tbuckley/cabot-search huggingface dataset:
Phase 1b study of H3B-6545 in combination with palbociclib in women with metastatic estrogen receptor–positive (ER+), human epidermal growth factor receptor 2 (HER2)-negative breast cancer.
Authors: Stephen R. D. Johnston, Timothy J. Pluard, Judy S. Wang, Erika P. Hamilton, Dejan Juric, Catherine Rose Scholz, Elizabeth Hnitecki, Lei Gao, Lisa Cantagallo, Manav Korpal, Benoit Destenaves, Jianjun Alan Xiao, Zhaojie Zhang, J. Marc Marc Pipas, Lihua Yu, Tarek Sahmoud, Antonio Gualberto
Journal: Journal of Clinical Oncology (2021)

e13025 Background: H3B-6545, a highly Selective ERα Covalent Antagonist (SERCA), inactivates both wild-type and mutant ERα by targeting cysteine 530 and enforcing a unique antagonist conformation. At the dose of 450 mg daily, H3B-6545 has a manageable safety profile and demonstrated preliminary single-agent antitumor activity in heavily pretreated ER+, HER2- mBC patients (Hamilton et al, San Antonio Breast Cancer Symposium, 2020). Methods: The study evaluates the safety, pharmacokinetics (PK), and efficacy of H3B-6545 in combination with palbociclib in patients with ER+, HER2- metastatic breast cancer (MBC). The escalation phase enrolls patients with 2 or more prior therapies in the metastatic setting. Up to one prior chemotherapy and up to one prior CDK4/6 inhibitor were allowed. Results: As of January 31, 2021, 10 patients were enrolled; 7 in Cohort 1 (H3B-6545 300 mg QD and palbociclib 100 mg QD) and 3 in Cohort 2 (H3B-6545 300 mg QD and palbociclib 125 mg QD). One patient in Cohort 1 was not evaluable for dose limiting toxicity (DLT) assessment and no DLT was observed in the 6 evaluable patients. One patient discontinued study treatment because of progression and no patients discontinued study treatment due to adverse events (AE). Grade 3 or 4 neutropenia and thrombocytopenia were observed in 4 patients and 1 patient, respectively. One patient had grade 3 hypercalcemia, generalized muscle weakness, hypophosphatemia, fall, and anemia and one patient had grade 3 lipase increase. Four patients had grade 1 bradycardia or sinus bradycardia (asymptomatic) 1 patient had grade 2 sinus bradycardia (symptomatic, no intervention required). Preliminary PK analysis suggested no clinically relevant drug-drug interactions between H3B-6545 and palbociclib, to be confirmed with data from additional cohorts. Recruitment is currently ongoing in Cohort 2. Updated results will be presented. Conclusions: H3B-6545, in combination with palbociclib, was well-tolerated. Clinical trial information: NCT04288089.
Repeat sequential oxaliplatin-based chemotherapy (FLOX) and nivolumab versus FLOX alone as first-line treatment of microsatellite-stable (MSS) metastatic colorectal cancer (mCRC): Initial results from the randomized METIMMOX study.
