Thymic gland carcinomas include a variety of histologic subtypes with variable clinical aggressiveness and response to local and systemic therapies. We queried whether CGP could refine tumor subtypes and uncover new targeted and immunotherapy options for patients with relapsed and metastatic disease (mTC).
FFPE sections of 174 consecutive cases of mTC was sequenced using hybridization-captured, adaptor ligation-based libraries to a mean coverage depth of > 500X for up to 315 cancer-related genes plus 37 introns from 28 genes frequently rearranged in cancer. Total mutational burden (TMB) was determined on 1.1 Mb. Clinically relevant genomic alterations (CRGA) were defined as GA linked to drugs on the market or under evaluation in mechanism driven clinical trials.
All mTC were clinically advanced and included 4% adenocarcinomas (TAC), 3% basaloid (TBC), 3% lymphoepitheliomatous (TLEC), 17% neuroendocrine (TNEC), 31% non-NE undifferentiated (TNOS), 40% squamous and 2% sarcomatoid (TSRC) carcinomas (Table). mTC were twice as common in men than women, had a peak incidence in late middle age, and featured an average of 4 GA/case and 0.9 CRGA/case. The most common molecular targets were KIT and PIK3CA. Other targets were PDGFRA, FGFR3, PTCH1, FBXW7, BRCA2, IDH1, ERBB2 and ERBB3. The more frequent subtypes (TNEC, TSCC and TNOS) tended to have more GA, with KIT targets in ∼ 10% of cases. Low TMB in mTC was common; only 6% of cases had >10 mut/Mb and 3% had >20 mut/Mb. Examples of mTC with responses to targeted therapies will be presented.Table:
|Median Age (y)||48||58||50||48||57||57||61|
|Gender||43% F||60% F||20% F||37% F||24% F||34% F||50%F|
|Significant GA||PDGFRA FGFR3 KIT MET PTCH1||CDKN2A FBXW7||CDKN2A MEN1||KIT BRCA2 IDH1 ERBB2 ERBB3||KIT PTEN PIK3CA||KIT FGFR3 PIK3CA||ERBB2 IDH1 KIT|
|TMB >10 mut/Mb||14%||0%||0%||3%||5%||9%||0%|
|TMB >20 mut/Mb||0%||0%||0%||3%||5%||9%||0%|
mTC histologic subtypes have varying GA and TMB status. The more common TSCC, TNEC and TNOS feature more GA, and when combined with TAC have more CRGA including KIT mutations and higher TMB. CGP shows promise to guide both targeted and immunotherapy selection for patients with this rare malignancy.
Clinical trial identification
Legal entity responsible for the study
Jeffrey S Ross
J.S. Ross, V.A. Miller, P.J. Stephens: Employee, leader and owns stock in Foundation Medicine. P. Vanden Borre, N. Almog, A.B. Schrock, J. Chung, J-A. Vergilio, J. Suh, S. Ramkissoon, E. Severson, S. Daniel, S.M. Ali, J.A. Elvin, L.M. Gay: Employee and owns stock in Foundation Medicine.