tbuckley/cabot-search huggingface dataset:
A retrospective study of characteristics and survival in patients with breast cancer brain metastases classified by subtype using NCI SEER registry.
Authors: Monika Devanaboyina, Morgan Marie Bailey, Danae M. Hamouda
Journal: Journal of Clinical Oncology (2021)

1031 Background: Breast cancer brain metastasis (BCBM) de novo is associated with the worst prognosis among all types of metastases in breast cancer (BC). Analysis of factors associated with BCBM stratified by subtype of BC could lead to earlier identification of metastasis. Methods: 1,268 patients with BCBM at the time of BC diagnosis and known clinical subtype (580 HR+/HER2-, 225 HR+/HER2+, 176 HR-/HER2+, and 287 HR-/HER2-) who were ≥ 20 years of age from 2010 to 2017 were identified using the NCI’s Surveillance, Epidemiology, and End Results (SEER) Program 18 registry. Baseline characteristics and survival were analyzed using Chi-Square and Kaplan-Meier methods. Results: Patients with HR-/HER2+ BC were the most likely to present with BCBM, compared to all BC patients (prevalence of 13.9% vs. 4.7%; p&lt;0.001). Further analysis demonstrated that HER2+ patients had an odds ratio of presenting with BCBM of 2.52 (95% CI: 2.24-2.84) compared to HER2- patients. Interestingly, in patients ages 20-39 with HR-/HER2+ BC, higher rates of brain metastases are noted within the BCBM group compared to all HR-/HER2+ breast cancer cases (28% vs. 7.6%; p&lt;0.001). The same trend is seen within the HR-/HER2+ African American population, with those in the BCBM group experiencing higher rates of brain metastases compared to all BC cases with the same subtype (14.3% vs. 5.9%; p&lt;0.001). Upon exploring insurance demographics, uninsured patients with HR-/HER2+ BCBM had much higher rates of brain metastases compared to all HR-/HER2+ BC cases (14.8% vs 6.4%; p=0.001). When examining TNM status, significant associations were noted between brain metastases and increased tumor and nodal status. Patients with T4 or N3 status with HR-/HER2+ BCBM exhibited much higher rates of metastasis compared to all BC cases with the same subtype (p&lt;0.001). Analysis of survival outcomes showed a median overall survival of 12 months for patients with HR-/HER2+ BCBM. The results displayed in the table below show that HR-/HER2- BCBM patients had the lowest 5-year percent survival, while HR+/HER2+ BCBM patients had the highest 5-year survival. Conclusions: This SEER database study provides insight into the demographics, clinical variables, and outcomes for BC clinical subtypes, specifically HR-/HER2+, from 2010 to 2017 in the United States. HR-/HER2+ breast cancer patients within the noted high-risk populations should be made aware of the increased rates of brain metastases compared to the general BC population, as earlier identification of brain metastases within the HR-/HER2+ cohort could improve patient survival.[Table: see text]
Association of homologous recombination deficiency in ovarian cancer with neoantigen load and expression of immune checkpoints.
