tbuckley/cabot-search huggingface dataset:
Clinicopathological and demographic factors associated with development of distant metastasis among patients with locoregional neuroendocrine tumor (NET).
Authors: A. Dasari, Daniel M. Halperin, Shouhao Zhou, Yiyi Chu, Ying Xu, Tina Shih, James C. Yao, Chan Shen
Journal: Journal of Clinical Oncology (2016)

4099 Background: Incidence oflocoregional NETs is increasing. However, the association between the risk of development of metastasis and clinicopathological/demographic factors remains poorly understood. We assessed the association between baseline characteristics at diagnosis and risk of metastatic spread. Methods: From the Surveillance, Epidemiology and End Results (SEER)-Medicare database, we identified NET patients diagnosed between 1/2002 and 12/2011 by ICD-O-3 codes. We further restricted the study cohort to patients with locoregional disease at diagnosis. We excluded patients under age 65, without continuous Medicare Parts A and B enrollment or enrolled in health maintenance organizations. Development of metastatic disease was identified by capturing at least two claims indicative of secondary malignant neoplasms until 12/31/2013. Demographic and clinical characteristics between patients with and without development of metastasis were compared using Chi-squared tests. Time to development of metastasis was assessed using the Kaplan Meier method and compared using log rank test. Results: At the time of diagnosis, of the 5472 eligible patients, 67% had localized disease, 70% were grade 1 or 2 and were either gastroenteropancreatic (53%), pulmonary (31%) or of unknown origin (15%). During the study period, 1618 (30%) patients developed metastatic disease. We found that the risk of developing distant metastasis varied significantly by grade (22% in grade 1 to 57% in grade 4), stage at diagnosis (15% in local vs 70% in regional), and primary site (13% in colon and rectum to 44% in pancreas). The log rank tests confirmed the significant differences in disease progression by the above tumor characteristics with p-values less than 0.01. Conclusions: This is the largest population-based study to date evaluating disease progression patterns among Medicare patients over 65 years old with locoregional NETs and showed that approximately 28% of patients developed distant metastases within two years from diagnosis. Histology grade, stage at diagnosis and primary site were significantly associated with risk of development of metastatic disease.
Circadian clock gene <i>PER1</i> mutations in colorectal cancer (CRC).
Authors: Francesca Battaglin, Joanne Xiu, Michelle Winerip, Richard M. Goldberg, Philip Agop Philip, Andreas Seeber, Alberto Puccini, Ryuma Tokunaga, Madiha Naseem, Shivani Soni, Michelle McSkane, Martin D. Berger, Afsaneh Barzi, Wu Zhang, Jimmy J. Hwang, Anthony Frank Shields, John Marshall, Wolfgang Michael Korn, Heinz-Josef Lenz
Journal: Journal of Clinical Oncology (2018)

12106 Background: PER1 encodes for one of the main negative regulator of the clock genes pathway, which modulates the circadian expression of key target genes at the cellular level. Downregulation of PER1 has been observed in CRC and lower expression levels have been associated with poor survival and increased incidence of liver metastases. Few data are available on PER1 gene mutations (PER1mut) in CRC. Therefore, we aimed to explore the clinical and molecular differences between PER1 mutated versus wild-type (WT) CRCs. Methods: 4079 CRCs tested with tumor profiling (Caris Life Sciences, Phoenix, AZ) were included in this analysis. NextGen sequencing (NGS) was performed on genomic DNA isolated from formalin-fixed paraffin-embedded tumor samples using the NextSeq platform (Illumina, Inc., San Diego, CA) on 592 genes. Microsatellite instability high (MSI-H) status was tested by NGS in 3996 tumors. Pathogenicity of PER1mut was estimated using Poly-Phen and SIFT. Results: Main characteristics in the global population were as follow: M/F 52.4/47.6%, median age 61 (16-90 yr), primary tumor right-sided 27.4%/left-sided 43.5%/NOS 29.1%, mutational status all WT 38.7%/RASmut 53.4%/BRAFmut 7.9%, MSI-H 6.6% (n = 262). Overall, 185 unique PER1mut/variants were identified in 304 samples (7.45%); 45 were classified as pathological/possibly pathological (PATHmut) according to predictive scores. PER1mut were significantly associated with right-sided tumor location (p < 0.001) and MSI-H (p < 0.001). Overall incidence of PER1mut and PATHmut in the MSI-H group were 24% and 3.4%, respectively. In the multivariate analyses PATHmut were independently associated with mutations in ARAF, BAP1, CHEK2, NF1, PIK3CA and POLE. Conclusions: Our results provide the first exploratory data on PER1mut association with clinical and molecular features in CRC, in a large population of patients with extensive genetic testing. A deeper understanding of PER1mut pathogenicity and functional role is necessary to guide future analyses. Nevertheless, our results suggest a significant association with MSI-H, possibly reflecting an interplay between mismatch repair status and the clock genes pathway in CRC, consistent with previous data and warranting further investigation.
