A Pilot/Phase II Trial of Hypofractionated Radiotherapy to the Whole Breast Alone Before Breast Conserving Surgery
Phase: PHASE2
Conditions: Anatomic Stage I Breast Cancer AJCC v8, Anatomic Stage IA Breast Cancer AJCC v8, Anatomic Stage IB Breast Cancer AJCC v8, Anatomic Stage IIA Breast Cancer AJCC v8, Prognostic Stage I Breast Cancer AJCC v8, Prognostic Stage IA Breast Cancer AJCC v8, Prognostic Stage IB Breast Cancer AJCC v8, Prognostic Stage IIA Breast Cancer AJCC v8
Sponsor: Mayo Clinic

 
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MC1732 
 
Mayo Clinic Radiation Oncology 
 
A pilot/phase II trial of hypofractionated radiotherapy to the whole breast alone before breast 
conserving surgery  
 
 
 
Study Chair Arizona: 
Carlos E. Vargas, M.D. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Study Co-Chair Surgery:  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
           Study Co-Chair Translational Research: 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Co-chair Arizona: 
 
 
 
 
 
 
 
 
 
 
 
 
 
                  
              Study Co-Chair Mayo Rochester: 
 
 
 
 
  
 
                 Study Co-Chair Mayo Florida:  
 
 
 
 
  
 
 
Study Co-Investigators: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Statistician: 
 
 
2nd Statistician: 
 
 
                                      Physics Chair Arizona:       
  
 
 
 
                                       
 
Study contributor(s) not responsible for patient care. 
 
 
Document History 
Effective Date 
Active 
Modification 1 
Modification 2 
Modification 3 
Modification 4 
7/17/2018 
11/12/2018 
12/14/2018 
10/14/2019 
6/1/2020 
 
 
 
 
 
 
 

 
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Protocol Resources 
 
Questions: 
Contact Name: 
Patient eligibility*, test schedule, 
treatment delays/interruptions/adjustments, 
dose modifications, adverse events, 
protocol document, consent form, 
regulatory issues, 
forms completion and submission 
Rad Onc Study Coordinator 
 

 
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Index 
Schema 
  1.0 
Background   
  2.0 
Goals 
  3.0 
Patient Eligibility 
  4.0 
Test Schedule 
  5.0  
Stratification Factors 
  6.0 
Registration/Randomization Procedures 
  7.0 
Protocol Treatment 
  8.0 
Radiotherapy Dose Modifications Based on Adverse Events  
  9.0 
Ancillary Treatment/Supportive Care 
10.0 
Adverse Event (AE) Reporting and Monitoring  
11.0 
Treatment Evaluation  
12.0 
Descriptive Factors 
13.0 
Treatment/Follow-up Decision at Evaluation of Patient  
14.0 
Body Fluid Biospecimens 
15.0 
Drug Information 
16.0 
Statistical Considerations and Methodology 
17.0 
Pathology Considerations 
18.0 
Records and Data Collection Procedures 
19.0 
Study Finances 
20.0 
Publication Plan 
21.0 
References 
Appendix I – ECOG Performance Status 
Appendix II – Mayo Breast Patient Survey 
Appendix III – Mayo Patient Survey PRO-CTCAE Mayo 10 
Appendix IV – Mayo Patient Survey 
 
 
 
 
 
 
 
 
 
 
 

 
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List of Abbreviations 
3DCRT 
3-D Conformal Radiation Therapy 
AE 
Adverse Event/Adverse Experience 
CBCT 
Cone Bean CT 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
CTV 
Clinical Target Volume 
DSMB 
Data and Safety Monitoring Board 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
IBTR 
Ipsilateral breast tumor recurrence 
IMRT 
Intensity Modulated Radiation Therapy 
IRB 
Institutional Review Board 
MRI 
Magnetic Resonance Imaging 
PHI 
Protected Health Information 
PI 
Principal Investigator 
PTV 
Planning Target Volume 
QOL 
Quality of Life  
RBE 
Relative biologic effectiveness 
RT 
Radiation Therapy 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SOP 
Standard Operating Procedure 
XRT 
X-ray Radiation Therapy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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N=25 patients  
cStage T1-T2 N0-M0 and indications 
for whole breast irradiation without 
regional nodal irradiation, before 
breast conserving surgery. 
5 Fraction 
Hypofractionation 
25 Gy in 5 daily fractions 
(n=25) 
Treatment 
Observation 
 
Event Monitoring 
(Section 18.0 –5 years total 
follow-up) 
SCHEMA 

 
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Study Design: This is a phase II trial to determine the effect of 25Gy in 5 fractions to the whole breast 
alone before breast conserving surgery.  
 
1.0 
Background 
 
Breast Conserving Therapy and Breast Radiation 
Breast cancer is the most common female malignancy in the United States with over 200,000 new cases 
being diagnosed annually. In the same manner, breast cancer mortality is one of the leading causes of 
cancer death among women. In breast cancer patients, the addition of whole breast radiotherapy after 
breast conserving surgery has been shown to result in improvement in rates of recurrence and survival for 
women with early stage and locally-advanced breast cancer.   
 
Breast conserving therapy (BCT) refers to breast conserving surgery (BCS) and radiation therapy (RT) to 
eradicate any microscopic residual disease. The aim of BCT is to achieve equivalent overall survival 
compared with patients undergoing a mastectomy, with acceptable rates of local recurrence and good to 
excellent cosmetic results. 
 
Six modern phase III trials have directly compared BCT to mastectomy and a meta-analysis of these trials 
has shown equivalent survival.1-11   Furthermore, the EBCTCG has shown the benefit of radiotherapy as 
an integral part of breast conserving therapy. Although the relative benefit of radiotherapy was similar for 
different patients, the absolute benefit will vary for different patient populations.12 
 
Radiation therapy is considered an integral part of BCT. Despite this, certain subsets of patients may elect 
to forego radiotherapy given a small absolute benefit. CALGB 9343 and PRIME II have shown that 
selected elderly patients with early stage favorable breast cancer may safely omit radiotherapy after 
BCT.13,14 
 
Interestingly, a subtype population in the previously described Canadian study looking at the omission of 
radiotherapy demonstrated that the luminal A subtype of breast cancer (as defined by immuno-
histochemical analysis) was prognostic but not predictive of response to radiotherapy.15  Although the 
importance of radiation in the management of breast cancer is unquestioned, the ideal timing and overall 
effect of radiation on breast cancer based on different gene expression signatures is unknown at the 
present time. 
 

 
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Neo-adjuvant Therapy for Breast Cancer 
Neo-adjuvant systemic therapy has been found to have similar outcomes to adjuvant chemotherapy after 
BCT16-18 However, certain advantages of neo-adjuvant systemic treatment may include downstaging the 
tumor to allow for less extensive surgery, improved cosmetic outcomes, and reduced postoperative 
complications such as lymphedema.16,19 Neo-adjuvant therapy also permits an early evaluation of the 
effectiveness of systemic therapy. The presence or absence of residual invasive cancer after neo-adjuvant 
chemotherapy is a strong prognostic factor for the risk of recurrence. 
 
In addition to the benefits as outlined above, neo-adjuvant therapy gives us the opportunity to obtain 
imaging, tumor specimens, and blood samples prior to, during, at the time of surgery, and after the 
preoperative treatment. This information has enabled us to understand the true effect of neo-adjuvant 
therapy on breast cancer. Furthermore, it has allowed us to understand tumor and patient-specific 
biomarkers with respect to response or resistance. Given the aforementioned findings, one would expect 
neo-adjuvant radiotherapy to result in similar outcomes as postoperative radiotherapy, as seen previously 
with neo-adjuvant systemic chemotherapy. The opportunity to treat patients with neo-adjuvant 
radiotherapy would provide vital information to help the cancer community better understand the effect of 
radiation on tumor response, biomarkers, and DNA profiling of breast cancer. This information is crucial 
if we wish to better define the effect of radiotherapy on breast cancer and tailor our treatment doses to 
individual patients and their specific type of breast cancer.  
 
Hypofractionated Breast Radiation 
 
The most robust data for hypofractionated breast radiation comes from the United Kingdom. The Start A 
and Start B trials compared different hypofractionated radiotherapy regimens with the conventional 
regimen of 50Gy in 25 treatments over 5 weeks. The Start B trial, analyzed patients receiving a 
hypofractionated regimen of 40Gy in 15 treatments over 3 weeks, and found that the hypofractionated 
regimen resulted in less breast shrinkage, telangiectasia, and breast edema as compared to the standard 
arm. 20 No difference in arm edema or shoulder stiffness was seen among any of the hypofractionated 
arms as compared to 50Gy over 5 weeks.  Interestingly, the hypofractionated 40Gy arm treated over 3 
weeks had fewer distant events, which translated into an overall survival benefit at 10-year followup.  The 
study concluded that hypofractionated radiotherapy of 40Gy in 15 treatments over 3 weeks was superior 
to the standard conventional 50Gy in 25 treatments over 5 weeks in terms of adverse events and cancer 
specific outcomes. 
 

 
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The UK Fast Trial published the cosmetic results of 390 patients undergoing conventional and 
hypofractionated radiotherapy. 21 A hypofractionated regimen of 30Gy and 28.5Gy in 5 treatments over 5 
weeks was compared to a longer conventional regimen of 50Gy in 25 treatments over 5 weeks. At 2 years 
post-randomization, 20.8% of patients had mild change and 6.2% had marked change in photographic 
breast appearance. There was no difference observed for any of the dosimetric parameters confirming the 
safety of a more hypofractionated approach.  Furthermore, the initial results showed three-year rates of 
physician-assessed moderate/marked adverse effects in the breast were similar for 28.5Gy in 5 treatments 
over 5 weeks when compared with 50Gy in 25 treatments over 5 weeks.22 
 
The Fast Forward Trial has also published comparable acute toxicity among 40Gy in 15 treatments over 3 
weeks, and 27Gy or 26Gy in 5 treatments over one week.23 190 and 162 patients were recruited for two 
studies. In the first sub-study, evaluable patients with grade 3 RTOG toxicity were: 13.6% with 40Gy in 
15 fractions; 9.8% with 27 Gy in 5 fractions; and 5.8% with 26 Gy in 5 fractions. In the second sub-study 
only one patient presented with G3 CTCAE toxicity in the 27 Gy in the 5 fraction arm. 
 
