NOTCH1 mutations define aggressive subtype of adenoid cystic carcinomas
NOTCH1 mutations defined a subgroup of patients with adenoid cystic carcinomas who harbored an aggressive disease phenotype, demonstrated a distinct pattern of metastatic spread, and who may be responsive to Notch1 inhibitors, according to a study published in Journal of Clinical Oncology.
Adenoid cystic carcinomas — common malignant salivary gland tumors — are characterized as a heterogeneous group of chemotherapy-refractory tumors, a subset of which have an aggressive phenotype. No standard of care exists for patients with recurrent or metastatic disease.
“Whole-exome sequencing of adenoid cystic carcinomas samples has shed light on the genetic landscape of this disease and provides evidence for Notch pathway alterations in 11% to 29% of patients,” Renata Ferrarotto, MD, assistant professor in the department of thoracic/head and neck medical oncology at The University of Texas MD Anderson Cancer Center, and colleagues wrote. “The Notch pathway is involved in cancer-relevant functions, including maintenance of stem cells, cell fate specification, proliferation and angiogenesis.”
Conversely, deregulation of the Notch1 pathway has been observed in multiple cancers, although its therapeutic role and value as a target vary.
Therefore, the researchers genotyped 102 patients with adenoid cystic carcinomas to investigate the molecular foundation of these chemotherapy-refractory tumors and to evaluate the Notch1 pathway as a potential therapeutic agent.
The researchers conducted genomic profiling in 102 tumors, whole-exome sequencing in an additional 46 samples, and targeted sequencing for gene panel that included NOTCH1 mutation in 32 samples.
Of those samples, 18 NOTCH1 mutations were identified in 15 tumors, and two patients harbored more than one NOTCH1 mutation. Seventeen mutations in 14 patients occurred in the T-cell acute lymphoblastic leukemias hotspots, “suggesting that they are gain-of-function mutations,” Ferrarotto and colleagues wrote.
To determine whether NOTCH1 mutations were activating, the researchers assessed associations between the mutations and Notch intracellular domain (NICD) immunohistochemical staining from tumor tissues in 72 patients.
Researchers observed a significant association between NOTCH1 mutation and NICD positivity, and all 10 tumors with NOTCH1 mutations predicted to be activating were NICD positive.
NOTCH1 mutations defined a distinct aggressive disease subgroup with a significantly higher likelihood of solid subtype (P < .001), advanced-stage disease at diagnosis (P = .02), and higher rates of liver and bone metastases (P .02) compared with NOTCH1 wild-type tumors.
The overall population demonstrated a median RFS of 30 months and OS of 108 months.
Patients with NOTCH1–mutant disease showed shorter RFS (12.5 vs. 33.9 months; P = .01) and OS (29.6 vs. 121.9 months; P = .001) compared with patients with NOTCH1 wild-type disease.
The patient-derived xenograft model demonstrated significant tumor growth inhibition with brontictuzumab (OMP-52M51, OncoMed Pharmaceuticals) — a humanized immunoglobin G2 antibody that inhibits Notch1 signaling — in those with a NOTCH1 activating mutation.
In addition, an index patient with NOTCH1-mutant adenoid cystic carcinomas had a partial response to brontictuzumab.
The researchers noted a need for further investigation of the activity of Notch1 inhibitors in biomarker-selected patients with adenoid cystic carcinomas.
“Our analysis integrating genomic, pathologic and clinical outcomes data in adenoid cystic carcinomas demonstrates that NOTCH1 mutations are activating and defines a subgroup of patients with an aggressive disease phenotype and distinct pattern of metastatic spread,” Ferrarotto and colleagues wrote. “Notch1 inhibition with a specific antibody demonstrated antitumor activity in preclinical models and an encouraging response in a NOTCH1-mutant patient.” – by Kristie L. Kahl
Disclosure: Ferrarotto reports research funding from AstraZeneca, EMD Serono, G1 Therapeutics and OncoMed Pharmaceuticals. Please see the full study for a list of all other researchers’ relevant financial disclosures.