TY - JOUR
T1 - Clinical outcomes of NOTCH pathway-activated adenoid cystic carcinoma with and without co-occurrent TP53 mutation
AU - Haider, syeda
AU - haigh, Joseph
AU - Patel, Karan
AU - Rack, Samuel
AU - spurgeon, laura
AU - betts, guy
AU - Harrington, Kevin J
AU - Metcalf, Robert
PY - 2024/6
Y1 - 2024/6
N2 - Background: Adenoid cystic carcinoma (ACC) is a salivary cancer with a variable disease course. Inoperable locally advanced, recurrent or metastatic ACC (LA-R/M-ACC) are its commonest manifestations. The disease course is typically indolent with patients remaining on surveillance for many years before initiating relatively ineffective systemic therapies. A sub-group of patients experience rapid disease progression and surveillance is not indicated. NOTCH gain-of-function mutation (NOTCH gof ) is well characterised, defining a genomic sub-group with shorter survival times. However, there remains a need to identify additional prognostic biomarkers to inform the clinical management of these patients. TP53 mutation (TP53 mt ) has been proposed as a prognostic biomarker warranting further evaluation. Methods: Clinical-genomic data from 349 ACC patients with LA-R/M-ACC were included. 198 patients provided written informed consent to an ethically approved study, and a further 151 were identified through cBioPortal (MetTropsim, Cell, 2021). ACC tumour samples were evaluated by next-generation sequencing (NGS) for the presence of NOTCH gof and TP53 mt . Kaplan-Meier analysis was performed, and p values calculated with the log-rank test, to calculate overall survival (OS) from inoperable LA or R/M disease for patients with either NOTCH gof alone, TP53 mt alone or both NOTCH gof /TP53 mt combined. Results: ACC tumours harboured NOTCH gof in 14.0% (49/349) and TP53 mt in 13.8% (48/349) of cases, respectively. Co-occurrence of TP53 mt was identified in 16% of ACC tumours with NOTCH gof (8/49), being in 2.3 % of all LA-R/M-ACC cases. Median OS from inoperable LA-R/M disease was significantly reduced for patients with co-occurrent NOTCH gof /TP53 mt (n=8, 10.0 mo; 95% CI 8–12), followed by NOTCH gof /TP53 wt (n=41, 15.2 mo; 95% CI 8–22), NOTCH wt /TP53 wt (n=262, 58.6 mo; 95% CI 52–65) and NOTCH wt /TP53 mt (n=40, 69 mo; 95% CI 13–125) (p=<0.001). TP53 alterations were available for functional classification in 33 patients and were classed as loss-of-function point mutations in 81.8% or truncating frameshift mutations in 18.2%. Truncating TP53 mt were mutually exclusive with NOTCH gof . Although the smaller number in this group limits statistical power, patients with truncating TP53 mt had shorter OS from recurrence (15.9 mo; 95% CI 0-39) compared with other TP53 mt (51.0 mo; 95% CI 0-108; p=0.41). Conclusions: A subgroup of LA-R/M ACC patients with co-occurrent TP53 mt and NOTCH gof were identified with significantly shorter OS from recurrence than either NOTCH gof or TP53 mt alone. Truncating TP53 mt may have greater prognostic value than other TP53 mt in NOTCH wt ACC. This study provides further evidence of the potential prognostic utility of some TP53 mutations in ACC and highlights groups of patients with aggressive disease who are potentially suitable for inclusion in therapeutic research programmes.
AB - Background: Adenoid cystic carcinoma (ACC) is a salivary cancer with a variable disease course. Inoperable locally advanced, recurrent or metastatic ACC (LA-R/M-ACC) are its commonest manifestations. The disease course is typically indolent with patients remaining on surveillance for many years before initiating relatively ineffective systemic therapies. A sub-group of patients experience rapid disease progression and surveillance is not indicated. NOTCH gain-of-function mutation (NOTCH gof ) is well characterised, defining a genomic sub-group with shorter survival times. However, there remains a need to identify additional prognostic biomarkers to inform the clinical management of these patients. TP53 mutation (TP53 mt ) has been proposed as a prognostic biomarker warranting further evaluation. Methods: Clinical-genomic data from 349 ACC patients with LA-R/M-ACC were included. 198 patients provided written informed consent to an ethically approved study, and a further 151 were identified through cBioPortal (MetTropsim, Cell, 2021). ACC tumour samples were evaluated by next-generation sequencing (NGS) for the presence of NOTCH gof and TP53 mt . Kaplan-Meier analysis was performed, and p values calculated with the log-rank test, to calculate overall survival (OS) from inoperable LA or R/M disease for patients with either NOTCH gof alone, TP53 mt alone or both NOTCH gof /TP53 mt combined. Results: ACC tumours harboured NOTCH gof in 14.0% (49/349) and TP53 mt in 13.8% (48/349) of cases, respectively. Co-occurrence of TP53 mt was identified in 16% of ACC tumours with NOTCH gof (8/49), being in 2.3 % of all LA-R/M-ACC cases. Median OS from inoperable LA-R/M disease was significantly reduced for patients with co-occurrent NOTCH gof /TP53 mt (n=8, 10.0 mo; 95% CI 8–12), followed by NOTCH gof /TP53 wt (n=41, 15.2 mo; 95% CI 8–22), NOTCH wt /TP53 wt (n=262, 58.6 mo; 95% CI 52–65) and NOTCH wt /TP53 mt (n=40, 69 mo; 95% CI 13–125) (p=<0.001). TP53 alterations were available for functional classification in 33 patients and were classed as loss-of-function point mutations in 81.8% or truncating frameshift mutations in 18.2%. Truncating TP53 mt were mutually exclusive with NOTCH gof . Although the smaller number in this group limits statistical power, patients with truncating TP53 mt had shorter OS from recurrence (15.9 mo; 95% CI 0-39) compared with other TP53 mt (51.0 mo; 95% CI 0-108; p=0.41). Conclusions: A subgroup of LA-R/M ACC patients with co-occurrent TP53 mt and NOTCH gof were identified with significantly shorter OS from recurrence than either NOTCH gof or TP53 mt alone. Truncating TP53 mt may have greater prognostic value than other TP53 mt in NOTCH wt ACC. This study provides further evidence of the potential prognostic utility of some TP53 mutations in ACC and highlights groups of patients with aggressive disease who are potentially suitable for inclusion in therapeutic research programmes.
U2 - 10.1200/JCO.2024.42.16_suppl.6101
DO - 10.1200/JCO.2024.42.16_suppl.6101
M3 - Meeting Abstract
SN - 0732-183X
VL - 42
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - 16
ER -