"Never doubt that a small group of thoughtful, committed citizens can change the world. Indeed, it is the only thing that ever has."

Margaret Mead
Review article
peer-reviewed

Management of the Positive Axilla in 2017



Abstract

The role of surgery in breast cancer treatment and axillary staging is changing. It is not very far from today, when axillary dissection was the standard treatment and staging procedure for all stages of breast cancer. Today, we are on the edge of omitting axillary dissection even in patients with the axillary disease. In this review, we walked through the changes in axillary management throughout the past hundred years.

Introduction & Background

Almost 100 years ago, routine removal of the axillary nodes in what is known as an axillary dissection (AD) became part of the standard surgical treatment of breast cancer after the publication of the autopsy studies performed by the German pathologist Rudolf Virchow’s (1821-1902). Virchow hypothesized that breast cancer had a centrifugal expansion invading first the axillary nodes and spreading to other sites after exceeding axillary nodal station’s loading capacity [1-2]. Soon after, William Stewart Halsted (1852-1922), one of the famous American surgeons at the time, based his "Radical Mastectomy" technique on Virchow's theory and argued that local structures should be extirpated as much as possible to reduce the recurrence risk [3]. From that time on, surgeons treated early stage breast cancer by removing both the whole breast and the axillary contents for almost a century.

Review

Despite the extensiveness of the surgery, the treatment results were far from being satisfying. One-third of clinically node negative patients had a relapse after MRM and only 18% of breast cancer patients had an annual death rate similar to the age-matched healthy population’s rate [4]. It was obvious that locoregional treatment of the disease was not sufficient for most patients and researchers turned their interest towards studies on systemic therapies. Meanwhile, they also started questioning the extent of surgery for early stage breast cancer. In the 80s, two large studies namely the NSABP-B04 and the King's-Cambridge trials published their 10-year follow-up results after comparing AD plus radiotherapy (RT) with no treatment to the axilla in clinically node-negative patients [5-6]. In both studies, treating the axilla did decrease the recurrence rate significantly (1.4% for AD, 3.1% for RT, and 14% for no treatment), but did not improve the survival rate in early stage breast cancer patients.

The NSABP-B04 trial also reported a 40% metastatic rate on final pathology in clinically node-negative patients but if the axilla did not receive any local treatment only a 15% axillary recurrence was identified [5]. After 1990s with breast cancer screening programs becoming more widely used, the rate of axillary positivity decreased to 22% [7]. AD, however, became an essential staging procedure enabling stratification of the patients to the appropriate adjuvant treatment. This procedure, however, also exposes 78% of early stage breast cancer patients to overtreatment with a 16% risk of lymphedema in five years [8]. With the appearance of the lymphatic mapping technique, three seminal studies, MILAN, NSABP-B32, and ALMANAC trials established sentinel lymph node biopsy (SLNB), a much less invasive procedure, as the new standard for staging of the axilla [9-12]. In all three studies, SLNB was compared to AD for axillary staging in clinically node-negative patients reporting a 5-10% false negative rate (FNR) and 90% identification rate (IR) with equivalent disease-free survival (DFS) and overall survival (OS). Those findings led to the replacement of AD with SLNB for the staging of the clinically negative axilla.

After implementation of SLNB in clinical practice, the quantity of lymph nodes sent to pathology decreased, while the intensity of the pathological examination increased. Utilization of multiple sectioning and immunohistochemical (IHC) staining methods led to upstaging of the axilla and the rate of axillary node positivity increased to 30% [13]. Detection of isolated tumor cells (ITC, tumor invasion size <0.2 mm) and micrometastasis (tumor invasion size >0.2 mm but <2 mm) was the main reason for this increase in axillary positivity. Nevertheless, the implication of this upstaging on survival and recurrence rates was unclear. In a second analysis of the NSABP-B32 trial, previously negative nodes by hematoxylin and eosin (H&E) were retrospectively re-examined using IHC staining [14]. The study reported an occult metastasis rate of 15.9%, with 2/3 of these diagnoses being ITC and 1/3 being micrometastasis. DFS rates for patients with occult metastasis were 94.6% compared to 95.8% for patients with negative nodes. This difference was statistically significant, but clinically not significant. The IBCSG 23-01 and the Spanish AATRM studies prospectively compared completion of AD with SLNB alone in the treatment of patients with micrometastasis and found equivalent results (five-year DFS 87.8% in the "No AD" group vs. 84.4% in the AD group, p = 0.16 in the IBCSG 23-01 trial; one percent recurrence rate in the AD group vs. 2.5% in the "No AD" group, p = 0.325 after five-year follow-up in the AATRM trial) [15-16]. It was recommended by the authors not to implement multiple sectioning and IHC staining methods in the routine examination of sentinel lymph nodes (SLN), since detection of micrometastasis and ITC did not impact the treatment outcomes.

