tbuckley/cabot-search huggingface dataset:
Role of resection of the primary in metastatic well/intermediate-differentiated neuroendocrine tumor (NET).
Authors: Walid Labib Shaib, Mckenna Penely, Katerina Mary Zakka, Renjian Jiang, Mehmet Akce, Christina Wu, Madhusmita Behera, Shishir K. Maithel, Juan Sarmiento, Olatunji B. Alese, Bassel F. El-Rayes
Journal: Journal of Clinical Oncology (2019)

e15693 Background: Resection of the primary tumor in metastatic neuroendocrine tumor (NET) is controversial. The aim of this study is to evaluate survival outcomes and identify prognostic variables of surgical resection of the primary tumor in metastatic NET patients. Methods: Data were obtained from all US hospitals that contributed to the National Cancer Database (NCDB) between 2004 and 2013. Chi-square and ANOVA tests were done to identify factors associated with surgical modality. Univariate and multivariate cox proportional hazards models were used for association between patient characteristics and survival. Kaplan-Meier curves were generated and log-rank tests conducted to compare the survival difference of patient characteristics. Results: A total of 2,361 patients between 18 and 90 years of age with stage IV well/intermediate-differentiated NET were identified. The mean age was 62.1 years (SD±13), with an equal male to female ratio (50.0%). Majority of NET primaries were in the small intestine (33.0%), pancreas (26.3%), and lung (24.4%). The majority were well differentiated tumors (69.6%) and 42.5% of patients underwent surgery at the primary site. On multivariate analysis total surgical resection of the primary (HR 0.44; 0.22-0.90; p &lt; 0.001), female sex, year of diagnosis 2010-2014, negative surgical margin, Charlson-Deyo score &lt; 2, and age &lt; 51 years at diagnosis were associated with better overall survival (OS). Conclusions: Resection of the primary in stage IV well/intermediate-differentiated NET was associated with improved 5-year OS compared to patients with no surgery in small intestine (60.1% vs 44.2%), lung (70.0% vs 20.2%), and pancreas tumors (59.3% vs 30.6%).
PIPA: A phase Ib study of selective ß-isoform sparing phosphatidylinositol 3-kinase (PI3K) inhibitor taselisib (T) plus palbociclib (P) in patients (pts) with advanced solid cancers—Safety, tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) analysis of the doublet combination.
Authors: Juanita Suzanne Lopez, Manuel SelviMiralles, Malaka Ameratunga, Anna Minchom, Javier Pascual, Udai Banerji, Hannah Bye, Florence I. Raynaud, Karen E Swales, Jason Malia, Michael Hubank, Isaac Garcia-Murillas, Mona Parmar, Sarah Emily Ward, Laura Finneran, Emma Hall, Alison Joanne Turner, Johann S. De Bono, Timothy A Yap, Nicholas C. Turner
Journal: Journal of Clinical Oncology (2019)

3087 Background: Oncogenic hyperactivation of the PI3K pathway is common in multiple cancers, with preclinical data showing that CDK4/6 inhibitors sensitise PIK3CA mutant cancers to PI3K inhibitors. We report the activity of the P+T in solid tumors with PI3K pathway activation, along with the PD biomarker analysis. Methods: We previously reported the dose escalation phase identifying 125mg P given 3-weeks-on, 1-week-off in combination with T 2mg as the recommended phase 2 dose (R2PD, Lim, ASCO 2017). We report the results in solid tumors with confirmed activating mutations (mts) in the PI3K pathway, from dose escalation and expansion, with no prior exposure to CDK4/6 or PI3K pathway inhibitors. PD studies include analyses of platelet-rich plasma (PRP) and paired tumour biopsies. Results: 20 pts (median age 61, range 34-72) were treated at the doublet RP2D, M/F 7/13, with a median 4 prior treatments (range 2-11). Tumour types included colorectal, breast, lung, endometrial,oligodendroglioma and head and neck cancers. Durable disease control occurred in 3 patients with ER+ advanced breast cancer with responses lasting &gt;6 months including 1 pt with a H1047R PIK3CAmt with an ongoing RECIST PR&gt;36 cycles, 2 pts with PIK3CAmt colorectal cancer had RECIST SD for &gt;5 months, and 1 patient with a PIK3CGmt anaplastic oligodendroglioma had clinical and radiological benefit lasting 5.5 months. Treatment was well tolerated with predictable G1-2 adverse events (AEs). G3 toxicities of neutropenia (n=6), thrombocytopenia (2), rash (2), mucositis (1) and raised transaminases (1 each) were all transient with no G4/5 AEs. Significant decreases in tumour pRb, and pAKT and pGSK3ß in PRP, confirmed modulation of both CDK4/6 and PI3K pathways at R2PD. Conclusions: Doublet P+T is well tolerated at the combination RP2D, with PD evidence of PI3K and CDK4/6 modulation in both plasma and tumor. Promising preliminary anti-tumor activity is seen in a mixed histology cohort selected for activating PIK3 mutations. Clinical trial information: NCT02389842.
