- Email: [email protected]
Thermal liquid biopsy as a valuable tool in lung cancer screening programs
abstracts
Annals of Oncology 1421P
A heptamethine cyanine dye is a potential diagnostic marker for myeloid-derived suppressor cells
C. Jung1, Y-S. Cho1, H. Kim2, H.H. Ha2 Anatomy, Chonnam National University Medical School, Gwangju, Republic of Korea, 2 Pharmacy, Sunchon National University, Sunchon, Republic of Korea
1
1422P
Molecular fingerprinting in breast cancer (BC) screening using Quantum Optics (QO) technology combined with an artificial intelligence (AI) approach applying the concept of “molecular profiles at n variables (MPnV)”: A prospective pilot study
J-M.A. Nabholtz1,2,5, K.A. Alsaleh1, S. Kullab1, N. Abdel-Aziz1, A. Abdelwarith1, A. Al Diab1, M.A. Hilal1, F. Dabouz2, V. Bajic3, R. Incitti3, M.R.K. Bahadoor2, A.M. Azeer4 1 Oncology Center, King Saud University Medical City, Riyadh, Saudi Arabia, 2Clinical Operations, International Cancer Research Group, ICRG, Sharjah, United Arab Emirates, 3 CBRC, Computational Bioscience Research Centre, King Abdallah University for Science and Technology (KAUST), Thuwal, Saudi Arabia, 4Physics & Astronomy Department / Attosecond Science Laboratory, King Saud University, Riyadh, Saudi Arabia, 5Faculty of Physics, Ludwig-Maximilians Universit€ at Mu¨nchen (LMU), Munich, Germany Background: BC screening by mammography is associated with a significant reduction in mortality (19 % overall reduction of the relative risk), however with significant limitations and debatable cost-effectiveness. Screening individuals for cancer using liquid biopsies (LB) represents an unmet need. We report the first prospective “proof of concept” study using the QO technology combined with an AI approach using the concept of “MPnV” applied to BC detection. Methods: QO (femto/atto-second infrared laser spectroscopy) on LB is a simple, noninvasive and reproducible method allowing to identify individualized molecular spectra (MS). These highly detailed MS can be correlated to physiological or pathological changes allowing detection and translation of differences. Integrated into a super-computational approach using a non-hierarchical deep data mining strategy (MPnV concept), MS could discriminate individuals with and without BC. The plasma of 68 controls and 27 BC patients, accrued at the King Saud University BC screening program, Riyadh, Saudi Arabia (KSA), were studied by QO (Max Planck Institute of Quantum Optics /Ludwig Maximillian University Munich, Garching, Germany). The MS were analysed on the Shaheen II supercomputer at King Abdallah University for Science and Technology (KAUST), KSA, in order to generate comparative algorithms. Results: The use of special feature selection, followed by class analysis allowed to differentiate profiles between the two groups with a sensitivity of 97% and a specificity of 72% (variables n ¼ 1,100). A more in-depth analysis led to 99% sensitivity, but with a lower specificity of 64%. Further analysis of the series, using an age-matched approach led to 97% sensitivity with 98% specificity in differentiating women with or without BC. Conclusions: These results warrant a large scale prospective validation BC screening trial (ongoing) and “proof of concept trials” in other frequent cancers, in particular those without existing screening programs. Editorial acknowledgement: Prof. Ferenc Krausz, Director, and Dr. Mihaela Zigman, Leader of the Broadband Infrared Diagnostics, Max Planck Institute of Quantum Optics (MPQ), Faculty of Physics at Ludwig-Maximilians Universit€at Mu¨nchen (LMU), Garching, Germany.
Volume 30 | Supplement 5 | October 2019
Pfizer; Advisory / Consultancy, Pancreas Expert Opinion Advisory: Baxter. All other authors have declared no conflicts of interest.
1423P
Inferring the correlation between incidence rates of melanoma and the average tumour-specific epitope binding ability of HLA class I molecules in different populations
I. Miklos1, L. Molnar2, J. Toth2, O. Lorincz3, Z. Csiszovszki3, P. Pales3, K. Pantya3, oke3 M. Megyesi3, E. Somogyi3, E.R. T} 1 Department of Stochastics, MTA Re´nyi Institute, Budapest, Hungary, 2Bioinformatics, Treos Bio Zrt., Veszpre´m, Hungary, 3Product Development, Treos Bio Zrt., Veszpre´m, Hungary Background: Human Leucocyte Antigen (HLA) molecules are encoded by the most polymorphic genes in the human genome. The genetic variation of these genes are considerable across different geographic subpopulations. We hypothesised that this genetic variation might contribute to the risk of melanoma both at population and subject level. Methods: We developed a cancer risk predictor based on the complete HLA class I genotype of individuals. The HLA-score, used in the predictor describes the ability of the HLA class I alleles of an individual to bind epitopes derived from 48 selected tumor antigens as an indicator of the breadth of the tumor-specific T-cell responses. We collected HLA data for subjects from 20 different geographic regions (ethnic populations) (n ¼ 3278) as well as the corresponding melanoma incidence rates. The average HLAscores were compared to the incidence rates. We also classified a mixed US population consisting of melanoma and healthy subjects based on their HLA-score. Results: On population level, we found significant correlation between the incidence rates of melanoma and average HLA-scores in different geographic regions (R2 ¼ 0.5005; p < 0.001; n ¼ 20; df ¼ 18). The highest average HLA-scores (range 75-140) were obtained for the Far East Asian and Pacific regions, where the incidence rates are low (0.4-3.4 per 100,000 per year). The lowest average HLA-scores (range 50-90) were obtained in