tbuckley/cabot-search huggingface dataset:
Correlation of benefit from immune checkpoint inhibitors with next gen sequencing (NGS) profiles in esophagogastric cancer (EGC) patients.
Authors: Geoffrey Yuyat Ku, Francisco Sanchez-Vega, Walid Chatila, Matthew Margolis, Carly Fein, David H. Ilson, Jaclyn Frances Hechtman, Yaelle Tuvy, Nancy Bouvier, Ritika Kundra, Jinru Shia, Zachary J. Heins, Sumit Middha, Ahmet Zehir, Marc Ladanyi, Michael F. Berger, Laura H. Tang, David B. Solit, Nikolaus Schultz, Yelena Yuriy Janjigian
Journal: Journal of Clinical Oncology (2017)

4025 Background: Immuno-oncology (IO) with anti-PD-1 and –PD-L1 antibodies (Abs) is active in EGC but only benefits a minority of Pts. Biomarkers are needed to identify responders. Methods: We reviewed our experience of Pts treated with anti-PD-1/PD-L1 Abs and correlated their outcomes with PD-L1 and mismatch repair protein (MMR) status by immunohistochemistry (IHC), as well as MSK-IMPACT (≥340-gene) NGS profile. MSIsensor from IMPACT assesses microsatellite instability phenotype, while ≥20 mutations (or 17 mutations/Mb) strongly correlates with MMR-deficiency (dMMR) by IHC (J Clin Oncol 2016;34:2141). Progression-free (PFS) and overall survival (OS) were analyzed from the start of IO. Results: 71 Pts were identified, with 3 Pts receiving 2 IO regimens. 66 had adenoCAs and 5 had squamous CAs. Median age 58, 77% male, 96% had received ≥2 prior chemo regimens. 39 (55%), 18 (25%) and 17 Pts (24%) respectively received anti-PD-1, anti-PD-L1 and anti-CTLA-4 plus anti-PD-1/PD-L1 Abs. 6 Pts (8%) had objective response (2 complete responses or CRs) and the median PFS and OS are 1.6 and 4.7 mos; 2-yr OS is 17%. PD-L1 IHC was performed in 16 Pts (23%; 7 +ve), MMR was tested in 20 Pts (28%; 4 dMMR) and IMPACT was obtained in 44 Pts (62%). All 4 dMMR tumors were also MSI by MSIsensor and had a median of 46 mutations (range, 29-63) or, equivalently, 33 mutations/Mb (range, 21-46); 2 of 2 dMMR tumors tested PD-L1 +ve. 3 of the 4 Pts with dMMR/MSI tumors had a response (including 1 CR) and the median OS of these 4 Pts is not reached with 23+ months of follow-up. Finally, a patient whose tumor is MMR-proficient, not MSI but has 15 mutations (including in POLD1), achieved an ongoing CR at 37+ mos. For the 44 Pts with IMPACT testing, there appeared to be improved OS for tumors with ≥10 vs. &lt;10 mutations/Mb (2-yr OS 80% vs. 12%, p=0.03). Conclusions: Pts with tumors that are MSI or have ≥10 mutations/Mb on MSK-IMPACT appear to derive significant benefit from IO. MSK-IMPACT can offer novel information, identify novel mutations (e.g. POLD1) and may be used to help select Pts for IO. We are seeking to define a mutation no. cut-off that can serve as a biomarker and updated data will be presented.
