bluuebunny/crossref_metadata_2025 huggingface dataset:
Activity of daily living of elderly patients with gastric cancer after surgery.
Authors: Okuyama Ayako , Mizutani Tomonori , Hamaguchi Tetsuya , Higashi Takahiro , Ogawa Asao
Published: June 2021

6588

Background: Elderly patients are concerned with the physical burden of cancer treatments. This study aimed at investigating the reduction of the activity of daily living (ADL), length of hospital stay and readmission rate after surgery for gastric cancer. Methods: Insurance claim data linked with hospital-based cancer registries in Japan for gastric cancer patients diagnosed in 2015 from 431 hospitals was used. This data is expected to cover 49.0% of new cancer cases in Japan. To compare the effect of the treatment by age group, we analyzed the reduction of ADL between admission and discharge, length of hospital stay and readmission rate after endoscopic submucosal dissection (ESD) or endoscopic mucosal resection (EMR) for patients with cT1N0M0, and open surgery for patients with cM0. Patients who aged 40 years or older with independent ADL at admission for their first-course treatment was included. ADL was assessed using Barthel index (0-100 points). ADL decrease by 10 points or more was identified as ADL reduction. Results: Overall, 25,521 patients receiving ESD/EMR and 10,527 patients receiving open surgery were identified. ADL reduction after ESD or EMR under 80 years old was less than 1%, while over 80 years old ADL reduction was more than 2.5%. Length of hospital stay (11 days) and unexpected readmission rate (2 to 3 %) was almost similar. ADL reduction after open surgery under 75 years old was less than 3%. This reduction rates have increased with age, 11.5% for over 85 years old. Length of hospital stay also tended to increase by age (21 days for under 65 years old, 29 days for over 85 years old). Unexpected readmission rate for over or 80 years old (1.4%) was slightly higher under 80 years old (less than 1%). Conclusions: The effect of ADL reduction after ESD/EMR was not so significant for patients over 80 years old. While ADL reduction after open surgery tended to increase for aged 80 years and older. Providing these information to elderly patients and their families can be important in deciding treatment options.[Table: see text]
Measurable residual disease response in acute myeloid leukemia treated with venetoclax and azacitidine.
Authors: Pratz Keith , Jonas Brian Andrew , Pullarkat Vinod , Recher Christian , Schuh Andre C. , Thirman Michael J. , Garcia Jacqueline Suen , Dinardo Courtney Denton , Vorobyev Vladimir , Fracchiolla Nicola , Yeh Su-Peng , Jang Jun Ho , Ozcan Muhit , Yamamoto Kazuhito , Illes Arpad , Zhou Ying , Dail Monique , Chyla Brenda , Potluri Jalaja , Dohner Hartmut
Published: June 2021

7018

Background: In the phase 3 VIALE-A trial, rates of composite complete remission (CRc; complete remission [CR] + CR with incomplete hematologic recovery [CRi]) and measurable residual disease response (MRD<10-3) were higher in patients (pts) treated with venetoclax (Ven) + azacitidine (Aza) compared to Aza alone (23.4%/7.6%, p<0.001). There is limited evidence of the clinical significance of MRD monitoring in pts receiving low-intensity chemotherapy. Herein, we explored the outcomes of pts treated with Ven+Aza who achieved both CRc and MRD<10-3 in the VIALE-A trial (NCT02993523). Methods: Enrolled pts were ≥18 years and unfit for intensive chemotherapy. Pts received Ven 400 mg orally; days 1–28 and Aza 75 mg/m2; days 1-7/28-day cycle. Bone marrow aspirate samples for multiparametric flow cytometry assessments by integrated leukemia-associated immunophenotypes and different than normal procedures were collected for central analysis (Covance Central Laboratory Services) at baseline, end of cycle 1, and every 3 cycles thereafter. Assessments were performed independent of disease responses. MRD response was defined as <1 residual blast /1000 leukocytes (<10-3). CRc, DoR, OS, and EFS were assessed. Disease assessments were per modified International Working Group response criteria for AML. Results: 211/286 (74%) pts treated with Ven+Aza with at least one valid post-baseline MRD assessment were considered MRD evaluable; 78/211 (37%) achieved MRD<10-3 and 133/211 (63%) had MRD≥10-3. Median age (MRD<10-3/ MRD≥10-3) was 76 (range: 49-89)/77 (58-91) yrs. Pts (MRD<10-3/ MRD≥10-3) received median of 14.5 (range: 1-28) /7.0 (1-30) cycles of Ven+Aza. At median follow-up of 22.0 (range: 20.1-23.0)/20.8 (19.8-22.3) months (mos), CRc + MRD<10-3/ MRD≥10-3 was achieved by 67 (86%)/ 97 (73%); 20/67 (30%) achieved CRc + MRD<10-3 by end of cycle 1. Median DoR, OS, and EFS were not reached in pts with CRc + MRD<10-3 response (Table). The 12-mo estimates for DoR, OS, and EFS for pts with CRc + MRD<10-3response were 81.2%, 94.0%, and 83.2%, respectively. Adverse events ≥grade 3 (MRD<10-3/ MRD≥10-3) were febrile neutropenia (50%/43%), neutropenia (50%/35%), and thrombocytopenia (44%/44%), similar to the overall population. Conclusions: Pts with best response of CRc who achieved MRD<10-3 response with Ven+Aza treatment had longer DoR, OS, and EFS than pts who were CRc and MRD positive. Clinical trial information: NCT02993523. [Table: see text]
Distress in a pandemic: The association of the coronavirus disease-2019 (COVID-19) pandemic with distress and quality of life in hematopoietic stem cell transplantation (HSCT).
Authors: Amonoo Hermioni L. , Topping Carlisle E. W. , Clay Madison A. , LeBlanc Thomas William , Greer Joseph A. , Lee Stephanie , Temel Jennifer , El-Jawahri Areej
Published: June 2021

