Michael , Davar Diwakar , Harb Wael A. , Yang Jing , Means Gary , Manjarrez Kristi , Tercero Almudena , Zayed Hany , Hillson Jan , Dela Cruz Christine , Perez Graciela Noemi , Peng Stanford L.
Published: June 2021

2547

Background: Strong preclinical rationale has emerged for combining checkpoint inhibition (CPI) with T cell costimulatory agonists, particularly CD28, a critical T cell costimulatory molecule recently recognized as a key target of checkpoint inhibition. ALPN-202 is a variant CD80 vIgD-Fc fusion that mediates PD-L1-dependent CD28 costimulation and inhibits the PD-L1 and CTLA-4 checkpoints. It has demonstrated superiority to CPI-only therapies in tumor models, while demonstrating favorable safety in preclinical toxicology studies. Methods: This is a cohort-based, open-label dose escalation and expansion study of ALPN-202 in adults with advanced solid tumors or lymphoma (NCT04186637). Subjects with cancers refractory to standard therapies (including approved CPIs), or cancers without available standard or curative therapy are eligible. After two planned single-subject cohorts, a standard 3+3 dose escalation has been implemented with two dose schedules in parallel, Q1W and Q3W. Objectives include evaluation of safety and tolerability, PK, PD and preliminary anticancer activity of ALPN-202. Disease assessments are evaluated by RECIST v1.1 for solid tumors or by Lugano Classification for lymphoma. Results: As of January 2021, 20 subjects with advanced malignancies have received ALPN-202. Dose-dependent PK and target saturation have been preliminarily observed. So far, ALPN-202 has been well tolerated at dose levels ranging from 0.001 to 1 mg/kg weekly, with no DLTs. Low-grade skin toxicities (grade 1-2 rash) have been observed in 4 subjects (20%). Among 11 evaluable subjects, an unconfirmed partial response has been observed in one subject with colorectal carcinoma, while stable disease has been observed in 5 subjects with colorectal carcinoma, mesothelioma (2), cholangiocarcinoma, and renal cell carcinoma -- for a preliminary clinical benefit (PR+SD) rate of 100% (4/4) at dose levels of 0.3 mg/kg and higher, or 54% (5/11) overall (table). The meeting presentation will update this data, which is expected to include the conclusion of Q1W dose escalation, as well as immune correlates. Conclusions: First-in-human dose escalation with ALPN-202 has been well tolerated at doses capable of engaging CD28 costimulation in vivo in association with dual PD-L1/CTLA-4 checkpoint inhibition, with early signs of anti-tumor activity. These findings suggest that CD28 agonism can be safely achieved in humans, and further suggest that dose expansion with ALPN-202 is warranted to assess the relevance of controlled CD28 costimulation as a novel approach to cancer immunotherapy. Clinical trial information: NCT04186637. [Table: see text]
Resetting the tumor microenvironment to favor anti-tumor immunity after local ablation.
Authors: Nief Corrine A. , Agudogo Júlia Sroda , Gonzales Alana , Previs Rebecca A. , Nair Smita K , Ramanujam Nimmi
Published: June 2021

2561

Background: Percutaneous tumor ablation is a non-surgical method of tumor destruction that leaves necrotic tumor debris in situ. Tumor associated antigens released after ablation have the potential to initiate a systemic anti-tumor immune response, however the hostile tumor microenvironment hinders antigen presentation and T cell activity. We hypothesized that resetting the tumor microenvironment with oral sodium bicarbonate to decrease tumor acidity and low-dose cyclophosphamide to deplete pro-tumor immune cells would improve the ability of ablation to initiate anti-tumor immunity. Methods: Tumor growth, overall survival, and metastatic burden was assessed in orthotopic tumor models of triple-negative breast cancer (67NR, 4T1, and E0771). Tumor ablation was performed on palpable tumors using percutaneous ethanol injection (PEI) with 6% ethylcellulose to improve retention in the tumor. Surgical excision was used as a negative control to test the role of in situ tumor debris. Before ablation mice were placed on 200 mM of sodium bicarbonate (SB) in their drinking water and received a single intraperitoneal injection of 200 mg/kg of cyclophosphamide (CP). Mice surviving to 60 days after tumor implant without a primary tumor or signs of metastases were considered "cured" and re-challenged with 50e5 tumor cells in the contralateral mammary pad. T cell dependance was assessed with in vivo CD8 depletions. Results: The combination of PEI+SB+CP produced a potent anti-tumor response, curing a majority of mice (5/7 of E0771, 8/12 of 67NR, 7/12 of 4T1). No mice were cured using PEI alone, SB alone, CP alone, or any combination of two therapies (0/51 of E0771, 0/73 of 67NR, 0/75 of 4T1,). Re-challenge tumor growth was hindered in mice cured with PEI+SB+CP. Mice receiving PEI+SB+CP had significantly less metastases and lived longer than mice receiving surgical excision alone or surgical excision with SB+CP. Additionally the anti-metastatic response of PEI+SB+CP was undone when CD8+ T cells were depleted. Conclusions: Here the anti-tumor response of local ablation produced by PEI was enhanced by priming the tumor with low-dose CP and oral SB in metastatic breast cancer. These results suggest that tumor ablation with CP and SB can create a T cell dependent, personalized immune response to a tumor using only low-cost, easily accessible supplies, and the host’s own tumor.
Phase 2 study of retifanlimab (INCMGA00012) in patients (pts) with selected solid tumors (POD1UM-203).
Authors: Maio Michele , Schenker Michael , Medioni Jacques , Mandziuk Slawomir , Majem Margarita , Gravis Gwenaelle , Cornfeld Mark J. , Ranganathan Sulabha , Yao Yubing , Yeh Howard Su-Hau , Csőszi Tibor
Published: June 2021

