The clinically negative axilla: The dilemma of occult metastases in sentinel nodes

When William Halsted, MD, FACS, performed radical mastectomies in the early 20th century, patients presented with locally advanced disease, often involving skin, muscle, and lymph nodes. Dr. Halsted’s palliative operation turned into a cure for some. The legacy of more radical surgery leading to more cures was to last another 75 years. Fast forward to the current era, a time when better screening and awareness have led to diagnosis at much earlier stages and a time when effective adjuvant and neoadjuvant therapies are available to treat the primary breast tumor and involved lymph nodes.

At this point in time, researchers are pondering whether we have more questions than answers—or perhaps we have new clinical practices informed by clinical trials? Specifically, what should physicians do with the axilla when at least 70 percent of patients have no clinically apparent axillary node metastasis? Is axillary node dissection always needed for occult disease? The Alliance for Clinical Trials in Oncology, formerly American College of Surgeons Oncology Group (ACOSOG), has clarified some of these issues.

ACOSOG trials Z0010 and Z0011

Almost since the group’s inception, clinical trials performed through ACOSOG have dealt with the critical role of axillary assessment in the breast cancer patient through two landmark trials—Z0010 and Z0011. Sentinel lymph node (SLN) mapping for breast cancer has replaced axillary lymph node dissection (ALND), allowing minimally invasive axillary staging. More thorough evaluation of the SLN has led to detection of micrometastases and isolated tumor cells (ITC) of questionable significance. Micrometastases are associated with the risk of additional non-SLN positivity, but researchers have been unclear as to the risk for locoregional or systemic recurrence or the benefit of completion ALND.

The National Surgical Adjuvant Breast and Bowel Project B-32 study showed occult metastases were associated with a small but statistically significant 1.2 percent decrease in five-year survival.1 The ACOSOG Z0010 trial analyzed the association between survival and metastasis detected by immunohistochemical (IHC) staining of SLNs and bone marrow specimens from patients with clinical early stage T1 to T2 N0 M0 invasive breast cancer. From May 1999 to May 2003, 126 sites enrolled 5,210 patients. ACOSOG encouraged community surgeons to participate, and they accounted for 29 percent of the patients in the trial.2

Of 3,326 SLNs that tested negative by hematoxylin-eosin staining in the ACOSOG Z0010 trial, 349 (10.5 percent) were positive for micrometastasis on IHC, but did not affect overall survival. Of 3,413 bone marrow specimens, 104 (3 percent) were positive for tumor on IHC and associated with decreased overall survival, but only when clinicopathological factors were not considered.3 Other retrospective studies have suggested decreased survival in patients with occult metastasis.4,5

A retrospective review based on cases in the American College of Surgeons’ National Cancer Data Base (1998–2005), however, shows that of 97,314 patients with clinically node-negative breast cancer, completion ALND does not appear to improve outcomes for patients with micrometastases when compared with those patients who undergo SLN biopsy alone.6 Although B-32 showed a 1.2 percent decrease in overall survival, chemotherapy would not seem worthwhile for perhaps a 25 percent benefit for these patients. In ACOSOG Z0010, adjuvant systemic therapy did not have a statistically significant association with the outcomes of patients with sentinel node occult metastasis. Five-year overall survival was 96.3 percent without adjuvant systemic therapy versus 95.7 percent with adjuvant systemic therapy; five-year disease-free survival was 91.4 percent versus 91.0 percent.3 At the end of the day, the clinician needs to know how to apply this and how to use it in his or her practice.

Indeed, findings from the Z0010 trial are important and should help guide clinical practice. Many laboratories still perform IHC, even though the College of American Pathologists does not recommend it. Highly sensitive testing of SLNs for micrometastases and bone marrow aspiration does not seem warranted in patients with early-stage breast cancer.

ACOSOG Z0011, a sister study to Z0010, randomized patients with clinical T1-2 N0 M0 breast cancer to ALND or SLN biopsy alone for patients with one or two nodes positive for occult metastasis with no extranodal extension.7 Patients received whole breast radiation therapy and adjuvant systemic therapy. This study showed no significant difference in locoregional control or survival with SLN alone compared with completion ALND.

