tbuckley/cabot-search huggingface dataset:
A phase II study of ipilimumab and nivolumab with radiation in microsatellite stable (MSS) metastatic colorectal adenocarcinoma (mCRC).
Authors: Aparna Raj Parikh, Jeffrey William Clark, Jennifer Yon-Li Wo, Beow Y Yeap, Jill N. Allen, Lawrence Scott Blaszkowsky, David P. Ryan, Bruce J. Giantonio, Colin D. Weekes, Andrew X. Zhu, Emily E. Van Seventer, Lauren Matlack, Bronwen Foreman, Leilana Ly, Lorraine C. Drapek, David Tsai Ting, Ryan Bruce Corcoran, Theodore S. Hong
Journal: Journal of Clinical Oncology (2019)

3514 Background: mCRC remains a lethal cancer and immunotherapy in MSS mCRC has yet to show significant activity. In preclinical models, radiation induced cellular damage may increase responsiveness to immunotherapy via the abscopal effect, with evidence for synergy between radiation therapy (RT) and dual checkpoint blockade. In this study, we assessed dual blockade of CTLA-4 and PD-1 combined with RT as a strategy to stimulate an immune response for patients with MSS mCRC. Methods: In this open-label, single arm phase-2 study, we enrolled 40 MSS mCRC patients (pts). Eligible pts had histologically-confirmed MSS mCRC, ECOG PS 0-1, and progression on at least two lines of therapy. Treatment (Tx) consisted of ipilimumab (1mg/kg q6 weeks), nivolumab (240 mg q2 weeks) and 3 fractions of 8 Gy of RT at cycle 2 every other day. Tx continued until progression, discontinuation or withdrawal. The primary endpoint was Disease Control Rate (DCR), with radiological evaluations every 3 months. Exploratory endpoints included ORR, PFS, OS and safety. Response was defined as disease control outside the radiation field. We obtained serial tumor biopsies pre-tx, during checkpoint blockade alone (cycle 1) and 2 weeks after initiation of radiation. Intention-to-treat analysis (ITT) includes all pts receiving at least one dose of study agent. Results: 40 pts (median age 59 years (26-83), 58% male) enrolled and started treatment from 7/2017 to 12/2018. DCR was 17.5% (7/40) with a 7.5% (3/40) ORR by ITT. Median duration of disease control was 77 days in the ITT; 252 days for those with disease control (n=7) based on the first re-staging scans at 3 months or censored (n=3) and 70.5 days for pts with PD (n=17) or who did not receive RT due to clinical progression (n=13). In the modified ITT (all pts receiving RT and restaged), N=24 pts, excluding 1 pt pending 1 st scans post-RT, DCR was 29.2% (7/24) and ORR 12.5% (3/24). Median duration of disease control in mITT was 77.5 days: 252 days for those with disease control and 77 days for those with PD. TRAEs were reported in 22/40 (55%). 20/40 (50%) with grade ≥3 toxicities, with fatigue, nausea, vomiting, diarrhea, infusion-related reaction and dyspnea being the most common. 1(2%) pt died of respiratory failure possibly related to tx. Conclusions: Dual blockade of CTLA-4 and PD-1 with RT is feasible and demonstrates durable activity in pts with MSS mCRC. There are 3 pts who have not completed RT or had their post-RT re-staging. We will report updated efficacy data and outcomes from correlative serial tumor biopsies upon trial completion. Clinical trial information: NCT03104439.
MET second-site mutations in EGFR-mutant, MET-amplified non-small cell lung cancer after resistance to combinatorial targeted therapy.
Authors: Jia-Tao Cheng, Jinji Yang, Yilong Wu
Journal: Journal of Clinical Oncology (2019)