Authors: Anne Hansen Ree, Hanne Hamre, Christian Kersten, Eva Hofsli, Marianne Grønlie Guren, Halfdan Sorbye, Christin Johansen, Anne Negård, Kjersti Flatmark, Sebastian Meltzer
Journal: Journal of Clinical Oncology (2021)

3556 Background: Immune checkpoint blockade (ICB) has revolutionized patient outcome for the small mCRC subgroup with highly immunogenic disease. The majority of mCRC cases, however, are MSS without innate ICB susceptibility. In our ongoing METIMMOX study, we hypothesize that MSS mCRC can be transformed into an immunogenic condition by short-course oxaliplatin-based therapy (FLOX), enabling patients with unresectable, previously untreated metastases to obtain durable disease control when adding ICB therapy. Here we present the protocol-planned interim analysis. Methods: Eligibility criteria include infradiaphragmatic metastasis and C-reactive protein &lt; 60 mg/L. At analysis 15 January 2021, 54 patients stratified according to primary tumor sidedness and mutational status and evaluable for the primary end point (progression-free survival; PFS) had been randomly assigned to a standard-of-care schedule of 8 FLOX cycles Q2W (control arm) or repeat sequential 2 FLOX cycles and 2 nivolumab cycles (240 mg Q2W) to a total of 8 cycles (experimental arm), for both arms before treatment break until disease progression and reintroduction of a new treatment sequence. Radiologic response assessment is every 8 weeks. Safety, tolerability, objective response rate, and duration of response are among secondary end points. Results: At median follow-up of 6.4 (range, 0.5-20) months, patients were well balanced between the treatment arms with regard to the predefined strata and single-organ or multiple-organ metastases. Median PFS for the entire groups of control and experimental arm patients was 5.6 (range, 0.5-15; n = 26) and 6.6 (range, 0.5-20; n = 28) months, respectively. The number of FLOX-related CTCAE grade 3 or higher adverse events, including 2 deaths after initial FLOX administration, was comparable in the two arms. Twelve immune-related grade 3-4 adverse events (no new safety signals) were recorded. In the experimental arm, 4 (16%) patients, all RAS/BRAF-mutant cases, had experienced complete response and 9 (32%) patients had ongoing objective response at 8 months. The control arm cases had 0 with complete response and 6 (23%) with ongoing objective response at 8 months, 1 of whom had proceeded to curative-intent liver surgery. Conclusions: MSS mCRC patients may hold the opportunity of ICB responsiveness evoked by short-course oxaliplatin-based chemotherapy. The search for predictive biomarkers of ICB responsiveness is ongoing in the specifically designed METIMMOX correlative study program. Clinical trial information: NCT03388190.
RARE-06. CLINICAL BURDEN AMONG PATIENTS WITH NEUROFIBROMATOSIS TYPE 1 (NF1) AND PLEXIFORM NEUROFIBROMA (PN) IN THE UNITED STATES (US)
Authors: Xiaoqin Yang, Hyun Kyoo Yoo, Suvina Amin, Wendy Cheng, Heather Sipsma, Sanjana Sundaresan, Lujia Zhang, Mei Sheng Duh
Journal: Neuro-Oncology (2021)

Abstract Background Plexiform neurofibromas (PNs) occur in 30–50% of pediatric patients with neurofibromatosis type 1 (NF1), often resulting in debilitating pain and dysfunction. Real-world evidence describing the clinical disease burden among these patients is limited. This study aimed to characterize this burden among pediatric NF1 PN patients in the United States (US). Methods Caregivers of 82 patients ages 2–18 years with NF1 PN in the US who were treatment naïve or new users of selumetinib (defined as ≤1 month of use) were recruited through the Children’s Tumor Foundation to participate in an online cross-sectional survey from December 1, 2020 through January 14, 2021. Participants responded to items measuring patient demographic and clinical characteristics and the burden of debulking surgeries. Results On average, patients were 11.5 [standard deviation (SD)=4.0] years old and predominantly treatment naïve (97.6%). Most were white/Caucasian (85.4%), and 53.7% were female. Most patients had been diagnosed with NF1 and PN for &amp;gt;5 years (80.5% and 68.3%, respectively). A majority of patients (58.5%) had &amp;gt;20 café-au-lait spots. Most patients (59.8%) had &amp;gt;1 PN, with 11.0% reporting &amp;gt;5 PNs, frequently located on the back (40.2%) and head (32.9%). Common symptoms included pain (64.6%), disfigurement (32.9%), and motor dysfunction (28.0%). Common comorbidities included attention-deficit disorder (56.1%) and headaches (47.6%). Few patients had received complete resections of their tumors (12.2%), and 39.0% reported ≥1 debulking surgery. Among the 32 patients with debulking surgeries, 5 patients (15.6%) reported complications, including acute complications (60.0%) and post-operative symptoms (40.0%). Debulking surgery-related emergency room visits and hospitalizations were common (25.0% and 53.1%, respectively); mean length of stay per hospitalization was 5.9 (SD=6.2) days. Conclusion The clinical disease burden of NF1 PN among this pediatric patient population is substantial. While debulking surgeries are used for symptom management, they were related to considerable clinical sequelae.
