Background: Advances in chemotherapeutic and targeted agents have increased pathologic complete response (pCR) rates after neoadjuvant systemic therapy (NST). The role of surgery is essential to remove cancer when residual tumor is present, but it may be limited to pathologic confirmation in those with a pCR. As an alternative, pCR can be accurately evaluated with vacuum-assisted biopsy (VAB) in patients suggested to have a pCR on imaging. We aim to show a non-inferiority of omitting breast surgery in patients evaluated to have a pCR on image-guided VAB. Methods: The OPTIMIST trial is a prospective, multicenter, single-arm, non-inferiority clinical study. Sixteen tertiary care hospitals in South Korea are participating. Women diagnosed with invasive ductal carcinoma, a clip marker placed in the tumor, and who had completed NST with exceptional response are screened for eligibility. Inclusion criteria: women aged 19-75; cT1-2N0-2M0; triple-negative, HER2+, or low estrogen receptor (<10%); post-NST MRI size ≤1cm and lesion-to-background signal enhancement ratio ≤1.6. Exclusion criteria: malignant calcification >2cm; multifocal, bilateral, or inflammatory breast cancer; other malignancy within five years; BRCA1/2 mutation carrier. Under ultrasound or stereotactic guidance, VAB is performed targeting the clip marker to obtain a minimum of 6 cores using 7-10 G needles. When pCR is confirmed, breast surgery is omitted. cN0 patients with post-NST MRI tumor size ≤0.5cm and no suspicious lymph nodes, axillary lymph node surgery could also be omitted. Patients with residual tumor or atypical cells proceed with routine surgery. All patients are required to receive whole breast irradiation with tumor bed boost. According to previous studies, the 5-year disease-free survival (DFS) for patients with a pCR after NST was assumed to be 88%. The one-sided test with a non-inferiority margin of 4% and statistical power of 80% at a significance level of 0.05 resulted in a sample size of 384 patients to forego breast surgery. An expected 20% residual tumor on VAB and a 10% dropout resulted in a total of 533 subjects. Primary endpoint: 5-year DFS. Secondary endpoint: 5-year ipsilateral breast tumor recurrence-free survival, 5-year overall survival, 5-year invasive DFS, residual axillary lymph node rate, quality of life scores, symptoms (VAS), and medical cost. An interim analysis is planned at 50% enrollment with a median follow-up period of 1 year. The data safety monitoring board will determine the continuation of the study considering the 1-year DFS.The first patient was enrolled on September 22, 2022, and 12 patients have been enrolled as of February 14, 2023. We plan to complete the target accrual by December 2025. Clinical trial information: NCT05505357.