tbuckley/cabot-search huggingface dataset:
Clinical usefulness of liquid biopsy for predictive response biomarkers identification in patients with advanced cancer.
Authors: Ivan Gonzalez, Sergio Sánchez-Sosa, Ismael Íñiguez-Galo, Jesús Vizcarra, Rebeca Ibarra-Hernández, Carolina Cruz-Reyes, Silvia Montilla-Fonseca, Sergio Sánchez-Barrera, Javier Cervantes-Bojalil
Journal: Journal of Clinical Oncology (2018)

e24025 Background: We conducted this study to describe and assess liquid biopsy’s clinical usefulness in the identification of predictive response biomarkers in patients with advanced cancer. Methods: Informed consent was obtained and LB was performed in peripheral blood of 29 patients with advanced cancer not candidates for primary tumor biopsy or which had insufficient tissue to perform a genetic study looking for predictive response biomarkers through digital sequencing in a 73 gene panel. Results: 11 patients were male and 18 were female with a mean age of 54.6 years. Clinical data was available for 27 patients, from them 92.6% (n = 25) were in clinical stage IV at the time of the LB. The patient’s follow up average was 42 months. 23 patients showed genomic alterations, from them 13 had an FDA approved target therapy while 31 alterations were target for alternative therapies. 44.4% of the patients had clinical usefulness, in 8 patients treatment was modified, in 2 patients it helped defining the primary tumor site and in 2 patients it served for follow up. Conclusions: Our study shows a clinical usefulness of 44% in patients with advanced cancer with results very similar to the ones previously published. Genre Primary tumor type Clinical Stage Lines of treatment Usefulness F Lung IV 3 Modified treatment F Lung IV - - M Liver II/IV 3 Treatment not modified M Lung III 3 Treatment not modified M Kidney II/IV 1 Treatment not modified F Jejunum IV 2 Treatment not modified F Breast II/IV 2 Modified treatment F Lung IV 1 Treatment not modified F Lung IV 1 Benefit in follow up F Breast IV 4 Modified treatment F Breast IV 1 Benefit in follow up F Cervical III/IV 6 Treatment not modified M Unknown IV 3 Treatment not modified M Sarcoma IV 3 Modified treatment F Ovary IV 4 Treatment not modified M Colorectal IV 3 Modified treatment F Breast IIa 1 Treatment not modified F Lung IV 1 Defined primary F Colorectal IV 3 Modified treatment F Breast IV 3 Modified treatment F Skin IV 7 Treatment not modified M Lung IV 2 Treatment not modified M Kidney IV 1 Define primary M Colorectal IV 2 Treatment not modified F Endometrium IV 4 Modified treatment M Prostate IV 6 Treatment not modified F Unknown IV 3 Treatment not modified M Unknown - - - F Lung - - -
Results of a phase I study of GS-5745 in combination with gemcitabine and nab-paclitaxel in patients (pts) with advanced pancreatic cancer.
