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Clinical application of routine comprehensive tumour molecular profiling in the management of cancer patients
abstracts
Annals of Oncology
99P
Likelihood of targeted therapy recommendations for advanced solid tumours
H. Taghizadeh1, G. Prager2, L. Mu¨llauer3, R.M. Mader4 Oncology, Medical University of Vienna, Vienna, Austria, 2Vienna General Hospital (AKH) - Medizinische Universit€ at Wien, Vienna, Austria, 3Pathology, Medical University of Vienna, Vienna, Austria, 4Divison of Clinical Oncology, Medical University of Vienna, Vienna, Austria
1
Background: Advanced therapy-refractory cancer diseases have a poor prognosis and constitute a major challenge for adequate treatment strategies. In this analysis, we aimed to show the potential and the likelihood of targeted therapy recommendations in patients with different types of advanced solid tumors for whom no standard treatment was available. Methods: In this single center, real-world retrospective analysis of our precision medicine platform, we describe the likelihood of targeted therapy recommendations for 519 patients diagnosed with 19 different types of advanced solid tumors with at least 10 patients per tumor type. Tumor samples of the patients were examined using next-generation sequencing panel, immunohistochemistry, fluorescence in situ hybridization, and RNA fusion panel. Results: In total, we identified 1200 molecular aberrations in 519 patients. The 10 predominant mutations were TP53 (n ¼ 238), KRAS (n ¼ 108), PIK3CA (n ¼ 57), PTEN (n ¼ 35), APC (n ¼ 32), ATM (n ¼ 30), CDKN2A (n ¼ 29), NOTCH1 (n ¼ 27), SMAD4 (n ¼ 21), and PIK3R1 (n ¼ 18) that accounted for nearly half of the molecular alterations (49.6%). For 55% of all patients a molecular driven targeted therapy approach was offered. In over half of the cases of 14 different solid tumor types a targeted therapy was recommended. The five highest rates for therapy suggestion were observed in thyroid cancer (92%), lung cancer (76%), hepatocellular carcinoma (72%), neuroendocrine tumors (65%), and primary brain tumors (64%). The lowest rates were seen in pancreatic ductal adenocarcinoma (38%), lymphoma (33%), and sarcoma (31%). Conclusions: Our platform for precision medicine provided meaningful moleculardriven therapy recommendations for most patients with advanced therapy refractory solid tumors for whom no standard therapy regimen was available. Legal entity responsible for the study: Medical University of Vienna. Funding: Has not received any funding. Disclosure: H. Taghizadeh: Travel / Accommodation / Expenses: Roche. All other authors have declared no conflicts of interest.
100P
Concordance between tissue analysis (TA) and liquid biopsy (LB) for RAS/BRAF and the optimization of its clinical application in such a heterogeneous tumour
I. Grilo1, R. Leite2, P. Gago1, S. Duarte1, A. Teira1, T. Sarmento1, M. Sousa1 Onco-Hematology Department, Centro Hospitalar Tras-os-Montes e Alto Douro, E.P.E., Vila Real, Portugal, 2Department of Genetics, CHTMAD, Vila Real, Portugal
1
Background: In metastatic CRC, the absence of RAS/BRAF mutation is indicative of a good response to anti-EGFR therapy. However, these patients have a distinct genomic profiles and tumors heterogeneity. This is probably the greatest difficulty regarding the detection of mutations in tumor tissue. LB can overcome this, detecting cDNA as well
Volume 30 | Supplement 7 | November 2019
as early changes in mutational status before the clinical progression. Dynamic molecular analysis may allow new therapeutic sequences. Methods: Non-randomized observational study since October 2014 - ongoing, for evaluation concordance of RAS/BRAF status between LB and TA and monitoring every 8 weeks using the IdyllaMT, in patients with metastatic CRC. Results: 148 liquid biopsies corresponding to 101 patients have been performed until now. Verification of concordance was possible only in 54 patients due to missions tissue biopsy (done outside the institution). The overall agreement was 70.2% (47/61), with 44.7% mutRAS patients. When we look at patients with liver metastasis, the agreement increases to 89%. Disagreement was found in 14 patients, and in 29.6%(4/14) TA was WT and LB mutRAS. When we reviewed the patients reassessed with LB at 8 weeks, 3 changed their status from mutated to WT. It was also found that one patient, initially