tbuckley/cabot-search huggingface dataset:
Distribution of CDH13, CDH1, MGMT and PTEN promoter methylation and KRAS, BRAF and EGFR mutation in colorectal cancer.
Authors: Garry Mahon, Brigitte Metzger, Mario-A Dicato
Journal: Journal of Clinical Oncology (2016)

e15073 Background: The adenocarcinoma sequence is associated with the accumulation of epigenetic and genetic changes as normal tissue becomes cancerous. We have been interested in variants in the methylation status of the promoters of the CDH1, CDH13, MGMT and PTEN genes, and mutations in the KRAS, BRAF, and EGFR genes. Methods: Ethical approval and informed consent were obtained. DNA was extracted from resected tumor samples and white blood cells from 86 patients. The stage of the disease was classified by the extended Dukes’ system: A, B1, B2, B3, C1, C2, C3, or D (8 stages). Promoter methylation was assessed by methylation-specific PCR, gel electrophoresis after Sybr green staining and UV photography. Statistical analysis was carried out for 2x8 tables and the chi-squared test, with a Bonferroni correction for multiple comparisons. Results: The frequency of promoter methylation for CDH13 was 74% of tumor samples; MGMT, 66%; CDH1, 58% and PTEN, 47%. The frequency of mutation for KRAS was 24%, BRAF, 13% and EGFR, 3%. All variants were tumor specific as all control samples were un-methylated and wild type. The frequency of variants across stage was found to be constant (with one exception). P values for MGMT, CDH1 and PTEN were 0.236, 0.690and 0.733, and for KRAS, BRAF and EGFR were 0.181, 0.520 and 0.631 respectively (not significant). The exception was CDH13; the P value was 0.000020, highly significant even after the Bonferroni correction. Although nearly 3/4 of tumor samples were CDH13 methylated, almost all samples of stages B3 or C3 were un-methylated. Conclusions: The Dukes’ system recognises four stages: A, tumor limited to muscularis propia; B, extending beyond muscularis propia but nodes not involved; C, as B but nodes involved, and D, distant metastatic spread. Stages B and C may be subdivided with B3 and C3 signifying invasion of adjacent structures. We have found that methylation of the CDH13 promoter is rare in tumors which have invaded adjacent structures but common at all other stages, both early and late. CDH13 is the gene for H-cadherin which is involved in vascularisation. The gene may often be inactivated in colorectal cancer but activity may be needed for the tumor to invade adjacent structures.
Nivolumab (NIVO) safety in patients with advanced melanoma (MEL) who have progressed on or after ipilimumab (IPI): A single-arm, open-label, multicenter, phase II study (CheckMate 172).
Authors: Paolo Antonio Ascierto, Lev V. Demidov, Claus Garbe, Paul Lorigan, Helen Gogas, Christoph Hoeller, John B. A. G. Haanen, Enrique Espinosa, Tormod Kyrre Guren, Eva Muñoz-Couselo, Andree Rorive, Piotr Rutkowski, Reinhard Dummer, Ana Carneiro, Geke Hospers, Frank Hermann, Joel Jiang, Dirk Schadendorf, Paul D. Nathan
Journal: Journal of Clinical Oncology (2016)

9526 Background: NIVO, a programmed death-1 immune checkpoint inhibitor, improved response rates and progression-free survival (PFS) compared with chemotherapy in MEL patients (pts) who progressed after IPI in the phase III CheckMate 037 trial (Lancet Oncol 2015;16:375). We assessed NIVO monotherapy in pts with MEL who had progressed on or after IPI, including pts with poor prognostic factors who have been largely excluded from clinical trials (eg, ECOG performance status [PS] 2, brain metastases). Methods: In this ongoing phase II, single-arm, open-label, multicenter study, European pts with MEL who progressed on or after IPI are treated with NIVO 3 mg/kg Q2W for up to 2 years until progression or unacceptable toxicity (NCT02156804). The primary endpoint is safety; secondary endpoints include objective response rate (ORR). We report safety in the first 307 treated pts (database lock, November 2015; minimum follow-up of 6 months). Results: At baseline, 8% of pts had ECOG PS 2, 65% had M1c disease, 15% had a history of brain metastases, and 29% had received ≥ 3 prior therapies. Overall, 256 (84%) patients received at least 4 doses of NIVO, while 241 (79%) received > 4 doses. The incidence of treatment-related any grade and grade 3/4 adverse events (AEs) were 58% and 11%, respectively. Discontinuations due to treatment-related AEs occurred in 3% of pts. No treatment-related deaths were reported. The most common treatment-related select AEs (ie, potentially immune-related) were dermatologic (19%), endocrine (9%), gastrointestinal (7%), and hepatic (5%). ORR data are planned to be available for the presentation. Conclusions: CheckMate 172 represents the largest study of NIVO safety and efficacy in pts with MEL who progressed on or after IPI. In this initial report, NIVO demonstrated a safety profile consistent with previously reported clinical trial data. Clinical trial information: NCT02156804.
CtDNA assay to detect EGFR mutations and mechanisms of resistance to EGFR tyrosine kinase inhibitors.
Authors: Lyudmila Bazhenova, Satya Das, Sandip Pravin Patel, Lyle Arnold, Veena M. Singh
Journal: Journal of Clinical Oncology (2016)

