tbuckley/cabot-search huggingface dataset:
Updated results from phase II study of combination of hyper-CVAD (HCVAD) with ponatinib in frontline therapy of patients (pts) with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL).
Authors: Koji Sasaki, Hagop M. Kantarjian, Farhad Ravandi, Deborah A. Thomas, Jorge E. Cortes, Naveen Pemmaraju, Tapan M. Kadia, Nicholas James Short, Ghayas C. Issa, Rebecca S. Garris, Vicky Jeanis, H. Gal Moore, Guillermo Garcia-Manero, Gautam Borthakur, William G. Wierda, Evguenia Gachimova, Susan Mary O'Brien, Elias Jabbour
Journal: Journal of Clinical Oncology (2016)

7036 Background: Combination of cytotoxic chemotherapy with a tyrosine kinase inhibitor is effective in the treatment of Ph+ ALL. Ponatinib is a more potent BCR-ABL1 inhibitor than imatinib and dasatinib. The combination of chemotherapy with ponatinib might improve response rate and clinical outcome. Methods: In this phase II trial, 52 pts with newly diagnosed Ph+ ALL received 8 cycles (cy) of HCVAD alternating with high-dose MTX/Ara-C every 21 days. Ponatinib was given at 45 mg po daily for the first 14 days of cy 1 then continuously for the subsequent 7 cy at the dose of 30 mg then 15 mg once a CMR is achieved. Pts in CMR received maintenance with ponatinib and vincristine and prednisone monthly for 2 years followed by ponatinib. Results: To date 49 pts with untreated Ph+ ALL and 3 previously treated (2 with prior cy of chemotherapy before Ph+/BCR-ABL status was known not in CR, and 1 post HCVAD-dasatinib in CR) have a median follow-up of 31 months (1-50) (table 1). All pts were in CR after cy 1. 42 of the 46 (91%) with Ph+ metaphases achieved a CCyR after 1 cy; 2 had a minor cytogenetic response only and 2 had no cytogenetic analysis at CR, both of them achieved a CCyR after cy 2. To date, 50 (96%) have achieved a MMR, of whom 41 (79%) have achieved a CMR at a median of 10 weeks from initiation of treatment (2 -96). MRD status by flow cytometry is negative in 50 of the 51 (98%) at a median of 3 weeks (2-14). Median time to neutrophil and platelet recovery for cy 1 was 18 and 22 days, and 16 and 22 days for subsequent cy, respectively. 10 underwent allogeneic transplantation after a median of 4 cy (3-19). 2 had grade 5 vascular events (VE) with no underlying risk factors (1, MI; 1, NSTEMI). No further VE were reported with ponatinib dose optimization. The 3-y CR duration and OS rates were 79% and 82%, respectively. Conclusions: The combination of HCVAD with ponatinib is safe and effective in achieving molecular remissions in pts with Ph+ ALL. Clinical trial information: NCT01424982.Pt characteristics. N (%)/Median [range] N=52 Age (yrs) 53 [25-80] Sex Female 23 (44) PS 2 8 (15) WBC (x109/L) 10 [1-629] CNS + 3 (6) CD20 + 17 (33) Transcript 190 37 (71) 210 15 (29) CG Ph + 46 (88) Diploid (FISH or PCR +) 6 (12)
Effect of inflammatory and nutritional (IN) status on induction chemotherapy (CT) followed by chemoradiotherapy (CRT) for locally advanced pancreatic cancer (LAPC): An exploratory subgroup analysis of JCOG1106.
Authors: Nobumasa Mizuno, Akira Fukutomi, Junki Mizusawa, Hiroshi Katayama, Satoaki Nakamura, Yoshinori Ito, Nobuyoshi Hiraoka, Tatsuya Ioka, Makoto Ueno, Masafumi Ikeda, Kazuya Sugimori, Kyoko Shimizu, Takuji Okusaka, Masato Ozaka, Hiroaki Yanagimoto, Shoji Nakamori, Takeshi Azuma, Ayumu Hosokawa, Hiroshi Ishii, Junji Furuse
Journal: Journal of Clinical Oncology (2017)

