tbuckley/cabot-search huggingface dataset:
Co-targeting mTORC and EGFR signaling as a therapeutic strategy in HNSCC.
Authors: Adam D Swick, Prashanth Jyothi Prabakaran, Margot Miller, Amal M Javaid, Michael Fisher, Emmanuel Sampene, Irene Ong, Mari Iida, Kwang-Ok P Nickel, Justine Yang Bruce, Deric Wheeler, Randall J. Kimple
Journal: Journal of Clinical Oncology (2017)

e17509 Background: Head and neck squamous cell carcinomas (HNSCCs) are frequently altered along the PI3K/AKT/mTORC signaling axis leading to development of therapeutics targeting this pathway. Despite excellent preclinical data, the use of these compounds as monotherapy has been underwhelming in initial clinical trials and identification of predictive biomarkers remains challenging. The EGFR monoclonal antibody cetuximab remains the only approved targeted agent for HNSCC and has potential use in combination therapy. Methods: Both catalytic mTORC (AZD8055) and PI3K/mTORC(NVP-BEZ-235) inhibitors were tested +/- cetuximab in a panel of HNSCC cell lines and patient derived xenografts (PDX) evaluated for potential biomarkers of PI3K/AKT/mTORC pathway. Cell lines were assayed for response to all three agents by multiple approaches, and confirmed by siRNA knockdown. Five PDX models that presented PIK3CA mutation or intrinsic cetuximab resistance were treated with a combination of cetuximab and AZD8055. Results: In HNSCC cells no likely sensitizing mutations were identified, whereas putative protein biomarkers were elevated in some lines. All lines showed similar response to both PI3K/mTORC and dual mTORC inhibition with cetuximab combination producing modest additive effect with similar results for siRNA knockdown. In PDX models, in vivo single agent mTORC inhibition inhibited growth of a PIK3CA mutant cancer, but had little effect on any PIK3CAWT or a second PIK3CA mutant model. In all models the combination therapy showed greater growth delay than monotherapy. Conclusions: The uniform ability of PI3K and mTORC inhibition to suppress the growth of HNSCC cells highlights the pathway’s role in driving proliferation. In vivo, despite some PDX models meeting likely selection criteria, the single agent therapy was largely ineffective. Conversely improved response of combination treatment suggests the potential for adding a catalytic mTORC inhibitor to cetuximab therapy. Overall, these results add to a growing body of evidence suggesting approaches that attempt to match biomarkers to the optimal therapy in HNSCC remains complex and challenging.
Recurrent <i>BRAF</i> mutations in bone marrow progenitors of patients with Erdheim-Chester disease.
Authors: Jean-François Emile, Fleur Cohen-Aubart, Claude Baillou, Damien Roos-Weil, Matthias Papo, Zofia Hélias-Rodzewicz, Omar Ibrahim Abdel-Wahab, Olivier A Bernard, Zahir Amoura, François M Lemoine, Julien Haroche
Journal: Journal of Clinical Oncology (2016)

7069 Background: Erdheim-Chester disease (ECD) and Langerhans cell histiocytosis (LCH) are disorders marked by tissue infiltration with macrophages or dendritic cells. > 80% of ECD and LCH patients have somatic activating mutations in BRAF or other genes involved in the MAP kinase pathway. Up to 20% of ECD patients also have LCH lesions, reported herein as mixed histiocytosis (MH). Although typically considered a disease of tissue infiltrating cells, circulating CD14+ monocytes have been occasionally reported to carry somatic mutations in LCH and ECD patients. We therefore analyzed hematopoetic stem/progenitor cells of adult patients with ECD or MH to identify a cell-of-origin for these disorders. Methods: Blood and/or bone marrow (BM) cells from adult patients with ECD (n = 12) or MH (n = 3) mutated for BRAF were collected and sorted by FACS into different cell fractions. Clonogenic progenitors from sorted BM CD34+ cells were assayed in methylcellulose cultures. BM CD34+ cells were also seeded in liquid culture under conditions allowing their differentiation into myeloid (mDC) or plasmacytoid (pDC) dendritic cells. BRAF mutations were detected by allele specific real time (RT) or picodroplet digital (pDD) polymerase chain reaction (PCR) in the different cell subsets. Results: BRAF mutations were detected in BM CD34+ cells or derived colonies in 7/15 patients, corresponding to 5/12 ECD and 2/3 MH. Among BM CD34-derived colonies or cells, the mutation was detected in CFU-M (n = 3), CFU-G (n = 1), CD14 cells (n = 3), pDC (n = 2), but not in BFU-E nor mDC. In 2/3 patients with ECD, low frequencies of BRAF mutants were detected within CD14+ and CD3+-sorted blood cells. Four patients received vemurafenib. One was on treatment at time of BM sampling and had no mutation in BM cells. The 3 others were no more treated since 3 to 6 months and had evidence of clinical relapse. Two of these later had BRAF mutant BM cells. Conclusions: BRAF mutations can be detected in hematopoietic/stem progenitor cells in patients with ECD and MH. These data suggests that these histiocytoses originate from altered BM progenitors.
