tbuckley/cabot-search huggingface dataset:
Immunophenotype and proliferation to predict for response to neoadjuvant chemotherapy in TNBC: Results from BrighTNess phase III study.
Authors: Otto Metzger Filho, Daniel G. Stover, Sarah Asad, Peter J Ansell, Mark Watson, Sibylle Loibl, Charles E. Geyer, Joyce O'Shaughnessy, Michael Untch, Hope S. Rugo, Jens Bodo Huober, Mehra Golshan, William M. Sikov, Gunter Von Minckwitz, Priya Rastogi, David Maag, Norman Wolmark, Carsten Denkert, William Fraser Symmans
Journal: Journal of Clinical Oncology (2019)

510 Background: In TNBC, the interplay between immunophenotype, tumor proliferation (prolif) and achievement of pathologic complete response (pCR) with neoadjuvant chemotherapy (NAC) remains unknown. Methods: RNA seq was performed on pre-tx research biopsies of stage II/III TNBC enrolled in BrighTNess. NAC regimens included paclitaxel alone or with carboplatin (Cb) or Cb plus veliparib, followed by AC. Computational analysis included subtyping (i.e. PAM50, Pietenpol), prolif (PAM50) and GeparSixto immune signature (GSIS). Cb-containing arms were combined due to similar pCR. Results: High quality RNA seq data was obtained from 482 of 634 pts. PAM50 classified 80.1% of tumors as basal-like. TNBC subtypes were mostly BL1 or BL2 (23.3%), IM (22.4%) or M/MSL (31.7%); 6% were LAR. pCR was higher for basal vs non-basal tumors (52.3% vs 35.4%, p = 0.003). IM had the highest pCR rate (64.2%, 95% CI 59.9%,68.5%). Basal-like was not a significant predictor for Cb benefit (p-interaction = 0.8). Prolif (OR = 0.30 p &lt; 0.001) and GSIS (OR 0.68 p &lt; 0.001) were significantly correlated with pCR but did not correlate with each other (Pearson’s r2 = 0.027). In multivariate analysis, prolif (HR = 0.36 95% CI, 0.21-0.61 p = 0.0002) and GSIS (HR = 0.62 95% CI, 0.49-0.79 p &lt; 0.0001) increased the ability to predict pCR beyond standard clinico-pathologic variables (likelihood ratio = 14.9, p = 0.0001115). Among all pts, those above the median for both prolif. and GSIS had the highest pCR (67%; 84/125) while those below the median for both had the lowest pCR rate (34%; 42/125). Tumors with higher inferred CD8 + T-cell infiltration demonstrated greater benefit from Cb using either TIMER (HR = 0.83 [0.73-0.95]) or CIBERSORT (HR = 0.83 [0.76-0.91]). Tumors with higher inferred total macrophages, particularly immune suppressive M2 macrophages had a higher pCR rate on the non-Cb arm (AC-T) using CIBERSORT (HR = 1.27 [1.07,1.50]). Conclusions: Immunophenotype and proliferation are independent predictors of pCR to standard NAC regimens in TNBC. PAM50 is not a significant predictor of Cb benefit. Exploratory findings suggest that tumor infiltrating immunophenotype (i.e. CD8 T cells and macrophages) may predict response to specific NAC regimens in TNBC. Clinical trial information: NCT02032277.
Epigenetic modifications of autophagy in cancer and cancer therapeutics
Authors: Chandra S. Bhol, Debasna P. Panigrahi, Prakash P. Praharaj, Kewal K. Mahapatra, Srimanta Patra, Soumya R. Mishra, Bishnu P. Behera, Sujit K. Bhutia
Journal: Seminars in Cancer Biology (2019)
Mutational landscape of cervical cancer identified by prospective clinical sequencing in a nationwide cancer network.
