tbuckley/cabot-search huggingface dataset:
Impact of multidisciplinary management in the diagnosis and treatment of neuroendocrine tumors (NET).
Authors: Gurprataap Singh Sandhu, Anuradha Krishnamurthy, Reed Weiss, Cheryl Lauren Meguid, S. Lindsey Davis, Stephen Leong, Alexis Diane Leal, Gentry Teng King, William T. Purcell, Karyn A. Goodman, Lia Head, Tracey E. Schefter, Thor Johnson, Steven Arthur Ahrendt, Matthew Brown, Ana Gleisner, Richard D. Schulick, Martin McCarter, Wells A. Messersmith, Christopher Hanyoung Lieu
Journal: Journal of Clinical Oncology (2019)

629 Background: The incidence and prevalence of NETs is increasing and diagnosis and pathologic evaluation of NETs is complex. Given the new advances in local and systemic therapies, multidisciplinary management models have been suggested to assist in treatment decisions. However, scientific data showing definite change in management with multidisciplinary clinic (MDC) review is lacking. We aim to address this need in this study. Methods: 113 GI-NET patients from 2012-18 were reviewed from a dedicated MDC where patients are seen simultaneously by multiple subspecialties, and data on patient characteristics, radiology, tumor pathology and treatment strategies were collected. Change in diagnosis was defined as any change in radiographic or pathologic findings that resulted in a change in the tumor type, grade, site or stage of cancer. Change in management was defined as any recommended change in treatment approach for NETs compared to the prior treatment plan. For patients who did not have a prior treatment plan or were seen directly at MDC, a change of management was considered as yes only if there was a change in diagnosis post MDC. Results: The mean age of patients evaluated was 61, with locally advanced or metastatic disease seen in 81% of patients. Small bowel and pancreatic NETs were the most common primaries (36% each). Significant proportion of NETs were well-differentiated (72%) with &lt; 2 mitosis/10 HPF (47.3%) and Ki-67 of &lt; 3% (36%). Patients were referred to MDC at an average of 2.5 years from diagnosis, with 23% having the MDC as their first visit. 40% had prior resection of primary, 25% were on somatostatin analogues (SSAs) previously and 9% of patients had received prior liver directed therapy (LDT). A significant proportion of patients had change in diagnosis post MDC evaluation: change in site (7%), stage of disease (7%), tumor type (3.5%) and grade (0.1%). A change in management was recommended in 50% of patients, with SSAs recommended in 43.8%, surgery in 25.4% and LDT in 17.5% of the patients. Conclusions: The use of a dedicated MDC to manage NETs had a substantial impact in change in management in a significant percentage of patients evaluated. MDC care for patients diagnosed with NET is recommended for optimal management.
Liquid biopsies (LB) across treatment of 29 metastatic colorectal cancer (mCRC) patients (pts) to reveal driver mutations and tumor evolution with anti-EGFR therapy: Experience in a GI oncology clinic at Fox Chase Cancer Center.
