Abstract
Background:
Axillary nodal status is an important prognostic factor in breast cancer (BC), guiding (neo)adjuvant systemic treatment and postoperative radiotherapy. As axillary surgery does not significantly affect BC mortality itself, it is considered as a staging procedure in clinically node-negative patients. The replacement of axillary lymph node dissection (ALND) by sentinel lymph node biopsy (SLNB) two decades ago and later omitting completion ALND (cALND) according to the ACOSOG Z0011 criteria led to surgical de-escalation. The Intergroup-Sentinel-Mamma (INSEMA) trial (NCT02466737) aims to investigate whether surgical axillary staging as part of breast-conserving therapy (BCT) for early BC can be avoided without compromising oncological safety.
Study Design:
The INSEMA trial was conducted between September 2015 and April 2019 in Germany and Austria. This prospective, randomized trial compares no axillary surgery with standard SLNB in pts with early invasive BC (tumor size ≤ 5 cm; c/iT1–2 c/iN0) scheduled for BCT, including postoperative whole-breast irradiation. The primary objective is to assess whether no axillary surgery is non-inferior to SLNB regarding invasive disease-free survival (iDFS). Clinical non-inferiority is a hazard ratio (HR) below 1.271 when comparing the non-SLNB with the SLNB group. The randomization was carried out in 4:1 allocation (SLNB vs. no SLNB) because pN1a(sn) pts in the SLNB arm underwent a second randomization to either SLNB alone or cALND (key secondary outcome). The primary analysis is based on the per-protocol (PP) set. Adjusting for 1:4 randomization, 5230 pts (PP set) are needed. Assuming a 5% exclusion rate from the PP set, about 5505 pts must be randomized.
Results:
5502 eligible pts were randomized to no SLNB (n=1101) vs. SLNB (n=4401). The drop-out rate was 6.3%, leading to an intent-to-treat (ITT) population of N=5154. After excluding 296 patients (n=252 without postoperative radiotherapy), 4858 patients (no SLNB: n=962, SLNB: n=3896) were included in the PP set. The median follow-up (FU) is 73.6 months (IQR 61.3-86.4).
Patient and tumor characteristics are well-balanced between treatment arms. The median age at diagnosis was 62.0 years (range 24.0–89.0). Most pts presented with low-risk BC (78.6% pT1 stage, 98.5% hormone receptor-positive, 3.6% HER2-positive, and 3.6% G3 tumors). Significantly more pts received adjuvant chemotherapy in the SLNB arm (13.2% vs 10.7% in the no SLNB arm).
The primary analysis in the PP established non-inferiority in iDFS between study arms with a HR=0.91 (95% CI: 0.73-1.14) for no SLNB to SLNB. The estimated 5-year iDFS rates are 91.9% (89.9%-93.5%) in the non-SLNB arm and 91.7% (90.8%-92.6%) in the SLNB arm. The first iDFS events (n=525, overall 10.8%) for no SLNB vs. SLNB consist of invasive locoregional recurrences (1.9% vs. 1.4%), including axillary recurrences (1.0% vs. 0.3%), invasive contralateral BCs (1.0% vs. 0.6%), distant metastases (2.7% vs. 2.7%), secondary malignancies (3.3% vs. 3.9%), and deaths (1.4% vs. 2.4%). The estimated 5-year overall survival (OS) rates are 98.2% (97.1%-98.9%) in the non-SLNB arm and 96.9% (96.3%-97.5%) in the SLNB arm.
Conclusion:
The INSEMA trial, enrolling 5500 pts, demonstrated that the omission of SLNB in clinically node-negative BC pts undergoing BCT resulted in a statistically significant non-inferior iDFS meeting the primary endpoint. INSEMA demonstrates oncological safety in all aspects when the axillary SLNB is omitted in cN0 patients with an early BC planned for primary BCT. This practice-changing concept is suitable for patients presenting with low-grade (G1/G2), hormone receptor-positive/HER2-negative invasive BC with tumor size up to 5 cm.