Long-term Glycemic Control and Dementia Risk in Type 1 Diabetes
Authors: Mary E. Lacy, Paola Gilsanz, Andrew J. Karter, Charles P. Quesenberry, Mark J. Pletcher, Rachel A. Whitmer
Journal: Diabetes Care (2018)

OBJECTIVE Individuals with type 1 diabetes have experienced an increase in life expectancy, yet it is unknown what level of glycemic control is ideal for maintaining late-life brain health. We investigated the association of long-term glycemic control with dementia in older individuals with type 1 diabetes. RESEARCH DESIGN AND METHODS We followed 3,433 members of a health care system with type 1 diabetes, aged ≥50 years, from 1996 to 2015. Repeated measurements of hemoglobin A1c (HbA1c), dementia diagnoses, and comorbidities were ascertained from health records. Cox proportional hazards models were fit to evaluate the association of time-varying glycemic exposure with dementia, with adjustment for age, sex, race/ethnicity, baseline health conditions, and frequency of HbA1c measurement. RESULTS Over a mean follow-up of 6.3 years, 155 individuals (4.5%) were diagnosed with dementia. Patients with ≥50% of HbA1c measurements at 8–8.9% (64–74 mmol/mol) and ≥9% (≥75 mmol/mol) had 65% and 79% higher risk of dementia, respectively, compared with those with &amp;lt;50% of measurements exposed (HbA1c 8–8.9% adjusted hazard ratio [aHR] 1.65 [95% CI 1.06, 2.57] and HbA1c ≥9% aHR 1.79 [95% CI 1.11, 2.90]). By contrast, patients with ≥50% of HbA1c measurements at 6–6.9% (42–52 mmol/mol) and 7–7.9% (53–63 mmol/mol) had a 45% lower risk of dementia (HbA1c 6–6.9% aHR 0.55 [95% CI 0.34, 0.88] and HbA1c 7–7.9% aHR 0.55 [95% CI 0.37, 0.82]). CONCLUSIONS Among older patients with type 1 diabetes, those with majority exposure to HbA1c 8–8.9% and ≥9% had increased dementia risk, while those with majority exposure to HbA1c 6–6.9% and 7–7.9% had reduced risk. Currently recommended glycemic targets for older patients with type 1 diabetes are consistent with healthy brain aging.
Cost of care for adult patients with relapsed acute lymphoblastic leukemia (rALL) in Germany.
Authors: Yun Su, Sarah Schmitter, Ana Navarro, Lukas Mayerhoff, Sigurd Prieur, Moritz Lehne, Fausto Rodriguez Loberiza
Journal: Journal of Clinical Oncology (2017)

e18504 Background: Adult ALL is a rare but progressive frequently fatal disease. For those who survive and respond to initial therapy, many experience relapse. For relapse ALL (rALL), stem cell transplant (SCT) is potentially curative. This retrospective observational study investigates the cost of care and the impact of SCT on total cost for rALL. Methods: A representative sample of German claims data covering approximately 7 million of the German population was used to identify patients 18 years and older with a new diagnosis of ALL (ICD-10-GM code: C91.0*) between Jan 2011 and Dec 2015 who had a relapse after remission to initial treatment. Mean health care cost per patient per quarter were determined by whether or not SCT was received after relapse. Costs were from the perspective of German statutory health insurance and included prescription, outpatient and inpatient treatment costs. Results: Of the total 116 incident adult ALL patients identified, 29 (25%) were determined to have had a relapse, 11 underwent SCT after the relapse (38%). Patients with a SCT appear to incur higher cost than those without SCT in each of the quarters after relapse was diagnosed (Table), with the highest in the first quarter, but decreasing in subsequent quarters. Inpatient cost accounted for the majority of the cost for the first three quarters for both SCT and non-SCT patients (64% in Q2 to 86% in Q1). The number of patients in the SCT cohort remained relatively stable, while the non-SCT cohort had only half the patients left by the third quarter post relapse. Conclusions: Current results inform the magnitude of cost in Germany associated with adult patients with rALL with or without a SCT after relapse. It would be important to determine the magnitude of benefit such as long-term survival associated with SCT as well. The cost estimates provide a benchmark against which new treatment options for rALL can be compared. [Table: see text]
A prospective, multicenter, randomized study of anti-CCR4 monoclonal antibody mogamulizumab (moga) vs investigator's choice (IC) in the treatment of patients (pts) with relapsed/refractory (R/R) adult T-cell leukemia-lymphoma (ATL).
