tbuckley/cabot-search huggingface dataset:
Apatinib plus ifosfamide and etoposide (IE) versus IE chemotherapy alone for relapsed or refractory osteosarcoma.
Authors: Lu Xie, Wei Guo, Jie Xu, Jin Gu, Xiaodong Tang, Yuan Li, Kunkun Sun
Journal: Journal of Clinical Oncology (2021)

e23502 Background: Results of previous study showed promising objective response but short-lived activity of apatinib in the treatment of osteosarcoma refractory to first-line chemotherapy, from which we observed the disease control of musculoskeletal lesions were worse than pulmonary lesions. This treatment failure has partly been overcome by the addition of Ifosfamide and etoposide in OLIE study. We aimed to retrospectively compare the activity of apatinib in combination with IE in relapsed or refractory osteosarcoma with synchronous patients receiving IE chemotherapy alone in two sarcoma centers in China. Methods: We retrospectively analyzed medical files and radiographic materials of patients with osteosarcoma relapsed or refractory to first-line chemotherapy, who had received combination of apatinib and IE regimen or IE chemotherapy alone between June 3rd, 2017 and July 17th, 2020. Seventy-nine patients were included, of whom 33 patients received apatinib in combination with IE and 46 patients received single IE chemotherapy. Results: Patients’ tumor burden and general status were obviously different between these two groups with 16/33 (48.5%) patients receiving apatinib+IE having both Lung and musculoskeletal lesions at baseline and 39/46 (84.8%) patients receiving single IE having just pulmonary lesions at baseline. However at last follow up 16/33 (48.5%) of patients receiving apatinib+IE had all lesions resected while 23/46 (50.0%) of patients receiving IE alone had their lesions resected, which might partly due to down-staging of the diseases. With median follow-up time of 28.4 (IQR, 16.1-38.3) months, 21/33 (63.6%) patients receiving apatinib+IE had objective responses while 13/46 (28.3%) patients receiving single IE chemotherapy had responses. The median event-free survivals (EFS) were respectively 11.4 (IQR, 6.7-18.4) months for apatinib+IE and 11.2 (IQR, 4.4-21.8) months for IE alone without significant statistical differences (P = 0.47). The overall survival (OS) was obviously different because of disease stage and tumor burden according to Kaplan-Meier analysis with median OS time of 30.4 (IQR, 21.8-not reached) months for IE alone and 19.8 (IQR, 13.1-30.6) months (P = 0.019). Conclusions: For osteosarcoma with multiple sites’ metastasis, apatinib plus IE demonstrated clinically meaningful antitumor activity in patients with recurrent or refractory osteosarcoma after failure of MAP/I chemotherapy or even single apatinib or IE treatment alone, with a positive effect on delaying disease progression. This combination deserves further investigation in prospective trials with manageable toxicity.
Relationship between loss-of-function mutation of the stromal antigen 2 gene and treatment in non-small cell lung cancer.
Authors: Minglei Zhuo, Xin Liu, Rongrong Chen, Xiong Xu, Bin Ni
Journal: Journal of Clinical Oncology (2021)

e20509 Background: The protein encoded by Stromal Antigen 2 ( STAG2) gene is a subunit of the cohesin complex, which regulates the separation of sister chromatids during cell division. Loss-of-function (LOF) mutations of STAG2 gene are commonly detected in different tumors including non-small-cell lung cancer. However, there is no relevant research on the impact of STAG2 alterations on lung cancer treatment. Here we explored the correlation between the LOF of STAG2 and clinical features, concomitant genetic alterations and treatment in NSCLC pts. Methods: A total of 2882 NSCLC pts were enrolled. All the tissue samples were detected by DNA based next generation sequencing (NGS) with a 1021 gene panel. Clinical information was obtained synchronously from physicians and surgeons. According to whether LOF of STAG2 is detected, pts were divided into LOF subgroup and wild type (WT) group. Results: All pts enrolled are Chinese, and median age at diagnosis of them is 63±11.21. Compared to the WT subgroup, a higher average TMB was observed in the LOF group (12.64muts/Mb vs. 6.66mut/Mb, P＜0.05). Between the LOF group and the WT group, there were no significantly difference in all clinical baseline characteristics including age at diagnosis, gender, tumor stage and pathological type. At the time of sample collection, there was no significant difference between the two groups of pts whether they had received systemic treatment (chemotherapy, targeted therapy or immunotherapy) and systemic treatment, and the number of systemic treatment lines received. Neither significant differences in driver gene alteration and other accompanying mutations were observed in the two groups. Conclusions: In NSCLC pts, LOF of STAG2 is not a change after drug resistance, but it may lead to an increase in TMB, which indicates that these pts may have more benefits from immunotherapy. But the influence on prognosis of NSCLC pts needs further research to clarify.
Targeted axillary lymph node dissection in breast cancer patients using I-125 microseeds for prostate cancer brachytherapy.
Authors: Alexander Emelyanov, Krivorotko Petr, Roman Pesotskiy, Alexander Bessonov, Viktor Gorelov, Vladimir Semiglazov
Journal: Journal of Clinical Oncology (2021)

