|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Originally published as JCO Early Release 10.1200/JCO.2009.23.0086 on August 31 2009 © 2009 American Society of Clinical Oncology.
If Sentinel Node Micrometastases Are the Question, Are Clinical Trials the Answer?Allegheny General Hospital, Pittsburgh, PA Even with the technologic advances in breast cancer diagnosis and care to date, the presence of axillary node metastases is still valued as the significant prognostic factor in determining outcomes in early-stage disease. For staging the majority of patients with breast cancer over the past decade, there has been a transition from routine axillary node dissection (AND) to the use of sentinel node biopsy (SNB) and selective AND in patients with positive sentinel nodes. The use of SNB now saves many patients with early-stage breast cancer the unnecessary morbidities of an AND. At the same time, closer examination of the SN has generated the increased detection of positive nodes through the identification of isolated tumor cell metastases, pN0 (i+; known as nanometastases), and micrometastases (pN1mi). Despite, or perhaps in part because of, numerous publications and nomograms from breast surgeons attempting to address the question of the need of completion AND, the presence of these putative amounts of metastatic disease of unknown bearing have wreaked havoc with medical oncologists. The need to treat patients with micrometastases with systemic adjuvant chemotherapy beyond what is required for node-negative (pN0) disease is complicated by the known toxicities of chemotherapy, where benefit must outweigh risk. Information available about the use of SNB for the most part is burdened by reports of small numbers of patients and confounded by mixed systemic adjuvant treatments with short follow-up using retrospective data. There is a need to determine whether sentinel node metastases other than macrometastases affect long-term patient outcomes. In this issue of Journal of Clinical Oncology, Hansen et al1 report on their effort to determine the impact of micrometastases in 790 sentinel node patients with early-stage, invasive breast cancer from a single institution. Patients were stratified into four groups based on the size of SNB metastases according to American Joint Commission on Cancer sixth edition staging system (pN0, pN0 [i+], pN1mi, and pN1). A majority of the patients received some form of systemic therapy. Factors that could be predictive of outcome were determined. At 72.5 months follow-up, SN metastasis size was a significant predictor of disease-free survival (DFS) and overall survival (OS), but only for the patients with macrometastases. Multivariate analysis identified SN macrometastases, tumor size, and histologic type as predictors for DFS. Macrometastases, patient age, and receptor status were predictive of OS. In this report, the impact of adjuvant system therapy or the low volume effect of metastases could not be measured. It is possible that benefit could result over time in the nano- and micrometastases groups, but this study has follow-up of only 8 years and no way to address untreated groups. Although use of SNB has improved staging in patients with early breast cancer, the prognostic significance of micrometastases and nanometastases is fuel for many debates. Pre-SNB era studies are limited by the minimal evaluation of lymph nodes based on single-slide hematoxylin and eosin (H&E) evaluations, each part of a bivalved node.2 Today, sentinel nodes undergo methodic serial sectioning from 50- to 250-µm intervals with both H&E and immunohistochemical (IHC) staining. This has resulted in increased detection of micrometastases and nanometastases and in staged migration.3–5 In addition, systemic adjuvant treatment has greatly improved with the use of endocrine therapy, anthracycline-based regimens, and targeted therapies, so that patients with less disease whose breast cancer is treated aggressively today have outcomes different from patients treated even several years ago. Thus, it may be difficult to actually determine the prognostic value of different degrees of micrometastatic disease. Current studies continue to propagate the controversy over the significance of both nano- and micrometastatic disease, some claiming they have no prognostic significance, some that pN1(mi) but not pN0(i+) are prognostic, and some that both are prognostic.6–9 Questions have also arisen over the possible predictive significance of menopausal status, as well as the addition of systemic therapy in nano- and micrometastatic disease. What answers we have are conflicting. To clarify these outcomes, two large and important SN clinical trials have completed accrual and are in follow-up. The National Adjuvant Breast and Bowel Project (NSABP) launched NSABP B-32, which randomly assigned 5,611 patients