ELSEVIER
Surgery
SURGERY
MOWEMBER 2018
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Response to Letter to the editor: “Identifying genomic signatures of recurrence in adrenocortical carcinoma after RO resection”
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The authors of this letter suggest valuable insights regarding the utility of targeted therapies in the setting of adrenocortical carci- noma (ACC) and the applicability of The Cancer Genome Atlas (TCGA) to diverse populations that reflect all the patients we treat. To address the question of statistical correction, we first performed x2 analyses to identify unadjusted P values of statistical signifi- cance. These values were .004 for WNT, .043 for Cell Cycle, and .009 for PI3K. To obtain adjusted P values, multivariable logistic re- gressions were performed for each pathway. For an outcome of recurrence in the setting of an R0 resection, each pathway was assessed while controlling for venous invasion, adjuvant radiation, and capsular invasion. Given these pathways’ (WNT, P = . 038; Cell Cycle, P =. 016; and PI3K, P =. 023) statistical significance when con- trolling for several clinically significant variables in the context of their known oncologic roles, we believe that there is significant clinical plausibility for our findings. While we did not initially pre- pare corrected P values, we would like to offer the following up- dates. Given the limited number of comparisons, a Bonferroni- Hochberg test was performed, which did not maintain statistical significance in retrospect (Cell Cycle = . 064, PI3K = . 092, WNT = . 152). This was somewhat expected given the conservative nature of this test in the setting of a small sample size. Further, the absence of this correction test permits more inclusive results as intended to produce new avenues for research. Although Bonferroni-Hochberg did not permit retaining statistical signifi- cance, the well-studied role of these canonical pathways as onco- logic drivers suggests that higher powered cohorts may be able to validate these findings. This is supported by the fact that WNT did not achieve statistical significance with correction despite being the only pathway previously implicated with driver mutations in ACC in current literature. Thus, although WNT mutations driving recurrence is a novel finding in the R0 setting, aberrancies in WNT are well described in ACC, despite not achieving significance with correction applied here. Consequently, although we may only be observing less rigorous associations, it is likely that these 3 pathways represent the most likely candidates requiring validation.
The authors of this letter also note that the feasibility of leveraging these pathways for targeted therapy should be explored. In this article, we detail the role of cyclin-dependent kinase and Ataxia telangiectasia-mutated kinase inhibitors (acting on the Cell Cycle pathway) and alpelisib (acting on the PI3K pathway). Simi- larly, although not yet standard of care, we described the possibility of CTNNB1 (a WNT pathway mutation) mutated tumors responding well to threonine tyrosine kinase inhibitors. Despite existing litera- ture describing their role collectively in other malignancies, such as breast cancer, we believe that these findings point to an exciting potential avenue for ACC treatment. However, as this letter indi- cated, this will require prospective clinical trials.
Ultimately, as with all retrospective database studies, these data are hypothesis generating, and we hope to see that future, prospec- tive works validate the prognostic value of these genetic signatures. Further, we must validate the efficacy of these targeted therapies to reduce the grave rate of recurrence we have observed despite R0 resection.
CRediT authorship contribution statement
Benjamin C. Greenspun: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Writing - original draft, Writing - review & editing. Brendan M. Finnerty: Conceptu- alization, Data curation, Formal analysis, Investigation, Methodol- ogy, Project administration, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing.
Benjamin C. Greenspun, MD*, Brendan M. Finnerty, MD, FACS Department of Surgery Weill Cornell Medicine New York, NY
* Corresponding author.
E-mail address: bcg9006@med.cornell.edu (B.C. Greenspun).
Accepted 24 November 2024