Impact of frontline treatment approach on outcomes of myeloid blast phase CML
Authors: Kapil Saxena, Elias Jabbour, Ghayas Issa, Koji Sasaki, Farhad Ravandi, Abhishek Maiti, Naval Daver, Tapan Kadia, Courtney D. DiNardo, Marina Konopleva, Jorge E. Cortes, Musa Yilmaz, Kelly Chien, Sherry Pierce, Hagop Kantarjian, Nicholas J. Short
Journal: Journal of Hematology & Oncology (2021)

The natural course of untreated chronic myeloid leukemia (CML) is progression to an aggressive blast phase. Even in the current era of BCR-ABL1 tyrosine kinase inhibitors (TKIs), the outcomes of blast phase CML remain poor with no consensus frontline treatment approach.We retrospectively analyzed the response rates and survival outcomes of 104 consecutive patients with myeloid blast phase CML (CML-MBP) treated from 2000 to 2019 based on 4 different frontline treatment approaches: intensive chemotherapy (IC) + TKI (n = 20), hypomethylating agent (HMA) + TKI (n = 20), TKI alone (n = 56), or IC alone (n = 8). We also evaluated the impact of TKI selection and subsequent allogeneic stem cell transplant (ASCT) on patient outcomes.Response rates were similar between patients treated with IC + TKI and HMA + TKI. Compared to treatment with TKI alone, treatment with IC/HMA + TKI resulted in a higher rate of complete remission (CR) or CR with incomplete count recovery (CRi) (57.5% vs 33.9%, p < 0.05), a higher complete cytogenetic response rate (45% vs 10.7%, p < 0.001), and more patients proceeding to ASCT (32.5% vs 10.7%, p < 0.01). With a median follow-up of 6.7 years, long-term outcomes were similar between the IC + TKI and HMA + TKI groups. Combination therapy with IC/HMA + TKI was superior to therapy with TKI alone, including when analysis was limited to those treated with a 2nd/3rd-generation TKI. When using a 2nd/3rd-generation TKI, IC/HMA + TKI led to lower 5-year cumulative incidence of relapse (CIR; 44% vs 86%, p < 0.05) and superior 5-year event-free survival (EFS; 28% vs 0%, p < 0.05) and overall survival (OS; 34% vs 8%, p = 0.23) compared to TKI alone. Among patients who received IC/HMA + TKI, EFS and OS was superior for patients who received a 2nd/3rd generation TKI compared to those who received imatinib-based therapy. In a landmark analysis, 5-year OS was higher for patients who proceeded to ASCT (58% vs 22%, p = 0.12).Compared to patients treated with TKI alone for CML-MBP, treatment with IC + TKI or HMA + TKI led to improved response rates, CIR, EFS, and OS, particularly for patients who received a 2nd/3rd-generation TKI. Combination therapy with IC + TKI or HMA + TKI, rather than a TKI alone, should be considered the optimal treatment strategy for patients with CML-MBP.
Frequency and Clinical Significance of P-Glycoprotein and Multidrug Resistance-Associated Protein-1 Expression in Leukemic Cells from Acute Myeloid Leukemia
Authors: Aldair Paiva, Gabriela Va Alves, Lenilton Silva Silveira, Leonardo Lima Fernandes, James Farley Rafael Maciel, Dany Gkc Silva, Rodrigo Villar Freitas, Frank Bahia, Marcelo Rocha Barbosa, Geraldo Barroso Cavalcanti
Journal: Blood (2017)
Cancer activation pathways of thymic epithelial tumors (TETs) by targeted gene expression analysis.