e20730 Background: MET second-site mutations were previously reported in a few cases of MET-amplified or exon 14-mutant advanced non-small-cell lung cancer (NSCLC) treated with MET inhibitors. However, both the frequency of MET second-site mutations and clinical outcome of patients with such genetic alterations have not been investigated, particularly in EGFR-mutant, MET-amplified advanced NSCLC treated with combinatorial targeted therapy. Methods: Retrospectively, from November 2016 to January 2019, 22 patients with EGFR-mutant, MET-amplified advanced NSCLC had sufficient tumor samples after resistance to a combinatorial therapy with both EGFR and MET inhibitors. All tissue samples were detected using Next-generation sequencing (NGS). The progression-free survival (PFS) was calculated the start of subsequent treatment to progressive disease or death from any cause. The overall survival (OS) was calculated from the start of subsequent treatment to death from any cause. Last follow-up was on January 31, 2019. Results: Five kinds of MET second-site mutations were found in 7 patients: D1246N D1228N, D1228H, D1231Y and Y1230H. The frequency of MET second-site mutations was 31.8% (7/22). The median PFS and OS were 3.7 (95%CI: 1.13-6.3) months and 6.9 (95%CI: 0.2-13.7) months respectively. The ORR of EGFR TKIs plus cabozantinib for suchsecond-site mutaant patients was 50% (2/4). However, the ORR of other treatments was 0% (0/3), Two of them received single agent cabozantinib, and PFS was 0.7 and 1.7 months respectively. One had a PFS of 2.5 months with pemetrexed/carboplatin plus bevacizumab. Conclusions: MET second-site mutation might be one of the commonly-seen molecular mechanisms of acquired resistance to combinatorial targeted therapy in EGFR-mutant, MET-amplified advanced NSCLC. Patients with such mutations could respond to cabozantinib plus EGFR TKI. Further more investigations are warranted to improve the efficacy.
Cardiac safety of the trastuzumab biosimilar ABP 980 in women with HER2-positive early breast cancer in the LILAC study.
Authors: Hans-Christian Kolberg, Marco Colleoni, Georgia Demetriou, Patricia Xavier Santi, Hans Tesch, Yasuhiro Fujiwara, Zorica Tomasevic, Vladimir Hanes
Journal: Journal of Clinical Oncology (2019)

557 Background: Although trastuzumab is generally well-tolerated, cardiotoxicity is the main limitation in its use, leading to a severe heart failure in 2-4% of patients in adjuvant trials. In the phase 3 LILAC trial, trastuzumab biosimilar ABP 980 demonstrated similar efficacy, safety, and immunogenicity to trastuzumab reference product (RP) in women with HER2-positive early breast cancer. Here we report analyses comparing cardiac safety of ABP 980 and RP. Methods: In the neoadjuvant phase, all 725 patients received 4 cycles of chemotherapy with epirubicin + cyclophosphamide Q3W and were then randomized 1:1 to ABP 980 (n = 364) or RP (n = 361) with a loading dose of 8 mg/kg, then 6 mg/kg IV Q3W for 3 cycles plus paclitaxel Q3W (4 cycles) or QW (12 cycles). After surgery, patients received investigational product (IP) Q3W for up to 1 year; ABP 980-treated patients continued ABP 980, and RP-treated patients either continued RP (n = 190) or switched to ABP 980 (RP/ABP 980; n = 171). AEs were assessed every 3 weeks and cardiac safety every 3 months. Cardiac safety was monitored by computerized 12-lead ECG; LVEF was assessed by 2D ECHO. LVEF decline was defined as LVEF value decrease from study baseline by ≥10 percentage points and to &lt; 50%. Results: Treatment groups were well balanced with regard to IP disposition. Over the entire study, 22 (3.1%) patients had LVEF decline by ≥10 percentage points compared to baseline and to &lt; 50%; no meaningful between-group differences were observed (ABP 980:10/359 [2.8%], RP: 6/184 [3.3%], RP/ABP 980: 6/171 [3.5%]). The incidence of cardiac AEs was low and comparable in treatment groups. One grade 3 cardiac failure event was reported in the RP/ABP 980 arm; another in the RP arm was coincident with LVEF decline. No patient discontinued IP during adjuvant phase because of cardiac failure. Conclusions: These pre-specified analyses confirm the tolerability of ABP 980 and demonstrate clinical similarity of ABP 980 and RP with respect to cardiac safety. The incidence of LVEF decline was consistent with the known cardiac safety profile of the RP. No new cardiac safety signals were observed whether patients were on ABP 980 or switched from RP to ABP 980. Clinical trial information: NCT01901146.
Oncotype DX testing in early-stage node-positive breast cancer and impact on chemotherapy use at a comprehensive cancer center.
Authors: Katya Losk, Rachel A. Freedman, Elizabeth A. Mittendorf, Zhenying Tan-Wasielewski, Lorenzo Trippa, Tari A. King
Journal: Journal of Clinical Oncology (2019)

