10 results on '"Grace Durenberger"'
Search Results
2. Data from Targeting BET Proteins BRD2 and BRD3 in Combination with PI3K-AKT Inhibition as a Therapeutic Strategy for Ovarian Clear Cell Carcinoma
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Christopher J. Kemp, Carla Grandori, Elizabeth M. Swisher, Tan A. Ince, Robert L. Diaz, Rachele Rosati, Grace Durenberger, Kay E. Gurley, Russell Moser, Reid Shaw, Goldie Y.L. Lui, and Shogo Shigeta
- Abstract
Ovarian clear cell carcinoma (OCCC) is a rare, chemo-resistant subtype of ovarian cancer. To identify novel therapeutic targets and combination therapies for OCCC, we subjected a set of patient-derived ovarian cancer cell lines to arrayed high-throughput siRNA and drug screening. The results indicated OCCC cells are vulnerable to knockdown of epigenetic gene targets such as bromodomain and extra-terminal domain (BET) proteins BRD2 and BRD3. Subsequent RNA interference assays, as well as BET inhibitor treatments, validated these BET proteins as potential therapeutic targets. Because development of resistance to single targeted agents is common, we next performed sensitizer drug screens to identify potential combination therapies with the BET inhibitor CPI0610. Several PI3K or AKT inhibitors were among the top drug combinations identified and subsequent work showed CPI0610 synergized with alpelisib or MK2206 by inducing p53-independent apoptosis. We further verified synergy between CPI0610 and PI3K–AKT pathway inhibitors alpelisib, MK2206, or ipatasertib in tumor organoids obtained directly from patients with OCCC. These findings indicate further preclinical evaluation of BET inhibitors, alone or in combination with PI3K-AKT inhibitors for OCCC, is warranted.
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- 2023
3. Abstract 3399: Tumor organoid based drug sensitivity testing in ovarian cancer identifies exceptional responders to targeted therapies
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Amanda M. Prechtl, Marwah Al-Aloosi, Payel Chatterjee, Rachele Rosati, Samantha Velazquez, Lauren Appleyard, Grace Durenberger, Cristina Cordero, Robert Diaz, Hallie Swan, Brady Bernard, Siddhartha Mukherjee, Barbara Goff, Elizabeth Swisher, Heidi Gray, Kalyan Banda, Christopher Kemp, and Carla Grandori
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Cancer Research ,Oncology - Abstract
Background: Over 50% of patients with ovarian cancer (OVCA) succumb to their disease within five years from diagnosis, highlighting the need for new approaches to identify therapeutic options. The PARIS® test is a CLIA certified organoid based high throughput drug sensitivity assay that can be used by oncologists to select personalized treatments. In this study our objectives were to: 1) demonstrate the feasibility of organoid based drug testing in the clinical setting; 2) highlight the clinical utility and the predictive value of the PARIS® test; and 3) identify new therapeutic options for OVCA patients. Methods: 93 patients, with a median age at diagnosis of 55 years (range 25-82) were selected as eligible for the PARIS® test at the discretion of the oncologists. The cohort included 74.1% high grade serous tumors, 6.9% low grade serous tumors, 6.0% clear cell carcinomas, 3.4% granulosa cell tumors, 2.5% Mullerian tumors, 1.7% carcinosarcomas and 2.5% fallopian tumors. 16.1% of patients were treatment naïve and 83.9% received one or more previous lines of treatment. 