tbuckley/cabot-search huggingface dataset:
Exploring racial disparities of actionable mutations in gynecologic cancers.
Authors: Vasanti Jhaveri, Dino Fanfan, Jared Addison Cotta, Sophia George, Brian M. Slomovitz, Marilyn Huang
Journal: Journal of Clinical Oncology (2019)

e17098 Background: Next Generation Sequencing (NGS) guides targeted therapy and clinical trial enrollment for patients with gynecologic malignancies. South Florida is a key region to explore biomarkers and molecular alterations common in Hispanic (H) patients due to the high proportion of H individuals. While NGS testing is increasingly used in clinical practice to aid in treatment planning, ethnic minorities are at risk for health disparity including clinical trial enrollment. The objective of this study was to determine if frequently reported mutations are also common in a predominantly H population with gynecologic cancers. Methods: Clinicopathologic data was obtained from women treated at our institution from Jan. 2014 to Jan 2019 for gynecologic malignancies. Women with ovarian (OC), endometrial (EC), and cervical cancer (CC) with NGS results from Caris Life Sciences were included for analysis. Women self-report ethnicity based on initial hospital intake form. Mutations based on point mutations, indels, fusions and copy number variations were identified. Descriptive statistics are reported. IRB approval was obtained. Results: A total of 233 patients with 117 ovarian (OC), 24 cervical (CC) and 92 endometrial cancers (EC) were included. Among the 233 women, 96 (41%) were H, 137 (59%) identified as NH. There were 38 H and 48 NH patients with EC; 50 H and 62 NH OC patients; and 8 H and 13 NH CC patients. Among EC patients, TP53 appeared in 42% vs. 47%, PTEN 26% vs. 30% , PIK3CA 32% vs. 17%, CTNNB1 32% vs. 17% , and KRAS 16% vs. 21% of H and NH cases respectively. In the OC cohort, TP53 appeared in 74% vs. 75% , BRCA1/2 10% vs. 19%, KRAS 16% vs. 16% and PIK3CA 8% vs. 6% of H and NH cases respectively. In CC patients, TP53 appeared in 25% vs. 23%, KMT2C 12.5% vs. 7.6% and PIK3CA 0 vs. 38% of H and NH cases respectively. There were no statistical differences in the mutation rates between the two groups. Conclusions: There is limited data reported on the variation of mutations based on ethnicity in women with gynecologic cancers. Our study suggests there may be different driver mutations based on ethnicity. Future studies in larger cohorts are needed to further assess genomic differences, potential responses to treatment and further increase H population enrollment into clinical trials.
The impact of smoking cessation on breast cancer patients’ survival.
Authors: Mazen Jizzini, Akshara Singareeka Raghavendra, Nuhad K. Ibrahim, George Kypriotakis, Paul M. Cinciripini, Kareem Seoudy, Maher A. Karam-Hage
Journal: Journal of Clinical Oncology (2019)

1542 Background: Breast cancer remains to be one of the highest causes of cancer mortality amongst females globally, second only to lung cancer. Smoking is strongly associated with increased all-cause mortality, including breast cancer related death. It has also been shown to have a negative influence on long-term survival after successful breast cancer treatment. Prior studies have shown that smoking cessation may lead to improved prognosis and better outcomes. Methods: This is a retrospective cohort study of breast cancer patients who were identified as smokers, some of who were referred to the tobacco treatment program (TTP) located at MD Anderson Cancer Center. TTP includes careful patient screening, motivational counseling, and pharmacotherapy. We complemented the original data collected by conducting in-depth chart reviews to extract data including patient demographics, date of diagnosis, stage of cancer, smoking status, duration of abstinence and dates of follow-up or death. We then examined associations between smoking status and survival status using multinomial regression models adjusting for biomarkers of disease and personal characteristics. Results: Among all breast cancer patients (N = 31069), we identified those who are smokers (n = 2320) by matching the TTP database with smoking status from our institutional electronic health records. Of those, 740 patients were referred to TTP. Amongst these, 242 patients quit smoking and remained abstinent at the 9 month follow-up. Compared with non-abstainers, those who quit were more likely to be alive with no evidence of disease during the observation time (RR = 1.62, p = 0.045). When analyzed at different stages, the RR went from 1.35 (p = 0.42) to 2.77 (p = 0.34) for stages 3 and 1, respectively. Although the strength of this relationship varied among disease stage, the direction of the relationship remain consistent. Conclusions: Our data shows that smoking cessation is associated with improved survival status amongst breast cancer survivors across all stages. Comprehensive smoking cessation services may improve survivorship when started as early as the time of diagnosis. Further analysis of the association between smoking cessation and other associated medical outcomes will be conducted to further determine the specific impact of cessation programs.
Does a food intervention makes abiraterone treatment affordable?
Authors: Nielka P. Van Erp, Guillemette Emma Benoist, Winald R. Gerritsen, Niven Mehra, David Burger, Paul Hamberg, Inge van Oort, Floor Lubberman
Journal: Journal of Clinical Oncology (2019)