e12601 Background: To date, targeted axillary lymph node dissection is one of the possible methods of de-escalation of surgical aggression on the areas of regional lymph flow in breast cancer patients with confirmed metastases in the axillary lymph nodes prior to the neoadjuvant chemotherapy. There are no specialized microseeds for targeted axillary dissection. The purpose of our study was to determine the possibility of using I-125 microseed for prostate cancer brachytherapy for targeted axillary dissection. Methods: A prospective study of patients with biopsy-confirmed nodal axillary metastases with a I-125 microseed placed in the node was performed. I-125 microseed for prostate cancer brachytherapy was used to mark the axillary lymph node. After neoadjuvant therapy, patients underwent targeted axillary lymph node dissection in combination with SLNB with pathomorphological examination of marked lymph node and total axillary lymph node dissection with pathomorphological examination of over lymph nodes for FNR evaluation. Results: 45 breast cancer patients stage cT1-3N1M0 were enrolled in the study. The frequency of reaching ypN0 was 58%. Residual disease identified in 19 patients. The clipped node revealed metastases in 18 patients, resulting in an FNR of 5.26% (95% CI, to 20.6) for the clipped node. CIs for FNR were calculated using exact (Clopper-Pearson) confidence limits for the binomial proportion. Conclusions: Marking the biopsy-confirmed lymph node using a I-125 microseed prior neoadjuvant chemotherapy and performing targeted axillary lymph node dissection in combination with SLNB is a safe method for diagnosing axillary lymph nodes and allows you to abandon routine ALD for ypN0 patients. Advantages of I-125 microseed for prostate cancer brachytherapy: fixation in the lymph node without migration, the ability to use a standard gamma-probe to locate the microseed during the operation, these microseeds are registered for the treatment of cancer patients.
The HOLA COVID-19 study: Evaluating the impact of caring for patients with COVID-19 on cancer care delivery in Latin America.
Authors: Carolina Bernabe Ramirez, Ana I. Velazquez Manana, Coral Olazagasti, Cristiane Decat Bergerot, Enrique Soto Perez De Celis, Jose Francisco Corona-Cruz, Ivy Riano, Christina Adaniel, Francisca Ramirez, Jesus Del Santo Anampa Mesias, Carmen Cajina, Evelin Mena, Elias Gracia, Alvaro G. Menendez, Henry Idrobo, Raimundo Bezares, Omar Orlando Castillo Fernandez, Liseth Duque Duran, Paulo Gustavo Bergerot, Narjust Duma
Journal: Journal of Clinical Oncology (2021)

1537 Background: The severe acute respiratory syndrome 2 (SARS-cov-2) virus causing COVID-19 has brought great challenges to global health services affecting cancer care delivery, outcomes, and increasing the burden in oncology providers (OP). Our study aimed to describe the challenges that OP faced while delivering cancer care in Latin America. Methods: We conducted an international cross-sectional study using an anonymous online survey in Spanish, Portuguese, and English. The questionnaire included 43 multiple choice questions. The sample was stratified by OP who have treated patients with COVID-19 versus those who have not treated patients with COVID-19. Data was analyzed with descriptive statistics and Chi-square tests. Results: A total of 704 OP from 20 Latin American countries completed the survey (77% of 913 who started the survey). Oncologists represented 46% of respondents, followed by 25% surgical-oncologists. Of the respondents, 56% treated patients with COVID-19. A significant proportion of OP reported newly adopting telemedicine during COVID-19 (14% vs 72%, p=0.001). More than half (58%) of OP reported making changes to the treatments they offered to patients with cancer. As shown in the table, caring for patients with COVID-19 significantly influenced practice patterns of OP. Access to specialty services and procedures was significantly reduced: 40% noted significantly decreased or no access to imaging, 20% significantly decreased or no access to biopsies, 65% reported delays in surgical oncology referrals, and 49% in radiation oncology referrals. A vast majority (82%) reported oncologic surgeries were delayed or cancelled, which was heightened among those treating patients with COVID-19 (87% vs 77%, p=0.001). Conclusions: The COVID-19 pandemic has significantly affected the way cancer care is delivered in globally. Although changes to healthcare delivery are necessary as a response to this global crisis, our study highlights the significant disruption and possible undertreatment of patients with cancer in Latin America that results from COVID-19.[Table: see text]
Pre-treatment status of inflammation-based biomarkers in the patients with advanced gastric cancer who will be treated with nivolumab.
Authors: Tetsuya Kusumoto, Kensuke Kudou, Sho Nanbara, Yasuo Tsuda, Eiji Kusumoto, Kenkichi Hashimoto, Yoshihisa Sakaguchi, Koji Ikejiri, Eiji Oki
Journal: Journal of Clinical Oncology (2021)

