APBI Proton Feasibility and Phase II Study

The purpose of the APBI Proton Therapy study is to examine the feasibility, side effects,
and clinical efficacy of using proton therapy on only the tumor bed of women being treated
for breast cancer after surgical removal of malignancy (as opposed to whole breast
treatment). The study's aim is to establish the effects of this type of therapy as it
compares to both traditional radiation and whole breast treatment therapies. In order to be
eligible, the patient must be a female older than 50 with either invasive ductal, medullary,
papillary, colloid (mucinous) or tubular histologies of stage IA-IIA breast cancer, ECOG
performance status of 0-2, have margins of greater than or equal to 2mm, be node negative or
have only microscopic node disease, have estrogen- or progesterone-positive breast cancer,
and other eligibility criteria must be met that is more detailed to describe herein.

Inclusion Criteria:

- Histologically confirmed diagnosis of invasive or non-invasive breast cancer.

- Invasive ductal, medullary, papillary, colloid (mucinous) or tubular histologies.

- AJCC T1 or T2; N0 or N1mic; Stage IA-IIA breast cancer or AJCC TIS (Stage 0) ductal
carcinoma in situ without invasion

- Gross disease must be unifocal with pathologic (invasive and/or DCIS) tumor size 3 cm
or less. (Patients with microscopic multifocality are eligible as long as total
pathological size is 3 cm or less).

- Estrogen and/or progesterone receptor positive invasive breast cancer. DCIS stage 0
does not require receptor testing.

- No evidence of distant metastatic disease as documented by history and physical
examination (radiographic staging only to be performed as indicated by symptoms or
physical findings.)

- Patients must have an ECOG Performance Status of 0, 1 or 2

- Age ≥ 50.

- Patients must be able to provide informed consent.

- Patients must have undergone breast-conserving surgery

- All tumors (invasive and non-invasive disease) must be excised with a minimum margin
width of ≥ 2 mm. Re-excision of surgical margins is permitted. Focally close (<2 mm)
or positive (tumor cells at the inked edge of the specimen) margins determined to be
at an anatomic boundary of resection by the surgeon, such as posterior fascia for
posterior margins or skin for anterior margins, are also acceptable.

- Patients with invasive breast cancer must be node-negative (N0) or have only
microscopic disease (≤2mm) in the nodes (N1mi). Patients with Stage IA - IIA are
required to have axillary staging but it will not be done for patients with Stage 0
DCIS. Options for axillary staging include:

1. Negative sentinel lymph node biopsy (SLNB)

2. Level I-II axillary lymph node dissection (ALND) (6 or more nodes removed).

3. Positive SLNB followed by completion ALND (6 or more nodes removed).

- Patients presenting with abnormal microcalcifications on a screening mammogram must
have radiographically confirmed excision of the suspicious microcalcifications,
either by specimen radiograph or post-biopsy mammograms.

- The patient must be enrolled on the study within 50 days following the last surgery
for breast cancer (lumpectomy, re-excision of margins, or axillary staging
procedure).

- The target lumpectomy cavity must be clearly delineated and the target lumpectomy
cavity/whole breast reference volume must be ≤ 30% based on the
postoperative/pre-enrollment CT scan.

- Patients must have bilateral mammogram and/or breast MRI within 3 months of diagnosis
of their breast cancer.

- CBC/differential obtained within 3 months prior to registration on study, with
adequate bone marrow function defined as follows: Absolute neutrophil count (ANC) ≥
1,800 cells/mm3; Platelets ≥ 75,000 cells/mm3; Hemoglobin ≥ 8.0 g/dl (Note: The use
of transfusion or other intervention to achieve Hgb ≥ 8.0 g/dl is acceptable).

- Patients with synchronous bilateral breast cancers who will be treated with
radiotherapy to each breast are eligible, provided such treatment can be performed in
a manner that avoids overlap between treatment fields. Both sides may be treated with
APBI if the pathologic eligibility criteria are met for both tumors, or only one side
may be treated with APBI if the criteria are met for only one tumor.

- Patients with a history of prior breast cancer in the opposite breast are eligible as
long as treatment can be performed without overlapping any prior RT fields.

- Patients with a history of prior breast cancer in the ipsilateral breast treated with
lumpectomy alone (no RT) are eligible as long as the other entry criteria for this
study are met.

- Patients with a history of non-breast malignancies are eligible as long as they have
not received prior radiotherapy to the thoracic region, and have a greater than 2
year interval without evidence of recurrence.

- Women of childbearing potential must be non-pregnant and non-lactating and willing to
exercise an effective form of birth control during radiation therapy (e.g. oral
contraceptive, IUD, condoms or other barrier methods etc.). Hysterectomy or menopause
must be clinically documented.

- Patient must provide study-specific informed consent prior to study entry.

Exclusion Criteria

- Male breast cancer

- T2 (>3cm), T3, T4, Node positive (other than N1mi), or M1 disease

- Lobular or mixed ductal and lobular histology.

- Multifocal primary tumor.

- Clear delineation of the extent of the lumpectomy cavity is not possible. Prior or
simultaneous malignancies within the past two years (other than carcinoma in situ of
the cervix, CIS of the colon, melanoma in situ, thyroid cancer, and basal cell or
squamous cell carcinoma of the skin).

- Any non-axillary sentinel node(s) positive. (Note that intramammary nodes are staged
as axillary nodes).

- Patients who have had a positive SLNB but decline completion ALND are not eligible.

- Patients treated with neoadjuvant chemotherapy are not eligible.

- Palpable or radiographically suspicious ipsilateral or contralateral axillary,
supraclavicular, infraclavicular, or internal mammary nodes, unless there is
histological confirmation that these nodes are negative for tumor.

- Suspicious microcalcifications, densities, or palpable abnormalities (in the
inpsilateral or contralateral breast) unless these were biopsied and found to be
benign.

- Proven multicentric carcinoma (invasive cancer or DCIS) in more than one quadrant or
two or more breast cancers not resectable through a single lumpectomy incision.

- Paget's disease of the nipple.

- Surgical margins that cannot be microscopically assessed or are positive at
pathological evaluation. A focally positive margin determined to be at an anatomic
boundary of resection by the surgeon, such as posterior fascia for posterior margins
and skin for anterior margins, is also acceptable. If surgical margins are rendered
free of disease by re-excision, the patient is eligible.

- Breast implants. (Patients who have implants removed are eligible).

- Prior ipsilateral breast or thoracic radiation for any condition.

- Collagen vascular disease, specifically dermatomyositis with a CPK level above normal
or with an active skin rash, systemic lupus erythematosis, or scleroderma.

- Pregnant women, women planning to become pregnant and women that are nursing.

- Psychiatric or addictive disorders or other conditions that, in the opinion of the
investigator, would preclude the patient from meeting the study requirements.

- Actively being treated on any other therapeutic research study.