to SNB with a mandatory AND or to SNB with AND for positive SNB only. There was a 26% positive SN rate by H&E in both arms of this trial. The negative SN of 3,889 patients are currently undergoing IHC analysis in a blinded review at the University of Vermont. Systemic treatment for these patients was based solely on primary tumor characteristics by investigators. Primary outcome results of OS and DFS will be linked to the SN IHC analysis when those outcome data are available. The second trial, the American College of Surgeons Oncology Group's (ACOSOG) study Z0010 prospectively enrolled 5,539 patients. Sentinel nodes were evaluated by H&E, and the SNB-positive rate was 24%. Slides of the negative SN for 3,738 patients have undergone central IHC analysis. As in B-32, investigators were blinded to the IHC results, and systemic therapy was based on primary tumor characteristics. This trial is in follow-up status pending OS and DFS outcomes that will also be linked to the IHC analysis. Results from both NSABP B-32 and ACOSOG Z0010 are expected to provide critical outcome data on patients with nano- and micrometastatic disease that has been systemically treated or not and to determine the clinical significance of the nodal disease. These outcomes, eagerly awaited, may help realistically guide systemic therapies. These data are due to mature in the next 6 to 18 months. As technology has progressed to the molecular level, long-term outcomes based on technology like OncotypeDx (Genomic Health, Redwood City, CA) and other multigene assays are establishing recommendations for systemic therapies.10–13 Perhaps as clinical trials more fully embrace molecular diagnostics used in trials such as TAILORx (Trial Assigning IndividuaLized Options for Treatment) and MINDACT (Microarray In Node-negative Disease may Avoid ChemoTherapy) to better determine predictors of outcome based on primary tumor biology, physicians will be able to apply the resulting data to systemically treat patients in a more selective and effective manner. This will likely move breast cancer therapy away from the "Shrine of the Holy Node," as the late Edwin Fisher, MD, used to say, and continue the retreat away from Halstedian therapy. AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a"U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: Thomas B. Julian, Veridex (C) Stock Ownership: None Honoraria: Thomas B. Julian, Veridex Research Funding: None Expert Testimony: None Other Remuneration: None REFERENCES
1. Hansen NM, Grube B, Ye X, et al: Impact of micrometastases in the sentinel node of patients with invasive breast cancer. J Clin Oncol 27:4679–4684, 2009. 2. International (Ludwig) Breast Cancer Study Group. Prognostic significant of occult axillary lymph node micrometastases from breast cancers. Lancet 335:1565–1568, 1990.[CrossRef][Medline] 3. Cote RJ, Peterson HF, Chaiwun B, et al: Role of immunohistochemical detection of lymph-node metastases in management of breast cancer: International Breast Cancer Study Group. Lancet 354:896–900, 1999.[CrossRef][Medline] 4. Nasser IA, Lee AK, Bosari S, et al: Occult axillary lymph node metastases in "node-negative" breast carcinoma. Hum Pathol 24:950–957, 1993.[CrossRef][Medline] 5. Cserni G: Metastases in axillary sentinel lymph nodes in breast cancer as detected by intense histopathological work up. J Clin Pathol 52:922–924, 1999.[Abstract] 6. Chen SL, Hoehne FM, Giuliano AE: The prognostic signficiance of micrometastases in breast cancer: A SEER population-based analysis. Ann Surg Oncol 14:3378–3384, 2007.[CrossRef][Medline] 7. Colleoni M, Rotmensz N, Peruzzotti G, et al: Size of breast cancer metastases in axillary lymph nodes: Clinical relevance of minimal lymph node involvement. J Clin Oncol 23:1379–1389, 2005. 8. Cox CE, Kiluk JV, Riker AI, et al: Significance of sentinel node micrometastases in human breast cancer. J Am Coll Surg 206:261–268, 2008.[CrossRef][Medline] 9. Gobardhan PD, Elias SG, Madsen EVE, et al: Prognostic value of micrometastases in sentinel lymph nodes of patients with breast carcinoma: A cohort study. Ann Oncol 20:41–48, 2009. 10. Paik S, Tang G, Shak S, et al: Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer. J Clin Oncol 24:3726–3734, 2006. 11. Paik S, Shak S, Tang G, et al: Expression of the 21 genes in the recurrence score assay and tamoxifen clinical benefit in the NSABP study B-14 of node-negative, estrogen receptor-positive breast cancer. J Clin Oncol 23:6s; 2005 abstr 510. 12. van't Veer LJ, Dai H, van de Vijver MJ, et al: Gene expression profiling predicts clinical outcome of breast cancer. Nature 412:530–536, 2002.[CrossRef] 13. van de Vijver, He YD, van't Veer LJ, et al: A gene-expression signature as a predictor of survival in breast cancer. N Engl J Med 347:1999–2009, 2002.
Related Article
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