e16107 Background: Nivolumab is currently proved to be one of the most recommended regimens as the third-line chemotherapy for patients with advanced gastric cancer (AGC) in Japan. A variety of scores based on the systemic inflammation-based biomarkers have been reported to reflect survival in cancer patients. Kudou et al. recently reported that newly designed combined score of 5 inflammation-based prognostic scores (IBPSs), composed of neutrophil to lymphocyte ratio, platelet to lymphocyte ratio, Glasgow prognostic scale, prognostic index and prognostic nutritional index, might be predictive for the prognosis of resected gastric cancer (Ann Surg Oncol, 2020). The aim of the study is to investigate the clinical significance of nivolumab monotherapy in patients with AGC, associated with pre-treatment status of IBPSs including Kudou’s combined score (min 0 to max 10). Methods: Thirty-six patients received nivolumab monotherapy in our institute and enrolled to this retrospective study. We conducted a retrospective review of the data of 24 patients with AGC who received ≧ 2 cycles of nivolumab as the 3rd-line chemotherapy. Adverse events, tumor responses, the IBPSs and survival data were analyzed. Results: Three patients quitted the continuation of nivolumab except for the progressive disease, due to non-hematological toxicities higher than grade 3 including myositis, hypothyroidism, dermatitis and liver dysfunction. The rate of hematological toxicities, which showed severe anemia of higher than grade 3 was 20.8%. The ORR and the DCR were 4.2% and 41.7%, respectively. The median PFS and the OS after nivolumab administration were 69 and 274 days, respectively. Pre-chemotherapeutic combined score of IBPSs below 7 was significantly associated with the longer OS (P=0.014) in exposure of nivolumab, compared with the patients group presenting more than 7. Conclusions: Nivolumab monotherapy as the 3rd-line is one of the best regimens for patients with AGC showing better PS or lower combined score of IBPSs.
CAR-T cells to deliver engineered peptide antigens and reprogram antigen specific T cell responses against solid tumors.
Authors: Daniel Lee, Andy J Minn, Lexus R Johnson
Journal: Journal of Clinical Oncology (2021)

2530 Background: Neoantigen depleted malignancies such as colorectal cancer demonstrate primary resistance to immune checkpoint blockade, and solid tumors in general have shown resistance to chimeric antigen receptor (CAR) T cell therapy. However, CAR-T cells have been shown to be capable of delivering various therapeutic molecules in a targeted fashion to the tumor microenvironment, in some cases through extracellular vesicles (EVs). In vivo studies have shown that the presentation of foreign viral peptides by solid tumors can reprogram bystander virus-specific cytotoxic T cells (CTLs) against tumor cells. In this study, we demonstrate that CAR-T cells can deliver engineered peptide antigens to solid tumors, leading to presentation on tumor cells and anti-tumor response. Methods: Second generation CAR-T cells (41BB endodomain) targeting human CD19 (19BBz) or human mesothelin (M5BBz) were generated via retroviral and lentiviral transduction respectively. CAR-T cells were engineered to co-express peptides such as SIINFEKL of ovalbumin and NLVPMVATV of CMV pp65 among others. Peptides were isolated from EVs via ultracentrifugation. For in vivo studies, C57BL/6 or NSG mice were injected on the flank with relevant tumors and treated with peptide-CAR-T cells. In vitro studies utilized flow cytometry and xCELLigence killing assays. Results: Murine 19BBz CAR-T cells expressing the SIINFEKL peptide of ovalbumin (ova-19BBz) were found to transfer SIINFEKL peptide to tumor cells via EVs in vitro and in vivo, leading to peptide presentation on MHC-I of tumor cells. This resulted in significantly delayed tumor growth in tumor bearing mice transfused with OT-I T cells to mimic an existing antigen specific T cell pool. We expanded on these findings by isolating EVs from human M5BBz CAR-T cells expressing CMV viral peptides. Peptide-CAR-T EVs were co-cultured with human ovarian cancer cells to assess presentation to Jurkat T cells. Finally, we utilized primary human T cells from CMV+ healthy donors to assess the clinical feasibility of our peptide delivery approach. Conclusions: CAR-T cells can be engineered to deliver peptides to tumor cells for presentation and subsequent targeting by antigen specific CTLs. This represents a novel strategy for the treatment of non-immunogenic tumors.
Clinical and pathological characteristics of breast cancer with resected brain metastasis.
Authors: Shiyuan Anabeth Liu, Jingqin Luo, Yu Tao, Sonika Dahiya, Cynthia X. Ma
Journal: Journal of Clinical Oncology (2021)