the European and US regions, where the rates are high (12.6-13.8 per 100,000 per year). On subject level, the risk ratio between the riskiest (HLA-score <34) and the most protected groups (HLA-score 96) was 5.69 comparing the top and bottom 20% of the HLA-score distribution (p < 0.05). These HLA-score ranges are consistent with the threshold values separating populations with low and high incidence rates of melanoma. Conclusions: By developing a novel HLA-score determined by autologous HLA allele binding epitopes of tumor antigens, we showed that individuals with HLA allele sets supporting broader tumor-specific T-cell responses have lower risk of developing melanoma. These results imply that the HLA genotype and HLA-score could be used to determine the immunogenetic risk of melanoma. Legal entity responsible for the study: Treos Bio Zrt. Funding: Treos Bio Zrt. Disclosure: L. Molnar: Shareholder / Stockholder / Stock options, Full / Part-time employment: Treos Bio Ltd. J. Toth: Shareholder / Stockholder / Stock options, Full / Part-time employment: Treos Bio Ltd. O. Lorincz: Shareholder / Stockholder / Stock options, Full / Part-time employment: Treos Bio Ltd. Z. Csiszovszki: Shareholder / Stockholder / Stock options, Full / Part-time employment: Treos Bio Ltd. P. Pales: Full / Part-time employment: Treos Bio Ltd. K. Pantya: Shareholder / Stockholder / Stock options, Full / Part-time employment: Treos Bio Ltd. M. Megyesi: Shareholder / Stockholder / Stock options, Full / Part-time employment: Treos Bio Ltd. E. Somogyi: Shareholder / Stockholder / Stock options, Full / Part-time employment: Treos Bio Ltd. E.R. T} oke: Shareholder / Stockholder / Stock options, Full / Part-time employment, Officer / Board of Directors: Treos Bio Ltd. All other authors have declared no conflicts of interest.
1424P
Thermal liquid biopsy as a valuable tool in lung cancer screening programs
A. Rodrigo1, S. Vega2, J. Ojeda Cabrera2, O. Sanchez-Gracia2, A. Callejo3, A. Fernandez4, P. Iranzo3, M. Cruellas Lapena4, E. Quilez Bielsa4, A. Velazquez-Campoy5, O. Abian6, D. Isla4 1 Dept. Medical Oncology, Hospital Universitario Arnau de Vilanova, Lleida, Spain, 2 University of Zaragoza, Instituto BIFI, Zaragoza, Spain, 3Medical Oncology, Vall d’Hebron Institute of Oncology and University Hospital, Barcelona, Spain, 4Medical Oncology, Hospital Clinico Universitario Lozano Blesa, Zaragoza, Spain, 5University of Zaragoza, ARAID Foundation, Zaragoza, Spain, 6University of Zaragoza, IACS-ISS Arag on, Zaragoza, Spain Background: Implementing screening programs for risk populations can reduce lung cancer mortality by detecting the disease at early stages, when surgical intervention or chemotherapy treatment can be conducted with best prognosis. Screening protocols
doi:10.1093/annonc/mdz257 | v579
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_5/mdz257.019/5576892 by guest on 25 October 2019
Background: Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells with inhibitory effects on T cell proliferation. MDSC are over-amplified in most cancer patients so that cancer cells avoid anticancer immunity. Unlike mouse MDSCs, however, specific surface markers to define human MDSCs is still controversial due its complexity of subsets. Heptamethine cyanine dyes are fluorescent dyes, particularly used for noninvasive in vivo imaging and detection of cancer. MHI-148 is known to be specifically retained by tumor cells but not by normal cells. In this study, we investigated the potential application of MHI-148 as a specific MDSC detection probe. Methods: Mice bearing 4T1 breast cancer cells were created in female BALB/c mice. Splenocytes were isolated at 21 days after injection. Cells were stained with anti-Gr-1FITC, anti-CD11b-PE antibodies for MDSCs or with MHI-148 dye followed by isolating positive cells with cell sorter. To determine whether MHI148-positive cells possess inhibitory effect on T-cell proliferation, EdU-based T cell proliferation assay was performed. Arginase assay and measurement of Nitrite production were also performed for assessing T cell activity inhibition. Results: Compared to normal mice, tumor-bearing mice showed tremendous increase of MDSCs (CD11bþ/Gr-1þ). Over 81% of these MDSCs in tumor bearing mice were reactive to MHI-148 dye. Most sorted cell for MHI-148 fluorescence was also CD11bþ/ Gr-1þ MDSCs (97.7 %). Notably, lymphocytes and monocytes were not reactive to MHI-148. In addition, MHI-148 dye-positive cells significantly reduced T cell proliferation with increased arginase activity and nitrites concentration, suggesting that MHI148 reacts to the cells possessing similar function of MDSCs. Conclusions: This study demonstrates that MHI-148 reacts to mouse CD11bþ/Gr-1þ PBMCs with the function of MDSC characteristics. Further studies have be focused on MHI148 affinity to human MDSC and outcome of which will result in a novel tool to detect MDSC to be utilized to predict cancer patient prognosis. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
Legal entity responsible for the study: Jean Marc Nabholtz, Oncology Centre, King Saud University, Riyadh, Saudi Arabia. Funding: 1. Oncology Centre, King Saud University Medical City, King Saud University, Saudi Arabia. 2. Max-Planck-Institut fu¨r Quantenoptik and Faculty of Physics at Ludwig-Maximilians Universit€at Mu¨nchen, Garching, Germany. 3. Computational Bioscience Research Centre, King Abdallah University for Science and Technology (KAUST), Thuwal, Saudi Arabia. Disclosure: M.R.K. Bahadoor: Travel / Accommodation / Expenses, ASCO Participation Funded:
abstracts
1425P
Towards a screening test for cancer by circulating DNA analysis