549 Background: The 21-gene Oncotype DX Recurrence Score (RS) is widely used to guide adjuvant chemotherapy decisions in hormone receptor positive (HR+), HER2-negtive (HER2-), lymph node negative (LN-) breast cancer. It’s adoption in lymph node positive (LN+) disease remains controversial. In 2016, we implemented ‘reflex’ RS testing for patients ≤65 years with HR+/HER2- breast cancer including T1/T2 N1 (grade 1 or 2) tumors. Providers can also order Oncotype DX outside of reflex criteria. We sought to assess RS distribution and factors associated with chemotherapy use in HR+/HER2-/LN+ breast cancer patients at our center. Methods: Patients with non-metastatic HR+/HER2-/LN+ breast cancer who underwent primary surgery at our center were identified from our prospective database. We examined the distribution of low (RS &lt; 18), intermediate (RS 18-30) and high (RS &gt; 30) RS and identified characteristics for those who did not meet reflex criteria. A multinomial logistic regression model was performed to identify factors associated with chemotherapy receipt among all LN+ patients. Results: From 1/2016-3/2018, we identified 296 consecutive patients with HR+/HER2-/LN+ breast cancer. 200 (68%) patients had RS testing and 128 (64%) met reflex criteria. Reasons for not meeting RS reflex criteria included age &gt; 65 (n = 35), grade III disease (n = 35) and N2/N3 tumors (n = 10). Among the 200 patients with RS, 122 (61%) had RS &lt; 18, 67 (34%) had RS 18-30, and 11 (6%) had RS &gt; 30. Only 68/200 (34%) patients with RS received chemotherapy as compared to 54/96 (56%) patients without RS (p = 0.0004). Compared to patients without RS testing, the odds of receiving chemotherapy were less with RS &lt; 18 (OR = 0.46). The odds of receiving chemotherapy were greater with ≥3 positive LNs versus 1 positive LN (OR = 3.40). Conclusions: The majority of HR+/HER2-/LN+ patients undergoing upfront surgery at our center receive RS testing (200/296), with 122 (61%) resulting in low risk RS. Patients with low risk scores (RS &lt; 18) were less likely to receive chemotherapy. While nodal involvement remains a common driver of chemotherapy use, our study demonstrates that RS testing provides clinically useful information in this population.
A new option in brain-metastases: Hippocampal-sparing whole-brain radiotherapy with simultaneous integrated boost VMAT-IGRT.
Authors: Alicia Marin, Margarita Martin, Emma Gonzalez, Lisselott Torres, David Hernandez, Margarita Casado, Miguel Montijano, Mario Lopez, Pablo Castro, Laura Cerezo, Leopoldo Perez, Maria Teresa Murillo
Journal: Journal of Clinical Oncology (2019)

e13589 Background: We report our experience with volumetric modulated arc therapy (VMAT-IGRT) use to plan and deliver whole brain radiotherapy whit a simultaneous integrated boost in patients with brain metastases, using hippocampal sparing. Methods: In this retrospective study 57 patients with brain metastases were treated with radiotherapy VMAT-IGRT were administered in 12 daily fractions of 2.7Gy for a total of 32.4Gy (EBD 40Gy) to whole-brain and simultaneous integrated boost to brain metastases, multiple targets, in 12 fractions to 3.4Gy for a total dose of 40.8Gy (EBD 60Gy). The primary endpoint was intracranial progression-free survival (PFS) and secondary endpoints were preserves neurocognitive function and overall survival (OS). Survival rates were determined by Kaplan-Meier method. Differences between survival curves were analyzed by the log-rank test. Results: From January 2015 to December 2018, 57 patients were enrolled. The median follow-up time was 7 months. PFS6, PFS12 and PFS18 were 91.3%, 70.8% and 70.8% respectively. mOS, OS6, OS12 and OS18 were 10 months (95% IC 4.2-15.7 months), 67.2%, 48.6% and 35.3% respectively. Response rates were as follows: 29RC (50.9%), 21RP (36.8%), 7SD (12.3%) and 0PD (0%). Long progression-free survival patients: PFS &gt; 12, 15 and 18 months for initial diagnosis 70%, 70% and 70% respectively. Conclusions: Whole-brain radiotherapy with simultaneous integrated boost to brain-metastases: VMAT-IGRT is safe and promising and possibly produces survival and tolerance benefits. Sparing the hippocampus during cranial irradiation poses important technical challenges with respect to contouring and treatment planning.
Circulating endothelial cells: Prognostic value in patients with glioblastoma.
Authors: María Ángeles Vaz Salgado, Julie Earl, Victor Rodriguez Berrocal, Freddy Salge, Ana Gomez, Elena Corral de la Fuente, Juan Manuel Manuel Sepulveda Sanchez, Angel Perez-Núñez, Alfonso Muriel, Daniel Lourido, Alfredo Carrato, Luis Ley
Journal: Journal of Clinical Oncology (2019)

