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Molecular Profiling and the Impact of Treatment on Outcomes in Adenoid Cystic Carcinoma Type I and II
Glenn J Hanna1, Punita Grover2, Andrew Elliott3
1Dana-Farber Cancer Institute, Boston, Massachusetts.
Purpose:
Adenoid cystic carcinoma (ACC) is an uncommon salivary gland cancer with no approved therapies available to treat advanced, incurable disease. Recent molecular profiling efforts have identified two important subtypes: the more aggressive ACC-I is characterized by Notch pathway alterations and MYC amplification whereas ACC-II demonstrates a more indolent phenotype and TP63 overexpression.
Experimental Design:
This retrospective observational cohort study involved de-identified samples from 438 patients with ACC with tumor samples sent for commercially-available molecular profiling (Caris Life Sciences). Next-generation whole-exome and whole-transcriptomic sequencing was performed on primary and metastatic samples. Immunostaining for PD-L1 and RNA deconvolution (quanTIseq) was used to explore the tumor immune microenvironment (TME). Real-world clinical and survival outcome metrics were extracted from insurance claims data.
Results:
MYC expression was 1.61-fold higher (39.8 vs. 24.7; P < 0.0001) among NOTCH1-mutant ACC-I tumors, whereas MYB/L1 fusion rates were similar among ACC-I/II. The median B-cell fraction in the TME was higher among ACC-II (7.1% vs. 5.8%; P < 0.01), although infiltrating T cells subsets were low among either ACC subgroup (both <1%). When pooling systemic treatment categories, ACC-I patients had worse outcomes with available therapies (HR, 3.06; 95% confidence interval, 1.65-5.68; P < 0.01), with no significant difference in overall survival between ACC-I/II based on chemotherapy or VEGFR tyrosine kinase inhibitor exposure in smaller subsets.
Conclusions:
We confirmed the previously reported associations with MYC and TP63 in the prognostically relevant subgroups of ACC-I and -II, respectively, and report immunologic differences among these subtypes. Survival outcomes are comparatively worse in ACC-I regardless of treatment type.
Insights
Adenoid cystic carcinoma (ACC) subtypes differ in molecular profiles and immune microenvironments. The aggressive ACC-I subtype shows worse survival outcomes compared to ACC-II, irrespective of treatment.
Area of Science:
- Oncology
- Molecular Pathology
- Cancer Immunology
Background:
- Adenoid cystic carcinoma (ACC) is a rare salivary gland cancer lacking approved treatments for advanced stages.
- Molecular profiling reveals two subtypes: ACC-I (aggressive, Notch pathway alterations, MYC amplification) and ACC-II (indolent, TP63 overexpression).
Purpose of the Study:
- To investigate molecular and immunological differences between ACC subtypes.
- To correlate these differences with clinical outcomes in a real-world setting.
Main Methods:
- Retrospective analysis of 438 ACC patient samples using next-generation sequencing.
- Immunohistochemistry for PD-L1 and RNA deconvolution (quanTIseq) to assess the tumor immune microenvironment (TME).
- Extraction of real-world clinical and survival data from insurance claims.
Main Results:
- MYC expression was significantly higher in NOTCH1-mutant ACC-I tumors.
- ACC-II tumors exhibited a higher median B-cell fraction in the TME.
- ACC-I patients experienced significantly worse survival outcomes compared to ACC-II, regardless of treatment received.
Conclusions:
- Confirmed associations of MYC with ACC-I and TP63 with ACC-II.
- Identified distinct immunologic profiles between ACC subtypes.
- Demonstrated poorer survival for ACC-I patients, highlighting the need for targeted therapies.