R. Tanos1, A. Otandault1, C. Mollevi1, A. Bauer1, G. Tousch1, L. Picque Lasorsa1, S. El Messaoudi1, J. Colinge1, P-E. Colombo1, W. Jacot1, T. Mazard1, J.M. Sayague´s2, B. Gillet3, D. Pezet3, M. Ychou1, A.R. Thierry1 1 IRCM (Institute of Cancer Research of Montpellier), ICM Regional Cancer Institute of Montpellier, Montpellier, France, 2Department of Medicine and Cancer Research Center, University Hospital, Salamanca, Spain, 3Oncologie Digestive et Dermatologie, CHU Clermont-Ferrand, Clermont-Ferrand, France Background: Circulating DNA (cfDNA) has emerged as a potential biomarker in cancer, and is the subject of extensive studies in translational and clinical research. Our group has been interested in its implication and clinical significance in the field of oncology for many years, and is now focused on evaluating its potential for early cancer detection. Methods: We recently developed a screening test (MNR: Multi Normalized Ratio), based on various cfDNA parameters determined by a specific q-PCR based method, targeting both nuclear and mitochondrial sequences. Results: When applied to the supernatant of cell culture, the MNR had a discriminative potential of 100% between normal and cancer cell lines. An extensive evaluation of this test was carried out in plasma samples of 289 healthy subjects and 987 cancer patients (CRC, breast, liver, pancreatic, ovarian) of all stages. Preliminary results revealed a high potential with an AUC of 0.81 (0.78-0.84, 95% CI), a 70% sensitivity (Se) and 77% specificity (Sp). In breast cancer (N ¼ 169), an AUC of 0.82 (0.78-0.86, 95% CI) with 72% Se and 80% Sp were observed. In all stages CRC patients (N ¼ 795), the results showed an AUC of 0.80 (0.78-0.84, 95%, CI), 75% Se and 70% Sp; for CRC stages 0/I/II (N ¼ 426), an AUC of 0.79 (0.75-0.82, 95% CI), 70% Se and 72% Sp; and for CRC stage IV (N ¼ 186), a 0.86 AUC (0.82-0.89, 95% CI) with 75% Se and 80% Sp. When combining the MNR to a total cfDNA concentration threshold value (AUC ¼ 0.81 (0.790.83, 95% CI), 72% Se and 76% Sp for all stage cancers (N ¼ 987)), in a test cohort of 173 stages 0/I/II CRC patients and 132 healthy individuals, we increased the sensitivity and specificity to 74% and 95% respectively. Furthermore we recently discovered that cfDNA fragmentation, as determined by Whole Genome Sequencing using either double or single strand library, is also a parameter enabling discrimination between healthy and cancer individuals. Conclusions: The implementation of a multi-parametric test combining total cfDNA quantification, MNR and fragmentation biomarkers, with help of a decision tree in machine learning, is currently on-going. Our data suggest that our strategy in targeting cfDNA structural features might be powerful for early cancer detection, and appears as an alternative or a synergistic combination to the detection of mutations. Legal entity responsible for the study: Alain R. Thierry - INSERM (Institut national de la sante´ et de la recherche me´dicale). Funding: MSDAvenir - Mitest / Alain R. Thierry is supported by INSERM (Institut national de la sante´ et de la recherche me´dicale). Disclosure: All authors have declared no conflicts of interest.
v580 | New Diagnostic Tools
1426P
Evaluation of a successful launch of the MammaPrint and BluePrint NGS kit
L. Delahaye1, A.T. Witteveen1, M. Snel1, T. Cavness2, B. Chan3, L. Mittempergher1, A.M. Glas1 1 Product Development, Agendia Inc., Amsterdam, Netherlands, 2Operations, Agendia Inc., Irvine, CA, USA, 3Product Support, Agendia Inc., Irvine, CA, USA Background: Centralized MammaPrint (MP) and BluePrint (BP) microarray-based genomic tests on FFPE RNA were succesfully translated to a targeted RNA NGS kit that can be performed locally in decentralized sites. Since the launch of the CE-marked MP and BP NGS test, more data has been generated on this platform as well as on the established FDA-cleared microarray platform. Furthermore, decentralized sites worldwide have been onboarded and are certified to locally run the MP and BP NGS test. Methods: Paired MP and BP results were generated from FFPE RNA samples using the standard microarray as well as the MP and BP NGS test. The results from both platforms were compared to assess the concordance. Since the launch of the MP and BP NGS kit several decentralized sites underwent the onboarding process. As part of the onboarding, these sites processed a set of RNA and FFPE tissue samples previously processed at Agendia using the MP and BP NGS test. A site could only be certified if NGS results showed a 100% concordance with the Agendia results. Results: To date, over 150 RNA FFPE samples were processed with both microarray and NGS tests and MP/BP results showed concordance above 97%. Onboarding results were available for the decentralized sites. The FASTQ files generated at the sites were uploaded into the cloud-based Agendia Data Analysis Pipeline Tool (ADAPT) to generate MP and BP results. Results showed 100% concordance between Agendia’s central laboratory and the decentralized laboratories. Conclusions: MP and BP NGS test delivers equivalent results to the standard microarray test. Additionally, NGS results generated at decentralized sites also show extremely high concordance. These results confirm the high quality and robustness of the MP and BP NGS test. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: L. Delahaye: Full / Part-time employment: Agendia. A.T. Witteveen: Full / Part-time employment: Agendia. M. Snel: Full / Part-time employment: Agendia. T. Cavness: Full / Part-time employment: Agendia. B. Chan: Full / Part-time employment: Agendia. L. Mittempergher: Full / Parttime employment: Agendia. A.M. Glas: Full / Part-time employment: Agendia.
