tbuckley/cabot-search huggingface dataset:
Outcome of neo-adjuvant chemotherapy in 225 surgical candidates with malignant pleural mesothelioma.
Authors: Nobuyuki Kondo, Toru Nakamichi, Akifumi Nakamura, Ayumi Kuroda, Masaki Hashimoto, Teruhisa Takuwa, Seiji Matsumoto, Yoshitomo Okumura, Kozo Kuribayashi, Takashi Kijima, Tohru Tsujimura, Seiki Hasegawa
Journal: Journal of Clinical Oncology (2019)

8548 Background: Since any surgery for malignant pleural mesothelioma (MPM) are cytoreductive, effective chemotherapy is a prerequisite for surgery. In this context, we give neo-adjuvant chemotherapy (NAC) to all surgical candidates. Methods: Hyogo College of Medicine MPM Surgery Program mandates all surgical candidates to receive NAC, and only patients with stable disease (SD) or better response proceeds to surgery. The program comprised NAC followed by extrapleural pneumonectomy (EPP) and hemithoracic radiation until 2012, and NAC followed by pleurectomy/decortication (P/D) and postoperative chemotherapy thereafter. Eligibility criteria are histologically confirmed non-sarcomatoid MPM, clinically resectable stage (T1-3N0-1M0), performance status 0–1, and no major comorbidity. Results: From December 2006 to December 2018, 225 patients were enrolled. Of 225, 24 patients (10.7%, Group A) did not proceed to surgery because of progressive disease (n=23) or serious adverse events (n=2). Of the remaining 201 patients with partial response (n=38, 16.9%) or stable disease (n=163, 72.4%), 19 refused surgery (Group B), 16 received exploratory thoracotomy (Group C), and 165 completed surgery (Group D, EPP58, P/D107). Surgical mortality rates at 30 and 90 days were 1.1% (n=2) and 2.8% (n=5), and surgical morbidity (≧grade 3) was 26.0% (n=47). Median survival time and survival rates of each group were shown in the table. Briefly, 2-yr survival competed among Group B,C and D, whereas 5-yr survival rapidly dropped in Group B and C. Conclusions: Approximately 90% of MPM patients with surgical intent successfully underwent either of EPP or P/D after effective chemotherapy with acceptable surgical mortality and morbidity. Comparison of patients who refused or accepted surgery suggested that surgery contributed to long-term survival. [Table: see text]
PSA decline and objective response rates in White (W), Black (B), and Asian men with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Susan Halabi, Sandipan Dutta, Kim N. Chi, Catherine M. Tangen, Mengdi Xuan, Daniel Peter Petrylak, John C. Araujo, Karim Fizazi, David I. Quinn, Michael J. Morris, Celestia S. Higano, Ian Tannock, Eric Jay Small, William Kevin Kelly
Journal: Journal of Clinical Oncology (2019)

5021 Background: We have shown previously in multivariable analysis that AA men had 19% lower risk of death than C men with metastatic castration resistant prostate cancer (mCRPC) treated with a docetaxel (D) and prednisone (P) based regimen. The primary goal of this analysis was to compare ≥50%PSA decline and objective response rate (ORR) in C men, AA men, and Asian men with mCRPC treated with a DP based regimen. Methods: Individual patient data from 8,151 mCRPC men randomized on eight phase III trials to a D containing regimen were combined. Race used in the analysis was based on self-report. The endpoints were ≥50% PSA decline from baseline defined by the PSA working group 2 and ORR (defined as complete or partial response). The logistic regression model was employed to assess the prognostic importance of race in predicting ≥50% PSA decline and ORR adjusting for treatment arm, performance status, and site of metastases. Results: Of 8,151, 7,687 (94%) patients had evaluable PSA data. Of 7,687 men, 6,535 (85%) were W, 445 (6%) were B, 395 (5%) were Asian and 312 (4%) had race unspecified. Men with race unspecified were excluded from the analysis, leaving 7,375 men. Percentage of patients who experienced PSA decline from baseline were: 64%, 58% and 62% in W, B and Asian men, respectively. In multivariable analysis adjusting for risk factors, the pooled odds ratios for PSA decline for AA vs. W were 0.9 (95% CI = 0.7-1.1, p = 0.16) and 1.0 (95% CI = 0.8-1.2, p = 0.92) for Asian vs. W. In 2,760 patients with measurable disease, the percentage of patients who had ORR were: 39%, 31% and 34% in W, B and Asian men, respectively. In multivariable analysis, the pooled odds ratios for ORR were 1.0 (95% CI = 0.7-1.4) for B vs. W and 0.9 (95% CI = 0.6-1.4) for Asian vs. W. Conclusions: There were no differences in PSA decline and ORR outcomes in W, B, or Asian men with mCRPC enrolled on these phase III clinical trials with DP. Clinical trial information: NCT00110214.
Phase II study of eribulin mesylate for treatment of CNS metastases (mets) in metastatic breast cancer (mBC).
Authors: Ariel Ann Nelson, Shivaprasad Manjappa, Yuvraj Choudhary, Cheryl L. Thompson, Jeanine Agler, Bethany Lawrence, Manmeet Singh Ahluwalia, Paula Silverman
Journal: Journal of Clinical Oncology (2019)

