Abstract
The American College of Surgeons Oncology Group Z0011 trial was designed to investigate the survival outcome of patients with sentinel lymph node (SLN) metastasis of breast cancer treated with complete axillary lymph node dissection (ALND).
The trial opened in 1999, enrolling 891 women with clinical T1–T2 invasive breast cancer with no palpable adenopathy and one or two SLNs containing metastases, which were identified by three techniques: touch preparation, frozen section or hematoxylin-eosin straining on permanent section [1]. Patients were not eligible if their SLN metastasis was only identifiable using immunohistochemistry or if they had three or more positive SLNs [2].
Each of the patients was treated with a lumpectomy and tangential whole-breast irradiation [1]. Patients with SLN metastases diagnosed using sentinel lymph node dissection (SLND) were randomized to either ALND of ten or more nodes, or to no further axillary treatment. Although the clinical and tumor characteristics were similar between these two groups, the average number of nodes removed was much higher in patients randomized to ALND (17 nodes) compared with those randomized to only SLND (two nodes).
Although the trial closed in 2004 due to slow accrual and a lower than expected event rate, the tested patients were followed up approximately 6.3 years post-treatment. In the group of patients randomized to ALND, the 5-year overall survival was 91.8%, whereas in the SLND-alone group the overall survival was 92.5% [1]. In the ALND group, the 5-year disease-free survival rate was 82.2% compared with 83.9% in the SLND-alone group, and the hazard ratio for treatment-related overall survival was 0.79 without adjustment and 0.87 after adjusting for age and adjuvant therapy. Therefore, no significant difference was observed between the ALND group and the SLND-alone group, leading the American College of Surgeons Oncology group to conclude that in patients with clinically node-negative disease who are found to have a positive SLN, the use of ALND is not justified as it does not result in superior survival.
Data interpretation
Some questions raise the difficulty in accruing patients to the Z0011 trial and the high rate of non-SLNs in 27.3% of the ALND patients. Less than 50% of the total number of patients initially planned were randomized and this may influence the power of the study. There are several explanations for why there was no significantly increased risk of locoregional recurrences in the SLND group, including elimination of residual diseases by adjuvant treatment, as well as a relatively short-term follow-up in this study given that longer follow-up is usually required to assess locoregional failures.
Future perspective
After the publication of the Z0011 trial results the fast practice-changing adaption of breast cancer treatment at the Monroe Dunaway (MD) Anderson Cancer Center (TX, USA), which has been ranked number one in cancer care for 7 of the last 9 years, suggests a rapid adaption of several other hospitals, surgeons and oncologists in ALND avoidance for selected patients. However, there is some skepticism regarding the high incidence of positive non-SNLs that may increase risk of ipsilateral axilla nodal recurrence that might be a source of disseminated tumor cells and distant metastasis. Although this risk is not increased in the Z0011 trial, the early close of the trial owing to low accrual and the short follow-up raise some concerns. Since the state-of-the-art adjuvant treatment decisions are based on molecular analysis of the primary tumor and not on the axilla lymph nodes, as for example in tamoxifen and/or an aromatase inhibitor for estrogen receptor or progesterone receptor-positive tumor and trastuzumab for HER2-positive disease, the omission of ALND will not influence adjuvant treatment decision. However, in particularly selected cases with small tumors (pT1) and negative SLND, decision on adjuvant chemotherapy avoidance can be influenced by the risk of residual disease in non-SLNs.
This trend towards less extensive surgery regarding ALND is currently in contrast with a trend for a more aggressive local treatment. Indeed, a dramatic increase in the rates of prophylactic contralateral mastectomy and ipsilateral mastectomy by corresponding reduction of breast-conserving surgery is observed in the USA even by negative BRCA1/2-testing or absence of family history [3].
Promise for personalized treatment of breast cancer with both surgery and adjuvant therapy comes from current and future advances of genomic medicine. Emerging biomedical research using powerful genome-wide mapping technological advances promises the discovery of robust genome-based biomarkers for individualizing therapeutic decisions. Indeed, high density genome-wide techniques in both cancer whole-genome sequencing and understanding how genetic and epigenetic changes dysregulate gene-expression patterns in cancer, provide rational optimism for novel biomarkers-based personalized management of cancer and other common complex diseases [4].
Executive summary
In selected patients with cT1, T2N0 tumor treated with breast-conserving surgery and a positive sentinel lymph node who will receive whole-breast irradiation, the potential of omitting completion axillary lymph node dissection can be considered and discussed with the individual patient.
Women with larger tumors, more than one positive sentinel lymph node, and family with a family history of breast cancer with or without positive BRCA1/2-testing are not eligible for completion axillary lymph node dissection avoidance.
Footnotes
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.