4123 Background: JCOG1106 is a randomized selection phase 2 trial to evaluate the efficacy and safety of CRT (S-1 concurrent RT) with (Arm B) or without (Arm A) induction CT of gemcitabine (GEM) for LAPC. In the final analysis, we selected Arm A as a promising regimen due to a poorer 2-year overall survival (OS) of Arm B, in spite of a favorable 1-year OS with crossing of the survival curves around 1-year (Ioka, ESMO2016). Therefore, this study aimed to explore subgroups benefit more from either treatment. IN statuses defined by such as serum C-reactive protein (CRP) and serum albumin (Alb) are recognized as prognostic and predictive factors in patients (pts) with various cancers receiving CT or CRT. We hypothesized that IN status may modify the effect of induction CT. Methods: Subjects were all eligible pts who were enrolled in JCOG1106 (n = 51/49 in Arm A/B). Glasgow Prognostic Score (GPS) was classified by baseline CRP and Alb. Pts with a CRP ≤ 10 mg/L and Alb ≥ 35 g/L were allocated to GPS 0, with a CRP &gt; 10 mg/L or Alb &lt; 35 g/L to GPS 1, and with a CRP &gt; 10 mg/L and Alb &lt; 35 g/L to GPS 2. This exploratory subgroup analysis was performed by Cox regression analysis to investigate the impact of IN status at baseline on OS. Less than 0.1 of P-value for interaction was regarded as significant. Results: GPS, CRP and Alb showed significant treatment interactions in terms of OS. HRs of Arm B to Arm A were 1.35 (0.82–2.23) and 0.59 (0.24–1.50) in the GPS 0 (n = 44/34 in Arm A/B) and GPS 1/2 group (n = 7/15) ( P-interaction = 0.06). HRs were 2.57 (1.36–4.86) and 0.70 (0.37–1.32) in the low CRP group (≤ 1.35 mg/L, n = 25/25) and high CRP ( &gt; 1.35 mg/L, n = 26/24) ( P= 0.01). HRs were 1.62 (0.77–3.40), 2.70 (1.17–6.23) and 0.52 (0.24–1.13) in the 1st (≤ 0.7 mg/L, n = 16/16), 2nd ( &gt; 0.7, ≤ 3.0 mg/L, n = 20/16), and 3rd tertiary CRP group ( &gt; 3.0 mg/L, n = 15/17) ( P= 0.01). HRs were 2.29 (1.11–4.69) and 0.89 (0.51–1.54) in the high Alb group ( &gt; 40 g/L, n = 23/17) and low Alb (≤ 40 g/L, n = 28/32) ( P= 0.04). Arm B showed better survival in subgroups of GPS 1/2, higher CRP or lower Alb compared to Arm A. Conclusions: Pts with poor IN status may have treatment benefit of induction CT followed by CRT for LAPC. Clinical trial information: UMIN000006811.
Racial disparities in treatment and outcomes of colorectal cancer in young adults.
Authors: Olatunji Boladale Alese, Renjian Jiang, Walid Labib Shaib, Christina Sing-Ying Wu, Madhusmita Behera, Bassel F. El-Rayes
Journal: Journal of Clinical Oncology (2017)