Synchronous esophageal cancer impact on survival of head and neck squamous cell carcinoma (HNSCC) patients.
Authors: Paulo Henrique Amor Divino, Gustavo Duarte Ramos Matos, Karolina Lima, Gilberto Castro, Gustavo Nader Marta, Flavio Roberto Takeda, Ivan Cecconello, Oddone Freitas Melro Braghiroli, Milena Perez Mak
Journal: Journal of Clinical Oncology (2019)

e17513 Background: Optimal treatment of synchronous tumors (ST) of the aerodigestive tract is debatable and care is often individualized. Our goal was to characterize patients with HNSCC and esophageal cancer (EC) ST and to establish prognostic factors that could aid therapeutic decision. Methods: In this retrospective observational study, we evaluated data from 1650 consecutive patients diagnosed with HNSCC from 2008 to 2016. Patients with ST of HNSCC and esophagus with an interval of ≤ 6 months between both diagnoses were included. Patients ≥ 6 months between both diagnoses, incomplete treatment information and presence of another tumor site were excluded. Results: 52 patients were eligible. Median age was 57 years (39-91). Most were male (98%), with smoking and drinking habits (98%) and ECOG 0-1 (73%). HNSCCs were mainly in oropharynx (54%) and locally advanced disease (LA, III-IVB) (88%). In contrast, EC was early stage (I-II, 62%), located in the thorax (94%) and squamous histology (96%). 14 (27%) had LA in both primaries. Most LA HNSCCs (85%) were treated with radiotherapy (RT) with a median dose of 70Gy (5-70Gy). 50% received platinum and taxane induction chemotherapy. 81% of initial EC received at least surgery, mucosectomy or RT (median 50.4Gy). Hospitalization due to toxicity occurred in 12 (23%) and 7 (14%) of HNSCC and EC treatments, respectively. 16 patients (31%) had no definitive treatment directed to EC, without apparent impact on survival. Median time to progression was 13.8 months, being HNSCC the most frequent site of progression/relapse (40%). Median survival was 23.9 months (IC 95% 9.2-38.6). Early HNSCC survival was comparable to LA HNSCC (17.3 vs. 23.9 mo, p = 0.98). In LA HNSCC, LA vs. initial EC carried a worse prognosis (16 vs. 36.3 mo, p = 0.008). Anemia, BMI, tobacco exposure had no impact on survival. Conclusions: The occurrence of EC and HNSCC ST leads to a dismal survival, even in patients with early stage HNSCC. The presentation of LA in both sites is particularly challenging and associated with worse prognosis. Given the rate of treatment-related toxicity in this population, cautious efforts should be employed when planning definitive treatment in ST pts.
Novel therapeutic strategies for spinal osteosarcomas
Authors: M. Akhtar Anwar, Chirine El-Baba, Muhammed H. Elnaggar, Yasmeen O. Elkholy, Mohamed Mottawea, Dina Johar, Tuqa S. Al Shehabi, Firas Kobeissy, Charbel Moussalem, Elie Massaad, Ibrahim Omeis, Nadine Darwiche, A.H. Eid
Journal: Seminars in Cancer Biology (2019)
Heterogeneity in signaling pathway activity within primary breast cancer and between primary and metastases.