Circulating tumor DNA as a prognostic biomarker in early stage pancreatic cancer.
Authors: Belinda Lee, Lara Rachel Lipton, Joshua Cohen, Jeanne Tie, Ammar Asrar Javed, Lu Li, David Goldstein, Prasad Cooray, Adnan Nagrial, Matthew E. Burge, Niall C. Tebbutt, Mehrdad Nikfarjam, Marion Harris, Anne Marie Lennon, Christopher Lee Wolfgang, Cristian Tomasetti, Nickolas Papadopoulos, Kenneth W. Kinzler, Bert Vogelstein, Peter Gibbs
Journal: Journal of Clinical Oncology (2018)

e16206 Background: While adjuvant therapy provides a survival benefit for patients (pts) with early-stage pancreatic cancer there are currently no biomarkers that define pts that are more or less likely to benefit from such treatment. This prospective study investigated the use of circulating tumour DNA (ctDNA) as a marker of residual disease, where detection could predict recurrence. Methods: Patients newly diagnosed with operable pancreatic adenocarcinoma were enrolled. PCR-based-SafeSeqS assays were used to identify mutations at codons 12, 13 and 61 of KRAS in the primary tumor and to detect ctDNA in plasma samples. Patient management was as per standard of care, blinded to ctDNA data. Results: From January 2015 to June 2017, 42 pts with matched plasma samples, collected pre- and post-operatively, and tumor tissue available were evaluated. The median time between surgery and post-op blood collection was 6.3 (range:4-8) weeks. RAS mutations were identified in 38 (90.5%) tumor samples. ctDNA was detected in 23/37 (62.2%) pre-op and 13/35 (37.1%) post-op plasma samples. In multivariate analysis including stage, and resection margin, ctDNA status was the only statistically significant variable. Pre-op ctDNA detection was associated with worse median recurrence free survival (RFS), 10.3 months versus not reached, (Hazard Ratio (HR),3.4; 95% confidence interval (CI), 1.5-7.6; P = 0.005) and 5.4 months versus 17.1 months, (HR, 5.4; 95% CI, 4.7-37.3; P < 0.0001) post-operatively. Similarly, the presence of ctDNA was associated with worse median overall survival (OS), 13.8 months versus not reached pre-operatively, (HR,3.4; 95% CI 1.1 to 8.3; P = 0.04) and 10.6 months versus not reached (HR,4.5; 95% CI 2.4-28.6; P = 0.001) post-operatively. Notably, recurrence occurred in 13 of 13 pts with detectable post-op ctDNA, despite more than half receiving standard adjuvant chemotherapy. Conclusions: ctDNA analysis is a promising prognostic marker in early-stage pancreatic cancer that could be used to stratify recurrence risk and guide risk-adaptive treatment strategies. ctDNA detection post-operatively may also define a pt subset destined to progress despite standard adjuvant chemotherapy, where novel approaches need to be explored Clinical trial information: ACTRN12612000763842.
Low utilization of pre-implantation genetic diagnosis in women with <i>BRCA</i> mutations.
