br Taken together our findings will aid
Taken together, our findings will aid clinicians in their initial discussions with patients on the likelihood that management rec-ommendations may change after surgery. For example, the National Comprehensive Cancer Network (NCCN) guidelines for treating breast cancer13 strongly recommend consideration of regional nodal irradiation if a patient has positive Ezatiostat nodes. In our study, 17.9% of clinically node-negative patients were found to have positive nodes, thus potentially changing management
recommendations for nearly 70,000 patients. Furthermore, the recommendation for anti-HER2 therapy, such as trastuzumab, is dependent on both tumor size and nodal status. The observed high rates of stage discordance in our study highlight the impor-tance of accurate staging, as it may significantly alter treatment recommendations.
Regardless of the staging tools employed, under-and over-esti-mation are common (noted in nearly one third of our study pop-ulation). Our study is one of the first to demonstrate that tumor biology may be associated with stage discordance in invasive breast cancer. Mustafa et al. demonstrated that patients with ER-positive/ PR-positive/HER2-negative disease were 50% less likely to be upstaged.14 These results are similar to those observed in our study, where stage concordance and discordance were associated with receptor status. Regarding HER2 specifically, HER2-negative status was associated with stage discordance after multivariate anal-ysis.14,15 In the current era of endocrine therapy and targeted anti-
Please cite this article as: Plichta JK et al., Clinical and pathological stage discordance among 433,514 breast cancer patients, The American Journal of Surgery, https://doi.org/10.1016/j.amjsurg.2019.07.016
6 J.K. Plichta et al. / The American Journal of Surgery xxx (xxxx) xxx
Fig. 1. Forest plot of generalized logistic regression results (N ¼ 397,979) based on data from patients with breast cancer in the National Cancer Database from 2004 to 2014;
(A) downstaged vs concordant; (B) upstaged vs concordant. Odds ratio (OR) > 1 in-dicates association with stage discordance (downstaged or upstaged) and OR <1 in-dicates association with stage concordance.
HER2 therapy, the prognostic implications of ER, PR, and HER2 status are now reflected in the staging guidelines.1 However, particularly for HER2-negative patients, the association between tumor biomarkers and stage concordance/discordance may require additional consideration.
In addition to tumor biology, patient race/ethnicity was associ-ated with stage discordance in our study. However, oxidation too may be partially explained by racial variation in breast cancer tumor biology, as black patients experience a higher incidence of triple negative and biologically aggressive tumors.16 Iqbal et al. reviewed 373,563 women diagnosed with invasive breast cancer from 2004 to 2011 in the Surveillance, Epidemiology, and End Results (SEER) 18 registries database.17 In this study, black women were less likely to be diagnosed with stage I breast cancer (OR 0.65, p < 0.001), and
were more likely to die of breast cancer with small tumors, even after adjusting for income and ER status (HR 1.96, p < 0.001).17 Similarly, we also found that race/ethnicity were associated with stage discordance (58.5% stage concordance for non-Hispanic black patients, 62% for Hispanic patients, vs 69.9% for non-Hispanic white patients). Some of these differences in race/ethnicity may also be attributed to variables not captured in our data set, such as types and frequency of pre-operative imaging, physical exam reliability, and access to care.
Currently, clinical staging is based primarily on physical exam-ination, imaging, and biopsies of affected sites. Physical exam re-mains an essential preoperative component of the evaluation of tumor size (T) and nodal involvement (N). In a retrospective review of 320 patients with palpable breast masses, Wai et al. reported that physical exam demonstrated a 92% accuracy in predicting malig-nancy.18 Though specific, the sensitivity of the physical exam in determining T and N stage is low.19 Therefore, diagnostic mam-mograms and breast ultrasound are conventionally used to sup-plement physical exam findings and to clinically stage new breast cancer patients.20,21 However, variation in staging protocols (by provider, institution, and insurance coverage) and imperfect stag-ing tools will inevitably result in some degree of stage discordance among providers and practice settings.
Some have advocated breast MRI and/or axillary ultrasound as superior tools for clinical staging. Some surgeons routinely order preoperative breast MRIs, due to its high negative predictive value and improved sensitivity in dense breast tissue.21e23 However, the benefits of routine preoperative MRIs remain uncertain due to high false positive rates, negligible added sensitivity to conven-tional imaging, and high associated costs.24e 27 Breast MRIs have been shown to increase mastectomy rates, but have not been shown to decrease the rates of positive margins, re-excision, or recurrence.28e30