6559 Background: The incidence of colorectal cancer (CRC) in young adults is increasing. Minority populations with CRC are known to have worse outcome. The objective of this study is to evaluate the impact of race on the outcome of young adults with CRC. Methods: Data were obtained from all US hospitals that contributed to the National Cancer Database (NCDB) between 2004 and 2013. Univariate and multivariate testing was done to identify factors associated with patient outcome. Kaplan-Meier analysis and Cox proportional hazards models were used for association between patient characteristics and survival. Results: A total of 83,449 patients between 18 and 50 years of age were identified. The mean age was 43.6 years (SD±6), with a male preponderance (53.9%). About 72% were non-Hispanic Whites (NHW) while African Americans (AA) made up 15.1%. Distribution across stages I-IV was 15.6%, 22.4%, 33.9% and 27% consecutively, similar among the races. 41.8% of NHW and 28.4% of AA had rectal cancers (p&lt;0.001). Despite equally receiving standard of care (SOC) as per NCCN guidelines, AA had significantly lower 5year survival rates (58.8%) compared to Hispanics (64.8%) and NHW (66.9%; HR 1.42; 1.38-1.46; p&lt;0.001). Patients with colon cancer had worse outcome compared to rectal cancer (HR 1.21; 1.18-1.24; P&lt;0.001). In terms of survival, NHW (HR 0.85; 0.81-0.88; p&lt;0.001) and Hispanics (HR 0.75; 0.70-0.79; p&lt;0.001) were more likely to benefit from chemotherapy compared to AA. As expected, SOC utilization was associated with improved survival across all racial groups, especially in AA with HR of 0.64 (0.60 – 0.69; p&lt;0.001). Conclusions: Despite comparable rates of standard of care utilization, AA young adults with CRC had worse outcomes compared to other races. Colon cancer was significantly more common in AA than rectal cancers, which may have contributed to their worse outcomes. [Table: see text]
Participation of elderly gynecological cancer patients in clinical trials.
Authors: Katharina Prieske, Fabian Trillsch, Gulten Oskay-Oezcelik, Radoslav Chekerov, Eva-Maria Schoening, Leticia Oliveira-Ferrer, Donata Grimm, Sasha Kuerti, Anna Suling, Barbara Schmalfeldt, Jalid Sehouli, Sven Mahner, Linn Lena Woelber
Journal: Journal of Clinical Oncology (2017)

e21520 Background: Elderly patients (pts) are underrepresented in clinical trials in gynecological cancer, even though they are disproportionally often affected. This study aimed to evaluate disposition and apprehension of elderly pts towards study participation. Methods: 112 elderly gynecological cancer pts (median age 70; range 65-92) were surveyed in a multicenter cross-sectional study. Besides fitness, state of disease, education and domestic situation, questions aimed at the general willingness to participate in a clinical trial. Personal reasons for rejection and suspected advantages/disadvantages that might evolve from participation were inquired. Results: Willingness to participate in a study was generally high (66.1%, 74/112). 42/112 (37.5%) had given their consent to participation in a study before, 12.5% (6/48) refused even though they were offered participation. Reasons for potential study participation were: ‘better monitoring of the disease’ (51/112), ‘better medical care’ (35/112), ‘to help medical research’ (31/112), ‘better medication’ (27/112) and ‘because of my doctor’s recommendation’ (17/112). Reasons for potential refusal were: ‘too time consuming’ (19/112), ‘fear of side effects’ (17/112), ‘misuse as experimental animal’ (14/112), ‘long distance to clinic’ (11/112) and ‘too little or unclear information’ (7/112). 26.1% (29/112) of pts stated, that they had ‘no objection’ against study participation. The question if pts anticipated having a longer life due to study participation was answered with ‘yes’ or ‘rather yes’ in 33.9% (38/112), 23.2% answered ‘no’ or ‘rather no’ (23.2% undecided). No relation between willingness to participate in a study and general fitness (p = 0.311), education (p = 0.631) or domestic situation (p = 0.195) could be observed. However, with increasing age, willingness decreased (p = 0.029). Conclusions: Elderly pts are generally willing to participate in clinical studies regardless of their fitness or educational background. Benefits of participation seem to be unclear among a majority of potential study participants. Therefore it might be decisive to provide more general information regarding benefits and safety for the elderly pts in a clinical trial.
A survival prediction nomogram for liposomal irinotecan (nal-IRI)+5-fluorouracil/leucovorin (5-FU/LV) in patients (pts) with metastatic pancreatic ductal adenocarcinoma (mPDAC) previously treated with gemcitabine-based therapy.
Authors: Andrea Wang-Gillam, Richard Hubner, Beloo Mirakhur, Floris de Jong, Bruce Belanger, Li-Tzong Chen
Journal: Journal of Clinical Oncology (2018)

