Clinical disease course and survival outcomes following disease recurrence in adenoid cystic carcinoma with and without NOTCH signaling pathway activation

Feeney, Laura; Hapuarachi, Brindley; Adderley, Helen; Rack, Samuel; Morgan, David; Walker, Russell G.; Rauch, Rami; Herz, Elad; Kaye, Joel; Harrington, Kevin; Metcalf, Robert

doi:10.1016/j.oraloncology.2022.106028

Cited by 16 publications

(11 citation statements)

References 17 publications

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“…This genetic diversity can affect clinical outcomes because some alterations are enriched in metastatic versus primary tumors and are associated with a worse prognosis 141 . The most common genetic alterations (apart from MYB/MYBL‐1) among recurrent and/or metastatic tumors are activating alterations in the NOTCH1 gene, which have been associated with a significantly worse prognosis 141,151–153 . Bulk RNA sequencing experiments have also demonstrated that tumors with MYC/NOTCH activation (ADCC‐I) have a worse prognosis than ADCC‐II tumors characterized by TP63 and receptor tyrosine kinases 154 .…”

Section: Immunotherapy For Salivary Gland Cancersmentioning

confidence: 99%

“…141 The most common genetic alterations (apart from MYB/MYBL-1) among recurrent and/or metastatic tumors are activating alterations in the NOTCH1 gene, which have been associated with a significantly worse prognosis. 141,[151][152][153] Bulk RNA sequencing experiments have also demonstrated that tumors with MYC/NOTCH activation (ADCC-I) have a worse prognosis than ADCC-II tumors characterized by TP63 and receptor tyrosine kinases. 154 This is one of a growing number of observations that gene expression signatures can effectively identify ADCC cohorts with a worse prognosis.…”

Section: Targeted Therapymentioning

confidence: 99%

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The evolving landscape of salivary gland tumors

Steuer

Hanna

Viswanathan

et al. 2023

CA A Cancer J Clinicians

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Salivary gland cancers are a rare, histologically diverse group of tumors. They range from indolent to aggressive and can cause significant morbidity and mortality. Surgical resection remains the mainstay of treatment, but radiation and systemic therapy are also critical parts of the care paradigm. Given the rarity and heterogeneity of these cancers, they are best managed in a multidisciplinary program. In this review, the authors highlight standards of care as well as exciting new research for salivary gland cancers that will strive for better patient outcomes.

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Section: Immunotherapy For Salivary Gland Cancersmentioning

confidence: 99%

Section: Targeted Therapymentioning

confidence: 99%

The evolving landscape of salivary gland tumors

Steuer

Hanna

Viswanathan

et al. 2023

CA A Cancer J Clinicians

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“…The NOTCH1 tumor suppressor gene encodes a conserved transmembrane protein that exerts pivotal regulatory roles during development and substantially contributes to tissue homeostasis [ 66 , 67 ]. Although activating mutations have been described for, e.g., NOTCH [ 62 , 68 ] and TP53 [ 38 , 55 ], it is a distinctive attribute of HNSCCs that the most commonly detected genetic events result in the inactivation of tumor suppressors or genes acting in associated pathways. This most likely reflects the fact that HNSCCs originate from basal keratinocytes of the mucosal epithelia which are capable to self-renew and to give rise to terminally differentiated epithelial cells [ 2 , 69 ].…”

Section: Genetics Of Hnsccmentioning

confidence: 99%

Circulating Tumor DNA in Head and Neck Squamous Cell Carcinoma

Brandt

Thiele

Daetwyler

et al. 2023

Cancers

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Tumors shed cell-free DNA (cfDNA) into the plasma. “Liquid biopsies” are a diagnostic test to analyze cfDNA in order to detect minimal residual cancer, profile the genomic tumor landscape, and monitor cancers non-invasively over time. This technique may be useful in patients with head and neck squamous cell carcinoma (HNSCC) due to genetic tumor heterogeneity and limitations in imaging sensitivity. However, there are technical challenges that need to be overcome for the widespread use of liquid biopsy in the clinical management of these patients. In this review, we discuss our current understanding of HNSCC genetics and the role of cfDNA genomic analyses as an emerging precision diagnostic tool.

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“…40 Approximately 18%-25% of R/M ACCs possess activating alterations in NOTCH1, which are associated with a significantly worse prognosis. 16,[40][41][42] Even in tumors without NOTCH gene alterations, NOTCH pathway activation has been observed in the luminal subcellular compartment of ACCs, 7 which may be activated by paracrine signals from the myoepithelial cell compartment in tumors that possess this biphasic cellular phenotype. 43 Preclinical experiments also suggest that high-grade, solid type ACCs, which are composed primarily of luminal cells and often possess NOTCH1 mutations, may be more resistant to MYB targeting alone.…”

Section: Gradementioning

confidence: 99%

A phase 2 study of MK‐2206 in patients with incurable adenoid cystic carcinoma (Alliance A091104)

Ho,

Foster,

Deraje Vasudeva

et al. 2023

Cancer

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BackgroundRecurrent/metastatic adenoid cystic carcinoma (ACC) is a rare, incurable disease. MYB is a putative oncogenic driver in ACC that is often overexpressed through an MYB‐NFIB rearrangement. The authors hypothesized that AKT inhibition with the allosteric inhibitor MK‐2206 could decrease MYB expression and induce tumor regression in patients with incurable ACC (ClinicalTrials.gov identifier NCT01604772).MethodsPatients with progressive, incurable ACC were enrolled and received MK‐2206 150 mg weekly; escalation to 200 mg was allowed. The primary end point was confirmed response. Secondary end points were progression‐free survival, overall survival, and safety. An exploratory analysis evaluating the effect of MK‐2206 on MYB expression was conducted in a subset of patients.ResultsSixteen patients were enrolled, and 14 were evaluable for efficacy. No confirmed responses were observed. Thirteen patients had stable disease, and one had disease progression as their best response. The median progression‐free survival was 9.7 months (95% CI, 3.8–11.8 months), and the median overall survival was 18.0 months (95% CI, 11.8–29.9 months). Nine of 16 patients (56%) had at least one grade 3 treatment‐related adverse event, and the most common were rash (38%), fatigue (19%), decreased lymphocyte count (13%), and hyperglycemia (13%). Twelve of 14 tumors (86%) had detectable MYB expression by immunohistochemistry, and seven of 14 tumors (50%) had an MYB‐NFIB gene rearrangement. Serial biopsies revealed decreased MYB levels with MK‐2206 in four of five patients.ConclusionsMK‐2206 failed to induce clinical responses in patients with incurable ACC. AKT inhibition may diminish MYB protein levels, although the effect was highly variable among patients. Novel approaches to target MYB in ACC are needed.

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Clinical disease course and survival outcomes following disease recurrence in adenoid cystic carcinoma with and without NOTCH signaling pathway activation

Cited by 16 publications

References 17 publications

The evolving landscape of salivary gland tumors

The evolving landscape of salivary gland tumors

Circulating Tumor DNA in Head and Neck Squamous Cell Carcinoma

A phase 2 study of MK‐2206 in patients with incurable adenoid cystic carcinoma (Alliance A091104)

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