Inclusion Criteria:

• The patient must have signed and dated an IRB-approved consent form that conforms to federal and institutional guidelines.
• The trial is open to female and male patients.
• Age ≥ 18 years old.
• The patient must have an ECOG Performance status of 0 or 1.
• Patients must have had ER analysis performed on the primary breast tumor collected prior to neoadjuvant therapy according to current ASCO/CAP Guideline Recommendations for hormone receptor testing. If negative for ER, assessment of PgR must also be performed according to current ASCO/CAP Guideline Recommendations for hormone receptor testing (http://www.asco.org). Patients who have a primary tumor that is hormone receptor-positive or hormone receptor-negative are eligible.
• Patients must have had HER2 testing performed on the primary breast tumor collected prior to neoadjuvant chemotherapy according to the current ASCO/CAP Guideline Recommendations for Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer (http://www.asco.org). Patients who have a primary tumor that is HER2-positive, HER2-equivocal, or HER2-negative are eligible.
• Patients must have had a biopsy marker placed within the tumor bed with imaging confirmation (preferably mammogram but ultrasound or MRI is acceptable) of marker placement prior to neoadjuvant chemotherapy.
• Patients with operable focal or multifocal (T1-T3, stage II or III invasive ductal carcinoma [all receptor phenotypes]), and who have completed neoadjuvant chemotherapy with a clinical complete response (by clinical examination).
• Patients with synchronous bilateral breast cancer are eligible if at least one of the synchronous breast cancers has a cCR, and the side with a cCR meets criteria 3.2.8 and 3.2.10. (Patients with previous contralateral invasive breast cancer treated with anti-cancer therapy are eligible.)
• Patients must have achieved a complete or near complete radiologic tumor response on breast imaging with mammogram, ultrasound, and MRI during or after completion of appropriate neoadjuvant chemotherapy defined as:
  • Mammogram with malignant appearing calcifications or mass ≤ 1 cm; and
  • Ultrasound with a hypoechoic area ≤ 2 cm; and
  • Breast MRI not demonstrating a residual mass with rapid rise and washout type III kinetics.
  • Note: A negative study (i.e., no evidence of abnormality) on each imaging modality is also acceptable.
• At the time of consent, the patient's intent must be to undergo breast conserving therapy.
• Patient must be able to undergo stereotactic-vacuum-assisted breast biopsy with clip placement after completion of neoadjuvant chemotherapy. (The patient must be enrolled on the study before performing the post-neoadjuvant stereotactic-vacuum-assisted breast biopsy.)
• Patient must have completed appropriate institutional neoadjuvant chemotherapy.
• Patients with HER2-positive tumors must have received neoadjuvant anti-HER2 therapy (either with all or with a portion of the neoadjuvant chemotherapy regimen), unless medically contraindicated.
• Patients treated with PD-1 or PD-L1 inhibitors, CDK 4/6 inhibitors, or other immune-based therapy are eligible.

Exclusion Criteria:

• T4 tumors including inflammatory breast cancer.
• Patients with distant metastatic disease.
• Lumpectomy performed prior to study entry.
• Patients with any history of prior radiation therapy in the affected breast.
• Patients with prior history of ipsilateral invasive breast cancer. (Patients with previous ipsilateral/contralateral DCIS or previous contralateral invasive breast cancer treated with anti-cancer therapy are eligible).
• Patients with invasive lobular carcinoma.
• Patients who have multicentric disease.
• Patients treated with neoadjuvant hormonal therapy only are not eligible.
• Patients who are medically unfit to undergo surgical resection.
• Patients without breast biopsy marker documented by imaging at tumor bed site prior to initiation of neoadjuvant therapy.
• Patients with one or more of the following imaging criteria from any of the 3 imaging modalities after completion of NCT demonstrating incomplete radiologic response are not eligible:
  • Mammogram with malignant appearing calcifications or mass > 1 cm; or
  • Ultrasound with a hypoechoic area > 2 cm; or
  • Breast MRI demonstrating a residual mass with rapid rise and washout type III kinetics.
• Psychiatric or addictive disorders or other conditions that, in the opinion of the investigator, would preclude the patient from meeting the study requirements or interfere with interpretation of study results.
• Pregnancy or lactation at the time of study registration.
  • Note: Pregnancy testing according to institutional standards for women of childbearing potential must be performed within 2 weeks prior to study registration.