2571

Background: Checkpoint inhibitors (CPIs) are an effective treatment (tx) for many tumor types. Retifanlimab, an investigational humanized anti–PD-1 monoclonal antibody, has shown safety, pharmacology, and clinical activity consistent with the class. POD1UM-203 (NCT03679767) assessed efficacy and safety of retifanlimab in pts with selected solid tumors where CPI monotherapy is highly active. Methods: Eligible pts (≥18 y) had tx-naïve metastatic non-small cell lung cancer (NSCLC) with high PD-L1 expression (tumor proportion score ≥50%), cisplatin ineligible locally-advanced/metastatic urothelial cancer (UC) with PD-L1 expression (combined positive score ≥10%), unresectable/metastatic melanoma, or tx-naïve locally advanced/metastatic clear-cell renal cell carcinoma (RCC). Measurable disease (RECIST v1.1) was required. ECOG PS >1 and prior PD-1/PD-L1 directed tx were exclusions. Retifanlimab was administered as an IV infusion at 500 mg every 4 wks over 30 min. Primary endpoint was investigator-assessed objective response rate (ORR). Secondary endpoints were duration of response (DOR), disease control rate (DCR), progression-free survival, overall survival, safety, and pharmacokinetics. Results: A total of 121 pts (35 melanoma, 23 NSCLC, 29 UC, 34 RCC) received ≥1 dose of retifanlimab and were included in the analyses. Median duration of tx was 169 d (range, 1–442). The efficacy cut-off for the primary analysis occurred once all pts had been followed for at least 6 mo from the time of initial tx. Confirmed RECIST v1.1 responses were observed in all tumor types (Table) and were consistent with published ORR for other CPIs; median DOR was not reached for any tumor cohort and tx was ongoing at the time of data cutoff for 17, 11, 9, and 15 pts with melanoma, NSCLC, UC, and RCC, respectively. The most common tx-emergent AEs (TEAEs, >10% incidence) were asthenia (17.4%), arthralgia (14.9%), decreased appetite (14.0%), pruritus (12.4%), rash (10.7%), and urinary tract infection (10.7%); majority of TEAEs were low grade (≤ grade 2) and none led to tx discontinuation. Immune-related AEs occurred in 23 pts (19.0%), most common (>1% incidence) were hypothyroidism (7.4%), rash (4.1%), hyperthyroidism (2.5%), and pruritus (1.7%). Immune-related AEs led to dose delay in 5 pts (4.1%), but none led to tx discontinuation and/or dose interruption. Conclusions: Retifanlimab demonstrated antitumor activity and was generally well-tolerated in pts with melanoma, NSCLC, UC, or RCC comparable with approved CPIs for these tumor types. These results support ongoing further development of retifanlimab. Clinical trial information: NCT03679767. [Table: see text]
Phase Ia/Ib dose-escalation study of IBI110 (anti-LAG-3 mAb) as a single agent and in combination with sintilimab (anti-PD-1 mAb) in patients (pts) with advanced solid tumors.
Authors: Zhou Cai , He Yayi , Ren Shengxiang , Li Wei , Zhu Jun , Yu Jia , Wang Lei , Xiong Anwen , Xu Nong , Mao Chenyu , Pan Beiqing , Liu Ying , Zhou Hui
Published: June 2021

2589

Background: Lymphocyte-activation gene 3 (LAG-3) is an immune checkpoint receptor protein that functions to control T cell response, activation and growth. Dual inhibition of PD-1 and LAG-3 may improve anti-tumor effect synergistically. In this first-in-human dose-escalation study, we report the preliminary safety and anti-tumor activity of IBI110 ± sintilimab in pts with advanced solid tumors. Methods: Enrolled pts, ECOG PS 0-1, had locally advanced, recurrent or metastatic solid tumors for whom standard therapy had failed. Pts received escalating doses of IBI110 (0.01/0.1/0.3/1/3/10/20mg/kg) IV Q3W in phase Ia and escalating doses of IBI110 (0.3/0.7/1.5/3/5 mg/kg) in combination with sintilimab 200 mg IV Q3W in phase Ib. Crossover from mono to combo was allowed at progression. The objectives were safety and tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and anti-tumor activity of IBI110 alone or IBI110+sintilimab (per RECIST v1.1). Results: Phase Ia: 21 pts (median age: 62 yr [range 43-72]; ECOG PS: 0 [n = 11], 1 [n = 10]) were enrolled. Dose escalation has completed and no dose-limiting toxicity (DLT) was observed in all dose cohorts. The most common treatment-related adverse event (TRAE) was anaemia (19.0%). TRAEs ≥G3 included anaemia (4.8%), ascites (4.8%) and hepatic function abnormal (4.8%). By investigator-assessment, best response was 1 confirmed partial response (PR) (ovarian cancer, 3 mg/kg IBI110 single agent) and 5 stable disease (SD) in monotherapy. After crossing from mono to combo at progression, 5 pts were observed to have SD. Phase Ib: 12 pts (median age: 60 yr [range 33-72]; ECOG PS: 0 [n = 7], 1 [n = 5]) were enrolled. All dose cohorts in dose escalation except IBI110 5mg/kg+ sintilimab have completed DLT observation and no DLT was observed. The most common TRAE was AST increased (41.7%). TRAEs ≥G3 included hyperglycaemia (8.3%), bilirubin conjugated increased (8.3%) and hepatic function abnormal (8.3%). By investigator-assessment, best response was 2 PR (small cell lung cancer and endometrial cancer) and 6 SD. Conclusions: IBI110 alone or plus sintilimab has acceptable toxicity and shows preliminary antitumor activity. Clinical trial information: NCT04085185.
Interleukin-1-beta concentration and neutrophil-lymphocyte ratio as possible predicting biomarkers of response to therapy with checkpoint inhibitors.
Authors: Orlova Rashida , Zhukova Natalia V. , Malkova Anna , Kaledina Ekaterina , Gubal Anna , Sharoyko Vladimir
Published: June 2021