e13517 Background: Glioblastoma (GB) is an aggressive tumor. Circulating Endothelial Cells (CECs) can be detected in peripheral blood and have been related to angiogenesis. CECs have an unclear prognostic value in patients with glioblastoma. The objective of this study was to quantify the presence and number of CECs in GB patients and determine its potential prognostic role. Methods: In this prospective, single center study, peripheral blood samples were obtained at the time of GB diagnosis. For the detection of CECs, 4 ml of blood was analyzed using the CellSearch system (Veridex). CEC blood samples were classified as CD146+, CD105+, CD45− and DAPI+. CEC detection was performed prior to surgery in a total of 26 patients and 22 patients with glioblastoma were included in the final analysis. We mesured progression free survival (PFS) and overall survival (OS). Results: Between 2014 and 2016, twenty two patients with histologically confirmed glioblastoma were studied. There were 14 males and 8 females with an average age of 63 years (range 42-81). A complete resection was achieved in 50% of cases, partial or subtotal resection in 31.8% and biopsy in 18%. The mean number of CECs was 59.3 cells/mL (range 0-954). Patients were classified into two groups depending on the number of CECs: group 1 had a CEC count below the mean and group 2 had a CEC count above the mean. A total of 17 patients (77.2%) were in group 1 and 5 patients (22.7%) were in group 2.The median OS was 14.4 months (range -0.36-33.36) for the entire study population. The median OS was 17.4 months (IC95% 11.47-23.37) for patients in group 1 and 8.12 months for patients in group 2 (IC 95% 4.38-11.85) p = 0.002. The median PFS was 8.94 m (IC95% 5.1-12.69) for group 1 and 3.95 for group 2 (IC 95% 2.91-4.98) p = 0.097. Conclusions: CECs can be detected in recently diagnosed GB patients. The present study demonstrates a possible prognostic value for CEC determination in GB cases at the time of diagnosis.
Expression of CD44 and CD133 in tumor сells of metastatic and non-metastatic gastric cancer.
Authors: Aleksandr B. Sagakyants, Oleg I. Kit, Elena P. Ulianova, Elena Yu. Zlatnik, Inna A. Novikova, Oksana G. Shulgina, Yuriy A. Gevorkyan, Natalya V. Soldatkina, Nikolay S. Samoylenko, Liubov Yu Vladimirova
Journal: Journal of Clinical Oncology (2019)

e15531 Background: High incidence and mortality rates of gastric cancer cause a constant search for the most informative and effective methods of diagnosis and treatment assessment. In this regard, studying the expression of markers with the stem phenotype in primary tumor tissues in patients with gastric cancer with and without metastases is of undoubted interest. Methods: The study included 20 gastric cancer patients aged 30-80 years: group 1 – gastric cancer T3-4аN0-3M0 (G2) without metastasis (58.9±9.7 years); group 2 – gastric cancer T3-4аN0-3M1 (G2) with peritoneal metastasis (53.4±11.9 years). Immunohistochemical study was performed on paraffin-embedded tumor tissue sections using mouse monoclonal antibodies to CD44 (156-3С11 Thermo Scientific) at a 1:2500 dilution and rabbit polyclonal antibodies to CD133 (Cloud-Clone Corp.) at a 1:700 dilution; the Thermo Scientific autostainer was used for staining. Membrane staining and staining intensity were assessed: 0, 1+ weak, 2+ moderate, 3+ strong staining. Positive expression was defined as ≥10% cut-off for CD44 and ˃5% for CD133. Results: Positive expression of CD44+ was detected in 67% (13) in group 2 vs. 20% (4) in group 1. In the metastatic group, the number of cells that stained positive for CD44 expression ranged from 9 to 15%, on average 10.0±3.08%, without metastases – from single cells to 13%, on average 6.0±2.3%. A chi-square test showed statistically significant association in the groups (8.256 at p = 0.004). Positive CD133+ expression in tumor tissues was registered in 100% (20) in group 2 and 80% (16) in group 1. The range of positively stained cells in group 2 was from 10 to 40%, on average 21.3±11.6%, in group 1 - from single cells to 14%, on average 10.0±2.4%. A chi-square test showed statistically significant association in the groups (4.444 at p = 0.036). Conclusions: Immunohistochemical study of the selected tumor cell markers in gastric cancer revealed some characteristics of their expression depending on the presence of metastases. The results can be the basis for further research for the most complete characterization of a heterogeneous tumor population in gastric cancer and the role of individual cells in the tumor growth, progression and metastasis.
Survival of patients with cervical cancer and diabetes: An exploratory study.
Authors: Maria Luisa Romero, Jose Luis Gonzalez Vela, David Hernandez Barajas, Ascary Velazquez-Pacheco, Abrham Josafath Hernández, Irma Anaid Villarreal Ondarza, Roberto Alejandro Escobedo Rodriguez, Oscar Vidal-Gutiérrez
Journal: Journal of Clinical Oncology (2019)