Preoperative Radiation 
Preoperative radiotherapy has been used successfully in the past for the management of breast cancer. 24-28 
Preoperative radiotherapy in patients with locally advanced breast cancer has shown excellent loco-
regional control rates even when few patients receive systemic therapy. Pathologic complete response 
(pCR) was also associated with improved outcomes in patients undergoing preoperative radiotherapy.28 
Matuschek et al. reported that pCR after neo-adjuvant chemo-radiation was 56% for node-positive cases 
(cN+).  The multivariate analysis of this study revealed that a longer time interval to surgery increased the 
probability for a pCR (HR 1.17 [95% CI 1.05–1.31], p < 0.01). Importantly, pCR was the strongest 
prognostic factor for long-term survival in patients (HR 0.28 [95% CI 0.19–0.56], p < 0.001).27   
 
Other studies have looked at hypofractionated preoperative radiation as well. Researchers at the 
University of Maryland evaluated the impact of preoperative hypofractionated radiation on pathologic 
complete response (NCT01014715). Bondiau et al 29 analyzed five different dose levels during 
preoperative chemotherapy in high-risk breast cancer patients.  Dose levels of 19.5Gy, 22.5Gy, 25.5Gy, 
28.5Gy and 31.5Gy were used, with only one grade 3 treatment related AE seen at 8 months. Moreover, 
pCR was seen in 36% of the patients. However, no pCR was observed in the first dose level of 19.5 Gy, 
and the majority of pCR (67%) were observed in level 3 (25.5Gy). Given the response with doses of 
25.5Gy and higher, a dose of 25.5Gy was selected for future hypofractionated preoperative trials. Horton 
et al also evaluated extreme preoperative hypofractionated radiation using a single treatment of intensity 

 
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modulated radiation therapy with 15 Gy, 18 Gy, or 21 Gy to the tumor with a 1.5-cm margin.30 No dose 
limiting toxicity was seen. Tumor response was difficult to evaluate given that surgery was done 10 days 
after radiotherapy.  Multiple studies have shown the safety and excellent cosmetic results of preoperative 
radiation either in a hypofractionated approach or with standard fractionation. Furthermore, the use of 
preoperative radiotherapy alone or concurrently with chemotherapy has also been tested and reveals 
excellent results with minimal toxicity. The literature provide a very compelling argument favoring the 
use of hypofractionated radiation therapy to a dose of 25Gy in 5 fractions, followed by surgery 8 weeks 
thereafter  to maximize radiation response, as proposed in our current study.  
 
To assess the response of hypofractionated radiation therapy before radiation we would use residual 
cancer burden in the surgical specimen. We defined a pathological complete response (pCR) as a residual 
tumor burden of 0-1.31 
 
Boost 
The EORTC trial showed a small improvement in local control with the use of a boost (4% at 10 years).   
However, severe breast fibrosis was increased by a similar magnitude at 10-years (3%). Furthermore, no 
difference was seen between the two groups in terms of breast cancer mortality, overall incidence of 
breast cancer–related events, disease-free survival, or overall survival.32  Since, the use of boost has 
shown an increase in severe breast fibrosis without an improvement in breast related outcomes, we have 
elected not to use a boost for this trial. 
 
Predicting response to RT 
There has been much interest recently in developing more useful biomarkers to identify patients risk and 
response to radiation therapy in breast cancer.  Clinico-pathologic factors as used in the CALGB 9343 
study or PRIME II, including age, tumor size, and hormone receptor status, remain imperfect in their risk 
stratification, and thus identifying overall risk and radiation response remains an unmet clinical need.13,14 
The Danish study has shown that post-mastectomy radiation improved survival in certain cohorts of 
patients over others.33,34 However, different studies suggest different benefits based on these biomarkers. 
These findings lend to the necessity of additional research regarding the response of radiation in cohorts 
of patients treated uniformly and for whom gene expression profiling is done.  Similar to chemotherapy 
tests such as OncotypeDx and Mammaprint, biomarker testing can ultimately prove beneficial to further 
delineate the benefit of radiotherapy in our breast cancer patients.  
 

 
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Ideally, breast cancer response to radiation should be addressed by studying the direct effect of radiation 
on the tumor cells. Gene profiling before and after radiotherapy would help better define the effect of 
radiation over breast cancer and associated predictive DNA signatures, which remains an active area of 
interest in the breast cancer field.  
 
Through our research, we hope to better define the breast cancer response to hypofractionated radiation 
without the confounding factors of other systemic treatments. This research would provide a unique 
opportunity to address the effect of radiation and describe DNA signatures more likely to be associated 
with response. We aim to further understand the effect of radiation on cancer cells and, thus individualize 
the dose and timing of radiation therapy that is necessary to eradicate breast cancer cells.  
 
 
 
Summary 
 
At the present time, very little data exists regarding the distinct changes that occur with radiotherapy in 
the cancer itself.  Breast cancer represents a heterogeneous disease with distinct clinical features that can 
be predicted by differences in the DNA. The analysis of tumor mutation signatures may lead to a better 
understanding of the effect of radiotherapy in breast cancer. Preoperative radiation of the intact tumor 
with a hypofractionated regimen can potentially decrease toxicity by allowing the delivery of treatment to 
intact breast tissue. The potential advantages of preoperative radiation therapy include the delivery of 
radiation in the intact breast when radiation can be more efficacious as more oxygen can be available in 
the tissue. Furthermore, complications and cosmetic results are expected to be lower in pre-operative 
radiotherapy before surgery, as there have been no changes in blood supply to the breast. This lends to the 
possibility of using lower doses of radiotherapy to patients, and potentially better cancer associated 
clinical outcomes for our breast cancer patients.  
 
 
2.0 
Goals  
 
2.1 
Primary Objectives 
 
2.1.1     To determine the pathologic complete response (pCR) rate after hypofractionated 
radiotherapy to the whole breast alone, based on the postsurgical specimen. We define a 
pCR as residual cancer tumor burden of 0-1. 
 
 
2.2 
Secondary Objectives  
 

 
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2.21 
To evaluate acute and late toxicity with preoperative radiation including grade ≥2 
pneumonitis.  
 
2.22 
To estimate the 5-year locoregional control, distant recurrence, invasive disease-
free survival, cause-specific survival, and overall survival. 
 
2.3 Correlative and Exploratory 
 
2.31  
To evaluate patient-reported outcomes. 
 
2.32  
To evaluate clinical features, treatment technique, dose-volume parameters, 
histologic and genetic variants associated with adverse events, and fair and poor 
cosmetic outcomes or unplanned surgical intervention.  
 
2.33  
Evaluate tumor mutation signatures before and after radiation; correlate tumor 
mutation signatures before and after radiation with pathologic information at the 
time of surgery. 
 
2.34  
To describe the pathologic changes seen in breast cancer patients with 
preoperative radiation.   
 
 
 
3.0 
Patient Eligibility    
 
3.1 Inclusion Criteria   
 
3.1.2 
Age ≥ 18 years. 
 
3.1.3  
Histological confirmation of breast cancer.  
 
3.1.4 
Clinical Stage T0-T2 N0 M0.  
 
 
3.1.5 
ECOG Performance Status (PS) 0 to 2. (Appendix I) 
 
3.1.6 
Able to and provides IRB approved study specific written informed consent. 
 
3.1.7a 
Study entry must be within 120 days of last biopsy (breast). 
 
 
3.1.7b 
Able to complete all mandatory tests listed in section 4.0. 
 
3.1.7c 
Willing to return to enrolling institution for follow-up (during the active 
monitoring phase of the study). 
 
3.1.8           Planned breast surgery and indications for whole breast radiotherapy. 
 
3.1.9 
No neo-adjuvant therapy 
 
 
 
 
 

 
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3.2 
Exclusion Criteria  
 
3.2.1 
Medical contraindication to receipt of radiotherapy. 
 
3.2.2 
Severe active co-morbid systemic illnesses or other severe concurrent disease 
which, in the judgment of the investigator, would make the patient inappropriate 
for entry into this study or interfere significantly with the proper assessment of 
safety and toxicity of the prescribed regimens. 
 
3.2.3 
Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situations that would limit compliance 
with study requirements or providing informed consent. 
3.2.4 
Active systemic lupus or scleroderma.  
 
3.2.5 
Pregnancy.  
 
3.2.6 
Women of childbearing potential who are unwilling to employ adequate 
contraception. 
 
3.2.7 
Prior receipt of ipsilateral breast or chest wall radiation.  
 
3.2.8 
Recurrent breast cancer. 
 
3.2.9  
Indications for comprehensive regional nodal irradiation. 
 
                    

 
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1 Highly suggested but not mandatory. 
2 Digital photographs can be done at any time before or after treatment at the discretion of the physician. 
3 Last day of treatment +/- 2 days, per discretion of the treating physician. 
4 Outside pathology must be reviewed at treating institution to confirm eligibility. 
5 For women of childbearing potential only, blood pregnancy test to be completed prior to start of radiation.  
6 Failure defined as recurrent disease. 
7 For tissue: total of 4 samples will be collected (2 at pre-RT and 2 at surgery), see section 17.1 for details. For blood: total of 12 samples 
will be collected (6 at pre-RT and 6 at surgery), see section 14.1 for details. 
 
 

 
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5.0 
Stratification Factors  
5.1  
None.  
  
  
6.0  
Registration  
6.1 
Registration Procedures 
6.1.1  Patient will be registered to the study when they have consented, met eligibility criteria, 
and have been logged into the Research Participant Tracking (Ptrax) system. 
6.1.2  Baseline tests/procedures (see section 4.0) will be completed within the guidelines 
specified on the test schedule. 
6.1.3  All patients meeting eligibility criteria who have signed a consent form and who have 
completed treatment will be evaluable for the primary analysis. All patients completing 
treatment as per the study pre-op RT followed by breast conserving surgery will used to 
determine the protocol accrual. 
6.1.4 
Patients consented and enrolled will be monitored in the registry, if patients signed our 
registry consent (IRB 16000492). All patient meeting accrual as defined in 6.1.3 will be 
analyzed per study. 
 
7.0 
Protocol Treatment 
 
Doses throughout will be prescribed in Gy or Gy(RBE). Radiation therapy must begin within 180 
days of the last biopsy date.  Concurrent cytotoxic chemotherapy with radiotherapy is not 
allowed.  
 
7.1       Radiation Therapy 
 
7.2 
Dose Specifications 
Whole breast irradiation  
7.211 Breast: 25 Gy (RBE) in 5 fractions of 5 Gy (RBE)  
 
7.3 
Treatment Technique 
7.31 
Radiation will be delivered using available scanning beam proton equipment at 
the treating institution or conventional radiation photon (x-ray) radiation. 
 
7.4 
Localization, Simulation, Immobilization 
7.41 
Simulation should be performed with the patient in the supine or prone position 
7.42 
Patients should be optimally positioned with a custom immobilization device at 
the discretion of the treating physician. 
7.43 
Arm position may be up or down. 
7.44 
The CT should extend cephalad to at least the level of the mandible to include 
both elbows and extend caudally to encompass the entire lung volume. The CT 
scan thickness will be 2mm. 

 
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7.45 
External skin markers, which may include permanent tattoos, are recommended 
for daily set-up. 
7.46 
KV image guidance will be performed daily. Other imaging modalities, such as 
CBCT and Vision RT, real time tracking or others should be performed based on 
institutional guidelines and/or physician preference.  
7.47 
Volumetric imaging may be performed with re-planning at the physician’s 
discretion. 
7.48 
CT simulation would be done with contrast to better define the tumor volume. 
 
