Clinical Benefit in Response to Palbociclib Treatment in Refractory Uterine Leiomyosarcomas with a Common CDKN2A Alteration

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 mm 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

Overcoming CDK4/6 inhibitor resistance in ER-positive breast cancer

“…The loss of p16 INK4A is postulated to be a marker of sensitivity as this protein inhibits cyclin D1 ). This is supported by two reported cases with homozygous deletion of the p16 INK4A gene CDKN2A, a collecting duct carcinoma and a uterine leiomyosarcoma, where both were exceptional responders to palbociclib treatment (Elvin et al 2017, Pal et al 2017. This observation has not been borne out in other studies.…”

Comprehensive Genomic Profiling of Adult Renal Sarcomas Provides Insight into Disease Biology and Opportunities for Targeted Therapies

“…The CDKN2A/B genes are one of the crucial defenses against the development of a number of human cancers, and their loss has been reported in 5% of soft tissue sarcomas [28]. The cyclin-dependent kinase 4/6 (CDK 4/6) inhibitor palbociclib has antitumor activity against breast cancer and uterine leiomyosarcoma harboring CDKN2A loss, demonstrating the clinical relevance of this finding as well as its potential therapeutic implication for renal sarcomas [29,30].…”

CDKN2Chomozygous loss identifies a distinct subtype ofTP53/RB1-wildtype leiomyosarcoma with frequentCICgenomic alterations and 1p/19q-codeletion

“…Well-known CDK4/6 inhibitors have previously shown effectiveness in a single case of LMS with a CDKN2A alteration. 10 Nearly half of the CDKN2C-null LMS harbored loss of CDKN2A; CDK4/6 inhibitors may be effective in targeting both alterations for these cases. A subset of CDKN2C-null and/or 1p/19q codeleted LMS also harbored activating fusions in ALK, for which ALK inhibitors may be of utility.…”

“…7 LMS has demonstrated occasional potentially targetable genomic alterations (GAs), but novel targeted therapeutic agents have not been widely used. 8,9,10 Herein, we describe a novel recurrent genomic signature of CDKN2C homozygous loss in leiomyosarcoma primarily from the uterus, with significantly low frequency of TP53 and RB1 genomic alterations.…”