tbuckley/cabot-search huggingface dataset:
Association of the addition of cetuximab to preoperative chemoradiotherapy (CRT) for locally advanced esophageal squamous cell carcinoma (SqCC) with rate of long term survival: Mature results of a prospective phase Ib/II trial.
Authors: Baruch Brenner, Ofer Purim, Noa Gordon, Tal Goshen Lago, Efraim Idelevich, Hanoch Kashtan, Nikolai Menasherov, Eyal Fenig, Aaron Sulkes, Yulia Kundel
Journal: Journal of Clinical Oncology (2017)

4057 Background: Current treatment results in locally advanced esophageal cancer (LAEC) are far from being satisfying. This prospective phase IB/II study evaluated the safety and efficacy of the addition of cetuximab to standard preoperative CRT in this disease. Methods: Patients (pts) with potentially resectable LAEC (T2-4N0-1M0, T1-4N1M0 or T1-4N0-1M1A) received an induction cycle of cisplatin 100 mg/m 2 , day 1, and 5-FU 1000 mg/m 2 /day as a continuous infusion (CI), days 1–5, followed 4 weeks later by 50.4 Gy radiotherapy given concurrently with 2 cycles of cisplatin 75 mg/m 2 and escalating doses of CI 5-FU, days 1–4 and 29-32. Pts received also 10 weekly infusions of cetuximab, 250 mg/m 2 , with a loading dose of 400 mg/m 2 , starting from the induction. The phase II part of the study started when the 5-FU dose during CRT was defined. Surgery was planned 6-8 weeks after CRT. Results: 64 pts were enrolled and 60 completed CRT. Median age was 65 years (range: 38-84 years) and 66% were males. The SqCC/adenocarcinoma ratio was 39%/61% (25/39). Pts had very advanced tumors: 95% T3-T4, 67% N1 and 19% M1A. The most common grade &gt; 3 toxicities were leucopenia (45% of pts) and neutropenia (41%). There were two cases (3%) of fatal toxicities (neutropenic sepsis and sudden death). Among the 55 operated pts, R0 resection was achieved in 51 (93%). There were 8 cases (14.5%) of postoperative mortality, due to infection (3 pts), esophageal leak (2), bleeding (2) and pulmonary insufficiency (1). Pathological down-staging was noted in 72% of pts and pathological complete response (pCR) in 33%. 5y-local control, progression-free survival (PFS) and overall survival (OS) rates for all pts were 94%, 40%, 39%, respectively. Pts with SqCC had a significantly higher pCR rate (52% vs 15%, p = 0.007), 5y-PFS (67% vs. 21%, p = 0.008) and 5y-OS (64% vs. 20%, p = 0.019). Conclusions: This study suggests that the addition of cetuximab to standard preoperative CRT is safe. R0, pCR, local control and long term PFS and OS rates in pts with SqCC tumors are encouraging. Further evaluation of this approach in this population seems warranted.
