Integrative Clinical Sequencing in the Management of Refractory or Relapsed Cancer in Youth.
OBJECTIVE
Cancer is caused by a diverse array of somatic and germline genomic aberrations. Advances in genomic sequencing technologies have improved the ability to detect these molecular aberrations with greater sensitivity. However, integrating them into clinical management in an individualized manner has proven challenging.


OBJECTIVE
To evaluate the use of integrative clinical sequencing and genetic counseling in the assessment and treatment of children and young adults with cancer.


METHODS
Single-site, observational, consecutive case series (May 2012-October 2014) involving 102 children and young adults (mean age, 10.6 years; median age, 11.5 years, range, 0-22 years) with relapsed, refractory, or rare cancer.


METHODS
Participants underwent integrative clinical exome (tumor and germline DNA) and transcriptome (tumor RNA) sequencing and genetic counseling. Results were discussed by a precision medicine tumor board, which made recommendations to families and their physicians.


METHODS
Proportion of patients with potentially actionable findings, results of clinical actions based on integrative clinical sequencing, and estimated proportion of patients or their families at risk of future cancer.


RESULTS
Of the 104 screened patients, 102 enrolled with 91 (89%) having adequate tumor tissue to complete sequencing. Only the 91 patients were included in all calculations, including 28 (31%) with hematological malignancies and 63 (69%) with solid tumors. Forty-two patients (46%) had actionable findings that changed their cancer management: 15 of 28 (54%) with hematological malignancies and 27 of 63 (43%) with solid tumors. Individualized actions were taken in 23 of the 91 (25%) based on actionable integrative clinical sequencing findings, including change in treatment for 14 patients (15%) and genetic counseling for future risk for 9 patients (10%). Nine of 91 (10%) of the personalized clinical interventions resulted in ongoing partial clinical remission of 8 to 16 months or helped sustain complete clinical remission of 6 to 21 months. All 9 patients and families with actionable incidental genetic findings agreed to genetic counseling and screening.


