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refractory mantle cell lymphoma: 7-year experience
abstracts
Annals of Oncology
56P
Ibrutinib for relapsed/refractory mantle cell lymphoma: 7-year experience
I.T. Grilo1, M.E. Couto2, J.F. Freitas3, D.P. Pereira2, C. Moreira2, S. Chacim2, N. Domingues2, A.E. Santo2, Aˆ. Martins2, L. Viterbo2, I. Oliveira2, I. Moreira2, J.M. Mariz2 1 Onco-Hematology Department, Centro Hospitalar Tras-os-Montes e Alto Douro, E.P.E., Chaves, Portugal, 2IPO-Porto, Porto, Portugal, 3Hemato-Oncology Department, IPOPorto, Porto, Portugal Background: Mantle cell lymphoma (MLC) is nowadays an aggressive and incurable Non-Hodgkin’s lymphoma, characterized by multiple relapses.The persistent activation of B-cell receptor pathway is critical for pathogenesis. Ibrutinib is a potent covalent inhibitor of Bruton’s tyrosine kinase (BTK) that inhibits B-cell antigen receptor signaling downstream of BTK and changed for better how MCL is treated in relapsed/refractory setting. However, resistance is common and response limited. Methods: Retrospective analysis and follow-up of all MCL patients treated with Ibrutinib in a Onco-Hematology Department. Results: Eleven patients were identified, with a median age of 68 years [58-78], the majority of them were males (83.3%). At diagnosis, 9% were in stage III of Ann Arbor while 81.8% were in stage IV. The median MIPI (MCL International Prognostic Index) was 5.5 [4-8]. These patients were exposed to a median of 3 treatments [3-5]. The majority of them performed as 1 line treatment R-FCM (18.2%) or R-CHOP (54.5%); as 2 line R-CHOP (45.5%), as 3 line Ibrutinib (63.6%), as 4 line PEPC (60%) and as 5 line Ibrutinib (100%). Ibrutinib therapy was prescribed as a 2 line in 9.1% of the patients, as a 3 line in 63.6%, as 4 line in 40% and as a 5 line in 100%. Ibrutinib achieved a complete response rate in 9.1%, a partial response in 45.5% (response rate, RR, of 54.5%), disease progression in 36.4%, stable disease in 9,1%. At the end of the study, 5 patients were alive and still doing Ibrutinib (4 of them in full dose 560 mg/ day). The median progression free survival (PFS) was 3 months [1-26]. Overall survival was not reached (3 patients died with disease progression). Conclusions: Although a larger sample and a longer follow-up are needed, these data showed worse results when compared to previous phase 2 trials demonstrating a 68% response rate (RR), including for high-risk patients and heavily pretreated. Most recently, a pooled analysis of the three open-label studies of ibrutinib in MCL, PCYC1104, SPARK, and RAY revealed an ORR of 68%, 63% and 72%. Ibrutinib may be changing the natural history of MCL as many other agents still under development. Enrollment in clinical trials is crucial not only for discovery of new agents and testing combinations but also to understand the natural history of relapsed MCL.
Legal entity responsible for the study: Onco-Hematology Service of Instituto Portugu^es de Oncologia do Porto, F.G., E.P.E. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
57P
Leukotriene B4 receptors abnormal gene expression is associated with either shorter or longer survival in breast cancer patients depending on the intrinsic tumour molecular subtype
A.I. Kalinkin1, M.V. Nemtsova2, D.V. Zaletaev2, V.O. Sigin1, E. Ignatova3, E.B. Kuznetsova1, V.V. Strelnikov1, A.S. Tanas1 1 Epigenetic Lab, Research Centre for Medical Genetics, Moscow, Russian Federation, 2 Medical Genetics Laboratory, Federal State Autonomous Educational Institution of Higher Education I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), Moscow, Russian Federation, 3 Clinical Pharmacology and Chemotherapy, FSBI-N. N. Blokhin Russian Cancer Research Center, Moscow, Russian Federation Background: Leukotrienes receptor signaling is involved in tumor development and progression. Expression of leukotriene B4 receptors 1 and 2 (LTB4R and LTB4R2) promotes cell proliferation, survival, migration and metastasis. Aberrant LTB4R gene expression blocks anti-proliferative responses of TGF-b1 in breast cancer (BC) cell lines. LTB4R2 ectopic expression is associated with increased invasiveness of BC cells. Earlier, we reported LTB4R and LTB4R2 genes abnormal demethylation that is potent of initiating ectopic gene expression in a subset of triple-negative BC (TNBC) samples. Methods: We acquired the TCGA BRCA level 3 RNA-seq data and clinical datasheet using TCGA data portal. LTB4R/LTB4R2 gene expression cut-off values were defined using maximally selected rank statistics. Kaplan-Meier overall survival (OS) curves were compared with Mantel-Cox (log-rank) method. Results: TNBC exhibit a significantly lower survival probability in LTB4R expressing group. Vice versa, in Normal-Like and LumB subtypes absence of LTB4R and LTB4R2 expression respectively is associated with shorter OS (Table). Conclusions: Our findings suggest that LTB4R/LTB4R2 gene expression is a new potential BC prognostic biomarker, yet its use requires proper molecular subtyping of the tumors, as far as prognosis would depend upon the intrinsic tumor subtype. This also applies to the potential use of LTB4R/LTB4R2 expression as a marker predictive of tumors sensitivity to leukotriene receptor inhibitors, in case they enter clinical studies. Legal entity responsible for the study: Research Centre for Medical Genetics. Funding: The research was carried out within the state assignment of Ministry of Science and Higher Education of the Russian Federation. Disclosure: All authors have declared no conflicts of interest.
