Breast cancer axillary lymph node management

Ipsilateral regional nodal status is an important independent prognostic factor for patients with breast cancer.

The 5-year survival rates can range from less than 65% for patients with more than four involved axillary lymph nodes to greater than 95% for breast cancer patients with pathologically negative nodal disease.

The National surgical Adjuvant Breast and Bowel Project (NSABP-04: patients with clinically negative node breast cancer were randomly assigned to one of three groups-radical mastectomy, total mastectomy with radiation, or total mastectomy alone.

In clinically node negative patients there was no difference in any of the groups in disease-free or overall survival, and no difference in survival for those patients who develop clinically evident axillary disease on follow up and subsequently underwent axillary dissection.

In the same study in patients who are clinically node positive randomly assigned to either radical mastectomy or total mastectomy with radiation, there was no difference in disease-free overall survival.

Axillary lymph node dissection (ALND) with removal of level I–II axillary nodes was previously standard surgical management for early breast cancer.

Sentinel lymph node biopsy (SLNB) is now the standard axillary procedure for T1-T2 clinically node-negative disease.

The role of SLNB in patients with large, locally advanced node-negative breast cancer (T3-T4 lesions) is not yet clear.

In general, ALND is recommended both for these patients and for those with clinically involved axillary nodes.

Two decisions are required for local therapy in clinically node-negative patients who are found to have pathologically involved SLN(s).

The first involves evaluation of the need for additional axillary treatment to establish local control, none vs ALND vs axillary radiation.

The second concerns the need for radiation therapy, including possible treatment to regional nodes and the chest wall.

Isolated tumor cells are clusters of tumor cells no greater than 0.2 mm, or 200 cells, occurring in axillary regional lymph node(s).

Tumor cell clusters can be identified by hematoxylin and eosin stain or immunohistochemistry.

According to the TNM staging system, isolated tumor cell clusters are designated as pN0(i+).

pN0(+) Stage includes positive molecular findings (by PCR) in the absence of regional lymph node metastases detected by histology or immunohistochemistry.

Patients with isolated tumor cell clusters in axillary lymph nodes appear to do as well as those with N0 disease, and decisions regarding systemic therapy, surgery, and radiotherapy for these patients should match those for node-negative patients.

Historically, patients with any nodal metastasis noted on SLNB underwent completion ALND.

Fewer than 40% of patients were found to have additional pathologically involved axillary lymph nodes on ALND.

Omission of ALND in many patients with node-positive breast cancer treated with breast conservation surgery (BCS) and adjuvant whole-breast radiation therapy (WBRT) does not compromise oncologic outcomes.

In the American College of Surgeons Oncology Group (ACOSOG) Z0011 trial, 891 patients with T1-T2 clinically node-negative breast cancer and one or two positive sentinel nodes, who were undergoing BCS followed by WBRT, were randomized to completion ALND after SLNB or SLNB alone: similar 5-year overall survival (OS) and disease-free survival (DFS) in the ALND and SLNB-alone arms, with no difference in 10-year cumulative incidence of locoregional recurrences between the two arms was demonstrated(6.2% for ALND, 5.3% for SLNB alone.

In the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-04 study, patients without lymph node dissection, who had a predicted risk of harboring axillary disease of about 40%, developed local recurrences in that region only 20% of the time.

The International Breast Cancer Study Group (IBCSG) 23-01 trial assigned 931 patients with T1-T2 clinically node-negative breast cancer and micrometastases seen on SLNB (N1mi) to either completion ALND or no further surgical intervention (SLNB alone). Similar to the Z0011 study, the IBCSG study found no significant difference in DFS and OS between the ALND and SLNB-alone groups.

The European Organization for Research and Treatment of Cancer (EORTC) After Mapping of the Axilla: Radiotherapy or Surgery? (AMAROS) trial: randomized T1-T2 clinically node-negative patients with a positive SLNB to completion dissection vs no further surgery. Unlike the Z0011 study, in AMAROS the radiation fields were required to include draining lymph nodes of the undissected axilla, as well as the supraclavicular region. Similar to the results of the Z0011 trial, aggressive surgery conferred no benefits in terms of local control, DFS, or OS.

Currently standard of care is to omit ALND for many patients with low-volume axillary nodal disease who undergo breast conservative therapy.

Presently practice guidelines state that ALND should not be recommended for women with T1-T2 (≤ 5 cm) breast cancer who have one or two SLN metastases and will receive BCS with conventionally fractionated WBRT.