7032

Background: The global COVID-19 pandemic has drastically disrupted cancer care, potentially exacerbating patients’ distress levels. Patients with hematologic malignancies undergoing HSCT may be especially vulnerable to this pandemic stress given their well-documented heightened psychological distress and impaired quality of life (QOL). However, the association of the COVID-19 pandemic with distress and QOL is not well understood. Methods: We conducted a cross-sectional analysis of data from 205 patients with hematologic malignancies undergoing HSCT who were enrolled in a multi-site, randomized supportive care trial. We compared baseline pre-HSCT distress (depression, anxiety, and posttraumatic stress disorder [PTSD] symptoms) and QOL between participants enrolled pre-COVID-19 (i.e., 03/2019-01/2020) and during the COVID-19 pandemic (i.e., 03/2020-01/2021). We used the Hospital Anxiety & Depression Scale, PTSD Checklist, and Functional Assessment of Cancer Therapy-Bone Marrow Transplant to assess symptoms of depression, anxiety, and PTSD, as well as QOL respectively. We used regression models adjusting for age, gender, race, relationship status, and cancer diagnosis to examine the relationship between the period of enrollment and patient-reported distress and QOL. Results: Prior to COVID-19, 124 participants enrolled, and 81 participants enrolled during the COVID-19 pandemic. The two cohorts had similar baseline demographic and disease risk factors. Most participants were non-Hispanic (n = 185; 90.2%), White (n = 138; 86.3%), and female (n = 131; 64.5%) with a mean (SD) age of 54.9 (11.7) years. In multivariate regression models, enrollment during COVID-19 was not associated with pre-HSCT depression (B = 0.004; 95% CI, -0.02 to 0.03; p = 0.73), anxiety (B = 0.008; 95% CI, -0.01 to 0.03; p = 0.44), PTSD (B = 0.004; 95% CI, -0.004 to 0.01; p = 0.35) symptoms or QOL (B = -0.003; 95% CI, -0.02 to 0.01; p = 0.68). Conclusions: Contrary to the widespread notion that the COVID-19 pandemic has worsened distress in patients with cancer, we found no differences in pre-HSCT distress or QOL in patients with hematologic malignancies undergoing HSCT prior to or during the COVID-19 pandemic. Our findings highlight the need to comprehensively explore the multifactorial causes (e.g., illness experience, treatment burden) of distress and QOL deficits in HSCT recipients irrespective of the COVID-19 pandemic.
Phase 1 trial of anti-CD22 recombinant immunotoxin moxetumomab pasudotox combined with rituximab for relapsed/refractory hairy cell leukemia.
Authors: Kreitman Robert J. , Stetler-Stevenson Maryalice , Yuan Constance , Wang Hao-Wei , Zhou Hong , Raffeld Mark , Xi Liqiang , Arons Evgeny , Feurtado Julie , James-Echenique Lacey , Braylan Raul , Calvo Katherine R. , Maric Irina , Dulau Alina , Pastan Ira
Published: June 2021

7036

Background: Anti-CD22 recombinant immunotoxin moxetumomab pasudotox (Moxe) is FDA-approved for hairy cell leukemia (HCL) patients who have received at least two prior systemic therapies including a purine nucleoside analog. In phase 3 testing the complete remission (CR) rate was 41%, and response was higher in patients with lower tumor burden and lower titers of antidrug antibodies (ADA). Phase 1 testing indicated that most CRs were without minimal residual disease (MRD) and eradication of MRD was associated with prolonged CR duration. Monoclonal antibody (Mab) rituximab binds to CD20 on HCL cells and induces apoptosis or immune-mediated killing, but as a single-agent achieved only 13% CRs in relapsed HCL requiring therapy. In a phase 1 trial to determine safety, rituximab was combined with Moxe, with the goal to help reduce tumor burden and to prevent or delay ADA by killing normal B-cells. Methods: To allow rituximab sufficient time to accomplish both goals, it was infused 3 days before day 1 of cycle 1 at 375 mg/m2, and Moxe was given by 30-minute infusion on days 1, 3 and 5. On repeat cycles of Moxe days 1, 3 and 5, rituximab was given on day 1. Cycles were generally spaced 4 weeks apart. Moxe was begun at a lower dose, 30 rather than the 40 mcg/kg dose used in phase 3 in case the rituximab would increase its toxicity. Bone marrow aspirate flow cytometry, which can detect 0.002% HCL cells, was the most sensitive test used for MRD detection, much more sensitive than BRAF V600E digital droplet PCR (ddPCR) or bone marrow biopsy immunohistochemistry (IHC). Patients could receive 4 cycles past MRD-free CR, but not more than 8 cycles. Results: Three patients received Moxe at 30 mcg/Kg/dose and 6 received 40 mcg/Kg/dose, all without dose limiting toxicity (DLT). There was no evidence of hemolytic uremic syndrome or capillary leak syndrome. To prevent intravascular hypovolemia due to expected third spacing, patients were encouraged to drink one cup per hour of water or other fluid from days 1 to 8 and take dexamethasone 4 mg orally if headache or nausea prevented good oral hydration. Of the 9 patients, 7 (78%) achieved CR after 2 (n = 6) or 3 (n = 1) cycles, and achieved MRD-free CR after 2 (n = 3), 4 (n = 3) or 6 (n = 1) cycles. No patients became infected with COVID-19. Conclusions: This phase 1 trial met its primary endpoint of determining whether rituximab could be safely combined with Moxe and will enroll 4 additional patients to further access clinical activity. Further testing will determine whether addition of a CD20 Mab to Moxe significantly improves clinical outcome compared to Moxe alone, particularly long-term MRD-free CR rate. Clinical trial information: NCT03805932.
Novel application of Kaplan-Meier methods to model tolerance for nonadherence to imatinib in patients with chronic myeloid leukemia (CML) in the ADAGIO study.
Authors: Obeng-Kusi Mavis , MacDonald Karen , van Lierde Marie-Anne , Abraham Ivo
Published: June 2021