This study also is markedly changing clinical practice. Z0011 does not support the routine use of ALND in patients with one to two postive nodes undergoing breast-conserving surgery with standard whole breast radiotherapy and adjuvant systemic therapy. In practice, there is little reason to obtain a frozen section on SLNs unless more than two seem suspicious, and many centers prefer to await permanent section results, which can be discussed with the patient postoperatively. Also, there is less reason for breast radiologists to perform ultrasound-guided axillary node biopsy preoperatively because this procedure only demands ALND if imaging suggests multiple node involvement.

Nonetheless, unresolved issues remain, particularly with regard to what to do with the patient with occult SLN metastases who is undergoing a mastectomy, not breast conservation with radiotherapy. A future study might randomize mastectomy patients with one to three nodes positive (N1) disease to observation or ALND and further the observation group to axillary radiation or no radiation.

These clinically relevant ACOSOG trials demonstrate the importance of clinical trials in establishing improved and safer standards of care. Surgeons are encouraged to practice evidence-based medicine, and clinical research provides that evidence. Participation in trials will keep the surgeon at the forefront of new ideas and ensure the outcomes analysis that is so important at this time. Community surgeons are in a perfect position to enroll patients and enhance the image of their practice and institution.

In 2011, ACOSOG, the Cancer and Leukemia Group B, and the North Central Cancer Treatment Group merged into the Alliance for Clinical Trials in Oncology. The purpose is to make these National Cancer Institute-funded cooperative groups more efficient in clinical studies to bring trial results to patients more quickly. Surgeons are strongly encouraged to become members and enroll in trials and educational and skills programs of the Alliance.


References

  1. Weaver DL, Ashikaga T, Krag DN, Skelly JM, Anderson SJ, Harlow SP, Julian TB, Mamounas EP, Wolmark N. Effect of occult metastases on survival in node-negative breast cancer. N Engl J Med. 2011;364(5):412-421.
  2. Leitch AM, Beitsch PD, McCall LM, Posther K, Newman LA, Herndon JE II, Hunt KK, Giuliano AE. Patterns of participation and successful patient recruitment to American College of Surgeons Oncology Group Z0010, a phase II trial for patients with early-stage breast cancer. Am J Surg. 2005;190:539-542.
  3. Giuliano AE, Hawes D, Hunt KK, Ballman KV, Whitworth PW, Blumencranz PW, Reintgen DS, Morrow M, Leitch AM, McCall LM, Abati A, Cote R. Association of occult metastases in sentinel lymph nodes and bone marrow with survival among women with early-stage invasive breast cancer. JAMA. 2011;306(4):385-393.
  4. Tan LK, Giri D, Hummer AJ, Panageas KS, Brogi E, Norton L, Hudis C, Borgen PI, Cody HS III. Occult axillary node metastases in breast cancer are prognostically significant: Results in 368 node-negative patients with 20-year follow-up. J Clin Oncol. 2008;26(11):1803-1809.
  5. De Boer M, van Duerzen CH, van Dijck JA, Borm GF, van Diest PJ, Adang EM, Nortier JW, Rutgers EJ, Seynaeve C, Menke-Pluymers MB, Bult P, Tjan-Heijnen VC. Micrometastases or isolated tumor cells and the outcome of breast cancer. N Eng J Med. 2009;361(7):653-663.
  6. Bilimoria KY, Bentrem DJ, Hansen NM, Bethke KP, Rademaker AW, Ko CY, Winchester DP, Winchester DJ. Comparison of sentinel lymph node biopsy alone and completion axillary node dissection for node-positive breast cancer. J Clin Oncol. 2009;27:2946-2953.
  7. Giuliano AE, Hunt KK, Ballman KV, Beitsch PD, Whitworth PW, Blumencranz PW, Leitch AM, Saha S, McCall LM, Morrow M. Axillary dissection vs. no axillary dissection in women with invasive breast cancer and sentinel node metastasis. JAMA. 2011;305(6):569-575.

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