tbuckley/cabot-search huggingface dataset:
Exome analysis of oncogenic pathways and tumor mutational burden (TMB) in triple-negative breast cancer (TNBC): Results of the translational biomarker program of the neoadjuvant double-blind placebo controlled GeparNuevo trial.
Authors: Sibylle Loibl, Bruno Valentin Sinn, Thomas Karn, Michael Untch, Hans-Peter Sinn, Karsten Ernst Weber, Claus Hanusch, Jens Bodo Huober, Peter Staib, Ralf Lorenz, Jens Uwe Blohmer, Frederik Marmé, Wolfgang D Schmitt, Kerstin Rhiem, Marion van Mackelenbergh, Peter A. Fasching, Song Wu, Brandon W. Higgs, Andreas Schneeweiss, Carsten Denkert
Journal: Journal of Clinical Oncology (2019)

509 Background: GeparNuevo (G9) showed a numerical increase in pCR rate of 53% vs 44%; p = 0.287 compared to placebo in TNBC with the addition of the anti-PD-L1 antibody durvalumab (D) to a neoadjuvant anthracycline-taxane containing chemotherapy (Loibl S et al. ASCO 2018). Somatic mutations in malignant cells manifest over the evolutionary history of a tumor. Reports in selected tumor types suggest that TMB may predict clinical outcomes on immune-checkpoint inhibitors (ICI). The clinical relevance of TMB in breast cancer has not been studied widely. Here, we investigated the hypothesis that TMB predicts response to ICI. Methods: Whole exome sequencing was conducted on patient-matched fresh-frozen core biopsies and blood samples with Illumina (n = 149/174). SNVs and indels were called with Mutect and pureCN was used for copy number calls. Mutational signatures were identified as described by Alexandrov et al. (Cell Rep. 3, 2013). Data from G9 were compared to The Cancer Genome Atlas (TCGA) TNBC cohort. Results: A similar genomic landscape was observed between G9 and TCGA with primary mutations in TP53 (69%), c-MYC (26%), BRCA1 (13%), BRCA2 (6%), PIK3CA (11%) and PTEN (11%). Median TMB was 1.52 mut/MB. TMB in G9 was slightly lower than TCGA TNBC. TMB correlated with older age, higher mutation rates in BRCA2, ARID1A, and TP53, and higher burden in variant signatures such as DDR, HRD, GFRs, APOBEC and Alexandrov’s signatures 3 and 6. Continuous TMB predicted pCR in univariate (OR = 1.62, 95%-CI: 1.20 - 2.20, p = 0.0018) and multivariate (OR = 2.06, 95%-CI: 1.33 - 3.20, p = 0.0012) logistic regression models, but did not predict a D effect. After dichotomisation of TMB at the top tertile, 50 patients had high TMB and 29 of these (58%) achieved a pCR, while 99 had low TMB and only 38 of these (38%) had a pCR (p = 0.0242). Conclusions: Results show that TMB may predict pCR in primary TNBC. The trial was financially supported by Astra Zeneca and Celgene. Clinical trial information: NCT02685059.
Delay in diagnosis and treatment of gastrointestinal cancer in Nepal.