1427P
Analysis of prognostic factors on overall survival in elderly women treated for early breast cancer using data mining and machine learning
P. Heudel1, D. Hooijenga2, R. Phan2, V. Augusto2, X. Xie2, C. Terret1, C. Faure3, S. Racadot4, O. Tredan1, T. Bachelot5 1 Department of Medical Oncology, Centre Le´on Be´rard, Lyon, France, 2CNRS, UMR 6158 LIMOS, Centre CIS, Mines Saint-Etienne, Univ Clermont Auvergne, Saint Etienne, France, 3 Surgical Oncology, Centre Le´on Be´rard, Lyon, France, 4Radiation Oncology, Centre Le´on Be´rard, Lyon, France, 5Department of Oncology, Centre Le´on Be´rard, Lyon, France Background: One third of early breast cancers (EBC) in women are diagnosed over 70 years (y) old. In this population, clinicians look not only at EBC characteristics but also antecedents and comorbidities to determine the best treatment. Methods: ConSoRe is a new generation data analytics solution using natural language processing and perform advanced data mining. It was used for data extraction from electronic patient record of 2048 patients (pts) of more than 70 years, operated for EBC in Centre Leon Berard since 1997. Patient and tumor characteristics, treatment and survival were extracted. Results: Mean age was 75.5 y (range 70-100 y). Main comorbidities described were coronary heart disease: 340 pts (16,6%) and diabetes: 321 pts (15,7%). Distribution of body mass index (BMI) was under 18.5: 56 pts (3,3%), 18.5-25: 677 pts (39,6%); 25-30: 620 (36,3%) and over 30: 356 (20,8%). Mean tumor size was 23,5 mm (range 6 to 150), SBR grading was distributed as well: grade 1: 317 (17%) ; grade 2: 1007 (55%) ; grade 3: 476 (26%) while estrogen receptor were positive (>10%) in 1553 pts (86%), progesteron receptor positive (>10%) in 1299 pts (71%) and HER2 positive in 101 pts (6,3%). Histological nodes staging was N0 in 1497 pts (72%); N1 in 414 pts (20%); N2 in 95 pts (5%); N3 in 52 pts (2%). 295 pts (14%) were treated by chemotherapy, 80 pts (3,9%) by trastuzumab, 1544 pts (75%) by radiotherapy and 1543 (75%) by hormonotherapy. Despite a limited mean follow-up of 5,1 y (range 0.3-20,7y), we observe 83 local relapse (4%), 144 metastatic relapse (7%) and 261 deaths (12.7%) with a mean overall survival (OS) of 4,6 y (10 days to 21,4 y). In the multivariate analysis, BMI under 19 and HER 2 positive were independent predictors of OS (HR: 0,85; p ¼ 2.49e-09). Using Multiple Correspondence Analysis, percentage of explained variances is very low with less than 10%. These results show the limit of classical approach by descriptive data analysis, that is why, we propose new method by machine learning and operational research to determine the best adjuvant treatment. Conclusions: This elderly population has a poor prognosis for which taking BMI into account is important when defining the therapeutic strategy. Classical approaches by data analysis reach their limits. Legal entity responsible for the study: Heudel Pierre. Funding: Has not received any funding.
Volume 30 | Supplement 5 | October 2019
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_5/mdz257.019/5576892 by guest on 25 October 2019
based on Low-Dose CT presents a series of drawbacks and needs complementary methods for improving sensitivity and specificity in the screening procedure. Thermal Liquid Biopsy (TLB) is as a complementary technique that, combined with imaging techniques, may improve the efficacy of the screening method. Methods: Blood samples from Healthy Controls (HC) and Lung Cancer Patients (LCP) were analyzed with a high sensitivity microcalorimeter VP-DSC (MicroCal – Malvern Panalytical). The data were processed in Origin 7.0 software. The plasma thermograms were analyzed through a multiparametric method developed by our research group. Statistical models allowed classifying the subjects according their serum thermograms. Results: 115 LCP subjects (average age 64.668.7, 83.0% men) with broad stage distribution (II: 5%, III: 26%; IV: 69%), smoking status (64% smoking, 7% non-smoking), histology distribution (37% adenocarcinoma, 29% squamous, 30% small cell) were compared to 119 HC subjects homogeneously distributed from a blood bank. TLB parameters obtained showed statistical differences between HC and LCP groups. Different statistical models were applied in order to establish the optimal TLB output, which is able to classify subjects according to their TLB thermogram: 92% success rate, 90% specificity, and 94% sensitivity (i.e., diagnostic odds ratio of 140). Conclusions: High positive association between clinical groups and TLB multiparametric model offers advantages over current diagnosis techniques (LDCT imaging), providing a powerful diagnostic approach with a minimally-invasive, low-risk, lowcost clinical test for LCP. Future promising applications, such as screening programs, could be developed from TLB. Legal entity responsible for the study: The authors. Funding: Instituto Carlos III (Spain). Disclosure: All authors have declared no conflicts of interest.
