ACOSOG Z1071 (Alliance)

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Judy Boughey. "Sentinel Lymph Node Surgery After Neoadjuvant Chemotherapy in Patients With Node-Positive Breast Cancer The ACOSOG Z1071 (Alliance) Clinical Trial". Journal of the American Medical Association. 2013. 310(4):1455-1461.
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Clinical Question

Among patients with axillary node positive breast cancer who have undergone neoadjuvant chemotherapy, is sentinel node biopsy a safe alternative to an axillary dissection?

Bottom Line

Sentinel node biopsy following neoadjuvant chemotherapy for node postitive breast cancer carries a false negative rate of 12.6%, above the pre-set accepted rate of 10%.

Major Points

Sentinel lymph node biopsy (SLNB), wherein blue dye (methylene or isosulfan blue) and/or radiocolloid are injected into the breast and used to trace lymphatics are a reliable means of staging the axilla. However, gross tumor burden can distort the lymphatic system, rendering the procedure less reliable. ACOSOG Z0011 established the safety of nodal observation in women with a positive sentinel node biopsy during breast conserving therapy in early stage breast cancer undergoing adjuvant radiation. This allowed avoidance of axillary dissections, which are the major source of morbidity (neuropathy, lymphedema) in breast surgery. However, the Z0011 trial notably excluded neoadjuvant treatment and gross pathologic disease.

Neoadjuvant anthracycline/taxane chemotherapy is estimated to eradicate disease in 30-40% of clinically node positive women (cN1) [1]. It was previously unknown if it would be safe to use SLNB to identify this population, thereby sparing them an axillary dissection. The major finding from Z1071 is that SLNB, with a false negative rate of 12% (disease not present in SLNB but present in the axillary dissection), is not currently a reliable method for identifying the appropriate patient population to omit axillary dissection.

Guidelines

  • American Society of Clinical Oncology Guidelines 2017/2014 [2], [3]
    • Clinicians may offer SLNB for women with operable breast cancer in the neoadjuvant systemic setting
    • Sentinel node technique following neoadjuvant treatment carries a high false negative rate, which may lead to understaging/undertreatment
    • The use of two markers and sampling ≥2 nodes can reduce false negative rates
  • European Society for Medical Oncology (ESMO) Guidelines [4]
    • can consider post-systemic therapy SLNB if axilla is negative on ultrasound/PET-CT

Design

  • N= 756 enrolled in study
    • N = 663 with cN1 disease
    • N = 525 with cN1 and ≥ 2 sentinel nodes
  • Prospective cohort study
  • 136 institutions
  • Setting: July 2009 to June 2011
  • Analysis: Bayesian clinical trial design, multivariate logistic regression, likelihood ratio tests, Fisher exact test
  • Primary outcome: False negative rate of SLNB among women with cN1, ≥2 lymph nodes excised

Population

Inclusion Criteria

  • ≥18 years old women
  • histologically proven clinical stage T0–T4, N1–N2 (fine needle aspiration or core needle biopsy)
  • exclusion of distal metastasis (M0)
  • neoadjuvant chemotherapy within 84 days
  • ECOG performance status 0/1