116 patient derived tumor organoids (PDTOs) were derived from surgical excisions, biopsies, or body fluids and subjected to functional testing with a panel of chemo- and targeted therapies that are FDA-approved or in clinical development. Drug responses were evaluated using a proprietary score ranking drugs from exceptional responses to no response. The median turnaround time from biopsy to report delivery was 19 days. Results: The success rate for deriving OVCA organoids was 92%; 81.0% of samples demonstrated exceptional/good response to at least one drug. PDTO drug sensitivities were highly concordant with both retrospective and prospective clinical response. Drugs that frequently showed exceptional/good responses included WEE1 inhibitors (28.4%), HDAC inhibitors (25.0%), and Pan-DNMT inhibitors (11.2%). Further, 12.9% of cases showed responses to the BTK/EGFR inhibitor ibrutinib and 23.3% to HER2 inhibitors lapatinib and neratinib. Two patients with advanced stage, recurrent low grade serous ovarian cancer showed exceptional and durable clinical responses to PARIS® guided treatments, ibrutinib and lapatinib, respectively. Conclusions: This study demonstrates the utility of organoid based drug testing to identify potentially effective drugs and to guide treatment choice for patients with ovarian cancer. Tumor organoid based personalized treatments lead to extraordinary responses in several patients, including a patient in hospice care who responded to ibrutinib monotherapy and is still alive after 27 months. Citation Format: Amanda M. Prechtl, Marwah Al-Aloosi, Payel Chatterjee, Rachele Rosati, Samantha Velazquez, Lauren Appleyard, Grace Durenberger, Cristina Cordero, Robert Diaz, Hallie Swan, Brady Bernard, Siddhartha Mukherjee, Barbara Goff, Elizabeth Swisher, Heidi Gray, Kalyan Banda, Christopher Kemp, Carla Grandori. Tumor organoid based drug sensitivity testing in ovarian cancer identifies exceptional responders to targeted therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3399.
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- 2023
4. Targeting BET Proteins BRD2 and BRD3 in Combination with PI3K-AKT Inhibition as a Therapeutic Strategy for Ovarian Clear Cell Carcinoma
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Rachele Rosati, Elizabeth M. Swisher, Goldie Y. L. Lui, Shogo Shigeta, Grace Durenberger, Robert L. Diaz, Christopher J. Kemp, Tan A. Ince, Carla Grandori, Kay E. Gurley, Reid Shaw, and Russell Moser
- Subjects
0301 basic medicine ,Cancer Research ,Transfection ,Ipatasertib ,Article ,BET inhibitor ,Phosphatidylinositol 3-Kinases ,03 medical and health sciences ,0302 clinical medicine ,RNA interference ,Humans ,Medicine ,Protein kinase B ,PI3K/AKT/mTOR pathway ,Ovarian Neoplasms ,Gene knockdown ,business.industry ,medicine.disease ,Bromodomain ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,Female ,business ,Ovarian cancer ,Proto-Oncogene Proteins c-akt ,Adenocarcinoma, Clear Cell ,Transcription Factors - Abstract
Ovarian clear cell carcinoma (OCCC) is a rare, chemo-resistant subtype of ovarian cancer. To identify novel therapeutic targets and combination therapies for OCCC, we subjected a set of patient-derived ovarian cancer cell lines to arrayed high-throughput siRNA and drug screening. The results indicated OCCC cells are vulnerable to knockdown of epigenetic gene targets such as bromodomain and extra-terminal domain (BET) proteins BRD2 and BRD3. Subsequent RNA interference assays, as well as BET inhibitor treatments, validated these BET proteins as potential therapeutic targets. Because development of resistance to single targeted agents is common, we next performed sensitizer drug screens to identify potential combination therapies with the BET inhibitor CPI0610. Several PI3K or AKT inhibitors were among the top drug combinations identified and subsequent work showed CPI0610 synergized with alpelisib or MK2206 by inducing p53-independent apoptosis. We further verified synergy between CPI0610 and PI3K–AKT pathway inhibitors alpelisib, MK2206, or ipatasertib in tumor organoids obtained directly from patients with OCCC. These findings indicate further preclinical evaluation of BET inhibitors, alone or in combination with PI3K-AKT inhibitors for OCCC, is warranted.