Annals of Oncology
Annals of Oncology 1421P
A heptamethine cyanine dye is a potential diagnostic marker for myeloid-derived suppressor cells
C. Jung1, Y-S. Cho1, H. Kim2, H.H. Ha2 Anatomy, Chonnam National University Medical School, Gwangju, Republic of Korea, 2 Pharmacy, Sunchon National University, Sunchon, Republic of Korea
1
1422P
Molecular fingerprinting in breast cancer (BC) screening using Quantum Optics (QO) technology combined with an artificial intelligence (AI) approach applying the concept of “molecular profiles at n variables (MPnV)”: A prospective pilot study
J-M.A. Nabholtz1,2,5, K.A. Alsaleh1, S. Kullab1, N. Abdel-Aziz1, A. Abdelwarith1, A. Al Diab1, M.A. Hilal1, F. Dabouz2, V. Bajic3, R. Incitti3, M.R.K. Bahadoor2, A.M. Azeer4 1 Oncology Center, King Saud University Medical City, Riyadh, Saudi Arabia, 2Clinical Operations, International Cancer Research Group, ICRG, Sharjah, United Arab Emirates, 3 CBRC, Computational Bioscience Research Centre, King Abdallah University for Science and Technology (KAUST), Thuwal, Saudi Arabia, 4Physics & Astronomy Department / Attosecond Science Laboratory, King Saud University, Riyadh, Saudi Arabia, 5Faculty of Physics, Ludwig-Maximilians Universit€ at Mu¨nchen (LMU), Munich, Germany Background: BC screening by mammography is associated with a significant reduction in mortality (19 % overall reduction of the relative risk), however with significant limitations and debatable cost-effectiveness. Screening individuals for cancer using liquid biopsies (LB) represents an unmet need. We report the first prospective “proof of concept” study using the QO technology combined with an AI approach using the concept of “MPnV” applied to BC detection. Methods: QO (femto/atto-second infrared laser spectroscopy) on LB is a simple, noninvasive and reproducible method allowing to identify individualized molecular spectra (MS). These highly detailed MS can be correlated to physiological or pathological changes allowing detection and translation of differences. Integrated into a super-computational approach using a non-hierarchical deep data mining strategy (MPnV concept), MS could discriminate individuals with and without BC. The plasma of 68 controls and 27 BC patients, accrued at the King Saud University BC screening program, Riyadh, Saudi Arabia (KSA), were studied by QO (Max Planck Institute of Quantum Optics /Ludwig Maximillian University Munich, Garching, Germany). The MS were analysed on the Shaheen II supercomputer at King Abdallah University for Science and Technology (KAUST), KSA, in order to generate comparative algorithms. Results: The use of special feature selection, followed by class analysis allowed to differentiate profiles between the two groups with a sensitivity of 97% and a specificity of 72% (variables n ¼ 1,100). A more in-depth analysis led to 99% sensitivity, but with a lower specificity of 64%. Further analysis of the series, using an age-matched approach led to 97% sensitivity with 98% specificity in differentiating women with or without BC. Conclusions: These results warrant a large scale prospective validation BC screening trial (ongoing) and “proof of concept trials” in other frequent cancers, in particular those without existing screening programs. Editorial acknowledgement: Prof. Ferenc Krausz, Director, and Dr. Mihaela Zigman, Leader of the Broadband Infrared Diagnostics, Max Planck Institute of Quantum Optics (MPQ), Faculty of Physics at Ludwig-Maximilians Universit€at Mu¨nchen (LMU), Garching, Germany.
Volume 30 | Supplement 5 | October 2019
Pfizer; Advisory / Consultancy, Pancreas Expert Opinion Advisory: Baxter. All other authors have declared no conflicts of interest.
1423P
Inferring the correlation between incidence rates of melanoma and the average tumour-specific epitope binding ability of HLA class I molecules in different populations
I. Miklos1, L. Molnar2, J. Toth2, O. Lorincz3, Z. Csiszovszki3, P. Pales3, K. Pantya3, oke3 M. Megyesi3, E. Somogyi3, E.R. T} 1 Department of Stochastics, MTA Re´nyi Institute, Budapest, Hungary, 2Bioinformatics, Treos Bio Zrt., Veszpre´m, Hungary, 3Product Development, Treos Bio Zrt., Veszpre´m, Hungary Background: Human Leucocyte Antigen (HLA) molecules are encoded by the most polymorphic genes in the human genome. The genetic variation of these genes are considerable across different geographic subpopulations. We hypothesised that this genetic variation might contribute to the risk of melanoma both at population and subject level. Methods: We developed a cancer risk predictor based on the complete HLA class I genotype of individuals. The HLA-score, used in the predictor describes the ability of the HLA class I alleles of an individual to bind epitopes derived from 48 selected tumor antigens as an indicator of the breadth of the tumor-specific T-cell responses. We collected HLA data for subjects from 20 different geographic regions (ethnic populations) (n ¼ 3278) as well as the corresponding melanoma incidence rates. The average HLAscores were compared to the incidence rates. We also classified a mixed US population consisting of melanoma and healthy subjects based on their HLA-score. Results: On population level, we found significant correlation between the incidence rates of melanoma and average HLA-scores in different geographic regions (R2 ¼ 0.5005; p < 0.001; n ¼ 20; df ¼ 18). The highest average HLA-scores (range 75-140) were obtained for the Far East Asian and Pacific regions, where the incidence rates are low (0.4-3.4 per 100,000 per year). The lowest average HLA-scores (range 50-90) were obtained in the European and US regions, where the rates are high (12.6-13.8 