7038

Background: Although adherence to imatinib treatment has been shown to be critical for attaining treatment response among patients with CML, some studies have suggested a 7.3-9.9% nonadherence tolerance margin before loss of treatment effects. We aimed to model probabilistically the margin of tolerance required to ensure treatment response among patients prescribed imatinib and the margin, if any, before treatment response is at risk. Methods: We performed a post hoc analysis of the ADAGIO study conducted in Belgium on 169 evaluable patients ( Blood 2009). Using the pill count ratio as, what in conventional survival analysis would be, the time variable, we modeled the cumulative likelihood of treatment response as a function of increasing pill count adherence. We applied Kaplan-Meier methods to model the likelihood of complete cytogenetic (CCyR), complete hematological (CHR), major molecular (MMR) and optimal (OR) (as defined by the European Leukemia Net) response as a function of 90-day pill count adherence. Kaplan-Meier methods thus estimated the tolerance for nonadherence to imatinib by calculating the 1 minus Kaplan-Meier estimate for treatment response. Results: Analyses (see Table) showed that ̃100% adherence of prescribed dose is associated with probabilities (rounded) of 0.84 for CHR, 0.83 for CCyR, 0.82 for OR, and 0.77 for MMR; compared to, 0.37 (CHR and CCyR), 0.35 (OR), and 0.39 (MMR) at 90% adherence. (of 0.7698 (MMR). Increasing the intake of imatinib from 90% to 100% of the prescribed dose increased the likelihood of the various treatment responses by 1.95 to 2.35-fold. Conclusions: Our findings challenge any previously estimated tolerance for nonadherence. There is virtually no margin for nonadherence if the objective is to optimize the likelihood of treatment response, and only a minimal margin to avoid impaired treatment response. Under such adherence, response rates similar to those in the pivotal IRIS trial can be obtained. Clinicians must assess and promote patient adherence, and patients must be perfectly adherent.[Table: see text]
Engineered immunostimulatory cells can convert PBMCs from chronic lymphocytic leukemia (CLL) patients into potent tumor killing immune cells.
Authors: Keegan Joshua W. , Borriello Frank , Fernandes Stacey M. , Brown Jennifer R. , Lederer James A.
Published: June 2021

7517

Background: Alloplex Biotherapeutics has developed a cellular therapeutic that uses ENgineered Leukocyte ImmunoSTimulatory cell lines called ENLIST cells to activate and expand populations of tumor killing effector cells from human peripheral blood mononuclear cells (PBMCs). This process leads to a 300-fold expansion of NK cells, CD8+ T cells, NKT cells, and TCRγδ T cells that are called SUPLEXA cells, which will be cryopreserved and transferred back into patients as an autologous immune cell therapy for cancer. In this study, PBMCs from CLL patients were used to generate SUPLEXA cells as a first approach to comparatively profile SUPLEXA cells from cancer patients and normal healthy volunteers (NHVs). Methods: ENLIST cell lines were engineered by expressing curated immunomodulatory proteins in the SK-MEL-2 melanoma cell line. Two million (M) PBMCs from 10 CLL patients or 2 NHVs were incubated with 0.4 M freeze/thaw killed ENLIST cells for 5 days in XVIVO-15 medium with 2% heat-inactivated human AB serum (XAB2) and then split 1:15 in XAB2 containing IL-7 and IL-15 to expand. After 9 days, SUPLEXA cells were harvested and cryopreserved. Results: Original PBMCs and matched SUPLEXA cells from each donor were thawed and characterized by mass cytometry (CyTOF) using a 47-marker antibody panel. CyTOF staining results of PBMCs from CLL patients demonstrated approximately 95% leukemia cells and few T cells, NK cells, B cells, and monocytes. CyTOF staining of SUPLEXA cells from all 10 CLL patients showed expansion of NK cells (17%), CD8 T cells (11%), and CD4 T cells (7.5%) that were similar in phenotype to SUPLEXA cells from NHVs showing high expression of granzymes and perforin that are indicative of potent tumor cell killing activity. Cancer cells in the original CLL PBMC samples were reduced to 0.78%. However, a population of non-T/non-B cells (60% ± 9.5%) was detected in SUPLEXA cells from all CLL patients that require further characterization. Next, SUPLEXA cells from CLL and NHV patients were comparatively tested for tumor cell killing activity at 2:1, 1:1, and 1:2 effector to target cell (MEL-14 melanoma cells expressing RFP) ratios. Percent killing of tumor cells by SUPLEXA cells prepared from CLL patients (77.8% ± 2.6% at 2:1) and NHVs (81.5% ± 0.3% at 2:1) were nearly identical at all effector to target ratios. Conclusions: We demonstrate for the first time that PBMCs from CLL patients can be converted into SUPLEXA cells despite low numbers of normal immune cells at baseline and the known immunologic impairment present in CLL patients. Importantly, SUPLEXA cells derived from CLL patients acquire potent tumor killing activity that is indistinguishable from SUPLEXA cells prepared from NHVs. Taken together, these findings support the feasibility of converting PBMCs from CLL patients with low percentages of NK and T cells into an autologous cellular therapy for cancer.
The clinical study of anti-BCMA CAR-T with single-domain antibody as antigen binding domain.
Authors: Han Lu , Gao Quanli , Zhou Keshu , Zhou Jian , Yin Qing-Song , Fang Baijun , Zhu Xing-Hu , Zhang Jishuai , Bao Chaolemeng , Song Yongping
Published: June 2021

