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Driving solo? Investigation into collaborating mutations in SDH-deficient neoplasia
abstracts employment: Hoffmann-La Roche Ltd. H. Moch: Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche. A. Kr€amer: Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche. All other authors have declared no conflicts of interest.
2038P
Incidence and outcome of chronic lymphocytic leukemia with deletion 17p: An Indian experience; challenges and opportunities
Annals of Oncology Results: 82 SDH-deficient neoplasms were analyzed (Table). 0 of 38 GIST had highly actionable GA. In one case a subclonal KIT variant was identified in a recurrence of an SDHA-mutant GIST treated with Imatinib for several years. No clonal canonical driver kinase mutations were identified in KIT, PDGFRA, NF1, BRAF, FGFR1 or NTRK1-3. 0 of 36 dSDH PGL/Pheo and 0 of 1 PAC had potential therapeutic options. 2 of 7 dSDH RCC reported potential treatment options for oncogenic variants in EGFR and CDK4. No dSDH tumors had high TMB, microsatellite instability, or LOH score indicative of homologous recombination defect (HRD). Overall, 2 of 82 tumors (2.4%) harbored highly actionable GA.
A. Gogia, L. Kumar, A. Sharma, R. Gupta, L. Rani Medical Oncology, B.R. Ambedkar Institute Rotary Cancer Hospital (AIMS), New Delhi, India
Table: 2039P
2039P
Driving solo? Investigation into collaborating mutations in SDHdeficient neoplasia
J.K. Killian1, D.C. Pavlick2, E.S. Sokol3, M. Montesion3, D.X. Jin3, B. Kaplan3, D. Lin1, JA. Vergilio1, J.A. Elvin1, N. Ngo1, E. Severson1, S. Ramkissoon1, D. Duncan1, C. Edgerly1, A. Hemmerich1, G.M. Frampton3, G. Bratslavsky4, V.A. Miller5, S.M. Ali5, J.S. Ross1 1 Pathology, Foundation Medicine, Cambridge, MA, USA, 2Cancer Genomics Research, Foundation Medicine, Cambridge, MA, USA, 3Cancer Genomics, Foundation Medicine, Cambridge, MA, USA, 4Urology, Upstate Medical University, Syracuse, NY, USA, 5Clinical Development, Foundation Medicine, Cambridge, MA, USA Background: Succinate dehydrogenase (SDH) is a highly conserved component of energy production and metabolism. Genetic or epigenetic inactivation of SDH (dSDH) creates a state of intracellular pseudohypoxia that is uniquely oncogenic for subtypes of GIST, renal cell carcinoma (RCC), paraganglioma/pheochromocytoma (PGL/Pheo), and pituitary adenoma/carcinoma (PAC). dSHD stems from homozygous loss of one of four subunit encoding genes SDHA, SDHB, SDHC, or SDHD (aka, SDHx). dSDH is not targetable, and preclinical models are poorly viable. In the current study we analyze comprehensive genomic profiles (CGP) from a dSDH pan-tumor cohort for potential therapy-enabling non-SDHx genomic alterations and biomarkers (GA). Methods: 231,706 clinical grade CGP were searched for dSDH GIST, RCC, PGL/Pheo, and PAC. GA were determined on 1.1 Mb genome sequence encompassing up to 324 cancer genes. dSDH was further established by histopathology review and analysis of SDHx homozygous loss. Germline and zygosity status of SDHx variants were performed by SGZ algorithm. Non-SDHx GA were assessed for therapeutic actionability.
