Abstract 2596
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.
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.Table:
2039P
82 SDH-deficient tumors | ||||
---|---|---|---|---|
GIST (n = 38) | PGL/Pheo (n = 36) | RCC (n = 7) | PAC (n = 1) | |
Age (mean) | 33 | 40 | 49 | 44 |
Sex ratio (M/F) | 16/21 | 24/12 | 4/3 | 0/1 |
SDHA | 11 | 12 | 3 | 1 |
SDHB | 7 | 21 | 3 | 0 |
SDHC | 4 | 1 | 1 | 0 |
SDHD | 2 | 2 | 0 | 0 |
SDHx-WT | 14 | 0 | 0 | 0 |
%SDHx germline | 69 | 64 | 100 | 50 |
GA/tumor (pathogenic non-SDHx) | 0.58 | 0.89 | 2.29 | 0 |
MSI | 0 | 0 | 0 | 0 |
TMB (mut/Mb, mean) | 1.86 | 2.4 | 3 | 0.9 |
HRD (LOHscore >16%) | 0 | 0 | 0 | 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.
Clinical trial identification
Editorial acknowledgement
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 / Part-time 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.
Resources from the same session
920 - Efficacy of intravenous (IV) NEPA, a fixed NK1/5-HT3 receptor antagonist (RA) combination, for prevention of CINV following cisplatin- and anthracycline cyclophosphamide (AC)-based chemotherapy (CT)
Presenter: Lee Schwartzberg
Session: Poster Display session 1
Resources:
Abstract
5146 - Efficacy of olanzapine combination in prevention of nausea & vomiting in highly emetogenic chemotherapy
Presenter: Smitha Saldanha
Session: Poster Display session 1
Resources:
Abstract
1947 - Patient-reported outcome data during real-world use of NEPA for prevention of chemotherapy-induced nausea and vomiting in high-risk platin-receiving patients - A prospective multicenter trial
Presenter: Meinolf Karthaus
Session: Poster Display session 1
Resources:
Abstract
6163 - A study evaluating steroid induced metabolic syndrome after antiemetic dexamethasone therapy in patients received high emetic risk chemotherapy
Presenter: Hee Jun Kim
Session: Poster Display session 1
Resources:
Abstract
2154 - High incidence of nausea during initial and repeated courses if intravenous chemotherapy in patients receiving guideline consistent antiemetic prophylaxis - a prospective, observational, real world study.
Presenter: Teresa Smit
Session: Poster Display session 1
Resources:
Abstract
1637 - "Randomised controlled trial of Scalp Cooling (SC) for the prevention of Chemotherapy Induced Alopecia (CIA)”
Presenter: Jyoti Bajpai
Session: Poster Display session 1
Resources:
Abstract
5351 - Performance of the ‘4S rule’ to predict short-term outcomes in cancer outpatients with unsuspected pulmonary embolism.
Presenter: David Pesántez Coronel
Session: Poster Display session 1
Resources:
Abstract
1189 - Prevalence of venous thromboembolism based on intensive screening for patients with advanced solid tumor in prospective observational study
Presenter: Shota Omori
Session: Poster Display session 1
Resources:
Abstract
4340 - Short-term outcomes of cancer patients with pulmonary embolism according to the setting (hospital-acquired vs. outpatient) at diagnosis.
Presenter: Diego Muñoz Guglielmetti
Session: Poster Display session 1
Resources:
Abstract
4658 - Patient-reported outcomes associated with switching to rivaroxaban for the treatment of venous thromboembolism (VTE) in patients with active cancer
Presenter: Alexander Cohen
Session: Poster Display session 1
Resources:
Abstract