e16204 Background: NAPOLI-1 (NCT01494506) was a global phase 3 study in pts with mPDAC previously treated with gemcitabine-based therapy that showed a significant improvement in overall survival (OS) in pts treated with nal-IRI+5-FU/LV vs 5-FU/LV alone. A nomogram assists in predicting individualized risk for prespecified events, such as OS, death, or adverse events. A post hoc analysis of NAPOLI-1 was conducted to develop a nomogram to predict OS for nal-IRI+5-FU/LV in the post-gemcitabine setting. Methods: In NAPOLI-1, pts received nal-IRI+5-FU/LV, nal-IRI, or 5-FU/LV. Univariate and multivariate analyses identified baseline factors that were significantly predictive of OS. A multivariable Cox regression model was created to develop a nomogram that assigned points equal to the weighted sum of relative significance of each variable. The predictive accuracy of the nomogram, as measured by the concordance index (c-index), was evaluated by internal bootstrap validation. Results: Data from pts in the univariate analysis (n = 417) and multivariate analysis (n = 399; n = 18 pts excluded for missing data) were used. Eight of 21 variables were retained in the multivariate analysis and re-tested through stratification (all factors significant at the P < 0.01 level, except BMI [P= 0.08]). Conclusions: Key predictors of OS in NAPOLI-1 were nal-IRI+5-FU/LV treatment, KPS, NLR, albumin level, baseline CA19-9, stage 4 at diagnosis, BMI, and presence of liver metastasis. Clinical trial information: NCT01494506.Stratified Multivariate Cox Regression of OS (N = 399)a Wald P-value HR 95% CI Karnofsky Performance Status (KPS) ≥ 90 vs 60–80 < 0.0001 0.58 0.46, 0.74 Albumin ≥4 g/dL vs < 4 g/dL 0.0013 0.68 0.54, 0.86 Neutrophil-to-lymphocyte ratio (NLR) > 5 vs ≤5 0.0001 0.61 0.47, 0.79 No liver metastasis vs Presence of liver metastases < 0.0001 0.59 0.45, 0.76 CA19-9 > median ≤ 1542 U/mL) vs > 1542 U/ml < 0.0001 0.63 0.50, 0.79 Stage < 4 vs Stage 4 at diagnosis < 0.0001 0.62 0.49, 0.78 Body mass index (BMI) > 25 vs ≤25 kg/m2 0.030 0.75 0.58, 0.97 nal-IRI+5-FU/LV vs 5-FU/LV or nal-IRI 0.0001 0.59 0.45, 0.77 aModel excluded pts with missing values.
Functional annotation of cancer driver genes in breast cancer patient-derived xenografts to identify a novel target for PARP inhibitors.
Authors: Xiaosong Zhang, Meng Li, Olga Momcilovic, Andrew Beardsley, Roman Camarda, Andrei Goga
Journal: Journal of Clinical Oncology (2016)

e23192 Background: Recent cancer genome sequencing efforts have discovered hundreds of driver-like mutations per tumor in most adult solid tumors. It is critical to identify the functionally important cancer driver genes in vivo within a background of several hundred putative “passenger” mutations. Methods: A selected human cancer gene panel including 262 cancer driver genes were sequenced in 15 clinically well-annotated breast cancer patient derived xenografts (PDXs) using next generation sequencing (NGS). All the mutations were further confirmed by Sanger sequencing. One of the most aggressive breast cancers, PDX HCI-002, harbors a bi-allelic inactivating mutation of BAP1 (BRCA Associated Protein 1). The role of BAP1 mutations on in vivo sensitivity of PDX breast cancer models has not been previously explored. Mice bearing orthotopically transplanted PDX HCI-002 were treated with either vehicle or BMN-673, a potent PARP inhibitor, for 14 days. Results: We have identified a total of 73 mutations in 15 breast cancer PDXs. The same mutations were not only identified in a single tumor sample but also in the early and late tumor passages of the same breast cancer PDX line. Pathway analysis based on the genetic mutation patterns showed that 80% (12/15) of breast cancer PDXs had at least one genetic mutation in the DNA damage repair pathway. Half of these mutations (50%, 9/18) are inactivating mutations. The fastest growing breast cancer harbors an inactivating mutation of BAP1 that causes loss of protein expression. BAP1 loss sensitizes the PDX model in vivo to PARP inhibition. At the end of 14 day treatment by BMN-763, mice bearing breast cancer PDX HCI-002 achieved 64% tumor weight reduction in comparison to the control arm. Conclusions: Our results suggest that BAP1 inactivating mutation might serve as a potential predictive biomarker for PARP inhibitor sensitivity. This work serves as a proof of concept that sequencing of human PDX models can identify novel therapeutic strategies based on genomic alterations.
Abstract 14633: MTOR Promotes Aortic Dissection Through Cell Proliferation
Authors: Makiko Hayashi, Hiroki Aoki, Satoko Ohno, Michihide Nishihara, Aya Furusho, Saki Hirakata, Norifumi Nishida, Sohei Ito, Yoshihiro Fukumoto
Journal: Circulation (2017)