Authors: Johanna C. Bendell, Xi Huang, Victoria Smith, Julia D. Maltzman, Alexander Starodub
Journal: Journal of Clinical Oncology (2016)

e15683 Background: GS-5745 is a monoclonal antibody that inhibits matrix metalloproteinase 9 (MMP9), an extracellular enzyme involved in matrix remodeling, tumor growth, and metastasis. Inhibiting MMP9 is hypothesized to block paracrine signaling and metastasis. Preclinical studies indicate that inhibition of MMP9 could alter both the tumor architecture and immune environment, allowing for both greater chemotherapy penetration and anti-tumor activity. Methods: Thirty six pts with locally advanced or metastatic pancreatic cancer were enrolled on this phase I study to receive the standard of care, gemcitabine (G) + nab-pactlitaxel (Abraxane, A) chemotherapy with GS-5745 800 mg IV every 2 weeks. All patients continued until disease progression or unacceptable toxicity. Clinical Trial Information: NCT01803282. Results: As of January 12, 2016, 36 pts with pancreatic cancer were treated (1 pt remains on therapy). The most common treatment-emergent AEs (TEAEs) included fatigue (75%), alopecia (56%), and peripheral edema (56%). TEAEs grade 3 or higher were neutropenia (25%), anemia (19%), and fatigue (14%). The most common serious TEAEs were pyrexia (14%), cellulitis (8%), dehydration (8%), and vomiting (8%). The median progression free survival (PFS) for all 36 subjects is 7.8 (90% confidence interval (CI) = [6.1, 11]) months, with an objective response rate (ORR) of 44%, and duration of response (DOR) of 5.8 months. Of these subjects, 31 did not receive prior chemotherapy for their metastatic disease, and had a median PFS of 9.2 (90% CI = [6.1, 11]) months, with a median DOR of 5.8 months and an ORR of 52%. Conclusions: Adding GS-5745 to GA does not appear to add additional toxicities beyond those seen with GA therapy alone. In this small group of 31 pts, the addition of this MMP9 antibody may improve the median PFS and ORR over standard of care in previously untreated pts. Further studies are needed to investigate these potential beneficial effects. Clinical trial information: NCT01803282.
Detection of inherited mutations in Brazilian breast cancer patients using multi-gene panel testing.
Authors: Rodrigo Santa Cruz Guindalini, Danilo Viana, João Paulo Kitajima, Andre Valim, David Schlesinger, Fernando Kok, Maria A. A. Koike Folgueira
Journal: Journal of Clinical Oncology (2018)

e13610 Background: Genetic diversity among populations in the spectrum and frequency of germline variants in BRCA1/2 genes has been well documented. It is unclear whether this extends to other breast cancer predisposition genes, particularly in Latin American populations, where access to genetic testing and counseling is very scarce. Methods: Study participants included a nationwide sample of 1554 Brazilian patients with breast cancer referred for hereditary cancer panel testing at a single clinical diagnostic laboratory from 2015 through 2017. NGS panels included comprehensive analysis of 21–39 known or proposed cancer susceptibility genes, depending on the panel ordered. De-identified data were used to determine the spectrum and frequencies of pathogenic germline variants and variants of uncertain significance (VUS) according to patients’ clinical variables. Results: In total, 153 (10%) participants carried germline pathogenic mutations in BRCA1/2 and 146 (9%) in other cancer predisposition genes. The prevalence of pathogenic variants in breast cancer patients diagnosed under 35 years-old was 27% (15% BRCA1/2, 4% TP53, 8% other genes). 315 distinctive pathogenic mutations were identified in 22 genes, most frequently in BRCA1 (29%), BRCA2 (21%), TP53 (11%), MUTYH heterozygous (10%), ATM (8%), CHEK2 (6%), and PALB2 (4%). The Brazilian TP53 c.1010G > A (p.Arg337His, R337H) founder mutation corresponded to 71% of all TP53 mutations, was related to 1.5% of all breast cancer cases, and was concentrated in South, Southeast and Central-West regions of Brazil. A total of 778 individuals had 1 or more VUS (50%). Conclusions: The inclusion of cancer susceptibility genes other than BRCA1/2 to the search for hereditary breast cancer through the use of panel testing almost doubled the identification of mutation carriers in Brazil. In our population, special attention has to be given to TP53 mutations which represented a substantial fraction of the total mutations identified and has the potential to impact significantly medical treatment options and screening recommendations for carriers and their relatives.
Comparison of blast clearance in peripheral blood and day 14 bone marrow biopsy for evaluation of disease response after 7+3 induction in acute myeloid leukemia (AML).