Authors: Julian C. Schink, Ricardo H. Alvarez, Julia Andrea Elvin, Amber Moran, Rebecca Rollins, John P. Geisler, David McIntosh, Natalie Godbee, Bradford A. Tan, Maurie Markman
Journal: Journal of Clinical Oncology (2019)

e17022 Background: Tumor genomic profiling is a critical component of precision oncology allowing the detection of genomic alterations (GA) that have the potential to be targeted therapeutically. We present an analysis of comprehensive genomic profiling (CGP) of a large series of cervical cancer (CC) patients assayed in a nationwide cancer network. Methods: 118 Pts with advanced CC underwent CGP with hybrid capture of up to 406 cancer-related genes on tumor tissue or for 62 genes on circulating tumor DNA ordered during clinical care for treatment decision-making between 01-2013 to 05-2018. Clinically relevant genomic alterations (CRGA) were defined as associated with targeted therapies or mechanism-driven clinical trials. The treatment histories for these patients were obtained with IRB-approved retrospective review. Results: Median age was 47 years (range, 27-71), 69% were Caucasian. GA were identified in 88% (104/118) of CC, of which 87 (74%) had a clinically relevant genomic alteration (CRGA). PI3K/AKT/mTOR pathway ( PIK3CA, AKT1/2/3, PIK3R1, PTEN, MTOR, STK11, FBXW7) CRGA were most commonpresent in 73.5% (64/87) of CC. CRGA in other targetable pathways were identified: 24.1% (21/87) in MEK ( KRAS, NRAS, HRAS, BRAF, RAF1, GNAS, NF1, NF2), 9.1% (8/87) in HRD (BRCA1/2, ATM, PALB2, BRIP1) and 24.1% (21/87) in ERBB ( ERBB2, ERBB3, ERBB4, EGFR). One patient was MSI-high and one patient was TMB-high. 29.8% (26/87) of CC patients were ordered a genomically-matched treatment, and 24 pts received treatment; 61.5% (16/26) were agents that were FDA approved in a different tumor type, and 34.6% (9/26) through referral to a matched mechanism driven clinical trial. With access to the clinical trial TAPUR, the frequency of matched treatment through clinical trials increased over time from 2013 to 2018. The PFS for non study related patients was 7 weeks and OS was 19 weeks. Conclusions: In a large series of Cervical Cancer patients assayed with CGP, 27.5% (24/87) of pts received matched treatment, which was predominantly targeted therapy. The comprehensive sensitive and unbiased nature of CGP, coupled with a multidisciplinary molecular tumor board and staff dedicated to genomic interpretation, assisted in achieving a high frequency of patients’ participation in clinical trials and gene-directed treatment.
Comparison of in vitro antitumor activity between SB3 (trastuzumab biosimilar, Ontruzant) and Herceptin combined with an antibody for subdomain II of HER2 in HER2-positive cancer cells.
Authors: Jae Hee Lee, Kyungyeol Paek, Eunji Kim, Inhee Kim, Juyeon Jeong, Seokkyun Kim
Journal: Journal of Clinical Oncology (2019)

e14001 Background: The human epidermal growth factor receptor (HER) family plays a critical role in proliferation and survival of cancer cells. Trastuzumab is a recombinant humanized monoclonal antibody that blocks signaling pathways of HER2 tyrosine kinase receptor via binding to subdomain IV of HER2 extracellular domain. A subdomain II targeting therapeutic antibody (DII antibody, pertuzumab) binds to a different region on the same protein. A combination of the two different antibodies might provide a more effective antitumor activity without binding interference [1] . In this study, we evaluate in vitro antitumor activity of SB3 used in the same manner as Herceptin, in combination with a DII antibody that complements the mechanism of action of trastuzumab. [1] Nahta et al, [CANCER RESEARCH 64, 2343–2346, April 1, 2004]. Methods: Similarity assessment of in vitro antitumor activity between SB3 and Herceptin was performed on HER2-overexpressing breast and gastric cancer cells through analyzing HER2 dimerization, cell proliferation and survival activities, and antibody-dependent cellular cytotoxicity (ADCC) in the presence of a DII antibody. Combination index was calculated to evaluate the synergistic effect. Results: SB3 and Herceptin in combination with a DII antibody, showed similar in vitro inhibition rate for HER2/HER3 heterodimerization. The HER2-overexpressing breast and gastric cancer cells growth inhibition rate was similar whether SB3 or Herceptin was used in combination with a DII antibody. This effect was also shown in apoptosis activity by measuring caspase 3/7 expression. In terms of biological effect via Fc function, cell killing activity was assessed by ADCC assay in the presence of a DII antibody, and non-synergistic effect was shown with both SB3 and Herceptin. Conclusions: This study has concluded that SB3, as a trastuzumab biosimilar, demonstrates highly similar in vitro antitumor activity in experimental conditions when combined with a DII antibody, resulting in enhanced cell growth inhibition and apoptosis activities by inhibiting HER2 dimerization in HER2-positive cancer cells.
