Detection of Occult Metastases in Lymph Nodes Not Associated With Overall Survival in Early-Stage Breast Cancer



Sentinel lymph node metastases detected with the diagnostic procedure of immunohistochemical staining were not associated with overall survival among women with early-stage breast cancer receiving breast-conserving therapy, according to a study in the July 27 issue of JAMA.1

“Sentinel lymph node (SLN) dissection has revolutionized the approach to early-stage breast cancer by allowing minimally invasive axillary staging and more intensive examination of the SLN. This has led to the detection of micro metastases and isolated tumor cells of uncertain significance,” according to background information in the article. “Immunochemical staining of SLNs and bone marrow identifies breast cancer metastases not seen with routine pathological or clinical examination.”

Armando E. Giuliano, M.D., formerly of the John Wayne Cancer Institute at Saint John's Health Center, Santa Monica, Calif., (and now with Cedars-Sinai Medical Center, Los Angeles), and colleagues conducted an observational study to examine the association between survival and metastases detected by immunochemical staining of SLNs and bone marrow specimens from patients with early-stage breast cancer. The study included data on women with clinical T1 to T2N0M0 invasive breast carcinoma enrolled in the American College of Surgeons Oncology Group Z0010 trial at 126 sites from May 1999 to May 2003. All 5,210 patients underwent breast-conserving surgery and SLN dissection. Bone marrow aspiration (removal of a sample through a needle) at the time of operation was initially optional and subsequently mandatory (March 2001). Sentinel lymph node specimens and bone marrow specimens were sent to a central laboratory for immunochemical staining. Results were blinded to treating physicians.

Of 5,119 SLN specimens (98.3 percent), 3,904 (76.3 percent) were tumor-negative by hematoxylin-eosin staining. Of 3,326 SLN specimens examined by immunohistochemistry (an assay that shows specific antigens in tissues by the use of markers that are either fluorescent dyes or enzymes), 349 (10.5 percent) were positive for tumor. Of 3,413 bone marrow specimens examined by immunocytochemistry, 104 (3.0 percent) were positive for tumors.

All women were followed-up until April 21, 2010. At a median (midpoint) follow-up of 6.3 years, there were 435 deaths and 376 women with disease recurrence. The researchers found that among patients with hematoxylin-eosin-negative SLNs, immunohistochemical evidence of occult metastases had no significant association with death or recurrence. “Five-year rates of overall survival for patients with immunohistochemistry-negative SLNs were 95.7 percent and for those with immunohistochemistry-positive SLNs were 95.1 percent. Corresponding 5-year rates of disease-free survival were 92.2 percent and 90.4 percent, respectively,” the authors write.

The researchers also found that occult bone marrow metastases were associated with decreased overall survival only when clinicopathological factors were not considered. “Bone marrow examination with immunocytochemistry may identify high-risk women; however, the incidence in the Z0010 trial was too low to recommend incorporating bone marrow aspiration biopsy into routine practice for patients with the earliest stages of breast cancer.”

The authors write that the findings of the Z0010 trial have important implications for clinical practice. “Many laboratories routinely perform-multiple sections and immunohistochemistry on hematoxylin-eosin-negative SLNs, even though the College of American Pathologists guidelines for SLN processing do not include their use. Data from Z0010 show that occult metastases detected by immunohistochemistry are not associated with survival differences in patients with the earliest stages of breast cancer. Although longer follow-up might reveal small differences in outcome, these are likely to be of no clinical significance as demonstrated by findings of National Surgical Adjuvant Breast and Bowel Project B-32 trial.”

“Routine immunohistochemical examination of hematoxylin-eosin negative SLNs and routine immunocytochemical examination of bone marrow are not clinically warranted for early-stage (clinical T1-T2N0) breast cancer.”

Ryan P. Merkow, M.D., and Clifford Y. Ko, M.D., M.S., M.S.H.S., of the American College of Surgeons, Chicago, write in an accompanying editorial2 that this study “serves as an ideal illustration of how well-designed observational research can be conducted in surgery.”

“Randomized controlled trials (RCTs) should not be considered the de facto and sole source of high-level evidence. By considering RCTs and observational study designs complimentary, and recognizing the opportunities to use observational research when appropriate, it might be possible to address questions faster, cheaper, and perhaps even better than either approach alone. Above all else, it will be patients who will ultimately benefit.”



1. JAMA. 2011;306[4]385-393

2. JAMA. 2011;306[4]436-437.