Authors: Kathleen Fenerty, Charlene Marie Fares, Gottfried E. Konecny
Journal: Journal of Clinical Oncology (2021)

5536 Background: Immune checkpoint blockade (ICB) is being explored as a treatment option in ovarian cancer, but objective response rates for single agent ICB are modest at around 10-15%. Validated biomarkers are needed to predict which patients will respond to ICB. BRCA mutations and homologous recombination deficiency (HRD) status are the only validated integral biomarkers in ovarian cancer. HRD tumors exhibit defective DNA repair mechanisms that promote increased mutational burden, which we postulate may correlate with higher neoantigen load and increased expression of targetable immune checkpoints. Methods: The Cancer Genome Atlas (TCGA) ovarian cancer dataset was evaluated and previously published, well annotated samples were obtained for HRD status. HLA type was determined with OptiType. Nonsynonymous mutations were annotated with Ensembl VEP. pVAC-Seq using NetMHCpan algorithm predicted neoepitopes 9 amino acids in length for MHC class I, reporting only those with a predicted IC50 less than 500 nM. Immune checkpoint gene expression counts were normalized with TCGAbiolinks. Correlation between HRD status and neoantigen load was assessed by Wilcoxon test. After log2 transformation, Wilcoxon tests evaluated for association between HRD status and expression of immune checkpoints. The relationship between HRD status and PD-L1 protein abundance with reverse phase protein array was measured. Results: Data from 154 HRD positive and 198 HRD negative tumors were analyzed. HRD positive status correlated with higher neoantigen load (p = 0.038) and increased expression of the immune checkpoints CTLA4 (p = 0.024), TIGIT (p = 0.027), and PVR (p = 0.002), but not PD-L1 (p = 0.238), LAG3 (p = 0.583), HVEM (p = 0.805), GAL9 (p = 0.750), NECTIN2 (p = 0.874), VSIG3 (p = 0.438), PSGL1 (p = 0.205) or VISTA (p = 0.531). TIM3 (p = 0.064) and B7H3 (p = 0.052) both demonstrated a trend towards increased expression in HRD tumors. Interestingly, HRD status showed a negative association with PVRIG (p = 0.028). There was no association between PD-L1 protein abundance and HRD status. Conclusions: HRD positive ovarian tumors demonstrate higher neoantigen load than HRD negative tumors, as well as increased expression of certain immune checkpoints. This supports the hypothesis that increased neoantigen load leads to compensatory induction of immune checkpoints, and suggests that HRD status may predict response to ICB, particularly to drugs that target CTLA4, TIGIT, PVR, TIM3 and B7H4.
Circulating tumor DNA as a prognostic factor in peritoneal carcinomatosis after hyperthermic intraperitoneal chemotherapy.
Authors: Zongyuan Li, Xiaolin Pu, Hua Jiang
Journal: Journal of Clinical Oncology (2021)

e16280 Background: Hyperthermic intraperitoneal chemotherapy (HIPEC) is the main treatment for peritoneal carcinomatosis (PC).However, It is still a major problem to predict the efficacy of HIPEC. Some studies have shown that peritoneal cancer index (PCI) can be used to predict the efficacy of HIPEC, but the invasiveness and inaccuracy are shortcomings. Therefore, we need a minimally invasive and accurate prediction biomarker. Many studies have confirmed that circulating tumor DNA (ctDNA) can accurately predict the efficacy and prognosis of various solid tumors. This study aimed to evaluate the predictive value of ctDNA from ascites and plasma for HIPEC. Methods: Eligible PC patients should be defintive diagnosed by pathology or cytology. Each patient was treated with HIPEC for 4 times, with an interval of 3 days each time. Plasma and ascites samples were collected before HIPEC and after the last HIPEC. All samples were detected by next generation sequencing (NGS). The molecular tumor burden index (mTBI) and main clone variant allele fraction (VAF) changes were used as the prediction indexes of efficacy. In addition, The changes of common tumor markers such as CEA during the same period were used as controls. Results: A total of 19 patients with PC were enrolled from November 2018 to January 2020. Firstly, the mTBI changes of 14 patients whom had plasma samples at two time points (baseline and postHIPEC)were analyzed. Among them, 3 patients had no gene mutation were detected in two time points. There were significant differences in mTBI before and after HIPEC in the remaining 11 patients (Wilcoxon， p = 0.026). the median Ascites progression free survival (PFS) was 3.35 months (95% CI: 2.34 – 5.13 months), and the median overall survival (OS) was 5.93 months (95% CI: 4.93 – 11.17 months). The mTBI decline was significantly positively correlated with ascites PFS (Spearman r = 0.673, p = 0.023) and moderately positively correlated with OS (Spearman r = 0.510, p = 0.109). The highest VAF in plasma samples was defined as the main clone mutation. The main clone VAF decline was moderately positively correlated with ascites PFS (Spearman r = 0.588, p = 0.057) and slightly positively correlated with OS (Spearman r = 0.386, p = 0.241). As the controls, We found that the common tumor markers decline was no correlated with ascites PFS(Spearman r = 0.091, p = 0.790) and OS (Spearman r = 0.287, p = 0.396). We further analyzed the correlation of VAF between ascites and plasma co-mutation genes in 12 patients. The VAF of co-mutated genes in plasma and ascites was positively correlated (Spearman r = 0.794, p = 0.001). Conclusions: Plasma ctDNA can be used as a biomarker for predicting the efficacy of HIPEC for peritoneal carcinomatosis, and its accuracy is significantly higher than comon tumor markers. However, a larger sample size study are needed to validate our results.