58P
A seven-gene methylation markers panel: An epigenetic predictor of neoadjuvant chemotherapy sensitivity in triple-negative breast cancer
V.O. Sigin1, A.I. Kalinkin1, E. Ignatova2, A.V. Sycheva1, I.I. Vinogradov3, M.I. Vinogradov4, I.Y. Vinogradov3, D.V. Zaletaev5, V.V. Strelnikov1, A.S. Tanas1 1 Epigenetics, Federal State Budgetary Institution "Research Centre for Medical Genetics", Moscow, Russian Federation, 2Clinical Pharmacology and Chemotherapy, FSBI-N. N. Blokhin Russian Cancer Research Center, Moscow, Russian Federation, 3Pathology and Anatomy, Ryazan Regional Clinical Oncology Dispensary, Ryazan, Russian Federation, 4 Ryazan State Medical University, Ryazan, Russian Federation, 5Medical Genetics Laboratory, Federal State Autonomous Educational Institution of Higher Education I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), Moscow, Russian Federation Background: Nowadays anthracycline and taxane-based chemotherapy remains the standard of care for TNBC, with pathological complete response (pCR) rates ranging 10–30%. pCR in TNBC is associated with better outcomes, while residual disease after
Table: 57P Overall survival comparison in various molecular BC subtypes. Asteriks (*) stand for p-value less then 0.05. Median OS are
Volume 30 | Supplement 7 | November 2019
doi:10.1093/annonc/mdz413 | vii17
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_7/mdz413.060/5613312 by guest on 25 December 2019
PolyPhen-2 were used to predict potential pathogenic effects of missense variants on protein structure and function. Results: We were able to detect 24 pathogenic/likely pathogenic mutations in 20 (16%) cases, out of which 8 were novel. Out of all mutations, five were detected in the APC gene, three in FANCI, three in BRCA2, two in BRCA1, two in MLH1, and one mutation each, in MSH6, MUTYH, BLM, NBN, ATM, BMPR1A, CHEK2, AIP, and DICER1 genes. The analysis of mutation type has revealed 10 frameshift mutations, 5 missense mutations, 5 stop-gain mutations, 1 in-frame deletion, and 3 mutations involving uncorrected splicing. All mutations were in the heterozygous state. Most of the mutations were not available in the 1000G, ESP6500 and ExAC databases. 5% were available in the dbSNP database, 29.1% in the COSMIC, and 38.4% in the ClinVar and/or LOVD. Pathogenic mutations in high penetrance CRC genes were higher in patients with family history of cancer (FHC) (21.1%, P ¼ 0.0002) and in patients with primary multiple tumors (20.0 %, P ¼ 0.0004) compared with patients without/unknown FHC (3.1%). Conclusions: Molecular genetic study of CRC in young patients using NGS allows to identify CRC cases with syndromic and sporadic nature, to stratify the level of risk for a particular patient and his/her relatives, to influence on the diagnostic and therapeutic approaches and clinical examinations. The findings from this study show the diagnostic value of the detected pathogenic mutations in key CRC genes from the Kazakhstan population as promising biomarkers for CRC diagnosis in young people. Legal entity responsible for the study: Institute of General Genetics and Cytology. Funding: Ministry of Healthcare of the Republic of Kazakhstan. Disclosure: All authors have declared no conflicts of interest.