- Published
- 2021
5. Abstract P6-10-17: Breast MRI as a radiomic biomarker of immune response in HER2+ breast cancer
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Savannah C. Partridge, Grace Durenberger, Sasha E. Stanton, Suzanne Dintzis, Shaveta Vinayak, Laura C Kennedy, and Vijayakrishna K. Gadi
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Oncology ,Cancer Research ,medicine.medical_specialty ,medicine.diagnostic_test ,business.industry ,medicine.disease ,Breast cancer ,Immune system ,Internal medicine ,medicine ,Biomarker (medicine) ,Breast MRI ,business - Abstract
Rationale/Objectives: Tumor immune infiltration in HER2+ breast cancer is associated with improved outcomes and better responses to treatment with drugs such as trastuzumab. Breast MRI is a non-invasive technique that is part of the standard evaluation for localized breast cancer. Breast MRI dynamic-contrast enhanced (DCE) and diffusion-weighted imaging (DWI) sequences may detect immune responses in the tumor microenvironment. Apparent diffusion coefficient (ADC), which is derived from DWI, has been associated with tumor cellularity. In this pilot study, we hypothesized that patients with low ADC would be more immune responsive (i.e. have greater TIL infiltration) to trastuzumab. We also performed an exploratory analysis looking at differences in the expression of immune-relevant genes between “low” and “high” ADC patients. Methods: Patients with localized HER2+ breast cancers 10 mm or larger and planned for curative-intent therapy were eligible to enroll. After enrollment, patients received a single run-in dose of trastuzumab with paired breast MRI exams before and after treatment that included DCE and DWI sequences. Post-trastuzumab tissue was obtained from the patient’s surgical specimen or from a second biopsy (if planned for additional neoadjuvant treatment). MRI images were analyzed to measure the functional tumor volume and peak signal enhancement ratio from DCE and mean apparent diffusion coefficient (ADC) from DWI. TIL content was assessed by a breast pathologist in both the pre- and post-trastuzumab tissue specimens. The pre- and post-treatment samples were also analyzed using an immune-focused RNA-based multiplex gene expression assay. Results: Twelve women have enrolled to date with a median age of 53 years (range 37-70 years old). Five out of the twelve patients (42%) had estrogen-receptor negative tumors. For the 8 patients with pre- and post-treatment tissue currently available for analysis, the average pre-treatment TIL percentage was 22% (range 1-70%), the average post-treatment TIL percentage was 42% (range 1-90%), and the average absolute increase between pre- and post-treatment TILs was 20% (range 0%-58%). Pre- and post-treatment ADC showed a strong negative correlation with the increase in TIL content after trastuzumab treatment (r = -0.71 and r = -0.93, respectively). At submission, preliminary gene expression analysis of pre- and post-treatment tissue is available in 6 patients. The patients were binned into “high” and “low” ADC groups with the median pre-treatment ADC as the cut-off. The magnitude of change in gene expression after trastuzumab treatment (small vs large change) clustered by high or low pre-treatment ADC; this suggests that pre-treatment ADC may differentiate between two distinct immune phenotypes. Further analysis showed that the low ADC group had relatively higher pre-treatment gene expression of CD8, CD4, and CD19 (T and B cell markers) when compared to the high ADC group. The low ADC group also had a decrease in FoxP3 expression (regulatory T cell marker) versus the high ADC group, which had an increase in FoxP3 expression. The high ADC group also had a notable increase in CCR4 expression (associated with a TH2 type immune response), while the low ADC group did not have an increase. The combination of an increase in FoxP3 expression and an increase in CCR4 expression suggests that the high ADC group may have a more immune-inhibited microenvironment in response to trastuzumab. Conclusions: These initial analyses suggest that the pre-treatment ADC calculated from DWI may identify HER2+ breast cancers that will have an anti-tumor immune response to trastuzumab therapy. Final data from the full planned cohort will be presented at the meeting and include discussion of the DCE metrics. Based on this preliminary data, further study of breast MRI as an immune biomarker is warranted. Citation Format: Laura Carpin Kennedy, Grace Durenberger, Sasha E. Stanton, Shaveta Vinayak, Suzanne Dintzis, Savannah Partridge, VK Gadi. Breast MRI as a radiomic biomarker of immune response in HER2+ breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-10-17.