Trastuzumab Emtansine (T-DM1) in Patients with Previously Treated HER2-Overexpressing Metastatic Non–Small Cell Lung Cancer: Efficacy, Safety, and Biomarkers
Authors: Solange Peters, Rolf Stahel, Lukas Bubendorf, Philip Bonomi, Augusto Villegas, Dariusz M. Kowalski, Christina S. Baik, Dolores Isla, Javier De Castro Carpeno, Pilar Garrido, Achim Rittmeyer, Marcello Tiseo, Christoph Meyenberg, Sanne de Haas, Lisa H. Lam, Michael W. Lu, Thomas E. Stinchcombe
Journal: Clinical Cancer Research (2018)

Abstract Purpose: HER2-targeted therapy is not standard of care for HER2-positive non–small cell lung cancer (NSCLC). This phase II study investigated efficacy and safety of the HER2-targeted antibody–drug conjugate trastuzumab emtansine (T-DM1) in patients with previously treated advanced HER2-overexpressing NSCLC. Patients and Methods: Eligible patients had HER2-overexpressing NSCLC (centrally tested IHC) and received previous platinum-based chemotherapy and targeted therapy in the case of EGFR mutation or ALK gene rearrangement. Patients were divided into cohorts based on HER2 IHC (2+, 3+). All patients received T-DM1 3.6 mg/kg intravenously every 3 weeks until disease progression or unacceptable toxicity. The primary endpoint was investigator-determined overall response rate (ORR) using RECIST v1.1. Results: Forty-nine patients received T-DM1 (29 IHC 2+, 20 IHC 3+). No treatment responses were observed in the IHC 2+ cohort. Four partial responses were observed in the IHC 3+ cohort (ORR, 20%; 95% confidence interval, 5.7%–43.7%). Clinical benefit rates were 7% and 30% in the IHC 2+ and 3+ cohorts, respectively. Response duration for the responders was 2.9, 7.3, 8.3, and 10.8 months. Median progression-free survival and overall survival were similar between cohorts. Three of 4 responders had HER2 gene amplification. No new safety signals were observed. Conclusions: T-DM1 showed a signal of activity in patients with HER2-overexpressing (IHC 3+) advanced NSCLC. Additional investigation into HER2 pathway alterations is needed to refine the target population for T-DM1 in NSCLC; however, HER2 IHC as a single parameter was an insufficient predictive biomarker.
Performance of Biocept's sample collection for tumor cell analysis.
Authors: Veena M. Singh, Edgar V. Sales, Lan Huynh, Cecile Rose T. Vibat, Anna E Barón, William Feser, Heather Malinowski, Daniel Merrick, Adrie van Bokhoven, Stephen Malkoski, York E Miller, Holly J Wolf, Marileila Varella-Garcia
Journal: Journal of Clinical Oncology (2017)

e23036 Background: Liquid biopsy is a minimally invasive and cost effective way to assess cancer biomarkers without the risk of surgical biopsy complications. Circulating tumor cell (CTC) analysis from body fluids can provide critical information towards early detection, prognosis and treatment decisions. Accurate CTC evaluations require optimal cell preservation. Cell lysis, DNA degradation, or membrane alterations compromise CTC analyses and accurate diagnoses. This work compares Biocept’s proprietary CEE-Sure BCT and Saccomanno's Cytology Fixative largely used for sputum collection. Methods: One million BT474 (HER2 amplified) or H3112 (ALK re-arranged) cells were spiked into 500 µl medium; 500 µl of CEE-Sure or Saccomanno fixative was added. Tubes were stored at 4°C for 1 day, 1 week, or 1 month. Cells were centrifuged, resuspended, and counted (Celigo). Around 150 cells in 15 µl of RPMI medium were flowed into Biocept's microfludic system for cell capture; recovery (%) was calculated. Captured cells were subjected to fluorescent in situ hybridization (FISH) analyses for qualitative signal evaluation. Results: As similar results were observed for both cell lines and all time points, combined data will be shown. Median cell recovery after CEE-Sure incubation was 14.1% (range 1.7–44%, n = 12) vs 5.4% (range 0.07–26.9%, n = 12) in Saccomanno's fixative. Median cell capture of ~150 cells fed into Biocept’s microchannel was 96% (range 72-98%) for CEE-Sure vs 82% (range 21-96%) for Saccomanno. Paired t-tests showed significant differences for both recovery and capture. FISH signals from CEE-Sure samples were qualitatively rated Fair to Good, while Saccomanno samples had Poor to Fair, grainy, non-specific signals. Conclusions: This preliminary work shows consistently higher cell recovery, better cell membrane maintenance, and higher quality FISH signals for samples stored in Biocept's CEE-Sure vs Saccomano’s fixative. With liquid biopsy testing gaining rapid traction, maximal cell stability during the transport and storage are crucial. Additional fixative comparison is ongoing in various patient specimen types. These results support expansion of molecular analyses in sputum samples enriched for lung epithelial cells.
P53 functional mutation type in high-grade serous ovarian cancer and clinical outcomes.