Authors: Soniya Dulal, Bishnu D. Paudel, Aarati Shah, Bibek Acharya, Sandhya Chapagain Acharya, Rameej Revanta Thapa, Lori Wood
Journal: Journal of Clinical Oncology (2019)

e18269 Background: Gastrointestinal (GI) cancers represent a major health challenge worldwide including Nepal where patients (pts) often present with advanced disease. The purpose of this study was to determine the time delay in diagnosis and treatment by evaluating time from first symptoms to diagnosis and treatment and to identify contributing factors from both pts and the health system in Nepal. Methods: An IRB approved cross sectional study was performed in pts with GI cancers. 50 newly diagnosed pts were enrolled and interviewed with a standardized questionnaire during the last 6 months of 2018. Diagnosis delay was defined as time from first symptoms to histopathological diagnosis. Treatment delay was defined as time from diagnosis to surgery and/or treatment by medical/ radiation oncologist. Results: The median age at diagnosis was 52.5 years. 52% had gastroesophageal cancer and 48% had colorectal cancer. 84% presented with Stage III/ IV disease. The median diagnosis delay was 217 days and the median treatment delay was 37 days. The median patient delay (time from first symptoms to first medical consultation) was 150 days. 64% were illiterate, 94% had a history of self medication prior to first medical consultation, 68% were from rural areas with limited healthcare facilities and 72% were unaware of causes of GI cancers. Reasons for diagnostic delay appear to be self diagnosis, self medication and lack of a prompt referral system. Reasons for treatment delay included financial constraint, prolonged wait times for procedures and treatment due to limited skilled manpower. Conclusions: Our data shows there is a significant delay in diagnosis and treatment especially in the time from first symptoms to first medical consultation. We found many preventable reasons for this that, if addressed appropriately, could have a significant impact on reducing the morbidity and mortality of GI cancers. There is an urgent need for intensive and comprehensive cancer education in Nepal and other developing countries.
Case 32-1977
Authors: Richard C. Cabot, Robert E. Scully, James J. Galdabini, Betty U. McNeely, Edwin P. Maynard, Austin L. Vickery
Journal: New England Journal of Medicine (1977)

Presentation of Case First admission (1966). A 47-year-old woman was admitted to the hospital because of diarrhea.She was well until two years earlier, when a cholecystectomy was followed by crampy lower abdominal pain and the urgent passage of loose, watery stools of small volume, often accompanied by mucus, without blood or pus. The attacks lasted for three to four days and were followed by a symptom-free interval during which she passed two to three stools daily. Eight months before entry she traveled to Mexico and noticed exacerbation of the symptoms. Repeated stool cultures gave no growth of pathogenic bacteria. . . .
Effect of LAT2 on glutamine-dependent mTOR activation to promote glycolysis and chemoresistance in pancreatic cancer.
Authors: Jiangdong Qiu, Mengyu Feng, Zhe Cao, Gang Yang, Yueze Liu, Taiping Zhang
Journal: Journal of Clinical Oncology (2019)

e15759 Background: Reprogrammed energy metabolism has become the characteristic of cancer recently. Transporters act as amino acid sensors involved in mTOR recruitment and activation, which is crucial for the growth of both normal and tumor cells. L-type amino acid transporter 2 (LAT2), a Na+ -independent neutral amino acid transporter, is encoded by the SLC7A8 gene and responsible for transporting neutral amino acids, including a mTOR activator, glutamine. LAT2 was reported to be overexpressed in gemcitabine-resistant pancreatic cancer cells. However, the role of LAT2 in chemoresistance in pancreatic cancer remains unclear. Methods: The effects of LAT2 on biological behaviors of pancreatic cancer cells were analyzed. LAT2 and LDHB levels in tissues were detected, and the clinical value was evaluated. Results: We demonstrated that LAT2 played an oncogenic role and decreased the gemcitabine sensitivity of pancreatic cancer cells in vitro and in vivo. Survival analysis indicated that high expression of both LAT2 and LDHB was related to a poor prognosis in patients with pancreatic cancer. Furthermore, we found that LAT2 could promote proliferation, inhibit apoptosis, activate glycolysis and alter glutamine metabolism to activate mTOR in vitro and in vivo. Next, the combination of gemcitabine with an mTOR inhibitor (RAD001) could reverse the decrease in chemosensitivity caused by LAT2 overexpression in pancreatic cancer cells. Mechanistically, LAT2 promoted glycolysis and decreased gemcitabine sensitivity via regulating two glutamine-dependent positive feedback loops (the LAT2/p-mTORSer2448 loop and the glutamine/p-mTORSer2448/glutamine synthetase loop) in pancreatic cancer. Conclusions: Our data indicates that LAT2 functions as an oncogenic protein and could regulate glutamine-dependent mTOR activation to promote glycolysis and decrease gemcitabine sensitivity in pancreatic cancer. The LAT2-mTOR-LDHB pathway might be a promising therapeutic target in pancreatic cancer.