Omission of ALND should be applied cautiously in patients with tumors larger than 5 cm or gross extranodal extension.

Patients with a positive SLNB and >5 cm tumors who do not have absolute indications for radiotherapy should undergo ALND.

Additional prospective trials are needed to validate whether node-positive patients undergoing mastectomy without radiation are candidates for SLNB alone.

Completion ALND for mastectomy patients with a positive SLNB remains the standard of care, with the exception of situations where there are indications for postmastectomy radiation therapy (PMRT) based on existing pathology.

In the SENOMAC trial the omission of completion of axillary lymph node dissection was noninferior to more extensive surgery in patients with clinically node negative breast cancer, who had sentinel node macro metastasis, most of whom received nodalradiation therapy.

Completion ALND is generally recommended for patients with T3-T4 disease and/or three or more positive SLNs.

Completion ALND is also recommended for patients who have one or two positive SLNs but will not undergo WBRT.

High-risk features that impact axillary surgery are the presence of extranodal extension of disease as it is associated with increased axillary nodal disease burden.

The ACOSOG Z0011 trial reported nonsentinel nodal metastases in 27% of patients, and the reported incidence of nonsentinel nodal metastases in patients with extranodal extension ranges from 58% to 84%.

It is recommended that ALND be considered in patients with sentinel node gross extranodal extension.

In the subset of T1-T2/N1mi-N1 breast cancers, high-risk factors include: extranodal extension, young age, negative hormone receptor status, high histologic grade, lymphovascular space invasion, and size of nodal metastatic deposit may be indicators of nonsentinel node involvement.

Studies have demonstrated that addition of regional nodal irradiation to whole breast, with lumpectomy, or chest wall fields, with mastectomy, in patients with node-positive disease reduces locoregional recurrence.

Although reduction in locoregional recurrence was noted in all trials, improvement in overall survival and breast cancer–specific survival rates was not noted uniformly across trials.

The Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) analysis demonstrated a relationship between local disease control and 15-year breast cancer mortality.

The Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) Indicated for every four local recurrences avoided, one breast cancer death over the next 15 years was avoided.

There was little difference in 15-year breast cancer mortality in situations where local treatment comparisons produced < 10% difference in 5-year local recurrence risk.

High axillary nodal disease burden (≥ N2 disease)

The absolute benefit of improvement in the rates of locoregional recurrence and overall survival from radiotherapy in patients with node-positive disease is dependent on the baseline risk of locoregional recurrence, which in turn is influenced to a large degree by the number of involved axillary nodes.

Meta-analyses of intergroup trials and EBCTCG review have shown that presence of four or more positive axillary lymph nodes, N2 and N3 disease, is associated with significantly increased risk of locoregional recurrence.

In the management of N2 or N3 disease, and the American College of Radiology guidelines recommend regional nodal irradiation for these patients.

Intermediate axillary nodal disease burden (T1-T2/N1 disease) the AMAROS comparing ALND against axillary node irradiation in 1,425 patients with T1-T2 clinically node-negative breast cancer and a positive SLNB.

Radiation fields were required to include draining lymph nodes of the undissected axilla as well as the supraclavicular region: results- there was no benefit for ALND over axillary irradiation in terms of local control, DFS, or OS.

By omitting ALND was a significant reduction in the rates of clinical lymphedema at 5 years, with 11% for radiation vs 23% for axillary dissection.

In general, radiation to the level I and II axilla in all patients who omit ALND is supported.

The National Cancer Institute of Canada MA.20 trial randomly assigned lumpectomy-treated patients mainly with one to three positive nodes (although 10% were high-risk node-negative and 5% had more than three positive nodes) to either WBRT or WBRT plus RNI.

This trial demonstrated a significant improvement with addition of regional nodal irradiation in 10-year locoregional recurrence–free survival, an absolute improvement of 3%, disease free survival, absolute improvement of 5% and distant disease-free survival, absolute improvement of 4%, but not in overall survival

The EORTC 22922 trial included lumpectomy and mastectomy patients with primarily N0 or N1 disease and similarly showed significant improvement in DFS, absolute improvement of 3%, distant DFS, absolute improvement of 3%), and breast cancer–specific mortality absolute improvement of 1.9%, with addition of regional nodal irradiation to radiation to the breast/chest wall.

The EORTC 22922 trial showed no improvement in OS.

It is important to identify subsets of patients for whom rates of locoregional recurrence are sufficiently low so as to permit the omission of regional nodal irradiation.