Authors: Victoria Mandilaras, Swati Garg, Julia Burnier, Katherine Karakasis, Lisa Wang, Helen Mackay, Neesha C. Dhani, Marcus O. Butler, Victor Rodriguez-Freixinos, Michelle K. Wilson, Cristina Martin-Lorente, Josee-Lyne Ethier, Philippe L. Bedard, Lillian L. Siu, Blaise Clarke, Patricia Ann Shaw, Tracy Stockley, Amit M. Oza, Stephanie Lheureux
Journal: Journal of Clinical Oncology (2016)

5550 Background: Somatic p53 mutations (TP53m) have been reported in most high grade serous ovarian cancers (HGSOC). We aim to investigate the impact of the type of functional TP53m on prognosis and determine if p53 immunohistochemistry (IHC) can be used as a surrogate for mutations. Methods: HGSOC patients (pts) enrolled in an institutional molecular screening program (NCT01505400) were evaluated. Functional mutations of TP53 were classified as gain of function (GOF), loss of function (LOF), loss of function dominant-negative (LOF-DN) and variants of unknown significance (VUS), as adapted from IARC TP53 database. A Cox proportional hazard model was used to see if the type of TP53m impacted overall survival (OS) and linear regression analysis for the correlation between first platinum free interval (PFI) and TP53m. IHC was performed for p53 using the D07 antibody. The functional type of TP53m was correlated with IHC (as reported in patient chart) germline BRCA1/2 (gBRCAm) mutation and the use of neoadjuvant chemotherapy using Fisher’s exact test. Illumina MiSeq next-generation sequencing (NGS) was used to detect TP53m. However, certain TP53 missense mutations or large deletions may not be detected with this technology. Results: 240 pts were available for analysis of TP53 by NGS. 183 (76%) were found to have a TP53m. Of these, the pts characteristics were: median age of 57 years, 170 pts (93%) with stage III/IV, 41 pts (22%) gBRCAm, median number of lines of chemotherapy 3 (1-8), and 93 pts (50%) had neoadjuvant chemotherapy. The distribution of TP53m by functional classification was 50 GOF (27%), 51 LOF (28%), 28 LOF-DN (15%) and 53 VUS (29%). OS was available for 132 (72%) pts and PFI for all. The type of functional mutation was not related to OS (p = 0.24) or PFI (p = 0.70). 90 (49%) pts had IHC done for TP53m. Overexpression on IHC (n = 69) was significantly correlated with GOF, LOF and LOF-DN and VUS were significantly correlated with null phenotype (n = 21) (p < 0.001). There was no correlation between TP53m function and gBRCAstatus (p = 0.93) or with prior chemotherapy use (0.62). Conclusions: The functionality of TP53m is not correlated to outcome in our cohort. Pts with null phenotype on IHC tend to have TP53m VUS which needs further characterization. .
A phase 1 open-label, safety, pharmacokinetic, and preliminary efficacy study of STRO-001, an anti-CD74 antibody drug conjugate, in patients with advanced B-cell malignancies.
Authors: Amrita Y. Krishnan, Nina Shah, Alexander I. Spira, Jonathan L. Kaufman, Ruben Niesvizky, Nirav Niranjan Shah, John M. Burke, Leslie Popplewell, Thomas G. Martin, Julee Cheung, Shannon L. Matheny, John Paul Leonard, Arturo Molina
Journal: Journal of Clinical Oncology (2018)

TPS7586 Background: Sutro’s cell-free antibody production system was used to make STRO-001, a novel CD74 targeting antibody drug conjugate. CD74 is expressed on B cells throughout differentiation, and is an attractive target for treatment of B cell malignancies. STRO-001 demonstrates potent cytotoxicity in non-Hodgkin lymphoma (NHL) and multiple myeloma (MM) cell lines and anti-tumor activity in xenograft models. Toxicology studies demonstrate dose-dependent B-cell depletion and reversible hematologic toxicity when STRO-001 is administered at up to 10 mg/kg. Methods: This study is a first-in-human Phase 1, open-label, multicenter, dose escalation (Part 1) study with dose expansion (Part 2) to identify the maximum tolerated dose (MTD), recommended phase 2 doses (RP2D) and to evaluate the safety, tolerability, and preliminary anti-tumor activity of STRO-001 in adults with B-cell malignancies (MM and NHL) who are refractory to, or intolerant of, all therapy known to provide clinical benefit. STRO-001 is given to all patients on study via intravenous infusion on Day 1 and Day 15 of each cycle until disease progression. Dose limiting toxicities will be assessed in the first cycle (Days 1-28) of dose escalation. In Part 1, 2 cohorts (1 for MM and 1 for NHL) will enroll 30 patients each to determine the MTD and RP2D for expansion while Part 2 will enroll 4 cohorts based on disease subtypes (MM, diffuse large B cell, mantle cell and follicular lymphomas). Efficacy will be evaluated per MM-specific or NHL-specific criteria. Key inclusion criteria include relapsed or relapsed/refractory disease, adequate bone marrow and renal function, and ability to comply with treatment, testing and pharmacokinetic (PK) schedules. NHL patients must have at least one measurable lesion. Key exclusion criteria include leukemic manifestations of lymphoma, need for ongoing anti-coagulants or immunotherapy including systemic corticosteroids and a history of CNS involvement. Samples will be collected to assess the PK and immunogenicity. No formal statistical hypothesis testing will be conducted in this study. This study is currently open for enrollment in the US. Clinical trial information: NCT03424603.
