This clinical trial tests how well ultra-hypofractionated (UF) whole breast irradiation (WBI) with lumpectomy cavity boost (CB) works in treating patients with stage I-III breast cancer. Breast conservation therapy (BCT) is the recommended treatment for patients with early stage breast cancer. BCT involves a lumpectomy followed by breast radiation. Radiation therapy uses high energy x-rays, particles, or radioactive seeds to kill tumor cells and shrink tumors. Traditionally, WBI has been given once daily over 5-6 weeks and then those at high-risk for recurrence receive additional radiation (boost) to the lumpectomy cavity daily over 4-8 days. This has now been replaced by moderate hypofractionated radiation. Hypofractionated radiation therapy delivers higher doses of radiation therapy over a shorter period of time and may kill more tumor cells and have fewer side effects. Although moderate hypofractionated radiation therapy reduces the length of treatment from 6-7 weeks to 3-4 weeks, the length of treatment still remains a barrier for many patients. UF-WBI with CB delivers radiation to the whole breast and the surgical cavity at the same time over 5 daily treatments. Giving UF-WBI with CB may prevent recurrence and prolong survival as well as improve the quality of life in patients with stage I-III breast cancer.

PRIMARY OBJECTIVE:

I. To evaluate the impact of UF-WBI + CB as assessed by patient-reported Global Cosmesis Score (GCS) at 1 year.

SECONDARY OBJECTIVES:

I. To characterize the patient-reported cosmetic appearance of the breast over time, as assessed by GCS.

II. To determine short- and long-term physician-reported cosmetic appearance of the breast, as assessed by GCS.

III. To evaluate the acute and late patient-reported radiation-associated toxicities.

IV. To evaluate the acute and late physician-reported radiation-associated toxicities.

V. To estimate:

Va. 5-year in-breast recurrence; Vb. 5-year distant recurrence; Vc. 5-year disease-free survival (DFS); Vd. 5-year overall survival (OS).

EXPLORATORY OBJECTIVES:

I. To evaluate patient-reported quality-of-life (QoL). II. To evaluate volumetric and dosimetric factors associated with acceptable breast cosmesis.

III. To evaluate volumetric and dosimetric factors associated with acute and late radiation-associated toxicities.

OUTLINE:

Patients undergo UF-WBI with CB once daily (QD) on consecutive business days for up to 5 fractions in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo cone-beam computed tomography (CBCT) prior to each radiation treatment.

After completion of study treatment, patients are followed up at 1 month, 6 months, then annually for up to 5 years.

Inclusion Criteria:

• Documented informed consent of the participant and/or legally authorized representative

• Age: ≥ 40 years

• Female

• Ability to read and understand English for questionnaires

• Histologically confirmed breast cancer

• Malignancy must be epithelial. Non-epithelial breast malignancies such as lymphoma or sarcoma are not allowed

• Patients must have undergone breast conserving surgery. Re-excision for negative margins is allowed

• Patients must have undergone surgical staging of the axilla (sentinel lymph node biopsy or axillary lymph node dissection)

• Must have at least one-high risk feature that would necessitate a lumpectomy cavity boost by the treating radiation oncologist

• Patient must have physician-reported "Excellent" or "Good" cosmesis post-lumpectomy and prior to radiation therapy based on the 4-point Global Cosmetic Score

• Women of childbearing potential (WOCBP): negative urine or serum pregnancy test

  • If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
  • Childbearing potential defined as not being surgically sterilized (men and women) or have not been free from menses for > 1 year (women only)

Exclusion Criteria:

• Prior radiation to the region of the involved breast that in the opinion of the investigator would preclude breast irradiation
• Pathologically or clinically involved regional lymph nodes necessitating comprehensive regional nodal irradiation that includes the supraclavicular fossa
• Clinically significant uncontrolled illness
• Stage IV breast cancer
• Diagnosis of Paget's disease of the nipple
• Other prior or active malignancy. Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
• Pregnant or breastfeeding
• Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)