e16523 Background: Abiraterone is registered for metastatic prostate cancer. It is used in a fixed oral dose of 1000mg OD in a fasted state in combination with 10mg prednisone daily. Although large differences in the effect of food on abiraterone exposure are reported (ranging from 1-10 fold increase in area under the concentration time curve (AUC)) it is generally accepted that abiraterone is much better absorbed in the presence of food. By administering abiraterone with food a reduced dose can be given while maintaining equivalent abiraterone exposure. Moreover aadministering abiraterone with food is more patient friendly and it could significantly reduce the treatment costs of abiraterone.The aim of this study was to establish the bio-equivalent lower dose of abiraterone when taken with a continental breakfast compared to the standard intake of 1000mg OD in fasted state. Methods: In this phase I cross-over multi-center study abiraterone pharmacokinetics (PK) were evaluated in patients with metastatic prostate cancer who were treated with 1000 mg abiraterone in a fasted state, followed by 500 mg taken with a continental breakfast. After both periods of 14 days, abiraterone plasma exposure was measured. Bioequivalence was assumed when the GMR (fed/fasted) of the AUC 0-24h and C max and their 90% confidence interval (CI) were within the range of 0.8 and 1.7. Results: 14 patients were enrolled into the study, of whom 12 were eligible for PK analysis. GMR (fed/fasted) AUC 0-24h was 0.88 (90% CI 0.73-1.07), GMR C max was 1.03 (CI 0.79-1.34) and the GMR of C trough was 0.81 (90% CI 0.60-1.10). Conclusions: Ingesting 500mg abiraterone with a continental breakfast was not considered bio-equivalence when compared to 1000mg taken fasted. The criteria for bio-equivalence could not be met due to the large variability in pharmacokinetics of abiraterone within and between patients. Due to this large variability in abiraterone exposure, we believe that dose optimization by food intake is not a feasible strategy for abiraterone. The intake of abiraterone with food could not be advised based on the results presented in our study. Clinical trial information: NCT02883166. [Table: see text]
A phase 3 randomized study of neoadjuvant chemotherapy (NAC) alone or in combination with nivolumab (NIVO) ± BMS-986205 in cisplatin-eligible muscle invasive bladder cancer (MIBC).
Authors: Guru Sonpavde, Andrea Necchi, Shilpa Gupta, Gary D. Steinberg, Juergen E. Gschwend, Michiel Simon Van Der Heijden, Nathalie Garzon, Ayanbola Elegbe, Bradley Raybold, Danny Liaw, Mark Rutstein, Matt D. Galsky
Journal: Journal of Clinical Oncology (2019)

TPS4587 Background: Immuno-oncology (IO) therapies have revolutionized the treatment (tx) of pts with advanced bladder cancer (advBC). For pts with cisplatin-eligible MIBC, the recommended tx regimen is cisplatin-based NAC prior to radical cystectomy (RC). However, since only ≈ 30% of pts achieve a pathologic complete response (pCR) translating to improved long-term outcomes with approved regimens, new therapies are needed. PD-L1 expression is associated with aggressive BC and has been shown to increase in BC after NAC, suggesting that the PD-1/PD-L1 axis is a valid therapeutic target. Additionally, expression of indoleamine 2,3-dioxygenase (IDO) is higher in BC than in normal bladder tissue and is associated with advanced disease and poor clinical outcome. BMS-986205, a selective, potent, once-daily oral IDO1 inhibitor that works early in the IDO1 pathway to reduce kynurenine production, has demonstrated clinical activity in combination with NIVO (anti–PD-1) in pts with IO tx–naive advBC who had ≥ 1 prior line of therapy (ORR, 37%). Taken together, these data provide a rationale for investigating NAC + NIVO + BMS-986205 in MIBC. Here we describe a randomized, partially blinded, phase 3 study evaluating the efficacy and safety of NAC ± NIVO ± BMS-986205 followed by RC and continued IO tx in pts with MIBC (NCT03661320). Methods: Pts aged ≥ 18 years with previously untreated MIBC (clinical stage T2-T4a, N0, M0), creatinine clearance ≥ 50 mL/min, and predominant UC histology who are eligible for cisplatin-based NAC and RC will be enrolled. Pts with evidence of positive lymph node; metastatic BC; or prior systemic therapy, radiotherapy, or surgery for BC other than TURBT are not eligible. Pts will be randomized to receive NAC (gemcitabine/cisplatin; arm A), NAC + NIVO + oral placebo (arm B), or NAC + NIVO + BMS-986205 (arm C) followed by RC (all arms); arms B and C will receive continued IO tx. Primary endpoints include pCR after neoadjuvant tx and event-free survival (arms C vs A; arms B vs A). Secondary endpoints are overall survival and safety. This global study in 28 countries began accrual in Nov 2018 and has a target enrollment of 1200 pts. Clinical trial information: NCT03661320.
Phase II trial of metronomic capecitabine and cyclophosphamide with lapatinib and trastuzumab in patients with HER2-positive metastatic breast cancer.
Authors: Irene Kang, Darcy V. Spicer, Janice M. Lu, Susan G. Groshen, Denice Tsao-Wei, Agustin A. Garcia
Journal: Journal of Clinical Oncology (2019)

