Clinical Benefit in Response to Palbociclib Treatment in Refractory Uterine Leiomyosarcomas with a Common CDKN2A Alteration. (10th March 2017)

• Record Type: Journal Article
• Authors: Elvin, Julia A.; Gay, Laurie M.; Ort, Rita; Shuluk, Joseph; Long, Jennifer; Shelley, Lauren; Lee, Ronald; Chalmers, Zachary R.; Frampton, Garrett M.; Ali, Siraj M.; Schrock, Alexa B.; Miller, Vincent A.; Stephens, Philip J.; Ross, Jeffrey S.; Frank, Richard
• Is Part Of: Oncologist. Volume 22:Number 4(2017)
• Page Start: 416
• Page End: 421
• Publication Date: 2017-03-10
• Subjects: Palbociclib -- Uterine leiomyosarcoma -- CDKN2A -- Comprehensive genomic profiling -- Targeted therapy -- Precision medicine; Oncology -- Periodicals; Tumors -- Periodicals; Cancérologie -- Périodiques; Tumeurs -- Périodiques; Oncology; Tumors; Neoplasms; Electronic journals; Periodicals; Periodicals; 616.994
• DOI: 10.1634/theoncologist.2016-0310
• Languages: English
• ISSNs: 1083-7159

Abstract

Abstract : Background: Uterine leiomyosarcoma (uLMS) responds poorly to conventional chemotherapeutic agents, and personalized therapies have yet to be systematically explored. Comprehensive genomic profiling (CGP) can identify therapeutic targets and provide insight into the biology of this highly aggressive tumor. We report a case of uLMS treated with the CGP‐matched therapy palbociclib, a CDK4/6 inhibitor, with sustained clinical benefit in this rare and deadly malignancy. Materials and Methods: This study analyzed 279 clinically advanced/recurrent uLMS samples. Median patient age was 54 years (range, 23–83 years). DNA was extracted from 40 µm of formalin‐fixed, paraffin‐embedded sections, and CGP was performed on hybridization‐captured, adaptor ligation‐based libraries for up to 405 cancer‐related genes plus introns from up to 31 genes frequently rearranged in cancer. Sequencing data were analyzed for base pair substitutions, insertions/deletions, copy number alterations, and rearrangements. Results: CGP shows that 97.1% of uLMS harbor at least one alteration, and approximately 57% harbor alterations in one or more therapeutically targetable pathways. CDKN2A mutations that inactivate p16INK4a were identified in 11% of uLMS. We report the first demonstration of clinical benefit in response to palbociclib treatment for a uLMS patient with a CDKN2A mutation, resulting in disease stabilization and significant symptom reduction. Conclusion: A patient with uLMS harboring a CDKN2A mutation experienced clinical benefit from treatment with palbociclib, and genomic analysis of 279 uLMS samples revealed that 19% of patients had mutations affecting the cyclin‐dependent kinase (CDK) pathway. These observations provide a rationale for a clinical trial investigating treatment with CDK pathway inhibitors for uLMS harboring relevant genomic alterations. Abstract : A patient with uLMS harboring a CDKN2A mutation experienced clinical benefit from treatment with palbociclib, and genomic analysis of 279 uterine leiomyosarcoma (uLMS) samples revealed that 19% of patients had mutations affecting the cyclin‐dependent kinase (CDK) pathway. These observations provide a rationale for a clinical trial investigating treatment with CDK pathway inhibitors for uLMS harboring relevant genomic alterations.