Subsequent to those changes and with improvements in the systemic therapy of breast cancer, researchers started investigating, whether there is a subgroup of patients with macrometastatic disease in the axilla, who could avoid a completion of AD without detriment in their clinical outcome. Two older studies from the 90s, the IBCSG 10-93 study and an Italian study, investigated the need for axillary clearance in elderly patients (over 60-65 years of age) [17-18]. IBCSG 10-93 published their six-year results and the Italian study published their 15-year results. Both studies revealed similar outcomes with and without axillary clearance after long follow-up periods. Most of the patients did not receive SLNB, since SLNB was not a part of the routine clinical practice at that time.

New prospective randomized studies were designed to investigate whether AD can also be omitted for some breast cancer patients with positive SLNB results. ACOSOG-Z0011 and AMAROS trials recruited patients with limited macrometastasis to the axilla [19-20]. ACOSOG-Z0011 reported no additional benefit in regional control of the axilla for completion of AD in this specific group of patients with low recurrence risk (0.9% vs. 0.5%, p > 0.05). The study was however closed early because of low accrual and was heavily criticized for being underpowered. It was also blamed for being unblinded, the reason for which most patients in the observation arm received RT with high breast tangents. AMAROS trial compared treating SLNB positive patients with AD vs. radiation treatment to the axilla. This trial also reported no additional benefit of AD compared to RT in DFS (86.9% in the AD group vs. 82.7% in the RT group, p = 0.18). The POSNOC trial is now recruiting patients with limited axillary disease and will provide more reliable evidence on the comparison of axillary clearance vs. no further surgery to axilla [21].

With the introduction of new chemotherapeutic agents, the success rate of breast cancer treatment improved significantly. Chemotherapy can be administered before (neoadjuvant chemotherapy [NAC]) or after the surgery (adjuvant chemotherapy). Both methods have their own pros and cons. One of the significant benefits of NAC is downstaging of the tumor in the breast and in the axillary nodes and thereby enabling breast conservation and possibly avoiding AD [22-23]. With certain tumor subtypes as triple negative and Her2 (+) breast cancer, axillary pathological complete response (pCR) rates of 30% have been reported when using anthracycline-based regimens reaching 40% with the use of taxane-based regimens [24-25]. In Her2 (+) patients, the addition of trastuzumab increases the pCR rates in the axilla to 70% [26]. In the largest single institutional study from Anderson, the researchers compared performing SLNB before and after NAC [27]. IR and FNR for SLNB before and after NAC were similar (98.7% vs. 97.4% [p = 0.017] and 4.1% vs. 5.9% [p = 0.39], respectively). Multicenter studies also reported concordant results. In a retrospective analysis of NSABP B-27, one of the largest studies comparing NAC to adjuvant therapy, SLNB performed after NAC was reported to be associated with an IR of 85% and an FNR of 11%. In the subgroup analysis, patients, who were clinically positive during the presentation, had a lower FNR in comparison to clinically negative patients (7% vs. 12.4%, p = 0.51). In addition, the use of radionuclide for lymphatic mapping decreased the FNR to nine percent in comparison to 14% when only lymphazurin was used (p = 0.5). In the GANEA study, which prospectively evaluated SLNB followed by confirmatory AD after NAC, the investigators reported an IR of 90% and an FNR of 11.5% [28]. In this study, patients, who did not have a palpable lymph node during presentation had a higher IR in comparison to cN1 patients (94.6% vs. 81.5%, p = 0.008). FNR was also lower in cN0 patients (9.4%) in comparison to cN1 patients (15%), but the difference was not statistically significant (p = 0.66). Combining results from NSABP-B27 and GANEA studies, an IR of 86.5% (lower than a priori SLNB) and an FNR of 10.9% (comparable to a priori SLNB) were found [29]. Two meta-analyses assessed the accuracy of SLNB after NAC. The first study summarized 21 studies/1273 patients and found an IR of 90% and an FNR of 12% [30]. The second study summarized 24 studies (1799 patients) and found an IR of 89.6% and an FNR of 8.4% [31].