WT treated with anti-EGFR in LB, was detected Gly12Ala / Gly12Val mutation, and in 2nd LB it was WT. Another patient initially detected A146P/T/V mutation was treated with oral fluropyrimidine, becoming WT in LB, progressed and started doubletþbevacizumab with partial response, and the same mutation was detected in 2nd LB. Conclusions: It appears that the site of metastases (liver, peritoneum, lung) has an impact on the detection of RAS/BRAF cDNA status. In cases of RAS/BRAF WT in TA, LB may better predict the response to anti-EGFR agents. In these preliminary results, the tumor has been shown to be clearly dynamic; the change of mutated RAS/BRAF status to WT was confirmed during the instituted therapy, opening a possible therapeutic window the for these patients with anti-EGFR therapy. This study included so far a small sample but demonstrates that personalized therapy with molecular/genomic analysis is undoubtedly valuable. Legal entity responsible for the study: CHTMAD - Onco-Hematology Department. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
101P
Clinical application of routine comprehensive tumour molecular profiling in the management of cancer patients
V. Mileyko1, E. Veselovsky2, E. Rozhavskaya2, E. Ignatova3, A. Kovtun2, M. Sharova2, M. Ivanov4 1 Atlas Oncodiagnostics, LLS, Moscow, Russian Federation, 2Atlas OncoDiagnostics ltd., Moscow, Russian Federation, 3Clinical Pharmacology and Chemotherapy, FSBI-N. N. Blokhin Russian Cancer Research Center, Moscow, Russian Federation, 4Moscow Institute of Physics and Technology, Dolgoprudny, Russian Federation Background: Along with the extension of the FDA approved molecular matched therapies, the evidence is building to support molecular profile-based off-label drug prescription or inclusion in a clinical trial. We report the findings from our real-world comprehensive molecular tumor profiling (CMTP) practice to assess how CMTP extends treatment options within and beyond standards of care. Methods: Pts with a confirmed diagnosis of advanced cancers are eligible. DNA was extracted from either archival or fresh collected tumor samples. Blood plasma was used for sequencing if the tumor sample was unavailable. CMTP included next generation sequencing. A panel of 409, 50 or 17 genes was used based on multidisciplinary molecular tumor board (MMTB) recommendations. Additional tests (IHC, FISH, MSI testing) were performed if recommended by MMTB. Results: 155 patients were eligible for the analysis (63% female, median age 57, range 17-90). Tumor types were gyneco (19%), colorectal (18%), lung (14%), pancreatic (10%), breast (9%), stomach (5%). A total of 94% actionable biomarker (AB) associated with potential benefit from approved therapy were identified across 68(44%) pts. 49 (72%) pts had only one AB while 19 had 2 or more AB (up to 5). The most common AB were BRCA1/2 mutation/deletion (14%), PIK3CA mutations (13%), PD-L1 overexpression (12.7%), microsatellite instability (11%) and ERBB2 mutation/amplification/overexpression (7%). 29/155 (19%) pts received in-label therapy recommendations (TR) (38% pts - lung, 31% pts – gyneco, 10% pts - colorectal). 28/ 126 (23%) pts without in-label TR received off-label TR (18% pts – gyneco, 18% pts colorectal, 14% pts – pancreatic, 10% pts – stomach) with a total of 56 TR (20% immunotherapy, 13% PARPi, 7% MEKi, 5% ERBB2i). 12/98 (12%) pts without in-label or off-label TR received profile-matched TR within a clinical trial. Across 19/155 (12%) pts we identified biomarkers associated with the resistance to standard therapy. Conclusions: CMTP was informative for 72/155 (46%) pts. 69/155(44%) pts received TR. Across tumor types least % of pts received TR with prostate (0/5, 0%), pancreatic (4/15, 26%) and breast (5/14, 36%) cancer, suggesting the need to define pts population who may benefit from CMTP. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: V. Mileyko: Full / Part-time employment: Atlas Oncology Diagnostics, ltd. E. Veselovsky: Full / Part-time employment: Atlas Oncology Diagnostics, ltd. E. Rozhavskaya: Full / Part-time employment: Atlas Oncology Diagnostics, ltd. A. Kovtun: Full / Part-time employment: Atlas Oncology Diagnostics, ltd. M. Sharova: Full / Part-time employment: Atlas Oncology Diagnostics, ltd. M. Ivanov: Full / Part-time employment: Atlas Oncology Diagnostics, ltd. All other authors have declared no conflicts of interest.
