tbuckley/cabot-search huggingface dataset:
The Stockholm-3 (STHLM3) model to improve prostate cancer testing in men 50-69 years compared to current clinical practice.
Authors: Henrik Gronberg, Jan Adolfsson, Markus Aly, Tobias Nordström, Peter Wiklund, Yvonne Brandberg, James Thompson, Fredrik Wiklund, Johan Lindberg, Mark Clements, Lars Egevad, Martin Eklund
Journal: Journal of Clinical Oncology (2016)

5050 The Stockholm-3 (STHLM3) Model can improve prostate cancer testing in men 50-69 years compared to current clinical practiceBackground: The Stockholm-3 model (STHLM3) is a combination of 6 plasma protein biomarkers, genetic polymorphisms and clinical variables that estimates the risk of Gleason Score (GS) ≥ 7 prostate cancer. This model was prospectively tested in 47,768 men without prostate cancer aged 50-69 in Stockholm, 2012-2014. The model reduced the proportion of men biopsied substantially while maintaining the same sensitivity for GS ≥ 7 prostate cancer as PSA ≥ 3 ng/ml (Grönberg et al, Lancet Oncology 2015). In this new analysis we compared the Stockholm-3 model to current unorganized PSA testing. Methods: Currently in Stockholm; PSA, free-PSA, family history, DRE and prostate volume are available when a prostate biopsy is done. In this analysis we aimed to estimate the impact of the Stockholm-3 model would have on the number of prostate cancer diagnosed and prostate biopsied performed if introduced in the unorganized testing in Stockholm. As a comparison cohort we identified men without prostate cancer in ages 50-69 years who had undergone PSA test and/or prostate biopsies during 2011 from the population-based PSA registry (STHLM0). Results: During 2011, 73.073 PSA tests were done in 57.019 men without prostate cancer, 2,796 prostate biopsies was performed, diagnosing 533 GS ≥ 7 cancers and 466 GS 6 cancers. Using the same sensitivity as current clinical practice to diagnose GS ≥ 7 prostate cancer, the Stockholm-3 Model reduces the number of biopsies by 55% (95% CI; 41 - 68%) and avoided 68% (59 - 76%) of the negative biopsies. The number of GS 6 cancers reduces by 26% (11 - 41%). Adjusted analyses on age, PSA and PSA naivety did not change the results materially. With a 20% increase sensitivity to identify men diagnosed with a GS ≥ 7 cancer compared to current clinical practice, the STHLM3 model reduces the number of biopsies by 37 % whilst the numbers of GS 6 cancers are the same. Conclusions: This analysis shows that the Stockholm-3 model has the potential to dramatically improve unorganized prostate cancer diagnostics in Stockholm by better selecting men with higher risk of GS ≥ 7 prostate cancer.
Clinical implications of the T790M mutation in disease characteristics and treatment response in patients with EGFR-mutated NSCLC.
Authors: Daria Gaut, Myung Shin Sim, Brian R. Wolf, Phillip A. Abarca, James M. Carroll, Jonathan Wade Goldman, Edward B. Garon
Journal: Journal of Clinical Oncology (2017)

9031 Background: The secondary T790M mutation accounts for more than 50% of acquired tyrosine kinase inhibitor (TKI) resistance in epidermal growth factor receptor (EGFR)-mutant NSCLC patients. Recent reports suggest this resistance mutation may be more common among patients with longer progression-free survival (PFS) on first-line TKI therapy, but much is still unknown about this resistance mechanism’s association with response to other therapies. Methods: Our group collected medical records from patients who underwent a biopsy for T790M mutation testing in the process of screening for clinical trials involving third generation EGFR inhibitors. Medical records were retrospectively analyzed for demographic data, PFS, best response (BR) to previous therapies, and presence or absence of an acquired T790M mutation. Progression-free survival was estimated using the Kaplan-Meier method and compared across two groups using the log-ranked test followed by univariate and multivariate cox proportional hazard regression analysis. Response rates were compared using Fisher’s exact test. Results: Out of 102 patients who obtained a diagnostic biopsy, 73 patients had a T790M mutation. Patients who later developed a T790M mutation had a longer PFS on first-line TKI therapy (12.0 months in T790M+ vs. 8.0 months in T790M-, p = 0.038, HR 1.66, 95% CI 1.03-2.67), though there was no difference in response rate (75.5% in T790M+ vs 77.3% in T790M-, p = 1.00). T790M+ patients also had a longer PFS on initial chemotherapy treatment (5.0 months in T790M+ vs. 4.0 months in T790M-, p = 0.020, HR 1.97, 95% CI 1.11-3.49) and a higher response rate to chemotherapy (22.7% in T790M+ vs 0% in T790M-, p = 0.033). Median PFS was short (3.0 months) for patients treated with immunotherapy with no difference based on T790M mutation status (p = 0.33). Conclusions: Our study confirms that tumors expressing T790M have a more indolent progression of disease compared to their T790M negative counterparts when treated with both first-line TKI and cytotoxic chemotherapy. This data provides context for therapeutic decision making in EGFR-mutant NSCLC patients.
Abstract 11719: “I Have to Live Like I’m Old” - Young Adults’ Perspectives on Managing Hypertension: A Multi-Center Qualitative Study
Authors: Heather M Johnson, Ryan Warner, Jamie LaMantia
Journal: Circulation (2015)