Eventually, after those studies, SLNB is usually performed following NAC in cN0 patients by most surgeons. One of the new questions arising when performing SLNB after NAC was how to manage the clinically positive axilla that became clinically negative after NAC. Although the standard of care was to perform an AD, the growing incidence of pCR in the axillary nodes led to the hypothesis that an SLNB could be justified in those patients. The ACOSOG-Z1071 study investigated the validity of SLNB after NAC for patients who were clinically positive before treatment but became clinically negative [32]. In this study, a pCR of 41% was found in the axilla after NAC. FNR was found to be 12.6% but when a dual agent was used, the FNR further decreased to 10.8%. In further subgroup analysis, when two or more SLNs were excised and SLNs were stained using IHC method, FNR was found to be as low as 8.7%. In 1/3 of the patients, a clip was placed into the biopsied lymph node prior to NAC and when the lymph node with clip placement was identified and excised during SLNB, the FNR decreased to 6.8%. In the same group of patients, who had a clip in the biopsied node, the FNR was as high as 39% if the clipped node was not found. In this same study, the significance of a micrometastasis in a sentinel node after NAC was found to be much different than in a non-treated patient. Indeed, further involvement of non-sentinel nodes was found to be present in 97.9% of the cases. The SENTINA study was the second prospective multicenter study investigating SLNB after NAC in patients, who were clinically positive during the presentation [33]. They found an IR of 80.1% and an FNR of 14.2%. When only one SLN was excised, the FNR was increased to 24.3%, while when three or more SLNs were excised the FNR was less than 10%. When a single lymphatic mapping tracer was used, the FNR was found to be 16%, while usage of double tracer decreased the FNR to 8.6%. The most recent prospective multicenter study investigating this topic was the SN-FNAC study [34]. In this study, IHC staining was mandatory. An IR of 87.6% and an FNR of 8.4% was reported. When one SLN was removed, the FNR was 18.2%, while when two SLNs were removed, the FNR was 4.9%. When only radionuclide tracer was used, the FNR was 16%, while usage of dual tracers decreased the FNR further to 5.2%.

These studies were summarized in a meta-analysis. The first one involved 2471 patients and found an IR of 89% and an FNR of 14% [35]. According to the first study, usage of IHC decreased FNR to 8.7%, while without IHC, the FNR was 16%. The second study included 3398 patients and reported a pCR of 39.2%, an IR of 90.9%, and an FNR of 13% [36]. Performing SLNB before NAC has the advantage of staging the axilla without the confounding effect of NAC, but postponing SLNB until completion of NAC, enables some patients to avoid an AD and the associated morbidity. In summary, recent studies demonstrated that SLNB can be safely performed in previously node positive patients (clinically or pathologically proven) who became clinically negative at the completion of NAC. Usage of dual tracer, removal of two SLNs, placement of clip during axillary biopsy and retrieving the clip placed LN during SLNB decreased FNR and increased IR significantly. When performing SLNB after NAC, all sizes of residual disease in the SLNB (macrometastasis, micrometastasis, and ITC) should be treated with completion axillary dissection, since only in two percent of patients is the micrometastasis, the only tumor burden in the axilla. Furthermore, the potential consequence of a false negative axillary staging after NAC might have a possibly negative regional effect on the nodal area but will not have a systemic impact since, in the current NAC practice, all the systemic therapy is usually administered prior to surgery. This, of course, would be different, when SLNB is performed before chemotherapy and when false negativity of SLNB might cause an erroneous down staging and a possible omission of systemic treatment.