Identification of mutation biomarkers underpinning colon cancer sidedness and cetuximab sensitivity.
Authors: Timothy Joseph Yeatman, Mingli Yang, Michael J. Schell, Andrey Loboda, Michael Nebozhyn, Jiannong Li, Jamie K. Teer, Caio Max S. Rocha Lima, Jack Pledger
Journal: Journal of Clinical Oncology (2018)

629 Background: Currently, extended RAS testing ( KRAS/ NRAS) in colorectal cancer (CRC) patients identifies only non-responders to EGFR inhibitor (EGFRi) therapies, and accurate prediction of drug-sensitive subpopulations remains problematic in patients, even with wild-type RAS. Moreover, the molecular basis for the laterality of anti-EGFR sensitivity is poorly understood. Methods: 468 CRCs were analyzed by global gene expression analysis, DNA sequencing (1321 cancer related genes) and MSI analysis. Tumors were stratified by a validated gene expression cetuximab sensitivity (CTX-S) score, and then correlated with identified high frequency mutations, resulting in a ranking of CTX-S score-associated mutated genes (see Table). Results: Ranking analysis revealed MSI-H status and KRAS mutation as the most negatively-correlated among all patients and MSS patients, respectively. Conversely, APC and TP53 were the most highly positively-correlated mutant genes in both all patient- and MSS-cases. Deeper analysis revealed that the combination of mutant APC + TP53 ( A + P) was more common in left vs. right CRCs (52% vs 21%), and even more pronounced in MSS vs MSI cases (47% vs 2%). CTX-S scores were highest in mutant A + P patients with WT RAS, but surprisingly, were nearly as high in mutant A + P patients with mutant RAS. CRC PDX models validated these results with a favorable CR/PR/SD vs PD association. Conclusions: Here we report the discovery of a cooperative role of APC and TP53 mutations in identifying EGFRi-sensitive CRC subpopulations. Our data suggest that addition of the routine sequencing of APC and TP53 to extended RAS testing may expand the EGFRi therapeutic opportunity (by up to 25%), regardless of RAS mutation status. [Table: see text]
CNS disease enrollment criteria on early phase clinical trials: A review of over 1100 clinical trials.