Personalized multimodality therapy (ICT) with immune checkpoint inhibitors (ICI), chemotherapy (CT), and targeted treatment (TT), in advanced/refractory cancer.
Authors: Philip A. Salem, Khaled W. Jabboury, Thomas M. Wheeler, Randall Stenoien
Journal: Journal of Clinical Oncology (2020)

e15150 Background: Therapy for advanced/refractory malignancies is associated with poor prognosis. The combination of ICI and CT has been shown in lung and several other cancers to be superior to CT alone. Since ICI, CT, and TT have a convergent efficacy with divergent toxicity, the combination was evaluated in the treatment of these diseases. Initial evaluation was reported in JCO. 2019 37.15 suppl. e14254. Methods: Treatment was highly personalized and based on diagnosis, prior therapy, and eligibility for TT. Genomic profiling was done to determine TT. ICI included pembrolizumab in 14, nivolumab in 8, and atezolizumab in 2. Chemotherapy was given in 28-day cycles. 23 received multiple agents. 17 received platinum, 11 taxanes. TT included erlotinib in 6, bevacizumab in 6, cetuximab in 2, everolimus 2, and 8 received others. From 04/2016 to 12/2019, 24 patients, median (M) age 62 (27-78) received ICT; 15 females, 9 males. Tumor type: lung 9, pancreas 4, colon 2, glioblastoma multiforme 2, melanoma 2, stomach 1, cervix 1, cholangiocarcinoma 1, thymoma 1, Hodgkin's lymphoma 1. 18 patients had prior therapy, M2 (1-11), of them 6 had ICI and 5 TT. Response evaluation was based on PET scan. Tumor regression occurred after the first cycle. Results: All patients responded. 12 (50%) achieved CR, M14 months (3-32+); 11 (45.8%) had PR, M5+ months (1+ - 20+); and 1 minor response 1+ month. CR + PR was 95.8%. All 3 patients with lung cancer and metastases to brain, achieved CR in brain. Of 3 patients with advanced gastrointestinal cancer, 2 achieved CR and 1 achieved more than 95% reduction in disease. Tolerance was reasonable. No unexpected side effects were noted. Adverse events were primarily hematologic and febrile events/infection. Conclusions: Personalized ICT combination in advanced/refractory and diverse cancer diagnoses is associated with more than 95% response rate. In particular, it was effective in primary and metastatic CNS disease.
Final results of a phase I study evaluating INVAC-1, a novel DNA vaccine expressing an inactive form of human telomerase reverse transcriptase (hTERT) in patients with advanced solid tumors.