e12571 Background: There is no approved drug therapy for CNS mets from mBC. Eribulin mesylate (eribulin) is a microtubule inhibitor approved for treatment of mBC patients (pts) who have received at least 2 prior chemotherapy regimens. Previously reported cases have demonstrated significant CNS responses in mBC pts treated with eribulin. This study evaluates the CNS response in pts with mBC treated with eribulin. Methods: CASE7113 was a prospective phase II single-arm study to evaluate the 12-week CNS progression free survival (12-wk CNS-PFS) of pts with mBC and CNS mets treated with eribulin. 20 pts were to be enrolled to demonstrate a 40% 12-wk CNS-PFS (95% CI, 8.5% - 61.5%). All pts had radiologically confirmed mBC CNS lesions with at least one lesion that did not receive prior radiation or surgical resection. Eribulin was administered at standard dose of 1.4mg/m 2 IV on days 1 and 8 of a 21 day-cycle. Pts underwent baseline and 12-week brain MRI. The study was closed due to slow accrual; an analysis of enrolled pts was performed. Results: 9 female pts were enrolled; median age was 56 (32-82) years. 55% and 67% had ER+ and/or PR+ and Her2+ mBC respectfully. 1 pt had triple negative breast cancer (TNBC). Median number of prior therapies was 3 (0-12). The 12-wk CNS-PFS (95% CI) was 88.9% (51.8% - 99.7%), the median PFS (95% CI) was 22.6 (4.3 - 31.9) weeks, the median OS (95% CI) was 15.7 (4.0 - 27.3) months. 4 pts achieved stable disease and 1 pt had a partial response. There were no unexpected toxicities. Conclusions: For mBCa pts with CNS mets, this estimate of 12-wk CNS-PFS suggests activity of eribulin and merits further investigation in this population in the context of clinical trials. Clinical trial information: NCT02581839.
Interlesional response assessment with <sup>18</sup>F-sodium fluoride (<sup>18</sup>F-NaF) PET/CT in men with chemotherapy-naive bone metastatic castration-resistant prostate cancer (mCRPC) treated with enzalutamide (ENZA).
Authors: Christos Kyriakopoulos, Elisabeth I. Heath, Anna C. Ferrari, Scott Perlman, Tina M. Mayer, Mark N. Stein, Katharina Modelska, William Duggan, Robert Jeraj, Glenn Liu
Journal: Journal of Clinical Oncology (2019)