Annals of Oncology
56P
Ibrutinib for relapsed/refractory mantle cell lymphoma: 7-year experience
I.T. Grilo1, M.E. Couto2, J.F. Freitas3, D.P. Pereira2, C. Moreira2, S. Chacim2, N. Domingues2, A.E. Santo2, Aˆ. Martins2, L. Viterbo2, I. Oliveira2, I. Moreira2, J.M. Mariz2 1 Onco-Hematology Department, Centro Hospitalar Tras-os-Montes e Alto Douro, E.P.E., Chaves, Portugal, 2IPO-Porto, Porto, Portugal, 3Hemato-Oncology Department, IPOPorto, Porto, Portugal Background: Mantle cell lymphoma (MLC) is nowadays an aggressive and incurable Non-Hodgkin’s lymphoma, characterized by multiple relapses.The persistent activation of B-cell receptor pathway is critical for pathogenesis. Ibrutinib is a potent covalent inhibitor of Bruton’s tyrosine kinase (BTK) that inhibits B-cell antigen receptor signaling downstream of BTK and changed for better how MCL is treated in relapsed/refractory setting. However, resistance is common and response limited. Methods: Retrospective analysis and follow-up of all MCL patients treated with Ibrutinib in a Onco-Hematology Department. Results: Eleven patients were identified, with a median age of 68 years [58-78], the majority of them were males (83.3%). At diagnosis, 9% were in stage III of Ann Arbor while 81.8% were in stage IV. The median MIPI (MCL International Prognostic Index) was 5.5 [4-8]. These patients were exposed to a median of 3 treatments [3-5]. The majority of them performed as 1 line treatment R-FCM (18.2%) or R-CHOP (54.5%); as 2 line R-CHOP (45.5%), as 3 line Ibrutinib (63.6%), as 4 line PEPC (60%) and as 5 line Ibrutinib (100%). Ibrutinib therapy was prescribed as a 2 line in 9.1% of the patients, as a 3 line in 63.6%, as 4 line in 40% and as a 5 line in 100%. Ibrutinib achieved a complete response rate in 9.1%, a partial response in 45.5% (response rate, RR, of 54.5%), disease progression in 36.4%, stable disease in 9,1%. At the end of the study, 5 patients were alive and still doing Ibrutinib (4 of them in full dose 560 mg/ day). The median progression free survival (PFS) was 3 months [1-26]. Overall survival was not reached (3 patients died with disease progression). Conclusions: Although a larger sample and a longer follow-up are needed, these data showed worse results when compared to previous phase 2 trials demonstrating a 68% response rate (RR), including for high-risk patients and heavily pretreated. Most recently, a pooled analysis of the three open-label studies of ibrutinib in MCL, PCYC1104, SPARK, and RAY revealed an ORR of 68%, 63% and 72%. Ibrutinib may be changing the natural history of MCL as many other agents still under development. Enrollment in clinical trials is crucial not only for discovery of new agents and testing combinations but also to understand the natural history of relapsed MCL.
Legal entity responsible for the study: Onco-Hematology Service of Instituto Portugu^es de Oncologia do Porto, F.G., E.P.E. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
57P
Leukotriene B4 receptors abnormal gene expression is associated with either shorter or longer survival in breast cancer patients depending on the intrinsic tumour molecular subtype
A.I. Kalinkin1, M.V. Nemtsova2, D.V. Zaletaev2, V.O. Sigin1, E. Ignatova3, E.B. Kuznetsova1, V.V. Strelnikov1, A.S. Tanas1 1 Epigenetic Lab, Research Centre for Medical Genetics, Moscow, Russian Federation, 2 Medical Genetics Laboratory, Federal State Autonomous Educational Institution of Higher Education I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), Moscow, Russian Federation, 3 Clinical Pharmacology and Chemotherapy, FSBI-N. N. Blokhin Russian Cancer Research Center, Moscow, Russian Federation Background: Leukotrienes receptor signaling is involved in tumor development and progression. Expression of leukotriene B4 receptors 1 and 2 (LTB4R and LTB4R2) promotes cell proliferation, survival, migration and metastasis. Aberrant LTB4R gene expression blocks anti-proliferative responses of TGF-b1 in breast cancer (BC) cell lines. LTB4R2 ectopic expression is associated with increased invasiveness of BC cells. Earlier, we reported LTB4R and LTB4R2 genes abnormal demethylation that is potent of initiating ectopic gene expression in a subset of triple-negative BC (TNBC) samples. Methods: We acquired the TCGA BRCA level 3 RNA-seq data and clinical datasheet using TCGA data portal. LTB4R/LTB4R2 gene expression cut-off values were defined using maximally selected rank statistics. Kaplan-Meier overall survival (OS) curves were compared with Mantel-Cox (log-rank) method. Results: TNBC exhibit a significantly lower survival probability in LTB4R expressing group. Vice versa, in Normal-Like and LumB subtypes absence of LTB4R and LTB4R2 expression respectively is associated with shorter OS (Table). Conclusions: Our findings suggest that LTB4R/LTB4R2 gene expression is a new potential BC prognostic biomarker, yet its use requires proper molecular subtyping of the tumors, as far as prognosis would depend upon the intrinsic tumor subtype. This also applies to the potential use of LTB4R/LTB4R2 expression as a marker predictive of tumors sensitivity to leukotriene receptor inhibitors, in case they enter clinical studies. Legal entity responsible for the study: Research Centre for Medical Genetics. Funding: The research was carried out within the state assignment of Ministry of Science and Higher Education of the Russian Federation. Disclosure: All authors have declared no conflicts of interest.
