Chromosomal copy number alterations for associations of ductal carcinoma in situ with invasive breast cancer.
BACKGROUND
Screening mammography has contributed to a significant increase in the diagnosis of ductal carcinoma in situ (DCIS), raising concerns about overdiagnosis and overtreatment. Building on prior observations from lineage evolution analysis, we examined whether measuring genomic features of DCIS would predict association with invasive breast carcinoma (IBC). The long-term goal is to enhance standard clinicopathologic measures of low- versus high-risk DCIS and to enable risk-appropriate treatment.


METHODS
We studied three common chromosomal copy number alterations (CNA) in IBC and designed fluorescence in situ hybridization-based assay to measure copy number at these loci in DCIS samples. Clinicopathologic data were extracted from the electronic medical records of Stanford Cancer Institute and linked to demographic data from the population-based California Cancer Registry; results were integrated with data from tissue microarrays of specimens containing DCIS that did not develop IBC versus DCIS with concurrent IBC. Multivariable logistic regression analysis was performed to describe associations of CNAs with these two groups of DCIS.


RESULTS
We examined 271 patients with DCIS (120 that did not develop IBC and 151 with concurrent IBC) for the presence of 1q, 8q24 and 11q13 copy number gains. Compared to DCIS-only patients, patients with concurrent IBC had higher frequencies of CNAs in their DCIS samples. On multivariable analysis with conventional clinicopathologic features, the copy number gains were significantly associated with concurrent IBC. The state of two of the three copy number gains in DCIS was associated with a risk of IBC that was 9.07 times that of no copy number gains, and the presence of gains at all three genomic loci in DCIS was associated with a more than 17-fold risk (P = 0.0013).


CONCLUSIONS
CNAs have the potential to improve the identification of high-risk DCIS, defined by presence of concurrent IBC. Expanding and validating this approach in both additional cross-sectional and longitudinal cohorts may enable improved risk stratification and risk-appropriate treatment in DCIS.
Department of Medicine, Stanford University School of Medicine, 291 Campus Drive, Stanford, CA, 94305, USA. anosheh@stanford.edu.
Anosheh
A
Afghahi
Department of Pathology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA, 94305, USA. eforgo@stanford.edu.
Erna
E
Forgó
Department of Medicine, Stanford University School of Medicine, 291 Campus Drive, Stanford, CA, 94305, USA. amitani@bu.edu.
Aya A
AA
Mitani
Department of Medicine, Stanford University School of Medicine, 291 Campus Drive, Stanford, CA, 94305, USA. manishad@stanford.edu.
Manisha
M
Desai
Department of Pathology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA, 94305, USA. svarma@stanford.edu.
Sushama
S
Varma
Department of Medicine, Stanford University School of Medicine, 291 Campus Drive, Stanford, CA, 94305, USA. tseto@stanford.edu.
Tina
T
Seto
Department of Medicine, Stanford University School of Medicine, 291 Campus Drive, Stanford, CA, 94305, USA. jrigdon@stanford.edu.
Joseph
J
Rigdon
Department of Pathology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA, 94305, USA. kjensen1@stanford.edu.|Pathology and Laboratory Medicine, Palo Alto Veterans Affairs Health Care System, 795 Willow Road, Palo Alto, CA, 94025, USA. kjensen1@stanford.edu.
Kristin C
KC
Jensen
Department of Pathology, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR, 97239, USA. troxellm@ohsu.edu.
Megan L
ML
Troxell
Department of Health Research and Policy, Stanford University School of Medicine, 900 Blake Wilbur Drive, Stanford, CA, 94305, USA. Scarlett.Gomez@cpic.org.|Cancer Prevention Institute of California (CPIC), 2201 Walnut Avenue, Fremont, CA, 94538, USA. Scarlett.Gomez@cpic.org.
Scarlett Lin
SL
Gomez
Department of Medicine, Stanford University School of Medicine, 291 Campus Drive, Stanford, CA, 94305, USA. Amarendra.K.Das@dartmouth.edu.|Department of Psychiatry and The Dartmouth Institute for Health Policy and Clinical Practice, Geisel School of Medicine, 1 Rope Ferry Road, Lebanon, NH, 03755, USA. Amarendra.K.Das@dartmouth.edu.
Amar K
AK
Das
Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, 330 Brookline Avenue, Boston, MA, 02215, USA. abeck2@bidmc.harvard.edu.
Andrew H
AH
Beck
Department of Medicine, Stanford University School of Medicine, 291 Campus Drive, Stanford, CA, 94305, USA. akurian@stanford.edu.|Department of Health Research and Policy, Stanford University School of Medicine, 900 Blake Wilbur Drive, Stanford, CA, 94305, USA. akurian@stanford.edu.
Allison W
AW
Kurian
Department of Pathology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA, 94305, USA. rbwest@stanford.edu.
Robert B
RB
West
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology*; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000235:genetics* / Q000473:pathology*; D002869:Chromosome Aberrations; D056915:DNA Copy Number Variations; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008875:Middle Aged; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D055815:Young Adult
D014408:Biomarkers, Tumor