8025

Background: Relapsed/refractory (RR) multiple myeloma (MM), RRMM, remains as an incurable disease and has a 5-year survival rate of nearly 50%. To address the unmet medical need, an autologous CAR-T cell therapy was developed previously with a humanized single-domain antibody (sdAb) targeting BCMA as the antigen binding domain, 4-1BB and CD3ζ as cytoplasmic domain. Methods: An investigator-initiated clinical trial (IIT) was conducted in China to assess the safety and efficacy of the sdAb-based CAR-T. The trail was started in June 2018 and the last patient infused in June 2019. As of 1 February 2021, 34 were treated and followed up. The patients had received multiple lines of prior treatment (including bortezomib, lenalidomide, and others). Following a lymphodepleting regimen of cyclophosphamide (300-600 mg/m2, d-5, -4) and fludarabine (25-30 mg/m2, d-5 to d-3), patients were infused with 2.5-10.0 × 106 CAR+ cells/kg body weight. CAR-T was infused immediately after preparation and quality control performed in all patients except one, who was infused a 10.0 × 106 CAR+ cells/kg dose of frozen cells. Efficacy was assessed based on the IMWG criteria, toxicity was graded by CTCAE 4.02, and CRS grading was based on the grading system by CARTOX working group. Results: All 34 patients had the tumor burden of plasma cells in bone marrow, or M protein or free light chains (FLCs) in serum, 7 patients were accompanied with extramedullary diseases. The efficacy shows the best ORR is 88.2% (30/34), sCR rate is 55.9% (19/34). The mPFS was 12.1 months, several patients shows continuous sCR after 2 years. No obvious correlation between efficacy and dosage were found in three dose groups of 2.5×106 CAR+ cells/kg (6 pts), 5.0×106 CAR+ cells/kg (23 pts) or 10.0×106 CAR+ cells/kg (5 pts). The observed adverse events include thrombocytopenia (≥grade 3, 38.2%), neutropenia (≥grade 3, 44.1%), leukopenia (≥grade 3, 32.4%), lymphopeniPa (≥grade 3, 26.5%), and anemia (≥grade 3, 20.6%). CRS was monitored occurring in 29 patients (any grade, 85.3%, ≥grade 3, 2.9%). Conclusions: Our result demonstrates that the CART employing one humanized sdAb targeting BCMA is safe and efficacious for clinical application. The phase I clinical trial has been initiated in China for searching the RP2D using the cryopreserved CAR-T cells. Clinical trial information: NCT03661554.
Molecular characteristics of EGFR exon 19 deletion subtypes in NSCLC patients.
Authors: Gu Weiquan , Lu Zhongyu , Shi Shulin , Ma Juan , Lu Guanghua , Deng Wanglong , Ding Ran , Bu Fanfeng
Published: June 2021

8530

Background: EGFR exon 19 deletion mutations are well characterized, known to be activating, and are associated with responses to EGFR tyrosine kinase inhibitors (TKIs). A variety of methods have been developed to identify EGFR mutations. Deletions of EGFR exon 19 are more complex compare to the other because they consist of different subtypes. Methods: In this study, we retrospectively analyzed the different subtypes of EGFR exon 19 deletions using next-generation sequencing(NGS). From May 2019 to December 2020, 3275 patients who were diagnosed with Non-small cell lung cancer (NSCLC)were detected. Results: In this analyzed cohort, the average age of patients was 62 years (range, 24-92 years). Most of the patients were female (61.07%) and were diagnosed with lung adenocarcinoma (82.60%). It is worth noting that the deletions in exon 19 of EGFR were also detected in 35 patients (1.07%) with squamous cell carcinoma and 1 patient (0.03%) with sarcomatoid. The most frequent EGFR exon 19 deletions were delE746-A750 (63.4%), followed by delL747-P753insS (9.7%) and L747-T751 (6.9%). The characteristics of the patients in this study are presented. Significantly, three samples with compound EGFR exon 19 deletions were detected: 1) S1:E746_A750delinsFP+E746_A750del; 2) S2: E746_S752delinsV+L747_P753delinsS; 3) S3:E746_P753delinsVS + L747_P753delinsS. Conclusions: EGFR exon 19 starting at codon 729 to 761, our data showed the deletions occur throughout almost the entire exon 19 amino acid. As our integrated data results, EGFR exon 19 has many different deletions and insertion subtypes could be defined as 79 subtypes. Among those subtypes,70 were complex with an accompanying insertion. The most frequent deletions were starting at E746 and L747. Based on several clinical researches, different deletion subtypes may have significantly different clinical responses after TKI treatment. However, more clinical research is needed to support this finding.
Outcomes of thymic epithelial tumors (TETs) with pleural metastases: Real-world insight from RYTHMIC.
Authors: Maury Jean-Michel , Benitez Jose Carlos , Boucher Marie Eve , Dansin Eric , Kerjouan Mallorie , Bigay-Game Laurence , Pichon Eric , Thillays Francois , Falcoz Pierre-Emmanuel , Svetlana Lyubimova , Oulkhouir Youssef , Fabien Calcagno , Thiberville Luc , Clément Duchene Christelle , Westeel Virginie , Missy Pascale , Thomas Pascal Alexandre , Molina Thierry , Girard Nicolas , Besse Benjamin
Published: June 2021