7.5 
Treatment Planning 
7.51 
Radiation Proton Planning 
7.511 For proton planning, 2 or more en face or oblique fields are 
recommended. 
7.52 
Radiation Photon (x-ray) Planning 
7.521 Planning would be done based on tangent fields. 
7.522 An inverse planned optimization is used to determine the beam weights 
to meet the target and critical structure dose-volume constraints and will 
be used for all left sided breast cancer patients pending insurance 
approval. 
7.523 If IMRT is combined with the standard open medial and lateral 
tangential fields for whole breast irradiation, the IMRT beam as defined 
in Section 7.522 (1) should deliver > 50% of the total number of monitor 
units for the beam orientation. 
7.524 3D field inside of a field would be used if IMRT is not approved by the 
insurance carriers. 
7.53 
Additional supraclavicular/axillary radiation 
7.531 In cases were more than two SLN are found to have disease or extra 
capsular extension is found additional radiation to the SCF/axilla area 
can be given at the discretion of the treating radiation oncologist. Doses 
fields and techniques would be defined by the treating physician.  A 
matching anterior oblique field with an IMRT gradient based on prior 
dose distribution is encouraged. 
7.54 
Image guidance 
7.541 Cone beam CT would be done daily pre-treatment. Alternatively, if is not 
available CT on rails can be used. Kv guidance can be used for proton 
therapy if volumetric guidance is not available. Kv guidance can be used 
if conebeam is not an option 
 
7.6 
Target Volumes 
The definitions for the CTV and normal structures for this protocol will generally follow the 
RTOG (Radiation Therapy Oncologic Group)-endorsed consensus guidelines for delineation 
for breast cancer 
 with 
exceptions described below. 
7.61 
Breast target volumes 
7.611 High tangents volume:  Alternatively, breast target volume can be 
defined by traditionally treated volume. All palpable breast tissue and all 
tissue encompassed by a standard tangent fields would be considered 
breast tissue.  A medial tangent would be placed at the costo-condral 

 
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junction and a lateral tangent would be placed at the mid axillary line or 
more posterior as necessary to cover all breast tissue laterally. The caudal 
border would be 1 cm below all breast tissue. The superior border would 
be placed at the second intercostal space. Position would be verified on 
CT and in general it should not be closer than 1.5 cm from the inferior 
border of the humeral head and no more than 2 cm distally.  
7.612 Manual modifications: alternatively, volumes can be defined using the 
RTOG breast atlas as above. However, for uniformity of the posterior 
margin the breast volume would include muscle tissue as needed to 
maintain a uniform distal edge. Please see breast CTV (section 7.6.1.3.2).  
7.613 Tumor: Contour around the radiologic marker(s) including architectural 
distortion.  
7.6.1.3.1 
Tumor  CTV:  Tumor  + 5mm 3 D expansion. Limit the 
CTV 5 mm from skin and not extending into the pectoralis 
muscle or chest wall. 
7.6.1.3.2 
Breast CTV: the breast would be the same as the CTV high 
tangents or low tangents without further expansions. The 
Tumor  CTV is also included. The breast CTV volume is 
limited 5mm from the skin. The breast CTV posteriorly, 
would be limited by the chest wall. 
 
7.7 
 
Critical Structures 
7.71 
Breast skin evaluation: Will be defined as the first 3 mm of tissue under the 
body surface anterior to the Breast CTV.   
 
7.72 
Heart: To be contoured on all cases. The contour should begin just inferior to the 
level in which the pulmonary trunk branches into the left and right pulmonary 
arteries (PA) and should extend to its most inferior extent near the diaphragm. 
The esophagus, ascending and descending aorta and inferior vena cava should be 
excluded from the heart contour.  
 
7.73 
Left anterior descending (LAD) interventricular branch (optional): To be 
contoured on left-sided cases. “Originates from the left coronary artery and runs 
in the interventricular groove between the right and left ventricles. If it is difficult 
to see, raising the level and lowering the window may help (e.g. level 50, 
window 150)”.35  
 
7.74 
Right coronary artery (RCA) (optional): To be contoured on all right-sided 
cases. “Originates from the right side of the ascending aorta. Due to the native 
heart position in the chest, on axilla CT, it appears to start inferior to the left 
coronary artery. It moves significantly with cardiac motion, so often the location 
can seem noncontiguous from axial CT slice to slice, as the position of the AV 
groove changes.”35 
 
7.75 
Ipsilateral lung: To be contoured on all cases, auto-segmentation with manual 
verification is permitted 
 

 
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7.76 
Contralateral lung: To be contoured on all cases, auto-segmentation with 
manual verification is permitted 
 
7.77 
Total lung: To be contoured on all cases, auto-segmentation with manual 
verification is permitted 
 
7.78 
Contralateral breast: Dose to the contralateral breast will not be constrained in 
treatment planning and therefore contouring of the contralateral breast is not 
required in this protocol. However, efforts should be made to limit inadvertent 
dosing of the contralateral breast. 
  
7.8 
 
Prescription and Normal Tissue Constraints 
 
7.8.1 
Breast CTV:  
7.8.1.1   Per protocol ≥ D95% will receive ≥95% of prescription; 
Variation acceptable ≥ D90% receives ≥ 90% of prescription 
 
7.8.2 
Tumor  CTV 
7.8.2.1   Per protocol   D95% receives ≥95% of dose; variation 
acceptable D90% receives ≥90% of the boost dose 
 
7.8.3 
Robustness analysis for Protons 
7.8.3.1   Breast CTV coverage would be evaluated for 5mm movements 
or 3% range changes. Per protocol Breast CTV V90% receives ≥95% of 
the prescription dose; variation acceptable ≥ V90% receives ≥90% of the 
prescription dose. 
 
7.8.3.2   Under the same robustness evaluation criteria, plans will be 
evaluated for D max.  Variation acceptable D0.01cc % ≤120% 
 
 
  
 
 
Protons DVH summary table 
 
 
 
Goal 
Major violation 
Breast CTV 
 
≥ V95% will receive 
≥95% of 
prescription 
V90% <90% of 
prescription 
 
 
Dmax <107% 
Dmax >115% 
Tumor CTV 
 
≥ V95% will receive 
≥95% of 
prescription 
V90% <90% of 
prescription 
 
 
Dmax <107% 
Dmax >115% 
Breast CTV 
robustness 
 
V90% >90% of 
prescription 
V90% <90% of 
prescription 
 
 
 
 
Heart 
Max dose 
≤25% of 
prescription 
>33% of 
prescription 
 
Mean 
<0.1Gy 
>1Gy 

 
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Breast Skin 
Max dose 
≤105% of 
prescription 
>110% of 
prescription 
 
 
 
 
Lung Ipsilateral 
V50% of prescription 
≤10%  
>15% 
 
V20 
record 
 
Lung contralateral 
V50% 
≤7%  
 
>10% 
Lung Total 
Mean dose 
record 
 
 
V20Gy 
record 
 
 
V50% 
record 
 
LAD (optional) 
Mean dose 
record 
 
 
Max dose 
record 
 
RCA 
Mean dose 
record 
 
 
Max dose 
record 
 
 
 
 
Photons (x-rays) DVH summary table 
 
 
 
Goal 
Major violation 
Breast CTV 
 
≥ V95% will receive 
≥95% of 
prescription 
V90% <90% of 
prescription 
 
 
Dmax <107% 
Dmax >115% 
Tumor CTV 
 
≥ V95% will receive 
≥95% of 
prescription 
V90% <90% of 
prescription 
 
 
Dmax <107% 
Dmax >115% 
Breast CTV 
robustness 
 
V90% >90% of 
prescription 
V90% <90% of 
prescription 
 
 
 
 
Heart 
Max dose 
≤33% of 
prescription 
>50% of 
prescription 
 
Mean 
<1Gy 
>2Gy 
Breast Skin 
Max dose 
≤107% of 
prescription 
>115% of 
prescription 
 
 
 
 
Lung Ipsilateral 
V50% of prescription 
≤10%  
>15% 
 
V20 
record 
 
Lung contralateral 
V50% 
≤7%  
 
>10% 
Lung Total 
Mean dose 
record 
 
 
V20Gy 
record 
 
 
V50% 
record 
 
LAD (optional) 
Mean dose 
record 
 
 
Max dose 
record 
 
RCA 
Mean dose 
record 
 
 
Max dose 
record 
 
 
 

 
21  
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7.9 
Quality Assurance Documentation 
7.9.1 
At a minimum, the initial 3 treatment plans per physician will be 
centrally reviewed by the principal investigator or designee prior to the 
start of treatment. 
 
7.10 Axillary management 
7.10.1 Only clinical N0 patients are eligible. If 2 or less positive LN are found 
in the SLNB without ECE no additional radiation would be considered 
 
7.11 Surgery 
7.11.1 Surgical treatment will be done at the discretion of the treating surgeon. 
7.11.2 Surgery will be done at 8 weeks after the completion of radiation. 
Acceptable range is 4-16 weeks after. 
7.12 Endocrine therapy or chemotherapy 
7.12.1 Systemic management would be done at the discretion of the treating 
medical oncologist after the surgery 
 
 
8 
Radiotherapy Dose Modifications Based on Adverse Events  
 
This study has no pre-specified interruptions due to adverse events. Treatment interruptions are 
discouraged. No dose modifications should be done for treatment interruptions. 
 
 
9.0 
Ancillary Treatment/Supportive Care 
 
Skin changes are common complications of breast cancer radiation therapy. Usual care will be 
provided as per the treating institution’s standard of practice. If the skin becomes erythematous 
and/or there is pruritus, topical steroid cream may be prescribed. The addition of antihistamines 
may be used for severe pruritus. Patients experiencing pain will be prescribed pain medication. 
 
 
10.0 
Adverse Event (AE) Reporting and Monitoring 
 
10.1 
Definitions 
Adverse Event- An untoward or undesirable experience associated with the use of a 
medical product (i.e. drug, device, biologic) in a patient or research subject. 
Serious Adverse Event – Any grade 4 or 5 adverse event as defined by CTC AE v4.0. 
Adverse events are classified as serious or non-serious.  Serious problems/events can be 
well defined and include in general: 
 
Death 
 
Life threatening adverse experience where emergent lifesaving treatment is 
necessary. 
 
 
Unanticipated Problems Involving Risks to Subjects or Others (UPIRTSO)- Any 
unanticipated problem or adverse event that meets the following three criteria:  
Serious: Serious problems or events that results in significant harm, (which may be 
physical, psychological, financial, social, economic, or legal) or increased risk for the 
subject or others (including individuals who are not research subjects). These include: (1) 

 
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death; (2) life threatening adverse experience; (3) hospitalization - inpatient, new, or 
prolonged; (4) disability/incapacity - persistent or significant; (5) birth defect/anomaly; (6) 
breach of confidentiality and (7) other problems, events, or new information (i.e. 
publications, DSMB reports, interim findings, product labeling change) that in the opinion 
of the local investigator may adversely affect the rights, safety, or welfare of the subjects 
or others, or substantially compromise the research data, AND 
Unanticipated: (i.e. unexpected) problems or events are those that are not already 
described as potential risks in the protocol, consent document, not listed in the 
Investigator’s Brochure, or not part of an underlying disease. A problem or event is 
"unanticipated" when it was unforeseeable at the time of its occurrence. A problem or 
event is "unanticipated" when it occurs at an increased frequency or at an increased 
severity than expected, AND 
Related: A problem or event is "related" if it is possibly related to the research procedures. 
 
Preexisting Condition- A preexisting condition is one that is present at the start of the 
study.  A preexisting condition should be recorded as an adverse event if the frequency, 
intensity, or the character of the condition worsens during the study period. At screening, 
any clinically significant abnormality should be recorded as a preexisting condition.  At 
the end of the study, any new clinically significant findings/abnormalities that meet the 
definition of an adverse event must also be recorded and documented as an adverse event.  
 