Authors: Adrienne Alise Phillips, Paul Fields, Olivier Hermine, Juan Carlos Ramos, Brady Ernesto Beltran, Juliana Pereira, Carlos Brites, Michael R. Kurman, Joyce George, Karen M. Dwyer, Kevin Conlon, Graham P. Taylor, Jason Parker Gonsky, Steven M. Horwitz
Journal: Journal of Clinical Oncology (2016)

7501 Background: ATL is a malignancy of T-cells infected with HTLV-1. Prognosis is poor and subtype related. There is no consensus treatment for R/R patients with aggressive ATL in whom median OS is < 3 months. Moga, a monoclonal antibody directed against CCR4 ( expressed in >90% of ATL patients), is approved in Japan for the treatment of CCR4+ ATL, PTCL, and CTCL. Methods: To evaluate moga outside of Japan, pts from sites in the USA, EU, and Latin America with aggressive R/R ATL (acute , lymphomatous, and chronic subtypes) were randomized 2:1 to treatment with moga, 1.0 mg/kg, given weekly for the first 4-week cycle and then biweekly, or to 1 of 3 investigator choice (IC) regimens (Gem/Ox, DHAP or pralatrexate). Due to the rarity of the disorder and lack of effective therapy, no power calculation was performed. Pts in the IC arm were permitted to cross-over to moga upon progression. The primary endpoint was objective response rate (ORR) based on modified Tsukasaki criteria. ORR was assessed by the treating investigator (IA) and in blinded fashion by independent review (IR). Results: 71 pts were randomized (47 to moga, 24 to IC). Tissue /blood from 65/71 pts (91.5%) expressed CCR4. In the moga treated group, ORR was 23.4% (11/47) by IR and 34.0% (16/47) by IA; in the IC group, ORR was 2/24 (8.3%) by IR and 0/24 by IA. Confirmed ORR (maintained response after 1 month) for moga was 10.6% by IR and 14.9% by IA; there were no confirmed responses in the IC group. 18 IC pts crossed over to moga and 3 responded. Median duration of response for moga was 5.0 months by IR (range: 3.8 – 9.6 mos) and 1 pt had CR lasting >9 months. Survival data are not yet mature. The most frequently observed treatment-emergent, drug-related adverse events in the moga arm were infusion reactions (46.8%), rash/drug eruption (25.5%) and infections (14.9%). Conclusions: This was the largest randomized clinical trial of R/R ATL thus far conducted. In patients with aggressive R/R ATL commonly used cytotoxic regimens provided limited therapeutic benefit whereas treatment with moga resulted in an ORR that supports its therapeutic potential in this setting. Clinical trial information: NCT01626664.
Tumor location and symmetry on prostate cancer progression in a racially diverse military cohort.
Authors: Jennifer Cullen, William Gesztes, Grant Williams, Allen Burke, Denise Young, Justin Mygatt, Yongmei Chen, Huai-Ching Kuo, Shiv Srivastava, Inger L. Rosner, Isabell Sesterhenn
Journal: Journal of Clinical Oncology (2018)

e17065 Background: Prostate cancer (CaP) tumor location (TL) and symmetry (TS) may help forecast CaP outcomes in radical prostatectomy (RP) patients. The study aim was to examine associations between CaP TL & TS with disease pathology and progression including whether such associations differ across race. Methods: This retrospective cohort study included 1140 patients enrolled at the Walter Reed National Military Medical Center who underwent RP between 1993 - 2008. TL & TS were recorded for index tumors (ie largest/highest grade) in whole-mounted RP specimen sections. TLs were divided into coronal versus axial planes. For coronal plane, TL was sub-divided into anterior (A), antero-lateral (AL), lateral (L), postero-lateral (PL), posterior (P) and diffuse (D) (spanning A, AL, L, PL & P). The axial plane locations included base (B), mid (M) and apex (A). Kaplan Meier (KM) estimation curves were used to model BCR-free and DM-free survival. Results: Mean age at diagnosis was 59 years, 27% were African-American (AA), 46% had PL, more than half of tumors in the axial plane included the M section and 77% were non-symmetric (NST). NST were associated with smaller volume (p < .0001), grade group ≥4 (p < .0001), nuclear grade 3 (p = 0.0002), fewer PL (p < .0001), and greater M (p < .0001). AA men had fewer NST than Caucasian-American (CA) men (72% vs. 78%, respectively, p < 0.03). Overall, AA- and CA-specific KM analyses revealed that NST predicted poorer BCR-free survival (p = 0.003, p = 0.02, & p = 0.04, respectively). NST trended toward DM-free survival (p = 0.055). For TL, KM analysis showed that patients with D or BMA tumors suffered worse BCR-free survival (p < .0001) & DM-free survival (p < .0001). Specifically, D tumors predicted BCR-free survival in CA men (p = 0.0001) but not in AA men (p = 0.069). BMA tumors also predicted BCR-free survival (overall p = 0.0001, CA p < .0001, AA p = 0.0004). Too few DM events were observed across tumor location categories for KM analysis. Conclusions: In this longitudinal, racially diverse cohort of RP patients, TL and TS were informative in predicting BCR and DM. However, this study did not find evidence of racial differences in these associations. These findings have implications for treatment stratification at time of RP.