Authors: Deanna Gerber, Olivia R Khouri, Meghan Smith, Jessica Lee, Julia Fehniger, James A Grifo, Bhavana Pothuri, Leslie R. Boyd
Journal: Journal of Clinical Oncology (2018)

e13619 Background: Identification of a BRCA mutation can profoundly impact family planning for women of reproductive age. Assisted reproductive technology (ART), including pre-implantation genetic diagnosis (PGD), provide chances to prevent BRCA carrier status in offspring. The patient (pt) may receive genetic information on embryos with option to select against BRCA mutations for implantation. Studies have found that about 60% of BRCA mutation carriers feel PGD should be offered, but only 35% would undergo PGD. We sought to evaluate the rates of counseling and utilization of PGD in pts with BRCA mutations at a high volume center for ART. Methods: We performed a retrospective chart review of reproductive age women with a BRCA mutation at a single institution from 8/2012 - 9/2017. Exclusion criteria were: history of risk-reducing salpingo-oophorectomy (RRSO), known ovarian cancer, or age ≥ 50 years. Results: We identified 343 pts for analysis, of whom 156 (45%) were counseled about reproductive options by an oncologist. Eighty-seven pts (25%) were offered referral to a reproductive endocrinology and infertility specialist (REI) and 47 had at least one REI visit. Women with a prior malignancy were less likely to be counseled about fertility and receive referral to REI (p = 0.02). Nulliparous pts were more likely to be offered REI referral than women with children (p < 0.001). After consultation with REI, 12 pts (3%) underwent oocyte preservation, 29 (8%) were offered PGD and 12 (3%) underwent PGD. Seven pts cited cost as the reason for not pursuing PGD, 2 cited personal beliefs. Women over age 35 were less likely to see REI than younger women (p < 0.001). For those seen by REI, age was not significantly associated with being offered or pursuing PGD. Conclusions: Only a quarter of reproductive-aged women were offered consultation with REI, and even fewer met with REI. A small percentage of pts underwent oocyte preservation or PGD. ART and PGD offer pts with a genetic cancer syndrome a unique opportunity to prevent transmission of the mutation, and associated cancer risks, to their offspring. Further study is needed to define pts’ priorities for reproductive planning, however our study supports strengthening provider engagement around fertility issues.
RELEVANCE: Phase III randomized study of lenalidomide plus rituximab (R<sup>2</sup>) versus chemotherapy plus rituximab, followed by rituximab maintenance, in patients with previously untreated follicular lymphoma.
Authors: Nathan Hale Fowler, Franck Morschhauser, Pierre Feugier, Reda Bouabdallah, Herve Tilly, Maria Lia Palomba, Christophe Fruchart, Edward N. Libby, Olivier Casasnovas, Maria Gomes Da Silva, Delphine Pranger, Pierre Zachee, Alejandro Martin Garcia-Sancho, Armando Lopez-Guillermo, Jean-Francois Larouche, Kiyoshi Ando, Dongfang Liu, Jianming Wang, Luc Xerri, Gilles A. Salles
Journal: Journal of Clinical Oncology (2018)

7500 Background: Immunochemotherapy induction followed by rituximab maintenance is the standard of care in previously untreated symptomatic FL. Phase II studies of chemo-free combination immunotherapy with lenalidomide and rituximab (R2) show promising activity. Methods: RELEVANCE is a global, randomized, phase III trial (NCT01650701) of R2 vs R-chemo followed by rituximab in previously untreated grade 1-3a FL patients requiring therapy according to GELF criteria. Lenalidomide dose was 20 mg/d, d2-22/28 for 6-12 cycles (c), continued in responders at 10 mg/d for a total of 18 c. Rituximab dose was 375 mg/m2 weekly c1 and d1 c2-6 and continued in responders for 12 additional c (q8wk). R-chemo was given per investigator’s choice of standard R-CHOP, R-bendamustine (R-B), or R-CVP, followed by 12 c of rituximab (q8wk). Co-primary endpoints of CR/CRu