Authors: Fahrettin Covut, Divya Gupta, Raisa Pinto, Nina Dambrosio, Najla H. El Jurdi, Masumi Ueda, Leland L. Metheny, Brenda W. Cooper, Paolo Fabrizio Caimi, Ehsan Malek, Folashade Otegbeye, Marcos J.G. De Lima, Ben Kent Tomlinson
Journal: Journal of Clinical Oncology (2018)

7052 Background: Peripheral blast clearance (PBC) and blast clearance in day 14 bone marrow biopsy (D14BM) are commonly used for early assessment of disease response after 7+3 induction in patients with AML. We compared both techniques in predicting disease response. Methods: We identified newly diagnosed AML patients (pts) between 2003 and 2016 at our institution. All pts underwent D14BM after median of 13 days (range: 12 - 17) from initiation of 7+3 induction and recovery bone marrow biopsy between days 28 and 42. PBC was defined as percentage of absolute count reduction after induction. Eventual outcome of induction was defined per Cheson criteria. Risk groups were determined by combining cytogenetic and molecular data based on the NCCN guidelines. Logistic regression analysis was performed to identify independent factors associated with complete remission (CR) at recovery biopsy. Results: Among 183 AML pts, 48 (26.2%) underwent early re-induction after D14BM, whereas 135 (73.8%) pts were observed without re-induction. Among observed pts, 105 (77.8%) pts had CR at recovery biopsy. On univariate logistic regression analysis, good/intermediate-risk versus poor-risk by cytogenetic and molecular data (OR 2.98, 95% CI 1.07 – 9.17, p = 0.042), per 1 g/dL increase in hemoglobin at diagnosis (OR 1.34, 95% CI 1.06 – 1.73, p = 0.015), day-3 PBC > 85% (OR 9.21, 95% CI 2.74 - 37.41, p = 0.0006), < 5% blast in D14BM (OR 5.10, 95% CI 1.93 - 13.63, p = 0.0009) and ≤10% cellularity in D14BM (OR 5.55, 95% CI 2.16 - 14.64, p = 0.0004) were more likely to achieve CR at recovery biopsy. On multivariate logistic regression analysis, only day-3 PBC > 85% (OR 32.81, 95% CI 4.09 – 669.3, p = 0.004) was significantly associated with achieving CR at recovery biopsy. Day-3 PBC > 85% was more sensitive (75% vs 44%) but less specific (75.4% vs 87.6%) compared to D14BM blast < 5% in predicting CR at recovery biopsy. Conclusions: In our cohort, day-3 PBC > 85% was only independent factor associated with CR. Our study suggests that PBC might be useful early non-invasive tool to evaluate disease response compared to blast clearance in D14BM, in patients with circulating blasts before initiation of 7+3 induction.
Efficiency of identifying cancer patients who need smoking cessation support.
Authors: Samuel Lewis Cooper, Sarah Annand, Kenneth Michael Cummings, David T. Marshall, Jennifer L. Harper, Joseph M. Jenrette, Anand K. Sharma, Georges El Nahas, Graham W. Warren
Journal: Journal of Clinical Oncology (2018)

e13542 Background: NCCN Guidelines recommend smoking cessation support for patients who report smoking within the past 30 days. However, few reports have evaluated the utility of standardized questions to identify cancer patients need referral for smoking cessation support. Methods: A standardized 13 item tobacco assessment questionnaire was instituted as a part of standard clinical assessment for cancer patients presenting for initial consultation in a radiation oncology clinic within an NCI Designated Cancer Center having a high rural constituency. The screening form included assessment of current smoking, other tobacco use, electronic cigarette (EC) use, and current cessation medications. Results: Between October 2016 and November 2017, a total of 1,203 patients completed assessments, representing approximately 70% of all patients seen for consultation. Comparative data was obtained on 1087 to evaluate assessment of smoking everyday, some days, or not at all vs. time since last cigarette. Overall, 12.2% of patients were identified as current smokers everyday (n = 95, 8.7%) or some days (n = 38, 3.5%). In contrast, 169 patients (15.5%) reported smoking within the past 30 days including 105 (9.7%) within the past day, 26 (2.4%) within the past 1-7 days, and 38 (3.5%) within the past 8-30 days. Of 82 patients who reported last smoking between 30 days and 1 year, only 1 reported being a current smoker. Of 169 patients who report smoking within the past 30 days, 42 (24.9%) answered ‘not at all’ for smoking every day or some days, and 51 (30.2%) reported currently using one or more FDA approved medication or EC to help them quit smoking including: 29 (17.1%) nicotine patch, 7 (4.1%) nicotine gum, 10 (5.9%) nicotine lozenge, 5 (3.0%) bupropion, 7 (4.1%) varenicline, and 12 (7.1%) EC. Of 82 patients reporting last having smoked between 30 days and 1 year, 17 (20.7%) report currently using one or more FDA medications or EC to help them quit smoking. Conclusions: Restricting the definition of a current smoker to those who report smoking everyday or some days misses approximately 25% of cancer patients who smoked within the past 30 days. Asking patients about time since last cigarette is more efficacious to determine who might benefit from smoking cessation support.
