Micrometastases Mangement


Background: Sentinel lymph node biopsy (SLNB) is now the standard of care used in the staging of the regional lymph nodes in breast cancer. As result of the wide adoption of SLNB attention turned into a detailed examination of the biopsied lymph node(s) and subsequent rise in the incidence of finding lymph node micrometastases. Micrometastases(pN1mi) is defined as a metastatic disease in the lymph node that is less than 2.0 mm but larger than 0.2mm. Isolated tumor cells (ITC) is defined as a metastatic disease in the lymph node that is smaller or equal to 0.2mm. With the rise of incidence of axillary micrometastases, there is a considerable debate on the prognostic significance and appropriate treatment recommendations for such patients.

Axillary lymph node dissection is not indicated when micrometastases is seen in SLNB

On this blog post, I will try to cover the current understanding and treatment recommendations by answering the following questions.

Is there any prognostic significance of finding axillary lymph node micrometastatic disease(pN1mi)? The short answer is definitely yes. While some older (predating the era of SLN biopsy) studies did not show the prognostic significance of micrometastases disease on either local recurrence or overall survival, all recently published studies indicate a worse prognosis for pN1mi when compared to pN0. The Swedish Sentinel Node Multicenter study was a large prospective multicenter study performed to evaluate local recurrence among pN0, pN1mi, pNitc, pN1. There was poor survival in patients with pN1mi compared to pN0, and the poor survival of patients with pN1mi was approaching that of pN1 with most of the worse survival outcomes noted in premenopausal women. In another review, M de Boer et al reviewed multiple cohort studies and concluded that pN1mi is associated with poorer disease-free survival (DFS) and overall survival (OS). Also, the NSABP B-32 study further confirmed poor DFS, and OS in patients with micrometastases, the study also showed that systemic therapy and particularly endocrine therapy along with radiation therapy appear to ameliorate such unfavorable outcome, something that I will discuss below.

Is axillary lymph node dissection (ALND) is required for patients with pN1mi? The answer is No, the NCCN guidelines do not recommend ALND for pN1mi, England association of breast surgery 2015 consensus statement do not recommend ALND in patients with pN1mi. In the IBCSG 23-01 trial investigators prospectively randomized pN1mi into either ALND or no ALND dissection, there was no difference in either DFS or OS with higher incidence of lymphedema and sensory neuropathy in the ALND, however, there was one interesting observation, there was a none SLN metastatic disease found in 13% of the ALND arm, the authors explain the still equal outcome of both arm on the role of systemic therapy.

Is chemotherapy is recommended for patients with pN1mi? The answer is extremely complex as I will try to explain. A. in the      MIRROR  (Micrometastases and Isolated Tumor Cells: Relevant and Robust or Rubbish?) this was retrospective cohort study, investigators came up with the following results,

  • Both pN1mi and isolated tumor cells tumors are associated with poor DFS compared to pN0.
  • Systemic adjuvant therapy (both endocrine and chemotherapy) improved outcome in pN1mi and isolated tumor cells.

B. In another large retrospective cohort study Mittendorf et al, demonstrated equal survival between stage IA (pT1N0) vs. stage IB(pT1N1mi), however, a large proportion of IB disease received chemotherapy, 70.5% in the pT1N1mi vs. 26.9% in pT1N0. The authors admit that this may be the reason for the observed outcome.

What I can conclude from A. and B.  and others would be the following,

  • Systemic therapy (endocrine and chemotherapy) does indeed improve outcome in patients with the pN1mi disease.
  • Both A. and B. or any other study up to date was not able to define with specificity which ER-positive patients with pN1mi can be spared chemotherapy, for example, pre vs. postmenopausal.
  • Not A. or B. or any other study up to date was able to utilize gene profile assay to define specific ER-positive patients with pN1mi who would benefit the most of the chemotherapy or can be spared chemotherapy.

Is nodal irradiation is recommended for patients with pN1mi? The answer is No. While no single study or review addressed that question specifically it is safe to say that the answer is no based on the MA.20 study, where it was shown that regional nodal irradiation plus whole breast irradiation in early-stage breast cancer (node positive were included) did not add any OS benefit.

Does whole breast radiation offer benefit for pN1mi? The answer is yes. While no single study or review addressed that question specifically it is safe to say that the answer is yes based on the Z11 study, where specific patients with small nodal burden were spared ALND but given whole breast radiation and systemic therapy.

Conclusion, based on my discussion above, there is clear need for randomized prospective trials to identify patients with pN1mi who would benefit from chemotherapy and who can be spared chemotherapy. As of this date, the NCCN guidelines recommend ER-positive patients with  T1N1mi to receive chemotherapy (category 2B)

As always refer to terms of use here