 
 
10.2 
Recording Adverse Events 
 
 
 
CTCAE term (AE description) and grade: The descriptions and grading scales 
  
 
found in the revised NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 will be utilized for AE reporting unless as otherwise stated in the 
table below. 
 
All appropriate treatment areas should have access to a copy of the CTCAE version 4.0. 
A copy of the CTCAE version 4.0 can be downloaded from the CTEP web site: 
 
 
10.21 Adverse event monitoring and reporting is a routine part of every clinical 
trial. First, identify and grade the severity of the event using the CTCAE 
version 4.0. Next, determine whether the event is expected or unexpected 
and if the adverse event is related to the medical treatment or procedure. With 
this information, determine whether the event must be reported as an expedited 
report (see Section 10.3). 
 
 
 
10.22 Assessment of Attribution 
Only G4 or G5 adverse events will require an attribution. Any change in the 
grade of an adverse event within the list of monitored AEs will be recorded and 
considered to be related to treatment. Any new adverse not listed occurring 
within the Radiated area or in close proximity will be graded and attribution 
defined by the study PI. 
Events determined to be possibly, probably or definitely attributed to a 
medical treatment suggest there is evidence to indicate a causal relationship 
between the treatment and the adverse event. 
 

 
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10.3 
Reporting of Serious Adverse Events and Unanticipated Problems 
 
When an adverse event has been identified, the study team will take appropriated action 
necessary to protect the study participant and then complete the Study Adverse Event 
Worksheet and log.  The sponsor-investigator will evaluate the event and determine the 
necessary follow-up and reporting required. 
 
a. Serious Adverse Events will be reported as part of regular adverse event 
reporting mechanisms via the data capture system and logged for review 
reporting. 
 
10.31 Investigator Reporting: Notifying the Mayo IRB: 
 
The IRB requirements reflect the guidance documents released by the Office of 
Human Research Protections (OHRP), and the Food and Drug Administration 
(FDA) in early 2007 and are respectively entitled “Guidance on Reviewing and 
Reporting Unanticipated Problems Involving Risks to Subjects or Others and 
Adverse Events” and “Guidance for Clinical Investigators, Sponsors, and IRBs: 
Adverse Event Reporting – Improving Human Subject Protection.” 
 
10.311 
According to Mayo IRB Policy any serious adverse event (SAE) 
which the Principal Investigator has determined to be a 
UPIRTSO must be reported to the Mayo IRB as soon as possible 
but no later than 5 working days after the investigator first learns 
of the problem/event. 
10.312 
Non-UPIRTSO – the investigator reports problems or events that 
do NOT meet criteria of an UPIRTSO in summary format at the 
time of the next continuing review. The investigator monitors the 
severity and frequency of subsequent non-UPIRTSOs. 
 
Consider the following information to collect when developing any forms for 
documentation of adverse events. 
Example 
Information collected on the adverse event worksheet (and entered in the 
research database):  
 
Subject’s name:  
 
Medical record number:  
 
Disease/histology (if applicable):  
 
The date the adverse event occurred:  
 
Description of the adverse event:  
 
Relationship of the adverse event to the research (drug, procedure, or 
intervention):  
 
If the adverse event was expected:  
 
The severity of the adverse event: (use a table to define severity scale 1-
5) 
 
If any intervention was necessary:  
 
Resolution: (was the incident resolved spontaneously, or after 
discontinuing treatment) 
 
Date of Resolution:  

 
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The investigator will review all adverse event reports to determine if specific 
reports need to be made to the IRB and FDA.  The investigator will sign and date 
the adverse event report when it is reviewed.  For this protocol, only directly 
related SAEs/UPIRTSOs will be reported to the IRB. 
 
 
10.4 
Adverse events to be graded at each evaluation and pretreatment symptoms/conditions to 
be evaluated at baseline per the CTCAE v4.0 grading unless otherwise stated in the table 
below: 
 
 
System 
Organ 
Class 
(SOC)  
 
Adverse 
event/Symptoms 
 
Baseline 
Each  
evaluation 
Grading scale 
(if not CTCAE) 
General 
Pain 
X 
X 
CTCAE 
Skin and subcutaneous 
tissue disorders 
Dermatitis Radiation 
X 
X 
CTCAE 
Skin 
hyperpigmentation 
X 
X 
CTCAE 
Skin 
hypopigmentation 
X 
X 
CTCAE 
Musculoskeletal 
Fibrosis 
X 
X 
CTCAE 
Vascular 
Lymphedema 
X 
X 
CTCAE 
Respiratory, thoracic and 
mediastinal disorders 
Pneumonitis  
X 
X 
CTCAE 
 
 
10.5 
Submit via appropriate reporting mechanisms the following AEs experienced by a patient 
and not specified in Section 10.4: 
 
 
 
 
10.52 
Grade 4 and 5 AEs regardless of attribution to the study 
treatment or procedure. 
 
10.53  
Grade 5 AEs (Death) 
 
 
10.531 
Any death within 30 days of the patient’s last 
study treatment or procedure regardless of 
attribution to the study treatment or procedure 
 
10.532 
Any death more than 30 days after the patients 
last study treatment or procedure that is felt to be 
at least possibly treatment related must also be 
submitted as a Grade 5 AE, with a CTCAE type 
and attribution assigned. 
 

 
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11.0 
Treatment Evaluation  
 
11.1 
Patients will be evaluated at baseline, then according to the Assessment Schedule 
(Section 4.0)  
 
11.2 
At the time of reevaluation, patients will be classified in the following manner: 
 
11.2.1 No evidence of disease (NED). 
 
11.2.2 Recurrence of disease (REC). Consider biopsy of the site and PET scan.  
 
11.2.3 The site of recurrence (or failure) will also be collected and classified as local vs. 
regional vs. distant recurrence.   
 
11.2.4 Secondary Treatment. The date of the first retreatment and extent of retreatment 
post-recurrence (i.e. secondary resection or re-irradiation for primary disease), 
will be collected. Pathology, if available, and operative reports are required to be 
submitted per Section 18.0. 
 
 
11.3 
Cosmesis evaluation and Patient Reported Outcomes 
 
11.3.1 The Harvard/NSABP/RTOG Cosmesis Scale will be used to score cosmesis by 
trained nurses for the primary endpoint according to the schedule outlined in 
section 4.0. 
 
 
Excellent: Treated breast nearly identical to untreated breast 
 
 
Good: Treated breast slightly different than untreated (minimal but 
identifiable effects of the treated breast). Mild reddening or darkening of 
the breast may be present. Thickening or scar tissue causes only a mild 
change in the shape or size. 
 
 
Fair: Obvious difference in the size and shape of the treated breast. The 
change involves one-quarter or less of the breast.  Severe thickening 
or scarring can be present.   
 
 
Poor:  Marked change in appearance or shape involving more than  
one-quarter or less of the breast. Treated breast seriously distorted 
(severe sequelae of breast tissue)  
 
11.3.2 Digital photographs should be performed according to the schedule outlined in 
section 4.0 and should include three poses: from the front with hands on hips, 
both oblique and lateral views with hands behind the back. Recommended 
framing should go from the sternal notch to the umbilicus. If possible, patients 
should be photographed against a solid colored background such as a white sheet. 
 
 
11.3.3 The Breast Cancer Treatment Outcome Scale (BCTOS) is a self-report 
instrument that has high reliability and validity and will be used for evaluating 
patient-rated cosmesis according to the schedule outlined in section 4.0.  

 
26  
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11.4 
Quality of life questionnaires are being done as part of the standard of care for all 
patients. We will correlate results of this standard of care questionnaires with clinical outcomes.  
 
Unplanned surgical intervention will be adjudicated by a plastic surgeon and a general 
surgeon. 
 
11.5     Pathologic complete response.  At time of surgery the residual tumor would be measured 
and a score of 0-1 would be considered a pCR.  Residual cancer burden (RCB) measurement is 
currently considered SOC for all three sites for surgical specimens after neo-adjuvant therapy.  
We would use the current grading used at the three Mayo sites to determine RCB.31 
 
 
12.0 
Descriptive Factors  
 
 
Breast: left vs. right 
 
Tumor Size: 0-2cm vs 2-5cm  
 
Pathologic Lymph Nodes: N0 vs N1  
 
Pathologic complete response:  yes vs. none 31 
 
 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient   
 
Follow-up data will collected and entered after the observation phase outlined in section 4.0. If 
the patient is still alive after 5 years have elapsed from the on-study date, no further follow-up is 
required by this protocol. 
 
13.1 
Patients who have a recurrence while receiving therapy or during observation will go to 
the event-monitoring phase and be followed  
13.2 
Patients who discontinue treatment or observation for reasons other than recurrence will 
go to the event-monitoring phase and be followed  
 
13.3 
Patients who will not receive any radiation treatment or who will receive radiation 
treatment elsewhere will move to event monitoring phase.  
 
13.4      A patient is deemed ineligible if after registration, it is determined that at the time of 
registration, the patient did not satisfy each and every eligibility criteria for study entry.  
The patient may continue treatment off-protocol at the discretion of the physician as long 
as there are no safety concerns, and the patient was properly registered. The patient will 
go directly to the event-monitoring phase of the study (or off study, if applicable).  
 
If the patient received treatment, all data up until the point of confirmation of ineligibility 
must be submitted.  Event monitoring will be required per Section 18.0 of the protocol.  
 
If the patient never received treatment, on-study material and the End of Active 
Treatment/Cancel Notification Form must be submitted.  No further data submission is 
necessary. 
 
13.5 
A patient is deemed a cancel if he/she is removed from the study for any reason before 
any study treatment is given.  On-study material and the End of Active Treatment/Cancel 
Notification Form must be submitted.  No further data submission is necessary. 

 
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14.0 
Body Fluid Bio-specimens   
 
14.1 
Summary Table of Research Blood and Body Fluid Specimens to be Collected for 
this Protocol 
 
Collection Tube 
Volume to Collect 
per Tube (Total 
Number of Tubes to 
Collect) 
Time point: 
Before radiation 
Time point: 
After radiation 
EDTA tubes 
10 mL (8) 
 
 
X(4) 
 
 
X(4) 
No additive tubes 
(for Serum) 
10 mL (4) 
 
 
X(2) 
 
 
X(2) 
 
14.2 
BAP will process and store specimens per standard operating procedures. 
The baseline sample will be obtained prior to the start of radiation.  It would be 
used as our control for the DNA exome sequencing section 17.0. 
 
 
 
14.3 
We will send to Rochester two EDTA tubes with 10cc of blood taken prior to 
radiation and two after radiation for a total of 4 EDTA tubes. 
 
 
15.0 
Drug Information 
 
 
 
Not Applicable 
 
 
16.0  
Statistical Considerations and Methodology  
16.1  
Overview:  This is a phase II trial to determine the pathologic complete response (pCR) 
rate (at time of definitive surgical procedure) seen in breast cancer patients with 
preoperative ionizing radiation.  
 
16.2 
Primary and Secondary Endpoints 
 
16.21 
Primary Endpoint:   The pathologic complete response (pCR) rate observed at 
time of definitive surgery in breast cancer patients receiving preoperative ionizing 
radiation.  A residual tumor cancer burden 0-1 would be considered a pCR.31 All patients 
meeting eligibility criteria who have signed a consent form and who have begun 
treatment will be evaluable for the endpoint. 