The opportunity cost (OC) of performing radical prostatectomy (RP) by low volume (LV) providers (Prov).
Authors: Sarmad Sadeghi, Eric A. Klein, Siamak Daneshmand, Inderbir Gill, David I. Quinn, Afsaneh Barzi
Journal: Journal of Clinical Oncology (2016)

6509 Background: Evidence suggests a link between experience and improved oncological and non-oncological outcomes for RP. We explored the frequencies of RPs by LV Prov that occur within 100 miles of highest volume Prov and the potential savings associated with referring them to highest volume Prov. Methods: We analyzed Medicare Provider Utilization and Payment Data for 2012 and 2013, SEER Data 2003-2012. A Markov model was used to compare outcomes of high and low volume Prov in terms of effectiveness (oncological and non-oncological) and cost of oncological treatment (Tx) failure. Medicare Prov were grouped according to the number of RPs. Prov with below median volume were designated as LV Prov. Using the Prov zip codes we calculated the travel distance required for referral. Results were extrapolated using SEER data to non Medicare patients. Opportunity costs of Tx failure were calculated for RPs within 100 miles of highest volume Prov. Results: 15% of Prov performed more than 30% of the RP with at least 30 cases per year. There were 241,740, and 238,590 prostate cancer cases, and 32 and 33% of these underwent RP, in 2012 and 2013. The Markov model projected that referral to high volume Prov was associated with 50 fewer biochemical failures resulting in $1.8 mil savings (over 20 years) as well as 233 fewer post-op hospitalization days per 1000 referrals. Conclusions: While reduced LOS does not impact reimbursement, it does free up societal resources and therefore results in savings. Costs of avoidable Tx failures also represent significant savings. The potential for improved outcomes and reduced costs of care represent an OC associated with performing RP by LV Prov. Referrals within 100 miles are feasible and can improve outcomes and save societal costs. Medicare Data National Extrapolations Opportunity for Prov Grp N Prov Prov Vol N RP (%) % RP <100m Referrals ↓LOS ↓Tx Failure 2012 All 499 11-255 10168 (100%) >=30 72 >=30 3374 (33%) 50th pctl 247 <16 3124 (31%) 18% 14,359 3,303 717 75th pctl 376 <23 5480 (54%) 31% 24,730 5,688 1,235 2013 All 470 11-236 9456 (100%) >=30 66 >=30 3021 (32%) 50th pctl 234 <16 2945 (31%) 17% 12,979 2,985 648 75th pctl 352 <23 5087 (54%) 31% 23,668 5,444 1,182 Grp, Group; LOS, Length of Stay; pctl, Percentile.
Precision oncology: Results of a phase I study of M2698, a p70S6K/AKT targeted agent in patients with advanced cancer and tumor PI3K/AKT/mTOR (PAM) pathway abnormalities.