Economic evaluation of anaplastic lymphoma kinase (ALK) inhibitors brigatinib, alectinib and crizotinib in non-small cell lung cancer (NSCLC): Analysis for intracranial metastasis-related progression free survival (CNSPFS).
Authors: Nimer S Alkhatib, Briana Choi, Elizabeth Pae, Hani M. Babiker, Linda L. Garland, Alyssa Henglefelt, Ali McBride, Ivo Abraham
Journal: Journal of Clinical Oncology (2019)

e20515 Background: ALK inhibitors (ALKI) have shown clinical benefit in preventing progression or death related to central nervous system (CNS) metastasis in NSCLC. We performed cost-effectiveness/utility analyses that consider CNS progression in comparing ALKIs. Methods: The Bücher method was used to indirectly estimate comparative hazard ratios (HR) for CNSPFS between the 3 agents. A 2-state Markov model (CNSPFS, CNS progression or death) was specified, survival curves were digitized, and Weibull distributions fitted with life time horizon. Drug costs were per RedBook (US$ 2018). Cost of adverse event management, disease progression and follow up were per published data. Outcomes included CNSPFS life years (CNSPFS LY) and quality adjusted life years (CNSPFS QALY). Incremental cost effectiveness/utility ratios (ICER/ICUR) of CNSPFS LY and CNSPFS QALY gained were estimated. Deterministic results were verified in probabilistic sensitivity analyses (PSA). Analyses were from the US payer perspective. Results: In indirect comparisons brigatinib was superior over crizotinib (CNSPFS HR = 0.27, 95%CI = 0.13-0.54) but comparable to alectinib (CNSPFS HR = 0.39, 95%CI = 0.12-1.31) in CNSPFS; whereas alectinib was comparable to crizotinib (CNSPFS HR = 0.68, 95%CI = 0.26-1.77). Deterministic (PSA) CNSPFS LY, CNSPFS QALY and cost estimates were 0.56 (0.69), 0.35 (0.42) and $126,430 ($153,870) for crizotinib; 0.68 (0.82), 0.39 (0.49) and $115,776 ($148,904) for alectinib; 0.80 (1.02), 0.51 (0.64) and $318,114 ($402,442) for brigatinib. See table for deterministic (PSA) ICER/ICUR results ($ in parentheses denote savings). Conclusions: This independent economic evaluation suggests that, despite the lower costs of per-label alectinib and crizotinib, greater gains in CNSPFS LYs and QALYs are achieved with per-label brigatinib in the setting of CNS metastasis. This assumes willingness to pay thresholds up to $1,152,445/CNSPFS LY and up to $1,198,025/CNSPFS QALY gained, which is above prevailing standards. [Table: see text]
Molecular analysis of advanced colorectal cancer in a patient cohort of Hispanics, African Americans, and Caucasians within a diverse single institution.