Authors: Jose Carlos Benitez, Bastien Job, Vincent Thomas de Montpreville, Ludovic Lacroix, Patrick Saulnier, Riad Arana, Olivier Lambotte, Sacha Mussot, Olaf Mercier, Elie Fadel, Jean-Yves Scoazec, Benjamin Besse
Journal: Journal of Clinical Oncology (2021)

8575 Background: TETs are rare malignancies of the anterior mediastinum. Clinical behavior varies from mild thymoma (T) A to aggressive thymic carcinoma (TC). The biology of TETs is poorly understood and knowledge of the transcriptomic fingerprint of T and TC is limited. Additionally, up to 30% of patients (pts) will develop associated autoimmune disorders (AIDs). We aimed to characterize the main cancer activation pathways of the TET subgroups. Methods: We selected a representative balanced set of Ts and TCs to analyze 24 main cancer activation pathways using HTG Oncology biomarkers panel (2562 genes) by RNA sequencing. Tumor representative paraffin-embedded blocks were macrodissected for gene expression analysis. We analyzed epidemiologic, clinical and pathological characteristics of pts with TET’s and correlated with genes expression based on cancer Hallmarks. Results: From January 2010 to December 2019, 219 pts were included in the cohort. Molecular results of 194 pts were available. Median age at diagnosis was 56 (9-83) years. 54.1% were women. 65/194 (33.5%) reported AIDs. T B2 was the most frequent (n=41, 21.1%), followed by B1, AB, B3, TC and A. RNA expression analysis identified 2 main clusters, corresponding mainly to T (cluster 2) and TC (cluster 1) respectively (p&lt;0.0001) (Table). Tumors of cluster 1 (TCs predominant) shown activated pathways (MYC [gene ratio= 0.5]; p&lt;0.0001). In cluster 2 (T predominant), activated pathways differed among subgroups: B1 (E2F[0.5], G2M checkpoint [0.45]; p&lt;0.001), B2 (E2F [&gt;0.4]; p&lt;0.0001). Routes were mostly suppressed: A (MYC [&gt;0.5], E2F[&gt;0.4], G2M checkpoint[&gt;0.45], mitotic spindle[&gt;0.35], MTOR [&lt;0.35]; p&lt;0.001), AB (INFα [&gt;0.5], inflammatory response [&gt;0.45], INTɣ [0.45], NFkb [&gt;0.4], MTOR[&gt;0.4]; p&lt;0.001), B1 (EMT [0.6], angiogenesis [&gt;0.5], INFα [0.5], homeostasis [0.5], NFkb [0.5], INTɣ [&gt;0.45], myogenesis [&lt;0.4]; p&lt;0.0001), B2 (INFα [&gt;0.65], INTɣ [&gt;0.5], NFkb [0.5], EMT [0.45], inflammatory response [&lt;0.4]; p&lt; 0.0001), B3 (EMT [0.6], MYC [0.45]; p&lt;0.001). Among pts reporting AIDs 61 and 4 were associated to cluster 2 and 1, respectively (p=0.017). Conclusions: We describe differential molecular characteristics among histological subgroups in 2 clusters. The analysis suggests new therapeutic venues. Additional analysis will be presented on outliers and response to treatment.[Table: see text]
Synergizing microdissection with ddPCR to advance precision oncology.
Authors: Donald Joseph Johann, Ik Jae Shin, Erich Peterson, Matthew V Steliga, Jason Muesse, Katy Marino, Sarah Laun, Valerie Greisman, Michael Emmert-Buck, Michael Tangrea
Journal: Journal of Clinical Oncology (2021)

e15083 Background: Improving patient treatment outcomes based on the application of advanced molecular profiling methodologies applied to pathological specimens is the purview of precision oncology. Optimal utilization of tumor tissue from diagnostic biopsies remains an unmet medical need. This is especially relevant today since precision oncology is a rapidly evolving field where timely tumor genotyping is essential for the indication of many advanced and targeted therapies. National Comprehensive Cancer Network (NCCN) guidelines now mandate molecular testing for clinically actionable targets in certain malignancies. Patients diagnosed with advanced non-small cell lung cancer (NSCLC) are commonly of an older age and have significant co-morbidities. Clinical dilemmas regarding the ability to obtain adequate amounts of tissue for tumor genotyping frequently occur. In these cases, the tumor tissue may have been obtained by an image-guided biopsy, and the diagnosis of NSCLC proper determined via cytology. Adequate tissue for tumor genotyping and/or a more advanced mutational analysis to identify oncogenic drivers may not be available, and the opportunity to explore more optimal therapy options (eg, TKI in lieu of chemotherapy) is lost. Methods: Following a formal pathology review formalin fixed paraffin embedded (FFPE) specimens were examined using advanced immuno-based laser capture microdissection (LCM). In preparation for droplet digital PCR (ddPCR), nucleic acids were extracted from samples and run with a series of positive and negative controls. Results: Utilizing lung cancer as an example, an improved genotyping approach for NSCLC solid tumors was developed and tested. The strategy involves optimization of the microdissection process and analysis of a large number of identical target cells from FFPE specimens sharing similar characteristics, in other words, single-cell subtype analysis. Immunostaining status, cell phenotype, and spatial location within a histological section are examples of shared characteristics that can guide cell procurement. Conclusions: With this approach, tumor molecular analysis is enhanced through the synergy between microdissection and ddPCR. Here we demonstrate a methodology that illustrates genotyping of a solid tumor from a small tissue biopsy sample in a time and cost-efficient manner, using immunohistochemistry-directed LCM along with the detection and absolute quantitation of mutations by ddPCR.
