Value of Molecular Classification for Prognostic Assessment of Adrenocortical Carcinoma

Abstract

The risk stratification of adrenocortical carcinoma (ACC) based on tumor proliferation index and stage is limited. Adjuvant therapy after surgery is recommended for most patients. Pan-genomic studies have identified distinct molecular groups closely associated with outcome. OBJECTIVE To compare the molecular classification for prognostic assessment of ACC with other known prognostic factors. DESIGN, SETTING, AND PARTICIPANTS In this retrospective biomarker analysis, ACC tumor samples from 368 patients who had undergone surgical tumor removal were collected from March 1, 2005, to September 30, 2015 (144 in the training cohort and 224 in the validation cohort) at 21 referral centers with a median follow-up of 35 months (interquartile range, 18-74 months). Data were analyzed from March 2016 to March 2018. EXPOSURES Meta-analysis of pan-genomic studies (transcriptome, methylome, chromosome alteration, and mutational profiles) was performed on the training cohort. Targeted biomarker analysis, including targeted gene expression (BUB1B and PINK1), targeted methylation (PAX5, GSTP1, PYCARD, and PAX6), and targeted next-generation sequencing, was performed on the training and validation cohorts. MAIN OUTCOMES AND MEASURES Disease-free survival. Cox proportional hazards regression and C indexes were used to assess the prognostic value of each model. RESULTS Of the 368 patients (mean [SD] age, 49 [16] years), 144 were in the training cohort (100 [69.4%] female) and 224 were in the validation cohort (142 [63.4%] female). In the training cohort, pan-genomic measures classified ACC into 3 molecular groups (A1, A2, and A3-B), with 5-year survival of 9% for group A1, 45% for group A2, and 82% for group A3-B (log-rank P < .001). Molecular class was an independent prognostic factor of recurrence in stage I to III ACC after complete surgery (hazard ratio, 55.91; 95% CI, 8.55-365.40; P < .001). The combination of European Network for the Study of Adrenal Tumors (ENSAT) stage, tumor proliferation index, and molecular class provided the most discriminant prognostic model (C index, 0.88). In the validation cohort, the molecular classification, determined by targeted biomarker measures, was confirmed as an independent prognostic factor of recurrence (hazard ratio, 5.96 [95% CI, 1.81-19.58], P = .003 for the targeted classifier combining expression, methylation, and chromosome alterations; and 2.61 [95% CI, 1.31-5.19], P = .006 for the targeted classifier combining methylation, chromosome alterations, and mutational profile). The prognostic value of the molecular markers was limited for patients with stage IV ACC. CONCLUSIONS AND RELEVANCE The findings suggest that in localized ACC, targeted classifiers may be used as independent markers of recurrence. The determination of molecular class may improve individual prognostic assessment and thus may spare unnecessary adjuvant treatment.

Adjuvant Therapy in Adrenocortical Carcinoma: Reflections and Future Directions

“…Most recently, a multicenter retrospective biomarker analysis included 368 patients who had undergone resection of localized ACC. For patients with stage I-III disease, molecular classification was an independent prognostic factor for disease-free survival and the combination of tumor stage, tumor grade, and molecular classification offered the best predictive model for disease-free survival [44]. Another approach recently divided prognostic factors into three groups: clinical factors (age, stage, and hormonal symptoms), pathological factors (Weiss Score, mitotic count, SF-1, Ki-67, AVA2, P53, beta-catenin, resection margin status), and molecular factors (methylation profile, chromosomal aberrations, and miRNA expression, gene mutations) [45].…”

Metastatic and recurrent adrenocortical cancer is not defined by its genomic landscape

“…1 b). Twenty-nine genes with non-silent alterations (missense, nonsense, insertions and deletions [indels] and splice variants within 3 bp of exon) present in > 9% of our cohort ( 4/43) were each validated by manual inspection in the Integrated Genome Viewer [ 14 , 15 ] and by PCR and Sanger sequencing. Figure 2 shows these mutations, with the upper set identified in at least 9% of patients in whom we had germline DNA, and the lower set the mutations identified in at least 9% of the whole population.…”

“…Importantly all survival curves have late plateaus that demonstrate “prolonged survival in occasional patients” with metastatic disease, although the biology for this phenomenon is not understood. The best prediction models integrate multiple of the above noted features [ 15 ].…”

Intratumor heterogeneity of prognostic DNA-based molecular markers in adrenocortical carcinoma

“…1, see section on supplementary materials given at the end of this article), including primary tumor (P), local recurrence (R) or distant metastasis (M). Tumor specimens were collected between 2001 and 2015 and were either frozen in the Cochin cohort or formalin-fixed paraffin-embedded (FFPE) samples in the Wuerzburg cohort, as previously described ( 9 , 11 ). The diagnosis of ACC was confirmed by an expert endocrine pathologist, according to Weiss criteria ( 18 ).…”

“…This subgroup is associated with a better outcome. Hence, targeted molecular markers have been proposed to complete the prognostic assessment of ACC ( 9 , 10 , 11 ). These markers are either measured at the tumor DNA level, including somatic mutations, chromosome alteration and DNA methylation profile, or at the RNA level, including transcriptome and targeted gene expression profiles.…”