Authors: Pooja Ghatalia, Arthur Winer, Chad Smith, Jiangtao Gou, Lesli Ann Kiedrowski, Patricia D Saltzberg, Nicole Bubes, Fern Anari, Vineela Kasireddy, Asya Varshavsky, Eric A. Ross, Wafik S. El-Deiry
Journal: Journal of Clinical Oncology (2018)

12047 Background: LB captures dynamic genomic alterations (alts) across mCRC therapy and may complement tissue biopsy (TB). We sought to describe the utility of LB and better understand mCRC biology. Methods: We identified 29 pts with mCRC who underwent LB (Guardant360; 2016-17). We used non-parametric methods to measure correlations between alts, highest allelic fraction (maxpct) and clinical variables. We used Kendall’s tau to describe correlations. Results: Of 29 pts, 14 (48.2%) were women; 17 (58.6%) had colon and the rest rectal cancer. Pts received a median of 2 (range 0-7) lines of therapy before LB. 15 pts had limited testing on TB (RAS/RAF/TP53/APC), 11 had extended NGS and 2 no TB. Of 3 pts with 0 alts in LB, only 1 had NED on CT. LB was performed due to inability to get TB in 5 pts and to assess mutation load or targetable alterations in 24 pts. Median maxpct was 11% (range 0-83.9%). Median number of alts was 5 (range 0-43). One pt with MSI-H on TB had LB 11 alts while a pt with 27 alts was MSS. MSI status was not done in 1 pt with 43 LB alts. Maxpct and alts correlated with CEA (p = 0.002, p < 0.001, respectively). In 3/5 pts with serial LB, CEA correlated with maxpct trend and CT tumor burden. In 6 pts mutant RAS was seen in LB only; 5/6 had received anti-EGFR therapy prior to LB, suggesting RAS alts developed post-therapy. In 2 pts RAS-mutated by TB, no RAS alts were detected on LB, due to low disease burden on CT at time of LB that also did not reveal APC or TP53 alts. In 1 pt with serial LB, a KRAS alt was found in TB and the first LB but subsequent LB showed no KRAS alts post-treatment. Mean number of alts was higher post anti-EGFR LB (n = 12) vs anti-EGFR naïve LB (n = 24) (10.6 vs 5.3, p = 0.009). More alts were also noted in post anti-EGFR therapy LB vs KRAS wt anti-EGFR-naïve LB (n = 8) (10.6 vs 4.9, p = 0.055) and KRAS mutant anti-EGFR-naïve LB (n = 16) (11.6 vs 5.6, p = 0.056). 1 pt had LB pre- and post-anti-EGFR therapy but alts remained the same. Conclusions: LB across mCRC therapy detects driver mutations, monitors disease burden, and identifies sub-clonal alts that reflect drug resistance, tumor evolution and heterogeneity.
The immune-profile of mismatch repair <i>deficient</i> (d<i>MMR</i>) colorectal cancers (CRCs) differs according to primary tumor sidedness.
Authors: Roberto Moretto, Riccardo Giannini, Gemma Zucchelli, Mirella Giordano, Filippo Pietrantonio, Carlotta Antoniotti, Clara Ugolini, Federica Morano, Federica Marmorino, Elisa Sensi, Antonino Belfiore, Daniele Rossini, Cristiana Lupi, Gianluca Masi, Beatrice Borelli, Elena Ongaro, Alessandra Boccaccino, Alfredo Falcone, Gabriella Fontanini, Chiara Cremolini
Journal: Journal of Clinical Oncology (2018)

e15593 Background: The high mutational load of dMMR CRCs elicits a considerable endogenous immune anti-tumor response, counterbalanced by immune inhibitory signals. We aimed at describing the immune-profile of dMMR CRCs through mRNA expression analysis. Methods: Treatment-naïve primary tumors of dMMR CRC patients were analyzed by means of NanoString nCounter® PanCancer Immune Profiling Panel (Seattle, WA, USA), including 770 immune-related genes. Both metastatic and non-metastatic patients (defined by a minimum follow-up duration of 3 years) were included. Results: Fifty patients were included (24 non-metastatic, 13 with metachronous metastases, 13 with synchronous metastases; 36 right-sided, 14 left-sided; 26 STAGE I – II, 10 STAGE III, 14 STAGE IV at the time of diagnosis; 16 RAS and BRAF wt, 12 RAS mut, 22 BRAF mut). Several immune-related genes (Table 1) were differentially expressed according to primary tumor location. No significant differences based on tumor stage or RAS and BRAF status were evident. Conclusions: Investigated immune-related genes are heterogeneously expressed in dMMR CRCs. Specific genes implicated in the immune system inhibition are more expressed among right- than left-sided CRCs, thus suggesting a different sensitivity to checkpoint inhibitors. These results need validation in clinical trials. Table 1 Differential expression of genes between right- and left-sided dMMR CRCs mRNA - GENE Log2 fold change (right- versus left-sided) p-value (x 10-6) Benjamini – Yakutieli p-value (multiple test correction) STAT1 1.37 1.67 0.0066 ATG5 0.55 5.37 0.0076 CXCL10 2.93 7.32 0.0076 IDO1 2.95 7.71 0.0076 KLRC2 1.93 23.30 0.014 GNLY 2.28 24.20 0.014 HLA-DPB1 1.31 25.50 0.014 PSMB7 0.37 85.90 0.037 MAP2K1 0.43 97.30 0.037 ITGAE 0.77 102.00 0.037 HLA-DPA1 1.26 103.00 0.037 MUC1 1.69 112.00 0.037 PTPRC 0.94 148.00 0.043 LAG3 1.63 161.00 0.043 CASP3 0.48 165.00 0.043 GZMA 1.58 176.00 0.043 CXCL13 1.90 187.00 0.043
Modified docetaxel, cisplatin and fluorouracil therapy as a first-line treatment for patients with recurrent/metastatic squamous cell carcinoma of the head and neck cancer: a retrospective study.