doi:10.1093/annonc/mdz413 | vii29
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_7/mdz413.105/5613286 by guest on 31 December 2019
NextSeq 500 sequencing device (all Illumina, CA, USA). Sequencing data were processed by an established pipeline. Tumour mutational burden (TMB) was calculated as a number of coding and splice-site nonsynonymous SNVs per megabase. FFPE samples from 35 patients previously examined by WES were independently examined also by F1Heme. Finally, we compared findings provided by WES and F1Heme with focus on clinically relevant information. Results: Clinically relevant SNVs were identified using both WES and F1Heme in 13 patients (37%). Among mutated genes were NRAS (5 patients), FGFR1 (2 patients), CTNNB1 (2 patients), PTPN11 (2 patients) BRAF (1 patient), IDH2 (1 patient) and HIST1H3B (1 patient). Nine patients carried also mutation in TP53. There was a significant correlation between TMB values obtained by WES and F1Heme (R2¼0.998, P < 0.001), whereas in 2 patients TMB was higher than 10 mut/Mb. F1Heme also reported gene rearrangements and amplifications. Conclusions: We found 100% match in detection of SNVs using both WES and F1Heme. TMBs obtained from WES and F1Heme were correlated with high statistical significance. Our data suggest that the molecular diagnostics based both on WES and F1Heme present valuable tools for individualized treatment planning for detecting SNVs in paediatric oncology. WES needs to be complemented by other profiling tools to detect other types of genomic alterations such as gene rearrangements or amplification. Legal entity responsible for the study: The authors. Funding: Roche supplies FoundationOne Heme with tests and by the Czech Ministry of Health, grant no 16-33209A. Disclosure: All authors have declared no conflicts of interest.
Annals of Oncology
99P
Likelihood of targeted therapy recommendations for advanced solid tumours
H. Taghizadeh1, G. Prager2, L. Mu¨llauer3, R.M. Mader4 Oncology, Medical University of Vienna, Vienna, Austria, 2Vienna General Hospital (AKH) - Medizinische Universit€ at Wien, Vienna, Austria, 3Pathology, Medical University of Vienna, Vienna, Austria, 4Divison of Clinical Oncology, Medical University of Vienna, Vienna, Austria
1
Background: Advanced therapy-refractory cancer diseases have a poor prognosis and constitute a major challenge for adequate treatment strategies. In this analysis, we aimed to show the potential and the likelihood of targeted therapy recommendations in patients with different types of advanced solid tumors for whom no standard treatment was available. Methods: In this single center, real-world retrospective analysis of our precision medicine platform, we describe the likelihood of targeted therapy recommendations for 519 patients diagnosed with 19 different types of advanced solid tumors with at least 10 patients per tumor type. Tumor samples of the patients were examined using next-generation sequencing panel, immunohistochemistry, fluorescence in situ hybridization, and RNA fusion panel. Results: In total, we identified 1200 molecular aberrations in 519 patients. The 10 predominant mutations were TP53 (n ¼ 238), KRAS (n ¼ 108), PIK3CA (n ¼ 57), PTEN (n ¼ 35), APC (n ¼ 32), ATM (n ¼ 30), CDKN2A (n ¼ 29), NOTCH1 (n ¼ 27), SMAD4 (n ¼ 21), and PIK3R1 (n ¼ 18) that accounted for nearly half of the molecular alterations (49.6%). For 55% of all patients a molecular driven targeted therapy approach was offered. In over half of the cases of 14 different solid tumor types a targeted therapy was recommended. The five highest rates for therapy suggestion were observed in thyroid cancer (92%), lung cancer (76%), hepatocellular carcinoma (72%), neuroendocrine tumors (65%), and primary brain tumors (64%). The lowest rates were seen in pancreatic ductal adenocarcinoma (38%), lymphoma (33%), and sarcoma (31%). Conclusions: Our platform for precision medicine provided meaningful moleculardriven therapy recommendations for most patients with advanced therapy refractory solid tumors for whom no standard therapy regimen was available. Legal entity responsible for the study: Medical University of Vienna. Funding: Has not received any funding. Disclosure: H. Taghizadeh: Travel / Accommodation / Expenses: Roche. All other authors have declared no conflicts of interest.
