title: Clinical Benefit in Response to Palbociclib Treatment in Refractory Uterine Leiomyosarcomas with a CommonCDKN2AAlteration.
abstract: 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.
  
  
  
  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.
  
  
  
  CGP shows that 97.1% of uLMS harbor at least one alteration, and approximately 57% harbor alterations in one or more therapeutically targetable pathways.CDKN2Amutations 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 aCDKN2Amutation, resulting in disease stabilization and significant symptom reduction.
  
  
  
  A patient with uLMS harboring aCDKN2Amutation 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.The Oncologist2017;22:416-421Implications for Practice:Comprehensive genomic profiling (CGP) of individuals with uterine leiomyosarcoma (uLMS) indicates that nearly 20% of patients may harbor a mutation affecting the cyclin-dependent kinase (CDK) pathway. The case presented demonstrates that a CDK inhibitory drug may provide clinical benefit to such individuals. Given the lack of curative therapies for uLMS, CGP could be performed on all cases of advanced uLMS and a CDK inhibitor could be recommended (preferably as part of a clinical trial) for individuals harboring a mutation in the CDK pathway.
authors.affiliation: Pathology Department, Foundation Medicine Inc., Cambridge, Massachusetts, USA.
authors.forename: Julia A
authors.initials: JA
authors.lastname: Elvin
authors.affiliation: Pathology Department, Foundation Medicine Inc., Cambridge, Massachusetts, USA.
authors.forename: Laurie M
authors.initials: LM
authors.lastname: Gay
authors.affiliation: Hematology and Oncology, Norwalk Hospital, Western Connecticut Health Network, Norwalk, Connecticut, USA.
authors.forename: Rita
authors.initials: R
authors.lastname: Ort
authors.affiliation: Hematology and Oncology, Norwalk Hospital, Western Connecticut Health Network, Norwalk, Connecticut, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Shuluk
authors.affiliation: Hematology and Oncology, Norwalk Hospital, Western Connecticut Health Network, Norwalk, Connecticut, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Long
authors.affiliation: Hematology and Oncology, Norwalk Hospital, Western Connecticut Health Network, Norwalk, Connecticut, USA.
authors.forename: Lauren
authors.initials: L
authors.lastname: Shelley
authors.affiliation: Radiology, Norwalk Hospital, Western Connecticut Health Network, Norwalk, Connecticut, USA.
authors.forename: Ronald
authors.initials: R
authors.lastname: Lee
authors.affiliation: Clinical Genomics, Foundation Medicine, Inc., Cambridge, Massachusetts, USA.
authors.forename: Zachary R
authors.initials: ZR
authors.lastname: Chalmers
authors.affiliation: Clinical Genomics, Foundation Medicine, Inc., Cambridge, Massachusetts, USA.
authors.forename: Garrett M
authors.initials: GM
authors.lastname: Frampton
authors.affiliation: Clinical Development, Foundation Medicine, Inc., Cambridge, Massachusetts, USA.
authors.forename: Siraj M
authors.initials: SM
authors.lastname: Ali
authors.affiliation: Clinical Development, Foundation Medicine, Inc., Cambridge, Massachusetts, USA.
authors.forename: Alexa B
authors.initials: AB
authors.lastname: Schrock
authors.affiliation: Clinical Development, Foundation Medicine, Inc., Cambridge, Massachusetts, USA.
authors.forename: Vincent A
authors.initials: VA
authors.lastname: Miller
authors.affiliation: Clinical Genomics, Foundation Medicine, Inc., Cambridge, Massachusetts, USA.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Stephens
authors.affiliation: Pathology Department, Foundation Medicine Inc., Cambridge, Massachusetts, USA.|Department of Pathology and Laboratory Medicine, Albany Medical Center, Albany.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Ross
authors.affiliation: Hematology and Oncology, Norwalk Hospital, Western Connecticut Health Network, Norwalk, Connecticut, USA Richard.Frank@wchn.org.
authors.forename: Richard
authors.initials: R
authors.lastname: Frank
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050763:Cyclin-Dependent Kinase Inhibitor p18 / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D023281:Genomics; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D007890:Leiomyosarcoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D010879:Piperazines / Q000008:administration & dosage*; D011725:Pyridines / Q000008:administration & dosage*; D014594:Uterine Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology
chemical_list: C000614131:CDKN2A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050763:Cyclin-Dependent Kinase Inhibitor p18; D010879:Piperazines; D011725:Pyridines; C500026:palbociclib
keywords: CDKN2A; Comprehensive genomic profiling; Palbociclib; Precision medicine; Targeted therapy; Uterine leiomyosarcoma