Aortic dissection (AD) is a fatal disease for which therapeutic options are limited because molecular pathogenesis remains unclear. To understand the molecular events during AD development, we crea...
Deep analysis to inconsistent results of EGFR mutation status in tumor tissues and plasma DNA in advanced NSCLC.
Authors: Jie Wang, Rui Wan, Hua Bai, Zhijie Wang, Jun Zhao, Minglei Zhuo, Tongtong An, Jianchun Duan
Journal: Journal of Clinical Oncology (2016)

e20591 Background: Around 30% patients with EGFR mutation presented inconsistent status of EGFR mutation between in tissues and plasma. Here, we explored the potential reason and clinical significance for the patients with EGFR mutation positive in cell-free tumor DNA(ctDNA) but negative in corresponding tumor tissues. Methods: A total of 472 NSCLC patients with EGFR mutation affirmed by Amplification Refractory Mutation System (ARMS) receiving EGFR-TKIs were assigned into the three subgroups. Patients with EGFR mutation T- and B+ were re-evaluated by droplet digital PCR (ddPCR) and next generation sequence(NGS), and seven surgical resection samples were microdissected to analyze heterogeneity of EGFRmutation distribution by ARMS, ddPCR and NGS. Results: Of all 472 patients, 312 harbored EGFR mutations in both tissue and blood(T+/B+ ), 160 patients carried mutation only in tissue (131 cases, T+/B-) or blood (29 cases, T-/B+) by ARMS. TheddPCR approach confirmed the EGFR mutation in ctDNA of 29 patients. And among their corresponding tumor tissues, 7 cases came from surgical resection and 22 cases were biopsy samples. 13 patients were detected EGFR mutation in biopsied primary tumor(n = 10), and live metastasis (n = 2) or CTC(n = 1), Five of the seven surgical resection samples had intratumoral EGFR mutation heterogeneity, and the fraction of EGFR mutated sequences in tumor foci ranged from 0.10% to 1.25% (median, 0.24%). For remaining 11 samples, 4 cases were detected low abundance of EGFR mutation by NGS and another 7 cases had no sufficient tissues for NGS analysis. The PFS to EGFR-TKIs was numerically inferior in patients carrying EGFRmutation T-/B+ (5.7months, 95% CI, 0.9 to 10.5), compared with that in the patients with T+ and B+/- [(9.1months, CI, 8.07 to 10.1; 9.7months, 95% CI, 8.9 to 10.6, p = 0.811). Conclusions: Intra-tumor heterogeneity of EGFR mutation and low sensitivity of detection methods may contribute to EGFR mutation T- and B+, and low content of EGFR mutation in this subgroup may associated with short PFS.
Incidence of secondary myelodysplastic syndrome and acute myeloid leukemia in patients with ovarian and breast cancer in real-world setting in the U.S.
Authors: Nicole Fulcher, Rahul A. Shenolikar, Emily Durden, Kathleen N. Moore
Journal: Journal of Clinical Oncology (2017)