3024

Background: One of the discussed predictive markers of the immune therapy efficacy is the index of neutrophils to lymphocytes ratio in peripheral blood (NLr), which reflects the activity of adaptive immunity and correlates with the level of tumor-infiltrating lymphocytes (TILs). High NLr and low TILs are associated with disease progression. Interleukin-1-beta (IL-1β) is one of the main cytokines produced by the tumor microenvironment (TMO). Overexpression of the cytokine leads to a local immunosuppression. For some tumors, elevated serum IL-1β levels have been associated with a poor prognosis. The aim of this work is to analyze the serum IL-1β level as a marker of TMO activity and the NLr as a marker of adaptive immunity activity in relation to the response to therapy with checkpoint inhibitors in patients with various solid tumors. Methods: The study involved 63 patients with various solid tumors who were treated at the City Oncological Dispensary and were prescribed checkpoint inhibitors (nivolumab (n = 33), pembrolizumab (n = 23), ipilimumab + nivolumab (n = 7)). The determination of the level of IL-1β was performed using the ELISA method ("Interleukin-1-beta, ELISA-best", Novosibirsk), a clinical blood test was performed in a dispensary. The response to treatment was assessed 3-6 months after the start of therapy. Statistical analysis was carried out in GraphPad Prism. Results: Among the examined patients 49.21% (31/63) achieved partial regression or stabilization of the process (group I), and 50.79% (32/63) progressed (group II). The mean concentration of IL-1β before treatment in group I was 2.21±0.3 pg/ml, in group II - 0.98±0.2 pg/ml. NLr was increased in 7 patients from group I and in 9 patients from group II, with the mean index level being 2.9±0.39 and 3.2±0.5, respectively. There was no statistically significant difference in the concentration of IL-1β and the NLr between the studied groups. In group II, the number of patients undergoing systemic anticancer therapy before immune therapy (n = 18) was statistically significantly higher than in group I (n = 8), p = 0.033. There was no statistically significant difference in IL-1β concentration and NLr relative to previous treatment. Conclusions: Our study showed that the level of IL-1β corresponds to that of healthy donors and its isolated determination has no prognostic value. The NLr in most patients from the progression group was higher than normal, in contrast to group I, which is confirmed in the literature. The presence of previous systemic anticancer therapy was found to be associated with disease progression. The described feature can be explained by the fact that patients who received therapy before, already have a longer period of illness, a more severe clinical condition. The presence of systemic anticancer therapy does not affect the level of IL-1β and NLr.
Antibiotic use reduces efficacy of tyrosine kinase inhibitors in patients with advanced melanoma and non-small cell lung cancer.
Authors: Tinsley Nadina , Cook Natalie , Zhou Cong , Nahm Sharon Hyo-Eun , Rack Samuel , Tan Grace Chin Lay , Lorigan Paul , Blackhall Fiona Helen
Published: June 2021

