RNIShortening Adjuvant Photon and Proton Irradiation (SAPPHIRe-II): A 4 Cohort, Randomized, Phase II Multi-center Trial Evaluating Shorter Schedules of Adjuvant Regional Nodal Irradiation Among Women and Men With Node-positive and High-risk Node-negative Invasive Breast Cancer

Inclusion Criteria:

Eligibility Criteria Applicable to All Cohorts

Histologically confirmed invasive breast cancer (nodal involvement from presumed invasive breast cancer in the setting of occult breast cancer is sufficient to meet this criteria)

1\. Regional nodal irradiation recommended by treating radiation oncologist. 2 Negative final surgical margins. 3 No more than 12 weeks have elapsed since final breast/lymph node surgery for patients treated with surgery alone or neoadjuvant chemotherapy. No more than 12 weeks have elapsed since final cytotoxic chemotherapy for patients who received adjuvant chemotherapy. 5. Age ≥18 years. Because breast cancer is exceedingly rare in patients < 18 years of age, children are excluded from this study. 6. Patients with a prior or concurrent malignancy are eligible provided that the natural history and treatment of the prior or concurrent malignancy does not interfere with the safety or efficacy assessment of the investigational radiation regimen used in this trial. 7. Ability to understand and the willingness to sign a written informed consent document. 8. Concurrent enrollment on other observational, translational, or therapeutic studies is allowed provided there is no direct conflict between the other protocol and the radiation regimen proscribed in this trial.

Eligibility Criteria for the Low-Risk Lumpectomy Cohort

1. For patients treated with upfront surgery, pathologic stage pT0-T4b N0-N3a breast cancer without infraclavicular or internal mammary nodal involvement.
2. For patients treated with neoadjuvant chemotherapy, clinical stage cT0-T4b N0-N2a breast cancer.
3. Treated with lumpectomy (or axillary surgery only in the case of occult primary breast cancer)
4. No nodal boost recommended by the treating radiation oncologist.

Eligibility Criteria for the High-Risk Lumpectomy Cohort

1. Treated with neoadjuvant chemotherapy
2. Clinical stage cT0-T4b N1-N3a/b/c
3. Treated with lumpectomy (or axillary surgery only in the case of occult primary breast cancer)
4. Nodal boost recommended by the treating radiation oncologist.

Eligibility Criteria for the Low-Risk Mastectomy Cohort

1. For patients treated with upfront surgery, pathologic stage T0-T2 N0-N2a
2. For patients treated with neoadjuvant chemotherapy, clinical stage T0-T3 N0- N2a
3. For patients treated with neoadjuvant chemotherapy, residual cellularity of primary tumor ≤ 20%.
4. Treated with mastectomy
5. Negative surgical margins ≥ 2 mm.
6. No or only focal lymphovascular space invasion.
7. Age ≥ 40 years
8. Chest wall boost NOT recommended by treating radiation oncologist.

Eligibility Criteria for High-Risk Mastectomy Cohort

1. For patients treated with upfront surgery, pathologic stage T0-T4d N0-N3c
2. For patients treated with neoadjuvant chemotherapy, clinical stage T0-T4d N0- N3c
3. Treated with mastectomy
4. Chest wall boost and/or nodal boost recommended by treating radiation oncologist

Pregnancy Status (applicable to all cohorts)

Therapeutic radiation is known to be teratogenic. As a result, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of radiation treatment. (Refer to Pregnancy Assessment Policy MD Anderson Institutional Policy # CLN1114). This includes all female patients, between the onset of menses (as early as 8 years of age) and 55 years unless the patient presents with an applicable exclusionary factor which may be one of the following:

• Postmenopausal (no menses in greater than or equal to 12 consecutive months).
• History of hysterectomy or bilateral salpingo-oophorectomy.
• Ovarian failure (Follicle Stimulating Hormone and Estradiol in menopausal range, who have received Whole Pelvic Radiation Therapy).
• History of bilateral tubal ligation or another surgical sterilization procedure.

Approved methods of birth control are as follows: Hormonal contraception (i.e. birth control pills, injection, implant, transdermal patch, vaginal ring), Intrauterine device (IUD), Tubal Ligation or hysterectomy, Subject/Partner post vasectomy, Implantable or injectable contraceptives, and condoms plus spermicide. Not engaging in sexual activity for the total duration of the radiation therapy course is an acceptable practice; however periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of birth control. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.

Men treated or enrolled on this protocol must also agree to use adequate contraception during the radiation treatment course.

Pregnancy testing at the time of study enrollment is not required of women who enroll. However, all patients must comply with the Institutional Pregnancy Assessment Policy (# CLN1114) which requires pregnancy testing within 7 days prior to simulation.

Exclusion Criteria:

History of therapeutic radiation overlapping with the index breast or nodal basins that require radiation therapy.

History of scleroderma

Pregnant women are excluded from this study because ionizing radiation has the potential for teratogenic or abortifacient effects.

Patients with psychiatric illness/social situations that would limit compliance with study requirements