per 100,000 per year). On subject level, the risk ratio between the riskiest (HLA-score <34) and the most protected groups (HLA-score 96) was 5.69 comparing the top and bottom 20% of the HLA-score distribution (p < 0.05). These HLA-score ranges are consistent with the threshold values separating populations with low and high incidence rates of melanoma. Conclusions: By developing a novel HLA-score determined by autologous HLA allele binding epitopes of tumor antigens, we showed that individuals with HLA allele sets supporting broader tumor-specific T-cell responses have lower risk of developing melanoma. These results imply that the HLA genotype and HLA-score could be used to determine the immunogenetic risk of melanoma. Legal entity responsible for the study: Treos Bio Zrt. Funding: Treos Bio Zrt. Disclosure: L. Molnar: Shareholder / Stockholder / Stock options, Full / Part-time employment: Treos Bio Ltd. J. Toth: Shareholder / Stockholder / Stock options, Full / Part-time employment: Treos Bio Ltd. O. Lorincz: Shareholder / Stockholder / Stock options, Full / Part-time employment: Treos Bio Ltd. Z. Csiszovszki: Shareholder / Stockholder / Stock options, Full / Part-time employment: Treos Bio Ltd. P. Pales: Full / Part-time employment: Treos Bio Ltd. K. Pantya: Shareholder / Stockholder / Stock options, Full / Part-time employment: Treos Bio Ltd. M. Megyesi: Shareholder / Stockholder / Stock options, Full / Part-time employment: Treos Bio Ltd. E. Somogyi: Shareholder / Stockholder / Stock options, Full / Part-time employment: Treos Bio Ltd. E.R. T} oke: Shareholder / Stockholder / Stock options, Full / Part-time employment, Officer / Board of Directors: Treos Bio Ltd. All other authors have declared no conflicts of interest.
1424P
Thermal liquid biopsy as a valuable tool in lung cancer screening programs
A. Rodrigo1, S. Vega2, J. Ojeda Cabrera2, O. Sanchez-Gracia2, A. Callejo3, A. Fernandez4, P. Iranzo3, M. Cruellas Lapena4, E. Quilez Bielsa4, A. Velazquez-Campoy5, O. Abian6, D. Isla4 1 Dept. Medical Oncology, Hospital Universitario Arnau de Vilanova, Lleida, Spain, 2 University of Zaragoza, Instituto BIFI, Zaragoza, Spain, 3Medical Oncology, Vall d’Hebron Institute of Oncology and University Hospital, Barcelona, Spain, 4Medical Oncology, Hospital Clinico Universitario Lozano Blesa, Zaragoza, Spain, 5University of Zaragoza, ARAID Foundation, Zaragoza, Spain, 6University of Zaragoza, IACS-ISS Arag on, Zaragoza, Spain Background: Implementing screening programs for risk populations can reduce lung cancer mortality by detecting the disease at early stages, when surgical intervention or chemotherapy treatment can be conducted with best prognosis. Screening protocols
doi:10.1093/annonc/mdz257 | v579
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_5/mdz257.019/5576892 by guest on 25 October 2019
Background: Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells with inhibitory effects on T cell proliferation. MDSC are over-amplified in most cancer patients so that cancer cells avoid anticancer immunity. Unlike mouse MDSCs, however, specific surface markers to define human MDSCs is still controversial due its complexity of subsets. Heptamethine cyanine dyes are fluorescent dyes, particularly used for noninvasive in vivo imaging and detection of cancer. MHI-148 is known to be specifically retained by tumor cells but not by normal cells. In this study, we investigated the potential application of MHI-148 as a specific MDSC detection probe. Methods: Mice bearing 4T1 breast cancer cells were created in female BALB/c mice. Splenocytes were isolated at 21 days after injection. Cells were stained with anti-Gr-1FITC, anti-CD11b-PE antibodies for MDSCs or with MHI-148 dye followed by isolating positive cells with cell sorter. To determine whether MHI148-positive cells possess inhibitory effect on T-cell proliferation, EdU-based T cell proliferation assay was performed. Arginase assay and measurement of Nitrite production were also performed for assessing T cell activity inhibition. Results: Compared to normal mice, tumor-bearing mice showed tremendous increase of MDSCs (CD11bþ/Gr-1þ). Over 81% of these MDSCs in tumor bearing mice were reactive to MHI-148 dye. Most sorted cell for MHI-148 fluorescence was also CD11bþ/ Gr-1þ MDSCs (97.7 %). Notably, lymphocytes and monocytes were not reactive to MHI-148. In addition, MHI-148 dye-positive cells significantly reduced T cell proliferation with increased arginase activity and nitrites concentration, suggesting that MHI148 reacts to the cells possessing similar function of MDSCs. Conclusions: This study demonstrates that MHI-148 reacts to mouse CD11bþ/Gr-1þ PBMCs with the function of MDSC characteristics. Further studies have be focused on MHI148 affinity to human MDSC and outcome of which will result in a novel tool to detect MDSC to be utilized to predict cancer patient prognosis. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
Legal entity responsible for the study: Jean Marc Nabholtz, Oncology Centre, King Saud University, Riyadh, Saudi Arabia. Funding: 1. Oncology Centre, King Saud University Medical City, King Saud University, Saudi Arabia. 2. Max-Planck-Institut fu¨r Quantenoptik and Faculty of Physics at Ludwig-Maximilians Universit€at Mu¨nchen, Garching, Germany. 3. Computational Bioscience Research Centre, King Abdallah University for Science and Technology (KAUST), Thuwal, Saudi Arabia. Disclosure: M.R.K. Bahadoor: Travel / Accommodation / Expenses, ASCO Participation Funded:
abstracts
1425P
Towards a screening test for cancer by circulating DNA analysis