e12508 Background: Metronomic chemotherapy is an emerging paradigm of cancer therapy in which low doses of chemotherapy are delivered at frequent intervals. Activity in patients with metastatic breast cancer (MBC) has been demonstrated in several phase II clinical trials. Methods: We proposed a regimen with metronomic chemotherapy and dual HER2 inhibition in HER2 positive patients with MBC. We hypothesized that this regimen will be highly active in MBC and have a favorable toxicity profile. Patients were treated on a 21-day cycle with capecitabine 1500mg PO daily, cyclophosphamide 50mg daily, lapatinib 1000mg PO daily and trastuzumab 6mg/kg IV once per 21-day cycle. This regimen was continued until disease progression or unacceptable toxicity. Primary endpoint was progression free survival (PFS). Secondary endpoints were overall response rate (ORR), clinical benefit rate (CBR), overall survival (OS), and safety and tolerability of this regimen. Eligibility criteria were patients 18 years of age and older who had histologically confirmed HER2-positive metastatic breast cancer with prior trastuzumab use in the adjuvant or metastatic setting with no more than two prior regimens for MBC. Results: Ten patients were accrued from Jan 2014-Oct 2016. Median age was 52 (range 38 - 79) years. Median number of chemotherapy regimens for metastatic disease was 0.5 (range 0-2). Median PFS was 13.7 (95% CI: 2.6, 16.6) months. Median OS was 29.6 (95% CI: 11.8, 60.5+) months. ORR was 30%, and CBR was 70%. Grade 3 or 4 toxicities were identified in 6 patients. The most common toxicities of any grade were fatigue (100%), diarrhea (80%), anemia, neutropenia, ALT increase, nausea and hand-foot syndrome 50% each. One patient achieved CR for over 3 years and continues on treatment at time of this report. 8 patients progressed and 1 patient withdrew from study without response evaluation. The trial was closed due to lack of accrual. Conclusions: The proposed regimen of metronomic capecitabine and cyclophosphamide with lapatinib and trastuzumab appears to be active in patients with HER2 positive MBC but with significant toxicity. Clinical trial information: NCT01873833.
Structured literature review (SLR) and meta-analyses of the prevalence of microsatellite instability high (MSI-H) and deficient mismatch repair (dMMR) in gastric, colorectal, and esophageal cancers.
Authors: Mayur Amonkar, Maria Lorenzi, Jacky Zhang, Shivani Mehta, Kai-Li Liaw
Journal: Journal of Clinical Oncology (2019)

