Chromosomal copy number alterations for associations of ductal carcinoma in situ with invasive breast cancer

Anosheh Afghahi¹, Erna Forgó², Aya A Mitani³, Manisha Desai⁴, Sushama Varma⁵, Tina Seto⁶, Joseph Rigdon⁷, Kristin C Jensen^{8

9}, Megan L Troxell¹⁰, Scarlett Lin Gomez^{11

12}, Amar K Das^{13

14}, Andrew H Beck¹⁵, Allison W Kurian^{16

17}, Robert B West¹⁸

Affiliations

¹ Department of Medicine, Stanford University School of Medicine, 291 Campus Drive, Stanford, CA, 94305, USA. anosheh@stanford.edu.
² Department of Pathology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA, 94305, USA. eforgo@stanford.edu.
³ Department of Medicine, Stanford University School of Medicine, 291 Campus Drive, Stanford, CA, 94305, USA. amitani@bu.edu.
⁴ Department of Medicine, Stanford University School of Medicine, 291 Campus Drive, Stanford, CA, 94305, USA. manishad@stanford.edu.
⁵ Department of Pathology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA, 94305, USA. svarma@stanford.edu.
⁶ Department of Medicine, Stanford University School of Medicine, 291 Campus Drive, Stanford, CA, 94305, USA. tseto@stanford.edu.
⁷ Department of Medicine, Stanford University School of Medicine, 291 Campus Drive, Stanford, CA, 94305, USA. jrigdon@stanford.edu.
⁸ Department of Pathology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA, 94305, USA. kjensen1@stanford.edu.
⁹ Pathology and Laboratory Medicine, Palo Alto Veterans Affairs Health Care System, 795 Willow Road, Palo Alto, CA, 94025, USA. kjensen1@stanford.edu.
¹⁰ Department of Pathology, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR, 97239, USA. troxellm@ohsu.edu.
¹¹ Department of Health Research and Policy, Stanford University School of Medicine, 900 Blake Wilbur Drive, Stanford, CA, 94305, USA. Scarlett.Gomez@cpic.org.
¹² Cancer Prevention Institute of California (CPIC), 2201 Walnut Avenue, Fremont, CA, 94538, USA. Scarlett.Gomez@cpic.org.
¹³ Department of Medicine, Stanford University School of Medicine, 291 Campus Drive, Stanford, CA, 94305, USA. Amarendra.K.Das@dartmouth.edu.
¹⁴ 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.
¹⁵ Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, 330 Brookline Avenue, Boston, MA, 02215, USA. abeck2@bidmc.harvard.edu.
¹⁶ Department of Medicine, Stanford University School of Medicine, 291 Campus Drive, Stanford, CA, 94305, USA. akurian@stanford.edu.
¹⁷ Department of Health Research and Policy, Stanford University School of Medicine, 900 Blake Wilbur Drive, Stanford, CA, 94305, USA. akurian@stanford.edu.
¹⁸ Department of Pathology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA, 94305, USA. rbwest@stanford.edu.

PMID: 26265211
PMCID: PMC4534146
DOI: 10.1186/s13058-015-0623-y

Chromosomal copy number alterations for associations of ductal carcinoma in situ with invasive breast cancer

Anosheh Afghahi et al. Breast Cancer Res. 2015.

. 2015 Aug 13;17(1):108.

doi: 10.1186/s13058-015-0623-y.

Authors

Affiliations

¹ Department of Medicine, Stanford University School of Medicine, 291 Campus Drive, Stanford, CA, 94305, USA. anosheh@stanford.edu.
² Department of Pathology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA, 94305, USA. eforgo@stanford.edu.
³ Department of Medicine, Stanford University School of Medicine, 291 Campus Drive, Stanford, CA, 94305, USA. amitani@bu.edu.
⁴ Department of Medicine, Stanford University School of Medicine, 291 Campus Drive, Stanford, CA, 94305, USA. manishad@stanford.edu.
⁵ Department of Pathology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA, 94305, USA. svarma@stanford.edu.
⁶ Department of Medicine, Stanford University School of Medicine, 291 Campus Drive, Stanford, CA, 94305, USA. tseto@stanford.edu.
⁷ Department of Medicine, Stanford University School of Medicine, 291 Campus Drive, Stanford, CA, 94305, USA. jrigdon@stanford.edu.
⁸ Department of Pathology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA, 94305, USA. kjensen1@stanford.edu.
⁹ Pathology and Laboratory Medicine, Palo Alto Veterans Affairs Health Care System, 795 Willow Road, Palo Alto, CA, 94025, USA. kjensen1@stanford.edu.
¹⁰ Department of Pathology, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR, 97239, USA. troxellm@ohsu.edu.
¹¹ Department of Health Research and Policy, Stanford University School of Medicine, 900 Blake Wilbur Drive, Stanford, CA, 94305, USA. Scarlett.Gomez@cpic.org.
¹² Cancer Prevention Institute of California (CPIC), 2201 Walnut Avenue, Fremont, CA, 94538, USA. Scarlett.Gomez@cpic.org.
¹³ Department of Medicine, Stanford University School of Medicine, 291 Campus Drive, Stanford, CA, 94305, USA. Amarendra.K.Das@dartmouth.edu.
¹⁴ 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.
¹⁵ Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, 330 Brookline Avenue, Boston, MA, 02215, USA. abeck2@bidmc.harvard.edu.
¹⁶ Department of Medicine, Stanford University School of Medicine, 291 Campus Drive, Stanford, CA, 94305, USA. akurian@stanford.edu.
¹⁷ Department of Health Research and Policy, Stanford University School of Medicine, 900 Blake Wilbur Drive, Stanford, CA, 94305, USA. akurian@stanford.edu.
¹⁸ Department of Pathology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA, 94305, USA. rbwest@stanford.edu.

PMID: 26265211
PMCID: PMC4534146
DOI: 10.1186/s13058-015-0623-y

Abstract

Introduction: 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.

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Figures

**Fig. 1**
Genomic predictor simulation experiment. We created three frequency-based classes of genomic alterations in ductal carcinoma *in situ* (DCIS): low frequency (LF) (5 %), mid frequency (MF) (15 %), and high frequency (HF) (30 %), and four classes of differential frequencies between cases and controls: highly differential (HD) (alteration frequency is threefold higher in cases versus controls), moderately differential (MD) (alteration frequency is 1.5-fold higher in cases versus controls), low-level differential (LD) (alteration is 1.25-fold higher in cases versus controls), and nondifferential (ND) (alteration frequency is generated from the same distribution in cases and controls). For each of 2000 simulations, we used L1-regularized logistic regression to build a predictor and performed tenfold cross-validation to select the optimal value for the λ tuning parameter. For each simulation, we recorded which types of features in terms of frequency (LF, MF, HF) and differential status (ND, LD, MD, HD) were active in the model. The results are displayed in the figure, with the feature types along the X-axis and the proportion of simulations in which each feature type was active in the model along the Y-axis

**Fig. 2**
a Hematoxylin and eosin (H&E) image of ductal carcinoma *in situ* (DCIS) with 11q13 gain. b Fluorescence *in situ* hybridization (FISH) image of DCIS with high level of copy number gain

See this image and copyright information in PMC

References

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Chromosomal copy number alterations for associations of ductal carcinoma in situ with invasive breast cancer

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Chromosomal copy number alterations for associations of ductal carcinoma in situ with invasive breast cancer

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