Axillary nodal status is an important prognostic factor in breast cancer (BC), guiding (neo)adjuvant systemic treatment and postoperative radiotherapy. As axillary surgery does not significantly affect BC mortality itself, it is considered as a staging procedure in clinically node-negative patients. The replacement of axillary lymph node dissection (ALND) by sentinel lymph node biopsy (SLNB) two decades ago and later omitting completion ALND (cALND) according to the ACOSOG Z0011 criteria led to surgical de-escalation. The Intergroup-Sentinel-Mamma (INSEMA) trial (NCT02466737) aims to investigate whether surgical axillary staging as part of breast-conserving therapy (BCT) for early BC can be avoided without compromising oncological safety.
Study Design:
The INSEMA trial was conducted between September 2015 and April 2019 in Germany and Austria. This prospective, randomized trial compares no axillary surgery with standard SLNB in pts with early invasive BC (tumor size ≤ 5 cm; c/iT1–2 c/iN0) scheduled for BCT, including postoperative whole-breast irradiation. The primary objective is to assess whether no axillary surgery is non-inferior to SLNB regarding invasive disease-free survival (iDFS). Clinical non-inferiority is a hazard ratio (HR) below 1.271 when comparing the non-SLNB with the SLNB group. The randomization was carried out in 4:1 allocation (SLNB vs. no SLNB) because pN1a(sn) pts in the SLNB arm underwent a second randomization to either SLNB alone or cALND (key secondary outcome). The primary analysis is based on the per-protocol (PP) set. Adjusting for 1:4 randomization, 5230 pts (PP set) are needed. Assuming a 5% exclusion rate from the PP set, about 5505 pts must be randomized.
Results:
5502 eligible pts were randomized to no SLNB (n=1101) vs. SLNB (n=4401). The drop-out rate was 6.3%, leading to an intent-to-treat (ITT) population of N=5154. After excluding 296 patients (n=252 without postoperative radiotherapy), 4858 patients (no SLNB: n=962, SLNB: n=3896) were included in the PP set. The median follow-up (FU) is 73.6 months (IQR 61.3-86.4).
Patient and tumor characteristics are well-balanced between treatment arms. The median age at diagnosis was 62.0 years (range 24.0–89.0). Most pts presented with low-risk BC (78.6% pT1 stage, 98.5% hormone receptor-positive, 3.6% HER2-positive, and 3.6% G3 tumors). Significantly more pts received adjuvant chemotherapy in the SLNB arm (13.2% vs 10.7% in the no SLNB arm).
The primary analysis in the PP established non-inferiority in iDFS between study arms with a HR=0.91 (95% CI: 0.73-1.14) for no SLNB to SLNB. The estimated 5-year iDFS rates are 91.9% (89.9%-93.5%) in the non-SLNB arm and 91.7% (90.8%-92.6%) in the SLNB arm. The first iDFS events (n=525, overall 10.8%) for no SLNB vs. SLNB consist of invasive locoregional recurrences (1.9% vs. 1.4%), including axillary recurrences (1.0% vs. 0.3%), invasive contralateral BCs (1.0% vs. 0.6%), distant metastases (2.7% vs. 2.7%), secondary malignancies (3.3% vs. 3.9%), and deaths (1.4% vs. 2.4%). The estimated 5-year overall survival (OS) rates are 98.2% (97.1%-98.9%) in the non-SLNB arm and 96.9% (96.3%-97.5%) in the SLNB arm.
Conclusion:
The INSEMA trial, enrolling 5500 pts, demonstrated that the omission of SLNB in clinically node-negative BC pts undergoing BCT resulted in a statistically significant non-inferior iDFS meeting the primary endpoint. INSEMA demonstrates oncological safety in all aspects when the axillary SLNB is omitted in cN0 patients with an early BC planned for primary BCT. This practice-changing concept is suitable for patients presenting with low-grade (G1/G2), hormone receptor-positive/HER2-negative invasive BC with tumor size up to 5 cm.