The AMAROS trial has similar efficiency with RT as with AD in the treatment of axillary disease. That same question is being addressed for patients with residual axillary positivity on SLNB after NAC. The ALLIANCE A011202 trial (https://clinicaltrials.gov/ct2/show/NCT01901094) is currently recruiting patients with breast cancer staged T1-3/N1/M0 at presentation who became clinically negative after NAC. All patients undergo an SLNB and if SLNB is positive, they are randomized to axillary RT or AD.

Although SLNB is a minimally invasive procedure it is still associated with some morbidity including a risk of lymphedema amounting to five percent at five years [8]. The SOUND trial at the European Institute of Oncology is investigating whether ultrasound staging of the axilla could substitute SLNB. Patients with breast cancer (cT1N0) are undergoing an axillary ultrasound followed by FNA if suspicious nodes are identified. Patients with N0 disease after ultrasound +/- FNA are then randomized to SLNB followed by AD as needed vs. axillary observation [37].

Conclusions

In conclusion, the role of surgery for axillary staging and for the treatment of minimal disease is changing. Breast surgeons should become familiar with the other emerging modalities in order to comprehensively treat breast cancer.


References

  1. Virchow RLK: Cellular Pathology as Based Upon Physiological and Pathological Histology: Twenty Lectures Delivered in the Pathological Institute of Berlin During the Months of February, March and April, 1858. JB Lippincott, Philadelphia; 1863. 10.5962/bhl.title.32770
  2. Virchow RLK: Die Krankhaften Geschwulste (In German). A Hirschwald, Berlin; 1863.
  3. Halsted WS: The results of operation for the cure of cancer of the breast performed at the John Hopkins Hospital from June 1889 to January 1894.. Ann Surg. 1894, 20:497–555.
  4. Brinkley D, Haybittle JL: Long-term survival of women with breast cancer. Lancet. 1984, 323:1118. 10.1016/S0140-6736(84)92525-X
  5. Fisher B, Redmond C, Fisher ER, et al.: Ten-year results of a randomized trial comparing radical mastectomy and total mastectomy with or without radiation. N Engl J Med. 1985, 312:674–681. 10.1056/NEJM198503143121102
  6. Cancer Research Campaign Working Party: Cancer research campaign (King's/Cambridge) trial for early breast cancer. A detailed update at the tenth year. Lancet. 1980, 316:55–60. 10.1016/S0140-6736(80)92939-6
  7. Hofvind S, Lee CI, Elmore JG: Stage-specific breast cancer incidence rates among participants and non-participants of a population-based mammographic screening program. Breast Cancer Res Treat. 2012, 135:291–299. 10.1007/s10549-012-2162-x
  8. McLaughlin SA, Wright MJ, Morris KT, et al.: Prevalence of lymphedema in women with breast cancer 5 years after sentinel lymph node biopsy or axillary dissection: objective measurements. J Clin Oncol. 2008, 26:5213–5219. 10.1200/JCO.2008.16.3766
  9. Hunt KK, Ballman KV, McCall LM, et al.: Factors associated with local-regional recurrence after a negative sentinel node dissection: results of the ACOSOG Z0010 trial. Ann Surg. 2012, 256:428–436. 10.1097/SLA.0b013e3182654494
  10. Veronesi U, Paganelli G, Viale G, et al.: A randomized comparison of sentinel-node biopsy with routine axillary dissection in breast cancer. N Engl J Med. 2003, 349:546–553. 10.1056/NEJMoa012782
  11. Krag DN, Anderson SJ, Julian TB, et al.: Sentinel-lymph-node resection compared with conventional axillary-lymph-node dissection in clinically node-negative patients with breast cancer: overall survival findings from the NSABP B-32 randomised phase 3 trial. Lancet Oncol. 2010, 11:927–933. 10.1016/S1470-2045(10)70207-2
