title: Genomic Evolution after Chemoradiotherapy in Anal Squamous Cell Carcinoma.
abstract: Purpose:Squamous cell carcinoma of the anal canal (ASCC) accounts for 2% to 4% of gastrointestinal malignancies in the United States and is increasing in incidence; however, genomic features of ASCC are incompletely characterized. Primary treatment of ASCC involves concurrent chemotherapy and radiation (CRT), but the mutational landscape of resistance to CRT is unknown. Here, we aim to compare mutational features of ASCC in the pre- and post-CRT setting.Experimental Design:We perform whole-exome sequencing of primary (n= 31) and recurrent (n= 30) ASCCs and correlate findings with clinical data. We compare genomic features of matched pre- and post-CRT tumors to identify genomic features of CRT response. Finally, we investigate the mutational underpinnings of an extraordinary ASCC response to immunotherapy.Results:We find that both primary and recurrent ASCC tumors harbor mutations in genes, such asPIK3CAandFBXW7, that are also mutated in other HPV-associated cancers. Overall mutational burden was not significantly different in pre- versus post-CRT tumors, and several examples of shared clonal driver mutations were identified. In two cases, clonally related pre- and post-CRT tumors harbored distinct oncogenic driver mutations in the same cancer gene (KRASorFBXW7). A patient with recurrent disease achieved an exceptional response to anti-programmed death (PD-1) therapy, and genomic dissection revealed high mutational burden and predicted neoantigen load.Conclusions:We perform comprehensive mutational analysis of ASCC and characterize mutational features associated with CRT. Although many primary and recurrent tumors share driver events, we identify several unique examples of clonal evolution in response to treatment.Clin Cancer Res; 23(12); 3214-22. ©2016 AACR.
authors.affiliation: Department of Radiation Oncology, Brigham and Women's Hospital, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Kent W
authors.initials: KW
authors.lastname: Mouw
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: James M
authors.initials: JM
authors.lastname: Cleary
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.|Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
authors.forename: Brendan
authors.initials: B
authors.lastname: Reardon
authors.affiliation: Department of Radiation Oncology, Brigham and Women's Hospital, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Pike
authors.affiliation: Department of Radiation Oncology, Brigham and Women's Hospital, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Lior Z
authors.initials: LZ
authors.lastname: Braunstein
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
authors.forename: Jaegil
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.|Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
authors.forename: Ali
authors.initials: A
authors.lastname: Amin-Mansour
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.|Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
authors.forename: Diana
authors.initials: D
authors.lastname: Miao
authors.affiliation: Department of Radiation Oncology, Brigham and Women's Hospital, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Alexis
authors.initials: A
authors.lastname: Damish
authors.affiliation: Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Joanna
authors.initials: J
authors.lastname: Chin
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Ott
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Charles S
authors.initials: CS
authors.lastname: Fuchs
authors.affiliation: Department of Radiation Oncology, Brigham and Women's Hospital, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Neil E
authors.initials: NE
authors.lastname: Martin
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
authors.forename: Gad
authors.initials: G
authors.lastname: Getz
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, Massachusetts.|Center for Cancer Precision Medicine, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Scott
authors.initials: S
authors.lastname: Carter
authors.affiliation: Department of Radiation Oncology, Brigham and Women's Hospital, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Harvey J
authors.initials: HJ
authors.lastname: Mamon
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Jason L
authors.initials: JL
authors.lastname: Hornick
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. alan_dandrea@dfci.harvard.edu eliezerm_vanallen@dfci.harvard.edu.|Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
authors.forename: Eliezer M
authors.initials: EM
authors.lastname: Van Allen
authors.affiliation: Department of Radiation Oncology, Brigham and Women's Hospital, Dana-Farber Cancer Institute, Boston, Massachusetts. alan_dandrea@dfci.harvard.edu eliezerm_vanallen@dfci.harvard.edu.|Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Boston, Massachusetts.|Ludwig Center at Harvard, Boston, Massachusetts.
authors.forename: Alan D
authors.initials: AD
authors.lastname: D'Andrea
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001005:Anus Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology / Q000532:radiotherapy; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology / Q000532:radiotherapy; D059248:Chemoradiotherapy / Q000009:adverse effects; D058534:Class I Phosphatidylinositol 3-Kinases / Q000235:genetics*; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D019143:Evolution, Molecular; D000073979:F-Box-WD Repeat-Containing Protein 7 / Q000235:genetics*; D005260:Female; D015894:Genome, Human / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000187:drug effects / Q000528:radiation effects; D009364:Neoplasm Recurrence, Local; D011836:Radiation Tolerance / Q000235:genetics
chemical_list: D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human