8578

Background: TETs are rare and potentially aggressive malignancies with high associated prevalence of autoimmune disorders (AIDs). The pleura is the main metastatic site at relapse, referred as Masaoka-Koga stage (MK) IVa. The benefit of surgical management is unknown, so we have collected outcomes of patients with MK IVa TETs in a large prospective database. Methods: RYTHMIC (Réseau tumeurs THYMiques et Cancer) is a French nationwide network mandated to systematically discuss every case of TETs. The database, hosted by IFCT (Intergroupe Francophone de Cancérologie Thoracique), prospectively includes all consecutive pts with a diagnosis of TET discussed in RYTHMIC national or regional tumor boards. We analyzed epidemiologic, clinical and pathological characteristics of patients (pts) with MK IVa TETs. Results: From January 2012 to December 2019, 2909 pts were included in the database, including 182 MK IVa (6.2%). The median age at diagnosis was 63.5 (range 9 to 91). 58/182 (32%) pts reported AIDs, 76% myasthenia gravis. 129/182 pts had synchronous pleural metastasis. 118/182 (65%) tumors were resected, of them 10 (8.4%) had only pericardial metastases. Thymoma (T) B2 rate was 35.6%, B3 17.8% and thymic carcinoma (TC) 13.5%. Induction chemotherapy (CT) was given in 46 (39%) T and 10 (8%) TC with response rate of 50% and 70% respectively. Thymectomy was performed in addition to pleurectomy in 44 pts (37.2%), pericardiectomy in 68 (57.6%), lung resection in 80 (67.8%) or pneumonectomy in 15 (12.7%). Node resection was performed in 57.6% (n = 67), 12 (18%) were positive. The complete resection rate assessed by surgeons was 57% with a median of 15 (0 to 28) resected pleural metastasis. Intrapleural chemotherapy was added for 19 (16%) pts. No mortality was reported 90 days after surgery procedure. Median follow-up was 36 months. Pleural recurrence was seen in 47 (72%) pts. Median disease-free survival (DFS) was 39 vs 16 months in resected vs not resected tumors (p < 0.0001), 5-years overall survival (OS) was 88 vs 66% (p = 0.28), respectively. Risk of relapse decreased by 60% with surgery (HR = 0.4, 95CI (0.25-0.62); p < 0.0001). Conclusions: The prevalence of MK IVa in our cohort was 6.2%. Surgery appears to be a safe and valid option for pts with MK IVa TET at diagnosis.
Response to immune checkpoint inhibition as monotherapy or in combination with chemotherapy in metastatic ROS1-rearranged lung cancers.
Authors: Choudhury Noura J. , Schneider Jaime Laurel , Patil Tejas , Zhu Viola Weijia , Goldman Debra A. , Yang Soo-Ryum , Falcon Christina , Do Andrew , Nie Yunan , Plodkowski Andrew J. , Chaft Jamie E. , Digumarthy Subba , Rekhtman Natasha , Arcila Maria E. , Iasonos Alexia , Ou Sai-Hong Ignatius , Lin Jessica Jiyeong , Drilon Alexander E.
Published: June 2021

9049

Background: ROS1 fusions are oncogenic drivers in various cancers types, including 1-3% of non-small cell lung cancers (NSCLCs). Immunotherapy approvals for NSCLC include ROS1-rearranged carcinomas, but the activity of immune checkpoint inhibition (ICI) as monotherapy or in combination with chemotherapy (chemo-ICI) therapy, as well as the immunophenotypic characteristics of these tumors, have not been described in a large data set. Methods: In this multi-institutional study, patients with ROS1-rearranged NSCLC were identified retrospectively. Tumor PD-L1 expression and tumor mutational burden (TMB) were assessed as part of routine clinical care. In patients who received ICI monotherapy or chemo-ICI in the metastatic setting, time to treatment discontinuation (TTD) and objective response rate (ORR; RECIST v. 1.1) were calculated. TTD was assessed with Kaplan-Meier methods; patients remaining on treatment were censored at last follow up. Results: 184 patients with ROS1-rearranged NSCLC were identified. Among 146 PD-L1 evaluable cases, PD-L1 expression was < 1% in 60 (41%), 1-49% in 35 (24%) and ≥50% in 51 (35%) tumors. Ninety-two of 100 (92%) TMB-evaluable tumors had < 10 mutations/megabase (mut/Mb). TMB was significantly lower for ROS1-rearranged NSCLCs (n = 97) vs. ROS1-wild type tumors (n = 5,380) evaluated with next-generation sequencing using MSK-IMPACT (median 2.6 vs. 5.9 mut/Mb, p < 0.001). Twenty-eight patients received ICI monotherapy and 11 patients received chemo-ICI. The median TTD was 2.1 months (95% CI: 1.0-4.2; n = 28) for single-agent ICI therapy and 10 months (95% CI: 4.7-14.1; n = 11) for chemo-ICI therapy. The ORR was 13% (2/16 RECIST-evaluable; 95% CI: 2-38%) for ICI monotherapy and 83% (5/6 RECIST-evaluable; 95% CI: 36-100%) for chemo-ICI therapy. There was no difference in PD-L1 tumor expression (p = 0.9) or TMB (p = 0.8) between responders and non-responders and no correlation between PD-L1 tumor expression (rho = 0.16, p = 0.6) or TMB (rho = 0.03, p = 0.9) and maximum change in sum of target lesions. Conclusions: Most ROS1-rearranged NSCLCs have low or no PD-L1 expression and low TMB. The activity of checkpoint inhibitor monotherapy is disappointing in ROS1-driven NSCLC. In contrast, combination chemoimmunotherapy can achieve clinically meaningful activity.
Discontinuation of immune checkpoint inhibitor (ICI) above 18 months of treatment in real-life patients with non-small cell lung cancer (NSCLC): INTEPI, a multicentric retrospective study.
Authors: Bilger Geoffroy , Girard Nicolas , Doubre Helene , Giaj Levra Matteo , Giroux Leprieur Etienne , Giraud Frédérique , Decroisette Chantal , Livartowski Alain , Massiani Marie Ange
Published: June 2021

