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High-resolution mapping of DNA breakpoints to define true recurrences among ipsilateral breast cancers.

BACKGROUND
To distinguish new primary breast cancers from true recurrences, pangenomic analyses of DNA copy number alterations (CNAs) using single-nucleotide polymorphism arrays have proven useful.


METHODS
The pangenomic profiles of 22 pairs of primary breast carcinoma (ductal or lobular) and ipsilateral breast cancers from the same patients were analyzed. Hierarchical clustering was performed using CNAs and DNA breakpoint information. A partial identity score developed using DNA breakpoint information was used to quantify partial identities between two tumors. The nature of ipsilateral breast cancers (true recurrence vs new primary tumor) as defined using the clustering methods and the partial identity score was compared with that based on clinical characteristics. Metastasis-free survival was compared among patients with primary tumors and true recurrences as defined using the partial identity score and by clinical characteristics. All statistical tests were two-sided.


RESULTS
All methods agreed on the nature of ipsilateral breast cancers for 14 pairs of samples. For five pairs, the clinical definition disagreed with both clustering methods. For three pairs, the two clustering methods were discordant and the one using DNA breakpoints agreed with the clinical definition. The partial identity score confirmed the nature of ipsilateral breast cancers as defined by clustering of DNA breakpoints in 21 of 22 pairs. The difference in metastasis-free survival of patients with new primary tumors and those with true recurrences was not statistically significant when tumors were defined based on clinical and histologic characteristics (5-year metastasis-free survival: 76%, 95% confidence interval [CI] = 52% to 100% for new primary tumors and 38%, 95% CI = 17% to 83% for true recurrences; P = .18; new primary tumor vs true recurrence, hazard ratio = 2.8, 95% CI = 0.6 to 13.7), but the difference was statistically significant when tumors were defined using the partial identity score (5-year metastasis-free survival: 100% for new primary tumors and 29%, 95% CI = 11% to 78% for true recurrences; P = .01).


CONCLUSIONS
DNA breakpoint information more often agreed with the clinical determination than CNAs in this population. The partial identity score, which was calculated based on DNA breakpoints, allows statistical discrimination between new primary tumors and true recurrences that could outperform the clinical determination in terms of prognosis.