Authors: Wim Verhaegh, Anne van Brussel, Cathy Moelans, Marcia Alves de Inda, Julie Gil, Jan Willem Bikker, Eveline den Biezen-Timmermans, Anja Van De Stolpe, Paul J. van Diest
Journal: Journal of Clinical Oncology (2019)

589 Background: Treatment with targeted drugs aims to block tumor driving signaling pathway(s). Drug choice is often based on a single preoperative primary breast cancer biopsy. It is important that biopsied cancer tissue is representative for the primary tumor (PT) or metastases to treat. Little is known about pathway heterogeneity within the PT, and between PT and metastatic tumors. A novel analysis method was developed to identify and quantify activity of signal transduction pathways in cancer tissue, based on Bayesian models that infer a pathway activity score from transcription factor target gene mRNA levels (Cancer Res 2014;74:2936-45). Methods: Pathway analysis, originally developed for AffymetrixU133Plus2.0, was adapted to RT-qPCR for use on formalin fixed paraffin embedded tissue. Estrogen (ER) and androgen (AR) receptor, PI3K, Hedgehog (HH), TGFβ and Wnt pathway activities were analyzed. Samples were from multiple locations (“quadrants”) in 15 luminal A, 9 luminal B, and 8 ER-negative primary breast cancers; from subdivided quadrant samples (4 “subquadrants”) of respectively 9, 4, and 4 PTs; and from 13 distant and 24 lymph node (LN) metastases of respectively 9 and 7 matched luminal PTs. Analysis of pathway activity score (PAS) variance was performed with linear mixed models with subgroup-dependent standard deviations. Results: In primary breast cancer intra-tumor PAS variance was not larger at macroscale (“quadrant”) than at microscale (“subquadrant”). For ER, AR, HH, and Wnt pathways, PAS variation was higher between distant metastases and PT than within the PT (p &lt; 0.0002). For HH and Wnt pathways, PAS variation was higher between LN metastases than within the PT (p &lt; 0.002). Correlation between primary and metastatic pathway activities ranged from -0.34 for ER to 0.47/0.50 for TGFβ/HH pathways. Conclusions: A single location tissue sample was representative for the whole primary tumor with respect to signaling pathway activity, suggesting one biopsy as generally sufficient for (neo)adjuvant therapy choice. Pathway activities varied between primary cancer and metastases, indicating the necessity of metastatic sample analysis (biopsies or liquid biopsy) to improve therapy choice.
Association of Genetic Risk for Rheumatoid Arthritis With Cognitive and Psychiatric Phenotypes Across Childhood and Adolescence
Authors: Hannah J. Jones, Leon Hubbard, Ruth E. Mitchell, Simon A. Jones, Nigel M. Williams, Stanley Zammit, Jeremy Hall
Journal: JAMA Network Open (2019)

The association of rheumatoid arthritis (RA) with cognitive and psychiatric phenotypes has been recognized. However, it is not known whether these phenotypes are a consequence of disease-related factors, such as pain, or reflect shared etiological factors.
Antitumor immune response induced by NBTXR3 activated by radiotherapy.
