Ipsilateral Breast Carcinoma Recurrence: True Recurrence or New Primary? A Clinicopathologic and Molecular Study

Determining whether an ipsilateral breast carcinoma recurrence is a true recurrence or a new primary remains challenging based solely on clinicopathologic features. Algorithms based on these features have estimated that up to 68% of recurrences might be new primaries. However, few studies have analyzed the clonal relationship between primary and secondary carcinomas to establish the true nature of recurrences. This study analyzed 70 breast carcinomas from 33 patients using immunohistochemistry, FISH, and massive parallel sequencing. We compared 35 primary carcinomas with the associated recurrences, identifying 24 (68.6%) as true recurrences, 7 (20%) as new primaries, and 4 (11%) as undetermined. Twenty-eight primary carcinomas were invasive carcinomas (22 of no special type, 5 invasive lobular, and 1 invasive micropapillary carcinoma), and 7 were in situ (6 ductal and 1 lobular). Time to recurrence was longer for new primaries (median 12.8 y) than for true recurrences (median 6.8 y). Among the new primary cases, 6 of 7 (85%) patients had undergone mastectomy as their initial treatment. Clinicopathologic classifications of invasive carcinomas overestimated the number of new primaries (41.6% to 68.6%), partially due to phenotype conversion in 14% of true recurrences. Although 41.7% of recurrences showed private mutations or amplifications relevant to tumor progression, such as PIK3CA, PIK3R1, MAP3K1, AKT1, GATA3, CCND1, MDM4 , or T P 5 3 ; a common mutational progression pattern was not identified. Further studies, including larger series, are necessary to evaluate the prognostic significance of the molecular classification of recurrences.