Authors: Nadia Ashai, Mateo Mejia Saldarriaga, Devika Rao, Matthew Stuart, Wei Zhang, Sanjay Goel, Balazs Halmos, Lakshmi Rajdev
Journal: Journal of Clinical Oncology (2019)

e15121 Background: CRC survival and treatment response differences have been noted across racial and ethnic groups, particularly between Hispanics (HA), non-Hispanic AA (AA), and non-Hispanic Caucasian (CA). We examined if there are differences in molecular drivers between these groups that could explain such differences in our diverse medical center. Methods: We retrospectively examined 361 HA, AA, CA patients at Montefiore Medical Center diagnosed with metastatic CRC (mCRC) from 2007 to 2018. Mismatch repair proficiency (MMR-P), deficiency (MMR-D) was determined by immunohistochemistry. KRAS, NRAS, BRAF were determined by polymerase chain reaction or next generation sequencing. Mutations were then correlated with overall survival (OS). Results: Across subgroups, there was no differences in MMR, KRAS, NRAS, BRAF incidence (Table). Using a univariate analysis, the median survival for RAS mutated (M) patients was 33 months (ms), compared to 69 ms for RAS wild-type (WT, p = 0.01). The median OS for RAS mutated HA patients was 41 ms, compared to 41 ms and 33 ms for CA and AA respectively (p = 0.14). There was also no statistically significant difference between median OS for RAS WT HA patients (69 ms), compared to AA patients (51 ms) and CA (not reached, p = 0.75). Conclusions: In our single institution study, we found no difference in incidence of RAS (KRAS and NRAS), BRAF, MMR amongst HA, AA, and CA. Delivery of uniform care may account for similar OS outcomes in our patient population. RAS WT and M disease had improved OS compared to previously established rates in the literature. Additional studies are needed to evaluate known differences in treatment response and survival in minority populations.[Table: see text]
Emerging roles and therapeutic value of exosomes in cancer metastasis
Authors: Miaowei Wu, Guosheng Wang, Weilei Hu, Yihan Yao, Xiao-Fang Yu
Journal: Molecular Cancer (2019)

Exosomes are cell-derived vesicles of 30 to 150 nm that contain diverse proteins, nucleic acids, and lipids. These vesicles facilitate effective intercellular communication and trigger profound environmental changes. In recent years, many studies have identified diverse roles for exosomes in tumor metastasis, a major cause of cancer-related deaths; furthermore, circulating tumor-derived exosomes can drive the initiation and progression of metastasis and determine the specific target organs affected. Fortunately, our growing understanding of exosomes and relevant modification technology have provided new ideas for potential treatment of tumor metastases. Here we review recent advances concerning the role of exosomes in metastasis, focusing on their regulatory mechanisms and therapeutic targeting in advanced cancer.
ALBAN: An open label, randomized, phase III trial, evaluating efficacy of atezolizumab in addition to one year BCG (bacillus Calmette-Guerin) bladder instillation in BCG-naive patients with high-risk nonmuscle invasive bladder cancer (AFU-GETUG 37).
Authors: Morgan Roupret, Yann Neuzillet, Aurelie Bertaut, Geraldine Pignot, Nadine Houede, Stephane Champiat, Soazig Nénan-Le Ficher, Maggy Chausson, Yohann Loriot
Journal: Journal of Clinical Oncology (2019)

TPS4589 Background: The majority of patients with bladder cancer are diagnosed with non-muscle invasive bladder cancer (NMIBC). Trans-urethral resection of bladder tumor (TURBT) followed by Bacillus Calmette-Guerin (BCG) therapy is the standard of care for most patients with high-risk NMIBC, although clinical outcomes remain poor. Data from preclinical and clinical studies suggest that programmed death-ligand 1 PD-L1 inhibition may enhance antitumor activity of BCG therapy. Atezolizumab, an anti–PD-L1 monoclonal antibody, is approved in the United States and the European Union as monotherapy when patients are ineligible for cisplatin or after prior platinum therapy. This approval was based on the results from phase II and III IMvigor210/211 trials. We have designed ALBAN, a phase III trial to evaluate the efficacy and safety of atezolizumab given in combination with BCG versus BCG alone in patients with high-risk NMIBC. Methods: In 30 centers in France, ALBAN (NCT03799835) is enrolling patients with histologically documented NMIBC who have not received prior BCG therapy. Eligible patients have to have high-risk features (T1 staging, high grade, or in situ carcinoma), ECOG PS 0-2, and a tissue sample for PD-L1 testing (by Ventana SP142 immunohistochemistry assay). Patients are randomized 1:1 to: (Arm A) BCG alone (six weekly instillations of BCG, followed by three weekly maintenance instillations at 3, 6, 12 months), or (Arm B) atezolizumab (1200 mg; IV; q3w for up to 1 year) combined with BCG given as in arm A. Treatment with atezolizumab and BCG are continued in the absence of unacceptable toxicity, for 1 year. The primary endpoint is recurrence-free survival in the intent-to-treat population. Secondary efficacy endpoints include overall survival, PFS, complete response, disease worsening, and quality of life. Safety, biomarkers, and other exploratory endpoints will also be evaluated. Enrollment began in December 2018 with a target of 614 pts. Clinical trial information: NCT03799835.