Authors: Narjust Duma, Sarah Lee, Zhen Wang, Sejal Kothadia, Veronica Mariotti, Brittany Gladney, Miguel Gonzalez Velez, Jieqi Liu, Rima Panchal, Komal Patel, Ricardo Parrondo, Ramya Undamatla, Jesyree Veitia Campos, Bryant Van Leeuwen, Marshall McKenna, Martin Gutierrez
Journal: Journal of Clinical Oncology (2016)

e14053 Background: CNS disease is common in multiple neoplasias, but clinical trials tend to exclude this patient population due to the increase in morbidity/mortality associated with CNS metastasis, subsequent reduction of PFS and a confounding of any drug benefit. The goal of this study was to determine the effect of CNS disease in the enrollment of patients (pts) in early phase trials. Methods: Trials were extracted from ClinicalTrials.gov in December 1st of 2015. We analyzed: trial phase, experimental therapy, location, sponsor, and inclusion/exclusion criteria. Exclusion of CNS metastasis was treated as a binary variable and grouped as strict exclusion vs. allowed CNS metastasis. Logistic regressions were used for statistical analysis. Results: 1114 trials were reviewed, 200 (18%) were phase I, 668 (60%) phase II and 246 (22%) combined phase I/II trials. 498 (45%) studied single agents and 616 (55%) combination regimens. 546 (49%) were in the US, 210 (19%) in Europe, 138 (12%) in Asia, and 220 (20%) were international. Cancers included: 452 (41%) breast, 349 (31%) colorectal, 217 (20%) lung and 94 (8%) trials included all solid tumors. Pts with CNS metastases were excluded in 441 (40%) of the trials, allowed after local treatment in 201 (18%), and allowed with no prior treatment in 179 (16%). CNS criteria were not referenced in 293 (26%) trials and were excluded from further analysis. On univariate analysis, the odds of CNS metastasis exclusion were significantly lower in targeted therapy trials and single vs. combined regimens (OR 0.62, 95%CI: 0.47-0.81, p < 0.001; OR 0.75, 95%CI: 0.57-0.93, p < 0.02) and significantly higher in phase II and European trials (OR: 1.61, 95%CI 1.12-2.34, p < 0.01; OR 1.41, 95%CI: 1.06-1.86, p < 0.02). In multivariate analysis, phase II trials had higher odds of exclusion of CNS disease (OR: 1.54, 95%CI: 1.07-2.21, p < 0.02). Conclusions: Only 34% of the trials allowed pts with CNS disease, leaving a great percentage of pts without the possibility of new treatment options. Class of therapy, trial phase, and location were found to impact the trial design - raising the question that exclusion of CNS disease may be based more on commercial/historical factors rather than patient characteristics.
Pregnancy after breast cancer: Results from a prospective cohort study.
Authors: Philip Daniel Poorvu, Shari I. Gelber, Shoshana M. Rosenberg, Kathryn Jean Ruddy, Rulla M Tamimi, Jeffrey M. Peppercorn, Lidia Schapira, Virginia F. Borges, Steven E. Come, Ann H. Partridge
Journal: Journal of Clinical Oncology (2017)

10065 Background: Prospective data regarding fertility and pregnancy after breast cancer are limited. Many young survivors are interested future fertility, but pregnancy rates among women attempting and not attempting pregnancy have not been studied prospectively. Methods: As part of a multicenter cohort study, women diagnosed age ≤40 with stage 0-3 breast cancer are surveyed at baseline then annually regarding fertility interest, attempts, and pregnancies. Chi-square tests were used to compare proportions attempting and achieving pregnancy. Results: At least once in the 5 years (yrs) after Dx, 334/959 (35%) women reported interest in future biologic children. The percent interested was stable in the first 3 yrs then declined: 256 (27%, baseline), 244 (27%, 1 year), 209 (25%, 2 yrs), 176 (25%, 3 yrs), 106 (18%, 4 yrs), and 72 (16%, 5 yrs). Pregnancy was attempted by 104/334 (31%) of women who reported interest and 4/625 (1%) who did not. Pregnancy occurred in 118 women (12%), including 76/108 (70%) who attempted and 42/851 (5%) who did not. Attempts and achieving pregnancy were associated with younger age, partnered status, and not having children prior to Dx (table). Lower stage was associated with attempting pregnancy and ER negative disease with achieving pregnancy. Conclusions: A substantial number of young women become pregnant in the 5 years after a breast cancer diagnosis. Given that over 1/3 of pregnancies were among women who did not report attempting, additional attention to contraception counseling should be considered. Further evaluation of assisted reproductive technology use, pregnancy and disease outcomes in this cohort, and the POSITIVE Trial (NCT02308085) will shed light on the feasibility and safety of pregnancy after breast cancer. [Table: see text]
HemOnc.org comes of age: User characteristics and comparative speed and accuracy to other hematology/oncology knowledge resources.