Authors: Juliette Thariat, Marick Laé, Sebastien Carrère, Zsuzsanna Papai, Anne Ducassou, Philippe Rochaix, Zoltan Sapi, Isabelle Birtwisle-Peyrottes, Colette J. Shen, Nishan H. Fernando, Bradford Perez, Tanguy Y. Seiwert, Marie-Christine Chateaux, Sunyach Marie, Peter Agoston, Hervé Brisse, Carmen Llacer-Moscardo, Axel Le Cesne, Sylvie Bonvalot
Journal: Journal of Clinical Oncology (2019)

e14609 Background: Radiotherapy (RT) can prime an anti-tumor immune response. Unfortunately, this response rarely generates total tumor destruction and abscopal effect. When activated by RT, intratumorally (IT) administered hafnium oxide nanoparticles (NBTXR3) locally increase radiation dose deposit and tumor cell death compared to RT alone. We hypothesized that NBTXR3 + RT could enhance the anti-tumor immune response, both in mice and humans. Methods: Murine CT26 cells were injected in both flanks of immunocompetent mice. When tumor volume reached 50-120mm3, NBTXR3 (or vehicle) was injected IT in right flank tumors only, then irradiated (3x4Gy). Mice were sacrificed when tumors reached 800mm3. Alternatively, tumors were collected 3 days after last RT fraction and immune cell infiltrates analyzed by immunohistochemistry (IHC). Patients (pts) with locally advanced Soft Tissue Sarcoma (STS) (NCT02379845) received NBTXR3 + RT or RT alone. Pre- and post-treatment (biopsy and resection, respectively) tumor tissues from pts were analyzed by IHC and Digital Pathology for immune biomarkers ( &gt; 16 pts per arm). Results: In mice, IHC analyses showed an increase of CD8+ T cells infiltrates in both flanks of mice treated with NBTXR3+RT, while this was not observed in animals treated with RT alone. Furthermore, ICH analysis of post- vs pre-treatment samples from STS pts showed a marked increase of CD8+ and PD1 biomarkers for pts treated with NBTXR3 + RT, while no differences were seen for pts treated with RT alone. Conclusions: NBTXR3 + RT markedly changes the tumor immune profile in a similar manner in mice and pts with STS. We hypothesize that this adaptive immune response could help convert a local tumor microenvironment to a “hot” phenotype and thus improve the efficacy of immune checkpoint inhibitors. These results led us to investigate the safety and systemic effect of NBTXR3 activated by stereotactic ablative RT (SABR) in combination with anti-PD-1 antibody in pts with locoregionally recurrent or metastatic (to lung or liver) Head and Neck squamous cell carcinoma HNSCC, as well as in metastatic non-small cell lung cancer (NSCLC) and liver metastasis patients [NCT03589339].
Induction chemotherapy with and without erlotinib in patients with oral cavity squamous cell carcinomas (OCSCCs) amenable for surgical resection.
Authors: Xiuning Le, Curtis R. Pickering, M. Laura Rubin, Frederico Netto, Merrill S. Kies, Faye M. Johnson, Charles Lu, George R. Blumenschein, Diana Bell, Lawrence E. Ginsberg, Kaye F Wilson, Jeff Lewis, Lei Feng, Jing Wang, J. Jack Lee, William Nassib William, Jeffrey Myers
Journal: Journal of Clinical Oncology (2019)

6067 Background: We have previously demonstrated activity of erlotinib in head and neck SCCs as monotherapy prior to surgical resection, or in combination with chemotherapy for recurrent/metastatic disease (William et al. ASCO 2011, 2017). The aim of this study was to evaluate the efficacy of induction chemotherapy with a platinum-taxane regimen and explore the potential benefit of erlotinib as part of induction therapy in patients with resectable OCSCCs. Methods: This was a randomized, placebo-controlled, phase II trial of induction chemotherapy (cisplatin 75 mg/m2 or carboplatin AUC 6 with docetaxel 75 mg/m2 every 3 weeks for 3 cycles) with erlotinib (150mg oral daily) or placebo in patients with OCSCCs stage III-IVB amenable for surgical resection. The primary endpoint was major pathological response (MPR, defined as &lt; 10% viable tumor cells in the surgical specimen). Secondary endpoints included safety and long-term efficacy outcomes. Results: From April 1, 2014, to June 7, 2017, 52 patients were enrolled, of whom 47 underwent planned surgery. MPR was achieved in 7/23 (30%) in the erlotinib group and 10/24 (41%) in the placebo group. With a median follow up of 26.5 months, the 2-year long-term progression-fee survival (PFS) were estimated at 75% (95% CI: 59.5-94.5) in the erlotinib arm, and 58.6% (95% CI: 40.9-84.1) in the placebo arm, and 2-year overall survival at 73.5% (95% CI: 57.2-94.5) for the erlotinib group and 73.1% (95% CI: 55.9-95.6) for the placebo group. In patients who achieved MPR (n = 17), the 2-year PFS was 77.4% (95% CI: 57.3-100), compared to 64.5% (95% CI: 49.0-84.8) in patients who did not achieve MPR (n = 29, p = .16). All 7 patients in the erlotinib group who achieved MPR remained disease-free. The majority of patients (87%) completed all 3 cycles of induction chemotherapy. The common side effects were expected and distributed similarly between erlotinib and placebo groups. As expected, rash, diarrhea and dehydration were more common in the erlotinib group. Conclusions: Platinum and docetaxel-based induction chemotherapy induced major pathological response in 17/47 (36%) of resectable OCSSC patients. Two-year overall survival was 73%. Responders had improved long-term outcome. Addition of erlotinib did not improve the rate of MPR, but might have contributed to improved PFS. Clinical trial information: NCT01927744.