3100

Background: Antibiotic (ABX) use and disruption of the gut microbiome has been demonstrated to reduce the efficacy of immune checkpoint inhibitors and chemotherapeutics in cancer patients. Little is known about the impact of ABX use in patients treated with targeted therapies, such as tyrosine kinase inhibitors (TKI). Methods: Retrospective data analysis was performed on advanced melanoma and non-small cell lung cancer (NSCLC) patients treated with TKIs between January 2015 and April 2017 at The Christie NHS Foundation Trust, UK. Demographics, prior systemic treatment, extent of disease, lactate dehydrogenase level (LDH), presence of brain metastases, performance status, comorbidities, TKI agent and the use of ABX (class, route, duration) were collected. Progression free survival (PFS) and overall survival (OS) were compared between the ABX+ group (defined as patients treated with ABX within 2 weeks of TKI initiation or 6 weeks after) and the ABX – group (patients with no ABX during specified period). Statistical analyses were performed with univariate and multivariable models. Results: In total, 168 patients were included; 89 patients (53%) with advanced NSCLC and 79 patients (47%) with melanoma. Over a third of patients, (57/168, 34%) received ABX in the specified period (ABX+). On univariable analysis, ABX use was associated with shorter PFS (208 days vs 357 days, p = 0.008) and OS (294 days vs 438 days, p = 0.024). Increased age, poorer performance status, and higher LDH were also associated with shorter PFS and OS. On multivariable analysis, ABX use was independently associated with shorter PFS (HR 1.57, 95% CI 1.05-2.34, p = 0.028) and OS (HR 2.19, 95% CI 1.44-3.32, p = 0.0002). The negative impact of ABX on OS was particularly pronounced for patients with worse performance status (HR 3.82, 95% CI 1.18-12.36, p = 0.025). Conclusions: To our knowledge, this is the largest multivariable analysis showing ABX use independently reduces PFS and OS in patients treated with TKIs. It is the first analysis to demonstrate this phenomenon across two distinct tumour sites. The data suggests that ABX use could be an independent predictor of shorter PFS and OS in cancer patients treated with TKIs, and warrants further validation in a larger cohort.
The genomic landscape of gene fusions across solid tumors and clinical outcome of targeted therapies: A real-world retrospective analysis.
Authors: Zhang Yumeng , Patel Bindiya G , Knepper Todd C , Chen Dung-Tsa , Gray Jhanelle Elaine , Hicks James Kevin
Published: June 2021

3132

Background: Oncogenic gene fusions can be observed across numerous solid tumor types with therapies targeting fusion events emerging as important treatment modalities. The occurrence of rare fusion events and response to targeted therapy inclusive of off-label drug use has not been fully elucidated. We describe a real-world (RW) landscape of gene fusions in solid tumors and treatment outcomes of targeted therapies. Methods: Patients with solid tumors harboring a gene fusion or rearrangement were retrospectively identified through review of a clinical molecular database housing sequencing data on 6,800 patients from a single-center between 1/1/2015 – 12/31/2019. Patients who received targeted therapy for gene fusions were divided into three arms: off-label, on-label, and clinical trial use. Clinical characteristics were summarized using descriptive statistics. Overall survival (OS) and Progression free survival (PFS) between the three arms were compared using the Kaplan-Meier estimates. Results: A total of 336 (4.9%) patients had a fusion positive solid tumor with 197 (2.9%) having a fusion event predicted to be oncogenic and could be targeted with a drug. Thirty different cancer types had targetable fusions with the three most common types being lung adenocarcinoma (41%), glioblastoma (10.2%), and melanoma (7.1%). The most common observed targetable fusions included ALK (21.3%), RET (11.7%), ROS1 (9.1%), and FGFR2 (8.1%). A total of 71 patients received targeted therapy; 37 (52%) received therapies on-label, 20 (28%) off-label, and 14 (20%) on-trial (Table). The median PFS was 4 months for off-label, 16 months for on-label, and 9 months for on trial-therapy (p=0.02). The median OS was 8 months for off-label, 51 months for on-label, and 11 months for on-trial therapy (p=0.001). Seven out of twenty patients (35%) in the off-label group had PFS for at least 6 months. Three patients had a response for more than one year. However, higher toxicity related discontinuation rate was observed (30%, 8%, 7% for off-label, on-label, and on-trial, p=0.03). Conclusions: Off-label targeted therapy had shorter PFS and OS when compared to on-label therapy. However, 35% patients in the off-label group had at least 6 months PFS. Off-label therapy remained a valuable option for patients who were not candidate for clinical trials or with rare fusions. Further studies are needed to determine which patients are most likely to benefit from targeting gene fusion events.[Table: see text]
HPV-mediated anal squamous cell carcinoma and precancerous lesions in HIV positive patients.
Authors: Bushara Omar , Finkelman Brian , Weinberg Sam , Krogh Katrina , Kalyan Aparna , Yang Guang-Yu
Published: June 2021

3520

Background: Anal cancer affects over 8,000 patients per year in the United States and the incidence is increasing. A significant risk factor for anal cancer and precancerous lesions is human papilloma virus (HPV), with up to 90% of cases being associated with HPV infection. Another emerging risk factor is HIV co-infection. In the present study, we further address if CD4 count is a significant factor for driving higher-grade HPV-mediated anal squamous lesions in HIV/HPV co-infection patients with a single institution large cohort. Methods: A retrospective cohort of HPV-positive patients with anal biopsies was obtained from 2002-2020. Information on the grade of their anal lesion, HIV status, and CD4 count (cells/mm3) were collected. In patients with HIV, the most recent CD4 count up to one year prior to or one month after their biopsy was utilized in our analysis. Lesions were grouped into low grade squamous intraepithelial lesions (LSIL) and higher grade squamous intraepithelial lesions (HSIL), carcinoma in situ (CIS), or squamous cell carcinoma (SCC). The Center for Disease Control CD4 count levels to define HIV status were utilized in our sub-analyses. The distribution of lesion grades was compared between HIV-negative and -positive patients, and between HIV-negative and three subgroups of HIV-positive patients using the Fisher’s exact test. Results: Our cohort comprised of 3,354 total HPV-positive patients. 2,036 of these patients were HIV-negative and 1318 were HIV-positive. The proportion of higher grade lesions was significantly higher in HIV/HPV co-infected patients regardless of CD4 count (Table). The full cohort of HIV-positive patients had lower rates of LSIL (60.8% vs. 74.0%) and higher rates of higher-grade lesions (39.2% vs. 26.0%) (p<0.001) compared to HIV-negative patients. The distribution of lesion grades was also significantly different between HIV-negative patients and all HIV-positive patient subgroups, with all subgroups having higher rates of higher-grade lesions than HIV-negative patients (all p<0.001). Conclusions: Our data show that HIV-HPV co-infection is a risk factor for higher grade anal lesions, regardless of CD4 status. This suggests that CD4 count is not the only factor responsible for the increased risk of higher-grade anal lesions, as the groups of HIV-positive patients with CD4 counts between 200-499 and above 499 still had a higher rate of higher-grade lesions than HIV-negative patients. Further research into other HIV-related immunologic changes that increase risk for higher-grade HPV-driven anal lesions is warranted.[Table: see text]
Impact of BRAF mutations on prognosis and immunotherapy response in microsatellite instability/mismatch repair deficient metastatic colorectal cancer: A systematic review and meta-analysis.
Authors: Park Robin , Lopes da Silva Laércio , Lee Sunggon , Saeed Anwaar
Published: June 2021