Authors: Richard Lewis Martin, Peter C. Yang, Aymen Elfiky, Jeremy Warner
Journal: Journal of Clinical Oncology (2018)

e18596 Background: Online resources have emerged as a primary tool for accessing hematology and oncology (H/O) knowledge, such as chemotherapy regimens and their primary references. We created and continue to develop HemOnc.org which is, to our knowledge, the largest freely available source of chemotherapy drug and regimen information. Given a marked increase in content and a 400% increase in visits since June 2014, we sought to 1) further understand the composition of HemOnc.org’s user base; 2) objectively evaluate how users rate HemOnc.org against other commonly used resources; and 3) gain insight about opportunities to better serve users. Methods: We opened a REDCap survey for 6 weeks, available directly from HemOnc.org; we also conducted targeted outreach of H/O fellowship programs. Descriptive statistics and the Wilcoxon signed-rank test were applied; all comparisons were two-sided and based on the null hypothesis of equivalence. Results: There were 206 respondents; 15 surveys were excluded for incompleteness (N = 9) or being filled out by a self-disclosed non-user (N = 6). The remaining 191 consisted primarily of healthcare professionals; see Table. The strongest aspects of HemOnc.org were speed, accuracy, ease of navigation, and links to published literature. Most respondents (93%) were able to find the information they needed in under 2 minutes. Respondents scored HemOnc.org as much faster than other resources (median 79 on a scale of 0-100, IQR: 52-85, P < 0.001). The majority of respondents (91%) were moderately or highly confident in the accuracy of HemOnc.org, more so than other resources (median 57 on a scale of 0-100, IQR: 49-73, P < 0.001). Conclusions: While potentially subject to response bias, HemOnc.org appears to serve a broad diversity of users and performs favorably to other resources. We plan to conduct focus groups to learn more about user needs. Table N % Demographics Pharmacist 67 35 Practicing MD/DO 57 30 H/O fellow 36 19 Other 31 16 Years in practice* 0-3 43 31 4-10 44 32 11-20 24 17 20+ 27 20 Most frequently used resources** HemOnc.org 166 87 NCCN Guidelines 166 87 UpToDate 109 57 PubMed 70 37 Primary literature 53 28 *Not including trainees **Up to 5 of 23 options could be chosen
The immunologic patterns of response to immunotherapy.
Authors: Anna A. Borunova
Journal: Journal of Clinical Oncology (2016)

e14502 Background: Dendritic cells (DC) play the major role in the immune response. As it was shown earlier DC vaccine can induce the antitumor immune response in many melanoma patients (pts) tending to provide the clinical benefit in pts with low tumor burden. We studied the immunophenotypic profile of peripheral blood lymphocytes of metastatic melanoma pts treated with DC vaccine after radical surgery to characterize the immunologic patterns of response to immunotherapy. Methods: 30 stage III-IV melanoma pts with no evidence of disease after surgery were analyzed for the phenotype of peripheral blood lymphocytes using multicolor flow cytometry. Blood samples were collected prior to DC therapy. Data from 30 healthy donors was used for reference. All melanoma pts were treated with DC vaccine based on mature autologous monocyte-derived DC loaded with autologous tumor lysate. The vaccine was administered intradermally every 2-6 weeks until the disease progression or up to 1 year. The immunological and clinical data had been collected from 2004 till 2014. Results: Most melanoma pts (n = 18, 60%) had normal values of CD3+ cells prior to DC therapy. However among them the normal ratio of CD4+/CD8+ cells was registered only in 12/18 pts. The remaining 6/18 pts had high CD8+ count and they all progressed soon. The analysis of pts with normal T-cell values and CD4+/CD8+ ratio revealed the elevated amounts of NKT cells (CD3+CD16+CD56+) in 3/12 pts and they also developed rapid progression, while the other 9/12 pts remained progression-free for the long time (up to 10 years). The inhibition of T-cell immunity was observed in 9 pts (30%) and none of them responded to DC vaccine. Another 3 pts (10%) had significantly higher numbers of T-cells and only one of them had normal CD4+/CD8+ ratio and no NKT cells. This patient currently remains progression-free after DC therapy lasting 7+ years. The rest of the pts had increased numbers of T-cells that was due to CD8+ and NKT cells. The vaccine for these patients was not effective. Conclusions: DC vaccine was effective and provided long-term progression-free survival in pts with the preserved structure of T-cell immunity (normal CD4+/CD8+ ratio) and low NKT cells. Clinical trial information: 052004DV.