at 120 wk and PFS (50% interim analysis by 1999 IWG) are reported here. Results: As of 31May2017, 1030 patients with high tumor burden were randomized to R2 (n = 513) and R-chemo (n = 517; 72% R-CHOP, 23% R-B, 5% R-CVP); baseline characteristics were similar in both groups. At a median follow-up of 37.9 mo, superiority for R2 over R-chemo was not established for both co-primary endpoints (Table). Toxicity profiles for R2 vs R-chemo differed, with higher grade 3/4 lab (34% vs 50%) and febrile (2% vs 6%) neutropenia with R-chemo, and higher grade 3/4 cutaneous events (7% vs 1%) with R2. SPMs were reported in 7% R2 and 9% R-chemo patients and grade 5 AEs were 1% for both. 69% R2 and 71% R-chemo patients completed treatment. Conclusions: In the first randomized phase III comparison of a chemo-free regimen vs standard R-chemo followed by rituximab maintenance in previously untreated FL, R2 showed similar efficacy and a different safety profile to R-chemo. Clinical trial information: NCT01650701.Primary efficacy results of R2 vs R-chemo in previously untreated FL. R2 (n = 513) R-chemo (n = 517) P value CR/CRu at 120 wk By IRC 48% 53% 0.13 By Inv 55% 58% 0.38 PFS R2 vs R-chemo: HR (95% CI) by IRC 1.10 (0.85, 1.43) 0.48 R2 vs R-chemo: HR (95% CI) by Inv 0.94 (0.73, 1.22) 0.63 2 y (IRC/Inv) 84%/84% 87%/83% — 3 y (IRC/Inv) 77%/77% 78%/78% — OS at 3 y 94% 94% —
Pantoprazole affecting docetaxel resistance pathways via autophagy (PANDORA): a phase II trial in men with castration resistant prostate cancer (mCRPC).
Authors: Aaron Richard Hansen, Ian Tannock, Amy Prawira, Jennifer J. Knox, Arnoud J. Templeton, Francisco Vera-Badillo, Eric Xueyu Chen, Mary-Beth Zavitz, Lisa Wang, Andrew Evans, Susie Tan, Brad Wouters, Srikala S. Sridhar, Anthony M. Joshua
Journal: Journal of Clinical Oncology (2016)

e16502 Background: Enhancing the effectiveness of docetaxel for men with mCRPC is an unmet clinical need. Preclinical studies in our laboratory demonstrated that high dose pantoprazole can prevent or delay resistance to docetaxel via the inhibition of autophagy in several solid tumor xenografts. Methods: Men with chemotherapy-naïve mCRPC with a PSA > 10ng/ml and adequate organ function were eligible for enrolment. The study regimen included intravenous pantoprazole (240mg) and docetaxel (75mg/m2) every 21 days, with continuous prednisone 5mg twice daily. The primary endpoint was a confirmed ≥ 50% decline of PSA. Progression free (PFS) and overall survival (OS) were assessed by the Kaplan-Meier method. This trial used a Simon’s 2-stage design. Results: Between November 2012 and March 2015, 21 men with a median age of 70 years (range 58-81 years) were treated (median 6 cycles, range 2 to 11). Participants (pts) had received prior systemic therapies (median 4, range 1 to 8) and 14 had received abiraterone and/or enzalutamide. The PSA response rate was 52% (11/21) which did not meet the prespecified criterion ( ≥ 13/21 responders) to proceed to stage 2 of the study. At interim analysis with a median follow-up of 12 months, 13 (62%) pts were deceased (10 CRPC, 2 unknown, 1 radiation complication). Of the pts with RECIST measurable disease, the radiographic partial response rate was 31% (4/13). The estimated median PFS was 5.3 months (95%CI: 2.6-12.9) and median OS was 15.7 months (95% CI: 9.3-19.6). There were no toxic deaths and most adverse events were attributed to docetaxel (hematological: 14% febrile neutropenia, 14% G4 neutropenia, 19% G3/4 anemia; non-hematological: 24% G3 fatigue and 5% G3 anorexia). Conclusions: The combination of docetaxel and pantoprazole was tolerable, but the resultant clinical activity was not sufficient to meet the ambitious predefined target to warrant further testing. Planned correlative studies to evaluate tumor samples for autophagy are in progress, and are expected to provide insights into autophagy in the context of docetaxel resistance. Clinical trial information: NCT01748500.