3557

Background: Mismatch repair deficient/microsatellite instability high (dMMR/MSI-H) colorectal cancer (CRC) defines a molecular subtype with distinct clinicopathologic characteristics including an excellent response to immunotherapy. Although BRAF mutations are established as a negative prognostic marker in CRC, whether they retain their negative prognostic impact in or alter the response to immunotherapy in dMMR/MSI-H CRC remains unknown. Herein, we present a systematic review and meta-analysis of the impact of BRAF mutations on the overall survival (OS) and immune checkpoint inhibitor (ICI) response in dMMR/MSI-H CRC. Methods: Studies published from inception to 26 January 2021 were searched in PubMed, Embase, and major conference proceedings (AACR, ASCO, and ESMO). Eligible studies included the following: 1) observational studies reporting outcomes based on BRAF mutation status in dMMR/MSI-H CRC patients and 2) experimental studies of ICI reporting outcomes based on BRAF mutation status in dMMR/MSI-H CRC patients. A summary hazard ratio (HR) was calculated for OS in BRAF mutated ( BRAFmut) vs. BRAF wild type ( BRAFwt) patients (pts) with the random effects meta-analysis (REM). A summary odds ratio (OR) was calculated for objective response rate (ORR) in BRAFmut vs. BRAFwt pts treated with ICI with the REM. Results: Database search conducted according to PRISMA guidelines found 4221 studies in total. Initial screening identified 30 studies and after full-text review, 9 studies (N = 4158 pts) were included for the meta-analysis of prognosis (analysis A) and 3 studies (N = 178 pts) were included for the meta-analysis of ICI response (analysis B). The outcome measures are summarized in the table below. Analysis A showed that in stage I-IV dMMR/MSI-H CRC pts, BRAFmut was associated with worse OS than BRAFwt (HR 1.57, 1.23-1.99). The heterogeneity was low (I2 = 21%). Subgroup analysis showed no significant difference in the prognostic impact of BRAF mutation status between stage IV only and stage I-IV CRC pts. Analysis B showed no difference in ORR (OR 1.04, 0.48-2.25) between BRAFmut vs. BRAFwt dMMR/MSI-H pts who received ICI. The heterogeneity was low (I2 = 0%). Conclusions: BRAF mutations retain their negative prognostic impact in dMMR/MSI-H stage I-IV and stage IV CRC but are not associated with differential ICI response. Limitations include the following: analysis A was based on retrospective studies; also, the impact of BRAF status on the survival outcome of ICI could not be assessed due to limited number of studies.[Table: see text]
Dietary fat in relation to overall and progression-free survival among patients (pts) with advanced or metastatic colorectal cancer (CRC): Data from CALGB 80405 (Alliance).
Authors: Van Blarigan Erin , Ma Chao , Ou Fang-Shu , Venook Alan P. , Ng Kimmie , Niedzwiecki Donna , Giovannucci Edward L. , Lenz Heinz-Josef , Innocenti Federico , Shaw James Edward , Polite Blase N. , Hochster Howard S. , Goldberg Richard M. , Mayer Robert J. , O'Reilly Eileen Mary , Fuchs Charles S. , Meyerhardt Jeffrey A.
Published: June 2021