v814 | Tumour Biology and Pathology
Age (mean) Sex ratio (M/F) SDHA SDHB SDHC SDHD SDHx-WT %SDHx germline GA/tumor (pathogenic non-SDHx) MSI TMB (mut/Mb, mean) HRD (LOHscore >16%)
GIST (n ¼ 38)
PGL/Pheo (n ¼ 36)
RCC (n ¼ 7)
PAC (n ¼ 1)
33 16/21 11 7 4 2 14 69 0.58
40 24/12 12 21 1 2 0 64 0.89
49 4/3 3 3 1 0 0 100 2.29
44 0/1 1 0 0 0 0 50 0
0 1.86 0
0 2.4 0
0 3 0
0 0.9 0
Conclusions: This study identifies SDH deficiency as a lone driver of malignancy and without associated actionable GA in > 97% of cases, and underscores the need for novel therapeutic approaches targeting SDH deficiency itself. Legal entity responsible for the study: Foundation Medicine. Funding: Foundation Medicine. Disclosure: J.K. Killian: Full / Part-time employment: Foundation Medicine. D.C. Pavlick: Full / Part-time employment: Foundation Medicine. E.S. Sokol: Full / Part-time employment: Foundation Medicine. M. Montesion: Full / Part-time employment: Foundation Medicine. D.X. Jin: Full / Parttime employment: Foundation Medicine. B. Kaplan: Full / Part-time employment: Foundation Medicine. D. Lin: Full / Part-time employment: Foundation Medicine. J. Vergilio: Full / Part-time employment: Foundation Medicine. J.A. Elvin: Full / Part-time employment: Foundation Medicine. N. Ngo: Full / Part-time employment: Foundation Medicine. E. Severson: Full / Part-time employment: Foundation Medicine. S. Ramkissoon: Full / Part-time employment: Foundation Medicine. D. Duncan: Full / Part-time employment: Foundation Medicine. C. Edgerly: Full / Part-time employment: Foundation Medicine. A. Hemmerich: Full / Part-time employment: Foundation Medicine. G.M. Frampton: Full / Part-time employment: Foundation Medicine. V.A. Miller: Full / Part-time employment: Foundation Medicine. S.M. Ali: Full / Part-time employment: Foundation Medicine. J.S. Ross: Full / Part-time employment: Foundation Medicine. All other authors have declared no conflicts of interest.
2040P
The potential of a novel antiangiogenic VEGFR1-D2 binding peptide in oncology therapeutics
A. Sadre Momtaz1, S.M. Asghari2, M.R. Groves1 Drug Design, University of Groningen, Groningen, Netherlands, 2Department of Biology, University of Guilan, Rasht, Iran 1
Background: Tumor growth depends on pro-angiogenic vascular endothelial growth factors (VEGF-A/-B) via binding to VEGF receptors (VEGFR1 and VEGFR2) that are biomarkers of tumor angiogenesis. Importantly, interfering with this interaction by small molecules impairs tumor growth and angiogenesis. Methods: A novel peptide (known as VGB3) was synthesized using a solid-phase peptide synthesis (SPPS) procedure on 2-chlorotrityl chloride (2-CTC) resin. A disulfide bridge was formed in the peptide and it was purified using RP-HPLC. Recombinant His-tagged VEGFR1D2 obtained from inclusion bodies and purified on a Ni2þ-NTA agarose resin. The equilibrium constant for the binding of VGB3 to VEGFR1-D2 molecule was determined by microscale thermophoresis (MST). The accumulation of the
Volume 30 | Supplement 5 | October 2019
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_5/mdz269.056/5577835 by guest on 25 October 2019
82 SDH-deficient tumors Background: Deletion 17p (del17p) is a rare genomic aberration found in patients with CLL and its incidence is 5-9% in untreated patients and 30- 50% of relapsed and refractory cases. The presence of del 17p correlates with poor response to chemotherapy and unfavourable outcome. There is a paucity of data regarding incidence and outcome of CLL patients with del 17p from India. Methods: This prospective study included consecutive treatmentnaı¨ve and relapsed/ refractory patients who were diagnosed with CLL and registered at the Department of Medical Oncology, Dr. BRAIRCH, All India Institute of Medical Sciences, New Delhi, between June 2013 and December 2018. Del 17p was assessed by FISH in peripheral blood samples. Results: Total 220 patients (150 new and 70 relapse/refractory) recruited in this study, del 17 p was found in 18 (12%) patients in new cases and 18 (25.5%) in relapsed/refractory cases. The median age in 36 cases were 57 years (35-80) with male:female ratio was 6:1. As per clinical Rai stage:5 cases were in stage 0 & I, 10 cases were in stage II, 8 cases were in stage III and 13 cases were in stage IV. ZAP-70 was positive in 58%, CD 38 was positive in 45%, CD49d was positive in 66% and 80% of cases were IGVH unmutated. Out of 18 newly diagnosed cases, 11 patients received treatment [ 4 – Ibrutinib, 4 Bendamustine þ Rituximab (BR), 2- Chlorambucil and Prednisolone (CP),1 Fludarabine, cyclophosphamide and rituximab (FCR)] while 7 patients were kept under observation. The overall response rate was 63.6% and complete response was 4 (36.36%). Out of 18 Relapse/refractory cases, 15 patients were required treatment (4Ibrutinib, 4- BR, 5 -RCHOP/RCVP, 2 CP] with an overall response rate of 40% and CR rate of 12%. Eighteen patients died (11-disease progression, 4 infections and 3 -other reasons). Eight patients developed Richter’s transformation and died. The median progression free survival and overall survival was 14 months and 24 months respectively. Conclusions: This is the first study on CLL with del17 p reported from India. Its incidence is 12 % in upfront cases and 25.5% in relapsed /refractory cases. Chemoimmunotherapy has dismal outcome and Ibrutinib was used in a limited number of patients because of financial constraints. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
2038P
Incidence and outcome of chronic lymphocytic leukemia with deletion 17p: An Indian experience; challenges and opportunities
Annals of Oncology Results: 82 SDH-deficient neoplasms were analyzed (Table). 0 of 38 GIST had highly actionable GA. In one case a subclonal KIT variant was identified in a recurrence of an SDHA-mutant GIST treated with Imatinib for several years. No clonal canonical driver kinase mutations were identified in KIT, PDGFRA, NF1, BRAF, FGFR1 or NTRK1-3. 0 of 36 dSDH PGL/Pheo and 0 of 1 PAC had potential therapeutic options. 2 of 7 dSDH RCC reported potential treatment options for oncogenic variants in EGFR and CDK4. No dSDH tumors had high TMB, microsatellite instability, or LOH score indicative of homologous recombination defect (HRD). Overall, 2 of 82 tumors (2.4%) harbored highly actionable GA.