 
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16.22 
Secondary Endpoints:  
16.221 Acute and late adverse events including grade ≥2 pneumonitis.  
16.223  Locoregional control, invasive disease-free, distant recurrence, disease- 
free survival, cause-specific survival, overall survival.  
The following definitions are used for the secondary endpoints of interest: 
 
Pathologic complete response: We defined a pathological complete 
response (pCR) as a residual tumor burden of 0-1 in the surgical 
specimen.31 
 
Acute adverse events (up to 180 days post-RT): any adverse event, 
regardless of attribution, that occurs in the first month post-RT. 
 
Late adverse events (up to 5 years post XRT): any adverse event that 
occurred after the first month post-RT and up to 5 years post-RT. 
 
Ipsilateral breast tumor recurrence (IBTR): this is defined as local 
recurrence from trial registration as a first event at 5 years. IBTR is 
defined as both invasive and non-invasive breast cancer involving the 
same breast parenchyma as the original tumor.  
 
Regional recurrence: invasive breast cancer in the axilla, regional lymph 
nodes, chest wall, and skin of the ipsilateral breast at 5 years. 
 
Distant recurrence: metastatic cancer that has either been biopsy 
confirmed or clinically diagnosed as recurrent invasive breast cancer at 5 
years. 
 
Invasive disease- free survival: this is defined as the time from study 
registration until the occurrence of one of the events in a composite 
endpoint. This endpoint includes invasive IBTR, regional invasive breast 
cancer recurrence, distant breast cancer recurrence, death due to any 
cause,  
 
Disease- free survival: this is defined as the time from study registration 
until the occurrence of one of the events in a composite endpoint. This 
endpoint includes any IBTR, regional invasive breast cancer recurrence, 
distant breast cancer recurrence, death due to any cause,  
 
Cause specific survival:  is defined as the time from registration to death 
due to breast cancer. If the cause of death is unknown or difficult to 
establish, patients with a distant failure at the time of death would be 
censored as dying from breast cancer 
 
Overall survival: is defined as the time from registration to death due to 
any cause. 
 
16.3 Exploratory endpoints:   
16.31 Patient self-reported cosmesis, i.e. fatigue, breast pain, and other patient reported 
outcomes.  
 

 
29  
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16.32  Clinical features, treatment technique, dose-volume parameters, histologic and 
genetic variants associated with adverse events, and fair and poor cosmetic outcomes or 
unplanned surgical intervention.  
 
16.33  Tumor mutation signatures before and after radiation; correlate tumor mutation 
signatures before and after radiation with pathologic information at the time of surgery. 
 
16.34  Pathologic changes seen in breast cancer patients with preoperative radiation.   
 
The following definitions are used for the exploratory endpoints of interest: 
 
Patient Reported Outcomes/Quality of life: Elements of the Patient-
Reported Outcomes Version of the Common Terminology Criteria for 
Adverse Events (PRO-CTCAE) will be used for patient self-reporting of 
toxicities. The Breast Cancer Treatment Outcomes Scale (BCTOS) will 
be used to measure patient reported functional status (pain, mobility). 
Other measures of fatigue, pain, and arm function are listed in the 
appendix.  

 
30  
MC1732 
 
 
 Provider reported cosmetic outcomes: the physician or mid-level 
reported outcome will be assessed using the Harvard Cosmesis Scale 
baseline, EOT, 3 months, 12 months, and yearly after.   
 
Patient self-reported cosmetic outcomes: the patient self-reported 
outcome will be assessed using a modified Harvard Cosmesis Scale and 
the BCTOS at baseline, 2 years, and 5 years.   
 
Panel assessed cosmetic outcome: in addition to patient self-reported and 
physician reported outcomes, cosmesis will be assessed by a panel of 
breast cancer medical providers using digital photographs from baseline 
and at 2 years.   
 
 
16.4 Statistical Design:  
Pathologic complete response (pCR) will be assessed at the time of definitive surgery.  The 
largest success proportion where the proposed treatment regimen would be considered ineffective 
in this population is 5%, and the smallest success proportion that would warrant subsequent 
studies with the proposed regimen would be 20%. The following Simon’s Optimum design uses 
22 evaluable patients to test the null hypothesis that the proportion of successes is at most 5%  
 
16.41 Decision Rules:  
16.411   If 2 or fewer successes are observed in the first 22 evaluable patients that have a 
definitive surgical procedure, we will consider this regimen to be ineffective in this 
patient population.  If 3 or more successes are observed in the first 22 evaluable patients, 
we may recommend further testing of this regimen in subsequent studies in this patient 
population.  
16.412   Over Accrual: If more than the target number of patients are accrued, the 
additional patients will not be used to evaluate the stopping rule or used in any decision 
making process.  
 
16.42 Sample Size  
The one-stage design to be utilized is fully described in Section 16.21. A minimum of 22 
evaluable patients will be accrued to this phase-II study unless undue toxicity is 
encountered. We anticipate accruing an additional 3 patients to account for ineligibility, 
cancellation, major treatment violation, or other reasons. Maximum projected accrual is 
therefore 25 patients. We anticipate pre-registering 40 patients to register a total of 25 
patients necessary for the study design.  
 
16.43 Accrual Time and Study Duration  
We anticipate enrolling 25 patients and thus plan to finish accrual of patients in 1.5-2 
years after opening the study, leaving year 5 for follow-up and analysis. Therefore, the 
overall study duration is expected to be 84 months.  
 
16.44 Power and Significance Levels  
Assuming the number of successes is binomially distributed, the significance level is 0.10 and 
the probability of declaring that this regimen warrants further studies (i.e. statistical power) 
under various success proportions and the probability of stopping accrual can be tabulated as 
a function of the true success proportion as shown in the following table. 
 
If the true success 
proportion is … 
0.05 
0.10 
0.15 
0.20 
0.25 

 
31  
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Then the probability of 
declaring that the 
regimen warrants 
further studies is… 
0.09 
0.38 
0.66 
0.85 
0.94 
 
 
16.45 Other Considerations  
Adverse events observed in this study as well as scientific discoveries or changes in standard care 
will be taken into account in any decision to terminate the study. 
  
16.5 Analysis Plan  
The analysis for this trial will commence at the planned time points (see 16.2) and at the time the 
patients have become evaluable for the primary endpoint. Such decision will be made by the 
Statistician and Study chair, in accord with the Cancer Center Statistics (CCS) Standard 
Operating procedures, availability of data for secondary endpoints, and the level of data maturity. 
It is anticipated that the earliest date in which the results will be made available via a manuscript, 
abstract, or presentation format is when 22 patients have had definitive surgical treatment.  
 
16.51 Primary Analysis:  The primary analysis will be to estimate the pathologic complete 
response (pCR) rate observed at time of definitive surgery in breast cancer patients receiving 
preoperative ionizing radiation.  All patients meeting eligibility criteria who have signed a 
consent form and who have begun treatment will be evaluable for the primary analysis.  
 
16.511 Estimation: The proportion of successes (number of patients achieving pCR at time of 
definitive surgery) will be estimated by the number of successes divided by the total number 
of evaluable patients. Confidence intervals for the true success proportion will be calculated 
according to the approach of Duffy and Santner [74].   
 
16.512 Over Accrual: If more than the target number of patients are accrued, the additional 
patients will not be used to evaluate the stopping rule or used in any decision making 
processes; however, they will be included in final point estimates and confidence limits.  
 
 
 
16.52 Secondary Analyses 
 
16.521 Acute adverse events (up to 180 days post-RT): All patients who were 
registered to the study and started treatment will be included in the acute 
adverse event analysis. An acute adverse event is an AE, regardless of 
attribution, that occurs up to 180 days post-RT. The maximum grade for 
each type of acute AE will be recorded for each patient. Data will be 
summarized as frequencies and relative frequencies. Additionally, the 
relationship of the adverse event(s) to the study treatment will be taken 
into consideration.  
   
16.522 Late adverse events: All patients who were registered to the study and 
started treatment will be included in the late adverse event analysis. A 
late adverse event is an AE, regardless of attribution, that after one 
month post-RT and up to 5 years post-RT. The maximum grade for each 
type of late AE will be recorded for each patient. Data will be 

 
32  
MC1732 
 
summarized as frequencies and relative frequencies by treatment arm. 
Additionally, the relationship of the adverse event(s) to the study 
treatment will be taken into consideration. 
 
16.523 Locoregional control: The cumulative incidence of locoregional 
recurrence will be estimated using a competing risks method (Gooley et 
al.). The competing risks will be distant breast cancer recurrence and 
death.   
 
16.524 Invasive disease-free survival: i-DFS is defined as the time from 
registration until the time of disease recurrence or death due to any 
cause. The i-DFS will be estimated with a Kaplan-Meier estimator and 
curve. Estimates will be given for specific time points along with 95% 
CIs.  
16.525  Disease-free survival: DFS is defined as the time from registration until 
the time of disease recurrence or death due to any cause. The DFS will 
be estimated with a Kaplan-Meier estimator and curve. Estimates will be 
given for specific time points along with 95% CIs. 
 
16.526  Cause specific survival: The CSS will be estimated with a Kaplan-Meier 
estimator and curve. Estimates will be given for specific time points 
along with 95% CIs.  
 
16.527 Overall survival: The OS will be estimated with a Kaplan-Meier 
estimator and curve. Estimates will be given for specific time points 
along with 95% CIs.  
 
16.53 Exploratory Analyses:  
16.531 Quality of life: The subscales of the BCTOS, elements from CTCAE-
PRO, and other patient reported measures such as fatigue, breast pain, 
breast shape, and arm related morbidity outlined in the appendix will be 
summarized as the mean ± SD and median (minimum value, maximum 
value). Scale score trajectories over time will be examined using stream 
plots and mean plots with standard deviation error bars overall. Analysis 
will include percent change from baseline using t-tests and generalized 
linear models to test for changes at each time point and non-zero slope 
respectfully.   
 
16.532 Cosmesis: The values of the cosmesis instruments (patient self-reported 
and panel-assessed) will be summarized with the frequencies and 
confidence intervals of fair or poor cosmesis events at baseline, 2 years, 
and 5 years.    
 
16.533 Tumor mutation signatures will be analyzed before and after 
radiotherapy as compared to pathologic information at the time of 
surgery.  Continuous variable will be compared using unpaired t tests and 
monimal variables will be compared using contingency tables and Chi 
square analyses.   
 
16.534 Pathologic changes due to preoperative radiotherapy observed at the time 
of definitive surgery will be described.   

 
33  
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16.6           Data & Safety Monitoring 
 
16.61  The study chair(s) and the study statistician will review the study at least twice a 
year to identify accrual, adverse event, and any endpoint problems that might be 
developing. The Mayo Clinic Cancer Center (MCCC) Data Safety Monitoring 
Board (DSMB) is responsible for reviewing accrual and safety data for this trial 
at least twice a year, based on reports provided by the MCCC Statistical Office.   
 
16.62 Adverse Event Stopping Rules: The stopping rules specified below are based on 
knowledge available at study development.  We note that the Adverse Event 
Stopping Rule may be adjusted in the event of either (1) the study re-opening to 
accrual or (2) at any time during the conduct of the trial and in consideration of 
newly acquired information regarding the adverse event profile of the 
treatment(s) under investigation.  The study team may choose to suspend accrual 
because of unexpected adverse event profiles that have not crossed the specified 
rule below. 
 