Introduction: In the U.S., young adults (18-39 year-olds) have the lowest hypertension control rates among hypertensive adults. The objectives of this multi-center study were to explore young adults’: 1) experiences receiving a hypertension diagnosis, 2) attitudes and beliefs about self-management and antihypertensive medication, and 3) opinions about their healthcare system’s hypertension education materials. Methods: Young adults (18-39 year-olds) with a known diagnosis of hypertension were recruited by the Wisconsin Research and Education Network. Two focus groups (one per age range: 18-29 years, 30-39 years) were conducted in three Midwestern practices (academic, rural, and urban clinics). Content analysis was performed. Results: In total, 35 young adults (mean: 30 [5.2] years old, 65% female, 47% Black, 45% with at least 1 year of college) identified barriers to managing hypertension. Emergent themes overlapped across ages and geographic regions. A majority of respondents were surprised and angry about a hypertension diagnosis; they expected to develop hypertension, but at a much older age. A hypertension diagnosis altered their “young” self-identity. Suggested behavior changes and antihypertensive medications made them feel “older” in health status. Young adults requested more resources for blood pressure self-monitoring to provide greater autonomy. Contrary to our hypothesis, most young adults disliked using social media or text messaging to support self-management; electronic patient portals were considered more personal, decreasing the risk of peers seeing their hypertension communications. Current hypertension education materials were described as not addressing young adults’ health questions; focus group respondents provided topics of interest. Conclusions: Targeting interventions to young adults’ unique needs are important next steps to improve healthcare delivery and hypertension control for young adults.
Interim results from a phase 1 trial of SL-801, a novel XPO-1 inhibitor, in patients with advanced solid tumors.
Authors: Judy Sing-Zan Wang, Minal A. Barve, E. Gabriela Chiorean, Patricia LoRusso, Kevin Dale Courtney, Dan Qi, Arturo Olguin, John Bullington, Megan Sardone, Vanessa Dunn, Shay Shemesh, Janice Chen, Christopher Brooks, Todd Michael Bauer
Journal: Journal of Clinical Oncology (2018)

2560 Background: SL-801 is a novel, oral, small molecule reversible inhibitor of Exportin-1 (XPO-1), a critical nuclear export protein overexpressed in many cancers. SL-801 has demonstrated potent in vitro and in vivo anti-tumor activity against a broad range of hematologic and solid cancers. SL-801's reversible inhibition of XPO-1 may translate to selective activity and potential safety benefits. Interim results from the dose-escalation study are reported. Methods: STML-801-0115 is a first-in-human, multicenter Phase 1 3x3 dose escalation study in patients with localized unresectable, or metastatic solid tumors resistant to or relapsed following standard therapy. Objectives are to evaluate safety and tolerability, identify maximum tolerated dose (MTD) or optimal dose/regimen for further evaluation, and assess pharmacokinetics and preliminary anti-tumor activity. SL-801 is orally administered on days 1-4 and 8-11 of a 21-day cycle. Starting dose was 5 mg and is currently 55 mg (escalation ongoing). Results: As of 1/6/18, 31 pretreated patients (range: 1-11 prior therapies; 71% ≥3rd line) received SL-801 (16 females, median age 63 years [range: 39-76]). No dose limiting toxicity (DLT) has been identified, and a MTD has not been reached. Median follow-up is 1.4 months (range: 0.2-8.5). Dose-dependent increases in Cmax and AUC have been observed. The most frequent treatment-related grade 1-2 adverse events (TRAEs) were nausea (45%), vomiting (32%), diarrhea (19%), fatigue (26%) and decreased appetite (19%). Grade 3 TRAEs included nausea (n = 3; 40, 45, 50 mg), vomiting (n = 1; 45 mg), diarrhea (n = 2; 10, 50 mg), acute renal injury (n = 1; 30 mg), and neutropenia (n = 1; 10 mg). There were no grade 4 or 5 TRAEs. Nine patients had stable disease (SD) for 3-12+ cycles. Five patients, with GE junction, colon, neuroendocrine, basal cell, and breast cancer, had SD ≥4 months. Radiographic tumor shrinkage > 10% was noted in 3 patients. Conclusions: SL-801 appears to be well tolerated in advanced solid tumor patients, and 29% of patients achieved SD as best reponse. Enrollment and dose escalation continue in an effort to identify an optimal dose and regimen. Clinical trial information: NCT02667873.
SYK(S) isoform as a prognostic marker for short liver metastasis free survival in patients with lymph node negative colon cancer.
Authors: Robert R.J. Coebergh van den Braak, Anieta M. Sieuwerts, Zarina S. Lalmahomed, Sandra I. Bril, Mieke A. Timmermans, Vanja de Weerd, Michelle van der Vlugt-Daane, Anne M. van Galen, Shanshan Xiang, Katharina Biermann, John W. M. Martens, John A. Foekens, Jan N.M. IJzermans
Journal: Journal of Clinical Oncology (2016)