Authors: Nebi Serkan Demirci, Sercan Aksoy, Nuriye Özdemir, Taner Babacan, Gokmen Umut Erdem, Yakup Bozkaya, Nurullah Zengin, Ibrahim Halil Gullu
Journal: Journal of Clinical Oncology (2016)

e17503 Background: Modified DCF (mDCF) therapy has been shown to be both a well-tolerated and highly effective regimen for metastatic gastric carcinoma. Here, we investigated the use of mDCF as first-line treatment for the treatment of metastatic squamous cell head and neck carcinomas. Methods: We performed a retrospective analysis of 35 patients with recurrent/metastatic squamous cell head and neck carcinoma treated with mDCF between June 2010 and December 2014. Patients were treated with 2-6 cycles of mDCF chemotherapy, which consisted of docetaxel 60 mg/m2 intravenously (IV) on day 1, cisplatin 60 mg/m2 IV on day 1, and 5-fluorouracil 600 mg/m2 IV for 5 days of continuous infusion, with cycles repeated every 21 days. Results: All of the patients were diagnosed with metastatic disease, with mDCF chemotherapy chosen as the first-line treatment for advanced disease in all patients. The most common toxicities were nephrotoxicity (17.1%) and hepatotoxicity (14%). Grade 3-4 neutropenia in six patients (16.2%). Grade 3-4 thrombocytopenia was not observed. 7 patients (20%) experienced a febrile neutropenic episode. No treatment-related deaths were reported. Dose modification was necessary in 11 (31.4%) patients due to toxicity. 8 patients were hospitalized due to febrile neutropenia (7 patients) or diarrhea (1 patient). Toxicity delayed treatment in 10 patients, although only 1 patient ceased treatment due to toxicity concerns. Seventeen patients experienced primary growth factor prophylaxis, with five patients experiencing secondary prophylaxis after neutropenic fever. A complete response with chemotherapy was not achieved in any patient, although partial and stable responses were reported in 51.4% and 28.6%, respectively, for a disease control rate of 80%. The median progression-free survival was 8 (range, 3-13) months, and the median overall survival was 13 (range, 10-16) months. Conclusions: mDCF chemotherapy for the treatment of advanced stage squamous cell head and neck carcinomas exhibited similar safety and efficacy profiles as those of other combined therapies.
Effect of abiraterone acetate (AA) and enzalutamide (EZ) administration on chemotherapy-naïve metastatic castration-resistant prostate cancer (CN-mCRPC) patient’s symptom burden.