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- 2020
6. Abstract 534: Functional drug screening of organoids from ovarian cancer patients demonstrates clinical and genomic concordance and identifies novel therapeutic vulnerabilities
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Rachele Rosati, Isabella N. Stork, Katannya Kapeli, Anne Louise Richardson, Payel Chatterjee, Barbara A. Goff, Madison Pollastro, Hallie A. Swan, Yasin Memari, Carla Grandori, Astrid Margossian, Elizabeth M. Swisher, Heidi J. Gray, Robert L. Diaz, Kalyan Banda, Serena Nik-Zainal, Danielle Peretti, Grace Durenberger, Goldie Y. L. Lui, Mia Lints, Adam Whitney, Kay E. Gurley, Helen Davies, Christopher J. Kemp, and Lauren Appleyard
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Oncology ,Cancer Research ,medicine.medical_specialty ,Bevacizumab ,business.industry ,Serous carcinoma ,Cancer ,Precision medicine ,medicine.disease ,Ovarian tumor ,Internal medicine ,PARP inhibitor ,Medicine ,Sample collection ,business ,Ovarian cancer ,medicine.drug - Abstract
Background: Clinically approved targeted therapies for ovarian cancer patients are currently limited to PARP inhibitors and bevacizumab. To improve treatment outcomes, a precision medicine approach is crucial to match effective drugs to patient-specific genetic features and vulnerabilities. This study aimed to: (1) demonstrate the feasibility of performing high-throughput drug screens on fresh patient organoids using a CLIA-approved assay, (2) assess concordance of responses with genomic and clinical information, and (3) reveal novel biomarkers of response to approved/experimental drugs and insights into ovarian cancer biology. Methods: From 2015 to 2020, 76 ovarian tumor samples were collected from 60 patients. To date, 50 evaluable samples were successfully screened at SEngine Precision Medicine. Drugs tested include a range of chemotherapies and targeted therapies that are FDA-approved or in clinical development, with an average of 61 drugs screened per assay (range: 6-135). Somatic and/or germline DNA sequencing is currently available for 30 samples. Sample collection, screening, and sequencing is ongoing. Results: The cohort included ovarian cancer patients with high grade serous (65%), low grade serous (7%), unknown grade serous (7%), clear cell (7%), carcinosarcoma (5%), stromal (5%), endometrioid (2%) subtypes, and one of unknown pathology. Whole genome mutational analysis of 5 tumor-derived organoids and their original tumors demonstrated a high degree of similarity between the tumor-organoid pairs. We present prospective and retrospective evidence from at least 18 cases that organoid drug screening can accurately predict clinical response to chemotherapy and targeted therapies. We also report a patient with platinum resistant serous carcinoma who responded to ibrutinib treatment after screening identified the drug as having excellent response in this patient's organoids. Three months into treatment, the patient's CA125 level was reduced from 250 to 125U/ml. In samples with available genomic information, we demonstrate high concordance between drug sensitivity and known biomarkers, e.g. 83% of samples with known BRCA1/BRCA2 mutation or high HRDetect showed sensitivity to a PARP inhibitor. Further, organoid screening can identify unique targets for every patient beyond established genomic biomarkers. Subsets of patients responded exceptionally to BET (41%), HDAC (28%), WEE1 (24%), and BTK (11%) inhibitors, indicating potential for these targeted therapies in ovarian cancer. Conclusions: The genomic and histopathological heterogeneity of ovarian cancer points to a need to evolve and prioritize the personalization of treatment. Our data demonstrates the utility of organoid based drug screening to nominate therapeutic options for individual patients with or without known genomic biomarkers. Citation Format: Goldie Lui, Anne Richardson, Payel Chatterjee, Madison Pollastro, Mia Lints, Danielle Peretti, Rachele Rosati, Lauren Appleyard, Grace Durenberger, Robert Diaz, Kay Gurley, Isabella Stork, Adam Whitney, Katannya Kapeli, Hallie Swan, Yasin Memari, Helen Davies, Serena Nik-Zainal, Kalyan Banda, Heidi Gray, Barbara Goff, Elizabeth Swisher, Astrid Margossian, Christopher Kemp, Carla Grandori. Functional drug screening of organoids from ovarian cancer patients demonstrates clinical and genomic concordance and identifies novel therapeutic vulnerabilities [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 534.