e23042 Background: For lung cancer patients with an EGFR activating mutation, EGFR tyrosine kinase inhibitors (TKI), are standard of care, but resistance to TKIs inevitably develops. Elucidating the mechanisms of resistance typically requires post-progression tissue biopsies, which are associated with complications, and tumor heterogeneity can obscure the true mechanism of resistance. Circulating cell-free tumor DNA (ctDNA) represents an alternative method to detect resistance mutations. Methods: Two 8–10 mL tubes of blood were collected from 21 patients with EGFR-mutated Stage IV lung adenocarcinoma, who have progressed on EGFR TKI. Patient samples were tested for the T790M resistance mutation using Target Selector, Biocept’s liquid biopsy. Results were compared to data from standard tissue biopsy. Results: Of the 21 patients 12/21 (57%) had deletion 19, 8/21 (38%) had the L858R mutation. EGFR status was unknown for 1 patient. CtDNA correctly identified EGFR mutation in 83 % of cases. Median duration of EGFR TKI therapy prior to ctDNA analysis was 17.3 months (range 5.2-64.4). Median time between ctDNA analysis and biopsy was 2.5 months (range 0.3-49.7). 19 patients underwent a post-progression biopsy. Tissue was T790M + in 12/19 (63%); negative in 5/19 (26%); 2/19 pending or not performed. The median mutant allele copy number of T790M in 3mL of plasma was 68 (range 7-20507). 17 patients had paired tissue and blood samples. Sensitivity of ctDNA to detect T790M mutation was 83%, specificity 40%, PPV 77%, NPV 50%. 13 patients received therapy with 3rd generation EGFR TKI. One ctDNA T790M +, but tissue negative patient was treated with 3rd generation EGFR TKI and has not responded. Two patients with ctDNA T790M negative but tissue T790M + were treated with 3rdgeneration EGFR TKI, one responded, one response TBD. Both of those patients had low systemic burden of the disease, potentially explaining negative liquid biopsy. The analytical validation has a sensitivity of 95% and specificity of 99% at 7 mutant copies against 14,000 copies of wild type EGFR. Conclusions: Biocept’s blood based assay to detect EGFR mutations and T790M from ctDNA is concordant with mutations present in post-progression tumor tissue biopsies.
Hypomagnesemia and exposure to romidepsin: A Research on Adverse Drug events and Reports (RADAR) project.
Authors: Dylan E. Lee, Linda Serrano, Estela Martinez-Escala, Jason B. Kaplan, Barbara Pro, Joan Guitart, William H. Temps, Dennis P. West, Steven M. Belknap
Journal: Journal of Clinical Oncology (2017)