  12. Mansel RE, Fallowfield L, Kissin M, et al.: Randomized multicenter trial of sentinel node biopsy versus standard axillary treatment in operable breast cancer: the ALMANAC Trial. J Natl Cancer Inst. 2006, 98:599–609. 10.1093/jnci/djj158
  13. Tvedskov TF: Staging of women with breast cancer after introduction of sentinel node guided axillary dissection. Dan Med J. 2012, 59:B4475.
  14. Julian TB, Anderson SJ, Krag DN, et al.: 10 year follow up of NSABP B-32, a randomized phase III clinical trial to compare sentinel node resection to conventional axillary dissection in clinically node negative breast cancer patients. J Clin Oncol. 2013, 31:100.
  15. Solá M, Alberro JA, Fraile M, et al. : Complete axillary lymph node dissection versus clinical follow up in breast cancer patients with sentinel node metastasis: final results from the multicentre clinical trial AATRM 048/13/2000. Ann Surg Oncol. 2013, 20:120–127. 10.1245/s10434-012-2569-y
  16. de Boer M, van Deurzen CH, van Dijck JA, et al.: Micrometastases or isolated tumor cells and the outcome of breast cancer. N Engl J Med. 2009, 361:653–663. 10.1056/NEJMoa0904832
  17. International Breast Cancer Study Group, Rudenstam CM, Zahrieh D, et al.: Randomized trial comparing axillary clearance versus no axillary clearance in older patients with breast cancer: first results of international breast cancer study group trial 10-93. J Clin Oncol. 2006, 24:337–344. 10.1200/JCO.2005.01.5784
  18. Martelli G, Boracchi P, Orenti A, et al.: Axillary dissection versus no axillary dissection in older T1N0 breast cancer patients: 15 year results of trial and out-trial patients. Eur J Surg Oncol. 2014, 40:805–812. 10.1016/j.ejso.2014.03.029
  19. Giuliano AE, Hunt KK, Ballman KV, et al.: Axillary dissection vs no axillary dissection in women with invasive breast cancer and sentinel node metastases: a randomized clinical trial. JAMA. 2011, 305:569-575. 10.1001/jama.2011.90
  20. Donker M, van Tienhoven G, Straver ME, et al.: Radiotherapy or surgery of the axilla after a positive sentinel node in breast cancer (EORTC 10981-22023 AMAROS): a randomized multicentre, open-label, phase 3 non-inferiority trial. Lancet Oncol. 2014, 15:1303–1310. 10.1016/S1470-2045(14)70460-7
  21. Goyal A: Protocol 14PRT/0519: POSNOC—POsitive Sentinel NOde-adjuvant therapy alone versus adjuvant therapy plus Clearance or axillary radiotherapy: a randomized controlled trial of axillary treatment in women with early stage breast cancer who have metastases in one or two sentinel nodes (ISRCTN54765244). The Lancet. Accessed: July, 2014: http://www.thelancet.com/protocol-reviews/14PRT-0519.
  22. Jatoi I, Benson JR, Toi M: De-escalation of axillary surgery in early breast cancer. Lancet Oncol. 2016, 17:e430-e441. 10.1016/S1470-2045(16)30311-4
  23. Mamounas ET: Optimal management of the axilla: a look at the evidence. Adv Surg. 2016, 50:29-40. 10.1016/j.yasu.2016.03.003
  24. Fisher B, Brown A, Mamounas E, et al.: Effect of preoperative chemotherapy on local-regional disease in women with operable breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-18. J Clin Oncol. 1997, 15:2483–2493. 10.1200/JCO.1997.15.7.2483
  25. Mamounas EP, Brown A, Anderson S, et al.: Sentinel node biopsy after neoadjuvant chemotherapy in breast cancer: results from National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol. 2005, 23:2694–2702. 10.1200/JCO.2005.05.188