TWISTT analysis of open labeled multicentric study of BIOMAb- EGFR [Nimotuzumab] in head and neck cancers with chemotherapy and/or radiotherapy.
Authors: Dilip Pawar, Suresh VS Attili, Chinnababu Sunkavalli
Journal: Journal of Clinical Oncology (2017)

e17505 Background: Head and neck Squamous Cell Cancer (HNSCC) have poor prognosis in recurrent and metastatic setting with limited treatment options. The treatment decision are predominantly driven by quality of life (QOL) issues, pharmaco-economics besides the survival and response rates. Present TWISTT analysis was based on the earlier “open labeled multicentric study of Nimotuzumab in head and neck cancers with chemotherapy and/or radiotherapy”, to evaluate the QOL outcomes Methods: The active part study was conducted between Nov 2007 and Jan 2009 followed by long term follow up. Patients received Nimotuzumab w at 200 mg/m2 / week along with RT or chemotherapy Results: A total of 150 patients received therapy, who met the eligibility criteria [ Ref-CTRI/2007/95] Overall adverse event rate is 24% [ 36 subjects who experienced any AE]. Mucosal inflammation [ related to RT] was most frequent AE and three were only 4 [2.7%] serious adverse events [ all of them not related to IP]. Skin rash was not apredictor for the response to BIOMAB and was observed in 1.3%. The median TWISTT score in responding patients was 246 days vs 128 days for non responders. PFS and OS were not presented as the main focus of the study is to report the QOL and TWISTT score. Conclusions: Based on the results of this analysis, Nimotuzumab in combination with chemo +/- radiotherapy appears as an attractive regimen for patients with metastatic HNSCC. Clinical trial information: CTRI/2007/95.
Oncologists’ perceptions of affordability in the NCCN evidence block value frameworks.
Authors: William Bruce Wong, Arliene Ravelo, Marco DiBonaventura, Bijal Shah-Manek
Journal: Journal of Clinical Oncology (2017)

6511 Background: The increasing prevalence of cancer coupled with approvals of new drugs and technologies used in therapy have brought increased scrutiny to the cost and value of treatments in oncology. To address the rising concern about oncology drug costs, NCCN has developed the Evidence Blocks (EB) framework to help assess the value of oncology regimens. The objective of this study was to assess and understand oncologist’s perceptions of affordability in the context of the NCCN EB framework. Methods: Data were collected from an electronic cross-sectional survey of 200 US-based oncologists recruited from an online panel. Using the NCCN EB framework, oncologists were asked to rate a variety of hypothetical cancer therapies and assign costs (in US dollars) to the five levels of affordability. Additional questions assessing perceived patient out-of-pocket costs and comfort level in assessing affordability were also included in the survey. Results: Oncologists’ ratings for an existing cancer immunotherapy were generally similar across the EBs (ratings of 4), however oncologists rated affordability higher (3: Moderately Expensive) vs. the actual NCCN panel affordability rating (1: Very Expensive). The affordability rating was similar across a variety of hypothetical cancer therapies and tumor types (rating of 3). Oncologists estimated the costs for this rating of 3 to range from $4600-$6000 per month, which was inconsistent with actual drug costs. Oncologists estimated the mean monthly out-of-pocket costs for patients with insurance to range from $1260 for a new oral medication to $1700 for a new infused medication. Only 26% of oncologists were comfortable or very comfortable with rating costs associated with affordability levels. Conclusions: Surveyed oncologists rated cancer therapies as more affordable than NCCN panel ratings. Costs associated with affordability were not consistent with actual treatment costs; however, most oncologists were not comfortable with rating affordability.
