Copy number analysis of ductal carcinoma in situ with and without recurrence

Abstract

Ductal carcinoma in situ (DCIS) is a non-obligate precursor of invasive breast cancer and a frequent mammographic finding requiring treatment. Up to 25% of DCIS can recur and half of recurrences are invasive, but there are no reliable biomarkers for recurrence. We hypothesised that copy number aberrations could predict likelihood of recurrence. We analysed a cohort of pure DCIS cases treated only with wide local excision for genome-wide copy number and loss of heterozygosity using Affymetrix OncoScan MIP arrays. Cases included those without recurrence within 7 years (n = 25) and with recurrence between 1 and 5 years after diagnosis (n = 15). Pure DCIS were broadly similar in copy number changes compared with invasive breast cancer, with the consistent exception of a greater frequency of ERBB2 amplification in DCIS. There were no significant differences in age or ER status between the cases with a recurrence vs those without. Overall, the DCIS cases with recurrence had more copy number events than the DCIS without recurrence. The increased copy number appeared non-random with several genomic regions showing an increase in frequency in recurrent cases, including 20q gain, ERBB2 amplification and 15q loss. Copy number changes may provide prognostic information for DCIS recurrence, but validation in additional cohorts is required. Modern Pathology (2015Pathology ( ) 28, 1174Pathology ( -1184 doi:10.1038/modpathol.2015 published online 19 June 2015 Ductal carcinoma in situ (DCIS) is a proliferation of malignant cells within breast ducts without invasion through the basement membrane. A number of lines of evidence demonstrate that DCIS is a non-obligate precursor of invasive breast cancer, including the natural history of untreated DCIS, 1 the high risk of ipsilateral invasive breast cancer after a diagnosis of DCIS and the common clonal genetic events found in DCIS and synchronous or recurrent invasive breast cancer. 2 Prior to population-based screening mammography, DCIS was an unusual finding comprising only 3-5% of all breast neoplasms. Currently,~20% of cases of screen-detected breast neoplasia are DCIS. 3 Standard treatment has become wide local excision of DCIS with or without adjuvant radiotherapy. 4 Recent clinical trials have found that~25% of DCIS treated with local excision only will recur within 15 years, with the greatest risk of recurrence in the first 5 years. 5 Approximately half of the recurrences will be invasive carcinoma, requiring more extensive treatment, and with a possible decrease in disease-specific survival. 6 Radiotherapy reduces the recurrence rate by about 50%, so despite the fact that only small a small proportion of patients will benefit, many clinicians recommend radiotherapy because of the implications of invasive recurrence. The most commonly used predictive models to estimate the recurrence risk with or without radiotherapy include DCIS grade, tumour size, width

Relationship of the Breast Ductal Carcinoma In Situ Immune Microenvironment with Clinicopathological and Genetic Features

“…Finally, the combination of low-FGA/low NTAI and low TILs could indicate a DCIS type that is unlikely to progress to invasive disease, and is therefore seldom observed in invasive cohorts. This possibility would be consistent with our previous observation that higher levels of copy number change are associated with increased likelihood of recurrence after DCIS (18), but considerably larger cohorts of DCIS are required to test this hypothesis, especially given the multiple interacting variables that will need to be considered (ER status, HER2 status, grade, therapy type, etc.). The utility of a biomarker panel combining tumor-intrinsic copy number data in combination with tumor-extrinsic immune markers remains to be investigated.…”

“…Prediction of those cases of DCIS likely to progress to invasive carcinoma is imprecise (17). Histopathologic factors such as nuclear grade, hormone receptor expression, and comedo necrosis and genomic alterations including copy number changes have been shown to correlate with disease progression (17,18). Less is known about the immune response to DCIS and its potential prognostic significance.…”

Breast ductal carcinoma in situ carry mutational driver events representative of invasive breast cancer

“…25 Two cases, P13 and P92, gave poor quality copy number output and were excluded from further analysis. All the remaining 18 cases had at least one copy number event, and the copy number profiles generated were similar to those we previously reported for pure DCIS 32 , including common gains on 1q, 8q, 17q, and 20q and frequent losses on 8p, 11q, 16q, and 17p. There was good correlation between the copy number values generated by the on-and off-target reads for the genes in the panel (Spearman r = 0.96, P o 0.0001, Figure 4), and ERBB2 amplifications detected by sequencing were consistent with SISH data.…”

“…Additional cases for GATA3 sequencing were obtained from Royal Melbourne Hospital as previously described. 16 Approval for the study was obtained from the ethics committee of Peter MacCallum Cancer Centre (project numbers 02/26, 10/16, and 00/81).…”

Utilization of the oncoscan microarray assay in cancer diagnostics

“…3b). The application also allows comparison of multiple test results to discern common and unique variations in population studies [3,21].…”