- Published
- 2021
7. A cancer organogram test as a guide for oncology treatments in SOLID tumors: An analysis of 628 tests in 419 patients
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Madison Pollastro, Kalyan Banda, Barbara A. Goff, Hallie A. Swan, Shalini Pereira, Christopher J. Kemp, Danielle Peretti, Payel Chatterjee, Astrid Margossian, Vijayakrishna K. Gadi, Grace Durenberger, Elizabeth M. Swisher, Carla Grandori, G. Adam Whitney, William P. Harris, Adam Diehl, Mia Lints, Annie Richardson, Lauren Appleyard, and Rachele Rosati
- Subjects
Oncology ,Drug ,Cancer Research ,medicine.medical_specialty ,business.industry ,media_common.quotation_subject ,Cancer ,medicine.disease ,Internal medicine ,medicine ,Organoid ,Endocrine system ,business ,media_common - Abstract
2602 Background: A CLIA-certified organoid based drug sensitivity assay (a cancer organogram) has been developed for all solid tumors. An actionable report of organogram sensitivities to endocrine, chemotherapy and targeted agents, produced a drug sensitivity score as a tool to inform therapy decision making. Objectives: To evaluate the success rate of organoid derivation, the organogram drug responses across cancer types and to analyze the impact of the organogram report on therapeutic decision making. Methods: From 2016 to 2020, 628 cancer organograms were performed, with 513 tumor samples from 419 cancer patients. Within 48 hours of collection, fresh samples of tumor cells obtained from core biopsies, surgical excisions, or fluids were cultured, the majority as 3D organoids. Drug screens were performed with a library of up to 220 drugs, and dose-response was evaluated across a range of concentrations for each drug. Organogram sensitivity was ranked as response in five categories based on SPM Score: Exceptional (SPM15/14), Good (13/12), Moderate to Low (11/9), and None( < 9). 118 drugs on average were tested per screen (range: 68-152), so in a total of 628 organograms, more than 70,000 individual drug trials have been performed. The median turnaround time was 28 days (range: 19.5-51.5). Results: Of the 513 collected samples, 314 were fresh specimens: 96 core biopsies, 151 surgical specimens, and 67 fluids (pleural effusions or ascites), with an organoid derivation success rate of 58.3%, 78%, and 88%, respectively. Overall success rate in organoid derivation was 70.2%. Samples with poor viability and low tumor cell count (22%) were rejected. The primary cancer types tested were ovarian (n = 92, 17.9%), breast (n = 73, 14.2%), colorectal (n = 70, 13.6%), pancreatic (n = 51, 9.9%), cholangiocarcinoma (n = 42, 8.1%), and other solid tumors (n = 185, 36%). Median age of patients was 56 years old (range: 5-83), most of them heavily pretreated. 20.45% of drugs screened had exceptional and good responses (SPM score 15-12) (SD: 17.92%). We reviewed genomic data from 374 third-party genomic reports. The most frequent genomic alterations found were TP53 (n = 143, 38.2%), BRCA1 and BRCA2 (n = 47, 12.5%) CDKN2A (n = 42, 11.2%), FGFR1/2/3/4 (n = 41, 10.9%), and PIK3CA (n = 38, 10.1%). Post-test treatment information is available for a subset of 61 patients. The treating physician made an organogram-guided therapeutic decision in 32/44 patients with post test treatment drugs scored (72%). Conclusions: The cancer organogram test has a high rate of success in generating an actionable report that identifies therapies for patients with limited therapeutic options, including those with no known genomic biomarkers. The organogram guided selection of therapeutics for a significant subset of patients, nearly 4 times the rate reported with genomic testing alone.