e14072 Background: Romidepsin (R) is indicated for cutaneous T-cell lymphoma (CTCL) and peripheral T-cell lymphoma. Hypomagnesemia (HM) is common in these patients and is also listed in the Full Prescribing Information (FPI) for R. Moreover, since cardiac arrhythmias are associated with HM, patients exposed to R may be at higher risk. This study assessed whether HM was causally related to R exposure and to what extent magnesium (M) supplementation was undertaken in those with HM. Methods: We searched a large, U.S. patient data repository to detect all patients (aged 20-94 years) exposed to R (10/2010-01/2017). For these patients, serum M, as well as M supplementation data, was collected. Baseline M was assessed at initial R exposure, and HM was defined as either, a decline in M to &lt; 1.8 mg/dL after R exposure or, in those with baseline M &lt; 1.8 mg/dL, a decline in M by ≥0.1 mg/dL after R exposure. For each patient with HM after R exposure, the validated Naranjo Adverse Drug Reaction Probability Scale (NADRPS) was used to determine the probability that HM was caused by R. Results: Of 51 R-exposed CTCL (or other lymphoma) patients, 25 (49.0%) had HM. Of these 25, NADRPS scores yielded: 1 doubtful, 16 possible, 8 probable and 0 definite. Additionally, 24 of 25 patients with HM had documentation for presence or absence of M supplementation: 9 (37.5%) had supplementation with M agents considered to be bioavailable, 12 (50%) received M agents considered to have low bioavailability, and 3 (12.5%) had no M supplementation. Conclusions: In this study population, 25 of 51 (49.0%) patients had HM after R exposure, which appears to nearly double the percentage of patients described in the FPI. Moreover, 8 of 25 (32%) patients with HM had causality attributed to R exposure. In addition, 15 of 24 (63%) patients with HM received M supplementation with agents considered to have low bioavailability or received no M supplementation. These findings support the need for ongoing monitoring of R-exposed patients with low M, as well as the importance of repleting M with agents considered to be adequately bioavailable. Also, given that HM appears to be more frequent in this study population compared to pre-marketing data in the FPI, further studies are warranted.
Event-free survival (EFS) and overall survival (OS) of MYCN-amplified stage 2/3 neuroblastoma with or without autologous stem-cell transplantation (ASCT).
Authors: Brian H. Kushner, Shakeel Modak, Michael P LaQuaglia, Suzanne L. Wolden, Ellen M. Basu, Stephen S. Roberts, Kim Kramer, Irene Y. Cheung, Nai-Kong V. Cheung
Journal: Journal of Clinical Oncology (2016)

10553 Background: The literature on MYCN-amplified stage 2/3 neuroblastoma is limited because this high-risk subset is uncommon. Its prognosis improved with ASCT. Reports on anti-GD2 immunotherapy do not provide details on this entity. We now present our experience since 2000 when anti-GD2 antibody 3F8/GM-CSF+isotretinoin became routine. ASCT was used 2000-2003 at our center but not thereafter, though patients transplanted elsewhere remained eligible for 3F8/GM-CSF. Methods: This report on MYCN-amplified stage 2/3 has two components. Part 1 covers an unselected series of 24 consecutive newly-diagnosed patients treated with dose-intensive induction chemotherapy. Part 2 concerns 3F8/GM-CSF+isotretinoin as consolidation of first complete remission (CR), including 20 (15 non-ASCT and 5 ASCT patients) of the aforementioned 24 newly-diagnosed patients, plus 6 patients referred post-ASCT. Consolidation included local radiotherapy. Results: Part 1: 21/24 (88%) newly-diagnosed patients achieved CR with induction; 20 received consolidation but one CR patient did not (social reasons) and eventually died of progressive disease (PD). Three patients had PD with induction and died early. At 5 years post-diagnosis, these 24 patients had EFS/OS 67%/77%. Part 2: Among the CR patients consolidated with 3F8/GM-CSF+isotretinoin, the 15 non-ASCT patients include 12 relapse-free 12-151 (median 40) months from diagnosis and two who relapsed but remain in 2ndCR at 24 and 84 months post-relapse (their salvage included 3F8/GM-CSF+isotretinoin again). These 15 non-ASCT patients had EFS/OS 72%/92% at five years from start of 3F8. Of 11 ASCT patients, 10 remain relapse-free 75-204 (median 164) months from diagnosis. These 11 ASCT patients had EFS/OS 91%/91% at 5 years from start of 3F8. There were no significant differences in EFS/OS between non-ASCT and ASCT cohorts (p = .34/.92). Minimal residual disease (bone marrow) was detected in only 3 patients, cleared with 3F8/GM-CSF, and did not predict relapse. Conclusions: This subset has a good prognosis with contemporary multi-modality therapy, even without ASCT. Anti-GD2 antibody may help improve outcome after relapse.
Modulation of autophagy with hydroxychloroquine in patients with advanced non-small cell lung cancer (NSCLC): A phase Ib study.
Authors: Jyoti Malhotra, Salma Jabbour, Michelle Orlick, Gregory Riedlinger, Sonali Joshi, Jessie Yanxiang Guo, Eileen White, Joseph Aisner
Journal: Journal of Clinical Oncology (2018)

