Reply to U.K. Ballehaninna et al
Authors: Kimberly J. Van Zee, Udo Rudloff
Journal: Journal of Clinical Oncology (2010)

We appreciate the insightful comments of Ballehaninna and Chamberlain 1 regarding biomarkers and their suggestion that they be included in our nomogram, recently published in Journal of Clinical Oncology. 2This nomogram estimates the risk of local recurrence for a woman with ductal carcinoma in situ (DCIS) undergoing breastconserving surgery.We agree with their hypothesis that "inclusion of endocrine and molecular variables" might further improve its ability to estimate risk.However, this is a goal that has not yet been achieved.To date, it has been difficult to identify molecular factors that predict recurrence of DCIS as either invasion or recurrent DCIS.For example, in the cited publication by Kerlikowske et al, 3 a simple clinical characteristic was more predictive of invasive recurrence than any of the seven endocrine/molecular variables studied.On multivariable analysis, only one combination of three different molecular markers (p16, COX-2, Ki67) was associated with invasive recurrence after lumpectomy for DCIS; its hazard ratio (HR) was of borderline significance (HR, 2.2; 95% CI, 1.1 to 4.5).In that same multivariable analysis, method of detection of the DCIS (palpation v mammography) was significant and was associated with a higher HR (HR, 2.7; 95% CI, 1.4 to 5.5).This variable is included in our nomogram.It is disappointing that none of the common molecular markers has consistently been found to be strongly associated with recurrence.Regarding the inclusion of estrogen receptor (ER) and progesterone receptor (PR) data in our nomogram, we point out that not until the past few years has ER/PR testing for DCIS been commonly performed.Even now, because this change in practice is based on data that have only been presented in abstract form, 4 the 2010 American Society of Clinical Oncology/College of American Pathologists guidelines do not make a formal recommendation to perform ER/PR testing in DCIS. 5 And, as Ballehaninna and Chamberlain point out, ER status can be correlated with various histologic factors; if these factors are included in a predictive model, any addedcontributionofERstatusislikelylessened.Becauseouranalysiswas performedonDCIScasesfrom1991to2006,hormonereceptordatawere not available for inclusion.Furthermore, although these hormone receptor characteristics might be prognostic, they also might not.For example, in Kerlikowske's study 3 of various molecular markers in DCIS, ER status was not associated with recurrence.And in invasive breast carcinoma, in which estrogen receptor positivity has long been considered to be a favorable prognostic factor, longer follow-up has suggested that although the pattern of recurrence is distinct from that of ER-negative tumors, the overall recurrence rate may ultimately be the same as that of ER-negative breast cancers. 6 Of course, like Ballehaninna and Chamberlain, 1 our hope is that additional molecular characteristics will be found that correlate more closely with biologic behavior and therefore will allow more accurate prediction of outcomes.At present, there are no generally available molecular markers for DCIS that have been proven to be prognostic.This is likely due to the difficulty in studying this entity; few DCIS popula-