e17008 Background: Mexico is the sixth country with the highest number of diabetics, this being the second cause of death. Between 8-18% of cancer patients have Diabetes (DM) as comorbidity. Studies have reported DM has worst prognosis in Overall Survival (OS) and Progression Free Survival (PFS) in patients with Cervical Cancer (CC). Aim: to compare OS in patients (pt) with a diagnosis of CC and DM, and to evaluate this outcome in relation to the clinical stage and the glycemic level at diagnosis of CC. Methods: data was obtained from pt treated for invasive CC between 2006 and 2016. Pt aged ≥20 years, with squamous, adenocarcinoma or adenosquamous histology. 59 pt with CC and DM in group 1 (G1), and 118 pt with CC without DM in group 2 (G2), paired 1:2 according to clinical stage, age and comorbidities. Results: Prevalence of DM in pt with CC was 16%. Follow-up of 142.2 months (median of 40.4 months), lower OS for G1 was seen (74.6% vs 77.1%), without statistical significance (p.803). PFS was similar for both groups (67.8% G1 vs 66.9% G2, p .608). In patients with locally advanced and metastatic disease, a lower OS and PFS were found in G1, without statistical significance. 42.4% diabetic pt had glycemic level &lt; 130 mg / dL). OS was lower in pt with higher glycemic level (70.6% vs 80%), not being statistically significant (p .32). PFS was similar in both groups (G1: 68% vs G2: 67.6%, p.852). Analysis for influence of metformin treatment, evidenced a higher OS among pt receiving metformin (84.8% vs 61.5%), without statistical significance (p 0.65). PFS was higher in the metformin group (78.8 vs 53.8%), with a trend towards statistical significance (p .052). Conclusions: Pt diagnosed with CC and DM do not have different OS compared to those without DM. There was a tendency towards the improvement of PFS in pt with CC and DM, who received metformin.
RNAseq and DNA whole-exome sequence analysis reveal novel response signatures to IO treatment in muscle invasive bladder cancer (MIBC) patients.
Authors: Gregory Mayhew, Yoichiro Shibata, Joshua M Uronis, Michele C Hayward, Tracy L Rose, William Y. Kim, Charles M. Perou, Myla Lai-Goldman, Michael Vance Milburn
Journal: Journal of Clinical Oncology (2019)

4558 Background: Objective: To examine in a cohort of anti-PD-(L)1 immune checkpoint inhibitors (ICP) treated urothelial cancer patients a strategy combining treatment outcomes with molecular alterations, pathways, and immune/tumor microenvironment features to determine potential responder and rapid-progression signatures. Methods: De-identified clinical history and treatment outcomes were collected on 109 MIBC patients treated with ICP agents. Archived FFPE samples from these patients were obtained and processed for mRNAseq, exome-seq, tumor mutation burden (TMB), microsatellite instability (MSI) and mutation panel testing. Comprehensive tumor/immune profiling is being analyzed in the context of ICP treatments and RECIST 1.1 outcomes. A 60 gene MIBC 4-typer expression subtyper and other response associated predictors are used to stratify and identify positive/negative ICP response indicators. Results: 109 patients were identified (median age 75, 64% male, 78% white, 17% black). 74% of patients had received prior platinum-based chemotherapy, and 12% had received 2 or more prior lines of therapy. At initiation of ICP, 28% of patients had hemoglobin &lt; 10, 30% had liver metastases, and 59% had ECOG performance status &gt; 0. Mutation analysis of the first 66 patients showed TP53 (n = 34, 52%), FGFR (n = 17, 26%), CDKN2A (n = 13, 20%) and RB1 (n = 12, 18%) as the top alterations. No patients (0/8) with known pathogenic mutations in FGFR3 (S249C and TACC3-fusion) responded to ICP. Of patients with T2 staging prior to ICP (37/66), overall survival was markedly shorter (2.7 years) in those possessing FGFR3 mutations (n = 6/37) compared to that for FGFR3 WT patients (5.7 years, n = 31/37; p = 0.045). Further analyses of molecular features relative to treatment outcomes are ongoing to characterize response signatures. Conclusions: Our preliminary cohort of patients with pathogenic FGFR3 alterations showed 0% favorable response to ICP. We are expanding on this observation with further comprehensive molecular analyses and retrospective treatments/outcomes data. We anticipate identifying expression signatures that reflect ICP patient responder/non-responder signatures that may aid in future therapy decisions.