Background:
Axillary nodal status is an important prognostic factor in breast cancer (BC), guiding (neo)adjuvant systemic treatment and postoperative radiotherapy. As axillary surgery does not significantly affect BC mortality itself, it is considered as a staging procedure in clinically node-negative patients. The replacement of axillary lymph node dissection (ALND) by sentinel lymph node biopsy (SLNB) two decades ago and later omitting completion ALND (cALND) according to the ACOSOG Z0011 criteria led to surgical de-escalation. The Intergroup-Sentinel-Mamma (INSEMA) trial (NCT02466737) aims to investigate whether surgical axillary staging as part of breast-conserving therapy (BCT) for early BC can be avoided without compromising oncological safety.
Study Design:
The INSEMA trial was conducted between September 2015 and April 2019 in Germany and Austria. This prospective, randomized trial compares no axillary surgery with standard SLNB in pts with early invasive BC (tumor size ≤ 5 cm; c/iT1–2 c/iN0) scheduled for BCT, including postoperative whole-breast irradiation. The primary objective is to assess whether no axillary surgery is non-inferior to SLNB regarding invasive disease-free survival (iDFS). Clinical non-inferiority is a hazard ratio (HR) below 1.271 when comparing the non-SLNB with the SLNB group. The randomization was carried out in 4:1 allocation (SLNB vs. no SLNB) because pN1a(sn) pts in the SLNB arm underwent a second randomization to either SLNB alone or cALND (key secondary outcome). The primary analysis is based on the per-protocol (PP) set. Adjusting for 1:4 randomization, 5230 pts (PP set) are needed. Assuming a 5% exclusion rate from the PP set, about 5505 pts must be randomized.
Results:
5502 eligible pts were randomized to no SLNB (n=1101) vs. SLNB (n=4401). The drop-out rate was 6.3%, leading to an intent-to-treat (ITT) population of N=5154. After excluding 296 patients (n=252 without postoperative radiotherapy), 4858 patients (no SLNB: n=962, SLNB: n=3896) were included in the PP set. The median follow-up (FU) is 73.6 months (IQR 61.3-86.4).
Patient and tumor characteristics are well-balanced between treatment arms. The median age at diagnosis was 62.0 years (range 24.0–89.0). Most pts presented with low-risk BC (78.6% pT1 stage, 98.5% hormone receptor-positive, 3.6% HER2-positive, and 3.6% G3 tumors). Significantly more pts received adjuvant chemotherapy in the SLNB arm (13.2% vs 10.7% in the no SLNB arm).
The primary analysis in the PP established non-inferiority in iDFS between study arms with a HR=0.91 (95% CI: 0.73-1.14) for no SLNB to SLNB. The estimated 5-year iDFS rates are 91.9% (89.9%-93.5%) in the non-SLNB arm and 91.7% (90.8%-92.6%) in the SLNB arm. The first iDFS events (n=525, overall 10.8%) for no SLNB vs. SLNB consist of invasive locoregional recurrences (1.9% vs. 1.4%), including axillary recurrences (1.0% vs. 0.3%), invasive contralateral BCs (1.0% vs. 0.6%), distant metastases (2.7% vs. 2.7%), secondary malignancies (3.3% vs. 3.9%), and deaths (1.4% vs. 2.4%). The estimated 5-year overall survival (OS) rates are 98.2% (97.1%-98.9%) in the non-SLNB arm and 96.9% (96.3%-97.5%) in the SLNB arm.
Conclusion:
The INSEMA trial, enrolling 5500 pts, demonstrated that the omission of SLNB in clinically node-negative BC pts undergoing BCT resulted in a statistically significant non-inferior iDFS meeting the primary endpoint. INSEMA demonstrates oncological safety in all aspects when the axillary SLNB is omitted in cN0 patients with an early BC planned for primary BCT. This practice-changing concept is suitable for patients presenting with low-grade (G1/G2), hormone receptor-positive/HER2-negative invasive BC with tumor size up to 5 cm.