A phase II trial of intermittent nivolumab in patients with metastatic renal cell carcinoma (mRCC) who have received prior anti-angiogenic therapy
Authors: Moshe C. Ornstein, Laura S. Wood, Brian P. Hobbs, Kimberly D. Allman, Allison Martin, Michael Bevan, Timothy D. Gilligan, Jorge A. Garcia, Brian I. Rini
Journal: Journal for ImmunoTherapy of Cancer (2019)

<h3>Background</h3> Nivolumab is approved for mRCC patients who have received prior anti-angiogenic therapy but the duration of therapy required for sustained clinical benefit is unknown. A phase II clinical trial to investigate the feasibility of intermittent nivolumab dosing was conducted. <h3>Methods</h3> Patients ≥18 years of age with mRCC who were previously treated with at least one antiangiogenic therapy were eligible. Patients were treated with nivolumab for twelve weeks. Patients who had RECIST PD were removed from the trial. Patients who did not initially achieve ≥10% reduction in tumor burden (TB) continued nivolumab per standard of care. Patients with ≥10% TB reduction entered a treatment-free observation phase with re-imaging every 12 weeks. Nivolumab was restarted in patients with a ≥ 10% TB increase and again held with TB reduction ≥10%. This intermittent nivolumab dosing continued until RECIST PD while on nivolumab. The primary objective was feasibility of intermittent nivolumab, defined as the proportion of patients eligible for intermittent therapy who elect to receive intermittent nivolumab. Intermittent nivolumab would be considered "feasible" if the acceptance rate was ≥80%. Forty patients provides &gt; 95% power with 0.05 type I error, assuming a null acceptance rate of 50%. With the approval of the combination of ipilimumab/nivolumab (April 2018) in front-line mRCC, this cohort was closed prior to completed pre-planned approval. <h3>Results</h3> Of the 14 patients enrolled, 13 (93%) were male with a median age 65. All had a prior nephrectomy and 12 (86%) were intermediate-risk by IMDC criteria. Five patients (36%) met the criteria for the intermittent phase of the trial (median TB decrease 46%) and all agreed to intermittent therapy. With a median follow-up of 48 weeks, only one patient restarted therapy. The four remaining patients have a sustained response for a median of 34 weeks (range, 16–53) off therapy. No patients developed RECIST PD while off therapy. <h3>Conclusions</h3> This prospective experience of intermittent nivolumab dosing in mRCC supports further investigation of intermittent immunotherapy dosing strategies in RCC. <h3>Trial registration</h3> NCT03126331 (Intermittent Nivolumab in Metastatic Renal Cell Carcinoma Patients; Date of registration 4/27/2017; https://clinicaltrials.gov/ct2/show/NCT03126331).
Randomized phase II trial of venetoclax + fulvestrant versus fulvestrant in estrogen receptor+, HER2– locally advanced or metastatic breast cancer following recurrence or progression during or after a CDK4/6 inhibitor: VERONICA.
