Context Sentinel lymph node dissection (SLND) accurately identifies nodal metastasis of early breast cancer. Objective To determine the impact of complete axillary lymph node dissection (ALND) on survival of patients with sentinel lymph node (SLN) metastasis of breast cancer. Design and Setting The 115 sites participating in the American College of Surgeons Oncology Group Z0011 trial enrolled patients from May 1999 to December 2004. In this phase III noninferiority trial, patients with SLN metastasis were randomized to ALND or no further axillary treatment. Targeted enrollment was 1900 women, with final analysis after 500 deaths, but the trial closed early because mortality rate was lower than expected. Patients Women with clinical T1–T2 invasive breast cancer, no palpable adenopathy, and 1–2 SLNs containing metastases identified by frozen section, touch preparation, or hematoxylin and eosin staining on permanent section. Interventions All patients underwent lumpectomy and tangential whole-breast irradiation. Those randomized to ALND underwent dissection of ≥10 nodes. Systemic therapy was at the discretion of the treating physician. Main Outcome Measures Overall survival (OS) was the primary endpoint, with a noninferiority margin of a one-sided hazard ratio of 1.3 or less favoring ALND. Disease-free survival (DFS) was a secondary endpoint. Results Clinical and tumor characteristics were similar between 445 patients randomized to ALND and 446 randomized to SLND alone. However, the median number of nodes removed was 17 with ALND and 2 with SLND alone. At a median follow-up of 6.3 years (last follow-up date 03/04/2010), 5-year OS was 91.8% (95% CI: 89.1 to 94.5) with ALND and 92.5% (95% CI: 90.0 to 95.1) with SLND alone; 5-year DFS was 82.2% (95% CI: 78.3 to 86.3) with ALND and 83.9% (95% CI: 80.2 to 87.9) with SLND alone. Hazard ratio for treatment-related OS was 0.79 (90% CI: 0.56 to 1.11) without adjustment and 0.87 (90% CI: 0.62 to 1.23) after adjusting for age and adjuvant therapy. Conclusions Among patients with limited SLN metastatic breast cancer treated with breast conservation and systemic therapy, the use of SLND compared with ALND did not result in inferior survival.

ACOSOG Z0011) trial were first reported in 2005 with a median follow-up of 6.3 years. Longer follow-up was necessary because the majority of the patients had estrogen receptor-positive tumors that may recur later in the disease course (the ACOSOG is now part of the Alliance for Clinical Trials in Oncology).OBJECTIVE To determine whether the 10-year overall survival of patients with sentinel lymph node metastases treated with breast-conserving therapy and sentinel lymph node dissection (SLND) alone without axillary lymph node dissection (ALND) is noninferior to that of women treated with axillary dissection. DESIGN, SETTING, AND PARTICIPANTSThe ACOSOG Z0011 phase 3 randomized clinical trial enrolled patients from May 1999 to December 2004 at 115 sites (both academic and community medical centers). The last date of follow-up was September 29, 2015, in the ACOSOG Z0011 (Alliance) trial. Eligible patients were women with clinical T1 or T2 invasive breast cancer, no palpable axillary adenopathy, and 1 or 2 sentinel lymph nodes containing metastases.INTERVENTIONS All patients had planned lumpectomy, planned tangential whole-breast irradiation, and adjuvant systemic therapy. Third-field radiation was prohibited. MAIN OUTCOMES AND MEASURESThe primary outcome was overall survival with a noninferiority hazard ratio (HR) margin of 1.3. The secondary outcome was disease-free survival. RESULTS Among 891 women who were randomized (median age, 55 years), 856 (96%) completed the trial (446 in the SLND alone group and 445 in the ALND group). At a median follow-up of 9.3 years (interquartile range, 6.93-10.34 years), the 10-year overall survival was 86.3% in the SLND alone group and 83.6% in the ALND group (HR, 0.85 [1-sided 95% CI, 0-1.16]; noninferiority P = .02). The 10-year disease-free survival was 80.2% in the SLND alone group and 78.2% in the ALND group (HR, 0.85 [95% CI, 0.62-1.17]; P = .32). Between year 5 and year 10, 1 regional recurrence was seen in the SLND alone group vs none in the ALND group. Ten-year regional recurrence did not differ significantly between the 2 groups.CONCLUSIONS AND RELEVANCE Among women with T1 or T2 invasive primary breast cancer, no palpable axillary adenopathy, and 1 or 2 sentinel lymph nodes containing metastases, 10-year overall survival for patients treated with sentinel lymph node dissection alone was noninferior to overall survival for those treated with axillary lymph node dissection. These findings do not support routine use of axillary lymph node dissection in this patient population based on 10-year outcomes.

Solid cancer cells commonly enter the blood and disseminate systemically but are highly inefficient at forming distant metastases for poorly understood reasons. We studied human melanomas that differed in their metastasis histories in patients and in their capacity to metastasize in NSG mice. All melanomas had high frequencies of cells that formed subcutaneous tumours, but much lower percentages of cells that formed tumours after intravenous or intrasplenic transplantation, particularly among inefficient metastasizers. Melanoma cells in the blood and visceral organs experienced oxidative stress not observed in established subcutaneous tumours. Successfully metastasizing melanomas underwent reversible metabolic changes during metastasis that increased their capacity to withstand oxidative stress, including increased dependence upon NADPH-generating enzymes in the folate pathway. Anti-oxidants promoted distant metastasis in NSG mice. Folate pathway inhibition using low-dose methotrexate, ALDH1L2 knockdown, or MTHFD1 knockdown inhibited distant metastasis without significantly affecting the growth of subcutaneous tumors in the same mice. Oxidative stress thus limits distant metastasis by melanoma cells in vivo.

Background and Objective Sentinel lymph node dissection (SLND) has eliminated the need for axillary dissection (ALND) in patients whose sentinel node (SN) is tumor-free. However, completion ALND for patients with tumor-involved SNs remains the standard to achieve locoregional control. Few studies have examined the outcome of patients who do not undergo ALND for positive SNs. We now report local and regional recurrence information from the American College of Surgeons Oncology Group (ACOSOG) Z0011 trial. Methods ACOSOG Z0011 was a prospective trial examining survival of patients with SN metastases detected by standard H&E who were randomized to undergo ALND after SLND versus SLND alone without specific axillary treatment. Locoregional recurrence was evaluated. Results There were 446 patients randomized to SLND alone and 445 to SLND + ALND. Patients in the two groups were similar with respect to age, Bloom-Richardson score, estrogen receptor status, use of adjuvant systemic therapy, tumor type, T stage, and tumor size. Patients randomized to SLND + ALND had a median of 17 axillary nodes removed compared to a median of only 2 SN removed with SLND alone (P < 0.001). ALND also removed more positive lymph nodes (P < 0.001). At a median follow-up time of 6.3 years, there were no statistically significant differences in local recurrence (P = 0.11) or regional recurrence (P = 0.45) between the two groups. Conclusion Despite the potential for residual axillary disease after SLND, SLND without ALND can offer excellent regional control and may be reasonable management for selected patients with early stage breast cancer treated with breast-conserving therapy and adjuvant systemic therapy.

In trial Z0011, the use of SLND + ALND resulted in more wound infections, axillary seromas, and paresthesias than SLND alone. Lymphedema was more common after SLND + ALND but was significantly different only by subjective report. The use of SLND alone resulted in fewer complications.