CONCLUSIONS
In this single-center case series involving young patients with relapsed or refractory cancer, incorporation of integrative clinical sequencing data into clinical management was feasible, revealed potentially actionable findings in 46% of patients, and was associated with change in treatment and family genetic counseling for a small proportion of patients. The lack of a control group limited assessing whether better clinical outcomes resulted from this approach than outcomes that would have occurred with standard care.
Department of Pediatrics, University of Michigan, Ann Arbor2Michigan Center for Translational Pathology, University of Michigan, Ann Arbor3Comprehensive Cancer Center, University of Michigan, Ann Arbor.
Rajen J
RJ
Mody
Michigan Center for Translational Pathology, University of Michigan, Ann Arbor4Department of Pathology, University of Michigan, Ann Arbor.
Yi-Mi
YM
Wu
Michigan Center for Translational Pathology, University of Michigan, Ann Arbor3Comprehensive Cancer Center, University of Michigan, Ann Arbor.
Robert J
RJ
Lonigro
Michigan Center for Translational Pathology, University of Michigan, Ann Arbor4Department of Pathology, University of Michigan, Ann Arbor5Howard Hughes Medical Institute, University of Michigan, Ann Arbor.
Xuhong
X
Cao
Department of Internal Medicine, Ohio State University, Columbus.
Sameek
S
Roychowdhury
Michigan Center for Translational Pathology, University of Michigan, Ann Arbor.
Pankaj
P
Vats
Department of Pediatrics, University of Michigan, Ann Arbor.
Kevin M
KM
Frank
Michigan Center for Translational Pathology, University of Michigan, Ann Arbor7Department of Pediatrics, Boston Children's Hospital, Boston, Massachusetts.
John R
JR
Prensner
Michigan Center for Translational Pathology, University of Michigan, Ann Arbor4Department of Pathology, University of Michigan, Ann Arbor.
Irfan
I
Asangani
Michigan Center for Translational Pathology, University of Michigan, Ann Arbor.
Nallasivam
N
Palanisamy
Department of Radiology, University of Michigan, Ann Arbor.
Jonathan R
JR
Dillman
Department of Pathology, University of Michigan, Ann Arbor.
Raja M
RM
Rabah
Department of Pathology, University of Michigan, Ann Arbor.
Laxmi Priya
LP
Kunju
Department of Internal Medicine, University of Michigan, Ann Arbor.
Jessica
J
Everett
Department of Internal Medicine, University of Michigan, Ann Arbor.
Victoria M
VM
Raymond
Michigan Center for Translational Pathology, University of Michigan, Ann Arbor.
Yu
Y
Ning
Michigan Center for Translational Pathology, University of Michigan, Ann Arbor.
Fengyun
F
Su
Michigan Center for Translational Pathology, University of Michigan, Ann Arbor.
Rui
R
Wang
Department of Internal Medicine, University of Michigan, Ann Arbor.
Elena M
EM
Stoffel
Department of Pediatrics, University of Michigan, Ann Arbor.
Jeffrey W
JW
Innis
Department of Health Behavior and Health Education, University of Michigan, Ann Arbor.
J Scott
JS
Roberts
Department of Pediatrics, University of Michigan, Ann Arbor3Comprehensive Cancer Center, University of Michigan, Ann Arbor.
Patricia L
PL
Robertson
Department of Pediatrics, University of Michigan, Ann Arbor3Comprehensive Cancer Center, University of Michigan, Ann Arbor.
Gregory
G
Yanik
Department of Pediatrics, Michigan State University, East Lansing.
Aghiad
A
Chamdin
Department of Pediatrics, University of Michigan, Ann Arbor3Comprehensive Cancer Center, University of Michigan, Ann Arbor.
James A
JA
Connelly
Department of Pediatrics, University of Michigan, Ann Arbor3Comprehensive Cancer Center, University of Michigan, Ann Arbor.
Sung
S
Choi
Department of Pediatrics, University of Michigan, Ann Arbor3Comprehensive Cancer Center, University of Michigan, Ann Arbor.
Andrew C
AC
Harris
Comprehensive Cancer Center, University of Michigan, Ann Arbor.
Carrie
C
Kitko
Department of Pediatrics, University of Michigan, Ann Arbor3Comprehensive Cancer Center, University of Michigan, Ann Arbor.
Rama Jasty
RJ
Rao
Department of Pediatrics, University of Michigan, Ann Arbor3Comprehensive Cancer Center, University of Michigan, Ann Arbor.
John E
JE
Levine
Department of Pediatrics, University of Michigan, Ann Arbor3Comprehensive Cancer Center, University of Michigan, Ann Arbor.
Valerie P
VP
Castle
Department of Pediatrics, University of Michigan, Ann Arbor3Comprehensive Cancer Center, University of Michigan, Ann Arbor.
Raymond J
RJ
Hutchinson
Comprehensive Cancer Center, University of Michigan, Ann Arbor6Department of Internal Medicine, Ohio State University, Columbus.
Moshe
M
Talpaz
Michigan Center for Translational Pathology, University of Michigan, Ann Arbor4Department of Pathology, University of Michigan, Ann Arbor.
Dan R
DR
Robinson
Michigan Center for Translational Pathology, University of Michigan, Ann Arbor3Comprehensive Cancer Center, University of Michigan, Ann Arbor4Department of Pathology, University of Michigan, Ann Arbor5Howard Hughes Medical Institute, University of Michiga.
Arul M
AM
Chinnaiyan
D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D002869:Chromosome Aberrations; D005190:Family; D005240:Feasibility Studies; D050939:Gene Fusion; D005817:Genetic Counseling; D019337:Hematologic Neoplasms / Q000235:genetics; D006801:Humans; D033162:Incidental Findings; D007223:Infant; D007231:Infant, Newborn; D058990:Molecular Targeted Therapy / Q000379:methods; D009364:Neoplasm Recurrence, Local / Q000235:genetics; D009369:Neoplasms / Q000235:genetics* / Q000628:therapy; D017063:Outcome Assessment, Health Care; D012074:Remission Induction; D017422:Sequence Analysis, DNA / Q000379:methods*; D055815:Young Adult