tbuckley/cabot-search huggingface dataset:
Analysis of use of a molecular reporting and treatment decision support tool in more than 1300 cancer cases.
Authors: Gabriel Alejandro Bien-Willner, Carolin Hülsewig, David B. Jackson, Sajo Kaduthanam, Stephan Brock, Martin A. Stein, Stephan Hettich, Michael Weber, Matthias Loehr
Journal: Journal of Clinical Oncology (2018)

6552 Background: Comprehensive characterization of the cancer genome has elucidated the molecular determinants driving response and resistance to targeted therapies. Current NGS-based personalized medicine requires a lot of manual work (e.g., publication and database review) to find relevant biomarker information necessary to create an impactful diagnostic report. Molecular Health Guide (MH Guide) allows for rapid and efficient variant interpretation and treatment support using referenced curated data including evaluation of various quality parameters. Methods: We constructed an integrated database of biologic and clinical data called Dataome, upon which we have developed a medical device (MH Guide) for medical reporting, wherein content can be used for clinical treatment decision support (registered medical device in Europe). We assess the clinical information provided by MH Guide in a cohort of patients including the number of recommended and contraindicated drugs and available clinical trials. Results: 1352 cancer patients with various solid tumor types (n = 107) were analyzed with MH Guide (2014-2017). The system identified 14,000, 4,800 and 2,300 tumor-type specific biomarkers associated with effective therapies, adverse events and ineffective therapies, respectively. These were based on clinical (10,300) as well as pre-clinical (11,400) data. Putative effective therapies were linked to > 4,700 clinical trials. Conclusions: Comprehensive characterization of the cancer genome has elucidated pathways that drive cancer, mechanisms of therapy resistance, and provided important insights for the development of new therapies. To benefit from this in routine medical practice, we need tools and technologies that efficiently assist with interpretation of clinico-molecular patient data against the rapidly growing biomedical knowledge. MH Guide can assist clinicians in making informed decisions about the benefits of therapies in an evidence driven manner. Based on its performance, German health insurance companies have agreed to support the clinical use of MH Guide in a study aimed to reduce non-responders and adverse events; thus, lowering the overall cost of care and improve quality of life.
Anti-tumor immune responses in metastatic breast cancer exceptional responder patients.
Authors: Alusha A Mamchak, Ngan Nguyen, Danhui Zhang, Felix Chu, Michael G Harbell, Beatriz Millare, Kevin S Williamson, Shuwei Jiang, Dongkyoon Kim, Sini Reponen, Sean Carroll, Nicole Haaser, Sarah Hippely, Maren K. Levin, Amy Manning-Bog, Jeff Defalco, Daniel Emerling, Norman M Greenberg, Guy Cavet, Joyce O'Shaughnessy
Journal: Journal of Clinical Oncology (2018)

e15161 Background: Analyzing anti-cancer immune responses can offer insights into the mechanisms that underlie successful cancer therapies. We studied the B and T cell responses of 11 metastatic breast cancer (MBC) patients who had exceptional responses to systemic therapy with multi-year benefit, all of whom were disease-free or long-term progression-free. These patients had diverse hormone receptor status, HER2 status, and treatment history. Methods: Using Immune Repertoire Capture® (IRC™) technology to study single cells from peripheral blood, paired chain IgG antibody (Ab) sequences were generated from plasmablasts, and paired chain a/b TCR sequences were generated from PD1+ T cells along with phenotypic profiles for HLA-DR, CD38 and TIGIT. Results: A total of 9160 expression-ready, native pairs of heavy and light immunoglobulin chains were identified. Abs were grouped into putative clonal families based on germline gene usage and other sequence features. 931 of these families had two or more cells. We sought similar Abs that had arisen independently in different donors by convergent selection, and identified 12 sets of Abs, each of which comprised sequences from more than one donor. By selecting Ab sequences and expressing them as recombinant proteins, patient-derived Abs were identified that bind to cancer cell lines. These Abs were screened for binding to non-autologous breast tumor sections. Several Abs were identified that bind specifically to breast tumor but not to adjacent breast tissue. Such tumor-specific Abs could form the basis of new cancer therapies. In the analysis of T cells, natively paired a/b TCR sequences and single cell phenotypes were generated for 3,119 PD1+ T cells. This revealed 138 expanded T cell clones that included examples of cells with identical TCRs but different phenotypic profiles, providing evidence for phenotypic plasticity within PD1+ T cell clones. Conclusions: Using IRC™ technology we have defined details of the adaptive immune response in patients responding well to systemic therapy for MBC. We are evaluating the therapeutic potential of tumor-specific Abs generated by these patients, and extending this data set to further characterize the immune response to breast cancer.
Financial toxicity and cancer-related distress among melanoma survivors.
Authors: Joanne S Buzaglo, Melissa F Miller, Alexandra K Zaleta, Jamese Johnson, Niraj K. Gupta
Journal: Journal of Clinical Oncology (2017)