Exclusion Criteria

  • history of axillary surgery (including SLNB/
  • no men included

Baseline Characteristics

  • Data presented for cN1 Cohhort (n=663)
  • Age
    • 18-39 18%
    • 40-49 32%
    • 50-59 30%
    • 60-69 17%
    • ≥ 70 3%
  • Race/Ethnicity
    • White 81%
    • Black 14%
    • Asian 3%
    • American Indian/Alaskan/Not reported 2%
  • BMI
    • < 25 28%
    • ≥ 25 71%
  • ECOG Performance Status
    • 0 81%
    • 1 19%
  • Smoking status
    • Never 68%
    • Current 12%
    • Past 16%
  • Concurrent Conditions
    • Cardiac disease 25%
    • Diabetes 8%
      • Arthritis 6%
  • Clinical T category
    • T0/Tis <1%
    • T1 13%
    • T2 56%
    • T3 26%
    • T4 4%
  • Subtype
    • HER2 30%
    • ER/PR +, HER2 negative 56%
    • ER/PR negative, HER2 negative 24%
  • Tumor Histology
    • Invasive ductal carcinoma 98%
    • Invasive lobular carcinoma 6%
    • IDC/ILC 1.7%
    • DCIS 0.3%
    • T0 0.5%
  • Type of axillary lymph node biopsy
    • Fine needle aspiration 39%
    • Core needle biopsy 61%
  • Clip in axilla
    • Yes 32%
  • Neoadjuvant Regimen
    • anthracycline + taxane 75%
    • anthracycline 6%
    • taxane 17%
    • no anthracycline/taxane 1.7%
  • Chemotherapy complete
    • Yes 92%
  • Findings on axilla after chemotherapy
    • No palpable adenopathy 84%
    • Palpable lymph nodes 11.5%
    • Fixed/matted ndoes <1%
    • Not reported 4%
  • Type of axillary surgery
    • SLN 0.3%
    • SLN not identified, and ALND 7%
    • SLN with SLN identified, and ALND 91%
    • ALND 1.8%
  • Mapping agent used
    • Blue dye 3.8%
    • Colloid 17%
    • Both 79%
  • Timing of radiolabeled collloid injection
    • Day before surgery 25%
    • Morning of surgery 72%
    • Not used 3.8%
  • Injection sites
    • Subareolar/periareolar 62%
    • Peritumoral 8.6%
    • intradermal 2.6%
    • Multiple sites 22.6%
    • Not specified 4%
  • Number of SLNs examined
    • 0 7%
    • 1 12%
    • 2 23.8%
    • 3 22.7%
    • 4 13.8%
    • ≥5 20.6%


Interventions

  • following chmotherapy and within 4 weeks of surgery patients had PE and axillary ultrasound
  • sentinel node biopsy performed with either blue dye and/or lymphoscintigraphy
  • 2 sentinel nodes removed
  • axillary dissection complete for all patients

Outcomes

Primary Outcomes

“cN1 disease is reported”

  • 39/310 (12.6%) patients had residual nodal disease on the axillary dissection despite 2 negative sentinel nodes
  • 2 SLN identified in 525/689 patients patient
    • 41% no residual disease
    • 31% node positive in sentinel node and axillary dissection
    • 20.6% nodal disease confined to sentinel node
    • 7.4% patients confined to ALND, no disease on sentinel node
  • Note: cN2 disease 26 women had 2 sentinel nodes excised, 12 had no residual disease, 14 to SLNB/SLNB and axillary dissection, no patients had negative sentinel nodes and disease present on axillary dissection

Secondary Outcomes

  • Pathologic complete response
    • cN1 = 41%
    • cN2 = 46%

“Factors Affecting Likelidhood of False-Negative SLN in women with cN1 disease, 2 nodes, residual nodal disease”:

Mapping Agents Used (Dual vs. Single)
27/251 (10.8%) vs 12/59 (20.3%), p = 0.05
Number of Sentinel Lymph Nodes examined (≥3 vs 2)
20/220 (9.1%) vs 19/90 (21.1%), p = 0.007
  • Age, BMI, T stage, Chemotherapy duration, Palpable nodes, and injection sites were examined and not found to be statistically significant

Adverse Events

  • 42 patients (6%) could not tolerate chemotherapy regimen due to intolerable adverse events

Criticisms

  • no specifications on type or length of chemotherapy
  • no exclusion criteria for nodal response after chemotherapy
  • unclear application to neoadjuvant endocrine therapy
  • no information included about radiographic response to chemotherapy

Funding

  • Grant U10 CA76001 National Cancer Institute Award to the American College of Surgeons Oncology Group

Further Reading

  1. Xing Y et al. Meta-analysis of sentinel lymph node biopsy after preoperative chemotherapy in patients with breast cancer. Br J Surg 2006. 93:539-46.
  2. Lyman GH et al. Sentinel Lymph Node Biopsy for Patients With Early-Stage Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update. J. Clin. Oncol. 2017. 35:561-564.
  3. Lyman GH et al. Sentinel lymph node biopsy for patients with early-stage breast cancer: American Society of Clinical Oncology clinical practice guideline update. J. Clin. Oncol. 2014. 32:1365-83.
  4. Senkus E et al. Primary breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 2015. 26 Suppl 5:v8-30.