Evaluation of chemotherapy tolerability for breast cancer patients who have received radiation as treatment for a prior Hodgkin lymphoma.
Authors: Allison Paige Watson, Bruce A. Peterson, Chung Kyu Kim Lee, Kathryn Baxstrom, Rachel Isaksson Vogel, Anne Hudson Blaes
Journal: Journal of Clinical Oncology (2016)

e21572 Background: Survivors of Hodgkin lymphoma (HL) treated with radiotherapy have a significantly increased risk of developing breast cancer (BC). With optimization of screening technology and guidelines for earlier BC screening in these patients, more survivors of HL will be diagnosed with BC. Currently, there are no studies of BC treatment practices in these individuals and there is limited data regarding complications and outcomes of BC treatment in these women. Methods: The goal of this observational study was to explore BC treatment modalities and outcomes in these patients. We retrospectively reviewed BC patients who survived HL with prior chest irradiation, treated at the University of Minnesota between 1969 and 2013. Patient demographics, breast tumor characteristics and tolerability of the chemotherapy were evaluated. Tolerability was defined as receiving all intended cycles with no dose reductions. Results: A total of 42 patients with BC and a history of radiation for HL were selected. We had data to support conclusions about chemotherapy tolerance on 14 patients who received chemotherapy as treatment for BC. Median ages at HL and BC diagnoses were 24 and 48 years, respectively. Most were stage I or II BC, and the majority were invasive ductal carcinomas. Four patients received anthracycline-based chemotherapy, 8 received taxane-based chemotherapy, and 2 received other types of chemotherapy. No patients received a combination of anthracycline and taxane chemotherapy. Of this cohort, 75% of patients tolerated both anthracycline- and taxane-based chemotherapy regimens, while 100% receiving chemotherapy without anthracyline or taxanes tolerated the regimen. Given small numbers, we were unable to conclude whether prior alkylating chemotherapy influenced chemotherapy tolerability. Conclusions: The majority of patients diagnosed with BC after radiation for prior HL tolerate chemotherapy for BC. Reasons for not tolerating chemotherapy in this subset of patients are similar to those without a history of HL or prior radiation. Further research on the impact of prior alkylating chemotherapy and tolerance of chemotherapy should be pursued in a larger patient cohort.
Author Correction: Regional variation limits applications of healthy gut microbiome reference ranges and disease models
Authors: Yan He, Wei Wu, Hui-Min Zheng, Pan Li, Daniel McDonald, Hua-Fang Sheng, Mu-Xuan Chen, Zi-Hui Chen, Gui-Yuan Ji, Zhong-Dai-Xi Zheng, Prabhakar Mujagond, Xiao-Jiao Chen, Zu-Hua Rong, Peng Chen, Li-Yi Lyu, Xian Wang, Chong-Bin Wu, Nan Yu, Yan-Jun Xu, Jia Yin, Jeroen Raes, Rob Knight, Wen-Jun Ma, Hong-Wei Zhou
Journal: Nature Medicine (2018)
Risk assessment based on the Risk Index for Serious Adverse Events (SAEs) in phase I trials.