Authors: Sepehr Salem, Maria Komisarenko, Narhari Timilshina, Frank Jiao, Ruby Grewal, Shabbir M.H. Alibhai, Antonio Finelli
Journal: Journal of Clinical Oncology (2016)

e16540 Background: Reliable evaluation of the disease burden throughout advanced PC is crucial to the assessment of treatment effectiveness and patient improvement. This study sought to further explore and compare the effect of AA and EZ administration on CN-mCRPC patient’s symptom burden using the Edmonton Symptom Assessment System (ESAS). Methods: 245 CN-mCRPC patients who had received AA (93) or EZ (152) at our center were included and their associated ESAS scores, baseline demographic information, comorbidities, Eastern Cooperative Oncology Group performance status (PS) and laboratory data along with pharmacological interventions were recorded. Univariate and multivariate linear regression analysis were conducted to determine and compare the impact of drug therapy on ESAS items. The minimal clinically important difference was also assessed. Results: Mean (SD) treatment duration in AA and EZ was 9.6 (6.8) and 9.4 (6.8) months, respectively. There were no statistically significant differences in the proportion of patients with clinically meaningful symptom improvement/deterioration following AA or EZ administration in all ESAS-based physical and psychological symptoms. Fatigue was rated the most distressing before and after treatment in both groups. In multivariate analysis, drug initiation, drowsiness and poor well-being were the most significant predictors of fatigue in the AA group, while in the EZ group, the factors were PS ≥ 2, prior treatment procedure, drug initiation, pain, drowsiness, dyspnea and poor well-being. Comparing coefficients, drug initiation and PS created the greatest worsening impact on fatigue in the AA and EZ groups, respectively. Clinically meaningful improvement, deterioration and no change in fatigue were reported in 13%, 46% and 41% of AA, and 16%, 44% and 40% of EZ group, respectively (p > 0.05). Median time to worsening of fatigue was 183 and 132 days following AA and EZ, respectively (p > 0.05). Conclusions: In CN-mCRPC patients, effects of AA and EZ on physical and psychological symptoms assessed by ESAS were comparable. Furthermore, fatigue progressed similarly in both groups over time.
Long-term androgen deprivation, with or without radiotherapy, in locally-advanced prostate cancer: Updated results from a phase III randomized trial.
Authors: Paul Sargos
Journal: Journal of Clinical Oncology (2018)

5080 Background: We previsously reported results of a randomized phase III trial comparing androgen-deprivation therapy (ADT) combined with external beam radiation therapy (EBRT) and ADT alone in patients treated with localized cancer. We report here long-term oncological outcomes of this trial. Methods: In this multicenter phase III trial, patients with biopsy-proven locally advanced prostate cancer (T3-4) randomly assigned to ADT alone or ADT+EBRT. In both arms, leuprorelin 11.25 mg, subcutaneous, was started within seven days of randomization and continued every three months for three years and oral flutamide (750 mg/day) was administered during the first month. For the ADT-EBRT arm, the whole pelvis was treated at a dose of 46+/-2 Gy and the prostate with a boost from 20 Gy to 28 Gy. Primary endpoint was progression-free Survival (PFS) which included biochemical and clinical events and deaths. Secondary endpoints included overall survival (OS), disease-specific survival (DSS), locoregional progression free survival (LPFS), metastasis-free survival (MFS), biochemical progression free survival (BPFS) and tolerance. Competing-risk analysis was used whenever appropriate. Results: With a median follow-up of 7.3 years, 263 patients were included in the Intent-to-treat analyses. The 8-year PFS rate was significantly higher in the ADT+EBRT arm than in the ADT arm (47.9% versus 7.0%; hazard ratio: 0.27, p < 0.0001). The risk of death from prostate cancer was significantly reduced for ADT+EBRT arm as compared to ADT alone (sub-hazard ratio (SHR): 0.48; p = 0.02). The 8-year OS rate was respectively 56.8% in the ADT arm and 65.1% in the ADT+EBRT arm (p = 0.43). LPFS was significantly in favor of ADT+EBRT arm (SHR = 0.61; p = 0.01). MFS was comparable between both arms (p = 0.88). Analysis of toxicities revealed acute lower tolerance (mainly gastro-intestinal and genito-urinary) in the ADT+EBRT arm with a gradual decrease in intensity during follow up from 6 months after the end of EBRT. Conclusions: These long-term results confirm the oncological benefit of combining EBRT with ADT in the treatment of locally advanced prostate cancer. Clinical trial information: NCT01122121.