58P
A seven-gene methylation markers panel: An epigenetic predictor of neoadjuvant chemotherapy sensitivity in triple-negative breast cancer
V.O. Sigin1, A.I. Kalinkin1, E. Ignatova2, A.V. Sycheva1, I.I. Vinogradov3, M.I. Vinogradov4, I.Y. Vinogradov3, D.V. Zaletaev5, V.V. Strelnikov1, A.S. Tanas1 1 Epigenetics, Federal State Budgetary Institution "Research Centre for Medical Genetics", Moscow, Russian Federation, 2Clinical Pharmacology and Chemotherapy, FSBI-N. N. Blokhin Russian Cancer Research Center, Moscow, Russian Federation, 3Pathology and Anatomy, Ryazan Regional Clinical Oncology Dispensary, Ryazan, Russian Federation, 4 Ryazan State Medical University, Ryazan, Russian Federation, 5Medical Genetics Laboratory, Federal State Autonomous Educational Institution of Higher Education I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), Moscow, Russian Federation Background: Nowadays anthracycline and taxane-based chemotherapy remains the standard of care for TNBC, with pathological complete response (pCR) rates ranging 10–30%. pCR in TNBC is associated with better outcomes, while residual disease after
Table: 57P Overall survival comparison in various molecular BC subtypes. Asteriks (*) stand for p-value less then 0.05. Median OS are
Volume 30 | Supplement 7 | November 2019
doi:10.1093/annonc/mdz413 | vii17
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_7/mdz413.060/5613312 by guest on 25 December 2019
PolyPhen-2 were used to predict potential pathogenic effects of missense variants on protein structure and function. Results: We were able to detect 24 pathogenic/likely pathogenic mutations in 20 (16%) cases, out of which 8 were novel. Out of all mutations, five were detected in the APC gene, three in FANCI, three in BRCA2, two in BRCA1, two in MLH1, and one mutation each, in MSH6, MUTYH, BLM, NBN, ATM, BMPR1A, CHEK2, AIP, and DICER1 genes. The analysis of mutation type has revealed 10 frameshift mutations, 5 missense mutations, 5 stop-gain mutations, 1 in-frame deletion, and 3 mutations involving uncorrected splicing. All mutations were in the heterozygous state. Most of the mutations were not available in the 1000G, ESP6500 and ExAC databases. 5% were available in the dbSNP database, 29.1% in the COSMIC, and 38.4% in the ClinVar and/or LOVD. Pathogenic mutations in high penetrance CRC genes were higher in patients with family history of cancer (FHC) (21.1%, P ¼ 0.0002) and in patients with primary multiple tumors (20.0 %, P ¼ 0.0004) compared with patients without/unknown FHC (3.1%). Conclusions: Molecular genetic study of CRC in young patients using NGS allows to identify CRC cases with syndromic and sporadic nature, to stratify the level of risk for a particular patient and his/her relatives, to influence on the diagnostic and therapeutic approaches and clinical examinations. The findings from this study show the diagnostic value of the detected pathogenic mutations in key CRC genes from the Kazakhstan population as promising biomarkers for CRC diagnosis in young people. Legal entity responsible for the study: Institute of General Genetics and Cytology. Funding: Ministry of Healthcare of the Republic of Kazakhstan. Disclosure: All authors have declared no conflicts of interest.