Oncolytic and preventive effect of a new strain of rotavirus (family Reoviridae) on Guerin carcinoma growth in the experiment.
Authors: Sergey A. Kolpakov, Elena P. Kolpakova, Elena Yurievna Zlatnik, Anastasia O. Sitkovskaya, Oksana G. Shulgina, Ekaterina I. Zolotareva
Journal: Journal of Clinical Oncology (2018)

e14534 Background: The purpose of the study was to assess a cancer preventive and oncolytic effect of a strain of a new group of rotaviruses (family Reoviridae) using a model of transplantable Guerin carcinoma. Methods: A new attenuated rotavirus strain (working title «group K»), transplantable on a cell culture with 5·109 viral particles/mL was studied (http://jbks.ru/archive/issue-10/article-6). It was previously confirmed to be apathogenic on suckling rats and volunteers. The tumor growth rates and survival of animals were studied in 15 white outbred male rats divided equally into three groups: g1 received rotavirus 7 days after the tumor transplantation, g2 – 21 days before the tumor transplantation, g3 – controls, received 0.85% NaCl solution. G1 received a total of 4, and g2 – a total of 3 intramuscular injections into the inner side of thigh (0.3 mL once a week). The oncolytic (therapeutic) effect of the virus was studied in g1, and its preventive (vaccinal) effect – in g2. Results: Tumor volumes in rats of g2 were smaller compared to controls on the first week after the transplantation (1.22±0.11 and 2.2±0.51 cm3 respectively, p < 0.05). Further on, significant differences were observed in tumor volumes between rats of g1 and g2 (38.1±4.6 and 17.6±5.7 cm3on the 16th day and 60.1±8.7 cm3 and 28.2±11.0 on the 21st day respectively; p < 0.05). All the animals of the g3 died on 16-33rd days, 4 rats of the g1 died on 22-27th days after transplantation; all rats of the g2 survived with the absence of tumor growth or with its` regression. All survivers were observed for 5 months, with normal health status; then they were inoculated by the double dose of Guerin carcinoma. This did not result in the tumor formation in any animal, in contrast to the control rats, which all died on days 33-35 of tumor growth. Conclusions: The study demonstrated a marked preventive (vaccinal) effect of the studied rotavirus strain on transplantable Guerin carcinoma in rats; its oncolytic (therapeutic) effect was weaker. The injections were tolerated well. The resistance of surviving rats to additional inoculation of a double number of Guerin's carcinoma cells is likely to indicate the formation of the long-term antitumor immunity.
Real-world clinical outcomes and treatment patterns among metastatic breast cancer (MBC) patients with germline <i>BRCA</i> mutation (g<i>BRCA<sup>mu</sup></i><sup>t</sup>).