Accrual will be temporarily suspended if at any time we observe the following 
events that are possibly, probably or definitely related to treatment:  
If 4 or more patients in the first 10 treated patients or 6 patients at any point in 
the study experience (end/during radiation, 3 months after radiation, at 12 months 
and yearly after)  a grade 3 or higher skin induced radiation dermatitis, pain over 
the treated area, swelling over the breast area, pneumonitis, radiation in-field 
wound infection,  or poor cosmetic outcome (change from excellent/good 
cosmesis to fair or poor, or from fair to poor via Harvard cosmesis scale). 
 
We note that we will review grade 4 and 5 adverse events deemed “unrelated” or 
“unlikely to be related”, to verify their attribution and to monitor the emergence 
of a previously unrecognized treatment-related adverse event. However, any 
grade 4 or higher regardless of the attribution could be used for temporary 
suspension of the protocol at that time. The study team will review all grade 4 or 
5 AEs, if they are clearly “unrelated” the study can remain active while the 
MCCC reviews the adverse event. In all other cases the grade 4 or 5 toxicity will 
determine a temporary closure of the study while it is reviewed by the MCCC 
DSMB. 
 
The study will continue to be monitored by the MCCC DSMB till all patients in 
the study complete treatment and are followed by 180 days. Patients will 
continue to be followed and monitored in the study for 5-years by the radiation 
oncology clinical research team. 
 
16.7  
Results Reporting on ClinicalTrials.gov: At study activation, this study will have been 
registered within the “ClincialTrails.gov” website. The Primary and Secondary Endpoints 
(i.e., “Outcome Measures”) along with other required information for this study will be 
reported on ClinicalTrials.gov. For purposes of timing of the Results Reporting, the 
initial estimated completion date for the Primary Endpoint of this study is 24 months after 
the study opens to accrual. The definition of “Primary Endpoint Completion Date” 
(PECD) for this study is at the time the last patient registered has undergone definitive 
surgical procedure. 

 
34  
MC1732 
 
 
 
16.8 
Inclusion of Women and Minorities 
 
16.81  This study will be available to all eligible patients, regardless of race,  or ethnic 
origin. 
 
16.82  There is no information currently available regarding differential effects of this 
regimen in subsets defined by race, or ethnicity, and there is no reason to expect 
such differences to exist. Male breast cancer is a relatively rare entity in whom 
APBI would not be appropriate therapy and male gender is an exclusion 
criteria.Although the planned analysis will, as always, look for differences in 
treatment effect based on racial groupings, the sample size is not increased in 
order to provide additional power for subset analyses. 
 
16.83   The geographical region served by the Mayo Clinic, has a population which 
includes approximately 5% minorities.  We expect about 5% of patients will be 
classified as minorities by race and about 100% of patients will be women. 
 
 
Accrual Estimates by Gender/Ethnicity/Race 
 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
2 
0 
2 
Not Hispanic or Latino 
23 
0 
23 
Ethnic Category: Total of all subjects 
25 
0 
25 
 
American Indian or Alaskan Native 
1 
0 
1 
Asian 
0 
0 
0 
Black or African American 
1 
0 
1 
Native Hawaiian or other Pacific Islander 
0 
0 
0 
White 
23 
0 
23 
Racial Category: Total of all subjects 
25 
0 
25 
 
Ethnic 
Categories: 
Hispanic or Latino – a person of Cuban, Mexican, Puerto Rican, South or Central 
American, or other Spanish culture or origin, regardless of race. The term “Spanish 
origin” can also be used in addition to “Hispanic or Latino.” 
Not Hispanic or Latino 

 
35  
MC1732 
 
Racial 
Categories: 
American Indian or Alaskan Native – a person having origins in any of the original 
peoples of North, Central, or South America, and who maintains tribal affiliations or 
community attachment. 
Asian – a person having origins in any of the original peoples of the Far East, 
Southeast Asia, or the Indian subcontinent including, for example, Cambodia, China, 
India, Japan, Korea, Malaysia, Pakistan, the Philippine Islands, Thailand, and 
Vietnam. (Note: Individuals from the Philippine Islands have been recorded as Pacific 
Islanders in previous data collection strategies.)  
Black or African American – a person having origins in any of the black racial 
groups of Africa. Terms such as “Haitian” or “Negro” can be used in addition to 
“Black or African American.” 
Native Hawaiian or other Pacific Islander – a person having origins in any of the 
original peoples of Hawaii, Guam, Samoa, or other Pacific Islands. 
White – a person having origins in any of the original peoples of Europe, the Middle 
East, or North Africa. 

 
36  
MC1732 
 
17.0  
Pathology Considerations/Tissue Biospecimens   
 
17.1  
Summary Table of Research Tissue Specimens 
 
 
Mandatory or 
Optional 
Type of Tissue to 
Collect 
Block, Slides, 
Core, etc. (# of 
each to submit) 
Process at 
Site? (Yes 
or No) 
 
Diagnostic 
 
Mandatory 
 
Formalin Fixed and 
Flash Frozen tumor 
See below 
 
Yes 
 
Definitive surgery 
 
Mandatory 
Formalin Fixed and 
Flash Frozen tumor 
See below 
 
Yes 
         
Tissue requirements: 
Paraffin blocks: Two (2) of the initial diagnostic core biopsy and two (2) blocks 
of the cancer at the time of surgery, if available. 
 
 
 
 
 
Alternate to paraffin blocks: 
Two 2 mm core sampling of the existing tumor block from an area rich in tumor 
cells or a similar size fragment cut from the original block 
 
Flash frozen tissue at the time of surgery: One 18g needle core of the initial 
diagnostic core biopsy and a 25-50mg tissue sample of the cancer at the time of 
surgery, if available. 
We will send 25 mgs of the tumor to RST. We will send 25-50 mgs of the tumor 
and sentinel lymph node tissue to RST, if available. 
 
 
 
17.2 
Flow cytometry 
 
For formalin fixed tissue samples excess paraffin is removed with a scalpel from either 
side of 40-60um scrolls then processed according to our published methods. Briefly each 
sectioned piece is collected into individual microcentrifuge tubes then washed three times 
with 1 ml Xylene for 5 minutes to remove remaining paraffin.  Each sample is rehydrated 
in sequential ethanol washes (100% 5 minutes x2, then 95%, 70%, 50% and 30% 
ethanol) and washed 2 times in 1ml 1 mM EDTA pH 8.0. A 1 ml aliquot of 1 mM EDTA 
pH 8.0 is added to the samples and incubated at 95oC for 80 minutes to facilitate the 
removal of protein cross-links present in FFPE tissue.  Samples are then cooled to room 
temperature for > 5 minutes, followed by addition of 300 ul PBS pH 7.4 and gentle 
centrifugation for 2 minutes at 3.6 x g.  The supernatant is carefully removed and the 
pellet washed three times with 1 ml PBS pH 7.4/0.5mM CaCl2 to remove EDTA. Each 
sample is digested overnight (6-17 hours) in 1ml of a freshly prepared enzymatic cocktail 
containing 50 units/ml of collagenase type 3, 80 units/ml of purified collagenase, and 100 
units/ml of hyaluronidase in PBS pH 7.4/0.5mM CaCl2 buffer. Following overnight 
digestion 500 ul NST is added to each sample to facilitate pelleting.  Samples are 
centrifuged for 5 minutes at 3000 x g, after which pellets are resuspended in 750 ul of 
NST/10% fetal bovine serum and then passed through a 25 G needle 10-20 times.  
 
Prior to sorting biopsies (formalin fixed or flash frozen) are minced in the presence of 
NST buffer and DAPI according to published protocols. Each sample is filtered through a 
35 um mesh and collected into a 5 ml Polypropylene round bottom tube. The mesh is 

 
37  
MC1732 
 
rinsed with an additional 750 ul of NST/10% fetal bovine serum and placed on ice while 
processing remaining samples.  The total volume in the tube for each sample is 
approximately 1.5 ml. An equal volume of 20ug/ml DAPI is added to each tube to 
achieve a final concentration of 10ug/ml DAPI for flow sorting with a BD Influx 
cytometer with ultraviolet excitation (Becton-Dickinson, San Jose, CA). The optimal 
settings for sorting FFPE samples with the Influx sorter are as follows: Drop formation 
was achieved with piezzo amplitude of 6-10 volts and a drop frequency of 30 khertz. The 
sort mode is set to purity yield with a drop delay of 31.5-32. Sheath fluid pressure was 
typically 17-18 psi with a 100 um nozzle. For single parameter DNA content assays 
DAPI emission is collected at >450nm. DNA content and cell cycle were then analyzed 
using the software program MultiCycle (Phoenix Flow Systems, San Diego, CA). All 
flow sorting will be done in the Barrett laboratory located in the Collaborative Research 
Building on the MCA Scottsdale campus. 
 
 
17.3 
DNA extraction 
 
DNA from sorted nuclei is extracted using an amended protocol from QIAamp® DNA 
Micro Kit from Qiagen (Valencia, CA).  Briefly each sorted sample is resuspended in 
180ul buffer ATL and 20ul proteinase K (20mg/ml) then incubated for 3 hours at 56°C 
for complete lysis.  Samples are bound and washed according to QIAamp® DNA Micro 
Kit instructions, eluted into 50ul of H20, then precipitated overnight with 5ul 3 M sodium 
acetate and 180 ul 100% EtOH.  Each sample is then centrifuged for 30 minutes at 20,000 
x g, washed in 1 ml of 70% EtOH for 30 minutes at 20,000 x g. The samples are carefully 
decanted and the DNA pellet is dried by speed vacuum then resuspended in a small 
volume (e.g. 10-50ul) of H20 for final concentrations suitable for accurate quantitation. 
All DNA extractions will be done in the
. 
 