9588 Background: Melanoma survivors are at risk for significant financial burden due to cancer care and out of pocket costs. We explored 1) the financial impact of melanoma and its relationship to cancer-related distress, and 2) survivors’ experiences discussing financial burden with their health care team. Methods: Of 110 melanoma survivors enrolled in the Cancer Support Community’s online Cancer Experience Registry, 56 completed questions about financial impact of cancer and cost of care communication. Participants rated concern (0 = not at all; 4 = very seriously) about 27 items encompassing psychological, emotional, physical and practical concerns; items were summed into a total distress score (mean = 33, SD = 21, range 0-88). Financial impact and overall distress were examined via regression analysis. Results: Participants were 71% female, 89% Caucasian, median age 54, and median time since diagnosis 2.5 years. Total annual income: 34% &lt; $60K; 46% $60K+; 20% not reported. 24% spent $101-250/month on melanoma out of pocket costs; 20% spent $251-500; and 24% spent ≥$500. The top concern was health insurance/money worries (69% moderately to very seriously concerned). Due to medical costs, 57% depleted their savings, 20% borrowed against or used retirement money, 20% used pharmaceutical assistance programs, 13% skipped medicine dosages at least sometimes, and 17% postponed filling prescriptions. Only 28% reported that their health care team spoke to them about cost of care, and 28% were asked about financial distress; 42% desired financial assistance. Financial impact was associated with an increase in overall distress for those with income &lt; $60K (p &lt; .05; interaction p &lt; 0.05). Conclusions: Substantial proportions of melanoma survivors experience financial burden that can impact quality of life, particularly lower income individuals. Although oncologists are encouraged to discuss treatment costs, most patients report they have not had these discussions with providers. These results support the development/evaluation of interventions to enhance doctor-patient communication, and financial counseling to minimize financial burden of melanoma and the risks it can confer for quality of life, course of cancer care, and health outcomes.
Multi-kinase RET inhibitor vandetanib combined with mTOR inhibitor everolimus in patients with RET rearranged non-small cell lung cancer.
Authors: Vivek Subbiah, Tina Cascone, Kenneth R. Hess, Ishwaria Mohan Subbiah, Sarah Nelson, Naoto Morikawa, Monique B. Nilsson, Tarak Bhatt, Siraj Ali, William Nassib William, Victoria M. Raymond, Richard B. Lanman, David Paul Carbone, Ravi Salgia, Taofeek Kunle Owonikoko, George R. Simon, Funda Meric-Bernstam, Robert Charles Doebele, John Heymach
Journal: Journal of Clinical Oncology (2018)

9035 Background: RET fusions (RET+) occur in 1-2% of NSCLCs. Tumors eventually become refractory to multi-kinase RET inhibitor monotherapy. We evaluated the pre-clinical and clinical activity of the combination of Vandetanib (V), an inhibitor of RET, VEGF, and EGFR, and the mTOR inhibitor everolimus (E). Methods: Clinical activity of V + E was evaluated in pts with advanced NSCLC in a Phase 1 trial. V and E were administered orally QD in a 28 day cycle. Responses were assessed by RECIST 1.1. RET fusions were detected by FISH and/or or Next generation sequencing (NGS) in tumor tissue and/or plasma. Preclinical studies were performed using the CCDC6-RET + LC-2/ad NSCLC cells. Results: Among 19 stage IV NSCLC pts enrolled, median age was 59 yrs & 8 pts (42%) were males. 13 pts (93%) were RET+ by NGS and/or FISH. Concordance rate between the two tests was 40%. The overall ORR in 13 RET+ pts was 54% (7 PR). The ORR in RET+ by NGS was 70% (7 PR/10 patients) while the ORR in FISH+ patients was 20% (1 PR/5 patients). No responses were seen in NGS-/FISH+ patients (0/3 = 0%). The combination was active in RET+ NSCLC brain metastases (3/3) and in a cabozantinib progressor. The median PFS of all 13 RET+ patients was 4.4 months (95% CI 3.4, NR); the median PFS of RET NGS+ patients (n = 10) was 8 months (95% CI 0.1, 1.1). Grade 3/4 toxicities included diarrhea (21%), thrombocytopenia (16%), QTc prolongation (5%) and rash (5%). 17/ 19 (89%) pts required dose modifications after cycle 1 due to toxicity. Preclinical studies demonstrated that resistance to RET inhibition was associated with activation of the EGFR, VEGFR, and downstream mTOR pathways and that the combination of everolimus with the RET/VEGFR/EGFR inhibitor vandetanib abrogated this resistance in preclinical models. Conclusions: V+E has significant activity in RET+ NSCLC identified by NGS, with an ORR of 70% and a median PFS of 8 months. Preclinical data shows the V+E combination to be superior to either drug alone and may target potential resistance pathways. The combination merits further investigation in RET+ NSCLC. Clinical trial information: NCT01582191.
Diagnosing deficits in quality of life and providing tailored therapeutic options: Results of a randomized trial including 220 patients with colorectal cancer.
Authors: Monika Klinkhammer-Schalke, Brunhilde Steinger, Michael Koller, Alois Fürst, Pompiliu Piso, Manfred Kästel, Julia Gumpp, Robert Obermaier, Ferdinand Hofstaedter, Patricia Lindberg
Journal: Journal of Clinical Oncology (2018)