Phase 1 trial of anti-CD22 recombinant immunotoxin moxetumomab pasudotox combined with rituximab for relapsed/refractory hairy cell leukemia.
Authors: Robert J. Kreitman, Maryalice Stetler-Stevenson, Constance Yuan, Hao-Wei Wang, Hong Zhou, Mark Raffeld, Liqiang Xi, Evgeny Arons, Julie Feurtado, Lacey James-Echenique, Raul Braylan, Katherine R. Calvo, Irina Maric, Alina Dulau, Ira Pastan
Journal: Journal of Clinical Oncology (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/m 2 , 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.
Abstract AP02: EXPOSING THE LOCAL FACTORS THAT CONTRIBUTE TO OVARIAN COLONIZATION OF FALLOPIAN TUBE-DERIVED TUMORS
Authors: Joanna E. Burdette, Katherine Zink, Matthew Dean, Laura M. Sanchez
Journal: Clinical Cancer Research (2019)

Abstract High grade serous cancer (HGSC) originates in the fallopian tube and typically invade and colonize the ovary as part of peritoneal metastasis. The purpose of this study was to define the factors that contribute to ovarian specific metastasis of fallopian tube HGSC. While protein factors have been explored that facilitate migration and invasion of fallopian tube cell to the ovary, the small molecule communication between the tissues during metastasis remains largely unexplored. Due to the proximity of ovarian primary metastasis, an experimental design was optimized using imaging mass spectrometry to capture the spatial composition of small molecules uniquely expressed when fallopian tube-derived tumor cells were grown in the microenvironment of the ovary as a model of primary metastasis. The observed mass-to-charge ratios (m/z's) that were induced specifically in co-culture represent small molecules that may contribute to the metastasis of HGSOC selectively to the ovary. Human fallopian tube epithelial HGSOC and tumorigenic murine oviductal epithelial cells, but not normal cell types, repeatedly induced a signal from the ovary at m/z 170. This signal was identified as norepinephrine, which was confirmed to simulate invasion of ovarian cancer cells lacking wildtype p53. Norepinephrine has an established role in ovarian cancer metastasis to secondary sites and the use of beta-blockers in women is associated with increased survival. The use of imaging mass spectrometry also revealed a series of new molecules that are specifically enhanced from the ovary or the fallopian tube during co-culture. These molecules may reveal pathways that contribute to metastasis and biological targets for therapeutic intervention to block ovarian metastasis of fallopian tube-derived HGSOC. The developed mass spectrometry method can be adapted to other mammalian-based model systems for investigation of untargeted metabolomics that facilitate metastasis. Citation Format: Joanna E. Burdette, Katherine Zink, Matthew Dean, and Laura M. Sanchez. EXPOSING THE LOCAL FACTORS THAT CONTRIBUTE TO OVARIAN COLONIZATION OF FALLOPIAN TUBE-DERIVED TUMORS [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr AP02.
Small cell lung cancer: Real-world data from two institutions in Lebanon for patients receiving carboplatin etoposide or atezolizumab in first line of treatment.