100P
Concordance between tissue analysis (TA) and liquid biopsy (LB) for RAS/BRAF and the optimization of its clinical application in such a heterogeneous tumour
I. Grilo1, R. Leite2, P. Gago1, S. Duarte1, A. Teira1, T. Sarmento1, M. Sousa1 Onco-Hematology Department, Centro Hospitalar Tras-os-Montes e Alto Douro, E.P.E., Vila Real, Portugal, 2Department of Genetics, CHTMAD, Vila Real, Portugal
1
Background: In metastatic CRC, the absence of RAS/BRAF mutation is indicative of a good response to anti-EGFR therapy. However, these patients have a distinct genomic profiles and tumors heterogeneity. This is probably the greatest difficulty regarding the detection of mutations in tumor tissue. LB can overcome this, detecting cDNA as well
Volume 30 | Supplement 7 | November 2019
as early changes in mutational status before the clinical progression. Dynamic molecular analysis may allow new therapeutic sequences. Methods: Non-randomized observational study since October 2014 - ongoing, for evaluation concordance of RAS/BRAF status between LB and TA and monitoring every 8 weeks using the IdyllaMT, in patients with metastatic CRC. Results: 148 liquid biopsies corresponding to 101 patients have been performed until now. Verification of concordance was possible only in 54 patients due to missions tissue biopsy (done outside the institution). The overall agreement was 70.2% (47/61), with 44.7% mutRAS patients. When we look at patients with liver metastasis, the agreement increases to 89%. Disagreement was found in 14 patients, and in 29.6%(4/14) TA was WT and LB mutRAS. When we reviewed the patients reassessed with LB at 8 weeks, 3 changed their status from mutated to WT. It was also found that one patient, initially WT treated with anti-EGFR in LB, was detected Gly12Ala / Gly12Val mutation, and in 2nd LB it was WT. Another patient initially detected A146P/T/V mutation was treated with oral fluropyrimidine, becoming WT in LB, progressed and started doubletþbevacizumab with partial response, and the same mutation was detected in 2nd LB. Conclusions: It appears that the site of metastases (liver, peritoneum, lung) has an impact on the detection of RAS/BRAF cDNA status. In cases of RAS/BRAF WT in TA, LB may better predict the response to anti-EGFR agents. In these preliminary results, the tumor has been shown to be clearly dynamic; the change of mutated RAS/BRAF status to WT was confirmed during the instituted therapy, opening a possible therapeutic window the for these patients with anti-EGFR therapy. This study included so far a small sample but demonstrates that personalized therapy with molecular/genomic analysis is undoubtedly valuable. Legal entity responsible for the study: CHTMAD - Onco-Hematology Department. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
101P
Clinical application of routine comprehensive tumour molecular profiling in the management of cancer patients
V. Mileyko1, E. Veselovsky2, E. Rozhavskaya2, E. Ignatova3, A. Kovtun2, M. Sharova2, M. Ivanov4 1 Atlas Oncodiagnostics, LLS, Moscow, Russian Federation, 2Atlas OncoDiagnostics ltd., Moscow, Russian Federation, 3Clinical Pharmacology and Chemotherapy, FSBI-N. N. Blokhin Russian Cancer Research Center, Moscow, Russian Federation, 4Moscow Institute of Physics and Technology, Dolgoprudny, Russian Federation Background: Along with the extension of the FDA approved molecular matched therapies, the evidence is building to support molecular profile-based off-label drug prescription or inclusion in a clinical trial. We report the findings from our real-world comprehensive molecular tumor profiling (CMTP) practice to assess how CMTP extends treatment options within and beyond standards of care. Methods: Pts with a confirmed diagnosis of advanced cancers are eligible. DNA was extracted from either archival or fresh collected tumor samples. Blood plasma was used for sequencing if the tumor sample was unavailable. CMTP included next generation sequencing. A panel