e21138 Background: A potential resistance mechanism to chemotherapy in NSCLC is through activation of cell survival pathways such as autophagy. Studies in genetically engineered mouse models demonstrate that autophagy inhibition suppresses lung tumor development and progression, especially in Kras mutated tumors. We report safety and efficacy of adding an autophagy inhibitor, hydroxychloroquine (HCQ) to front-line platinum-based chemotherapy in a phase Ib single arm study in patients with metastatic NSCLC. Methods: Patients with newly diagnosed metastatic NSCLC were treated with carboplatin, paclitaxel (and bevacizumab if meeting criteria) and HCQ 200 to 600 mg BID for the escalation part and 600 mg BID for the expansion. Patients continued on HCQ (+/- bevacizumab) maintenance after 4-6 cycles of therapy. Results: Of the 40 patients enrolled (8 on escalation; 32 on expansion), 58% were male; 31% had squamous histology. Median age was 62 years. Sixteen patients (40%) had at least one grade 3 or higher treatment-related adverse event with the most common being neutropenia (35%), anemia (15%), thrombocytopenia (10%) and dehydration (10%). The objective response rate (ORR) was 47% in the 34 patients evaluable for response. Additionally, 21% patients demonstrated stable disease for a total clinical benefit rate of 68%. The median PFS was 3.7 months (95% CI 3.2 to 5.8 months). Patients with non-squamous histology had a higher ORR (52% vs. 33%) and improved PFS compared to those with squamous histology (4.7 vs. 2.3 months). Twenty-one of the 40 patients' tumors were assessed for Kras mutations; 9 of the 21 tumors were Kras mutated. The ORR according to Kras was 44% for mutated and 42% for wild-type: PFS was 3.7 vs. 2.8 months. Conclusions: Addition of HCQ has a similar toxicity profile compared to chemotherapy alone. The response rate to therapy in Kras mutated and wild type tumors was similar; even though Kras mutated tumors usually demonstrate worse responses and PFS to chemotherapy. Autophagy inhibition may help overcome chemotherapy resistance in patients with non-squamous NSCLC especially if Kras mutated. Further study with autophagy inhibiton in a more selected population appears warranted. Clinical trial information: NCT01649947, NCT00728845.
Evaluation of the concordance between centrosome amplification and mitotic frequency between patient tumors and cultured cancer cells.
Authors: Karuna Mittal, Da Hoon Choi, Michelle D. Reid, Angela Ogden, Meenakshi Vij Gupta, Guilherme Cantuaria, Kristin Jonsdottir, Emiel A Janssen, Padmashree C.G. Rida, Ritu Aneja
Journal: Journal of Clinical Oncology (2016)

e23285 Background: Centrosome amplification (CA) and aberrant mitotic figures are well recognized as beacons of malignancy. However, it has recently been brought to light that mitotic indices are much lower in patient tumors than in continuously cultured cells, which may explain the clinical failure of many mitosis-targeted drugs that exhibited preclinical efficacy. We investigated the concordance between clinical tumor samples and cultured cancer cells by evaluating mitotic activity and CA. Methods: Using indirect immunofluorescence confocal imaging, we compared the number of mitotic figures (phosphohistone H3 staining) and CA (γ-tubulin staining), in formalin-fixed paraffin-embedded clinical tumor samples of breast, pancreas and bladder (n = 20 for each cancer type), immortalized cancer cell lines (MDA-MB-231-breast, MIA PaCa-pancreas and T24-bladder), tumor xenograft (derived from MDA-MB-231) and patient-derived cell line (breast). Results: We found while < 5% cells were mitotically active in clinical tumors, 5-15% of cultured cells were mitotically active. By contrast, CA ranged from 35-50% in tumor samples and xenografts as opposed to only 5-15% in continuous cell cultures. Patient-derived tumor cells displayed the highest CA (~50%), consonant with human tumors, albeit at low passage numbers only. Mechanistically, we found that hypoxia can induce CA; thus intratumoral hypoxia may explain the discordance between the extent of CA in patient tumors and cultured cancer cells. These findings were validated in silico by probing the publicly-available Kao microarray (n = 327) dataset using Gene Set Enrichment Analysis. Results suggested that high hypoxic breast tumors are associated with (a) high expression of genes related to CA and chromosomal instability (CIN25 gene signature), and (b) worse distant metastasis-free survival. Conclusions: These results bring to light the previously unrecognized discordance in mitotic frequency and CA between various cancer model systems and highlight the importance of utilizing low-passage-number cell lines, preferably patient-derived, in the study of CA to more accurately represent cellular phenotypes in patient tumors.
C-Methionine PET (Met-PET) for a diagnosis algorithm for pseudoprogression (PsP), radiations necrosis (RN) and progression (P) after an indeterminate magnetic resonance imaging (MRI) in glioblastoma (GBM).
Authors: Eudald Felip-Falg s, Iris Teruel, Sira Domenech, Carlos Erasun, Jose Ramon Garcia-Garzon, Juan José García Mosquera, Fidel Nuñez, Salvador Villa, Anna Massuet, Jose Maria Velarde, Anna Estival, Carmen Balana
Journal: Journal of Clinical Oncology (2018)

