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Pathologic Response to Preoperative Systemic Therapy: The New Biological Paradigm for Predicting Outcome and Planning Therapy

From the Department of Surgery, University of Washington, Seattle, Washington.

Correspondence: Address correspondence to: Benjamin O. Anderson, MD, FACS, Department of Surgery, University of Washington, Box 356410, Seattle, WA 98195; Fax: 206-543-8136; E-mail: banderso{at}u.washington.edu

Although breast cancer staging of the primary tumor (T stage) and lymph nodes (N stage) remains the single best predictor of relapse and survival, these staging studies are at best indirect measures of what we really need to know about the cancers we are treating. Breast cancer mortality is due neither to the presence of cancer in the breast nor in the axilla. Death is due to metastatic progression of drug-resistant cancer to distant organs, where gross disease burden ultimately overwhelms host defenses. As was shown in the breast conservation trials of the 1980s, systemic dissemination of invasive cancer occurs early in the course of progression, typically before the patient is ever diagnosed.¹ Thus, tumor size and nodal staging of cancer really are in vivo markers of biological aggression, representing the biological properties of micrometastatic cells already disseminated through the lymphatic and hematogenous circulations.

Restated, the ultimate determinant of outcome for breast cancer patients is (1) the underlying biological aggressiveness of the cancer, counterbalanced by (2) the degree to which systemic therapy down-regulates or kills micrometastatic cancer cell clones. Unfortunately, we lack the technology to test for the presence of viable micrometastatic disease in distant organs and also lack the ability to conclusively predict before treatment which drug regimens will eradicate which cancers. Thus, one significant benefit of preoperative systemic therapy is that it provides direct in vivo evidence of chemosensitivity or chemoresistance for a given cancer and drug regimen within the host.

In this issue of the Annals of Surgical Oncology, Newman and colleagues² reaffirm the emerging recognition that the underlying determinant of final outcome, beyond stage of cancer at presentation, is response of that cancer to systemic chemotherapy. Among node-positive patients, improved outcome is predicted by the degree of response to systemic therapy, as measured by evidence of disease regression in lymph nodes. These results suggest that, in addition to staging at diagnosis, we should also consider pathologic evidence of disease regression, indicating that the systemic treatment has been effective, at least for a significant portion of the primary tumor and nodal metastases.

FINDINGS OF THE NEWMAN STUDY

Patients with locally advanced breast cancer were treated with preoperative chemotherapy followed by surgical extirpation of disease, including a complete level I/II axillary lymph node dissection. The patients without histologic evidence of nodal disease either before or following systemic treatment had the best outcome (27% relapse rate; 31.5 months disease-free survival), presumably because these patients had less aggressive node-negative disease. Patients with nodal disease that also had evidence of nodal disease regression had an intermediate outcome (32% relapse rate; 22.1 months disease-free survival). Patients with residual nodal disease and no evidence of nodal disease regression had the worst outcome (55% relapse rate; 19.8 months disease-free survival). Relapse occurred in 32% of patients with evidence of nodal tumor regression but in 49% of those without it. Regression of nodal disease, as a risk factor for recurrence, failed to achieve statistical significance because the study patient population was limited to 71 patients. Nonetheless, the clinical interpretation of the study is clear.

IMPLICATIONS FOR CURRENT THERAPY AND FUTURE RESEARCH

A primary benefit of preoperative chemotherapy is that the tumor’s response to systemic therapy can directly be observed. This information is lost when systemic therapy is not given until after surgery, which is the standard for treatment of early-staged breast cancer. The National Surgical Adjuvant Breast and Bowel Project B-18 trial, which randomized women to preoperative versus postoperative chemotherapy, showed that the pathological response to chemotherapy directly corresponds to disease-free recurrence and survival.³ Thus, in theory, the opportunity exists to provide more or different postoperative systemic therapy to those patients who fail to demonstrate response to the first line drug therapy. This shifting paradigm in clinical rationale has practical applications for both clinical therapy and future research:

1. Pathology reporting. When providing a surgical specimen, the surgeon needs to inform the pathologist regarding the use of preoperative therapy. The pathologist, in turn, should then explicitly comment on evidence of disease regression, both in the breast primary and in the nodal bed. In the case of lymph nodes, evidence of tumor regression includes the presence of nodal fibrosis, mucin pools, or aggregates of foamy histiocytes.
   