Axillary nodal status is an important prognostic factor in breast cancer (BC), guiding (neo)adjuvant systemic treatment and postoperative radiotherapy. As axillary surgery does not significantly affect BC mortality itself, it is considered as a staging procedure in clinically node-negative patients. The replacement of axillary lymph node dissection (ALND) by sentinel lymph node biopsy (SLNB) two decades ago and later omitting completion ALND (cALND) according to the ACOSOG Z0011 criteria led to surgical de-escalation. The Intergroup-Sentinel-Mamma (INSEMA) trial (NCT02466737) aims to investigate whether surgical axillary staging as part of breast-conserving therapy (BCT) for early BC can be avoided without compromising oncological safety.
Study Design:
The INSEMA trial was conducted between September 2015 and April 2019 in Germany and Austria. This prospective, randomized trial compares no axillary surgery with standard SLNB in pts with early invasive BC (tumor size ≤ 5 cm; c/iT1–2 c/iN0) scheduled for BCT, including postoperative whole-breast irradiation. The primary objective is to assess whether no axillary surgery is non-inferior to SLNB regarding invasive disease-free survival (iDFS). Clinical non-inferiority is a hazard ratio (HR) below 1.271 when comparing the non-SLNB with the SLNB group. The randomization was carried out in 4:1 allocation (SLNB vs. no SLNB) because pN1a(sn) pts in the SLNB arm underwent a second randomization to either SLNB alone or cALND (key secondary outcome). The primary analysis is based on the per-protocol (PP) set. Adjusting for 1:4 randomization, 5230 pts (PP set) are needed. Assuming a 5% exclusion rate from the PP set, about 5505 pts must be randomized.
Results:
5502 eligible pts were randomized to no SLNB (n=1101) vs. SLNB (n=4401). The drop-out rate was 6.3%, leading to an intent-to-treat (ITT) population of N=5154. After excluding 296 patients (n=252 without postoperative radiotherapy), 4858 patients (no SLNB: n=962, SLNB: n=3896) were included in the PP set. The median follow-up (FU) is 73.6 months (IQR 61.3-86.4).
Patient and tumor characteristics are well-balanced between treatment arms. The median age at diagnosis was 62.0 years (range 24.0–89.0). Most pts presented with low-risk BC (78.6% pT1 stage, 98.5% hormone receptor-positive, 3.6% HER2-positive, and 3.6% G3 tumors). Significantly more pts received adjuvant chemotherapy in the SLNB arm (13.2% vs 10.7% in the no SLNB arm).
The primary analysis in the PP established non-inferiority in iDFS between study arms with a HR=0.91 (95% CI: 0.73-1.14) for no SLNB to SLNB. The estimated 5-year iDFS rates are 91.9% (89.9%-93.5%) in the non-SLNB arm and 91.7% (90.8%-92.6%) in the SLNB arm. The first iDFS events (n=525, overall 10.8%) for no SLNB vs. SLNB consist of invasive locoregional recurrences (1.9% vs. 1.4%), including axillary recurrences (1.0% vs. 0.3%), invasive contralateral BCs (1.0% vs. 0.6%), distant metastases (2.7% vs. 2.7%), secondary malignancies (3.3% vs. 3.9%), and deaths (1.4% vs. 2.4%). The estimated 5-year overall survival (OS) rates are 98.2% (97.1%-98.9%) in the non-SLNB arm and 96.9% (96.3%-97.5%) in the SLNB arm.
Conclusion:
The INSEMA trial, enrolling 5500 pts, demonstrated that the omission of SLNB in clinically node-negative BC pts undergoing BCT resulted in a statistically significant non-inferior iDFS meeting the primary endpoint. INSEMA demonstrates oncological safety in all aspects when the axillary SLNB is omitted in cN0 patients with an early BC planned for primary BCT. This practice-changing concept is suitable for patients presenting with low-grade (G1/G2), hormone receptor-positive/HER2-negative invasive BC with tumor size up to 5 cm.