Authors: Luis Teixeira, Jacques Medioni, Ludovic Doucet, Antoine Angelergues, Stephane Culine, Stephane Oudard, Mara Brizard, Zineb Ghrieb, Olivier Adotevi, Caroline Laheurte, Marie-Agnès Dragon Durey, Pierre Laurent-Puig, Jean-Jacques Kiladjian, Simon wain-Hobson, Valérie Doppler, Rémy DeFrance, Julie Garibal, Thierry Huet, Pierre Langlade Demoyen
Journal: Journal of Clinical Oncology (2019)

2642 Background: INVAC-1 is an optimized DNA plasmid encoding an inactive form of human Telomerase Reverse Transcriptase (hTERT), a universal tumor antigen expressed in most of human tumors with little or no expression in somatic cells. We report here the final results of a First-In-Human Phase I study evaluating INVAC-1 as a single agent in patients (pts) with advanced solid tumors, ended in June 2018. Methods: A two center Phase I trial evaluated INVAC-1 given monthly for a minimum of 3 cycles and up to 9 cycles by intradermal injection followed by electroporation (n = 20) or using a needle-free injection system (n = 6). Primary objectives included safety, tolerability and dose limiting toxicities to identify the maximum tolerated dose and recommended phase 2 dose. Secondary objectives included immune response (assessed by IFN-γ Elispot) and anti-tumor activity. Immuno-monitoring included detection of autoantibodies, lymphocyte phenotyping and inflammatory cytokine levels in blood. Anti-tumor activity was evaluated through RECIST 1.1 adapted to immune response, and plasma circulating tumor DNA (ctDNA). Results: 26 pts with refractory/progressive tumors were enrolled and treated with 3 escalating doses of 100, 400 and 800 µg. 15 pts experienced stable disease according to RECIST. For 11 of them, the treatment was extended, up to 9 months. INVAC-1 was well tolerated with no dose-limiting toxicities. No significant biological signs of autoimmunity were observed. No significant modification in inflammatory plasma cytokines levels was observed after INVAC-1 administration. INVAC-1 triggered de novo or enhanced pre-existing CD4/CD8 specific anti-hTERT response in 63% of pts. This specific anti-hTERT immune response was enhanced ex vivo by adding the immune checkpoint inhibitor nivolumab. ctDNA was evaluated in 17 pts. We observed a ctDNA decrease in 6 cases, a stable level in 5 cases and an increase in 6 cases. Conclusions: Results indicate that INVAC-1 was well tolerated and immunogenic at the doses and schedule tested. Disease stabilization was obtained for the majority of pts (58%) according to RECIST criteria or ctDNA levels. Clinical trial information: NCT02301754.
NRG-BR002: A phase IIR/III trial of standard of care therapy with or without stereotactic body radiotherapy (SBRT) and/or surgical ablation for newly oligometastatic breast cancer (NCT02364557).
Authors: Steven J. Chmura, Kathryn A. Winter, Hania A Al-Hallaq, Virginia F. Borges, Nora T. Jaskowiak, Martha Matuszak, Michael T. Milano, Joseph Kamel Salama, Wendy A. Woodward, Julia R. White
Journal: Journal of Clinical Oncology (2019)

TPS1117 Background: This is a randomized Phase II/III trial to evaluate if stereotactic body radiotherapy (SBRT) and/or surgical resection (SR) of all metastatic sites in newly oligo-metastatic breast cancer who have received up to 12 months of first line systemic therapy without progression will significantly improve median progression free survival (PFS). If this aim is met the trial continues as a phase III to evaluate if SBRT/SR improves 5 year overall survival. Secondary aims include local control in the metastatic site, new distant metastatic rate, and technical quality. Translational primary endpoint is to determine whether &lt; 5 CTCs is an independent prognostic marker for improved PFS and OS. Methods: Women with pathologically confirmed metastatic breast cancer to ≤ 4 sites who have been diagnosed within 365 days with metastatic disease and the primary tumor site disease is controlled. CNS metastases are ineligible. ER/PR and HER-2 neu status is required. Site radiation credentialing with a facility questionnaire and pre-treatment review of first case is required. Randomization is to standard systemic therapy with local radiotherapy/ surgery for palliation when necessary versus ablative therapy of all metastases with SBRT and/or SR. For the phase IIR portion to detect a signal for improved median PFS from 10.5 months to 19 months with 95% power and a 1-sided alpha of 0.15 and accounting for ineligible/lost patients, 128 patients will be required. For the Phase III, an additional 232 patients will be required to definitively determine if ablative therapy improves 5-year overall survival from 28% to 42.5% (HR=0.67), with 85% power and a one-sided type I error of 0.025. For the translational research assuming a two-sided probability of type I error of 0.05, the number of patients accrued in the Phase II-R and Phase III portions will provide sufficient power of at least 91% and 93% to detect whether &lt; 5 CTC’s is prognostic for PFS and OS, respectively. Present accrual (1-31-2019): 105. Contact Information: Protocol: CTSU member web site https://www.ctsu.org . Enrollment: OPEN at https://open.ctsu.org . Support: This project is supported by NRG Oncology grants U10CA180868 and U10CA180822 from the National Cancer Institute (NCI). Translational science is supported by the Ludwig Foundation for Cancer Research. Clinical trial information: NCT02364557.