R. Tanos1, A. Otandault1, C. Mollevi1, A. Bauer1, G. Tousch1, L. Picque Lasorsa1, S. El Messaoudi1, J. Colinge1, P-E. Colombo1, W. Jacot1, T. Mazard1, J.M. Sayague´s2, B. Gillet3, D. Pezet3, M. Ychou1, A.R. Thierry1 1 IRCM (Institute of Cancer Research of Montpellier), ICM Regional Cancer Institute of Montpellier, Montpellier, France, 2Department of Medicine and Cancer Research Center, University Hospital, Salamanca, Spain, 3Oncologie Digestive et Dermatologie, CHU Clermont-Ferrand, Clermont-Ferrand, France Background: Circulating DNA (cfDNA) has emerged as a potential biomarker in cancer, and is the subject of extensive studies in translational and clinical research. Our group has been interested in its implication and clinical significance in the field of oncology for many years, and is now focused on evaluating its potential for early cancer detection. Methods: We recently developed a screening test (MNR: Multi Normalized Ratio), based on various cfDNA parameters determined by a specific q-PCR based method, targeting both nuclear and mitochondrial sequences. Results: When applied to the supernatant of cell culture, the MNR had a discriminative potential of 100% between normal and cancer cell lines. An extensive evaluation of this test was carried out in plasma samples of 289 healthy subjects and 987 cancer patients (CRC, breast, liver, pancreatic, ovarian) of all stages. Preliminary results revealed a high potential with an AUC of 0.81 (0.78-0.84, 95% CI), a 70% sensitivity (Se) and 77% specificity (Sp). In breast cancer (N ¼ 169), an AUC of 0.82 (0.78-0.86, 95% CI) with 72% Se and 80% Sp were observed. In all stages CRC patients (N ¼ 795), the results showed an AUC of 0.80 (0.78-0.84, 95%, CI), 75% Se and 70% Sp; for CRC stages 0/I/II (N ¼ 426), an AUC of 0.79 (0.75-0.82, 95% CI), 70% Se and 72% Sp; and for CRC stage IV (N ¼ 186), a 0.86 AUC (0.82-0.89, 95% CI) with 75% Se and 80% Sp. When combining the MNR to a total cfDNA concentration threshold value (AUC ¼ 0.81 (0.790.83, 95% CI), 72% Se and 76% Sp for all stage cancers (N ¼ 987)), in a test cohort of 173 stages 0/I/II CRC patients and 132 healthy individuals, we increased the sensitivity and specificity to 74% and 95% respectively. Furthermore we recently discovered that cfDNA fragmentation, as determined by Whole Genome Sequencing using either double or single strand library, is also a parameter enabling discrimination between healthy and cancer individuals. Conclusions: The implementation of a multi-parametric test combining total cfDNA quantification, MNR and fragmentation biomarkers, with help of a decision tree in machine learning, is currently on-going. Our data suggest that our strategy in targeting cfDNA structural features might be powerful for early cancer detection, and appears as an alternative or a synergistic combination to the detection of mutations. Legal entity responsible for the study: Alain R. Thierry - INSERM (Institut national de la sante´ et de la recherche me´dicale). Funding: MSDAvenir - Mitest / Alain R. Thierry is supported by INSERM (Institut national de la sante´ et de la recherche me´dicale). Disclosure: All authors have declared no conflicts of interest.
v580 | New Diagnostic Tools
1426P
Evaluation of a successful launch of the MammaPrint and BluePrint NGS kit
L. Delahaye1, A.T. Witteveen1, M. Snel1, T. Cavness2, B. Chan3, L. Mittempergher1, A.M. Glas1 1 Product Development, Agendia Inc., Amsterdam, Netherlands, 2Operations, Agendia Inc., Irvine, CA, USA, 3Product Support, Agendia Inc., Irvine, CA, USA Background: Centralized MammaPrint (MP) and BluePrint (BP) microarray-based genomic tests on FFPE RNA were succesfully translated to a targeted RNA NGS kit that can be performed locally in decentralized sites. Since the launch of the CE-marked MP and BP NGS test, more data has been generated on this platform as well as on the established FDA-cleared microarray platform. Furthermore, decentralized sites worldwide have been onboarded and are certified to locally run the MP and BP NGS test. Methods: Paired MP and BP results were generated from FFPE RNA samples using the standard microarray as well as the MP and BP NGS test. The results from both platforms were compared to assess the concordance. Since the launch of the MP and BP NGS kit several decentralized sites underwent the onboarding process. As part of the onboarding, these sites processed a set of RNA and FFPE tissue samples previously processed at Agendia using the MP and BP NGS test. A site could only be certified if NGS results showed a 100% concordance with the Agendia results. Results: To date, over 150 RNA FFPE samples were processed with both microarray and NGS tests and MP/BP results showed concordance above 97%. Onboarding results were available for the decentralized sites. The FASTQ files generated at the sites were uploaded into the cloud-based Agendia Data Analysis Pipeline Tool (ADAPT) to generate MP and BP results. Results showed 100% concordance between Agendia’s central laboratory and the decentralized laboratories. Conclusions: MP and BP NGS test delivers equivalent results to the standard microarray test. Additionally, NGS results generated at decentralized sites also show extremely high concordance. These results confirm the high quality and robustness of the MP and BP NGS test. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: L. Delahaye: Full / Part-time employment: Agendia. A.T. Witteveen: Full / Part-time employment: Agendia. M. Snel: Full / Part-time employment: Agendia. T. Cavness: Full / Part-time employment: Agendia. B. Chan: Full / Part-time employment: Agendia. L. Mittempergher: Full / Parttime employment: Agendia. A.M. Glas: Full / Part-time employment: Agendia.