9082

Background: The optimal treatment duration of ICIs for patients with NSCLC remains uncertain. In phase 3 clinical trials, treatment continued for two years or until disease progression, and results from CheckMate 153 trial suggest to continue beyond one year. Real life data are missing. Methods: This multi-centric retrospective study presents data on real-life patients who discontinued treatment after at least 18 months of ICI monotherapy, their tumour being still controlled. Their characteristics, the causes of discontinuation of ICI, and their outcome are described. Results: Between July 2015 and May 2018, 107 patients had their tumour controlled after at least 18 months of treatment. Among them, 54 (50%) patients discontinued ICI: 76% male, median age 63, 91% PS 0-1, 54% adenocarcinoma, 20% with brain metastases, PD-L1 expression level available for 18 (33%) patients (2 < 1%, 8 btw 1-50% and 8 > 50%), 93% treated after 1st line. The median duration of treatment was 26 months. Treatment was stopped by choice of the prescriber and toxicity in 46% and 22% respectively. With a median follow up of 21 months from ICI discontinuation, 18 (33%) patients had a tumor progression with a median time of 10 months (2-33). From discontinuation, overall survival (OS) and progression free survival (PFS) were 90% and 71% respectively at 12 months and 84% and 63% respectively at 24 months. Duration of disease control after ICI cessation seemed to be correlated to the best tumor response at treatment discontinuation, with a PFS rates at 12 months of 73% for complete response (CR n = 11), 77% for partial response (PR n = 37), 22% for patients with stable disease (SD n = 6), 80% for CR and/or complete metabolic response with 18F-FDG PET/CT (CMR) and 65% for others. Fourteen patients out of the 18 in the relapse group received a subsequent treatment : 7 were retreated with ICI (with best response 14% PR and 86% SD) and 5 received a localized therapy with 60% CR. Conclusions: Our study in real life provides new insight into the long-term outcomes of patients treated with ICI for at least 18 months before discontinuation in the absence of PD. CR and CMR with FDG-PET before therapy discontinuation may be a positive factor for a prolonged disease control upon discontinuation.
Checkpoint inhibition in immunosuppressed or immunocompromised patients with advanced cutaneous squamous cell carcinoma (CSCC): Data from prospective CemiplimAb-rwlc Survivorship and Epidemiology (C.A.S.E.) study.
Authors: Rabinowits Guilherme , Park Soo J , Ellison David M. , Worden Francis P. , Gentry Rhonda W. , Strasswimmer John , Venna Suraj S. , Migden Michael Robert , Chandra Sunandana , Ruiz Emily S. , Mehta Nikita , Zhang Haixin Raymond , McGinniss Jennifer , Desai Jigar
Published: June 2021

9547

Background: Immunosuppressed and/or immunocompromised patients are at increased risk for solid tumors and cutaneous malignancies. Limited data exist on the safety and effectiveness of immune checkpoint inhibitors (ICIs) in these patients because they are frequently excluded from clinical trials. Here, we describe the safety and effectiveness results from the initial cohort of immunosuppressed and/or immunocompromised patients with advanced CSCC enrolled in the C.A.S.E. study (NCT03836105). Methods: C.A.S.E. is a prospective, real-world, multi-center, longitudinal study evaluating the effectiveness, safety, quality of life, and survivorship in patients with advanced CSCC treated with cemiplimab. Patients received cemiplimab 350 mg intravenously every 3 weeks per routine standard of care. Patient demographics, disease characteristics, immunosuppression, and relevant medical history were collected. Immunosuppressive regimens varied amongst patients. Investigator assessment of objective response rate (ORR), safety, and tolerability was conducted. Data from 26 immunosuppressed and/or immunocompromised patients with advanced CSCC treated with cemiplimab are presented. Recruitment is ongoing. Results: As of November 17, 2020, 121 patients were enrolled in the C.A.S.E. study, of which 26 patients (median age: 74 years [IQR: 71-84]; 85% male; 89% Caucasian) were designated as immunocompromised or immunosuppressed due to a history of solid organ transplant (n = 6), autoimmune disorder (n = 11), or hematologic malignancy (n = 9). Median duration of cemiplimab exposure was 14 months (IQR: 9.1–42, range: 0, 67). Among 19 immunocompromised or immunosuppressed patients who enrolled in C.A.S.E. prior to their third dose of cemiplimab, ORR per investigator assessment was 47% (95% CI: 24–71); 1 (5%) patient had complete response; 8 (42%) had partial response. One patient had a treatment-related serious adverse reaction of organ transplant rejection. One (3.8%) patient discontinued treatment due to increased alanine aminotransferase (not treatment-related). Immune-related AEs (irAEs) occurred in 23% of patients. No treatment-related AEs led to death. Conclusions: The safety, tolerability, and effectiveness of cemiplimab in this initial cohort of immunosuppressed and/or immunocompromised patients with advanced CSCC appear to be consistent with those observed in clinical trials that excluded these patients. Further follow-up and additional data would add to our general understanding of safety and effectiveness of anti-PD1 therapy in immunocompromised and/or immunosuppressed patient populations overall. Clinical trial information: NCT03836105.
Use of strain rate imaging for early detection of epirubicin-induced cardiotoxicity in patients with breast cancer.
Authors: Michalaki Vasiliki , Koutroulis George , Kontis Ioannis , Dafnios Nikolaos , Tiniakos Dina , Papadimitriou Christos
Published: June 2021