3588

Background: Growing data suggest dietary factors are associated with survival among pts with non-metastatic CRC. However, data on diet and survival among pts with advanced or metastatic disease are very limited. Methods: We prospectively examined dietary fat intake assessed at initiation of treatment for advanced or metastatic CRC in relation to OS and PFS. This analysis was conducted among 1,149 pts in the CALGB 80405 randomized controlled trial who completed a validated food frequency questionnaire. We examined intakes of saturated, monounsaturated, and polyunsaturated (total n-3, long-chain n-3, and total n-6) fats as well as animal and vegetable fats. Based on data from non-metastatic CRC and other cancers, we hypothesized that higher intakes of long-chain n-3 fatty acids and vegetable fats would be associated with longer OS and PFS and higher intakes of saturated fat and animal fat would be associated with shorter OS and PFS. We used Cox proportional hazards regression to estimate adjusted hazard ratios (HR) and 95% confidence intervals (CI). Results: Over a median follow-up of 6.1 years [y; interquartile range (IQR): 5.3, 7.2 y], we observed 974 deaths and 103 events of progression without death during follow-up. Participants in this analysis had a median age of 59 y (IQR: 51 to 67 y); 41% were female and 86% identified as white. We observed no statistically significant associations between any type of dietary fat and OS. However, vegetable fat was non-linearly associated with longer PFS (HR comparing 4th to 1st quartile: 0.78; 95% CI: 0.64, 0.96; p-trend: 0.10). We also observed a linear association between continuous saturated fat and PFS (HR per 5% kcal/d: 1.21; 95% CI: 1.03, 1.42; p-value: 0.02), perhaps driven by pts with high saturated fat intake. Conclusions: We observed no statistically significant associations between types of dietary fat and OS among pts with advanced or metastatic CRC. However, a healthy diet that includes vegetable fat and is modest in saturated fat may be associated with longer PFS. Future studies to replicate these findings and examine diet in relation to cancer survival in racially/ethnically diverse populations are needed. Support: K07CA197077, U10CA180821, U10CA180882, https://acknowledgments.alliancefound.org . Clinical trial information: NCT00265850.
Preoperative chemoradiotherapy to improve overall survival in pancreatic cancer: Long-term results of the multicenter randomized phase III PREOPANC trial.
Authors: Van Eijck Casper H.J. , Versteijne Eva , Suker Mustafa , Groothuis Karin , Besselink Marc G.H. , Busch Olivier R.C. , Bonsing Bert A. , Groot Koerkamp Bas , de Hingh Ignace H.J.T. , Festen Sebastiaan , Patijn Gijs A. , de Vos-Geelen Judith , Zwinderman Aeilko H. , Punt Cornelis J. A. , van Tienhoven Geertjan ,   Dutch Pancreatic Cancer Group
Published: June 2021

4016

Background: Preoperative chemoradiotherapy (CRT) may improve overall survival in resectable pancreatic cancer (RPC) and borderline resectable pancreatic cancer (BRPC). Long term results are presented. Methods: In this multicenter phase III trial, patients with RPC or BRPC were randomized between preoperative CRT, (gemcitabine 1000 mg/m2 weekly for 7 of 10 weeks, and 15x2.4 Gy radiotherapy in week 4 to 6), followed by surgery and four cycles of adjuvant gemcitabine (1000 mg/m2 weekly for 3 of 4 weeks), or immediate surgery followed by 6 cycles of adjuvant gemcitabine (1000 mg/m2 weekly for 3 of 4 weeks). Primary endpoint was overall survival by intention-to-treat (ITT). Results: From April 2013 to July 2017, 246 eligible patients were accrued by 16 Dutch centers and randomized, 119 to preoperative CRT and 127 to immediate surgery. After a median follow up of 56 months (35.3-92.0 months), 210 patients have died, 93 (78%) in the preoperative CRT arm and 117 (92%) in the immediate surgery arm. Three- and five-year overall survival ITT was 27.7% and 20.5% after preoperative CRT versus 16.5% and 6.5% after immediate surgery (HR 0.73; 95% CI 0.56 to 0.96; p = 0.025). In addition, disease-free survival (HR 0.70; p = 0.009) locoregional failure-free interval (HR 0.57; p = 0.004) and distant metastases free interval (HR 0.74; p = 0.071) improved after preoperative CRT. Also in the stratified subsets RPC and BRPC, preoperative CRT improved OS: RPC (n = 133, HR 0.79; 95% CI 0.54 to 1.16; P = 0.23). BRPC (n = 113, HR 0.67; 95% CI 0.45 to 0.99; p = 0.045). We could not demonstrate a difference in treatment effect between these subsets (interaction test p = 0.56). Conclusions: Preoperative gemcitabine-based CRT for RPC or BRPC improves long term overall survival compared to immediate surgery with adjuvant gemcitabine. Clinical trial information: NTR3709.
Randomized phase II study comparing docetaxel versus paclitaxel in patients with esophageal squamous cell carcinoma who are refractory to fluoropyrimidine and platinum-based chemotherapy: OGSG1201.
Authors: Kii Takayuki , Yamamoto Sachiko , Hara Hiroki , Kawabata Ryohei , Kawada Junji , Takeno Atsushi , Matsuyama Jin , Ueda Shugo , Kawakami Hisato , Okita Yoshihiro , Endo Shunji , Kimura Yutaka , Yanagihara Kazuhiro , Okuno Tatsuya , Shimokawa Toshio , Satoh Taroh
Published: June 2021