Randomized phase II study comparing mannitol with furosemide for the prevention of cisplatin-induced renal toxicity in advanced non-small cell lung cancer: The OLCSG1406 trial.
Authors: Go Makimoto, Katsuyuki Hotta, Isao Oze, Kiichiro Ninomiya, Takashi Ninomiya, Toshio Kubo, Kadoaki Ohashi, Eiki Ichihara, Kammei Rai, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura
Journal: Journal of Clinical Oncology (2019)

e23105 Background: Although cisplatin-based chemotherapy has been the mainstay in the treatment of advanced non-small cell lung cancer (NSCLC), it is still controversial as to whether furosemide (FUR) or mannitol (MAN) is better as a forced diuresis for avoiding cisplatin-induced nephrotoxicity. We conducted a randomized phase II trial to clarify this issue in candidates. Methods: Those with advanced NSCLC, suitable for receiving cisplatin-based chemotherapy with an adequate renal function were randomly assigned either to the FUR arm or the MAN arm. Either of forced diuretics was administered with an appropriate hydration in cisplatin administration. The primary endpoint of the study was a proportion of ≥ grade 1 serum Creatinine (Cr) elevation in the first cycle, defined by the CTCAE v4.0. Results: The trial was terminated early with 44 (FUR arm; 22 and MAN arm; 22) of the planned 66 patients because of slow accrual. The patient demographics are listed in Table1. In the first cycle, 2 (9%) and 4 patients (18%) developed grade 1 Cr elevation, respectively (P = 0.33), despite no ≥ grade 2 toxicity. The median time to develop the worst Cr score was 29 (range: 26-31) and 12 (range: 8-28) days, respectively. All patients recovered within 3 to 330 days, respectively. Cisplatin induced grade 3 emesis was observed in 3 patients (14%) in MAN arm, whilst none developed in FUR arm. No treatment related deaths were observed. Conclusions: In this setting, the preventive effect of the two types of forced diuretics on cisplatin-induced renal toxicity was not significantly different. Clinical trial information: UMIN000015293. [Table: see text]
Prospective comparative effectiveness trial of multidisciplinary lung cancer (LC) care.
Authors: Raymond U. Osarogiagbon, Nicholas Ryan Faris, Matthew Smeltzer, Meredith Ray, Kenneth Daniel Ward, Fedoria Rugless, Bianca Michelle Jackson, Meghan Brooke Meadows, Courtney Berryman, Carrie Fehnel, Cheryl Houston-Harris, Laura McHugh, Lisa Klesges, Edward T Robbins
Journal: Journal of Clinical Oncology (2019)

6549 Background: LC is common and lethal; care-delivery is complex, varies in quality and outcomes, stimulating calls for multidisciplinary treatment planning (MTP) involving key specialists. This much-advocated model lacks rigorous evaluation. We conducted a prospective cohort study of MTP v Serial Care (SC) in a community healthcare system. Methods: Newly-diagnosed LC patients with performance status (PS) 0-2, and their caregivers, were enrolled from a LC multispecialty group clinic (MGC) or single-specialty general oncology clinics. A subset of general oncology clinic patients were discussed in a Multidisciplinary Thoracic Oncology Conference (MTOC), others were not (Serial Care [SC]). In this analysis, we compare MGC and MTOC patients (MTP recipients) to SC patients. Primary endpoint was overall survival (OS); secondary endpoints were measures of quality: staging practices, guideline-concordant treatment, timeliness of care, patient and caregiver satisfaction. We adjusted proportional hazards and logistic models for age, sex, histology, stage, PS, insurance, and race. Results: 254 patients received