e15074 Background: Pembrolizumab is approved in the US for treatment of unresectable/metastatic MSI-H/dMMR solid tumors progressing after standard prior treatment. While some data exist on MSI-H/dMMR prevalence in colorectal cancer (CRC), data on other gastrointestinal (GI) cancers is sparse. Methods: An SLR covering solid tumor types identified English language publications using immunohistochemistry (IHC) for all 4 MMR proteins or polymerase chain reaction (PCR) techniques using specified NCI or Promega marker panels. A targeted review was conducted for CRC due to larger volume of publications in this tumor type. MEDLINE, EMBASE, Cochrane databases and key cancer congresses were searched for relevant articles. Among eligible studies, meta-analyses were performed (random effects model) on the prevalence of MSI-H and dMMR among gastric, colorectal and esophageal cancers. If possible, prevalence estimates were also obtained by geography, disease stage, and histology. Results: Of 1,176 citations retrieved in the full review, 35, 17 and 6 studies reported prevalence of MSI-H and/or dMMR in gastric, CRC, and esophageal cancers, respectively. Among gastric cancers, MSI-H pooled prevalence (with 95% CI) from 32 studies (16,308 patients) was estimated at 11% (9-12%) and dMMR pooled prevalence from 4 studies (854 patients) was estimated at 8% (2-17%); in stage 4 cancers, the prevalence was 7% (4-9%; 10 studies; 383 patients). In CRC, MSI-H pooled prevalence from 14 studies (8,156 patients) was estimated at 13% (10-16%) and dMMR pooled prevalence from 4 studies (11,434 patients) was estimated at 10% (5-15%). For stage 4 CRC, the prevalence was 5% (1-10%; 4 studies; 252 patients). Among esophageal cancers, MSI-H pooled prevalence from 6 studies (731 patients) was estimated at 4% (0-11%). Conclusions: This comprehensive SLR provides prevalence estimates of MSI-H and dMMR across 3 key GI tumors based on published data. The prevalence estimates of MSI-H among gastric cancer and CRC were similar to their corresponding dMMR prevalence estimates. MSI-H prevalence appeared to be lower for advanced stage gastric cancer and CRC.
Three-year overall survival update from the PACIFIC trial.
Authors: Jhanelle Elaine Gray, Augusto E. Villegas, Davey B. Daniel, David Vicente, Shuji Murakami, Rina Hui, Takayasu Kurata, Alberto Chiappori, Ki Hyeong Lee, Byoung Chul Cho, David Planchard, Luis G. Paz-Ares, Corinne Faivre-Finn, Johan F. Vansteenkiste, David R. Spigel, Catherine Wadsworth, Maria Taboada, Phillip A. Dennis, Mustafa Ozguroglu, Scott Joseph Antonia
Journal: Journal of Clinical Oncology (2019)

8526 Background: In the phase 3 PACIFIC study of patients with unresectable, Stage III NSCLC without progression after chemoradiotherapy (CRT), durvalumab demonstrated significant improvements versus placebo in the primary endpoints of progression-free survival (HR, 0.52; 95% CI, 0.42–65; P &lt; 0.0001) and overall survival (OS; HR, 0.68; 95% CI, 0.53–0.87; P = 0.00251). Safety was similar and durvalumab had no detrimental effect on patient-reported outcomes. Here, we report 3-year OS rates for all patients randomized in the PACIFIC study. Methods: Patients with WHO PS 0/1 (any tumor PD-L1 status) who received ≥2 cycles of platinum-based CRT were randomized (2:1), 1–42 days following CRT, to receive durvalumab 10 mg/kg intravenously every 2 weeks or placebo, up to 12 months, and stratified by age, sex, and smoking history. OS was analyzed using a stratified log-rank test in the ITT population. Medians and OS rates at 12, 24 and 36 months were estimated by Kaplan-Meier method. Results: In total, 713 patients were randomized of whom 709 received treatment (durvalumab, n = 473; placebo, n = 236). The last patient had completed the protocol-defined 12 months of study treatment in May 2017. As of January 31, 2019 (data cutoff), 48.2% of patients had died (44.1% and 56.5% in the durvalumab and placebo groups, respectively). The median duration of follow-up was 33.3 months (range, 0.2–51.3). Updated OS remained consistent with that previously reported (stratified HR 0.69, 95% CI, 0.55–0.86), with the median not reached (NR; 95% CI, 38.4 months–NR) with durvalumab versus 29.1 months (95% CI, 22.1–35.1) with placebo. The 12-, 24- and 36-month OS rates with durvalumab and placebo were 83.1% versus 74.6%, 66.3% versus 55.3%, and 57.0% versus 43.5%, respectively. After discontinuation, 43.3% and 57.8% in the durvalumab and placebo groups, respectively, received subsequent anticancer therapy (9.7% and 26.6% subsequently received immunotherapy). OS subgroup results will be presented. Conclusions: Updated OS data from PACIFIC, including 3-year survival rates, underscore the long-term clinical benefit with durvalumab following CRT and further establish the PACIFIC regimen as the standard of care in this population. Clinical trial information: NCT02125461.
Trial in progress abstract phase I trial of 5-aza-4’-thio-2’-deoxycytidine (Aza-TdC) in patients with advanced solid tumors.
Authors: M. Cecilia Monge B., Geraldine Helen O'Sullivan Coyne, Richard Piekarz, Naoko Takebe, Ashley Bruns, Arjun Mittra, Sabrina Sharmin Khan, Jerry M. Collins, Larry Anderson, Lamin Juwara, Brandon Miller, Robert J. Kinders, Larry Rubinstein, Alice P. Chen, James H. Doroshow
Journal: Journal of Clinical Oncology (2019)