Authors: Shigehiro Koganemaru, Yasutoshi Kuboki, Kohei Shitara, Shogo Nomura, Kenichi Harano, Hideaki Takahashi, Takahiro Kogawa, Yoichi Naito, Takahiro Sakai, Yukie Kimura, Kiyotaka Yoh, Toshihiko Doi
Journal: Journal of Clinical Oncology (2017)

e14032 Background: Although patients (pts) in phase I trials may have expectations about their chance to benefit, they sometimes experience serious adverse events (SAEs). These events impact on their quality of life negatively as well as their clinical management and survival, if once occurred, regardless of timing of occurrence or relation to study drugs. Therefore, paying close attention for pts who are more likely to experience SAEs may be required; however, little is known about which clinical features are related to SAEs in phase I trials. The aim of this study is to construct a risk index for SAEs prediction. Methods: We collected medical records of 418 pts with solid tumor who participated in phase I trials for the first time and were treated at our hospital from January 2011 to December 2015. The time to first SAE (TTS), defined as the time from registration to first SAE, was analyzed. Stepwise Cox regression model was applied to screen out the factors to build a risk index. Internal validation was performed using a bootstrap procedure. Results: Four hundred and seven pts were analyzed for building a risk index. Median age was 63 years (range 22-81). Predominant primary tumor site was gastrointestinal cancer (65.1%), followed by lung cancer (8.4%) and genitourinary cancer (5.7%). A total of 251 pts (61.7%) were treated with small molecule compounds, while 136 pts (33.4%) were treated with antibody therapy including immune therapy. A total of 101 pts (24.8%) experienced SAEs included 18 events related to study drugs. Four independent risk factors (use of antibody therapy, 60 &lt; age &lt; 70, higher serum albumin concentration and lower serum alkaline phosphatase concentration), identified by stepwise Cox regression model, were combined into simple ternary risk index that stratified pts into low- (n = 93), intermediate- (n = 175) and high-risk group (n = 139). Hazard ratios for high-risk and intermediate-risk relative to low-risk group and their 95% confidence intervals were 5.25 (2.64-10.42; high-risk) and 2.00 (0.99-4.07; intermediate-risk). Conclusions: Risk assessment based on the risk index for SAEs may be useful for patient management in phase I trials. Further research is needed to validate this risk index.
Randomized study of conventional versus hypo-fractionated radiotherapy in diffuse intrinsic pontine glioma.
Authors: Yousra Izzuddeen, Subhash Gupta, KP Haresh, Prashanth Giridhar, Lakhan Kashyap, Goura Kisor Rath
Journal: Journal of Clinical Oncology (2018)

e14075 Background: Diffuse intrinsic pontine glioma is a poor prognostic disease with median survival < 1 year with conventional radiation. We attempted to improve outcomes with hypofractionated radiotherapy and concurrent Temozolomide followed by adjuvant Temozolomide. The study is on-going and we are presenting the interim results. Methods: This is a phase II randomized study. The patients were randomized to receive either conventional fractionated radiotherapy 60Gy/30# over 6 weeks or hypofractioanted radiotherapy 39 Gy/13 # over 2.6 weeks with concurrent Temozolomide 75 mg/m2daily throughout the course of radiation. The hypofractionated arm also received six cycles adjuvant Temozolomide 200 mg/m2given three weekly. Prophylactic co-trimoxazole was not given to patients. The response rates, survival and toxicity were assessed at six weeks and six months and are presented. Results: 28 patients were randomized. The median follow up of the entire cohort is 184 days (Range 25 days – 488 days). All patients except 2 (one in each arm) had radiologically stable disease at six weeks. 2 patients had partial response as per RANO criteria. The median follow up of conventional arm is 204 days while for experimental arm is 176 days. The median survival for conventional treatment is 315 days (95 % CI: 206 - 423 days) and experimental arm is 488 days (95 %CI: Not defined) with a p value on log rank test 0.401. Two patients in the experimental arm developed Grade 4 hematological toxicity (CTCAE v4.1) of neutropenia and thrombocytopenia. Conclusions: Temozolomide and hypofractionated radiotherapy may improve outcomes in pontine glioma with tolerable side effects. Longer follow up with bigger study dataset is necessary for conclusion Clinical trial information: REF/2017/12/016526.