Authors: Apostolia Maria Tsimberidou, Claire F. Verschraegen, Amy M. Weise, John Sarantopoulos, Gilberto Lopes, John J. Nemunaitis, Christine Hicking, Jamie Shaw, Remigiusz Kaleta, Razelle Kurzrock
Journal: Journal of Clinical Oncology (2018)

2584 Background: M2698 is a potent and selective dual inhibitor of p70S6K and AKT1/3 in the PAM pathway. M2698 has the advantages of being an oral, brain penetrant, PAM pathway inhibitor, which can mitigate the effects of the AKT feedback loop, a potential escape mechanism in tumors resistant to standard therapies. Methods: Patients (pts) with advanced cancer received once-daily oral M2698 (15–380 mg; 9 dose levels) in 21-day cycles. The 3+3 dose escalation [DE] design was followed by an expansion phase (240 mg/day) in a pt population enriched with tumors that have PAM molecular alterations (PAM+). PAM+ profiles, potential resistance markers (RM), including EGFR, KRAS and Akt2, safety and efficacy were investigated (cut-off Nov 2017). Results: From 12/2013 to 3/2017, of 66 pts screened, 50 received M2698 (DE [n = 40] and expansion [n = 10]); 18 men, 32 women, 78% were < 65 years old. Of these 50 pts, 44 were PAM+ (37 without RM, 7 with RM). M2698 was well tolerated. Adverse events were transient. The maximum tolerated dose was not reached at the maximum dose tested. Efficacy outcomes are shown in the table. In addition, 5 pts in the PAM+ without RM subgroup had tumor control > 6 months (mo; range, 6.9–15.2 mo), whereas no pts in the PAM+ with RM subgroup had such prolonged tumor control. Clinical trial information: NCT01971515. PFS, progression free survival; SD, stable disease. Conclusions: M2698 was well tolerated. PAM+ pts without RM were more likely to have sustained tumor control. Molecular characterization of tumor resistance signals may help identify patients who are likely to benefit from M2698. All pts (n = 50) PAM+ pts (n = 44) PAM+ pts with RM (n = 7) PAM+ pts without RM (n = 37) Best overall response, SD, n (%) 20 (40) 18 (41) 1 (14) 17 (46) SD at week 12, n (%) 16 (32) 14 (32) 1 (14) 13 (35) Median PFS, mo [95% CI] 2.4 [1.4, 3.7] 2.8 [1.4, 4.1] 1.4 [1.3, -] 2.8 [1.8, 4.1] Median time on treatment, mo (range) 1.9 (0.2, 16.6) 2.1 (0.2, 16.6) 1.4 (0.8, 3.0) 2.3 (0.2, 16.6)
Cost-Effectiveness Analysis of Brentuximab Vedotin With Chemotherapy in Newly Diagnosed Stage III and IV Hodgkin Lymphoma
Authors: Scott F. Huntington, Gottfried von Keudell, Amy J. Davidoff, Cary P. Gross, Sapna A. Prasad
Journal: Journal of Clinical Oncology (2018)

In a recent randomized, open-label trial (ECHELON-1), brentuximab vedotin (BV) combined with doxorubicin, vinblastine, and dacarbazine (AVD+BV) decreased the risk of progression in adults diagnosed with stage III or IV Hodgkin lymphoma (HL) compared with standard bleomycin-containing chemotherapy (doxorubicin, bleomycin, vinblastine, and dacarbazine [ABVD]). However, the cost effectiveness of incorporating BV (US$6,970 per 50-mg vial) into the first-line setting is unknown.
Monitoring anti-PD-1 therapy efficacy by circulating tumor DNA: a prospective cohort.