No axillary surgery versus axillary sentinel lymph node biopsy in patients with early invasive breast cancer and breast-conserving surgery: Final primary results of the Intergroup-Sentinel-Mamma (INSEMA) trial
Toralf Reimer
Abstract
Background:
Axillary nodal status is an important prognostic factor in breast cancer (BC), guiding (neo)adjuvant systemic treatment and postoperative radiotherapy. As axillary surgery does not significantly affect BC mortality itself, it is considered as a staging procedure in clinically node-negative patients. The replacement of axillary lymph node dissection (ALND) by sentinel lymph node biopsy (SLNB) two decades ago and later omitting completion ALND (cALND) according to the ACOSOG Z0011 criteria led to surgical de-escalation. The Intergroup-Sentinel-Mamma (INSEMA) trial (NCT02466737) aims to investigate whether surgical axillary staging as part of breast-conserving therapy (BCT) for early BC can be avoided without compromising oncological safety.
Study Design:
The INSEMA trial was conducted between September 2015 and April 2019 in Germany and Austria. This prospective, randomized trial compares no axillary surgery with standard SLNB in pts with early invasive BC (tumor size ≤ 5 cm; c/iT1–2 c/iN0) scheduled for BCT, including postoperative whole-breast irradiation. The primary objective is to assess whether no axillary surgery is non-inferior to SLNB regarding invasive disease-free survival (iDFS). Clinical non-inferiority is a hazard ratio (HR) below 1.271 when comparing the non-SLNB with the SLNB group. The randomization was carried out in 4:1 allocation (SLNB vs. no SLNB) because pN1a(sn) pts in the SLNB arm underwent a second randomization to either SLNB alone or cALND (key secondary outcome). The primary analysis is based on the per-protocol (PP) set. Adjusting for 1:4 randomization, 5230 pts (PP set) are needed. Assuming a 5% exclusion rate from the PP set, about 5505 pts must be randomized.
Results:
5502 eligible pts were randomized to no SLNB (n=1101) vs. SLNB (n=4401). The drop-out rate was 6.3%, leading to an intent-to-treat (ITT) population of N=5154. After excluding 296 patients (n=252 without postoperative radiotherapy), 4858 patients (no SLNB: n=962, SLNB: n=3896) were included in the PP set. The median follow-up (FU) is 73.6 months (IQR 61.3-86.4).
Patient and tumor characteristics are well-balanced between treatment arms. The median age at diagnosis was 62.0 years (range 24.0–89.0). Most pts presented with low-risk BC (78.6% pT1 stage, 98.5% hormone receptor-positive, 3.6% HER2-positive, and 3.6% G3 tumors). Significantly more pts received adjuvant chemotherapy in the SLNB arm (13.2% vs 10.7% in the no SLNB arm).
The primary analysis in the PP established non-inferiority in iDFS between study arms with a HR=0.91 (95% CI: 0.73-1.14) for no SLNB to SLNB. The estimated 5-year iDFS rates are 91.9% (89.9%-93.5%) in the non-SLNB arm and 91.7% (90.8%-92.6%) in the SLNB arm. The first iDFS events (n=525, overall 10.8%) for no SLNB vs. SLNB consist of invasive locoregional recurrences (1.9% vs. 1.4%), including axillary recurrences (1.0% vs. 0.3%), invasive contralateral BCs (1.0% vs. 0.6%), distant metastases (2.7% vs. 2.7%), secondary malignancies (3.3% vs. 3.9%), and deaths (1.4% vs. 2.4%). The estimated 5-year overall survival (OS) rates are 98.2% (97.1%-98.9%) in the non-SLNB arm and 96.9% (96.3%-97.5%) in the SLNB arm.
Conclusion:
The INSEMA trial, enrolling 5500 pts, demonstrated that the omission of SLNB in clinically node-negative BC pts undergoing BCT resulted in a statistically significant non-inferior iDFS meeting the primary endpoint. INSEMA demonstrates oncological safety in all aspects when the axillary SLNB is omitted in cN0 patients with an early BC planned for primary BCT. This practice-changing concept is suitable for patients presenting with low-grade (G1/G2), hormone receptor-positive/HER2-negative invasive BC with tumor size up to 5 cm.