e15117 Background: Surgery without adjuvant therapy is the current treatment for lymph node negative (LNN) colon cancer. However, 20% of these patients will develop recurrence of disease. Identification of these patients is an unmet need. Spleen Tyrosine Kinase (SYK) gene has been described both as tumor promotor and tumor suppressor in epithelial malignancies, and is part of the recently published consensus molecular subtypes signature. SYK has 4 splice variants coding for 2 isoforms, SYK short [SYK(S)] and SYK long [SYK(L)]. This is the first study to assess the purely prognostic value of mRNA of SYK and its splice variants in primary LNN chemonaive colon cancer. Methods: Patients were recruited from a prospective cohort study. Inclusion criteria were: age > 55 years, no adjuvant therapy, fresh frozen sample with > 40% tumor cells available, and recurrence of disease or > 30 months disease free survival. mRNA levels of SYK total [SYK(T)], SYK(S) and SYK(L) were measured with RT-qPCR using validated Taqman assays. The endpoints were defined as time between surgery and recurrence of any disease (DFS), the development of distant metastases (MFS) or hepatic metastases (HFS), and death (OS). Results: In total 163 patients met the criteria. No significant correlation of mRNA levels of SYK(T), SYK(S) of SYK(L) and OS were found. mRNA levels of SYK(T) were not significantly correlated with DFS [Hazard Ratio (HR) = 1.3 ; 95% Confidence Interval (CI) = 0.8-2.2 ; p = 0.30] or MFS [HR = 1.3 ; 95% CI = 0.8-2.2 ; p = 0.26], but did significantly correlate with HFS [HR = 2.1 ; 95% CI = 1.0-4.1 ; p = 0.037]. Of the two splice variants, the mRNA levels of SYK(S) did significantly correlate with HFS [HR = 2.2 ; 95% CI = 1.2-4.0 ; p = 0.013] in contrast to SYK(L) [HR = 1.4 ; 95% CI = 0.7-2.7 ; p = 0.32]. Conclusions: This study shows that mRNA levels of SYK(T) and more specifically SYK(S) are a prognostic marker for HFS in primary LNN chemonaive colon cancer. Future studies are needed to validate the prognostic value and biological significance of SYK(S) for the development of hepatic metastases.
<i>BRCA2</i>-<i>RB1</i> co-loss and ADT resistance in aggressive prostate cancer.
Authors: Goutam Chakraborty, Joshua Armenia, Ying Zhang Mazzu, Konrad Hermann Stopsack, Mohammad Omar Atiq, Kalyani Chadalavada, Gouri Nanjangud, Nabeela Khan, Kazumasa Komura, Yuki Yoshikawa, Shin-Yi Du, Gwo-Shu Mary Lee, Philip W. Kantoff
Journal: Journal of Clinical Oncology (2018)