10050 Background: There have been increasing efforts to develop interventions that improve patients` quality of life (QoL) in routine cancer care. The Tumor Center Regensburg has designed and implemented an intervention consisting of the systematic diagnosis and tailored therapy of QoL. The efficacy of this intervention has been demonstrated in a randomized trial of patients with breast cancer. To generalize and strengthen the external validity of these findings, this intervention system was applied to a cohort of patients with colorectal cancer. Methods: In a 2-arm randomized controlled trial, 2x110 patients with primary colorectal cancer were recruited in four colorectal cancer centers and randomized into an intervention group (IG) or a control group (CG). QoL (EORTC QLQ-C30 and QLQ-CR29) was measured in both arms before clinical discharge and at the 3-, 6-, 12-, and 18-months routine follow-up. A network of local healthcare providers of QoL therapy was established that encompassed physiotherapy, psychotherapy, pain therapy, social support, nutrition, stoma care, and fitness. In the IG, the treating physician received printouts of QoL results (QoL profile including 15 scales). If a need for QoL therapy was diagnosed (cutoff < 50 points in scales of 0-100), specific QoL therapies were recommended. In the CG, QoL was also measured, but the treating physician neither received QoL profiles nor recommendations on QoL therapy. Results: At clinical discharge, a need for QoL therapy was diagnosed in 92% (96/104) of IG patients and in 85% (88/104) of CG patients. At 12 months (primary endpoint), the intervention had reduced the rate of patients with a need for QoL therapy to 50% (41/82) compared to 66% (57/87) in CG (χ2-Test p = .041, number needed to treat (NNT) = 7). Conclusions: Patients with primary colorectal cancer benefited from the intervention with QoL diagnosis and therapy in terms of faster improvement of their QoL during the first year after surgery. The NNT was exactly the same as for patients with breast cancer, indicating high external validity of these results. Clinical trial information: NCT02321813.
NuTide 302: A phase IB study to assess the safety, pharmacokinetics and clinical activity of NUC-3373 in combination with standard agents used in colorectal cancer treatment.
Authors: Sarah Patricia Blagden, T.R. Jeffry Evans, Essam Ahmed Ghazaly, Chathunissa Gnanaranjan, Aimery De Gramont, Josep Tabernero, Jordan Berlin
Journal: Journal of Clinical Oncology (2018)