  26. Dominici LS, Negron Gonzalez VM, Buzdar AU, et al.: Cytologically proven axillary lymph node metastases are eradicated in patients receiving preoperative chemotherapy with concurrent trastuzumab for HER2 positive breast cancer. Cancer. 2010, 116:2884–2889. 10.1002/cncr.25152
  27. Hunt KK, Yi M, Mittendorf EA, et al.: Sentinel lymph node surgery after neoadjuvant chemotherapy is accurate and reduces the need for axillary dissection in breast cancer patients. Ann Surg. 2009, 250:558–566. 10.1097/SLA.0b013e3181b8fd5e
  28. Classe JM, Bordes V, Campion L, et al.: Sentinel lymph node biopsy after neoadjuvant chemotherapy for advanced breast cancer: results of Ganglion Sentinelle et Chimiotherapie Neoadjuvante, a French prospective multicentric study. J Clin Oncol. 2009, 27:726–732. 10.1200/JCO.2008.18.3228
  29. Mamounas EP: Impact of neoadjuvant chemotherapy on locoregional surgical treatment of breast cancer. Ann Surg Oncol. 2015, 22:1425–1433. 10.1245/s10434-015-4406-6
  30. Xing Y, Foy M, Cox DD, et al.: Meta-analysis of sentinel lymph node biopsy after preoperative chemotherapy in patients with breast cancer. Br J Surg. 2004, 93:539–546. 10.1002/bjs.5209
  31. Kelly AM, Dwamena B, Cronin P, et al.: Breast cancer: sentinel node identification and classification after neoadjuvant chemotherapy-systematic review and meta-analysis. Acad Radiol. 2009, 16:551–563. 10.1016/j.acra.2009.01.026
  32. Boughey JC, Suman VJ, Mittendorf EA, et al.: Sentinel lymph node surgery after neoadjuvant chemotherapy in patients with node-positive breast cancer: the ACOSOG Z1071 (Alliance) clinical trial. JAMA. 2013, 310:1455–1461. 10.1001/jama.2013.278932
  33. Kuehn T, Bauerfeind I, Fehm T, et al.: Sentinel-lymph-node biopsy in patients with breast cancer before and after neoadjuvant chemotherapy (SENTINA): a prospective, multicenter cohort study. Lancet Oncol. 2013, 14:609–618. 10.1016/S1470-2045(13)70166-9
  34. Boileau JF, Poirier B, Basik M, et al.: Sentinel node biopsy after neoadjuvant chemotherapy in biopsy-proven node-positive breast cancer: the SN FNAC study. J Clin Oncol. 2015, 33:258–264. 10.1200/JCO.2014.55.7827
  35. Fu JF, Chen HL, Yang J, et al.: Feasibility and accuracy of sentinel lymph node biopsy in clinically node-positive breast cancer after neoadjuvant chemotherapy: a meta-analysis. PLoS One. 2014, 9:e105316. 10.1371/journal.pone.0105316
  36. El Hage Chehade H, Headon H, El Tokhy O, et al.: Is sentinel lymph node biopsy a viable alternative to complete axillary dissection following neoadjuvant chemotherapy in women with node-positive breast cancer at diagnosis? An updated meta-analysis involving 3,398 patients. Am J Surg. 2016, 212:969–981. 10.1016/j.amjsurg.2016.07.018
  37. Gentilini O, Veronesi U: Abandoning sentinel lymph node biopsy in early breast cancer? A new trial in progress at the European Institute of Oncology of Milan (SOUND: Sentinel node vs Observation after axillary UltraSouND). Breast. 2012, 12:678–681. 10.1016/j.breast.2012.06.013
Review article
peer-reviewed

Management of the Positive Axilla in 2017


Author Information

Tolga Ozmen Corresponding Author

Surgical Oncology, University of Miami, Miller School of Medicine

Alicia Huff Vinyard

Surgical Oncology, University of Miami, Miller School of Medicine

Eli Avisar

Department of Surgery, University of Miami, Miller School of Medicine


Ethics Statement and Conflict of Interest Disclosures

Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.


SIQ
-
RATED BY 0 READERS
CONTRIBUTE RATING

Scholary Impact Quotient™ (SIQ™) is our unique post-publication peer review rating process. Learn more here.