2. Sentinel lymph node biopsy. The use of sentinel node biopsy in conjunction with preoperative chemotherapy has been evaluated in multiple studies. Although initial studies of sentinel node mapping following preoperative chemotherapy suggested that the false-negative rate might be unduly increased,⁴ subsequent larger studies suggest that the rate remains at more reasonable rates, at least for T1 and T2 tumors.⁵ Nonetheless, some groups now perform sentinel node mapping routinely as a separate procedure without removal of the breast primary before the initiation of drug treatment, to more clearly define which patients are actually node positive before systemic therapy is initiated.⁶ Completion axillary dissection is then performed at the time of primary cancer resection in those women who had a positive sentinel node before drug therapy. The Newman study supports the rationale of this approach in that it helps stratify patients into one of three groups: node negative, node positive with evidence of drug-induced disease regression, and node positive without evidence of disease regression.
   
3. Implications of residual disease at surgery for subsequent systemic therapy. While it seems logical to provide additional systemic therapy to those patients having little or no response to a given preoperative drug regimen, the choice of additional systemic therapy would be based upon clinical or biological rationale rather than clinical trial data. A next generation of systemic therapy protocols should help define how such drug regimens should be selected as stratified by level of tumor regression in the breast and axillary nodes.
   
4. Increasing use of preoperative systemic therapy for early-staged breast cancer. The prognostic benefit of observed tumor response seen in locally advanced cancer could also exist for women with earlier-staged disease. However, increased use of preoperative chemotherapy among women with early-staged disease also creates the potential that a growing group of patients would end up receiving more drug therapy than they really need. The risks of overtreatment are directly related to the toxicity of the regimen. Less toxic endocrine or biologic therapy regimens could potentially be used before surgery with a greater margin of safety. Additional clinical research is needed.
   
5. Imaging studies demonstrating response to therapy. A new generation of nuclear medicine imaging tests may facilitate accurate assessment of in vivo drug response.^7,8 The development and refinement of this technology is ongoing. As evidence of therapeutic response during systemic therapy can better be obtained through noninvasive means, the opportunity to adjust treatment at the point of "best response" will improve. To this end, the use of positron emission tomography, sestamibi scintimammography, or other specialized nuclear imaging studies could significantly impact how we integrate systemic and local-regional therapy in our breast cancer patients with advanced stage or perhaps even early-staged disease.
   

Overall, there is a paradigm shift in oncologic thinking regarding breast cancer. The recognition that response to systemic therapy is a key variable in predicting outcome implies a dynamic relationship between cancer and therapy. Stage of disease at diagnosis is no longer the final end point to determine a patient’s fate. Instead, it represents a starting point for treatment. Response to systemic therapy, and documentation therein, becomes a major focus of cancer management as we move toward new approaches to inhibit breast cancer progression and find new cures.

Received for publication May 30, 2003. Accepted for publication June 4, 2003.

REFERENCES

1. Fisher B, Anderson S, Bryant J, et al. Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med 2002; 347: 1233–41.[Abstract/Free Full Text]
2. Newman LA, Pernick NL, Adsay V, et al. Histopathologic evidence of tumor regression in the axillary lymph nodes of patients treated with preoperative chemotherapy correlates with breast cancer outcome. Ann Surg Oncol 2003; 10: 734–9.[Abstract/Free Full Text]
3. Fisher B, Bryant J, Wolmark N, et al. Effect of preoperative chemotherapy on the outcome of women with operable breast cancer. J Clin Oncol 1998; 16: 2672–85.[Abstract]
4. Nason KS, Anderson BO, Byrd DR, et al. Increased false negative sentinel node biopsy rates after preoperative chemotherapy for invasive breast carcinoma. Cancer 2000; 89: 2187–94.[CrossRef][Medline]
5. Olson JA Jr., Fey J, Winawer J, et al. Sentinel lymphadenectomy accurately predicts nodal status in T2 breast cancer. J Am Coll Surg 2000; 191: 593–9.[CrossRef][Medline]
6. Toi M, Bando H, Saji S. Decision tree and paradigms of primary breast cancer: changes elicited by preoperative therapy. Med Sci Monit 2003; 9: RA90–5.[Medline]
7. Mankoff DA, Dunnwald LK, Gralow JR, Ellis GK, Drucker MJ, Livingston RB. Monitoring the response of patients with locally advanced breast carcinoma to neoadjuvant chemotherapy using [technetium 99m]-sestamibi scintimammography. Cancer 1999; 85: 2410–23.[CrossRef][Medline]
8. Mankoff DA, Dunnwald LK, Gralow JR, et al. Blood flow and metabolism in locally advanced breast cancer: relationship to response to therapy. J Nucl Med 2002; 43: 500–9.[Abstract/Free Full Text]

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