Biomarkers of prognosis in patients with differentiated thyroid cancer: Results from the DECISION trial.
Authors: Carol Elaine Pena, Scott Wilhelm, Gerold Meinhardt, Martin Schlumberger, Marcia S. Brose
Journal: Journal of Clinical Oncology (2016)

6059 Background: Sorafenib (SOR) is a multikinase inhibitor approved to treat locally recurrent or metastatic, progressive, differentiated thyroid cancer (DTC) refractory to radioactive iodine treatment. We examined serum thyroglobulin (Tg) and candidate plasma biomarkers to identify prognostic and/or predictive biomarkers in patients (pts) from the Phase 3 DECISION trial of SOR in DTC. Methods: Serum for Tg was collected at baseline (BL) and during treatment. 15 plasma proteins were tested in BL samples. Biomarkers were analyzed by Cox regression for correlation with PFS, OS and disease control rate (DCR). Optimal biomarker cutoffs (OBC) were determined using a maximum chi-square method testing between the 25th and 75th percentiles. Results: BL Tg and plasma biomarker data were available for 403 (96.6%) and 395 (94.7%) of the 417 DECISION pts, respectively. Elevated BL Tg was robustly associated with poor prognosis in terms of PFS (HR = 2.03 for high vs low Tg, p < 0.0001; using OBC of 1547 pmol/L, equivalent to the 58th %ile) and DCR (odds ratio [OR] = 0.32, p = 0.01; OBC, 3047 pmol/L = 68th%ile) in multivariate analyses including both treatment arms. Pts experiencing a ≥ 30% reduction in Tg during treatment had longer PFS than those not reaching a 30% decrease in both the placebo (HR = 0.49, p = 0.009) and SOR (0.61, p = 0.022) cohorts. 76% of SOR pts achieved a Tg decrease ≥ 30% vs 14% of placebo pts (p < 0.001). Elevated BL VEGF-A (higher than the OBC) was also strongly associated with poor PFS (HR = 1.82, p = 0.0003), OS (HR = 2.13, p = 0.0067), and DCR (OR = 0.30, p = 0.0046). Baseline Tg and VEGF-A together were prognostic for PFS (HR = 2.12, p < 0.00001). Elevated BL VEGF-C (above OBC) and TGF-β1 (continuous variable) and low BL E-cadherin (continuous variable) were associated with poor DCR, while elevated BL vimentin was associated with poor OS (continuous variable). None of the biomarkers examined were able to predict benefit from SOR in DTC. Conclusions: Elevated BL Tg and VEGF-A were associated with poor prognosis in DTC, as were elevated VEGF-C, TGF-β1, and low E-cadherin. None of the biomarkers were predictive of response to sorafenib. Serum Tg changes over time may be a pharmacodynamic biomarker of tumor response and/or progression. Clinical trial information: NCT00984282.
Antiplatelet Therapy After Coronary Artery Bypass Grafting
Authors: Rahman Shah, Kirstin Hesterberg
Journal: JAMA (2018)

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Survival trends among patients with metastatic melanoma in the United States: A population based study.