Coronary CT Angiography and 5-Year Risk of Myocardial Infarction
Journal: New England Journal of Medicine (2018)

Although coronary computed tomographic angiography (CTA) improves diagnostic certainty in the assessment of patients with stable chest pain, its effect on 5-year clinical outcomes is unknown.In an open-label, multicenter, parallel-group trial, we randomly assigned 4146 patients with stable chest pain who had been referred to a cardiology clinic for evaluation to standard care plus CTA (2073 patients) or to standard care alone (2073 patients). Investigations, treatments, and clinical outcomes were assessed over 3 to 7 years of follow-up. The primary end point was death from coronary heart disease or nonfatal myocardial infarction at 5 years.The median duration of follow-up was 4.8 years, which yielded 20,254 patient-years of follow-up. The 5-year rate of the primary end point was lower in the CTA group than in the standard-care group (2.3% [48 patients] vs. 3.9% [81 patients]; hazard ratio, 0.59; 95% confidence interval [CI], 0.41 to 0.84; P=0.004). Although the rates of invasive coronary angiography and coronary revascularization were higher in the CTA group than in the standard-care group in the first few months of follow-up, overall rates were similar at 5 years: invasive coronary angiography was performed in 491 patients in the CTA group and in 502 patients in the standard-care group (hazard ratio, 1.00; 95% CI, 0.88 to 1.13), and coronary revascularization was performed in 279 patients in the CTA group and in 267 in the standard-care group (hazard ratio, 1.07; 95% CI, 0.91 to 1.27). However, more preventive therapies were initiated in patients in the CTA group (odds ratio, 1.40; 95% CI, 1.19 to 1.65), as were more antianginal therapies (odds ratio, 1.27; 95% CI, 1.05 to 1.54). There were no significant between-group differences in the rates of cardiovascular or noncardiovascular deaths or deaths from any cause.In this trial, the use of CTA in addition to standard care in patients with stable chest pain resulted in a significantly lower rate of death from coronary heart disease or nonfatal myocardial infarction at 5 years than standard care alone, without resulting in a significantly higher rate of coronary angiography or coronary revascularization. (Funded by the Scottish Government Chief Scientist Office and others; SCOT-HEART ClinicalTrials.gov number, NCT01149590 .).
Tumor mutation burden and efficacy of targeted therapy in patients with <i>EGFR</i> mutant lung cancers.
Authors: Michael David Offin, Hira Rizvi, Megan Tenet, Ai Ni, Francisco Sanchez Vega, Mark G. Kris, Charles M. Rudin, Gregory J. Riely, Helena Alexandra Yu, Matthew David Hellmann
Journal: Journal of Clinical Oncology (2018)

9042 Background: Tumor mutation burden (TMB) is a biomarker of response to immune checkpoint blockade. The impact of TMB on outcomes with targeted therapies has not been explored. We hypothesized that TMB would inversely correlate with efficacy of targeted therapy in patients with EGFR mutant lung cancers proposing that additional mutations represent potential pathways for resistance with targeted therapies. Methods: We studied patients (pts) with metastatic EGFR mutant lung cancers with sensitizing exon 19 deletion (ex19del) or L858R variants treated with first/second generation tyrosine kinase inhibitors (TKIs) with pre-treatment targeted next generation sequencing (NGS; IMPACT) identified between January 2010 and September 2017. TMB was assessed in pre-TKI tissue defined as total non-synonymous mutations/Mb as assessed by the IMPACT platform. The effect of TMB on time on treatment (ToT) and overall survival (OS) were evaluated in univariate and multivariate analyses. Results: We identified 153 pts with metastatic EGFR mutant lung cancers profiled with MSK-IMPACT. Median TMB was 3.8 mutations/Mb (7.4 mutations/Mb for unselected lung cancers), but exhibited a wide range (0.82-17.9). In those with ≤ median TMB, ToT and OS were higher compared to those with > median TMB (ToT 17 vs. 10 months, HR 0.56, p = 0.006; OS 41 vs. 29 months, HR 0.52, p = 0.03). Within subgroups (never smokers, former smokers, TP53 co-mutant, age ≥ or < 65, man and woman), efficacy was consistently higher in those with ≤ median TMB. In multivariate analysis incorporating TMB, TP53 status, and EGFR ex19del vs. L858R, ToT remained improved in those with TMB ≤ median (HR 0.93, p = 0.02) but OS was not significant (HR 0.94, p = 0.3). Conclusions: Low TMB is associated with longer time on treatment in patients with metastatic EGFR mutant lung cancers treated with targeted therapy. This relationship is the reverse of that is seen with immune checkpoint blockade. TMB can serve as a relevant biomarker in lung cancers, with varied implications based on the nature of therapy being used.