TPS3148 Background: The nucleoside analog 5-aza-4’-thio-2’-deoxycytidine (Aza-TdC) inhibits DNA methyltransferase 1 (DNMT1), a methyltransferase involved in methylation-mediated silencing of tumor suppressor genes. Attenuation of DNA methylation via DNMT1 inhibitors results in reactivation of silenced tumor suppressor genes and can lead to tumor growth arrest and apoptosis. The DNMT1 inhibitors decitabine and 5-azacytdine are currently FDA-approved for use in myelodysplastic syndromes and are also used in patients with acute myeloid leukemia. Relative to these compounds, Aza-TdC exhibits enhanced stability and incorporation into DNA and has shown improved preclinical antitumor activity in both leukemia and solid tumor xenograft models. This study seeks to evaluate the safety and maximum tolerated dose (MTD) of oral Aza-TdC in patients with advanced solid tumors. Secondary study objectives include assessing objective response by RECIST 1.1, pharmacokinetic (PK) analysis, and examining re-expression of tumor suppressor genes inhibited by methylation in circulating tumor cells (CTCs). Methods: Patients are treated with Aza-TdC on days 1-5 and 8-12 of each 21-day cycle. The study follows Simon accelerated titration design 3, with 100% dose increments and 1 patient per dose level. Accelerated titration will continue until 1 patient experiences a dose-limiting toxicity (DLT) or 2 patients experience drug-related grade 2 toxicity at any dose level, after which, a 3 + 3 dose escalation design will be used. Blood samples are collected for PK and CTC analyses. An MTD expansion cohort is planned, in which tumor biopsies will be collected for further pharmacodynamic assessments. Patients included in this study must be ≥18 years old and have histologically documented solid tumors that have progressed on standard therapy and for which there is no other standard therapy available. Dose level 3 has been completed without any DLTs; enrollment to dose level 4 began in February 2019. Funded by NCI Contract No. HHSN261200800001E. Clinical trial information: NCT03366116.
Comparative genomic profiling of paired tissue and blood samples from advanced non-small cell lung cancer patients.
Authors: Xiaoyun Wang, Chan Gao, Guoqiang Wang, Shangli Cai, Zheng Fang
Journal: Journal of Clinical Oncology (2019)

e20521 Background: While tissue-based next generation sequencing (NGS) ushered in a new era of precision medicine, profiling of circulating tumor DNA (ctDNA) has also emerged as a minimally invasive alternative to inform clinical decisions. In non-small cell lung cancer (NSCLC), data describing comparison between mutational profiles of paired tissue and blood samples remained scarce. Methods: Matched formalin-fixed paraffin-embedded tissue and peripheral blood samples (≤14 days apart) were collected from treatment naïve advanced NSCLC patients. Genomic profiling was performed using whole exome sequencing (WES) for tissues and a 150-gene panel for ctDNA, with a mean sequencing depth of 239× and 3417× respectively. Tumor- and blood-based tumor mutational burdens (tTMB and bTMB) were defined as the sum of missense, stop-loss, in-frame and frameshift mutations in protein coding regions and the number of somatic single nucleotide variations and indels in targeted coding regions respectively. Maximum somatic allele frequency (MSAF) was also determined for each case as a measure of ctDNA quantity. Results: Matched tissue and blood samples from 48 patients were included for sequencing. A total of 410 mutations were identified, where 84 (20.5%) were covered in both sample types. Sixty-three (15.4%) alterations were only detected in tissues while 263 (64.1%) were exclusively seen in ctDNA. The most frequently altered genes were SMARCA2 (62.5%), TP53 (54.2%), and AR (47.9%) in ctDNA and were TP53 (37.5%) and EGFR (22.9%) in tissues. Aberrations in all genes, except for FAT1 and KRAS, occurred at a higher frequency in ctDNA. The median tTMB and bTMB were 75 and 7, respectively. bTMB displayed a moderate linear relationship with tTMB as indicated by a Spearman correlation of 0.62 (P &lt; 0.01). Patients with bTMB ≥ 7 had significantly higher MSAF (Mann-Whitney P &lt; 0.001), suggesting a positive correlation between bTMB and ctDNA fraction in blood. Conclusions: Mutational profiles as well as TMB levels were in general consistent between blood and tissue samples, further corroborating a role for ctDNA testing as a complementary approach to tissue testing in advanced NSCLC.