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- 2021
8. Abstract PS4-01: Clinical and genomic correlation of a CLIA certified organoid based functional test in breast cancer patients
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Eric Gamboa, Rachele Rosati, Grace Durenberger, Hallie A. Swan, Lauren Appleyard, Madison Pollastro, Shalini Pereira, Michael Churchill, Carla Grandori, Astrid Margossian, G. Adam Whitney, Robert L. Diaz, Christopher J. Kemp, Trevor Ainge, Vijayakrishna K. Gadi, Anne Louise Richardson, Alex Federation, Natasha B. Hunter, Payel Chatterjee, and Franz X. Schaub
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Correlation ,Oncology ,Cancer Research ,medicine.medical_specialty ,Breast cancer ,business.industry ,Internal medicine ,medicine ,Organoid ,medicine.disease ,business ,Test (assessment) - Abstract
The goal of precision medicine is to match the right drug to the right patient. However, every individual cancer carries a unique and complex mosaic of genetic and molecular changes making it difficult to identify the right drug based solely on genomic analysis. We developed a CLIA-certified functional drug assay (PARIS® test) for solid tumors which provides an actionable report of tumor derived organoid sensitivities to targeted, endocrine and chemotherapy agents as a tool for clinical therapeutic decisions. Objectives:1.To establish the concordance between organoid drug sensitivity with well-known genomic or immunohistochemical IHC biomarkers 2.To correlate organoid drug sensitivity with clinical outcomes.Methods: From 2015 to 2020, organoids from 410 tumor samples were subjected to functional testing at SEngine Precision Medicine, including 61 breast tumor samples from 48 patients. Fresh samples of tumor cells from core biopsies, surgical excisions, or from fluids arrived 90%.Conclusions: Organoid based drug testing exhibits strong concordance with genomic or IHC biomarkers and clinical response. In addition, functional testing identifies candidate therapies in patients lacking biomarkers and can nominate variants of unknown significance as candidate biomarkers. This study highlights the utility of functional assays to support clinical decision making in a genetically heterogenous cancer such as breast cancer. Citation Format: Astrid Margossian, Anne Richardson, Madison Pollastro, Michael Churchill, Franz Schaub, Shalini Pereira, Payel Chatterjee, Rachele Rosati, Lauren Appleyard, Grace Durenberger, Alex Federation, G. Adam Whitney, Hallie Swan, Trevor Ainge, Robert Diaz, Natasha Hunter, Eric Gamboa, Chris Kemp, Vijayakrishna Gadi, Carla Grandori. Clinical and genomic correlation of a CLIA certified organoid based functional test in breast cancer patients [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS4-01.
- Published
- 2021
9. Circulating tumor cell (CTC) PD-L1 and interferon regulatory factor-1 (IRF-1) expression as biomarkers of anti-PD-(L)1 response
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Lance U'Ren, Yao Sun, Laura Q.M. Chow, Vijayakrishna K. Gadi, Grace Durenberger, Petros Grivas, Laura C Kennedy, and Arturo Ramirez
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Cancer Research ,Circulating tumor cell ,IRF1 ,Oncology ,Tolerability ,biology ,business.industry ,Immune checkpoint inhibitors ,PD-L1 ,biology.protein ,Cancer research ,Medicine ,business - Abstract
e14032 Background: Anti-PD-(L)1 checkpoint inhibitors (CPI) are remarkable due to durable responses, tolerability, and improvements in survival across multiple solid tumors. Unfortunately, CPI produce objective responses in only a small subset of solid tumors patients (pts). We hypothesized that PD-L1 and IRF-1 expression on CTC may correlate with CPI response, and evaluate their expression in this pilot study. Methods: Pts with metastatic solid tumors initiating anti-PD(L)-1 mono- or combination therapy were eligible. Pts had 7.5 cc of blood drawn for CTC evaluation at 3 timepoints: baseline, after 1 CPI dose, and 3-6 months after starting CPI or at time of CPI discontinuation. Peripheral blood CTC were isolated with the AccuCyte kit and stained for CK/EpCAM, anti-CD45, nuclear dye, PD-L1, and IRF-1. CTCs were then identified with CyteFinder software. Results: 16 pts have enrolled to date with median age 71 years (range 28-83) and median ECOG = 1 (range 0-3). 