Outcomes of patients (pts) with metastatic renal cell carcinoma (mRCC) and sarcomatoid dedifferentiation (sRCC) after treatment with immune checkpoint inhibitors (ICI): A single-institution retrospective study.
Authors: Jeremy Aaron Ross, Barrett Z. McCormick, Jianjun Gao, Pavlos Msaouel, Matthew T. Campbell, Amado J. Zurita, Amishi Yogesh Shah, Eric Jonasch, Surena F. Matin, Christopher G. Wood, Jose A. Karam, Padmanee Sharma, Nizar M. Tannir
Journal: Journal of Clinical Oncology (2018)

4583 Background: Pts with mRCC and sarcomatoid dedifferentiation (sRCC) have a poor prognosis with approved targeted therapies (Keskin et al. JU 2017). The response to ICIs in mRCC pts with sRCC is unknown. Methods: This is a retrospective study of pts with metastatic sRCC who received ICIs (2013-2017). Data collected include tumor histology, demographics, type of ICI, response to ICI, and efficacy outcomes (response, progression-free survival [PFS], and overall survival [OS]). Descriptive statistics were used. Results: 33 pts (85%) had clear-cell RCC (ccRCC); 6 pts had variant histology RCC (vhRCC) including chromophobe (2), mucinous tubular and spindle cell carcinoma (1), and unclassified (3). All pts but 2 had intermediate- or poor- risk disease by International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria. 15 pts (38%) had greater than 50% sarcomatoid component (sarc) in primary tumor of nephrectomy specimen, 5 (13%) had > 80%, and 2 (5%) had 100%. 22 pts (56%) received nivolumab (nivo) as a single agent. 15 pts (38%) received nivo in combination with ipilimumab and 2 pts (5%) received pembrolizumab. 24 pts (62%) responded to treatment with ICIs. Of these, 14 (58%) received ICIs at first-line therapy, 9 pts in second, 1 in fourth. Median PFS was 8.3 months (95% CI 3.6 – 13.1). 5/33 pts with ccRCC (15%) achieved a complete response (CR) and 4 remain in CR at 52, 31, 31, and 22 months from start of ICI. 1 pt was not followed at our institution after 24 months of CR. These pts had 90%, 1%, 30%, 50%, and 90% sarc, respectively. 1 of these patients remains on treatment. 5/6 pts with vhRCC did not respond to therapy; 1 pt with unclassified histology had stable disease for 5 months 28 pts (77%) are alive at time of this analysis. The median OS was not reached. Conclusions: In pts with sRCC, ICIs appear to be effective in ccRCC with up to 15% achieving durable CR. The prognosis of vhRCC with sRCC remains poor despite treatment with ICI, underscoring the need to develop more effective therapies for these patients.