Implementation of HPV vaccination pilot project in Kazakhstan: Successes and challenges.
Authors: Dilyara Kaidarova, Zhanna Chingissova, Zaure Dushimova, Yerlan Kukubassov, Alma Zhylkaidarova, Tolkyn Sadykova, Raikhan Bolatbekova
Journal: Journal of Clinical Oncology (2019)

e13056 Background: Cervical cancer (CC) is the second most frequent cancer of women after breast cancer. Prophylactic vaccines for human papillomavirus (HPV) are being introduced in many countries more than 10 years ago. The standardized incidence of СС in Kazakhstan (KZ) in 2017 was 17.1 per 100,000 women. From 2013 to 2016, there was a pilot project of school-based HPV vaccination of adolescent girls in four districts of KZ. Vaccination was carried out with two vaccines (Gardasil and Cervarix) on the choice of parents in a three-dose regimen. Due to the high rejection of vaccination, this program was completed in 2016. Aim of study was to analyze the results of HPV vaccination in KZ. Methods: The results of vaccination of adolescent girls from 9 to 15 years old were evaluated. We analyzed database registry of Kazakhstani vaccinated girls to evaluate vaccine coverage in four district of KZ. Results: A total 11,648 adolescent girls were fully vaccinated during the pilot program for 2013-2016. The average age of the vaccinated is 12.67 ± 1.04. In 2013, immunization was performed for 1,816 girls aged 11–13 years. In 2014, the age range of the target group was expanded to 15 years. The number of vaccinated girls increased to 5,699 adolescent girls. 7,136 girls were fully vaccinated in 2015. 10,004 girls have not received full doses of vaccine. Overall coverage rates of fully vaccinated were 14.8%. The majority of coverage results was stastically similar except for Almaty, where coverage was higher than the average coverage (17.9% vs. 14.8%, p &lt; 0.05). Conclusions: Pilot project of vaccination in Kazakhstan was declared unsuccessful. This situation is associated with a lack of information campaigns on vaccination. This findings highlights the need for phased implementation of vaccination through an educational campaign of parents.
Bacillus Calmette-Guerin (BCG) with or without pembrolizumab (pembro) for high-risk (HR) nonmuscle invasive bladder cancer (NMIBC) that is persistent or recurrent following BCG induction: Phase III KEYNOTE-676 study.