Authors: Francesca Riva, Charlotte Proudhon, Aurore Rampanou, Jean-Yves Pierga, Marc-Henri Stern, Maud Milder, Sophie Piperno-Neumann, Catherine Daniel, Alain Livartowski, Sophie Beaucaire-Danel, Emanuela Romano, Ivan Bieche, Vincent Servois, Olivier Lantz, Delphine Loirat, Francois-Clement Bidard
Journal: Journal of Clinical Oncology (2016)

11535 Background: Initial flare-ups of cancer deposits have been observed under nivolumab and pembrolizumab therapy, making imaging evaluations uneasy. In that setting, we hypothesized that circulating tumor DNA (ctDNA) levels during PD1 blockade could reflect the tumor burden and may even differentiate lymphocytic infiltrates of tumor deposits from true tumor progressions. Methods: All patients (pts) starting a therapy with on-label nivolumab or pembrolizumab at Institut Curie were eligible for this ethically approved prospective study. After signed informed consent, patients had up to four blood draws: (i) before therapy; (ii) after 2 months; (iii) at tumor progression; (iv) in case of toxicity. Optimized pre-analytical procedures were applied on EDTA tubes. Circulating DNA was extracted using the QIAamp kit and quantified by Qubit. ctDNA was then quantified by detecting either (subgroup A) previously characterized point mutations for which ddPCR or biPAP-PCR (Madic, Clin Cancer Res 2012) probes were available or (subgroup B) previously unknown mutations discovered by a targeted massively parallel sequencing of cancer-related genes in plasma (Lebofsky, Mol Oncol 2015). Results were correlated with prospectively registered radiological evaluations (RECIST & irRC) and clinical outcomes. Results: Thirty-six pts (N = 23 NSCLC, N = 11 melanoma, N = 2 MSI-H GI cancers) have been included from July to November 2015. ddPCR and biPAP-PCR was performed in the first seven pts with known KRAS, BRAF, GNAQ or GNA11 mutations in (subgroup A). The only pt with rising ctDNA levels in the first two months of therapy (50 to 1200 copies/ml of plasma) experienced a tumor progression. The two other pts with confirmed tumor progression had stable (600 to 500 copies/ml) or undetectable (0 to 0 copy/ml) ctDNA levels. As expected, stable disease and partial responses (N = 4) were associated with decreased (210 to 0) or undetectable (0 to 0) levels. Mutation discovery by targeted massively parallel sequencing (subgroup B) is ongoing and will be presented at the meeting. Conclusions: This first proof of concept study suggests that early ctDNA levels changes may be a tool to manage anti-PD1 therapy efficacy.
Community socioeconomic status to identify higher-risk patients with malignant glioma.
Authors: Aaron Stephen Bower, Caleb Yelton, Christina Cramer, Michael Henry Soike, Emory McTyre, Robert Wicks, Rebecca Merrill, Sunday Azagba, Stephen B Tatter, Adrian W Laxton, Glenn Jay Lesser, Michael D Chan, Roy E. Strowd
Journal: Journal of Clinical Oncology (2018)

2060 Background: Patients living in rural areas face barriers to accessing optimal, guideline driven care including proximity to tertiary centers and lower socioeconomic status. We sought to examine the impact of geographic and economic variables on clinical outcomes in a cohort of primary malignant glioma patients. Methods: A retrospective cohort study of patients newly diagnosed with WHO grade 3-4 glioma between 1999 – 2017 was performed. Relevant clinical and demographic data including marital status, employment, insurance, race, ethnicity, primary physician, and treatment factors were collected. Median household income was obtained from the US Census Bureau, linked to each patient by home zip code, and used to estimate patients residing in advantaged (above median state income, MSI) and disadvantaged (below MSI) communities. Median overall survival (OS) was assessed by Kaplan-Meier method. Results: Of the 310 patients identified, 27% resided in high MSI communities (n = 85). Age, sex, WHO grade, radiation and chemotherapy received did not differ by MSI status (all p > 0.19). Patients from high MSI communities were more likely to have undergone any resection compared to biopsy (80% vs 68%, p = 0.04). Median OS was 3.1 months longer for patients from high MSI (22.1 months vs 19.0, Hazard Ratio [HR] 0.81, 95% CI 0.61-1.09, p = 0.16). This survival difference was observed for grade 4 (HR 0.75, 0.54-1.04, p = 0.09) and not grade 3 gliomas (HR 0.97, 0.52-0.82, p = 0.92). When stratified by MSI status, men from high MSI communities showed a trend towards survival advantage (HR 0.71, 0.46-1.08, p = 0.10); this was not observed for women (HR 0.86, 0.51-1.45, p = 0.57). Conclusions: Male patients with glioblastoma residing in economically disadvantaged communities in NC experience worse outcomes than similar patients from advantaged areas. Further efforts to understand the patient-specific, community, and socioeconomic barriers are warranted. Characteristic Hazard Ratio (95% CI) P-Value High vs Low MSI 0.77 (0.57 – 1.03) 0.08 WHO Grade 4 vs 3 2.85 (2.01 – 4.03) < 0.001 Age (by decade) 1.41 (1.26 – 1.57) < 0.001 Era of Treatment (Pre- vs Post-Temozolomide) 1.28 (0.96 – 1.70) 0.09