 
 
17.4 
Exome capture and sequencing 
 
 
For each patient we will prepare sufficient DNAs from each sorted tumor population, as 
well as a patient matched control sample, for exome sequencing. Residual DNAs will be 
stored at MCA for future studies. All sequencing will be done within Mayo Clinic 
Medical Genome Facility (MGF) using established protocols for whole exome analysis. 
Briefly, whole exon capture is carried out using the protocol for Agilent’s SureSelect 
Human All Exon 71 MB v6 kit. 500 ng of the prepped library is incubated with whole 
exon biotinylated RNA capture baits supplied in the kit for 24 hours at 65 °C. The 
captured DNA: RNA hybrids are recovered using Dynabeads MyOne Streptavidin T1 
(Dynal). The DNA is eluted from the beads and desalted using purified using Ampure XP 
beads (Agencourt). The purified capture products are then amplified using the SureSelect 
Post-Capture Indexing forward and Index PCR reverse primers (Agilent) for 12 cycles. 
Libraries are loaded onto paired end flow cells at concentrations of 4-5 pM to generate 
cluster densities of 600,000-800,000/mm2 using the Illumina cBot and HiSeq Paired end 
cluster kit version 3.The flow cells are sequenced as 101 X 2 paired end reads on an 
Illumina HiSeq 4000 using TruSeq SBS sequencing kit version 3 and HiSeq data 
collection version 1.4.8 software. Base-calling is performed using Illumina’s RTA 
version 1.12.4.2 
 
 

 
38  
MC1732 
 
18.0 
Records and Data Collection Procedures   
 
18.1 
Submission Timetable 
 
Initial Material(s) 
 
CRF 
Treatment 
(Compliance with Test Schedule Section 4.0) 
 
Institutional Contacts 
 
 
 
2 weeks after registration  
 
 
 
 
 
 
 
*6 months after accrual 
 
 
Patient Eligibility 
Demographics 
On-Study 
 
Pathology of Ipsilateral Breast 
Adverse Events- Baseline 
Patient Status: Baseline 
Patient Assessment 
 
 
 
Off Treatment 
Submit 2 weeks after registration if withdrawal/refusal 
occurs prior to beginning protocol therapy 
 
 
Test Schedule Material(s) 
 
CRF 
 
End of Treatment 
12 weeks post-RT / 
Observation Phase4  
Event Monitoring5 
Radiation Therapy 
X 
 
 
Radiation Lumpectomy Therapy 
X 
 
 
Patient Assessment 
X 
X 
 
Adverse Events Solicited 
X 
X 
 
Adverse Events: Other 
X2 
X2 
 
Off Treatment 
X2 
X2 
 
Patient Status Form 
X 
X 
X 
Specimen Submission: Tissue 
(Recurrence) 
 
X2 
 
Consent Withdrawal  
X2 
X2 
 
Lost to Follow-up 
X2 
X2 
 
Breast Radiotherapy Questionnaire3 
X 
X 
 

 
39  
MC1732 
 
1 
Complete at each evaluation during Active Treatment (see Section 4.0). 
2 
When applicable 
3 
Survey will need to be entered manually if has not alternately been  scanned or entered electronically 
4 
Active monitoring observation phase, Day 15 (+/-3 days), D90 (+/- 1 month), D180 (+/- 2 months), 
D365 (+/- three months), annually for 4 years (+/-6 months, total 5 years follow-up). If patient 
progresses within observation, they will move to the event monitoring phase where they will be 
followed until 5 years of follow-up information has been completed from the end of treatment time 
point. 
5 
If patient has a recurrence prior to being off radiation therapy for 5 years, continue to follow yearly. 
 
 
18.2 
Data Handling and Record Keeping 
 
18.21 Confidentiality 
Information about study subjects will be kept confidential and managed according 
to the requirements of the Health Insurance Portability and Accountability Act of 
1996 (HIPAA).  Those regulations require a signed subject authorization informing 
the subject of the following:  
 What protected health information (PHI) will be collected from subjects in 
this study 
 Who will have access to that information and why 
 Who will use or disclose that information 
 The rights of a research subject to revoke their authorization for use of 
their PHI.  
(This information is contained within the Mayo IRB Informed Consent Template 
Section 14) 
In the event that a subject revokes authorization to collect or use PHI, the 
investigator, by regulation, retains the ability to use all information collected 
prior to the revocation of subject authorization.  For subjects that have revoked 
authorization to collect or use PHI, attempts should be made to obtain permission 
to collect at least vital status (long term survival status that the subject is alive) at 
the end of their scheduled study period. 
 
18.22 Source Documents 
Source data is all information, original records of clinical findings, observations, 
or other activities in a clinical trial necessary for the reconstruction and 
evaluation of the trial.  Source data are contained in source documents.  
Examples of these original documents, and data records include: hospital records, 
clinical and office charts, laboratory notes, memoranda, subjects’ diaries or 
evaluation checklists, pharmacy dispensing records, recorded data from 
automated instruments, copies or transcriptions certified after verification as 
being accurate and complete, microfiches, photographic negatives, microfilm or 
magnetic media, x-rays, subject files, and records kept at the pharmacy, at the 
laboratories, and at medico-technical departments involved in the clinical trial. 
Source documents are kept in a secure location that is locked and requires 
approved access.  
 
18.23 Case Report Forms  
The study case report form (CRF) is the primary data collection instrument for 
the study.  All data requested on the CRF must be recorded.  All missing data 
must be explained.  If a space on the CRF is left blank because the procedure was 

 
40  
MC1732 
 
not done or the question was not asked, write “N/D”.  If the item is not applicable 
to the individual case, write “N/A”.  All entries should be printed legibly in black 
ink.  If any entry error has been made, to correct such an error, draw a single 
straight line through the incorrect entry and enter the correct data above it.  All 
such changes must be initialed and dated.  Do not erase or use “white-out” for 
errors.  For clarification of illegible or uncertain entries, print the clarification 
above the item, then initial and date it.  If the reason for the correction is not clear 
or needs additional explanation, neatly include the details to justify the 
correction. 
 
 
 
18.24 Records Retention 
 
The investigator will maintain records and essential documents related to the 
conduct of the study.  These will include subject case histories and regulatory 
documents. 
 
The investigator will retain the specified records and reports for; 
1. As outlined in the Mayo Clinic Research Policy Manual –“Retention of and 
Access to Research Data Policy” 
   
 
 
19.0  
Study Finances 
 
 
19.1 
Costs charged to patient:  routine clinical care 
 
 
19.2 
Tests to be research funded: Venipuncture, DNA analysis, and Biobanking 
 
19.3 
Other budget notes: The Marley Grant and the Mayo Clinic Radiation Oncology Unit are 
funding this study and will cover all costs related to running this study 
 
 
20.0 
Publication Plan 
The principal investigators hold primary responsibility for publication of the results of this study 
and approval from the principal investigators must be obtained before any information can be 
used or passed on to a third party.  The principal investigator would maintain control and use of 
all data used in the study during the study and after the study has been completed. 
 
 
 
21.0 
References 
 
1. 
Arriagada R, Le MG, Rochard F, Contesso G. Conservative treatment versus mastectomy in early 
breast cancer: patterns of failure with 15 years of follow-up data. Institut Gustave-Roussy Breast Cancer 
Group. J Clin Oncol 1996;14:1558-64. 
2. 
Blichert-Toft M, Nielsen M, During M, et al. Long-term results of breast conserving surgery vs. 
mastectomy for early stage invasive breast cancer: 20-year follow-up of the Danish randomized DBCG-
82TM protocol. Acta Oncol 2008;47:672-81. 
3. 
Blichert-Toft M, Rose C, Andersen JA, et al. Danish randomized trial comparing breast 
conservation therapy with mastectomy: six years of life-table analysis. Danish Breast Cancer Cooperative 
Group. J Natl Cancer Inst Monogr 1992:19-25. 

 
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MC1732 
 
4. 
Clarke M, Collins R, Darby S, et al. Effects of radiotherapy and of differences in the extent of 
surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised 
trials. Lancet 2005;366:2087-106. 
5. 
Fisher B, Anderson S, Bryant J, et al. Twenty-year follow-up of a randomized trial comparing 
total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast 
cancer. N Engl J Med 2002;347:1233-41. 
6. 
Fisher B, Anderson S, Redmond CK, Wolmark N, Wickerham DL, Cronin WM. Reanalysis and 
results after 12 years of follow-up in a randomized clinical trial comparing total mastectomy with 
lumpectomy with or without irradiation in the treatment of breast cancer. N Engl J Med 1995;333:1456-
61. 
7. 
Jacobson JA, Danforth DN, Cowan KH, et al. Ten-year results of a comparison of conservation 
with mastectomy in the treatment of stage I and II breast cancer. N Engl J Med 1995;332:907-11. 
8. 
Poggi MM, Danforth DN, Sciuto LC, et al. Eighteen-year results in the treatment of early breast 
carcinoma with mastectomy versus breast conservation therapy: the National Cancer Institute 
Randomized Trial. Cancer 2003;98:697-702. 
9. 
van Dongen JA, Voogd AC, Fentiman IS, et al. Long-term results of a randomized trial 
comparing breast-conserving therapy with mastectomy: European Organization for Research and 
Treatment of Cancer 10801 trial. J Natl Cancer Inst 2000;92:1143-50. 
10. 
Veronesi U, Cascinelli N, Mariani L, et al. Twenty-year follow-up of a randomized study 
comparing breast-conserving surgery with radical mastectomy for early breast cancer. N Engl J Med 
2002;347:1227-32. 
11. 
Veronesi U, Salvadori B, Luini A, et al. Breast conservation is a safe method in patients with 
small cancer of the breast. Long-term results of three randomised trials on 1,973 patients. Eur J Cancer 
1995;31A:1574-9. 
12. 
Early Breast Cancer Trialists' Collaborative G, Darby S, McGale P, et al. Effect of radiotherapy 
after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis of 
individual patient data for 10,801 women in 17 randomised trials. Lancet 2011;378:1707-16. 
13. 
Hughes KS, Schnaper LA, Bellon JR, et al. Lumpectomy plus tamoxifen with or without 
irradiation in women age 70 years or older with early breast cancer: long-term follow-up of CALGB 
9343. J Clin Oncol 2013;31:2382-7. 
14. 
Kunkler IH, Williams LJ, Jack WJ, Cameron DA, Dixon JM, investigators PI. Breast-conserving 
surgery with or without irradiation in women aged 65 years or older with early breast cancer (PRIME II): 
a randomised controlled trial. Lancet Oncol 2015;16:266-73. 
15. 
Liu FF, Shi W, Done SJ, et al. Identification of a Low-Risk Luminal A Breast Cancer Cohort 
That May Not Benefit From Breast Radiotherapy. J Clin Oncol 2015;33:2035-40. 
16. 
Gralow JR, Burstein HJ, Wood W, et al. Preoperative therapy in invasive breast cancer: 
pathologic assessment and systemic therapy issues in operable disease. J Clin Oncol 2008;26:814-9. 
17. 
Mauri D, Pavlidis N, Ioannidis JP. Neoadjuvant versus adjuvant systemic treatment in breast 
cancer: a meta-analysis. J Natl Cancer Inst 2005;97:188-94. 
18. 
Rastogi P, Anderson SJ, Bear HD, et al. Preoperative chemotherapy: updates of National Surgical 
Adjuvant Breast and Bowel Project Protocols B-18 and B-27. J Clin Oncol 2008;26:778-85. 
19. 
Mamtani A, Barrio AV, King TA, et al. How Often Does Neoadjuvant Chemotherapy Avoid 
Axillary Dissection in Patients With Histologically Confirmed Nodal Metastases? Results of a 
Prospective Study. Ann Surg Oncol 2016;23:3467-74. 
20. 
Haviland JS, Owen JR, Dewar JA, et al. The UK Standardisation of Breast Radiotherapy 
(START) trials of radiotherapy hypofractionation for treatment of early breast cancer: 10-year follow-up 
results of two randomised controlled trials. Lancet Oncol 2013;14:1086-94. 
21. 
Tsang Y, Haviland J, Venables K, Yarnold J, Group FTM. The impact of dose heterogeneity on 
late normal tissue complication risk after hypofractionated whole breast radiotherapy. Radiother Oncol 
2012;104:143-7. 