Axillary nodal status is an important prognostic factor in breast cancer (BC), guiding (neo)adjuvant systemic treatment and postoperative radiotherapy. As axillary surgery does not significantly affect BC mortality itself, it is considered as a staging procedure in clinically node-negative patients. The replacement of axillary lymph node dissection (ALND) by sentinel lymph node biopsy (SLNB) two decades ago and later omitting completion ALND (cALND) according to the ACOSOG Z0011 criteria led to surgical de-escalation. The Intergroup-Sentinel-Mamma (INSEMA) trial (NCT02466737) aims to investigate whether surgical axillary staging as part of breast-conserving therapy (BCT) for early BC can be avoided without compromising oncological safety.
Study Design:
The INSEMA trial was conducted between September 2015 and April 2019 in Germany and Austria. This prospective, randomized trial compares no axillary surgery with standard SLNB in pts with early invasive BC (tumor size ≤ 5 cm; c/iT1–2 c/iN0) scheduled for BCT, including postoperative whole-breast irradiation. The primary objective is to assess whether no axillary surgery is non-inferior to SLNB regarding invasive disease-free survival (iDFS). Clinical non-inferiority is a hazard ratio (HR) below 1.271 when comparing the non-SLNB with the SLNB group. The randomization was carried out in 4:1 allocation (SLNB vs. no SLNB) because pN1a(sn) pts in the SLNB arm underwent a second randomization to either SLNB alone or cALND (key secondary outcome). The primary analysis is based on the per-protocol (PP) set. Adjusting for 1:4 randomization, 5230 pts (PP set) are needed. Assuming a 5% exclusion rate from the PP set, about 5505 pts must be randomized.
Results:
5502 eligible pts were randomized to no SLNB (n=1101) vs. SLNB (n=4401). The drop-out rate was 6.3%, leading to an intent-to-treat (ITT) population of N=5154. After excluding 296 patients (n=252 without postoperative radiotherapy), 4858 patients (no SLNB: n=962, SLNB: n=3896) were included in the PP set. The median follow-up (FU) is 73.6 months (IQR 61.3-86.4).
Patient and tumor characteristics are well-balanced between treatment arms. The median age at diagnosis was 62.0 years (range 24.0–89.0). Most pts presented with low-risk BC (78.6% pT1 stage, 98.5% hormone receptor-positive, 3.6% HER2-positive, and 3.6% G3 tumors). Significantly more pts received adjuvant chemotherapy in the SLNB arm (13.2% vs 10.7% in the no SLNB arm).
The primary analysis in the PP established non-inferiority in iDFS between study arms with a HR=0.91 (95% CI: 0.73-1.14) for no SLNB to SLNB. The estimated 5-year iDFS rates are 91.9% (89.9%-93.5%) in the non-SLNB arm and 91.7% (90.8%-92.6%) in the SLNB arm. The first iDFS events (n=525, overall 10.8%) for no SLNB vs. SLNB consist of invasive locoregional recurrences (1.9% vs. 1.4%), including axillary recurrences (1.0% vs. 0.3%), invasive contralateral BCs (1.0% vs. 0.6%), distant metastases (2.7% vs. 2.7%), secondary malignancies (3.3% vs. 3.9%), and deaths (1.4% vs. 2.4%). The estimated 5-year overall survival (OS) rates are 98.2% (97.1%-98.9%) in the non-SLNB arm and 96.9% (96.3%-97.5%) in the SLNB arm.
Conclusion:
The INSEMA trial, enrolling 5500 pts, demonstrated that the omission of SLNB in clinically node-negative BC pts undergoing BCT resulted in a statistically significant non-inferior iDFS meeting the primary endpoint. INSEMA demonstrates oncological safety in all aspects when the axillary SLNB is omitted in cN0 patients with an early BC planned for primary BCT. This practice-changing concept is suitable for patients presenting with low-grade (G1/G2), hormone receptor-positive/HER2-negative invasive BC with tumor size up to 5 cm.