MTP v 272 SC. After a median 30 months’ follow up, there was no difference in OS (adjusted hazard ratio 1.10 [CI 0.87-1.40], p = .43). Stage-confirmatory biopsy was done in 61% MTP v 45% SC patients (adjusted odds ratio [aOR] 2.59, CI 1.74-3.86, p &lt; .0001); 81% MTP v 68% SC patients received guideline-concordant treatment (aOR 2.04, CI 1.31-3.19, p &lt; .002). Although the time from lesion detection to diagnostic biopsy (25 v 15 days, p = .004) or staging biopsy (29 v 20 days, p = .007) was higher with MTP, there was no difference in time to definitive treatment (60 v 57 days, p = .06). MTP patients and their caregivers reported greater satisfaction with the combined quality of care received from all team members (p &lt; .0001) at baseline, 3 and 6 months. Conclusions: MTP for LC significantly improved the quality of care including the thoroughness of staging, use of guideline-concordant care, and patient satisfaction. Contrary to reports from retrospective analyses, timeliness of care was worse with MTP. Patient and caregiver satisfaction was superior with MTP. Despite improved quality, MTP was not associated with improved LC survival. Clinical trial information: NCT02123797.
Effect of tart cherry on aromatase inhibitor-induced arthralgia (AIA) in nonmetastatic hormone-positive breast cancer patients: A randomized double-blind placebo-controlled trial.
Authors: Mina Shenouda, Maria R. B. Tria Tirona
Journal: Journal of Clinical Oncology (2019)

525 Background: Aromatase inhibitors (AI) are the standard treatment for hormone receptor‐positive breast cancer in postmenopausal women. About half of patients (pts) taking AI suffer from AIA which can be severe enough to cause noncompliance. Suboptimal AI adherence is associated with decreased disease-free and overall survival, suggesting that improving adherence will lead to improved breast cancer outcomes. Effective interventions for AIA are still limited. In clinical trials, tart cherry (TC) showed beneficial effect on musculoskeletal pain associated with osteoarthritis, gout, and strenuous exercise. The flavonoids and anthocyanins in TC reportedly exert an anti-inflammatory effect that may lessen adverse effects of estrogen deficiency. This trial aimed to investigate whether TC can reduce AIA in non-metastatic hormone positive breast cancer (NMHPBC) pts. Methods: This is a randomized, placebo-controlled, double-blind trial. Eligible Pts with NMHPBC on AI for at least 4 weeks were randomized to TC concentrate (equivalent to 50 tart cherries) versus placebo (P) [syrup] in a 1:1 model. Pts were instructed to take 1 Oz of TC or P in 8 Oz water daily for 6 weeks, and to document their pain intensity at baseline, weekly and at study completion in a diary using a Visual Analog Scale (VAS), with 0 mm indicating no pain, and 100 mm indicating highest pain. Results: 60 pts were enrolled from May 2016 to August 2018. 2 pts did not complete the study due to diarrhea. 10 pts were non-compliant. 48 pts were included in the final analysis. TC group (23 pts) had 34.7% mean decrease in pain compared to 1.4% in P group (25 pts). This difference was statistically significant (Mann-Whitney U Test P = 0.034). Conclusions: Tart cherry can significantly improve AIA in non-metastatic breast cancer patients.
Acceleration of β Cell Aging Determines Diabetes and Senolysis Improves Disease Outcomes
Authors: Cristina Aguayo-Mazzucato, Joshua Andle, Terrence B. Lee, Ayush Midha, Lindsay Talemal, Vaja Chipashvili, Jennifer Hollister-Lock, Jan van Deursen, Gordon Weir, Susan Bonner-Weir
Journal: Cell Metabolism (2019)