title: Clinical and genetic determinants of ovarian metastases from colorectal cancer.
abstract: Ovarian metastases from colorectal cancer (OM-CRC) often are unresponsive to chemotherapy and are associated with poor survival. To the authors' knowledge, the clinicopathologic and genomic predictors of OM-CRC are poorly characterized and optimal clinical management remains unclear.
  
  
  
  Women with a histopathological diagnosis of OM-CRC who were treated at Memorial Sloan Kettering Cancer Center from 1999 to 2015 were identified. Next-generation somatic mutation profiling (Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets [MSK-IMPACT]) was performed on 38 OM-CRC cases, including 21 matched tumor pairs/trios. Regression models were used to analyze variables associated with progression-free survival and overall survival (OS).
  
  
  
  Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS), SMAD family member 4 (SMAD4), and neurotrophic receptor tyrosine kinase 1 (NTRK1) mutations were more frequent in cases of OM-CRC than in instances of CRC occurring without OM. SMAD4 and lysine methyltransferase 2D (KMT2D) mutations were associated with reduced OS. Matched multisite tumor sequencing did not identify OM-specific genomic alterations. Of the 195 patients who underwent oophorectomy for OM-CRC (median age, 49 years with a progression-free survival of 9.4 months and an OS of 23 months from oophorectomy), 76% had extraovarian metastasis (EOM). In multivariable analysis, residual disease after surgery (R2 resection) was associated with worse survival. Patients with EOM were less likely to achieve R0/R1 surgical resection status (complete macroscopic resection without clinical/radiological evidence of disease) (48% vs 94%). However, if R0/R1 resection status was achieved, both patients with (35.9 months vs 12 months) and without (43.2 months vs 14.5 months) EOM were found to have better OS. Among 114 patients with R0/R1 resection status, 23 (20%) had no disease recurrence, including 10 patients (9%) with > 3 years of follow-up.
  
  
  
  Loss-of-function alterations in SMAD4 are frequent and predictive of worse survival in patients with OM-CRC. Similar to oligometastatic CRC to the lung or liver, surgical resection of OM-CRC is associated with a better outcome only if all macroscopic metastatic disease is resected. Cancer 2017;123:1134-1143. © 2016 American Cancer Society.
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Karuna
authors.initials: K
authors.lastname: Ganesh
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Ronak H
authors.identifier: 0000-0001-9042-6213
authors.initials: RH
authors.lastname: Shah
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Efsevia
authors.initials: E
authors.lastname: Vakiani
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Garrett M
authors.initials: GM
authors.lastname: Nash
authors.forename: Hugh P
authors.initials: HP
authors.lastname: Skottowe
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Rona
authors.initials: R
authors.lastname: Yaeger
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Andrea
authors.initials: A
authors.lastname: Cercek
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Anne
authors.initials: A
authors.lastname: Lincoln
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Christina
authors.initials: C
authors.lastname: Tran
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Neil H
authors.initials: NH
authors.lastname: Segal
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Diane L
authors.initials: DL
authors.lastname: Reidy
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Anna
authors.initials: A
authors.lastname: Varghese
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Epstein
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Sonoda
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Dennis
authors.initials: D
authors.lastname: Chi
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Jose
authors.initials: J
authors.lastname: Guillem
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Larissa
authors.initials: L
authors.lastname: Temple
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Philip
authors.initials: P
authors.lastname: Paty
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Jaclyn
authors.initials: J
authors.lastname: Hechtman
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Jinru
authors.initials: J
authors.lastname: Shia
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Martin
authors.initials: M
authors.lastname: Weiser
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Julio Garcia
authors.initials: JG
authors.lastname: Aguilar
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Nancy
authors.initials: N
authors.lastname: Kemeny
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Berger
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Leonard
authors.initials: L
authors.lastname: Saltz
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Zsofia K
authors.initials: ZK
authors.lastname: Stadler
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology* / Q000628:therapy; D003131:Combined Modality Therapy / Q000379:methods; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000175:diagnosis / Q000209:etiology* / Q000401:mortality / Q000628:therapy; D011379:Prognosis; D016016:Proportional Hazards Models; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D051901:Smad4 Protein / Q000235:genetics; D016896:Treatment Outcome; D047368:Tumor Burden; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D051901:Smad4 Protein; D016283:Proto-Oncogene Proteins p21(ras)
keywords: Krukenberg tumor; clinical prognosis; colorectal neoplasms; decision making; high-throughput nucleotide sequencing; metastasis