1427P
Analysis of prognostic factors on overall survival in elderly women treated for early breast cancer using data mining and machine learning
P. Heudel1, D. Hooijenga2, R. Phan2, V. Augusto2, X. Xie2, C. Terret1, C. Faure3, S. Racadot4, O. Tredan1, T. Bachelot5 1 Department of Medical Oncology, Centre Le´on Be´rard, Lyon, France, 2CNRS, UMR 6158 LIMOS, Centre CIS, Mines Saint-Etienne, Univ Clermont Auvergne, Saint Etienne, France, 3 Surgical Oncology, Centre Le´on Be´rard, Lyon, France, 4Radiation Oncology, Centre Le´on Be´rard, Lyon, France, 5Department of Oncology, Centre Le´on Be´rard, Lyon, France Background: One third of early breast cancers (EBC) in women are diagnosed over 70 years (y) old. In this population, clinicians look not only at EBC characteristics but also antecedents and comorbidities to determine the best treatment. Methods: ConSoRe is a new generation data analytics solution using natural language processing and perform advanced data mining. It was used for data extraction from electronic patient record of 2048 patients (pts) of more than 70 years, operated for EBC in Centre Leon Berard since 1997. Patient and tumor characteristics, treatment and survival were extracted. Results: Mean age was 75.5 y (range 70-100 y). Main comorbidities described were coronary heart disease: 340 pts (16,6%) and diabetes: 321 pts (15,7%). Distribution of body mass index (BMI) was under 18.5: 56 pts (3,3%), 18.5-25: 677 pts (39,6%); 25-30: 620 (36,3%) and over 30: 356 (20,8%). Mean tumor size was 23,5 mm (range 6 to 150), SBR grading was distributed as well: grade 1: 317 (17%) ; grade 2: 1007 (55%) ; grade 3: 476 (26%) while estrogen receptor were positive (>10%) in 1553 pts (86%), progesteron receptor positive (>10%) in 1299 pts (71%) and HER2 positive in 101 pts (6,3%). Histological nodes staging was N0 in 1497 pts (72%); N1 in 414 pts (20%); N2 in 95 pts (5%); N3 in 52 pts (2%). 295 pts (14%) were treated by chemotherapy, 80 pts (3,9%) by trastuzumab, 1544 pts (75%) by radiotherapy and 1543 (75%) by hormonotherapy. Despite a limited mean follow-up of 5,1 y (range 0.3-20,7y), we observe 83 local relapse (4%), 144 metastatic relapse (7%) and 261 deaths (12.7%) with a mean overall survival (OS) of 4,6 y (10 days to 21,4 y). In the multivariate analysis, BMI under 19 and HER 2 positive were independent predictors of OS (HR: 0,85; p ¼ 2.49e-09). Using Multiple Correspondence Analysis, percentage of explained variances is very low with less than 10%. These results show the limit of classical approach by descriptive data analysis, that is why, we propose new method by machine learning and operational research to determine the best adjuvant treatment. Conclusions: This elderly population has a poor prognosis for which taking BMI into account is important when defining the therapeutic strategy. Classical approaches by data analysis reach their limits. Legal entity responsible for the study: Heudel Pierre. Funding: Has not received any funding.
Volume 30 | Supplement 5 | October 2019
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_5/mdz257.019/5576892 by guest on 25 October 2019
based on Low-Dose CT presents a series of drawbacks and needs complementary methods for improving sensitivity and specificity in the screening procedure. Thermal Liquid Biopsy (TLB) is as a complementary technique that, combined with imaging techniques, may improve the efficacy of the screening method. Methods: Blood samples from Healthy Controls (HC) and Lung Cancer Patients (LCP) were analyzed with a high sensitivity microcalorimeter VP-DSC (MicroCal – Malvern Panalytical). The data were processed in Origin 7.0 software. The plasma thermograms were analyzed through a multiparametric method developed by our research group. Statistical models allowed classifying the subjects according their serum thermograms. Results: 115 LCP subjects (average age 64.668.7, 83.0% men) with broad stage distribution (II: 5%, III: 26%; IV: 69%), smoking status (64% smoking, 7% non-smoking), histology distribution (37% adenocarcinoma, 29% squamous, 30% small cell) were compared to 119 HC subjects homogeneously distributed from a blood bank. TLB parameters obtained showed statistical differences between HC and LCP groups. Different statistical models were applied in order to establish the optimal TLB output, which is able to classify subjects according to their TLB thermogram: 92% success rate, 90% specificity, and 94% sensitivity (i.e., diagnostic odds ratio of 140). Conclusions: High positive association between clinical groups and TLB multiparametric model offers advantages over current diagnosis techniques (LDCT imaging), providing a powerful diagnostic approach with a minimally-invasive, low-risk, lowcost clinical test for LCP. Future promising applications, such as screening programs, could be developed from TLB. Legal entity responsible for the study: The authors. Funding: Instituto Carlos III (Spain). Disclosure: All authors have declared no conflicts of interest.
Annals of Oncology