Authors: Ranju Kunwor, Mahesh Nepal, Dominic Ho, Krishna Bilas Ghimire
Journal: Journal of Clinical Oncology (2017)

9555 Background: Ipilimumab was approved by FDA in March 2011 for the treatment of Metastatic Melanoma. We conducted this study to compare survival outcome in patients with Metastatic Melanoma in pre- (1973-2010) and post- (2011-2013) ipilimumab era in the United States using U.S. Surveillance, Epidemiology, and End Result (SEER) registry database. Methods: We selected patients with metastatic melanoma age ≥ 20 years from the SEER database. We used SEER 18 registry database to evaluate relative survival (RS) rate during 1973-2010 and 2011-2013. The RS rate at 1year and 2 year were analyzed for cohorts by age (20-49 years, 50-74 and ≥75 years), race [White, African American (AA), and others] and gender. The RS rates (%) accompany standard error (SE). We used SEER Stat software for statistical analysis. Results: There were a total of 129,362 (106,516 and 22,846 in pre and post ipilimumab era) metastatic melanoma patients, male (n = 71,220), female (n = 58,142), white (n = 121,843), AA (n = 854) other (n = 1,315) reported in the registry. RS in pre vs post-ipilimumab era for age group 20-49 was: 96.50 ± 0.1% vs 97.20 ±0.3%, P = 0.013; and 94.10 ± 0.1% to 95.60 ±0.40, P = 0.0009; for age group 50-74 was: 94.10 ± 0.1% vs 95.30 ± 0.2%, P = 0.0001; and 90.70 ± 0.1%vs 92.90 ± 0.3%, P = 0.0001; and for age group ≥75 was 90.80 ± 0.3% vs 91.40 ± 0.7%, P = 0.23; and 85.0 ± 0.4% vs 88.10 ± 1.0%, P = 0.011 at 1 and 2 years respectively. Overall RS in pre and post ipilimumab era for white population was: 93.83 ± 0.16% vs 94.567 ± 0.4%, P = 0.017; and 90.0 ± 0.2% vs 92.033 ± 0.6%, P = 0.0008 at 1 and 2 years respectively. Similarly RS for AA was: 78.07 ± 2.93% vs 73.33 ± 8.23%, P = 0.37; and 65.87 ± 3.47% vs 65.33 ± 9.73%, P = 0.94; and for other race was: 85.2 ± 2.13% vs 77.97 ± 5.6%, P = 0.04; and 74.43 ± 5.2% vs 69.67 ± 6.7%, P = 0.1 at 1 year and 2 years. Conclusions: Our study showed that younger (20-74 years) patients with metastatic melanoma have improvement in 1 and 2-year RS rates in post ipilimumab era. Subgroup analysis by race showed no improvement in RS in AA and other races patients during this period. There was also no significant survival benefit seen in older (≥ 75 years) patients of all races and gender in post ipilimumab era.
Chemotherapy in nonagenarians palliative care: Single institutional experience in development country.
Authors: Juliana Souza, Daniele Neves, Sabrina Chagas
Journal: Journal of Clinical Oncology (2018)

e22016 Background: With an aging population, cancer treatment management in the older aged person is an increasing. However, they are often excluded from clinical trials and there are very few data to guide the management of these frail patients, especially the nonagenarians. Methods: We identified all patients with 90 years or more treated with chemotherapy in palliative care between 2013 and 2017 in our oncology clinic, ONCOCLINICA. We retrospectively reviewed their records. Geriatric assessment was not reported for our patients. Results: Of 104 nonagenarians patients evaluated at ONCOCLINICA, 15 patients received chemotherapy in palliative care (n:1 rectal cancer; n:2 pancreatic; n:3 lung; n:1 peritoneal; n:4 breast; n:1 ovarian; n:1 prostate; 1 bladder). Six patients (40%) did not have metastasis, but was not eligible to surgical/radiotherapy treatment due advanced disease (n: 3 - lung, bladder and pancreatic cancer) or advanced age (n: 3 breast cancer). Two lung cancer patients (13%) received targeted therapy as first-line treatment and .13 patients (86.6%) receives chemotherapy (10 pts with dose reduction and 1 pts metronomic chemotherapy). Six pts (40%) had toxicity with chemotherapy treatment, 4 pts (26.6%) had to interrupt the treatment, but there were no chemotherapy-related death. Median duration of first-line treatment was 6 months (0.21-11.91m), and progression-free survival ranged from 1-16.1 months. Patient’s benefit due symptoms decrease was reported in 11 pts (73.3%). Three patients received second-line treatment (2 patients with chemotherapy) and 2 pts received third-line treatment with chemotherapy. Conclusions: Treatment choice should be individualized, based on functional reserve, life expectancy, comorbid conditions, and patients assortment. Treatment goals in elderly patients should be symptoms relief and enhance quality of life.