5036 Background: 18 F-NaF PET/CT provides spatial and quantitative information on osteoblastic activity in men with bone mCRPC; thus, it can be used to assess interlesional response heterogeneity, a critical clinical issue. Here we assess the proportion of men treated with ENZA with responding lesions by 18 F-NaF PET/CT at the time of prostate-specific antigen (PSA), standard radiographic, or clinical progression. Methods: Men with progressive mCRPC with ≥ 2 lesions on bone scintigraphy were enrolled and treated with ENZA 160 mg daily at 3 US sites. 18 F-NaF PET/CT scans were obtained at baseline (PET1), week 13 (PET2), and at the time of PSA progression (increase of ≥ 25% and ≥ 2.0 ng/mL above nadir), standard radiographic or clinical progression, or at 2 years without progression (PET3) using Quantitative Total Bone Imaging (QTBI). The primary endpoint was the proportion of men with ≥ 1 responding bone lesion (defined as a lesion with a total NaF standardized uptake value [SUV] less than baseline) on PET3. Evaluable men had scans at PET1 and PET3. Results: A total of 23 men (median age, 72 years [range, 51-93]; median PSA, 20.5 ng/mL [range, 3.9-133.6]) were enrolled. The study met its primary objective; 22 of 22 (100%) evaluable men had ≥ 1 responding bone lesion on QTBI at PET3. Total disease burden changed from a mean baseline SUV of 5700 (range, 507-22,850) to 5590 (range, 213-17,090) at PET2 and 6020 (range, 118-16,650) at PET3. The proportion of progressive lesions increased from a mean 7.8% (range, 0-29) at PET2 to 9.4% (range, 0-32) at PET3. Conclusions: Although PSA response with ENZA is high, many men experience a mixed response to treatment. While overall functional disease burden improves during treatment, an eventual increase in global burden is seen at the time of progression as measured by 18 F-NaF PET/CT. At the primary endpoint analysis the proportion of progressing lesions is low, supporting both the hypothesis that a substantial number of lesions continue to benefit from treatment and the concept of treating beyond progression and selectively targeting nonresponding lesions while keeping patients on ENZA. Clinical trial information: NCT02384382.
A phase 1/2a study of GEN-009, a neoantigen vaccine based on autologous peptide immune responses.
Authors: Roger B. Cohen, Melissa Lynne Johnson, Przemyslaw Twardowski, Mark N. Stein, Ulka N. Vaishampayan, Jason R. Dobson, James Foti, Parul Agnihotri, Louisa Dowal, Wendy Broom, Lisa McNeil, Thomas A. Davis, Jessica Flechtner
Journal: Journal of Clinical Oncology (2019)

2611 Background: Tumor-specific neoantigens provide individualized targets for immunotherapy. In silico selection methods are sub-optimal at predicting immunogenic targets, missing up to 70% of true neoantigens. ATLAS is a powerful tool that screens all candidate neoantigens for pre-existing patient-specific CD4 or CD8 responses in an HLA agnostic assessment. ATLAS also identifies inhibitory peptides that may suppress tumor immunity and accelerate tumor progression. The GEN-009 vaccine contains stimulatory but no inhibitory peptide antigens. Methods: GEN-009-101 is a first-in-human phase 1/2a study testing platform feasibility, safety, immunogenicity and clinical activity in selected solid tumors. After next-generation tumor sequencing and cytokine-based ATLAS assessment using autologous T cells and APCs, up to 20 stimulatory synthetic long peptides are used in each personalized vaccine. GEN-009 is administered with poly-ICLC on weeks 0, 3, 6, 12 and 24. Part A, a safety and immunogenicity pilot, has completed target enrollment of patients without evidence of disease to receive GEN-009; Part B has 5 tumor-specific cohorts of up to 15 pts naïve to PD-1 blockade who will receive GEN-009 with a SOC immunotherapy; Part C: up to 15 pts refractory to PD-1 inhibitors will receive GEN-009 monotherapy. Results: GEN-009 has been successfully generated for patients. Repeated dosing has been well tolerated with mild local discomfort and no DLT. ATLAS screening results below show notable interpatient variability; one subject had only CD4 neoantigens, one had only CD8, another had a strong CD8 bias, and one patient had prominent inhibitory peptides. Conclusions: GEN-009 is a neoantigen vaccine that personalizes tumor specific targets and the individual patient’s capacity to respond. Immunogenicity data will assess CD4 and CD8 T cell responses to each vaccine neoantigen. Clinical trial information: NCT03633110. [Table: see text]
DNA repair deficiency in neuropathogenesis: when all roads lead to mitochondria
Authors: Luis Bermúdez-Guzmán, Alejandro Leal
Journal: Translational Neurodegeneration (2019)

Mutations in DNA repair enzymes can cause two neurological clinical manifestations: a developmental impairment and a degenerative disease. Polynucleotide kinase 3′-phosphatase (PNKP) is an enzyme that is actively involved in DNA repair in both single and double strand break repair systems. Mutations in this protein or others in the same pathway are responsible for a complex group of diseases with a broad clinical spectrum. Besides, mitochondrial dysfunction also has been consolidated as a hallmark of brain degeneration. Here we provide evidence that supports a shared role between mitochondrial dysfunction and DNA repair defects in the pathogenesis of the nervous system. As models, we analyze PNKP-related disorders, focusing on Charcot-Marie-Tooth disease and ataxia. A better understanding of the molecular dynamics of this relationship could provide improved diagnosis and treatment for neurological diseases.
Analysis of racial distribution amongst patients in phase III cancer clinical trials.
Authors: Swathi Gopishetty, Shruti Gupta, Vamsi Kota, Achuta Kumar Guddati
Journal: Journal of Clinical Oncology (2019)