A greater treatment effect for regional nodal irradiation was noted in patients with estrogen receptor (ER)-negative disease, compared with patients with ER-positive disease.

Hormone receptor status should be strongly weighed in the decision to treat with comprehensive nodal radiation.

In the analysis from NSABP B-28 demonstrated that lumpectomy patients with hormone receptor–positive, node-positive breast cancer who receive WBRT and contemporary adjuvant chemotherapy plus endocrine therapy have a low 11-year rate of locoregional recurrence (6.5%).

The Oncotype DX 21-gene recurrence score and others predict risk of breast cancer recurrence and aid in systemic therapy decisions for patients with hormone receptor–positive disease.

Gene expression assays can independently predict locoregional recurrence.

Investigators from the NSABP B-28 trial recently reported locoregional recurrence to be associated with the 21-gene recurrence score in ER-positive, node-positive patients treated with adjuvant chemotherapy plus tamoxifen.

Recurrence score was a statistically significant predictor of locoregional recurrence, with 10-year cumulative incidence rates at 3.3%, 7.2%, and 12.2% for low, intermediate, and high recurrence scores, respectively.

In multivariable regression analysis, recurrence score remained an independent predictor of locoregional recurrence, along with pathologic nodal status and tumor size.

Additional factors beyond hormone receptor status, such as age, histologic grade, lymphovascular invasion, extranodal extension, size of node metastasis, and tumor size, have been reported to be associated with risk of locoregional recurrence and are considered in regional nodal irradiation decision making for individual patients.

Randomized trials suggest that Postmastecomy radiation therapy improves outcomes for patients with T1-T2 breast cancer and one to three positive lymph nodes; however, controversy exists regarding the applicability of these older studies to patients treated in the modern era.

Rates of locoregional recurrence in the control arm which patients did not receive radiation, in the historical PMRT trials and overview analyses are considerably higher (21%) than those reported in more recent adjuvant trials such as NSABP B-28 (7.2%).

Retrospective data also suggest that PMRT may not benefit patients with N1 disease treated in the modern era.

A retrospective study reported locoregional recurrence rates in patients with T1-T2/N1 breast cancer treated with mastectomy and adjuvant chemotherapy with or without Post mastectomy radiation therapy during an early era (1978–1997) and a later era (2000–2007).

PMRT reduced the rate of locoregional recurrence in the early cohort (5-year rate of 9.5% without PMRT and 3.4% with PMRT).

It did not appear to benefit patients treated in the later cohort, with very low 5-year rates of 2.8% without PMRT and 4.2% with PMRT.

This decrease in local recurrence rates is thought to be multifactorial; improvement in adjuvant systemic therapy and from more sensitive clinical and pathologic nodal staging.

Given the low event rates noted for the average patient with N1 breast cancer in the modern era, there is unlikely to be a significant survival advantage from adding PMRT for unselected N1 patients.

PMRT decisions in mastectomy patients with one to three positive nodes require consideration of hormone receptor status, tumor biology, and high-risk factors.

In candidates for PMRT, comprehensive radiation to include the supraclavicular region and internal mammary nodes is recommended, based on trials that have shown that this approach yields a significant improvement in disease free survival.

Neoadjuvant chemotherapy has resulted in DFS and OS rates equivalent to those achieved with adjuvant chemotherapy, while yielding a 10% to 30% increase in eligibility for breast conservation treatment.

Response to neoadjuvant chemotherapy represents an additional indicator of prognosis, with pathologic complete response (pCR) in the primary tumor and lymph nodes being associated with significantly improved disease free survival and overall survival.

In the NSABP B-18 and B-27 trials, patients treated with neoadjuvant chemotherapy had a 30% to 40% reduction in axillary node positivity compared with those who received adjuvant chemotherapy.

The ability of neoadjuvant chemotherapy to reduce the extent of axillary disease adds complexity to local therapy decision making.

For patients with clinically node-negative disease, SLNB following neoadjuvant chemotherapy is considered an acceptable approach.

Sentinel node identification and false-negative rates for SLNB after neoadjuvant chemotherapy are similar to those obtained with SLNB at the time of primary surgery.

Patients with clinically node-negative disease and negative SLNB after neoadjuvant chemotherapy do not require further axillary treatment.

In the SENOMAC trial patients who had early stage, node negative breast cancer with one or two macrometastases assigned to completion axillary  lymph node dissection or its omission and receiving standard radiation found no statistical advantage with completion axillary lymph node dissection over sentinel node biopsy only, with regard to recurrence free survival.

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