Authors: Ruben Quek, Jack Mardekian
Journal: Journal of Clinical Oncology (2018)

e13075 Background: MBC with gBRCAmutremains a heterogeneous disease, with variations in clinical management and survival outcomes. gBRCA mut are most likely to manifest among patients (pts) with triple negative breast cancer (TNBC); some pts, however, are HR+/HER2-. We present gBRCAmut testing rates among MBC pts and treatment patterns and clinical outcomes in gBRCAmut MBC adult pts with TNBC and HR+/HER2-. Methods: The Flatiron Health database was used in a real-world retrospective analysis of HR+ HER2- and triple negative MBC pts, ≥18 years old, diagnosed between Jan 2011-Nov 2017. Rates of gBRCA testing were assessed. One- through 5-year post MBC diagnosis product-limit OS estimates were calculated for gBRCAmut HR+/HER2- and triple negative MBC patients and compared using log rank test. Antineoplastic treatment patterns were also analyzed. Results: The study included 11,542 MBC pts, (9836 HR+/HER2-; 1706 TNBC). Results for gBRCA testing were available for 15.3% of patients overall; (14.1% within HR+/HER2- and 21.9% within TNBC); 1718/1763 (97.4%) were female. The most common first line treatments for gBRCAmut TNBC were carboplatin/gemcitabine (16%) and capecitibine (16%). First line treatments for gBRCAmutHR+/HER2- included letrozole (10%) and fulvestrant (8%). Patient counts and OS estimates for gBRCAmutcarriers are shown in the table; log rank test showed significantly lower OS for gBRCAmut triple negative MBC patients vs gBRCAmut HR+/HER2- MBC patients; 5-year survival rates are 21.3% and 33.0% for gBRCAmut triple negative and HR+/HER2- MBC patients respectively. Conclusions: In this real-world study of patients with MBC, gBRCA testing rates were low. Five-year OS rates were < 35% for both groups with gBRCAmut; patients with triple negative MBC having significantly worse OS rates compared to HR+/HER2- MBC patients. Poor prognosis among patients with gBRCAmut MBC demonstrates a significant unmet need for more targeted treatment options. Pts with gBRCA test results (N = 1763) by hormonal subtype, n (%) HR+/HER2- 1389 (78.8) TNBC 374 (21.2) gBRCA1/2mut 159 (11.4) gBRCA1/2mut 60 (16.0) Year Survival Estimates (%) 1 94.6 79.1 2 79.7 52.5 3 53.1 35.5 4 36.3 21.3 5 33.0 21.3
Human leukocyte antigen (HLA) B44 supertype and immunotherapy outcomes in non-small cell lung cancer (NSCLC).
Authors: Henry Lu, Amy Lauren Cummings, Jonathan Wade Goldman, Aaron Elliott Lisberg, Siwen Hu-Lieskovan, Tristan Grogan, Jaklin Gukasyan, John Madrigal, James M. Carroll, Krikor Bornazyan, Benjamin Jones, Zorawar Singh Noor, Jesse Meir Zaretsky, David Elashoff, Dennis J. Slamon, Steven M. Dubinett, Edward B. Garon
Journal: Journal of Clinical Oncology (2018)

3026 Background: In melanoma (mel) patients (pts) treated with immune checkpoint inhibitors, presence of HLA class I (HLA-1) B44 supertype (B44+) correlated with survival (Chowell, Science). B44 preferentially binds negatively charged (neg) peptides and those with glutamic acid (E) at the anchor position. Positively charged (pos) peptides impede binding. In mel, B44 benefit was driven by glycine (G) > E changes. We evaluated the predictive role of HLA-I supertypes in NSCLC as neoepitopes are likely different as tranversions (Tv) predominate in smokers compared to transitions (Ti) in mel. Methods: 58 advanced NSCLC pts treated with pembrolizumab with 3 years follow up and sufficient PBMCs and/or tumor sample had multiplexed paired-end WES with Illumina HiSeq 2000/3000. HLA typing used BWA-ALN and Athlates software; supertype was determined by 2008 criteria (Sidney, BMC Immunol). Overall survival (OS) and progression-free survival (PFS) were compared by supertype using non-parametric log-rank tests. Tumor variant amino acids (vAA) were identified by GATK best practices, and AA charge was derived from standard charts with stop codons considered uncharged (unc). Ti/Tv and charge change analysis used two-proportion z-tests. Statistical analyses were performed with SPSS V24 (Armonk, NY). Results: Of 9 supertypes evaluated, only absence of B44 supertype (B44-) had longer OS [median OS of 14.9 months (m) vs 9.2 m in B44+ (HR 0.55, 95% CI 0.30-0.99, p = 0.048)], driven by B44- smokers [median OS 21.5 m vs 8.5 m in all other pts (HR 0.50, 95% CI 0.26-0.995, p = 0.048)]. PFS and response rate trends were similar to OS. vAA charge changes from unc/pos to neg in 14/384 (3.6%) Tv and 8/192 (4.2%) Ti (NS) and from unc/neg to pos in 48/384 (12.5%) Tv vs 12/192 (6.3%) Ti (p = 0.019). G > E is not possible from Tv. Among pts with evaluated tumors, Ti/Tv, vAA charge, and G > E were as predicted. Conclusions: Like mel, the B44 supertype associates with OS in NSCLC, however with the opposite effect direction, driven by favorable OS in B44- smokers. A potential mechanism for these histology-specific results is the greater likelihood of Tv in smokers that may lead to neoepitopes with characteristics less favorable for presentation on HLA B44.
