The presence of axillary disease is the most important prognostic factor in breast cancer. Disease in the axilla can indicate biological aggressiveness and extent of tumor involvement, often suggesting systemic spread and the need for additional therapy. In addition, the link between locoregional disease control and overall survival in breast cancer has been firmly established by meta-analyses of randomized data [18
]. The potential importance of ALND in select patients is underscored by a recent analysis which suggested a survival benefit for women with macroscopic nodal disease that received ALND as compared to women with SLN biopsy alone [19
]. Additionally the NCIC CTG MA.20 trial which randomized patients with high-risk breast cancer to postoperative whole-breast (WB) radiotherapy alone versus WB plus regional nodal irradiation showed improved locoregional control and an even greater improvement in distant disease control in the arm with regional nodal irradiation [20
]. Therefore, the risks of more extensive axillary treatment versus the risks of missing occult disease must be carefully considered.
Our nomogram is intended to be flexible and enable increased personalization of cancer care. Specifically, our analysis is most applicable to two clinical scenarios and argues that
- for a patient who had a negative SLN biopsy, but still has a high posttest probability of axillary disease, comprehensive axillary radiation may be warranted;
- for a patient who has not yet undergone any axillary surgery, who has a high pretest probability of positive axillary nodes based on clinical features and who also has clinical characteristics that might decrease the sensitivity of SLN biopsy (as in ), expanded axillary assessment up front may be warranted.
These conclusions seek to limit overtreatment in the form of multiple surgeries (SLN biopsy followed by ALND) and undertreatment in the form of omission of axillary radiation in breast patients with high-risk disease.
We created a nomogram to estimate the risk of residual axillary disease despite a negative SLN biopsy as a function of the sensitivity of the SLN biopsy procedure and the pretest probability of axillary disease prior to axillary evaluation. Our nomogram reveals that for patients with a high pretest probability of axillary metastases and factors associated with a lower SLN biopsy sensitivity, the posttest probability of axillary disease often remains high despite a negative biopsy. While SLN biopsy is the appropriate test for most breast cancer patients, a preemptive expanded assessment of the axilla may be a better choice for high-risk patients or in cases where an SLN biopsy is predicted to be less sensitive ().
In contrast to other probability calculators which estimate the risk of nonsentinel axillary nodal disease in a woman with breast cancer only after
a positive SLN, our decision tool estimates the probability of nonsentinel axillary nodal disease without
prior pathologic assessment of the axilla [15
]. The posttest probability obtained from the nomogram presented can then be assessed to be acceptable or not based on the specific clinical scenario. For example, a predicted posttest probability greater than 20–25% may warrant consideration of a more thorough axillary assessment upfront. Similarly, in cases where a negative SLN biopsy has already been obtained, a posttest probability of greater than 10% may suggest the need for the addition of axillary radiation.
In patients identified by the nomogram to have an unacceptably high-risk of residual axillary disease despite negative SLN biopsy, more aggressive preemptive exploration of the axilla will necessarily mean a higher risk of lymphedema, nerve injury and general surgical complications compared to SLN biopsy; nevertheless, with modern ALND where only levels I-II are removed, these risks are less than observed historically [20
]. Another option may be a less morbid lymph node sampling procedure as was reported in the UK, where at least 4 palpable lymph nodes are obtained by dissection starting at the axillary tail [22
]. For patients where a negative SLN biopsy has already been obtained, but a high posttest probability of axillary disease remains, the addition of axillary radiation therapy could be considered in lieu of completion axillary dissection.
Use of this nomogram after a breast biopsy is not expected to result in excessive axillary treatment because it is likely to slightly underestimate rather than overestimate the probability of residual nodal disease. This is because the MSKCC risk calculator used above to obtain a pretest probability of having nodal disease was validated with information from complete pathologic specimens whereas, in practice, physicians are likely to substitute incomplete biopsy specimens such as findings from core needle biopsy, resulting in underdetection (due to undersampling) of certain negative prognostic factors, such as lymphovascular invasion, multifocality, and higher-grade tumor areas, which if found, increase the probability of having nodal disease. Therefore, use of only biopsy information would lead to underestimation of the pretest probability of having axillary involvement, which in turn would lead to underestimation of the posttest probability when using the nomogram. Another possible source of error associated with the use of incomplete biopsy specimens is that tumor size estimate entered into the MSKCC risk calculator must be estimated indirectly, based on imaging. However, assessment of tumor size by MRI, mammography and ultrasound does appear to correlate well with size as determined by pathologic exam [23
Although the recently published ACOSOG Z0011 and NSABP B-32 trials show similar rates of local control in both their SLN alone and ALND arms, the patients included in these trials were conservatively chosen and by definition had a low-risk profile [6
]. For the average patient in these trials, the risk of additional nodal disease after a negative SLN biopsy according to our nomogram would be under 6% even when using a low value of 85% as the sensitivity for SLN biopsy. Therefore our nomogram would not change the management of the average patient on these trials.
For high-risk patients systemic therapy recommendations are also unlikely to change based on the output of this nomogram, because many of the factors which prompt addition of adjuvant therapy are the same factors that increase the pretest (and therefore also posttest) probability of having axillary disease. However, with regard to local management of the axilla, using this nomogram may change management, especially in light of the NCIC CTG MA.20 trial which included high-risk patients and suggests that residual untreated nodal disease may affect distant disease even in the absence of a clinically evident nodal recurrence.
This nomogram is anticipated to apply to the small proportion of breast cancer patients who present with clinically high-risk disease. Randomized studies for this subset are difficult to perform because most breast cancer patients present with early-stage disease. Therefore, Bayesian estimation of risk based on a mathematically sound extrapolation from available data is especially useful in this clinical situation. Our nomogram is a particularly important tool for this group of high-risk patients because they may benefit from more extensive surgery or axillary radiation.