TPS3617 Background: 5-FU and its other forms, floxuridine and capecitabine, exert their anti-cancer activity mainly due to the active metabolite, fluorodeoxyuridine-monophosphate (FUDR-MP), which inhibits the enzyme thymidylate synthase (TS). Although these agents remain the cornerstone of combination treatments for colorectal cancer (CRC), key cancer resistance mechanisms of breakdown, activation and transport limit their effectiveness. NUC-3373 is a phosphoramidate transformation of FUDR-MP designed to bypass the key resistance mechanisms associated with 5-FU. NuTide 301 is an ongoing first-in-human study of NUC-3373 in patients with advanced solid tumors. PK/PD data obtained to date demonstrate NUC-3373 has a long plasma t1/2 (9.7 h v 8-14 mins for 5-FU) and generates high levels of the active intracellular anti-cancer metabolite, FUDR-MP (Ghazaly et al ESMO, 2017). TS is efficiently inhibited and sequestered into TS-ternary complexes (TS-T), depleting the pool of dTMP within 2-4 hours. Methods: NuTide:302 is a two-part, Phase Ib study in patients with CRC who have relapsed after ≥2 prior lines of therapy. The primary objective is to identify a recommended NUC-3373 dose when administered every 2 weeks in combination with standard agents used in CRC treatment. Secondary objectives included safety, PK/PD and anti‐tumor activity. In Part 1, NUC-3373 is being administered with leucovorin (LV) to determine if the folate is beneficial in the formation of TS-T. Approximately 12 patients will be enrolled in Part 1 of the study. If LV augments TS-T formation, it will be administered in Part 2. In Part 2, the following combination agents will be administered with NUC-3373 (±LV): oxaliplatin; oxaliplatin + bevacizumab; oxaliplatin + panitumumab; irinotecan; and irinotecan + cetuximab. In Part 2, patients will be enrolled in cohorts of 3-6, in a modified 3+3 design. Up to 62 patients will be recruited, depending on cohort expansion. Clinical trial information: NCT03428958.
QUADRA: A phase 2, open-label, single-arm study to evaluate niraparib in patients (pts) with relapsed ovarian cancer (ROC) who have received ≥3 prior chemotherapy regimens.
Authors: Kathleen N. Moore, Angeles Alvarez Secord, Melissa Ann Geller, David S. Miller, Noelle Gillette Cloven, Gini F. Fleming, Andrea Elisabeth Wahner Hendrickson, Masoud Azodi, Paul DiSilvestro, Amit M. Oza, Mihaela C. Cristea, Jonathan S. Berek, John K. Chan, Yong Li, Romnee Clark, Ursula A. Matulonis, Bradley J. Monk
Journal: Journal of Clinical Oncology (2018)

5514 Background: PARP inhibitors (PARPi) are approved as active treatment only for pts with BRCA mutations. The PARPi niraparib demonstrated increased PFS vs placebo in the maintenance setting of platinum (plat) responsive ROC. Niraparib was effective regardless of BRCAmut or homologous recombination deficiency (HRD) status, but an increased treatment effect was observed in the HRDpos population. QUADRA (NCT02354586) evaluated niraparib active treatment in ROC pts. Based on the results of NOVA, the primary objective in QUADRA was to determine ORR in plat sensitive, HRDpos patients. Methods: Eligible pts had grade 2 or 3 serous ROC, ≥3 prior lines of chemo and measurable disease. Pts were evaluated for BRCAmut and HRD status (MyChoice HRD Test). HRDpos included germline or tumor BRCA mutation or an HRD score ≥42. Pts received niraparib 300 mg once daily until progression; treatment emergent adverse events (TEAEs) were managed with dose reduction to 200 or 100 mg. The primary endpoint was ORR per RECIST v1.1. Results: 463 pts were treated. Median age was 65 (range: 29-91). 162 pts were plat refractory; 152 plat resistant; 118 plat sensitive; 31 unknown. In HRDpos, plat sensitive pts who had received ≥3 regimens (median: 3 [range: 3-9]), without prior PARPi (N = 51) ORR was 27.5% (95% CI: 15.9%, 41.7%); DCR was 68.6%; DOR was 9.2 mos. Of the 51 pts, ORR was 38.9% (7/18) in BRCAmut and 21.2% in BRCAwt pts (7/33). 260 (56.2%) pts had grade ≥3 treatment-related TEAEs. The most common grade ≥3 TEAEs were thrombocytopenia (27.9%), anemia (24.9%), and neutropenia (12.4%). Grade ≥3 thrombocytopenia was 27.5% at 300 mg, 4.7% at 200 mg, and 2.7% at 100 mg. Hematologic TEAEs were most frequent in the first month and decreased in frequency and severity after dose reduction during months 2-3. Conclusions: Niraparib demonstrated durable anti-cancer activity in this heavily treated, HRDpos ROC population (4th line or greater), including BRCAwt pts. Toxicities, consistent with previous niraparib studies, were manageable with dose reduction and generally resolved within 3 mos. Final data including ORR in the total population (N = 463) and results in other subgroups will be presented. Disclosure Funded by TESARO, Inc. Clinical trial information: NCT02354586.
Phase II study of ipilimumab (IPI) in children and adolescents with unresectable stage III or IV malignant melanoma (MEL).
Authors: Alberto S. Pappo, Christophe Bergeron, Lia Gore, Leonard S. Sender, Ira J. Dunkel, Cynthia E. Herzog, Lieve Brochez, Ofelia Cruz, Karsten Nysom, Elmer Berghorn, Burcin Simsek, Jun Shen, Birgit Geoerger
Journal: Journal of Clinical Oncology (2017)

