Age and lymph node status in breast cancer: not a straightforward relationship.

Despite decades of clinical investigations of prognostic factors for recurrence in patients with operable breast cancer, the status of axillary lymph nodes has remained the single most important independent predictor of outcome. None of the newer innovative imaging modalities (eg, ultrasound, magnetic resonance imaging, positron emission tomography scans, or sestamibi scans) have been shown to be of similar value compared with pathologic assessment in determining axillary lymph node status. Because of the morbidity of axillary lymph node dissection and the fact that a majority of patients with operable breast cancer and clinically negative axilla have histologically negative axillary nodes, multiple attempts have been made to identify predictors of axillary nodal involvement that could lead to more selective use of axillary dissection. Although several patient and tumor characteristics have been associated with risk of axillary nodal involvement in patients with invasive breast cancer (such as tumor size, lymphovascular invasion, histologic type, tumor grade, age, hormone receptor status, and human epidermal growth factor receptor 2 (HER-2)/neu status), identifying meaningful subgroups with low risk of axillary nodal involvement (in which axillary staging can be omitted) has remained an elusive goal. On another front, the development and validation of sentinel lymph node biopsy as the optimal surgical approach to staging the axilla (with associated decreased morbidity compared with axillary dissection) have led to a shift in research priorities relative to identifying predictors of axillary nodal involvement. Thus, the currently pursued research question is not who does or does not need a sentinel lymph node biopsy but rather who does or does not need a completion axillary dissection if the sentinel node is positive. However, the identification of factors associated with axillary involvement may also provide insight into the biology of tumor growth and metastasis that could eventually lead to therapeutic interventions in addition to those related to surgical management of the disease. To that extent, in this issue of Journal of Clinical Oncology, Wildiers et al present the results of a well-done study examining the relationship between patient age and risk of axillary lymph node involvement. In a large cohort of patients with breast cancer from the University Hospitals of Leuven database (2,568 patients), they identified an interesting effect of age on lymph node positivity. Women age 70 years or younger were less likely to be lymph node positive with increasing age (odds ratio per 10-year increase, 0.87), but women older than age 70 years were more likely to be lymph node positive with increasing age. Interestingly, in older women, the effect of age interacted with tumor size, suggesting that increasing age is associated with higher risk of lymph node involvement mainly in patients with small tumors, whereas for those with larger tumors, the effect of age on lymph node involvement was similar between the younger and older groups of patients. An important part of the study, adding strength to the authors’ conclusions, is that their findings were validated in a similarly large cohort of patients from the Einthoven Cancer Registry database (3,334 patients). Thus, it is fair to say that the observations in this study are not the result of statistical chance and represent true findings for the populations studied. To put these results in perspective, we must ask what some of the reasons for these findings might be. First, it is possible that patients older than age 70 years are more likely to incur a delay in diagnosis as a result of less frequent use of screening mammography or longer waiting period before medical attention is sought. In fact, Wildiers et al report that primary breast tumor size at diagnosis increased with age. However, the observed interaction between age and tumor size on lymph node involvement in older patients suggests that the increase in nodal positivity in older women was mostly observed in patients with small tumors ( 2 cm), whereas for large tumors, the effect of age even became negative (ie, in patients with large tumors, nodal positivity steadily decreased with increasing age). This argues against delay in diagnosis as a major contributor to the findings of the study. Second, it is possible that some of the observed effects could be explained by imbalances in the expression of certain tumor biomarkers according to age (such as grade, proliferation, and estrogen receptor (ER), progesterone receptor, and HER-2/neu status). Complex relationships have been recently described between ER status, HER-2/neu status, grade, and lymph node status in patients with operable breast cancer. However, given that there were no consistent differences between younger and older patients in the distribution of ER, progesterone receptor, and HER-2/neu status or grade in either of the data sets in the study by Wildiers et al, it is also unlikely that imbalances in the distribution of these biomarkers could have accounted for the observed findings. Finally, there a possibility that selection bias (present in both data sets) could have contributed to these findings. Because the study required information on axillary nodal status for inclusion in the data set, patients who did not have an axillary dissection or who had missing information on axillary nodal status were excluded. A total of 3.2% of patients in the Leuven cohort and 9.2% of patients in the Einthoven cohort had missing values for axillary nodal status. Although the authors tried to compensate for this in the JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 27 NUMBER 18 JUNE 2