5574 Background: Limited real-world data are available on cancer patients withsecondary malignancies such as myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) caused by use of certain chemotherapeutic agents that interfere with DNA. This study assessedthe incidence of secondary MDS and AML in patients (pts) with ovarian cancer (OC) or breast cancer (BC), including subcohorts tested for BRCA mutations and those exposed to DNA damaging therapy. Methods: Adult females with OC or BC between 1/1/2000 and 6/30/2014 (first observed diagnosis of OC or BC = index date) were identified from the MarketScan Commercial and Medicare claims databases. Patients had ≥12 months of pre- and ≥1 month of post-index continuous health plan enrollment. The incidence of MDS and AML (per 1000 person-years [PY]) was assessed using ICD-9 codes over a variable-length post-index period for each cancer cohort and separately for pts with BRCA testing and those exposed to DNA damaging therapy. Results: The study identified 23,862 OC pts (mean [SD] follow-up: 35.8 [31.4] months), and 281,473 BC pts (mean [SD] follow-up: 46.0 [37.2] months). Among OC pts, 10.9% had BRCA testing (OC- BRCA) and 56.6% had exposure to DNA damaging therapy (OC-DNA); 12.9% of BC pts were BRCA tested (BC- BRCA) and 28.1% had exposure to DNA damaging therapy (BC-DNA). The incidence of MDS and AML expressed as cases per 1,000 PY in the OC cohort was 0.51 (0.2%) and 0.39 (0.1%); in OC- BRCA pts, 0.62 and 0.25; and in OC-DNA pts, 0.68 and 0.41. In the BC cohort, the incidence of MDS and AML was 0.33 (0.1%) and 0.19 (0.1%); in BC- BRCA pts, 0.07 and 0.15; and in BC-DNA pts, 0.60 and 0.50. Conclusions: In addition to providing background rates in OC and BC pts, these data suggest that the incidence of MDS and AML in OC and BC pts was higher in patient subcohorts exposed to DNA damaging agents than in the overall cohort.
Nonverbal synchrony as a marker of patient racial attitudes in oncology interactions.
Authors: Lauren M. Hamel, Robert Moulder, Terrance Lynn Albrecht, Steven Boker, Tanina Foster, Susan Eggly, Allison Magnuson, Louis Penner
Journal: Journal of Clinical Oncology (2018)

e22126 Background: Patient-physician communication during racially discordant oncology interactions (about 80% of Black patients’ interactions) is often poorer than in racially concordant interactions, and likely contributes to well-documented treatment disparities. Racial attitudes influence communication but the mechanisms, and in particular the role of nonverbal communication, are not well understood. We posit that one mechanism is variation in subtle and non-conscious behavioral coordination, or “nonverbal synchrony”, between Black patients and non-Black physicians during treatment discussions. Methods: Oncologists (n = 16) provided demographics and completed a measure of implicit racial bias. Patients (n = 68) provided demographic information and completed measures of trust in physicians, group-based suspicion of medical care, and previous discrimination. Video recordings of their interactions were submitted to Motion Energy Analysis (MEA) software to measure nonverbal synchrony. MEA provides indices of global synchrony (all correlated motion), peak synchrony (positively correlated motion), and the extent to which patients and physicians switch speaking and listening roles. We investigated whether racial attitudes influence nonverbal synchrony. Results: We found a positive relationship between patients’ trust in physicians and global synchrony (p = .05), but a negative relationship between patients’ previous discrimination and peak synchrony (p = .007); and a positive relationship between suspicion and peak synchrony (p = .03). There was a positive relationship between previous discrimination and the extent to which patients and physicians switched speaking and listening roles (p = .03). Oncologists’ implicit bias did not influence synchrony. Conclusions: This is one of few studies to examine the reciprocal nature of communication using a dynamic, jointly determined measure. It shows that racial attitudes minority patients bring to clinical interactions affect non-conscious nonverbal synchrony with their physician. This channel of communication provides a new research tool for studying and understanding communication in racially discordant oncology interactions.
Reduced intrinsic DNA curvature leads to increased mutation rate
Authors: Chaorui Duan, Qing Huan, Xiaoshu Chen, Shaohuan Wu, Lucas B. Carey, Xionglei He, Wenfeng Qian
Journal: Genome biology (2018)

Mutation rates vary across the genome. Many trans factors that influence mutation rates have been identified, as have specific sequence motifs at the 1–7-bp scale, but cis elements remain poorly characterized. The lack of understanding regarding why different sequences have different mutation rates hampers our ability to identify positive selection in evolution and to identify driver mutations in tumorigenesis. Here, we use a combination of synthetic genes and sequences of thousands of isolated yeast colonies to show that intrinsic DNA curvature is a major cis determinant of mutation rate. Mutation rate negatively correlates with DNA curvature within genes, and a 10% decrease in curvature results in a 70% increase in mutation rate. Consistently, both yeast and humans accumulate mutations in regions with small curvature. We further show that this effect is due to differences in the intrinsic mutation rate, likely due to differences in mutagen sensitivity and not due to differences in the local activity of DNA repair. Our study establishes a framework for understanding the cis properties of DNA sequence in modulating the local mutation rate and identifies a novel causal source of non-uniform mutation rates across the genome.