1089 Background: Breast cancer brain metastasis (BCBM) has poor prognosis and limited therapeutic options. Studies have shown that BCBM may differ from their matched primary tumors in receptor subtypes and genomic characteristics. However, studies have been limited by the tissue availability of BCBM. Taking advantage of our institutional database of resected BCBM with matched primary breast samples, this study aimed to investigate the clinical and pathological characteristics of patients with resected BCBM. Methods: We performed retrospective chart review for all breast cancer patients who had resected BCBM samples at our institution over the last 20 years. Hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) status of the primary breast and BCBM samples, location of BCBM, and extracranial metastases at time of BCBM diagnosis were categorized. Overall survival (OS) from time of BCBM diagnosis was calculated using the Kaplan-Meier method. Progression interval and receptor subtype switching from primary diagnosis to brain metastasis were computed and compared using Wilcoxon rank sum test and Fisher’s exact test, respectively. Results: Eighty-six patients were included in this study (median age at time of BCBM diagnosis 54.3 [range 28.3-84.0] years, median follow up 26.0 months). These included 47 HR+, 15 HER2+, 20 triple negative (TN), 4 unknown subtype breast samples, and 42 HR+, 18 HER2+, 17 TN and 9 unknown subtype brain samples. OS was significantly shorter in patients with TN compared to HR+ or HER2+ subtype, whether the TN status was in the primary breast tumor (median 20.5 vs 34.0 months, p = 0.04, thresholded at year 2) or in the brain metastasis (median 16.0 vs 34.0 months, p = 0.02, thresholded at year 2). No significant difference in OS was observed between HR+ and HER2+ groups. There was no significant difference in the progression interval from primary diagnosis to brain metastasis among receptor subtypes. From primary tumor to brain metastasis, receptor subtype switching occurred in 10 out of 73 patients (13.7%) for estrogen, 20 out of 70 (28.6%) for progesterone (PR), and 6 out of 72 (8.3%) for HER2. Receptor subtype switching did not significantly correlate with OS. Presence of extracranial metastases at time of BCBM diagnosis corresponded to significantly lower OS compared to no extracranial metastasis (16.5 vs 36.0 months, p = 0.01). No significant difference in OS was observed between patients with cerebral vs cerebellar brain metastases. Conclusions: These data indicate that patients with TN BCBM disease have the worst overall survival among all receptor subtypes. Metastases in extracranial sites at time of BCBM diagnosis significantly decreased survival. Location of the brain metastasis and receptor subtype switching from primary diagnosis to BCBM, which was relatively infrequent outside of the PR group, did not significantly correlate with OS in this limited data set.
A Phase 0 ‘trigger’ trial of CDK4/6 plus ERK1/2 inhibitors in recurrent glioblastoma.
Authors: Nader Sanai, Yu-Wei Chang, Tigran Margaryan, Anita DeSantis, Mackenna Elliott, Chelsea Pennington-Krygier, Garry Hook, Wonsuk Yoo, An-Chi Tien, Artak Tovmasyan, Shwetal Mehta
Journal: Journal of Clinical Oncology (2021)