4037

Background: Fluoropyrimidine and platinum-based chemotherapy are considered first-line therapy options for patients with unresectable advanced or recurrent metastatic esophageal squamous cell carcinoma(ESCC). After fluoropyrimidine and platinum-based chemotherapy is failed, taxanes (docetaxel(DTX) and paclitaxel(PTX)) was mainly used as a second-line treatment for ESCC. Therefore, we conducted a trial to compare DTX and PTX in patients with unresectable advanced or recurrent ESCC who were failed to previous fluoropyrimidine and platinum-based chemotherapy. Methods: We did a randomized, an open-labeled and multicentre phase 2 study. Inclusion criteria included age 20 to 80 years with unresectable advanced or recurrent ESCC, Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1. Patients who were refractory to fluoropyrimidine and platinum-based chemotherapy. Treatment consisted of DTX 70 mg/m2 repeated every 21 days or PTX 100 mg/m2 once weekly on days 1, 8, 15, 22, 29, and 36 of a 49-day cycle. Results: 80 patients were enrolled between May 2012 and April 2019. 41 patients received DTX and 39 patients received PTX. After assessment of eligibility, two patients proved uneligible (one for double cancer, one for contraindication to DTX) and were excluded from the analysis. But, 80 patients were evaluable for the toxicity analyses. A median follow-up time was 32 months. Overall survival was significantly longer in the PTX group than in the DTX group (median, 8.8 months vs. 7.3 months; hazard ratio, 0.62; 95% CI, 0.38 to 0.9998; P = 0.047). The median progression-free survival was significantly longer in the PTX group than in the DTX group (median, 4.4 months vs. 2.1 months; hazard ratio, 0.49; 95% CI, 0.30 to 0.78; P = 0.002). The median time to treatment failure was significantly longer in the PTX group than in the DTX group (median, 3.8 months vs. 2.1 months; hazard ratio, 0.45; 95% CI, 0.28 to 0.73; P＜0.001). The most common adverse events of grade 3 or higher were a decreased neutrophil count (in 28% of the PTX group and in 80% of the DTX group). Febrile neutropenia was also more frequent in the DTX group than the PTX group (46％ vs. 0%). There was one death from sudden death in which treatment-related mortality could not be ruled out. Conclusions: Secound-line treatment with PTX, as compared with DTX, reduced the risk of ESCC. Clinical trial information: UMIN000007940.
Real-world data (RWD) reveals benefit for adjuvant chemotherapy with docetaxel, oxaliplatin and fluorouracil/leucovorin (FLOT) is limited to those with tumour regression grade (TRG) ≥3 in oesophago-gastric cancer (OGC).
Authors: Hapuarachi Brindley Sonal , Lee Rebecca , Khan Adeel , Woodhouse Laura , Kounnis Valentinos , Britton Fiona , Coyle Jessica , Connors Kathleen , Billy Graham Mariam Neethu , Weaver Jamie , Waddell Tom , Hubner Richard , Kamposioras Konstantinos , Mansoor Wasat
Published: June 2021

4039

Background: Despite potentially curative surgery, long-term survival from OGC remains poor due to high relapse rate. Neoadjuvant (naFLOT) and adjuvant (aFLOT) FLOT is currently standard treatment for resectable OGC based on data from the FLOT-4 trial. We explored whether TRG was associated with FLOT-outcome using RWD. Methods: Pts with OGC treated with naFLOT +/- aFLOT at a tertiary UK centre were identified following institutional board approval. Clinical and laboratory data were extracted from the patient record. TRG was evaluated by a histopathologist. Median overall survival (OS) and median progression-free survival (PFS) were evaluated using Kaplan-Meier and Log-rank tests; time taken from start of naFLOT, and associations between factors with Fisher’s exact (FE) test. Results: 171 pts were identified, median FU 30 mths. 144 (84%) male; median age 66 (32-84); oesophagus 66 (38%), junctional (GOJ) 73 (43%), gastric 32 (19%); stage IB 3 (2%), stage IIB 26 (15%), stage III 91 (53%), stage IVA 47 (28%) and unknown 4 (2%). Pts had median of 2 comorbidities (range 0-6); performance status (PS) 0: 95 (56%), PS 1: 71 (41%), PS 2: 3 (2%) and PS unknown 2 (1%). 132/171 pts completed 4 cycles of naFLOT and this was significantly associated with undergoing surgery (p = 0.02). Those who had surgery (140/171) had significantly improved PFS (not reached (NR) vs. 6 mths; 95% CI 2-10; p < 0.001) and OS (NR vs. 12 mths; 95% CI 6-18; p < 0.001). TRG was reported for 126/140 patients who underwent surgery. TRG 1/2 (42/126) vs. TRG ≥3 was significantly associated with improved PFS (NR vs. 35 mths; 95% CI NR; p < 0.001) and OS (median NR either group; p < 0.001). Pts with TRG 1/2 who commenced aFLOT (≥1 cycle; n = 31/42) or completed 4 cycles of aFLOT (17/31) did not have improved PFS or OS vs. those who did not. Those with TRG ≥3 who commenced aFLOT (≥1 cycle; n = 62/85) had improved PFS (median NR vs. 22 mths; 95% CI 13-31 p = 0.006) and OS (median NR vs. 25 mths; 95% CI 18-32 p = 0.019). Those with TRG ≥3 who completed 4 cycles of aFLOT (n = 38/62) had significantly improved PFS (median NR vs. 25 mths; 95% CI 14-36 p = 0.016) and OS (median NR vs. 36 mths; 95% CI 16-55 p = 0.012). There was no difference in PFS or OS in pts with TRG ≥3 who had a dose reduction at any time during aFLOT. Conclusions: TRG is a predictor of outcome following naFLOT + surgery with superior outcomes in those with TRG 1/2. Our analyses suggest that only pts with TRG >3 following naFLOT + surgery benefit from adjuvant FLOT. Prospective randomised studies are required to confirm whether pts with TRG 1/2 require treatment with aFLOT.
Long-term quality of life and nutritional results after laparoscopic sentinel node navigation surgery versus laparoscopic standard gastrectomy for early gastric cancer: Secondary outcomes of a multicenter, randomized phase 3 trial (SENORITA).
Authors: Eom Bang Wool , Yoon Hong Man , Kim Young-Woo , Min Jae Seok , An Ji Yeong , Hur Hoon , Lee Young-Joon , Cho Gyu Seok , Park Young-Kyu , Jung Mi Ran , Park Ji-Ho , Hyung Woo Jin , Jeong Sang-Ho , Kook Myeong-Cherl , Han Mira , Nam Byung-Ho , Ryu Keun Won
Published: June 2021