Background:
Axillary nodal status is an important prognostic factor in breast cancer (BC), guiding (neo)adjuvant systemic treatment and postoperative radiotherapy. As axillary surgery does not significantly affect BC mortality itself, it is considered as a staging procedure in clinically node-negative patients. The replacement of axillary lymph node dissection (ALND) by sentinel lymph node biopsy (SLNB) two decades ago and later omitting completion ALND (cALND) according to the ACOSOG Z0011 criteria led to surgical de-escalation. The Intergroup-Sentinel-Mamma (INSEMA) trial (NCT02466737) aims to investigate whether surgical axillary staging as part of breast-conserving therapy (BCT) for early BC can be avoided without compromising oncological safety.
Study Design:
The INSEMA trial was conducted between September 2015 and April 2019 in Germany and Austria. This prospective, randomized trial compares no axillary surgery with standard SLNB in pts with early invasive BC (tumor size ≤ 5 cm; c/iT1–2 c/iN0) scheduled for BCT, including postoperative whole-breast irradiation. The primary objective is to assess whether no axillary surgery is non-inferior to SLNB regarding invasive disease-free survival (iDFS). Clinical non-inferiority is a hazard ratio (HR) below 1.271 when comparing the non-SLNB with the SLNB group. The randomization was carried out in 4:1 allocation (SLNB vs. no SLNB) because pN1a(sn) pts in the SLNB arm underwent a second randomization to either SLNB alone or cALND (key secondary outcome). The primary analysis is based on the per-protocol (PP) set. Adjusting for 1:4 randomization, 5230 pts (PP set) are needed. Assuming a 5% exclusion rate from the PP set, about 5505 pts must be randomized.
Results:
5502 eligible pts were randomized to no SLNB (n=1101) vs. SLNB (n=4401). The drop-out rate was 6.3%, leading to an intent-to-treat (ITT) population of N=5154. After excluding 296 patients (n=252 without postoperative radiotherapy), 4858 patients (no SLNB: n=962, SLNB: n=3896) were included in the PP set. The median follow-up (FU) is 73.6 months (IQR 61.3-86.4).
Patient and tumor characteristics are well-balanced between treatment arms. The median age at diagnosis was 62.0 years (range 24.0–89.0). Most pts presented with low-risk BC (78.6% pT1 stage, 98.5% hormone receptor-positive, 3.6% HER2-positive, and 3.6% G3 tumors). Significantly more pts received adjuvant chemotherapy in the SLNB arm (13.2% vs 10.7% in the no SLNB arm).
The primary analysis in the PP established non-inferiority in iDFS between study arms with a HR=0.91 (95% CI: 0.73-1.14) for no SLNB to SLNB. The estimated 5-year iDFS rates are 91.9% (89.9%-93.5%) in the non-SLNB arm and 91.7% (90.8%-92.6%) in the SLNB arm. The first iDFS events (n=525, overall 10.8%) for no SLNB vs. SLNB consist of invasive locoregional recurrences (1.9% vs. 1.4%), including axillary recurrences (1.0% vs. 0.3%), invasive contralateral BCs (1.0% vs. 0.6%), distant metastases (2.7% vs. 2.7%), secondary malignancies (3.3% vs. 3.9%), and deaths (1.4% vs. 2.4%). The estimated 5-year overall survival (OS) rates are 98.2% (97.1%-98.9%) in the non-SLNB arm and 96.9% (96.3%-97.5%) in the SLNB arm.
Conclusion:
The INSEMA trial, enrolling 5500 pts, demonstrated that the omission of SLNB in clinically node-negative BC pts undergoing BCT resulted in a statistically significant non-inferior iDFS meeting the primary endpoint. INSEMA demonstrates oncological safety in all aspects when the axillary SLNB is omitted in cN0 patients with an early BC planned for primary BCT. This practice-changing concept is suitable for patients presenting with low-grade (G1/G2), hormone receptor-positive/HER2-negative invasive BC with tumor size up to 5 cm.