2005 Background: The RB-CDK4/6 and MAPK signaling pathways are dysregulated in glioblastoma (GBM). Our recent phase 0 study of ribociclib in recurrent GBM patients suggested that CDK4/6 inhibitor monotherapy is not durable. In this ongoing, dual-drug phase 0 study (NCT04391595), we evaluate the tumor pharmacokinetics (PK) and tumor pharmacodynamics (PD) of abemaciclib, a selective CDK4/6-inhibitor, plus LY3214996, a selective ERK1/2 inhibitor, in recurrent GBM patients. Methods: Adult patients eligible for this open-label, multi-center phase 0 protocol had recurrent GBM with (1) intact RB expression, (2) &gt;30% pERK expression, and (3) CDKN2A/B deletion or CDK4/6 amplification. Prior to a planned resection, patients received six days of abemaciclib (150mg BID) plus LY3214996 (200mg QD). In a Time-Escalation Arm, ten patients were assigned to 3-5 hour or 7-9 hour intervals from final drug dose to tumor removal. Tumor tissue (gadolinium [Gd]-enhancing and nonenhancing regions), cerebrospinal fluid (CSF), and plasma were collected. Total and unbound drug concentrations were measured using validated LC-MS/MS methods. Tumor PD effects, including RB and RSK phosphorylation, were compared to matched archival or pre-treatment biopsied tissue. A PK ‘trigger’ ( i.e., unbound concentration &gt; 5x biochemical IC 50 ) was set for each drug. Gd-nonenhancing tumor tissue exhibiting abemaciclib and LY3214996 concentrations in excess of their trigger threshold qualified patients for postoperative dual-drug therapy. Results: In this interim analysis, no dose-limiting toxicities were observed. In Gd-nonenhancing tumor regions, median unbound concentrations of abemaciclib (including its equipotent M2 and M20 metabolites) were 31.2 nM (3-5 hour cohort) and 25.1 nM (7-9 hour cohort). In the same tissue, median unbound concentrations of LY3214996 were 52.0 nM (3-5 hour cohort) and 10.2 nM (7-9 hour cohort). Tumor RB and RSK phosphorylation decreased in 6/10 and 2/10 patients, respectively. Gd-enhancing tumor proliferation (MIB-1) was decreased in 8/10 patients. 5/10 patients exceeded PK thresholds for both abemaciclib (12 nM) and LY3214996 (25 nM), thereby entering the study’s therapeutic expansion phase. Conclusion: Abemaciclib and LY3214996 achieve pharmacologically-relevant concentrations in Gd-non-enhancing GBM tissue and are associated with suppression of the RB pathway and tumor proliferation. Following 6 days of presurgical drug exposure, the Optimal Time Interval (OTI) for tissue sampling was 3-5 hours after the final drug dose. Based on this interim analysis, the trial will accrue an additional 25 patients at this OTI. Clinical trial information: NCT04391595.
Outcomes of radiotherapy combined with systemic therapy for stage IV NSCLC: A real-world study.
Authors: Hongyuan Jia, Jiahua Lv, Long Liang
Journal: Journal of Clinical Oncology (2021)

e24084 Background: Although systemic therapy is standard treatment for stage IV NSCLC, radiation therapy can also play an important role. In the practice of our institute, radiotherapy to local diseases has been extensively used. In this study, we observed and analyzed the outcomes of systemic therapy combined with radiotherapy in stage IV non-small cell lung cancer. Methods: Patients with stage IV non-small cell lung cancer treated with combination of systemic therapy and radiotherapy were enrolled in this study. Radiotherapy was delivered using sIMRT or VMAT technique with CBCT image guidance. SBRT or hypofractionated radiation was used according to lesion site and patients general condition. For patients with driving gene mutations TKIs were used, and for these without chemotherapy of cisplatin/carboplatin plus paclitaxel or pemetrexed was given. Results: From 2016 to 2018, 105 patients were included in this study. Sites mostly irradiated included pulmonary lesions or mediastinal lymph nodes(48%), intracranial metastatic lesions(33%), bone metastatic lesions (20%). 42% of all patients received one course of radiotherapy to a single lesion site and others received multiple courses of radiation to different sites. Median follow-up was 39.1 months. Median OS for whole cohort was 18.6 months. In subgroup analysis, the survival of TKIs+radiotherapy group as significantly better than that of chemotherapy+radiotherapy group (median OS: 35.2 months vs 11.1 months, p &lt; 0.001). The survival of patients with oligometastasis was also significantly better than these with extensive diseases( median OS 25.3 months vs 7.9 months, p &lt; 0.001). The local control rate of irradiated sites was 82%. The incidence of ≥Grade 2 radiation esophagitis and pneumonitis were 33.2% and 24.2% for thoracic radiotherapy. Conclusions: Radiotherapy combined with systemic therapy is feasible and well tolerated for stage IV NSCLC, especially for patients with driving gene mutations and oligometastasis. It needs to be further confirmed by large randomized controlled clinical studies.