Authors: Geoffrey J Lindeman, Aditya Bardia, Rebecca Bowen, Aulde Flechais, Guiyuan Lei, Alexandra Hogea, Mehrdad Mobasher, Saeed Rafii
Journal: Journal of Clinical Oncology (2019)

TPS1108 Background: CDK4/6 inhibitors (CDK4/6is) administered with endocrine therapy have demonstrated improvements in progression-free survival (PFS) for estrogen receptor (ER)+ advanced breast cancer (BC), but resistance occurs, and new options are needed in the post-CDK4/6i setting. BCL2 is an estrogen-responsive anti-apoptotic molecule overexpressed in 75% of BCs. The BCL2 inhibitor venetoclax (Ven) has shown improved outcomes and tolerability in hematological malignancies such as chronic lymphocytic leukemia, and has been investigated in BC. A phase 1b study of Ven + tamoxifen demonstrated safety and an efficacy signal in ER+, BCL2+ metastatic BC (mBC). Preclinical data for Ven + fulvestrant (Ful) have also shown synergy. Based on these proof-of-principle data, the current study evaluates safety and efficacy of Ven + Ful vs Ful in women with ER+, HER2– locally advanced (LA)/mBC progressing after first- or second-line of prior therapy for metastatic disease, including ≥8 wks of a CDK4/6i. Methods: VERONICA is a global, randomized, phase 2, multicenter, open-label study. Eligible patients (pts) are aged ≥18 yrs with confirmed ER+, HER2–, inoperable LA/mBC, ≥1 measurable lesion, tissue evaluable for BCL2, and ECOG performance status 0–1. Prior Ful or Ven, or prior chemotherapy for LA/mBC are prohibited. Stratified by BCL2 expression (low vs high) and number of prior lines of mBC therapy (1 vs 2), pts are randomized 1:1 to Ven 800 mg PO daily + Ful 500 mg IM (cycle 1 days 1 and 15, and day 1 of each subsequent 28-day cycle) vs Ful 500 mg IM alone. Treatment continues until disease progression or intolerable toxicity. Primary endpoint is clinical benefit rate defined as complete/partial response + stable disease for ≥24 wks from randomization. Secondary efficacy endpoints include PFS, objective response rate, duration of response, and overall survival. Safety, pharmacokinetic, biomarker (e.g. BCL2 and PI3K expression) and patient-reported outcome analyses will also be conducted. Currently, 21 of the planned 100 pts have been enrolled; enrollment is ongoing. Clinical trial information: NCT03584009.
Adjuvant nab-paclitaxel plus gemcitabine versus gemcitabine in resected pancreatic ductal adenocarcinoma: A Chinese single institution.
Authors: Zhuzeng Yin, Rong Liu
Journal: Journal of Clinical Oncology (2019)

e15740 Background: Adjuvant chemotherapy with gemcitabine (GEM) is standard care for resected pancreatic ductal adenocarcinoma (PDAC). Nab-paclitaxel plus gemcitabine (AG) vs gemcitabine (GEM) have shown better survival and tumor response with in advanced or metastatic PDAC. We aimed to determine the efficacy and safety of AG compared with GEM for resected PDAC. Methods: We retrospectively reviewed resectable PDAC patients (pts) who received AG or GEM as adjuvant chemotherapy from January 2013 to December 2016 at the Chinese PLA General Hospital, Bei Jing, China. Pts received nab-paclitaxel (125mg/m 2 ) followed by GEM (1,000 mg/m 2 ) on days 1, 8 every 3 weeks or GEM (1,000 mg/m 2 ) alone on days 1, 8 every 3 weeks for 6 cycles unless disease progression or there was unacceptable level of adverse events. Disease free survival (DFS), overall survival (OS) and toxicity were analyzed. Results: Among 70 pts received AG or GEM as adjuvant chemotherapy, 10 pts were excluded due to the serious complication or R2 resection. The analysis was based on 30 pts in each group undergone complete macroscopic (R0 or R1) resection. Median DFS was 15.8 months (95% CI 13.1-18.5) in AG group (6 pts not arrived) compared with 12.2 months in GEM group (95% CI 9.6-14.8, P= 0.039, 3 pts not arrived). Median OS was 28.3 months (95% CI 21.9-34.6) in AG group (11 pts not arrived) as compared with 20.6 months in GEM group (95% CI 11.2-29.9, P= 0.028, 7 pts not arrived). The 2 years survival rate was 63.3% versus 43.3% in AG group versus GEM group. The most common adverse events of grade 3 or higher were leukopenia (32.3% in AG group vs. 20.7% in GEM group, P= 0.387), neutropenia (45.2% vs.31%, P= 0.298), G-CSF use (41.9% vs. 24.1%, P= 0.177), sensory peripheral neuropathy (51.6% vs. 24.1%, P= 0.036) and fatigue (3.2% vs. 3.4%, P= 0.737). Conclusions: Our results provide the first evidence that the adjuvant combination of nab-paclitaxel plus gemcitabine significantly improved DFS and OS of resected PDAC. Future RCTs with multi-center participation, particularly focused on adjuvant AG, can further provide information to confirm and strengthen these data.