In the past, early stage breast cancer patients have been surgically treated with radical mastectomy and axillary lymph node dissection (ALND), based on the premise that wider resections optimise the chances of cure and provide prognostic information about nodal status. However, this procedure is responsible for functional sequelae with negative impact on quality of life, such as pain, upper limb oedema, and impairment of shoulder mobility as well psychological implications. More recently, randomised clinical trials showed that breast conservative surgery could replace mastectomy without compromising patient’s prognosis and, progressively, ALND has been replaced by sentinel lymph node dissection (SLND). Importantly, advances in early diagnosis methods have helped to identify many breast cancer patients with clinically negative axillary nodes, putting in doubt the real benefit of that surgical approach (ALND).
This matter was first challenged by NSABP B-04 trial, which randomised women with primary operable breast cancer, who had clinically negative axillary nodes, into three groups: 1) radical mastectomy plus ALND; 2) total mastectomy without ALND plus irradiation; and 3) total mastectomy alone, followed by ALND if axillary recurrence. After 25 years of follow-up, there were no significant differences in relapse-free overall survival among study groups. Similar findings were seen on Institut Curie randomised trial, with no difference in long-term survival between ALND and axillary irradiation.
As the understanding of the biology of breast cancer expands, aggressive surgical therapy alone has been considered inadequate and somewhat too aggressive. In addition, improvements in adjuvant chemotherapy regimens and better irradiation techniques have contributed to extremely low regional failure rate and increased long-term disease-free survival observed in these patients. In fact, emerging data support the hypothesis that remaining low burden axillary metastases neither increase the axillary recurrence rate nor compromise overall survival.
Exploring this question, Giuliano et al. conducted ACOSOG Z0011, a phase III non-inferiority clinical trial that included 891 women from 115 sites in the United States. All patients had clinical T1-2 invasive breast cancer candidates for breast conservative surgery, mostly hormone receptor positive (approximately 85%), no clinical palpable adenopathy, and 1 to 2 sentinel lymph nodes (SLNs) positive for metastasis (no hematoxylin-eosin staining alone was allowed). Lumpectomy and tangential whole-breast irradiation were performed for all women. The target population of the study was 1,900 women, with final analysis planned after a total of 500 deaths. However, after many years of recruitment (over 5 years), the independent monitoring committee recommended to stop including patients based on the lower than expected mortality rate.
After SLND and nodal metastasis confirmation, patients were randomised for ALND (n = 445) or no further axillary treatment (n = 446). Adjuvant chemotherapy was at the discretion of the treating physician. There were no differences in the proportion of women receiving endocrine therapy, chemotherapy, or both treatments, in the two arms. Clinical and pathological characteristics were similar between the two groups, except for median number of nodes removed: 17 with ALND and 2 with SNLD alone. At a median follow-up of 6.3 years, 5-year overall survival was 91.8% (95% CI 89.1%-94.5%)with ALND and 92.5% (95% CI 90.0%-95.1%) with SLND alone. Five-year disease-free survival was 82.2% (95% CI 78.3%-86.3%) with ALND and 83.9% (95% CI 80.2%-87.9%) with SLND alone. The hazard ratio for treatment-related overall survival – the primary endpoint of Z0011 – was 0.79 (90% CI 0.56-1.11) without adjustment and 0.87 (90% CI, 0.62-1.23) after adjusting for age and adjuvant therapy. Both values respect the one-sided hazard ratio non-inferiority margin of 1.3, indicating that SLND alone is not inferior to ALND. Notably, none of the four interim analyses were performed and the overall study significance was maintained at 0.05.
Interestingly, 27.3% of patients in the ALND group had additional metastasis in lymph nodes removed by ALND, including 10% of patients with SLN micrometastasis who had macroscopically involved non-SLNs removed. This suggests that about a quarter of patients submitted to SLND alone harboured positive nodes. Despite this data, axillary recurrence was similar between both groups (3.6% with ALND, and 2.5% with SLND alone), and authors suggest it is unlikely that further follow-up would generate differences in recurrence and survival. Also, axillary recurrence seems to be an early event in breast cancer natural history (median of 15 months in some trials and 30 months in others).
Regarding lower-than-expected accrual, an acceptable explanation for this trial limitation would be clinical bias of physicians and patients to standard ALND, as raised by authors, even knowing almost three quarters of patients had no additional positive nodes and extensive nodal disease was infrequent.
These findings also raise important questions regarding the number of positive lymph nodes. Previous studies have showed that lymph node ratio (LNR), defined as the number of positive nodes divided by the number of examined nodes, has recently been proposed to be a better prognostic factor than the number of positive nodes, though acknowledgements on surgical procedures morbidities are made. Whether this will have implications on patient’s outcome and treatment decision is still unknown. Notably, in the era of dissecting breast cancer disease in four major subtypes (luminal A and B, HER2 positive and basal like tumours), and knowing that some subtypes are more prone to develop locoregional relapses, the absence of information on HER2 status limits the observation to which subgroup of patients may derive the most benefit from this surgical approach.
In summary, patients carrying good prognosis tumours and presenting SLND positive for metastasis, treated with lumpectomy, followed by adjuvant chemotherapy and radiation therapy, may not need axillary dissection and may obtain excellent locoregional control and similar survival rates compared to ALND. However, the subgroup of patients who would fall into this benefit category is yet to be defined. Prognostic information gained from ALND is obtained at the cost of a significant increase in morbidity, as mentioned above, impacting on quality of life. However, because this is the first and only trial, which has been prematurely stopped after the inclusion of less than 50% of the planned sample population, the data should be view with caution. In the era of personalised medicine, discussion with surgeons, pathologists, medical oncologists and particularly patients, should prevail. Even if a patient is to be considered suitable for this “less aggressive” surgical strategy, this patient must fulfil the inclusion criteria used in the present trial and this strategy should not be applied to all patients.