e17024 Background: Recent data suggests an association between BRCA2 aberration and aggressive prostate cancer (PC). Interestingly, a recent ctDNA sequencing study revealed a strong association between BRCA2 defects and primary resistance to enzalutamide and abiraterone in metastatic castration resistant prostate cancer (mCRPC; Annala et al, 2018). Herein, we identify a subset of primary PC characterized byconcomitant deletions (homozygous and hemizygous) of BRCA2 and RB1 which was previously unrecognized. This subset of PC patients is associated with a shorter disease-free survival and their tumors exhibit increased genomic instability, indicating that BRCA2-RB1 deleted PC are likely very aggressive in nature. Methods: We investigated the underlying molecular mechanisms and genomic consequences of BRCA2 and RB1 co-deletion in PC. We used CRISPR-CAS9 and RNAi based methods to eliminate these two genes in PC cell lines and subjected them to various in-vitro studies, transcriptomic analyses and kinase arrays. We also developed a 3-color FISH assay to detect genomic deletions of BRCA2 and RB1 in PC cells and archived tissues. Results: BRCA2-RB1 null PC cells exhibit androgen independence as evidenced by relative resistance to enzalutamide and growth in androgen depleted medium but show-enhanced sensitivity to PARPi or platinum. Moreover, these cells induce an EMT like invasive phenotype. RNA-seq and kinase array results showed significant activation of EMT related oncogenic signaling pathways including an unexpected activation of Wnk1. More importantly, we showed that PARPi or platinum in combination with a pan-Wnk inhibitor significantly abrogated BRCA2-RB1 null LNCaP growth in vitro rather than the Wnk inhibitor or PARPi/platinum treatment alone. Our FISH assay also revealed significant co-deletion of BRCA2-RB1 in ADT resistant PC cells. Conclusions: Our findings suggest that co-deletion of BRCA2-RB1 is a genomic driver of therapy resistant aggressive PC rather than the consequence of exposure to therapy. We propose that early screening of BRCA2-RB1 deletion could identify those at highest risk of aggressive PC and thus provide an opportunity for early intervention and targeted treatment.
Ataxia in long term survivors of lung cancer after whole brain radiation therapy (WBRT).
Authors: Vivek Kumar, Deepa Vincent, James S. Butler, Yiqing Xu
Journal: Journal of Clinical Oncology (2016)

e20656 Background: Ataxia is a delayed neurological adverse effect of whole brain radiation therapy (WBRT). It has not been well studied in lung cancer survivors due to the short survival after brain metastases. We aimed to evaluate its incidence, clinical characteristics and predictors in lung cancer patients who survived beyond 2 years after WBRT. Methods: Patients with metastatic NSCLC or limited stage SCLC after prophylactic cranial radiation (PCI) treated between 1/2006 and 1/2014 were eligible. The presence of ataxia was determined by chart review for documentation of “off balance”, “unsteady gait”, “falls” or “positive Romberg’s sign” in physical examination. Mini Mental State Examination (MMSE) and MRI findings were recorded and correlated with ataxia. Results: Twenty-two patients (8 m and 14 F), with a median age of 59.5 years (inter-quartile range 58-64.7) were identified. The median Karnofsky Performance Status on diagnosis was 80. Sixteen (73%) patients had NSCLC and received 3750 cGy in 15 fractions, while 6 (27%) SCLC patients received 2500 cGy in 10 fractions. Eleven patients (50%) developed ataxia, 8(36%) with NSCLC and 3(14%) with SCLC (p = .3). Five patients had “falls”, 7 needed assistance for ambulation and 1 patient developed urinary incontinence. Median MMSE at onset of ataxia was 30. 3 patients developed severe cognitive dysfunction and had MMSE < 26. The median interval of onset was 34 months (95% CI; 19.98-48) for the whole group, 26 m (95% CI; 12.8-39) for NSCLC and 47 m (95% CI; 2.2-91.8) for SCLC (p = .4). The median survival for NSCLC patients was 54 m (95%CI; 50.34-57.7), and 4 out of 8 had EGFR mutations. Radiological signs of post-radiation changes were seen in 17 patients, including 10 of 11 patients with ataxia. The development of ataxia showed no correlation with age, gender, tumor histology, craniotomy, number and timing (synchronous or metachronous) of brain lesions, MMSE scores or chemotherapy on univariate analysis. Conclusions: Ataxia is a late manifestation of CNS radiotoxicity and can affect up to 50% of long term survivors of lung cancer after WBRT. Ataxia in these patients is independent of cognitive dysfunction. Early recognition and intervention is warranted to decrease morbidity.
Is marital status as impactful as chemotherapy among patients with head and neck cancer?
Authors: Nosayaba Osazuwa-Peters, Matthew H Keller, Matthew C Simpson, Eric Adjei Boakye, Kahee A. Mohammed, Rebecca Rohde, Katherine M. Polednik, Jay F Piccirillo
Journal: Journal of Clinical Oncology (2018)