e21006 Background: IPI (anti-CTLA4) is approved for treatment of advanced MEL in adults, and more information on efficacy and safety of IPI in younger patients (pts) is needed. Methods: Pts from study CA184-178 (NCT01696045) age 12 to &lt;18 yrs with previously treated or untreated, unresectable stage III or IV malignant MEL received up to 4 doses of IPI at 3 or 10 mg/kg Q3W. Key exclusion criteria were ocular MEL, active brain metastases, or autoimmune disease. Primary endpoints were 1-yr overall survival (OS) and safety. Results: From April 2013 to June 2016, 12 pts received either IPI 3 mg/kg (n=4) or 10 mg/kg (n=8); 2 did not meet study criteria and were not treated. For the 3 and 10 mg/kg groups, median age was 13 yrs and 15 yrs, 50% and 63% were male, 25% and 13% had elevated baseline lactate dehydrogenase, and 75% and 50% had prior systemic therapy, respectively. Median number of IPI doses received was 4.0 (range: 2–4) for 3 mg/kg and 3.0 (range: 1–4) for 10 mg/kg. At 1 yr, 3/4 pts on 3 mg/kg and 5/8 pts on 10 mg/kg were alive (Table). Two pts on 10 mg/kg had partial response and 1 pt from each group had stable disease (Table). One pt had ongoing partial response &gt;2 yrs without further treatment. Treatment-related grade 1-4 adverse events were reported in 2/4 and 7/8 pts in 3 and 10 mg/kg groups, respectively. There was 1 grade 3-4 immune-mediated adverse reaction with 3 mg/kg (hepatitis) and 5 with 10 mg/kg (hepatitis [2] and pyrexia [2] were most common). The study was stopped early due to slow accrual. Conclusions: At &gt;1 yr of follow-up, IPI demonstrated activity in MEL pts aged 12 to &lt;18 yrs, with a safety profile consistent with that observed in adults. Our trial highlights the difficulties of enrolling children with rare diseases in clinical trials for drugs that are approved in adults, suggesting adolescents should be included earlier in adult trials of promising new drugs. Clinical trial information: NCT01696045. [Table: see text]
Global impact of a clinical informatics system: Scalable delivery of on-time access to evidence-based multidisciplinary expert treatment decisions for all cancers.
Authors: Rajendra A. Badwe, Pramesh CS, Sudeep Gupta, Nita S. Nair, Nancy Renee Feldman, Anil D'Cruz
Journal: Journal of Clinical Oncology (2017)

6502 Background: There is a scarcity of expert oncologists in the world. Patients in nonurban areas have poor access to evidence-based treatment decisions and worse outcomes. In India, there are ~1600 experts for 1.8 Million patients. Created in May 2014, “TMC NCG Navya Online” is an expert opinion service based on an informatics system. We prospectively study its real-world impact. Methods: Navya exhaustively searches and outputs evidence and experience based treatment options for an individual patient. Its accuracy was validated in trials at TMC (one of the world’s largest tertiary care centers) and UCLA-OVMC. Navya’s patient data summary and treatment options are rapidly reviewed and vetted (1-2 minutes) on mobile by experts from TMC and NCG, (consortium of 104 cancer centers in India). Expert decisions are converted into a simple language report for patients. System generated evidence based information on diagnostics, regimens, side effects etc are also provided. To prospectively assess impact, from July to December 2016, all patients were asked via phone follow-up: 1. If report was shared with treating provider, 2. Final treatments delivered. Results: 9361patients from 22 developing countries registered with TMC NCG Navya Online. 3402 expert decisions were provided and converted into 2614 simple language reports. 5229 patients received system generated evidence based information. Median time to deliver a report was 24 hours. The prospective sample was 582 decisions with a 75% (n = 436) follow-up rate. 74% of reports were shared with treating providers. 73% of TMC NCG Navya’s decisions, (n = 306), were the final treatments delivered. Common reasons for non-implementation included decline in ECOG status and not testing biomarkers (ER/PR etc). Conclusions: Expert oncologists use Navya to provide rapid online opinions to patients across 22 developing countries. Patients shared the expert opinions with their providers and received evidence-based treatments. Expanding the reach and impact of such a service to nonurban USA and the world, can maximize outcomes for patients without ready access to expertise.