e12531

Background: Although epirubicin has improved outcome in breast cancer (BC) patients, its application is limited by its cardiotoxicity . Assessment of left ventricular (LV) ejection fraction (EF) is performed to demonstrate cardiac dysfunction. Changes in cardiac function induced by this therapy, however, are difficult to quantitate by conventional echocacardiography. Tissue Doppler myocardial imaging (TDI) derived wall motion velocity, and strain rate (SR) have been shown to sensitively quantify abnormalities in cardiac function. The aim of this study was to determine if sensitive indices of LV dysfunction, would be useful for addressing the early detection of cardiotoxic side effects of epirubicin. Methods: BC patients (N = 45 median age 60.2years) without cardiovascular risk factors were prospectively included. All patients received epirubicin. Twenty patients received further trastuzumab. Conventional and TDI echocardiography were obtained at baseline , every 2cycles of treatment and 3 months after chemotherapy. Segmental peak systolic longitudinal and radial velocity, SR and strain, were measured. Results: at baseline, median LV-EF was > 55 %. There was no overall change in LV dimensions, EF and peak systolic velocity. In contrast, a significant reduction in longitudinal and radial SR and strain was found after 3 cycles (longitudinal strain -10.2% +/- 1.3 % vs baseline 22 +/- 4.1 %, P = .001; radial strain 26.1% +/-4,2% vs baseline 47.3% +/- 9.2 %, P < .001). Changes in radial strain appeared earlier and were more pronounced than longitudinal strain. Conclusions: In this study we confirm the clinical use of TDI parameters for early detection of epirubicin mediated cardiac dysfunction. TDI detected subtle changes of LV function after 3 cycles of therapy. Use of Strain Rate Imaging detects subclinical LV dysfunction and can predict further changes in EF ,therefore can be used to monitor epirubicin-induced cardiotoxicity.
Tolerance of aromatase inhibitors in post-menopausal patients with early-stage hormone receptor positive (HR+) breast cancer: A real-world retrospective analysis in a large oncotype database.
Authors: Berwick Shana , Zimmerman Brittney Shulman , Hovstadius Sara Malin , Blanter Julia , Moshier Erin , Berkalieva Asem , Berger Natalie S , Jaffer Shabnam , Cascetta Krystal Pauline , Tiersten Amy
Published: June 2021

e12532

Background: Aromatase inhibitors (AIs) compose the backbone of adjuvant endocrine therapy for early-stage HR+ breast cancer. Prior studies have demonstrated equivalence in efficacy between aromatase inhibitors in current clinical use. Thus choice of aromatase inhibitors is initially influenced by provider patterns and tailored based on adverse side effects. This study retrospectively evaluates the prevalence of intolerance to AIs warranting a change in therapy. Methods: We identified 181 post-menopausal patients with early-stage, HR+ breast cancer within a database of women who underwent oncotype testing at a large, urban medical center, with 167 (92%) receiving an AI. Patients were excluded if they had received chemotherapy. The Kaplan-Meier method was used to estimate median duration of endocrine therapy (ET). The Fisher’s exact test was used to compare proportions of patients requiring a switch in adjuvant AI and the Wilcoxon rank-sum test was used to compare age distributions. Results: Of the patients identified, 153 (90%) had stage IA disease with a median oncotype RS of 19. 167 (92%) patients received an AI as adjuvant therapy. Median duration of endocrine therapy (ET) was 83.5 months, with over 90% of patients on ET more than 5 years. Among the 152 patients with available data on ET interruptions, 52 (34%) patients had a change or interruption in their ET of these 40 (77%) were attributed to a medication side effect. The AI prescribed most frequently as initial therapy was anastrozole 138/165 (84%). 33 (24%) of patients who received anastrozole required a drug switch within the class, (no sig difference based on initial adjuvant therapy; p=0.4281). 12 (7%) patients required a switch from an AI to tamoxifen at some point during therapy. Changes in AI adjuvant therapy were most commonly attributed to joint pains 24 (46%), followed by hot flashes 2 (4%) and weight gain, 2 (4%). There was no statistically significant difference in median age between patients who interrupted ET due to medication side effect or other reason; p=0.2906. Conclusions: This study enforces previous findings that a significant proportion of women require a change in their adjuvant ET, most commonly due to adverse medication effects such as joint pain. The majority of the women in this database were initiated on anastrozole as initial adjuvant ET of whom 24% required a drug switch.[Table: see text]
Recurrence rate according to Oncotype Dx recurrence score (RS) in women with estrogen receptor (ER) positive, Her2 negative and 1 to 3 positive nodes: Real-world data in a Mexican private institution.
Authors: Amador Geovani , Andrade Moreno Raul Alejandro , Martínez-Herrera José Fabián , Gerson Raquel , Serrano Juan Alberto
Published: June 2021

e12536

Background: Oncotype Dx is a 21 gene assay that evaluates de expression of 21 genes associated with recurrence in early breast cancer (EBC). In women with ER positive, HER2 negative and no lymph node involvement, it has demonstrated it prognostic value and has shown to predict the benefit of adjuvant chemotherapy in high-risk patients, sparing toxicity to patients with low risk of recurrence. Nevertheless, in women with ER positive, HER2 negative and 1 to 3 nodes, the role of de 21 gene assay was not clear until recently. Methods: Retrospective review of medical records of patients with ER +, HER2 negative and 1 to 3 positive nodes breast cancer treated at our institution. Clinicopathological characteristics and 21 gene recurrence score (RS) were collected and a survival analysis by the Kaplan-Meier method was performed in patients with RS < 25 and according to menopausal status as in RxPONDER in SPSS v 25.0 IBM. Results: From January 2008 to December 2018, data from 136 patients with EBC clinical stage (IA-IIB), HR +/ HER2-, N0-1 with Oncotype Dx performed were collected, of which only 25 patients had 1-3 nodal involvement and were included in the statistical analysis. Mean age at diagnosis was 54 years (35-73), the most frequent histology in the general population was invasive ductal carcinoma (92.0%), followed by lobular carcinoma (8.0%), 72.0% of patients presented in stage IIA, followed by stage IB in 20.0%. RE were positive in all patients and progesterone receptors were positive in 72.0%, none of the patients had HER2 overexpression, mean Ki-67 expression was 17.4% (4.0-50.0%). Most tumors were modemoderately differentiated (72.0%). Lymphovascular and perineural invasion were present in 44.0% and 24.0% respectively. Follow up data was available for 17 patients of which 12 had a RS of 25 or less. Recurrence was present in only 3 patients in this group of patients representing 25%. During the first 5 years only 1 patient recurred, which represents a 5-year Recurrence rate (RR) of 8.3% with a 5-year RFS of 91.7%. 10-year Recurrence free survival (RFS) was 75.0% with a median RFS that has not been reached. RFS was 80.0% in postmenopausal women compared 71.4% for those premenopausal at 10 years follow-up (p=0.735). None of the patients in this group received adjuvant chemotherapy. Conclusions: We report our experience at a comprehensive cancer center in a time lapse of 10 years. RFS at 5 years was 91.7% and at 10 years of follow up was 75%. This in accordance with the results of RxPONDER trial that reported a 5-year progression free survival of 92.4% in patients with chemo-endocrine adjuvant therapy and 91.0% in patients in the endocrine therapy only arm. This supports the use of this trial for decision making outside of the controlled clinical trials setting.
Impact of updated 2013 human epidermal growth factor receptor-2 testing guidelines on HER2 positive invasive breast cancer diagnosis: A three year retrospective study.
Authors: Mhadgut Hemendra , Sharma Purva , Tawadros Fady , Brooks Bill , Yakubenko Anna , Jaishankar Devapiran
Published: June 2021