A phase II and co-clinical study of an AKT inhibitor in patients (pts) with biomarker-enriched, previously treated metastatic colorectal cancer (mCRC).
Authors: A. Dasari, Michael J. Overman, David R. Fogelman, Bryan K. Kee, David Menter, Kanwal Pratap Singh Raghav, Van Karlyle Morris, Jisu Oh, Ji Wu, Zhiqin Jiang, Feng Tian, Liana Adam, Mary Brimer, Jeffrey Morris, Funda Meric-Bernstam, Scott Kopetz
Journal: Journal of Clinical Oncology (2016)

3563 Background: The PI3K / AKT pathway has several roles in CRC growth and progression through downstream targets including the MAPK pathway. Based on strong preclinical mCRC and non-mCRC clinical data, we hypothesized that PI3K pathway inhibition may have clinical activity in mCRC pts with biomarkers of PI3K pathway activation. Methods: Previously treated mCRC pts were enrolled into 2 cohorts (A: PTEN loss by IHC; B: PIK3CA mutation, mt; table). Since MAPK pathway mts have been shown to reduce sensitivity to PI3K pathway inhibition, KRAS and BRAF mts were used as negative selectors. Pts were administered the oral, allosteric AKT inhibitor, MK2206 in this single institution, CTEP-sponsored trial. Primary end point was response rate and secondary end points were progression free survival (PFS), overall survival (OS) and safety. Paired biopsies were used to establish patient derived xenografts (PDX) for a co-clinical trial. Other planned translational studies included correlation of biomarkers in primary & metastatic sites and pharmacodynamic assessment of PI3K pathway inhibition. Results: In 18 pts (median age 56; median prior systemic therapies 3), common treatment related adverse events (AEs) were hyperglycemia, nausea / vomiting (67% each) diarrhea (61%) and rash (50%) Grade ≥ 3 AEs were uncommon and included hyperglycemia, elevated liver tests (17% each) and fatigue (11%). Of these, 2 were grade 4 AEs of diarrhea and elevated bilirubin. There were no radiographic responses; all pts in cohort A had progressive disease (PD) while 2 in cohort B had stable disease (SD) as best response (table). Median PFS was 1.8 months (m) and median OS was 6.8 m. Translational work in PDX, paired tumor biopsies and peripheral blood samples is ongoing and will be presented at the conference. Conclusions: In contrast to robust preclinical data, single agent MK-2206 does not have activity in mCRC pts even when carefully enriched. However, extensive, pre-planned translational studies provide us with a unique opportunity to evaluate the reasons for this discrepancy. Clinical trial information: NCT01802320.Cohort PIK3CA AKT KRAS BRAF PTEN IHC Enrolment Best Response A wt wt wt wt Loss 9 PD x 9 B mt wt wt wt Any 9 SD x 2