Lymph node and visceral progression without erythroderma or blood worsening in erythrodermic cutaneous T‐cell lymphoma: nine cases
Authors: C. Skayem, M. Beylot‐Barry, A. Masson, O. Dereure, C. Ram‐Wolff, M. Bagot, B. Vergier, M. Battistella, N. Ortonne, S. Ingen‐Housz‐Oro
Journal: British Journal of Dermatology (2021)
Cilta-cel versus conventional treatment in patients with relapse/refractory multiple myeloma.
Authors: Luciano J. Costa, Yi Lin, Thomas G. Martin, Saurabh Chhabra, Saad Zafar Usmani, Sundar Jagannath, Natalie Scott Callander, Jesus G. Berdeja, Yubin Kang, Ravi Vij, Hong Tian, Satish Valluri, Jennifer Marino, Carolyn Chang Jackson, Arnob Banerjee, Ankit Kansagra, Jordan Mark Schecter, Shaji Kumar, Parameswaran Hari
Journal: Journal of Clinical Oncology (2021)

8030 Background: CARTITUDE-1 is a single arm study of Ciltacabtagene autoleucel (cilta-cel; JNJ-68284528) anti-BCMA CAR-T cell therapy in US patients (pts) with relapsed multiple myeloma (RRMM) refractory to both IMiD and proteasome inhibitor (PI) or with at least 3 prior lines of therapy and previously exposed to anti-CD38 monoclonal antibody (MoAb). While recently reported efficacy results of cilta-cel were encouraging, it is unknown how they compare with similar pts receiving conventional (non CAR-T) treatment. Methods: We utilized a contemporary US-based dataset of pts with MM refractory to anti-CD38 MoAb (MAMMOTH) to identify pts who would meet eligibility for CARTITUDE-1 and who received conventional therapy. We analyzed the intent-to-treat population (ITT) in CARTITUDE-1, defined as pts who underwent apheresis (N=113) and a modified ITT population (mITT) defined as subset of pts who received cilta-cel at the RP2D (N=97). From the MAMMOTH dataset, we identified a population corresponding to CARTITUDE-1 ITT (N=190) and a mITT population, pts without death or progression within 47 days (median time between apheresis and cilta-cel infusion) from onset of therapy (N=122). We calculated propensity scores (PS) with demographics, N of prior therapies, cytogenetics and refractoriness to MM agents as covariates. An analyst blinded to outcomes performed nearest neighbor 1:1 PS matching. We analyzed overall response rate (ORR), progression-free (PFS) and overall survival (OS) for ITT and mITT in CARTITUDE-1 vs matching MAMMOTH cohorts. Results: Ninety-five ITT (75 received bridging therapy, 82 received cilta-cel) and 69 mITT (54 received bridging) CARTITUDE-1 pts matched MAMMOTH pts (Table). Among the pts in the MAMMOTH ITT cohort 34% received pomalidomide, 24% anti-CD38 MoAb, 19% carfilzomib and 35% cytotoxic chemotherapy in next therapy. ORR in the ITT cohorts was higher in CARTITUDE-1 (84% vs. 28%). Compared to their MAMMOTH counterparts, pts in CARTITUDE-1 ITT cohort had improved PFS (12 mo. 73% vs. 12%) and OS (12 mo. 83% vs 39%). Between the mITT cohorts, CARTITUDE-1 pts had superior ORR (96% vs. 30%), PFS (12 mo 79% vs. 15%) and OS (12 mo. 88% vs. 41%). Conclusions: In pts with RRMM beyond therapy with IMID, PI, and anti-CD38 MoAb, treatment with cilta-cel is associated with higher response rate and superior PFS and OS when compared to conventional treatment.[Table: see text]
Neo-AEGIS (Neoadjuvant trial in Adenocarcinoma of the Esophagus and Esophago-Gastric Junction International Study): Preliminary results of phase III RCT of CROSS versus perioperative chemotherapy (Modified MAGIC or FLOT protocol). (NCT01726452).