Authors: Fadi Nasr, Reem El Khoury, Intissar Yehia, Saada Diab, Ahmad Al Ghoche, Lewis Nasr
Journal: Journal of Clinical Oncology (2021)

e20578 Background: Small-cell lung cancer (SCLC), accounts for approximately 15% to 17% of all diagnosed lung cancers. It is an aggressive high-grade neuroendocrine carcinoma, diagnosed during advanced stages in the majority of patients. Despite the fact that first line treatment provides response rates of up to 80%, the majority of patients relapse within 6 months after completion of initial treatment. Few advances have been made in the management of recurrent disease and treatments patterns are poor and limited in each line of the disease. The aim of this study is to present real world data regards survival outcomes such as progression free survival and overall survival in SCLC patients receiving carboplatine etoposide or tecentriq carboplatin etoposide regimens as first line of treatment. Methods: This is a retrospective (descriptive) study on 56 patients aged ≥ 18 years and with confirmed histological SCLC. Patients with extensive stage of SCLC were enrolled in this cohort study from 2 health institutions in Lebanon from July 2007 to December 2019 and followed up until progression or death. Primary end points were overall survival (time from randomization to death from any cause) and progression free survival at 6 and 12 months (time from randomization to disease progression). Secondary endpoints included objective response rate and the duration of response. Exploratory analyses included the assessment of survival outcomes of each type of treatment according to liver and brain metastasis. Results: Overall, 56 SCLC patients, diagnosed between 2003 and 2019, were observed (age &lt;65: (27.0%, 10 patients); ≥65 (73.0%, 41 patients)). Most often prescribed treatment were etoposide-carboplatyl (80.8%, 42 patients) and atezolizumab (19.2%10 patients). Regarding metastasis at diagnosis, liver and brain metastasis were respectively (26.8%, 11 patients) and (17.1%, 7 patients). 27patients (71.1%) were alive at 6 months without progressive disease and 13 patients (34.21 %) alive at 12 months without PD. Median progression free survival incidence since diagnosis was 8.8 months. Overall survival was 10.86 months. Objective response rate after first line was 84.2%. In a cox regression analysis, liver metastasis, brain metastasis, survival at 6 or 12 months without progressive disease did not decrease significantly PFS or OS since diagnosis. Conclusions: To our knowledge, this is the first real world clinical data on SCLC in Lebanon. This study showed limited treatment options and short survival outcomes with PFS= 8.8months and OS= 10.86 months respectively for carboplatin etoposide regimen and tecentriq carboplatin etoposide regimen. There is an essential needs for clinical comparative studies in real world practicing between treatments at each line, specially for novel treatment like atezolizumab that may present new hope and directions for SCLC.
Review of cohort diversity in the development and validation of cancer risk assessment models.
Authors: Ambreen Khan, Gammon Amanda, Joanne M. Jeter
Journal: Journal of Clinical Oncology (2021)

e18570 Background: Multiple validated models have been proposed to quantify an individual's lifetime risk of breast and colon cancer. However, an evaluation of the race and ethnicity of the cohorts studied in the development and validation of each of these models has not been reviewed. Predicting cancer risks accurately in Black, Indigenous and People of Color (BIPOC) can be crucial in helping to reduce cancer mortality rates and improving access to preventative care for these individuals. Methods: A literature search was conducted to identify published development and validation studies for the following cancer risk assessment models: Breast Cancer Surveillance Consortium (BCSC) Risk Calculator, Tyrer-Cuzick, Gail, Claus, CanRisk/BOADICEA, BRCAPRO and MMRPRO. Articles included were identified through review of a number of electronic databases and websites for the cancer risk prediction models. Authors were contacted for data not readily available through literature search. Results: A total of 15 development studies and 19 validation studies of the cancer risk prediction models were reviewed for the seven models listed above. Out of the 19 validation studies, seven were internal and twelve were external validation studies. 