6588 Background: Minority races are often under-represented in cancer clinical trials as enrollment often occurs in large centers. Racial diversity may vary by geographical location and socio-economically backward areas may have a very different racial mix. This study explores the representation of different races in phase 3 clinical trials conducted in the past 10 years. Methods: Details about adult patients involved in phase 3 trials was extracted from the clinical trials.gov for 3 common solid organs and 3 hematological malignancies [breast, colon, lung, diffuse large B-cell lymphoma (DLBCL), acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL)]. The racial distribution of the patient population in these trials was analyzed. Results: African American and Asian patients are under-represented in all phase 3 cancer clinical trials. The table shows the average racial distribution in clinical trials for each organ specific malignancy. Conclusions: Most phase 3 clinical trials except for lung cancer, predominantly consisted of Caucasian patients. Applying the results of these trails to patients of other races should be done with caution. This study highlights the disparity of race in patients enrolled in clinical trials when compared to diverse and different populations that are encountered in practice. [Table: see text]
Correlation of peripheral blood markers of DNA damage and immune response with chemoradiation response in patients with locally advanced rectal cancer.
Authors: Sanjeevani Arora, Elena Demidova, Vladimir Avkshtol, Randy Lesh, Amanda J Browne, Elizabeth A. Handorf, Erica Golemis, Joshua E. Meyer
Journal: Journal of Clinical Oncology (2019)

e15109 Background: Approximately 60% of newly diagnosed rectal cancers are locally advanced. The standard of care for these malignancies is neoadjuvant chemoradiation therapy (nCRT) followed by surgery. Unfortunately, only approximately 20% of patients experience a complete response, but all are at risk for toxicity. There are no biomarkers to predict who will derive the greatest benefit from CRT. We hypothesized that inherent DNA damage recognition and repair (DNA-DRR) capacity contributes to CRT response in rectal cancer. Methods: We used primary peripheral blood lymphocytes (pPBLs) from rectal cancer patients to study differences in DNA-DRR capacity. The blood samples used were either drawn prior to nCRT or post a standard course of ~5.5 weeks of nCRT. We used immunofluorescence and Luminex-based multianalyte approaches to study DNA-DRR capacity in pPBLs. To determine if the tested biomarkers correlated with CRT response, we segregated patients by neoadjuvant rectal (NAR) score, a validated surrogate endpoint in rectal cancer. Results: Using pPBLs, we found that a subset of patients had elevated phosphorylated histone H2AX (γ-H2AX) foci, a well-described marker of DNA double strand breaks. We found that poor responders (PoR; NAR score &gt; 14; n = 21) had lower γ-H2AX foci then complete responders (CR; NAR score &lt; 1; n = 21) (P &lt; 0.0001, Kruskal-Wallis test). We also did not observe any significant differences in γ-H2AX foci from pPBLs drawn prior to CRT versus post nCRT (p = 0.519, n = 11, Wilcoxon rank sum test). Next, by multianalyte testing, we found that a combined score derived from six DNA-DRR markers (ATR, MDM2, phosphorylated forms of H2AX (γ), p53, Chk1, Chk2) strongly correlated with CR (p &lt; 0.001). Finally, by multianalyte testing, we also detected a serum signature of inflammatory markers that significantly correlated with CRT response (p &lt; 0.05). Conclusions: Our data suggest that rectal cancer patients who differ in their response to CRT differ in global, inherent DNA-DRR capacity, suggesting that DNA-DRR capacity in pre-treatment pPBLs can form the basis of a predictive biomarker. This predictive capacity may reflect underlying epigenetic or genetic differences, or inflammatory state. Validation and further development of this novel assay is warranted, as it has the capacity to substantially improve patient selection in an era with growing treatment options for these patients.
Benefit from letrozole as extended adjuvant therapy after sequential endocrine therapy: A randomized, phase III study of Gruppo Italiano Mammella (GIM).
Authors: Lucia Del Mastro, Mauro Mansutti, Giancarlo Bisagni, Riccardo Ponzone, Antonio Durando, Laura Amaducci, Alessandra Fabi, Antonio Frassoldati, Andrea Michelotti, Antonio Pazzola, Enrichetta Valle, Giovanni Sanna, Stefania Gori, Sabino De Placido, Ornella Garrone, Michela Donadio, Paolo Bruzzi, Claudia Bighin, Matteo Lambertini, Francesca Poggio
Journal: Journal of Clinical Oncology (2019)