Authors: Ashish M. Kamat, Neal D. Shore, Noah M. Hahn, Shaheen Riadh Alanee, Hiroyuki Nishiyama, Shahrokh F. Shariat, Kijoeng Nam, Ekta Kapadia, Tara L. Frenkl, Gary D. Steinberg
Journal: Journal of Clinical Oncology (2019)

TPS4591 Background: Intravesical instillation of BCG is standard of care for patients (pts) with HR NMIBC. However, many pts have persistent/recurrent HR NMIBC after BCG induction and are at increased risk for progression to muscle-invasive disease. Interim data from the phase 2 KEYNOTE-057 study has shown that the PD-1 inhibitor pembro had promising efficacy in HR NMIBC as monotherapy. KEYNOTE-676 (NCT03711032) is a randomized, comparator-controlled, phase 3 trial to evaluate efficacy and safety of pembro plus BCG in pts with persistent/recurrent HR NMIBC after BCG induction therapy. Methods: Pts are randomly assigned 1:1 to continue BCG therapy alone or receive BCG plus pembro 200 mg every 3 weeks. Treatment is stratified by carcinoma in situ (CIS) histology (presence/absence), PD-L1 combined positive score (≥10/˂10), and timing of NMIBC persistence/recurrence (0 to ≤6, ˃6 to ≤12, or ˃12 to ≤24 mo). Pts are eligible if they are ≥18 years of age with histologically confirmed persistent/recurrent HR NMIBC of the bladder after adequate BCG induction therapy, have undergone cystoscopy/transurethral resection of bladder tumor within 12 weeks before randomization, have no concurrent extravesical disease, and have an ECOG PS score of 0-2. Responses are assessed by cystoscopy and blinded independent central review of urine cytology and biopsy (as applicable) every 12 weeks for years 1-2 and every 24 weeks for years 3-5 and by computed tomography urography every 18 months through year 5. Treatment will continue with pembro for up to 2 years and BCG for 3 years or until confirmed HR NMIBC persistence, recurrence, or disease progression, unacceptable toxicity, or pt/physician decision to withdraw. Primary end point is complete response rate in pts with CIS. Secondary end points are event-free survival (EFS), recurrence-free survival, overall survival, disease-specific survival, time to cystectomy, 12-month EFS rate in all pts, duration of response (DOR), 12-month DOR rate in pts with CR and safety and tolerability. Recruitment began in November 2018 and will continue until ~550 pts are enrolled. Clinical trial information: NCT03711032.
Real-world study of cetuximab used every other week versus weekly in US patients with metastatic colorectal cancer (mCRC).
Authors: Francois-Xavier Lamy, Michael Batech, Shaista Salim, Emmanuelle Boutmy, Chris Pescott, Philippe Ronga
Journal: Journal of Clinical Oncology (2019)

e15087 Background: After an initial dose of 400 mg/m², cetuximab (CET) at a dose of 250 mg/m² in combination with chemotherapy (CT) is approved for once-weekly (q1w) use in the treatment of RAS wild-type metastatic colorectal cancer (mCRC). However, off-label use of CET 500 mg/m 2 administered every other week (q2w) has been observed in clinical practice. This study aimed to test the noninferiority of q2w vs q1w administration on overall survival (OS) using US claims data. Methods: Using IBM MarketScan, a large US insurance claims database, a cohort of patients with mCRC treated with CET + CT between 2010 and 2016 was identified and classified as q1w or q2w based on observed infusion patterns. The initial CET prescription was defined as the index date, and patient death was determined using a previously published algorithm. Confounding was accounted for using high-dimensional propensity scoring (hdPS) methodology with inverse probability of treatment weighting (IPTW). OS for both groups was compared using Cox proportional hazards regression. Confounders that remained imbalanced after hdPS with IPTW were added to the Cox model. The noninferiority of the q2w regimen was tested with a margin hazard ratio (HR) of 1.25 for q2w vs q1w. Results: 2,869 patients with mCRC exposed to CET were identified of which 1,865 (65.0%) and 1,004 (35.0%) were classified in the q1w and q2w groups, respectively. The mean age of patients was 60.1±11.7 years for q1w and 58.1±11.1 years for q2w. Most patients were male: 57.5% and 60.8% in q1w and q2w, respectively. Approximately 70% of patients in both groups had received prior treatment for mCRC. The most frequently used CT with CET was irinotecan based (64.5% in q1w and 76.5% in q2w). There were 1,628 deaths observed during follow-up (56.7%). After hdPS with IPTW adjustment, differences remained in associated CT (standardized difference &lt;0.25). Crude HR for OS was 1.05 (95% CI, 0.94-1.18), and adjusted HR for OS was 1.04 (95% CI, 0.93-1.17). The inferiority hypothesis was rejected at p&lt;0.001. Conclusions: In this large US claims database, when assessing OS, the q2w administration schedule was found to be noninferior to the q1w schedule in patients with mCRC.