of 409, 50 or 17 genes was used based on multidisciplinary molecular tumor board (MMTB) recommendations. Additional tests (IHC, FISH, MSI testing) were performed if recommended by MMTB. Results: 155 patients were eligible for the analysis (63% female, median age 57, range 17-90). Tumor types were gyneco (19%), colorectal (18%), lung (14%), pancreatic (10%), breast (9%), stomach (5%). A total of 94% actionable biomarker (AB) associated with potential benefit from approved therapy were identified across 68(44%) pts. 49 (72%) pts had only one AB while 19 had 2 or more AB (up to 5). The most common AB were BRCA1/2 mutation/deletion (14%), PIK3CA mutations (13%), PD-L1 overexpression (12.7%), microsatellite instability (11%) and ERBB2 mutation/amplification/overexpression (7%). 29/155 (19%) pts received in-label therapy recommendations (TR) (38% pts - lung, 31% pts – gyneco, 10% pts - colorectal). 28/ 126 (23%) pts without in-label TR received off-label TR (18% pts – gyneco, 18% pts colorectal, 14% pts – pancreatic, 10% pts – stomach) with a total of 56 TR (20% immunotherapy, 13% PARPi, 7% MEKi, 5% ERBB2i). 12/98 (12%) pts without in-label or off-label TR received profile-matched TR within a clinical trial. Across 19/155 (12%) pts we identified biomarkers associated with the resistance to standard therapy. Conclusions: CMTP was informative for 72/155 (46%) pts. 69/155(44%) pts received TR. Across tumor types least % of pts received TR with prostate (0/5, 0%), pancreatic (4/15, 26%) and breast (5/14, 36%) cancer, suggesting the need to define pts population who may benefit from CMTP. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: V. Mileyko: Full / Part-time employment: Atlas Oncology Diagnostics, ltd. E. Veselovsky: Full / Part-time employment: Atlas Oncology Diagnostics, ltd. E. Rozhavskaya: Full / Part-time employment: Atlas Oncology Diagnostics, ltd. A. Kovtun: Full / Part-time employment: Atlas Oncology Diagnostics, ltd. M. Sharova: Full / Part-time employment: Atlas Oncology Diagnostics, ltd. M. Ivanov: Full / Part-time employment: Atlas Oncology Diagnostics, ltd. All other authors have declared no conflicts of interest.
doi:10.1093/annonc/mdz413 | vii29
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_7/mdz413.105/5613286 by guest on 31 December 2019
NextSeq 500 sequencing device (all Illumina, CA, USA). Sequencing data were processed by an established pipeline. Tumour mutational burden (TMB) was calculated as a number of coding and splice-site nonsynonymous SNVs per megabase. FFPE samples from 35 patients previously examined by WES were independently examined also by F1Heme. Finally, we compared findings provided by WES and F1Heme with focus on clinically relevant information. Results: Clinically relevant SNVs were identified using both WES and F1Heme in 13 patients (37%). Among mutated genes were NRAS (5 patients), FGFR1 (2 patients), CTNNB1 (2 patients), PTPN11 (2 patients) BRAF (1 patient), IDH2 (1 patient) and HIST1H3B (1 patient). Nine patients carried also mutation in TP53. There was a significant correlation between TMB values obtained by WES and F1Heme (R2¼0.998, P < 0.001), whereas in 2 patients TMB was higher than 10 mut/Mb. F1Heme also reported gene rearrangements and amplifications. Conclusions: We found 100% match in detection of SNVs using both WES and F1Heme. TMBs obtained from WES and F1Heme were correlated with high statistical significance. Our data suggest that the molecular diagnostics based both on WES and F1Heme present valuable tools for individualized treatment planning for detecting SNVs in paediatric oncology. WES needs to be complemented by other profiling tools to detect other types of genomic alterations such as gene rearrangements or amplification. Legal entity responsible for the study: The authors. Funding: Roche supplies FoundationOne Heme with tests and by the Czech Ministry of Health, grant no 16-33209A. Disclosure: All authors have declared no conflicts of interest.