Authors: John V. Reynolds, Shaun R. Preston, Brian O'Neill, Maeve Aine Lowery, Lene Baeksgaard, Thomas Crosby, Moya Cunningham, Sinead Cuffe, Gareth Owen Griffiths, Rajarshi Roy, Stephen Falk, George Hanna, Frederick R. Bartlett, Imelda Parker, Alberto Alvarez-Iglesias, Magnus Nilsson, Guillaume Piessen, Signe Risum, Narayanasamy Ravi, Raymond S. McDermott
Journal: Journal of Clinical Oncology (2021)

4004 Background: The optimum combination curative approach to locally advanced adenocarcinoma of the esophagus and esophago-gastric junction (AEG) is unknown. A key question is whether neoadjuvant multimodal therapy, specifically CROSS (carboplatin/paclitaxel, 41.4Gy radiation therapy), is superior to optimum peri-operative chemotherapeutic regimens including modified MAGIC (epirubicin, cisplatin (oxaliplatin), 5-FU (capecitabine)) and more latterly FLOT (docetaxel, 5-FU, leucovorin, oxaliplatin). Neo-AEGIS was designed as the first randomised controlled trial to address this question. Methods: 377 patients with cT 2-3 N 0-3 M 0 AEG were randomly assigned to CROSS or peri-operative chemotherapy (ECF/ECX/EOF/EOX pre-2018, FLOT option 2019/20) at 24 sites (Ireland, UK, Denmark, France, Sweden). The primary outcome was overall survival. The initial power calculation was based on CROSS superiority of 10%. This was modified after the first futility analysis (70 events) to a non-inferiority margin of 5%. Secondary end points included toxicity, pathologic measures of response, and postoperative complications as per the Esophageal Complications Consensus Group (ECCG) definitions and Clavien-Dindo severity grade. Results: Of 362 evaluable patients, 178 CROSS, 184 MAGIC/FLOT (157/27), 90% were male, median (range) age 64 (35-83), 84% were cT3, and 58% cN1. At a median (range) follow up of 24.5 (1-92) months, at the second futility analysis (60% of planned events), there were 143 deaths, 70 CROSS and 73 MAGIC/FLOT arm, with 3-year estimated survival probability of 56% (95% CI 47,64) and 57% (95% CI 48,65), respectively [(HR 1.02 (95%CI. 0.74-1.42))]. Based on the absence of futility evidenced in this data the DSMB recommended closure of recruitment in December 2020. Conclusions: This RCT reveals no evidence that peri-operative chemotherapy is unacceptably inferior to multimodal therapy, notwithstanding greater proxy markers of local tumour response in the CROSS arm. Oncologic and operative outcomes were consistent with optimum modern benchmarks. These data strongly suggest non-inferiority and support equipoise in decision making in modern practice. Clinical trial information: NCT01726452. [Table: see text]
Characterization of Potential Endocrine-Related Health Effects at Low-Dose Levels of Exposure to PCBs
Authors: Abraham Brouwer, Matthew P. Longnecker, Linda S. Birnbaum, Jim Cogliano, Paul Kostyniak, Jack Moore, Suzan Schantz, Gerhard Winneke
Journal: Environmental Health Perspectives (1999)

This article addresses issues related to the characterization of endocrine-related health effects resulting from low-level exposures to polychlorinated biphenyls (PCBs).It is not intended to be a comprehensive review of the literature but reflects workshop discussions."The Characterizing the Effects of Endocrine Disruptors on Human Health at Environmental Exposure Levels," workshop provided a forum to discuss the methods and data needed to improve risk assessments of endocrine disruptors.This article contains an overview of endocrine-related (estrogen and thyroid system) interactions and other low-dose effects of PCBs.The data set on endocrine effects includes results obtained from mechanistic methods/ and models (receptor based, metabolism based, and transport protein based), as well as from in vivo models, including studies with experimental animals and wildlife species.Other low-dose effects induced by PCBs, such as neurodevelopmental and reproductive effects and endocrine-sensitive tumors, have been evaluated with respect to a possible causative linkage with PCB-induced alterations in endocrine systems.In addition, studies of low-dose exposure and effects in human populations are presented and critically evaluated.A list of conclusions and recommendations is included.