A. Gogia, L. Kumar, A. Sharma, R. Gupta, L. Rani Medical Oncology, B.R. Ambedkar Institute Rotary Cancer Hospital (AIMS), New Delhi, India
Table: 2039P
2039P
Driving solo? Investigation into collaborating mutations in SDHdeficient neoplasia
J.K. Killian1, D.C. Pavlick2, E.S. Sokol3, M. Montesion3, D.X. Jin3, B. Kaplan3, D. Lin1, JA. Vergilio1, J.A. Elvin1, N. Ngo1, E. Severson1, S. Ramkissoon1, D. Duncan1, C. Edgerly1, A. Hemmerich1, G.M. Frampton3, G. Bratslavsky4, V.A. Miller5, S.M. Ali5, J.S. Ross1 1 Pathology, Foundation Medicine, Cambridge, MA, USA, 2Cancer Genomics Research, Foundation Medicine, Cambridge, MA, USA, 3Cancer Genomics, Foundation Medicine, Cambridge, MA, USA, 4Urology, Upstate Medical University, Syracuse, NY, USA, 5Clinical Development, Foundation Medicine, Cambridge, MA, USA Background: Succinate dehydrogenase (SDH) is a highly conserved component of energy production and metabolism. Genetic or epigenetic inactivation of SDH (dSDH) creates a state of intracellular pseudohypoxia that is uniquely oncogenic for subtypes of GIST, renal cell carcinoma (RCC), paraganglioma/pheochromocytoma (PGL/Pheo), and pituitary adenoma/carcinoma (PAC). dSHD stems from homozygous loss of one of four subunit encoding genes SDHA, SDHB, SDHC, or SDHD (aka, SDHx). dSDH is not targetable, and preclinical models are poorly viable. In the current study we analyze comprehensive genomic profiles (CGP) from a dSDH pan-tumor cohort for potential therapy-enabling non-SDHx genomic alterations and biomarkers (GA). Methods: 231,706 clinical grade CGP were searched for dSDH GIST, RCC, PGL/Pheo, and PAC. GA were determined on 1.1 Mb genome sequence encompassing up to 324 cancer genes. dSDH was further established by histopathology review and analysis of SDHx homozygous loss. Germline and zygosity status of SDHx variants were performed by SGZ algorithm. Non-SDHx GA were assessed for therapeutic actionability.
v814 | Tumour Biology and Pathology
Age (mean) Sex ratio (M/F) SDHA SDHB SDHC SDHD SDHx-WT %SDHx germline GA/tumor (pathogenic non-SDHx) MSI TMB (mut/Mb, mean) HRD (LOHscore >16%)
GIST (n ¼ 38)
PGL/Pheo (n ¼ 36)
RCC (n ¼ 7)
PAC (n ¼ 1)
33 16/21 11 7 4 2 14 69 0.58
40 24/12 12 21 1 2 0 64 0.89
49 4/3 3 3 1 0 0 100 2.29
44 0/1 1 0 0 0 0 50 0
0 1.86 0
0 2.4 0
0 3 0
0 0.9 0
Conclusions: This study identifies SDH deficiency as a lone driver of malignancy and without associated actionable GA in > 97% of cases, and underscores the need for novel therapeutic approaches targeting SDH deficiency itself. Legal entity responsible for the study: Foundation Medicine. Funding: Foundation Medicine. Disclosure: J.K. Killian: Full / Part-time employment: Foundation Medicine. D.C. Pavlick: Full / Part-time employment: Foundation Medicine. E.S. Sokol: Full / Part-time employment: Foundation Medicine. M. Montesion: Full / Part-time employment: Foundation Medicine. D.X. Jin: Full / Parttime employment: Foundation Medicine. B. Kaplan: Full / Part-time employment: Foundation Medicine. D. Lin: Full / Part-time employment: Foundation Medicine. J. Vergilio: Full / Part-time employment: Foundation Medicine. J.A. Elvin: Full / Part-time employment: Foundation Medicine. N. Ngo: Full / Part-time employment: Foundation Medicine. E. Severson: Full / Part-time employment: Foundation Medicine. S. Ramkissoon: Full / Part-time employment: Foundation Medicine. D. Duncan: Full / Part-time employment: Foundation Medicine. C. Edgerly: Full / Part-time employment: Foundation Medicine. A. Hemmerich: Full / Part-time employment: Foundation Medicine. G.M. Frampton: Full / Part-time employment: Foundation Medicine. V.A. Miller: Full / Part-time employment: Foundation Medicine. S.M. Ali: Full / Part-time employment: Foundation Medicine. J.S. Ross: Full / Part-time employment: Foundation Medicine. All other authors have declared no conflicts of interest.