80% (12/15) of development studies and 68% (13/19) of validation studies did not include information on racial and ethnic composition of the cohorts. After obtaining additional information from authors, 53% (8/15) of the development studies were conducted solely in non-Hispanic White (NHW) cohort. The development cohorts ranged from 50%-100% NHW, 0%-7% non-Hispanic Black (NHB), 0%-8% Hispanic/Latinx, 0%-3% Asian and 0%-1% Indigenous participants. 58% (7/12) of external validation studies included ethnically and racially diverse populations compared to 14% (1/7) of internal validation studies. The BCBS, Gail, BRCAPRO and MMRPRO models were the only models with external validation studies conducted in ethnically or racially diverse populations. Overall, the model that had the most diverse cohort for its development and internal validation studies was the BCBS with 70% NHW, 6.7% NHB, 7.5% Hispanic/Latinx, 2.7% Asian, 0.8% Indigenous and 11.5% mixed/other ethnicities. Conclusions: The majority of the models reviewed did not have ethnically or racially diverse populations in their development and validation cohorts. Awareness of the under-representation of ethnically and racially diverse populations in these models is an important precaution for extrapolating data when using these models in medical decision making for BIPOC individuals. Although several barriers exist for participation of BIPOC individuals in clinical studies, these findings highlight the critical, yet unmet need for the development and use of appropriate cancer risk models in racially and ethnically diverse populations as a means to reduce health-related disparities.
Institutional experience with <i>nab</i>-sirolimus in patients with malignancies harboring <i>TSC1</i> or <i>TSC2</i> mutations.
Authors: Mark Andrew Dickson, Vinod Ravi, Kristen N. Ganjoo, Gopa Iyer
Journal: Journal of Clinical Oncology (2021)

3111 Background: TSC1/ TSC2 genes are tumor suppressors in the mTOR pathway; mutated at low frequency across tumor types (̃1–2%). Retrospective analyses of patients (pts) with mTOR pathway mutations treated with everolimus did not show improved outcomes vs the wild type (Voss et al. Clin Cancer Res 2019. PMID 30327302). In NCT02201212, pts with TSC1/TSC2 mutations treated with everolimus had a 7% (2/30) response rate. In the AMPECT study, pts with advanced PEComa treated with a novel mTOR inhibitor (mTORi), nab-sirolimus ( nab-S, ABI-009), the subset of pts with TSC1/TSC2 mutations had a response rate of 64% (9/14) (Wagner et al. CTOS 2020. #3463014). In a xenograft model, nab-S showed significantly higher tumor accumulation, target suppression (pS6) and antitumor activity vs everolimus or sirolimus (Hou et al. AACR 2019. #348). In an expanded access program (NCT03817515), pts with advanced tumors bearing TSC1/ TSC2 mutations were treated with nab-S and outcomes in pts with malignancies other than PEComa are reported herein. Methods: Eligible pts (ECOG 0–2) received nab-S 100 mg/m 2 IV, once weekly for 2 of every 3 weeks at 3 US sites between 7/2019 and 11/2020. Results: 7 pts with TSC1/ TSC2 mutations have been consecutively enrolled and are reported here. 6/7 pts had multiple prior therapies including 2 pts previously progressing on an mTORi. 4/7 pts had partial response (PR), all in mTORi naïve pts. 2/7 pts had stable disease (SD). In 2 pts previously treated with an mTORi, 1 had SD and 1 came off treatment after 1 cycle (CA125 ↑) with no follow-up scan. Treatment-related serious adverse events (SAEs; hyperglycemia and infection) and dose reduction were reported in 1 pt with metastatic angiosarcoma; SAEs resolved and the pt continued Rx. No other SAE or dose limiting event was reported Conclusions: Patients with various malignancies bearing TSC1 or TSC2 mutations, most with progression on multiple prior therapies, showed evidence of response and manageable toxicities during treatment with nab-S. A basket trial of nab-S in malignancies with TSC1/ TSC2 mutations is planned. Clinical trial information: NCT03817515. [Table: see text]