e18058 Background: Both clinical and nonclinical factors are known to impact survival of head and neck cancer (HNC). We aimed to compare survival benefits of chemotherapy vs. marital status among patients with HNC. Methods: HNC patients ages ≥ 18 years in the Surveillance, Epidemiology, and End Results 18 database (2000-2014) were included. Kaplan-Meier curves compared cancer-specific survival between marital status (married/partnered, divorced/separated, widowed, never married). A multivariable competing risks proportional hazards model tested the main effect of chemotherapy. Another model tested an interaction between marital status and chemotherapy, controlling for sex, race, age, insurance, surgery, radiation, stage, site, and year of diagnosis. With a significant interaction term (p < 0.01), the final model was stratified by marital status, examining effect of chemotherapy in each marital group. A sensitivity analysis tested similar effect (chemotherapy vs. marital status) on oropharyngeal only cases. Results: There were 84,959 patients with HNC in our analysis; 43% received chemotherapy, and 52% of patients were married. Median survival was 89 months; married/partnered patients had significantly higher survival. Patients who did not receive chemotherapy were 11% more likely to die during follow-up compared with those who did (aHR = 1.11, 95% CI: 1.06, 1.15). Patients who were divorced/separated (aHR = 1.20, 95% CI: 1.09, 1.33), never married (aHR = 1.20, 95% CI: 1.11, 1.30), or widowed (aHR = 1.22, 95% CI 1.10, 1.35) and did not receive chemotherapy had an increased hazard of death compared with patients who received chemotherapy. However, non-receipt of chemotherapy did not significantly increase hazard of death among married/partnered patients (aHR = 0.96, 95% CI 0.90, 1.03). The lack of chemotherapy also did not significantly impact hazard of death among patients married/partnered with oropharyngeal cancer (aHR = 1.07, 95% CI 0.95, 1.20). Conclusions: Being married/partnered may be as impactful, if not more impactful than chemotherapy among patients with HNC, including those with oropharyngeal cancer. It is important that unmarried patients receive as much social support as possible to optimize survivorship.
Impact of patient age on molecular alterations in left-sided colorectal tumors.
Authors: Benjamin Adam Weinberg, Kelsey Poorman, David Arguello, John Marshall, Mohamed E. Salem
Journal: Journal of Clinical Oncology (2017)

3592 Background: The incidence of colorectal cancer (CRC) in younger patients (pts) is rising. This increase is most pronounced in tumors arising from the distal colon and rectum. Since tumor sidedness has emerged as an important prognostic and predictive biomarker in CRC, we aim to explore the impact of age on the tumor biology of left-sided colon cancer (LCC). Herein, we compare profiles of LCC from younger (≤ 45 years) and older pts (≥ 65 years). Methods: LCCs (splenic flexure to rectum; n = 1,602) were examined by NextGen sequencing, protein expression, gene amplification, and microsatellite instability fragment analyses. Tumor mutational load (TML) was calculated using only somatic nonsynonymous missense mutations. Chi-square tests were used for comparisons. Results: LCCs from younger (median age 40, range 22-45 years, n = 229) and older (median age 71, range 65-89, n = 503) pts were studied. The most frequently mutated genes included APC, TP53, KRAS, PIK3CA, ARID1A, FBXW7, SMAD4, ATM, BRAF, and NRAS. Comparing younger v. older pts, there were no significant differences in the rates of APC (75.3% v. 82.9%, P = 0.139), TP53 (79.5% v. 73.1%, P = 0.261), KRAS (37.6% v. 43.0%, P = 0.403), PIK3CA (9.4% v. 14.6%, P = 0.234), ARID1A (14.3% v. 13.2%, P = 0.884), FBXW7 (11.4% v. 10.5%, P = 0.830), SMAD4 (13.1% v. 7.4%, P = 0.129), BRAF (4.8% v. 5.7%, P = 0.762), or NRAS (3.5% v. 2.6%, P = 0.680) mutations. Additionally there were no significant differences in protein overexpression. However, there was a trend towards increased HER2 amplification in younger pts (5.7% v. 2.1%, P = 0.05). MSH6 (4.8% v. 0.5%, P = 0.015), MSH2 (2.4% v. 0%, P = 0.032), POLE (2.4% v. 0%, P = 0.032), and NF1 (7.9% v. 0%, P &lt; 0.001) mutations were observed at higher rates in younger pts. High TML (≥ 17 mutations per megabase) was seen more frequently in younger pts (8.2% v. 2.6%, P = 0.02). Conclusions: The molecular differences between LCC in younger and older pts are mostly due to mutations in mismatch repair genes. Higher TML may predict a higher response rate to checkpoint inhibitors in younger pts with LCC. The differences in tumor biology observed here warrant further study and may eventually be used to tailor therapy.