e12554

Background: Breast cancer is a frequently diagnosed malignancy in the United States accounting for approximately 266,000 cases and 40,000 deaths annually. Human epidermal growth factor receptor 2 (HER2) is a surface protein shown to affect cell proliferation, migration and survival - the hallmarks of neoplastic cells. HER2 is overexpressed in 20-35% of breast cancer cases and has a strong prognostic and therapeutic significance. This discovery led to development of therapeutic agents targeting HER 2 receptor. In 2013, College of American Pathologists (CAP) updated their recommendations for HER2 testing by incorporating an algorithm with immunohistochemistry (IHC) and In situ hybridization (ISH). The primary objective of our study was to assess for variance in HER2 interpretation by applying the updated 2013 criteria to all diagnosed cases in our hospital for the immediate previous three years. Methods: We retrospectively reviewed charts of patients diagnosed with invasive breast carcinoma from January 1, 2010 to December 31, 2012 at our hospital. The new American college of pathology criteria assessing FISH HER2 copy number and HER2/CEP ratio for each patient was compared to the old criteria to assess for variance in HER2 interpretation. Categorical variables are presented as percentages and kappa statistic was used to assess for variance. Results: We reviewed 526 charts with an invasive breast cancer diagnosis over a 3-year period. 10.83% of patients were HER2 amplified, 86.12% were non-amplified and 3.04% were equivocal. Applying the updated 2013 CAP criteria, we found that 11.21% were amplified, 74.33% were non amplified, and 14.44% remained equivocal. Kappa statistic indicated substantial agreement (0.804) between the old and new criteria. A review of our cohort revealed an overall lower level of HER2 positive cases at 10.83% (old criteria) and 11.21% (updated criteria) when compared to historical studies. The increase in equivocal cases from 3.04% to 14.44% with the new criteria suggests under diagnosis of HER2 positive cases. Due to the lack of IHC performed (as per old standards), further classification of equivocal cases (based on new criteria) was not possible. While we saw some movement in our data from non-amplified to equivocal, our analysis indicated substantial statistical agreement between the old and the new diagnostic criteria Conclusions: Our study did not show a variance in HER2 interpretation between the 2007 and 2013 CAP criteria which is reassuring. An increase of 11.4% cases in the equivocal category was noted and may reveal a significant difference if further delineation is feasible. This variance could be important given the prognostic and therapeutic implications in HER2 positive breast cancer.[Table: see text]
Predominance of RAD21 and ERBB2 amplification and progesterone receptor positivity in tumors of the right breast support breast cancer lateralization.
Authors: Spigelman Zachary , Murphy Jo-Ellen
Published: June 2021

e12557

Background: Biologic lateralization broadly impacts breast cancer. Malignancies originating in the left breast compared to the right breast tend to be more frequent, larger and of poorer prognosis. Left breast tumors respond differently to HER2-neu signaling and have lateralized Ki67 expression. In a prior study a right-left asymmetry in the neutrophil/lymphocyte ratio (NLR) of breast cancers was identified (ASCO 2018, e13094). As a follow-up, retrospective analysis of results from comprehensive genomic profiling (CGP) of right and left side breast cancer specimens was performed to determine a potential genomic etiology for the observed NLR lateralization. Methods: Tumors from 43 consecutive breast cancer patients underwent analysis for all classes of genomic alterations by hybrid capture-based CGP (Foundation Medicine). The CGP results from the 25 left- and 18 right-sided breast cancer samples were analyzed along with the histologic grade and status of estrogen receptor (ER), progesterone receptor (PR), and HER2 expression. Results: In this cohort of advanced breast cancer patients (stage 3-4), no statistically significant differences in lateralization were identified based on patient age, tumor stage, or frequency of ER or Her2 expression (Table). A predominance of PR positivity (p=0.14 chi square analysis) and amplifications in the ERBB2 (p=0.37) and RAD21 (p=0.08) genes were detected in right side tumors. Conclusions: Together with the prior study, trends in asymmetry based on genomic, pathologic, and immunohistologic differences have been detected in breast cancers, including an increased incidence of ERBB2 and RAD21 amplification in right-side breast tumors in this cohort. The predominance of lower PR positivity in the left breast tumors may be due to preferential hypermethylation, consistent with reports that it mediates biologic lateralization changes, downregulates PR expression, and alters amplification rates. Epigenetic methylation, may contribute to asymmetric breast cancer biology and have implications for therapeutic strategy. Further study is warranted.[Table: see text]