2040P
The potential of a novel antiangiogenic VEGFR1-D2 binding peptide in oncology therapeutics
A. Sadre Momtaz1, S.M. Asghari2, M.R. Groves1 Drug Design, University of Groningen, Groningen, Netherlands, 2Department of Biology, University of Guilan, Rasht, Iran 1
Background: Tumor growth depends on pro-angiogenic vascular endothelial growth factors (VEGF-A/-B) via binding to VEGF receptors (VEGFR1 and VEGFR2) that are biomarkers of tumor angiogenesis. Importantly, interfering with this interaction by small molecules impairs tumor growth and angiogenesis. Methods: A novel peptide (known as VGB3) was synthesized using a solid-phase peptide synthesis (SPPS) procedure on 2-chlorotrityl chloride (2-CTC) resin. A disulfide bridge was formed in the peptide and it was purified using RP-HPLC. Recombinant His-tagged VEGFR1D2 obtained from inclusion bodies and purified on a Ni2þ-NTA agarose resin. The equilibrium constant for the binding of VGB3 to VEGFR1-D2 molecule was determined by microscale thermophoresis (MST). The accumulation of the
Volume 30 | Supplement 5 | October 2019
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_5/mdz269.056/5577835 by guest on 25 October 2019
82 SDH-deficient tumors Background: Deletion 17p (del17p) is a rare genomic aberration found in patients with CLL and its incidence is 5-9% in untreated patients and 30- 50% of relapsed and refractory cases. The presence of del 17p correlates with poor response to chemotherapy and unfavourable outcome. There is a paucity of data regarding incidence and outcome of CLL patients with del 17p from India. Methods: This prospective study included consecutive treatmentnaı¨ve and relapsed/ refractory patients who were diagnosed with CLL and registered at the Department of Medical Oncology, Dr. BRAIRCH, All India Institute of Medical Sciences, New Delhi, between June 2013 and December 2018. Del 17p was assessed by FISH in peripheral blood samples. Results: Total 220 patients (150 new and 70 relapse/refractory) recruited in this study, del 17 p was found in 18 (12%) patients in new cases and 18 (25.5%) in relapsed/refractory cases. The median age in 36 cases were 57 years (35-80) with male:female ratio was 6:1. As per clinical Rai stage:5 cases were in stage 0 & I, 10 cases were in stage II, 8 cases were in stage III and 13 cases were in stage IV. ZAP-70 was positive in 58%, CD 38 was positive in 45%, CD49d was positive in 66% and 80% of cases were IGVH unmutated. Out of 18 newly diagnosed cases, 11 patients received treatment [ 4 – Ibrutinib, 4 Bendamustine þ Rituximab (BR), 2- Chlorambucil and Prednisolone (CP),1 Fludarabine, cyclophosphamide and rituximab (FCR)] while 7 patients were kept under observation. The overall response rate was 63.6% and complete response was 4 (36.36%). Out of 18 Relapse/refractory cases, 15 patients were required treatment (4Ibrutinib, 4- BR, 5 -RCHOP/RCVP, 2 CP] with an overall response rate of 40% and CR rate of 12%. Eighteen patients died (11-disease progression, 4 infections and 3 -other reasons). Eight patients developed Richter’s transformation and died. The median progression free survival and overall survival was 14 months and 24 months respectively. Conclusions: This is the first study on CLL with del17 p reported from India. Its incidence is 12 % in upfront cases and 25.5% in relapsed /refractory cases. Chemoimmunotherapy has dismal outcome and Ibrutinib was used in a limited number of patients because of financial constraints. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.