50% were female. Diagnoses include NSCLC (50%), head and neck cancer (13%), breast cancer (13%), and others (24%). CTC were identified at baseline in 13/16 pts (# CTCs range 0-101). 12 pts with baseline CTC have had restaging scans since starting CPI. By RECIST 1.1, 3 pts had partial response (PR), 1 had stable disease (SD), and 8 had progressive disease (PD). The pts with PR more frequently had IRF-1 staining on baseline CTC (Table), and 1/3 had PD-L1 staining. 6 pts had tumor PD-L1 staining available for correlation, and 3/6 of those pts were PD-L1+ (tissue PD-L1 ≥ 1%). 1/3 pts with PD-L1+ tumor staining had CTCs that were PD-L1+. In the 3 pts with negative PD-L1 tumor staining, 1 pt had a mixed PD-L1+/PD-L1- CTC population and the others had no PD-L1 staining. Conclusions: CTC isolation and enumeration seem feasible across tumor types. Pts with PR to anti-PD-(L)1/ might have higher prevalence of IRF-1+ CTC; however, results are preliminary and more pts and samples are being evaluated. [Table: see text]
- Published
- 2019
10. Breast MRI as a radiomic biomarker of immune enrichment in HER2+ breast cancer
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Grace Durenberger, Savannah C. Partridge, Vijayakrishna K. Gadi, Laura C Kennedy, Sasha E. Stanton, Shaveta Vinayak, and Suzanne M. Dintzis
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Oncology ,Drug ,Cancer Research ,medicine.medical_specialty ,medicine.diagnostic_test ,business.industry ,media_common.quotation_subject ,medicine.disease ,Immune system ,Breast cancer ,Trastuzumab ,Internal medicine ,medicine ,Breast MRI ,Biomarker (medicine) ,skin and connective tissue diseases ,business ,medicine.drug ,media_common - Abstract
e14281 Background: Trastuzumab is an important drug in the treatment (tx) of HER2+ breast cancer, but not all tumors are responsive. Immune-enriched tumors have a better response to tx, and a biomarker to identify these tumors would be valuable. Multiparametric functional MRI is a non-invasive technique that can assess the entire tumor without the sampling error of biopsy. In this pilot study, we evaluate breast MRI as a potential biomarker for tumor immune response to trastuzumab. Methods: Women with de novo cT1-2N0 HER2+ breast cancer were enrolled and received paired multiparametric breast MRI examinations (including DWI and DCE sequences) prior to and ~2 weeks after a single dose of trastuzumab, followed by surgery or biopsy (if additional neoadjuvant tx planned). Tumor peak signal enhancement ratio (SER) and mean apparent diffusion coefficient (ADC), reflecting tissue perfusion and tissue cellularity, were determined from the images. Pre- and post-tx tissue were immunologically profiled with TIL counts and an immune-focused RNA gene expression panel. SER and ADC were correlated with TIL and RNA gene expression using Spearman’s rho. Results: To date, 8 women have enrolled and 6 had pre- and post-tx tissue available. The primary endpoint was correlation between SER and ADC measurements with tumor TILs. Secondary endpoints included correlating SER with angiogenesis and inflammation markers and correlating changes in SER and ADC with apoptosis/cell death markers. About half of the patients had TIL-enriched (TIL≥ 50%) tumors at baseline, and after trastuzumab the majority of tumors remained enriched or had an increase in TILs. Results suggest that pre-tx ADC had a negative correlation with TILs by histology and gene expression, although correlations did not reach statistical significance in this small cohort. Results also suggest a strong correlation between pre-tx SER and VEGF-A (r = 0.83) with a trend towards significance (P = 0.10). A decrease in SER post-tx had a strong correlation with an increase in caspase 3 expression (r = -0.85, p = 0.05), which suggested tx effect. Conclusions: Functional MRI may provide a novel biomarker of breast tumor immune response to trastuzumab. Results from additional patients will be available at the meeting.
- Published
- 2019
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