4054

Background: Laparoscopic sentinel node navigation surgery (LSNNS) has been suggested as an alternative to laparoscopic standard gastrectomy (LSG) in early gastric cancer patients to improve long-term quality of life (QOL) and nutritional outcomes. Here, we present 3-year results of patient-reported quality of life (QOL) and nutrition, secondary endpoints of SENORITA trial. Methods: SENORITA is a prospective multicenter randomized phase 3 trial. Patients diagnosed with early gastric cancer of 3 cm or less were randomly allocated (1:1) to LSNNS for stomach preservation or LSG. The primary endpoint was 3-year disease-free survival. In this study, we analyzed QOL assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and EORTC stomach module (STO22) and nutritional parameters at 3, 12, 24, and 36 months after surgery. Linear mixed model analyses was used to evaluate differences between the two groups. This trial is registered with ClinicalTrials.gov, NCT01804998. Results: From March 2013 to March 2017, a total of 580 patients were randomly assigned and 527 patients were included in the modified intention-to-treat analysis population (258 in LSNNS and 269 in LSG group). QOL questionnaires were available for 99.4% of patients at baseline and then for 92.2%, 83.2%, 72.8%, and 66.9% at 3, 12, 24, and 36 months after surgery, respectively. The LSNNS group had higher physical function score than the LSG group at all time points (p = 0.002). However, there were no significant differences in other scales of EORTC QLQ-C30. Regarding EORTC QLQ-STO22, pain, eating restriction, anxiety, and taste scores were lower (better QOL) at all time points in the LSNNS group than in the LSG group (p = 0.002, < 0.001, < 0.001, and < 0.001, respectively). The summary score of EORTC QLQ-STO22 was also higher in the LSNNS group representing better QOL (p < 0.001). Body mass index, hemoglobin and total protein were significantly higher in the LSNNS group compared with the LSG group. Conclusions: The LSNNS group had better physical function and less symptoms, including pain, eating restriction, anxiety, and taste change compared with the LSG group. Moreover, the nutritional parameters were better maintained in the LSNNS group than in the LSG group. These findings showed benefits of stomach preserving surgery in LSNNS and can be used to help decision making about treatment for patients with early gastric cancer. Clinical trial information: NCT01804998.
Association of cell-free DNA dominant clone allele frequency with poor outcomes in advanced biliary cancers treated with platinum-based chemotherapy.
Authors: Majeed Umair , Uson Junior Pedro Luiz Serrano , Yin Jun , Sonbol Mohamad Bassam , Ahn Daniel H. , Bekaii-Saab Tanios S. , Starr Jason S. , Jones Jeremy C , Inabinett Samantha R , Wylie Natasha , Boyle Ashton WR , Borad Mitesh J. , Mody Kabir
Published: June 2021

4079

Background: Cell-free circulating tumor DNA (ctDNA) holds significant promise and is being used for clinical decision making in multiple tumors. This study aimed to evaluate the prognostic value of pre-treatment ctDNA in metastatic biliary tract cancers (BTC) treated with platinum based first-line chemotherapy treatment. Methods: We performed a retrospective analysis of 67 patients who underwent ctDNA testing before platinum-based chemotherapy for first-line treatment for metastatic BTC. For analysis we considered the detected gene with highest variant allele frequency (VAF). Results of ctDNA analysis were correlated with patients’ demographics, progression-free survival (PFS) and overall survival (OS). Results: The median age of patients was 67 y/o (27-90). 54 (80.6%) of 67 patients evaluated had intrahepatic cholangiocarcinoma; seven had extrahepatic cholangiocarcinoma and six gallbladder cancer. 46 (68.6%) of the patients were treated with cisplatin plus gemcitabine, 14 (21%) patients received gemcitabine and other platinum (carboplatin or oxaliplatin) combinations while 7 (10.4%) patients were treated on a clinical trial with gemcitabine and cisplatin plus additional targeted agents (CX4945 or PEGPH20). TP53, KRAS, APC, FGFR2 and IDH1 were the genes with highest frequency as dominant clone. The median dominant clone allele frequency (DCAF) was 3% (0-97%). DCAF >3% was associated with statistically significant worse PFS (median PFS: 4.05 vs. 7.70 months, p=0.046) and OS (median OS: 10.8 vs. 18.8 months, p=0.056). Each 1% increase in DCAF is associated with a hazard ratio of 26.21 in OS when adjusting for subtypes, age, treatment type, and CA19-9 [Table]. Conclusions: Patients with metastatic BTC with DCAF > 3% at diagnosis have worse PFS and OS compared to patients with low ctDNA when treated with upfront platinum-based chemotherapy.[Table: see text]