504 Background: The effect of extended adjuvant endocrine therapy (ET) with aromatase inhibitors (AI) after sequential ET with tamoxifen (Tam) followed by AI for 5 years is still controversial. We conduct a clinical trial to assess different durations of ET of letrozole after tam. Methods: The GIM4 LEAD (Gruppo Italiano Mammella 4- Letrozole adjuvant therapy duration study, ClinicalTrials.gov:NCT01064635 ) was a prospective, randomized, Italian multicentric trial. Post-menopausal patients (pts) with hormone receptor positive early breast cancer free of recurrence after 2-3 years of adjuvant tam, were randomized in a 1:1 ratio to receive 3-2 years (short arm, S) or 5 years (long arm, L) of letrozole. The primary study end point was disease-free survival (DFS). Results: Between August 2005 and May 2010, 2056 pts were randomly assigned to receive 3-2 years (n=1030) or 5 years (n=1026) of letrozole. Main patients characteristics in the S and L arms were, respectively: median age 60 vs 61 years, node negative 56 vs 56%, (neo)adjuvant chemotherapy 53.4 vs 54.1%. The median follow-up was 10 years (IQR range: 8.6-11.4). The 8-year DFS was 80% (95% CI:77.3-82.7) and 85% (95% CI:82.9-87.6) in the S and L arm, respectively (hazard ratio, HR 0.82; 95% CI:0.68-0.98; p=0.031). This effect did not change in a multivariate Cox model that included nodal status, grading and age. No evidence of interaction between random assignment and nodal status, age and grading was observed. Among 1960 pts evaluable for toxicity, osteoporosis was diagnosed in 47 (4.8%) in S arm and 81 (8.3%) pts in L arm (chi-square=9.88; p=0.002). Bone fractures occurred in 5 (0.5%) and 9 (0.9%) pts in S and L arm, respectively ( p=0.29, Fisher exact test). Conclusions: After 2-3 years of adjuvant tam, extended treatment with 5 years of letrozole resulted in significant improvement in DFS compared to the standard duration of 2-3 years of letrozole. Clinical trial information: NCT01064635.
Phase I trial of chloroquine (CQ)/hydroxychloroquine (HCQ) in combination with carboplatin-gemcitabine (CG) in patients with advanced solid tumors.
Authors: Nagla Fawzy Abdel Karim, Imran Ahmad, Ola Gaber, Ihab Eldessouki, Olugbenga Olanrele Olowokure, Maria Farooq, John Charles Morris
Journal: Journal of Clinical Oncology (2019)

3027 Background: Autophagy is a catabolic process triggered in cells during periods of stress to enable their survival. Established tumors utilize autophagy to survive periods of metabolic or hypoxic stress. Inhibition of early stage autophagy can rescue cancer cells, while inhibition of late stage autophagy will lead to cell death due to accumulation of damaged organelles. The antimalarial drugs CQ and HCQ inhibit late phase autophagy. The goal of our study is to assess the safety, tolerability and activity of combining CQ/HCQ with CG in advanced solid tumor patients who either progressed on other therapies or in whom CG is a therapeutic option. Methods: This single institution phase 1 dose-escalation study was designed to evaluate the maximum tolerated dose (MTD) of CQ, later substituted with HCQ, in combination with CG in patients with previously treated advanced solid tumors. Secondary objectives were to determine ORR, PFS and OS. A starting dose of 50 mg of CQ/HCQ was used in conjunction with CG, and increased in increments of 50 mg in each dose cohort. Grade 3 or greater toxicity that is treatment-related, and was not self-limited, or controlled in less than 7 days was considered dose limiting toxicity (DLT). Results: Twenty-three patients were enrolled with a median follow up of 6 months. HCQ 100 mg was found to be the MTD in combination with CG with ≥Grade 3 thrombocytopenia and/or neutropenia as dose-limiting. Median OS was 11 months, and the 1- and 3- year overall survival rates were 30% and 7%, respectively. Median progression free survival was 5 months and the 6-, 12-, and 18-months progression-free survivals were 48%, 21% and 14%, respectively (Table). Conclusions: The MTD identified for CQ/HCQ was lower than previously reported with concomitant use of chemotherapeutic regimes, likely due to the myelosuppressive nature of CG. Clinical trial information: NCT02071537. [Table: see text]