Axillary nodal status is an important prognostic factor in breast cancer (BC), guiding (neo)adjuvant systemic treatment and postoperative radiotherapy. As axillary surgery does not significantly affect BC mortality itself, it is considered as a staging procedure in clinically node-negative patients. The replacement of axillary lymph node dissection (ALND) by sentinel lymph node biopsy (SLNB) two decades ago and later omitting completion ALND (cALND) according to the ACOSOG Z0011 criteria led to surgical de-escalation. The Intergroup-Sentinel-Mamma (INSEMA) trial (NCT02466737) aims to investigate whether surgical axillary staging as part of breast-conserving therapy (BCT) for early BC can be avoided without compromising oncological safety.
Study Design:
The INSEMA trial was conducted between September 2015 and April 2019 in Germany and Austria. This prospective, randomized trial compares no axillary surgery with standard SLNB in pts with early invasive BC (tumor size ≤ 5 cm; c/iT1–2 c/iN0) scheduled for BCT, including postoperative whole-breast irradiation. The primary objective is to assess whether no axillary surgery is non-inferior to SLNB regarding invasive disease-free survival (iDFS). Clinical non-inferiority is a hazard ratio (HR) below 1.271 when comparing the non-SLNB with the SLNB group. The randomization was carried out in 4:1 allocation (SLNB vs. no SLNB) because pN1a(sn) pts in the SLNB arm underwent a second randomization to either SLNB alone or cALND (key secondary outcome). The primary analysis is based on the per-protocol (PP) set. Adjusting for 1:4 randomization, 5230 pts (PP set) are needed. Assuming a 5% exclusion rate from the PP set, about 5505 pts must be randomized.
Results:
5502 eligible pts were randomized to no SLNB (n=1101) vs. SLNB (n=4401). The drop-out rate was 6.3%, leading to an intent-to-treat (ITT) population of N=5154. After excluding 296 patients (n=252 without postoperative radiotherapy), 4858 patients (no SLNB: n=962, SLNB: n=3896) were included in the PP set. The median follow-up (FU) is 73.6 months (IQR 61.3-86.4).
Patient and tumor characteristics are well-balanced between treatment arms. The median age at diagnosis was 62.0 years (range 24.0–89.0). Most pts presented with low-risk BC (78.6% pT1 stage, 98.5% hormone receptor-positive, 3.6% HER2-positive, and 3.6% G3 tumors). Significantly more pts received adjuvant chemotherapy in the SLNB arm (13.2% vs 10.7% in the no SLNB arm).
The primary analysis in the PP established non-inferiority in iDFS between study arms with a HR=0.91 (95% CI: 0.73-1.14) for no SLNB to SLNB. The estimated 5-year iDFS rates are 91.9% (89.9%-93.5%) in the non-SLNB arm and 91.7% (90.8%-92.6%) in the SLNB arm. The first iDFS events (n=525, overall 10.8%) for no SLNB vs. SLNB consist of invasive locoregional recurrences (1.9% vs. 1.4%), including axillary recurrences (1.0% vs. 0.3%), invasive contralateral BCs (1.0% vs. 0.6%), distant metastases (2.7% vs. 2.7%), secondary malignancies (3.3% vs. 3.9%), and deaths (1.4% vs. 2.4%). The estimated 5-year overall survival (OS) rates are 98.2% (97.1%-98.9%) in the non-SLNB arm and 96.9% (96.3%-97.5%) in the SLNB arm.
Conclusion:
The INSEMA trial, enrolling 5500 pts, demonstrated that the omission of SLNB in clinically node-negative BC pts undergoing BCT resulted in a statistically significant non-inferior iDFS meeting the primary endpoint. INSEMA demonstrates oncological safety in all aspects when the axillary SLNB is omitted in cN0 patients with an early BC planned for primary BCT. This practice-changing concept is suitable for patients presenting with low-grade (G1/G2), hormone receptor-positive/HER2-negative invasive BC with tumor size up to 5 cm.
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