e14039 Background: GBM is associated with a uniformly poor prognosis. The evaluation of response to treatment by MRI is imperfect some results may difficulties to deciding changing treatment. We analyse the role of Met-PET after indeterminate MRI to distinguish among PsP, RN or P. Methods: We performed a retrospective analysis of 34 GBM MRIs (corresponding to 23 different patients) performed between 2014-2016, which generated doubts about PSP, RN and P. The study was complemented by a Met-PET which was decided by a neuro-oncology committee. We evaluated contrast enhancing images, diffusion restriction, ADC values (DWI/DTI) and dynamic contrast enhancement perfusion (rCBV) from MRI; and metabolic activity and morphology uptake from Met-PET, to reach a presumptive diagnosis. One month later Met-PET, there was a new revaluation clinical and MRI evaluation to verify the prior decision. Consequently, we evaluated the role of Met-PET (sensibility, specificity) to get a correct decision about eventual treatment modifications. Results: Data showed that 23/34 cases (67.7%) had an alteration in the DWI-MRI and only 9/34 (26.55%) had an increase rCBV. In 5/34 of cases (14,7%) both DWR-MRI and rCBW were pathologic. In 4/34 of cases (11,8%) both values were non-pathological, and Met-PET was completed to clarify doubts, and in 3 of these 4 cases (75%) Met-PET discriminated the diagnosis. In totally, Met-PET found in 24/34 (70.6%) of studies, an abnormal exploration, and in 23/24 of these cases (95.8%) lead to a modification of treatment. Comparing Met-PET with the subsequent posterior study, we can assess Met-PET with a sensibility of 86% and a specificity of 66% as a diagnosis test. Conclusions: Met-PET adds additional information to an indeterminate MRI and could be essential to take a decision about changing treatment. Having and initial Met-PET at GBM could improve sensibility and specificity of Met-PET; subsequently, it could be a the best diagnosis test in those cases.
Racial differences in the financial impact of breast cancer.
Authors: Stephanie B. Wheeler, Jennifer Spencer, Laura C Pinheiro, Lisa A. Carey, Andrew F Olshan, Katherine Elizabeth Reeder-Hayes
Journal: Journal of Clinical Oncology (2017)

e18293 Background: Racial variation in the adverse financial impact of cancer may contribute to observed differences in the initiation and completion of guideline-recommended adjuvant treatments. We describe racial differences in the financial impact of breast cancer diagnosis in a large, population-based, prospective cohort study. Methods: Patients were recruited via rapid case ascertainment through the North Carolina cancer registry as part of the Carolina Breast Cancer Study, with oversampling of black women and women younger than 50. Participants provided medical records and survey data on demographics, socioeconomic status, treatments, and financial impact of cancer. We used chi-square tests and multivariable logistic regression to understand racial differences in financial impact of breast cancer through 25 months post-diagnosis. Results: Our sample included 1,196 non-Hispanic blacks and 1,236 non-Hispanic whites. Since diagnosis, compared to white women, black women more often reported: any adverse financial impact of cancer (59% vs 39%, p &lt; 0.0001); lost income (49% vs 35%, p &lt; 0.0001); lost job due to cancer (13% vs 6%, p &lt; 0.0001); financial barriers to treatment (24% vs 10%, p &lt; 0.0001); transportation barriers to treatment (15% vs 3%, p &lt; 0.0001); and lost health insurance (9% vs 3%, p &lt; 0.0001). In multivariable models, black women had higher odds of: experiencing any adverse financial impact of cancer (Adjusted Odds Ratio [AOR]: 1.9 (1.6-2.3)); losing income (AOR: 1.5 (1.3-1.9)); losing their job (AOR: 2.1 (1.5-2.8)); experiencing financial barriers to treatment (AOR: 2.2 (1.7-2.9)); experiencing transportation barriers to treatment (AOR: 4.8 (3.2-7.1)); and losing their health insurance (AOR: 2.6 (1.7-4.1)). Conclusions: Compared to whites, black women with breast cancer experience significantly worse financial impact of cancer. Disproportionate financial strain may contribute to higher stress, lower treatment compliance, and worse outcomes, among black women. Efforts to alleviate the adverse financial impact of cancer treatment and to improve communication between patients and providers about potential financial distress may be particularly valuable for black women, due to their greater financial vulnerability.