Genetic variants of <i>Pin1</i> to predict benefit from irinotecan and oxaliplatin based treatment in patients with metastatic colorectal cancer (mCRC).
Authors: Mitsukuni Suenaga, Marta Schirripa, Shu Cao, Wu Zhang, Dongyun Yang, Martin D. Berger, Jordan David West, Chiara Cremolini, Sara Lonardi, Francesca Battaglin, Yan Ning, Yuki Horiike, Noriko Yamamoto, Satoshi Okazaki, Yuji Miyamoto, Diana L. Hanna, Afsaneh Barzi, Fotios Loupakis, Alfredo Falcone, Heinz-Josef Lenz
Journal: Journal of Clinical Oncology (2016)

11589 Background: Peptidyl-Prolyl Cis/Trans Isomerase NIMA-Interacting 1 (Pin1) is associated with cell cycle progression, cellular proliferation and neoplastic transformation. Pin1 is also involved in repair of DNA double-strand breaks (DSBs). We hypothesized that Pin1 isomerization might affect repair of DSBs induced by chemotherapy. We tested whether gene polymorphisms in Pin1 and its substrates will predict efficacy of CPT-11 and L-OHP-based treatment in patients with metastatic colorectal cancer (mCRC). Methods: We analyzed genomic DNA extracted from 602 blood or tissue samples of three different cohorts: 145 Japanese patients receiving first-line (1L) FOLFOX+/-BEV (median age 61 years; male/female, 71/74; median follow-up, 45.1 months) as discovery set; 228 patients receiving 1L FOLFIRI/BEV (TRIBE arm A: median age, 60 years; male/female, 138/90; median follow-up, 49.3 months); and 229 patients receiving 1L FOLFOXIRI/BEV (TRIBE arm B: median age, 60 years; male/female, 137/92; median follow-up, 46.6 months). Eight single nucleotide polymorphisms of six genes (Pin1, p53, Che1, CSNK2A1, CSNK2B, TOP1) were analyzed by PCR-based direct sequencing. Results: In univariate analysis of the discovery set, median progression-free survival (PFS) of patients carrying any Pin1 rs2233678 C allele was 7.4 vs. 15.0 months for those with the G/G variant (HR 3.24, 95%CI: 1.60-6.54, p < 0.001). Median overall survival (OS) was 16.9 vs. 31.5 months in both groups, respectively (HR 2.38, 95%CI: 1.32-4.30, p = 0.003). In multivariate analysis, Pin1 rs2233678 remained significant for PFS and OS. In the FOLFIRI/BEV cohort, patients with any Pin1 rs2233678 C allele had a longer PFS compared to those with the G/G variant (median 11.9 vs. 9.4 months, HR 0.64, 95%CI: 0.45-0.91, p = 0.009). In the FOLFOXIRI/BEV cohort, there was no significant difference in PFS and OS by Pin1 genotype. Conclusions: Germline Pin1 polymorphisms may serve as prognostic markers in mCRC patients receiving oxaliplatin or irinotecan-based chemotherapy.
Role of nutrition in incidence and management of cancer therapy-induced diarrhea (CTID): HEAT (Health Eat and Toxicity) prospective interventional study and preliminary data.
Authors: Aurora Mirabile, Erika Vecchio, Stefania Falvella, Lucia Barbarini, Chiara Butti, Fabrizio Ciambelli, Antonella Bovio, Sergio Pauli, Isabella Ricci, Fiorenza Frigo, Elisabetta Del Grosso, Enrica Aloisio, Giovanna Oliva, Salvatore Agatino Artale
Journal: Journal of Clinical Oncology (2017)

e18251 Background: Metastatic colorectal cancer (mCRC) patients (pts) are at high risk of CTID influencing treatment outcome. The primary end-point of our study was the decrease of grade 3-4 (G3-4 from Common Terminology Criteria for Adverse Events 4.0) CTID incidence to 50% in respect to literature data. A predefined nutritional regimen was planned and administrated to each pts. In explorative analyses, we investigated the correlation between Vitamin D deficiency and CTID incidence and between dihydropyrimidine dehydrogenase (DpD) mutations and CTID. Methods: All mCRC pts undergoing chemotherapy (CT) with an expected G3-4 CTID incidence of about 17% were enrolled. During CT the nutritionist administered a predefined, slag free diet according to Italian Society of Human Nutrition indications and within World Cancer Research Found recommendations. Results: Fifty consecutive pts were enrolled within 11 months. Pts characteristics are summarized in the table. A significant decrease (p-value 0.00096; IC 95% 0.059) of G3-4 CTID incidence to 95% was obtained in respect to literature data. No CT modification or admissions/supportive care were needed. Due to strict diet adherence (96%) &gt; 50% pts had no diarrhea and no one had G4 diarrhea. BMI improved in 35% over-weights and in 40% obese, no changes in normal-weights. The correlation analysis showed the decrease of CTID incidence with the increase of vitamin D levels, but did not reveal a relation between DpD mutations and diarrhea. Conclusions: The preliminary results suggest a possible role of the diet on CTID prevention and a correlation with vitamin D levels. [Table: see text]
P05.27 Reirradiation of brain metastases with stereotactic radiosurgery
Authors: J B Jeppesen, H Roed, F Kjær-Kristoffersen, J Lauritsen, A Muhic
Journal: Neuro-Oncology (2018)

Little is known about the outcome following a second course of stereotactic radiosurgery (SRS) for recurrence of brain metastases (BM) at the previously irradiated site. We retrospectively analyzed overall survival (OS) and the clinical factors and radiosurgical parameters likely to influence OS. Between December 2012 and January 2017, 40 patients (28 women and 12 men) received second SRS at the previously irradiated site at Copenhagen University Hospital. Fourteen had breast cancer, twenty lung cancer and six with miscellaneous types of cancer. SRS prescribed dose was 18 Gy x 1 in both first and second course. Age, primary cancer, extracranial disease status, prednisolone dosage, ECOG Performance Status score, presence of neurological symptoms, time between first and second course of SRS, number of targets and target size were evaluated as prognostic factors. Median age at time of second SRS was 58 years (range 29–79). Median OS was 1.2 years (95% Cl 0.7–1.7). At time of data retrieval 11 out of 40 patients were still alive. Univariate COX analyses revealed that patients with miscellaneous cancers lived significantly shorter than the rest. Other significant factors which negatively influenced survival included target size (range, 0.1–59.6 cm3), prednisolone dosage ≥ 50 mg, ECOG Performance Status score ≥ 1 and presence of neurological symptoms at the time of second SRS. Multivariate Cox analyses revealed that higher prednisolone dose was associated with shorter survival: < 50 mg (HR: 4.1, p=0.043) and ≥ 50 mg (HR 8.049, P<0.001) compared to no prednisolone. Furthermore, compared to breast cancer, patients with lung cancer (HR 2.812, P=0.042) and miscellaneous types of cancer (HR 10.275, P<0.001), had significantly shorter survival. All other possible prognostic factors did not reach statistical significance in multivariate analyses. Second SRS of recurrent BM at the previously irradiated site is an effective treatment for selected patients with a median OS of more than a year. Low prednisolone dosage, breast cancer, small target size, ECOG Performance Status score 0, and no neurological symptoms at the time of repeat SRS were significant predictive factors for longer survival.