 
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22. 
group FT, Agrawal RK, Alhasso A, et al. First results of the randomised UK FAST Trial of 
radiotherapy hypofractionation for treatment of early breast cancer (CRUKE/04/015). Radiother Oncol 
2011;100:93-100. 
23. 
Brunt AM, Wheatley D, Yarnold J, et al. Acute skin toxicity associated with a 1-week schedule of 
whole breast radiotherapy compared with a standard 3-week regimen delivered in the UK FAST-Forward 
Trial. Radiother Oncol 2016;120:114-8. 
24. 
Calitchi E, Kirova YM, Otmezguine Y, Feuilhade F, Piedbois Y, Le Bourgeois JP. Long-term 
results of neoadjuvant radiation therapy for breast cancer. Int J Cancer 2001;96:253-9. 
25. 
Cance WG, Carey LA, Calvo BF, et al. Long-term outcome of neoadjuvant therapy for locally 
advanced breast carcinoma: effective clinical downstaging allows breast preservation and predicts 
outstanding local control and survival. Ann Surg 2002;236:295-302; discussion -3. 
26. 
Courdi A, Ortholan C, Hannoun-Levi JM, et al. Long-term results of hypofractionated 
radiotherapy and hormonal therapy without surgery for breast cancer in elderly patients. Radiother Oncol 
2006;79:156-61. 
27. 
Matuschek C, Bolke E, Roth SL, et al. Long-term outcome after neoadjuvant radiochemotherapy 
in locally advanced noninflammatory breast cancer and predictive factors for a pathologic complete 
remission : results of a multivariate analysis. Strahlenther Onkol 2012;188:777-81. 
28. 
Santos M, Heymann S, Fayard F, et al. Preoperative radiotherapy in patients with locally 
advanced breast cancer: Tumor response and patient outcome after 26 years of median follow-up. J Clin 
Oncol 2011;29:113. 
29. 
Bondiau PY, Courdi A, Bahadoran P, et al. Phase 1 clinical trial of stereotactic body radiation 
therapy concomitant with neoadjuvant chemotherapy for breast cancer. Int J Radiat Oncol Biol Phys 
2013;85:1193-9. 
30. 
Horton JK, Blitzblau RC, Yoo S, et al. Preoperative Single-Fraction Partial Breast Radiation 
Therapy: A Novel Phase 1, Dose-Escalation Protocol With Radiation Response Biomarkers. International 
journal of radiation oncology, biology, physics 2015;92:846-55. 
31. 
Symmans WF, Peintinger F, Hatzis C, et al. Measurement of residual breast cancer burden to 
predict survival after neoadjuvant chemotherapy. J Clin Oncol 2007;25:4414-22. 
32. 
Bartelink H, Horiot JC, Poortmans PM, et al. Impact of a higher radiation dose on local control 
and survival in breast-conserving therapy of early breast cancer: 10-year results of the randomized boost 
versus no boost EORTC 22881-10882 trial. J Clin Oncol 2007;25:3259-65. 
33. 
Kyndi M, Sorensen FB, Knudsen H, et al. Estrogen receptor, progesterone receptor, HER-2, and 
response to postmastectomy radiotherapy in high-risk breast cancer: the Danish Breast Cancer 
Cooperative Group. J Clin Oncol 2008;26:1419-26. 
34. 
Tramm T, Mohammed H, Myhre S, et al. Development and validation of a gene profile predicting 
benefit of postmastectomy radiotherapy in patients with high-risk breast cancer: a study of gene 
expression in the DBCG82bc cohort. Clin Cancer Res 2014;20:5272-80. 
35. 
Feng M, Moran JM, Koelling T, et al. Development and validation of a heart atlas to study 
cardiac exposure to radiation following treatment for breast cancer. Int J Radiat Oncol Biol Phys 
2011;79:10-8. 
 
 
 
 
 
 
 
 
 
 
 

 
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44  
MC1732 
 
Appendix I 
 
ECOG PERFORMANCE STATUS 
 
Grade 
0  
Fully active, able to carry on all pre-disease activities without restriction 
(Karnofsky 90-100). 
 
1  
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light housework, office work (Karnofsky 
70-80). 
 
2  
Ambulatory and capable of all self-care, but unable to carry out any work 
activities.  Up and about more than 50 percent of waking hours   (Karnofsky 50-
60). 
 
3  
Capable of only limited self-care, confined to bed or chair 50 percent or more of 
waking hours (Karnofsky 30-40). 
 
4  
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed or 
chair (Karnofsky 10-20). 
 
5  
Dead 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
45  
MC1732 
 
Appendix II 
Mayo Breast Patient Survey 
 
Mayo Breast Patient Survey 
 
Survey Date (mm/dd/yyyy): 
 
DIRECTIONS: For each question below, please mark one response that describes how you would rate 
your symptoms DURING THE PAST DAY. 
 
1. 
How you would describe… 
 
 
Your overall quality of life? Response scale 1 to 10, with 1 = as bad as it could be; 10 = 
as good as it could be 
 
 
The severity of your pain, on average? Response scale 1 to 10, with 1 = no pain; 10 = 
Pain as bad as it could be 
 
Your level of fatigue, on average? Response scale 1 to 10, with 1 = no fatigue; 10 = 
fatigue as bad as it could be 
 
 
DIRECTIONS: For each question below, please mark one response that describes how you would rate 
your symptoms IN THE LAST 7 DAYS. 
 
2. 
In the last 7 days, how much did anxiety interfere with your usual or daily activities? 
 
Not at all 
 
A little bit 
 
Somewhat 
 
Quite a bit 
 
Very much 
 
3. 
In the last 7 days, how much did insomnia, including falling asleep, staying asleep, or  
 
waking up early INTERFERE with your usual or daily activities? 
 
Not at all 
 
A little bit 
 
Somewhat 
 
Quite a bit 
 
Very much 
 
4. 
In the last 7 days, what was the SEVERITY of your shortness of breath at its WORST? 
 
Not at all 
 
A little bit 
 
Somewhat 
 
Quite a bit 
 
Very much 
 
5. 
In the last 7 days, what was the SEVERITY of your cough at its WORST? 
 
Not at all 
 
A little bit 
 
Somewhat 
 
Quite a bit 
 
Very much 

 
46  
MC1732 
 
 
6. 
In the last 7 days, how much did problems with concentration INTERFERE with your  
 
usual or daily activities? 
 
Not at all 
 
A little bit 
 
Somewhat 
 
Quite a bit 
 
Very much 
 
7. 
In the last 7 days, how much did sad or unhappy feelings INTERFERE with your usual  
 
or daily activities? 
 
Not at all 
 
A little bit 
 
Somewhat 
 
Quite a bit 
 
Very much 
 
8. 
In the last 7 days, what was the SEVERITY of your skin burns from radiation at their  
 
worst? 
 
Not at all 
 
A little bit 
 
Somewhat 
 
Quite a bit 
 
Very much 
 
9. 
In the last 7 days, what was the SEVERITY of your difficulty swallowing at its  
 
WORST? 
 
Not at all 
 
A little bit 
 
Somewhat 
 
Quite a bit 
 
Very much 
 
10. 
In the last 7 days, how SEVERE have the following problems been (at their WORST)? 
 
Flaking or peeling of the treated breast or chest wall; response options 0 to 10, 0 = not at 
all, 10 = flaking as much as could be 
 
Bleeding of or leaking fluid from the treatment breast or chest wall; response options 0 to 
10, 0 = not at all, 10 = bleeding as much as could be 
 
Blistering of the treated breast or chest wall; response options 0 to 10, 0 = not at all, 10 = 
blistering as much as could be 
 
Itching of the treated breast or chest wall; response options 0 to 10, 0 = not at all, 10 = 
as itchy as it could be 
 
Skin burns from radiation on your back; response options 0 to 10, 0 = not at all, 10 = as 
itchy as it could be 
 
11. 
If you had to do it all over again, would you have this RADIATION treatment again? 
 
Yes 
 
No 

 
47  
MC1732 
 
 
12. 
Have you been diagnosed with an infection at your breast cancer surgical site that 
required treatment with antibiotics or surgery? 
 
Yes 
 
No 
 
We are interested in your evaluation of your physical appearance and functioning. Please rate the 
following items from 0 to 10, according to how you feel AT THIS POINT IN TIME. 
 
Is the color of your treated breast/chest wall skin different than the other side (red, tan, or 
lighter)? response options 0 to 10, 0 = not at all, 10 = as different as it could be 
 
 
Do you have visible small blood vessels (spider veins) on your treated breast/chest wall? 
response options 0 to 10, 0 = not at all, 10 = as many as it could be 
 
Do you have pain with swallowing? response options 0 to 10, 0 = not at all, 10 = as 
painful as could be 
 
Do you have numbness or a tingling sensation in the arm on the side that was treated? 
response options 0 to 10, 0 = not at all, 10 = as much as it could be 
 
Do you have tightness, pulling, or stretching in the arm, breast, or chest area (in the side 
that was treated?) response options 0 to 10, 0 = not at all, 10 = as much as it could be 
 
Do you have tenderness or discomfort on the treated breast/chest wall? response options 
0 to 10, 0 = not at all, 10 = as much as it could be 
 
 
Overall, how would you rate the cosmetic results of your breast treatment? 
 
Excellent  Good Fair Poor 
 
Please rate the following items according to your evaluation at this point in time: 
 
 
 
 
 
 
Breast/chest wall texture (hardening) 
 None 
 Slight 
Moderate 
Large 
Arm heaviness 
 None 
 Slight 
Moderate 
Large 
Shoulder movement 
 None 
 Slight 
Moderate 
Large 
Arm movement 
 None 
 Slight 
Moderate 
Large 
Breast/chest wall pain 
 None 
 Slight 
Moderate 
Large 
Ability to lift objects 
 None 
 Slight 
Moderate 
Large 
Fit of shirt sleeve 
 None 
 Slight 
Moderate 
Large 
Breast/chest wall tenderness 
 None 
 Slight 
Moderate 
Large 
Shoulder stiffness 
 None 
 Slight 
Moderate 
Large 
Scar tissue 
 None 
 Slight 
Moderate 
Large 
Shoulder pain 
 None 
 Slight 
Moderate 
Large 
Arm pain 
 None 
 Slight 
Moderate 
Large 
Arm swelling 
 None 
 Slight 
Moderate 
Large 
Breast/chest wall swelling 
 None 
 Slight 
Moderate 
Large 
Arm stiffness 
 None 
 Slight 
Moderate 
Large 
Breast/chest wall sensitivity 
 None 
 Slight 
Moderate 
Large 
Fit of clothing 
 None 
 Slight 
Moderate 
Large 
Axillary (arm pit) fullness or numbness 
 None 
 Slight 
Moderate 
Large 
 

 
48  
MC1732 
 
Please complete the following questions if you had breast conserving therapy or mastectomy with 
reconstruction. 
 
Please rate the following items according to your evaluation at this point in time 
 
Breast size 
 None 
 Slight 
Moderate 
Large 
Nipple appearance 
 None 
 Slight 
Moderate 
Large 
Breast shape 
 None 
 Slight 
Moderate 
Large 
Breast elevation (how 
high the breast is) 
 None 
 Slight 
Moderate 
Large 
Fit of bra 
 None 
 Slight 
Moderate 
Large 
Breast heaviness 
 None 
 Slight 
Moderate 
Large 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
49  
MC1732 
 
Appendix III 
Mayo Patient Survey PRO-CTCAE Mayo 10 
 
Survey Date (mm/dd/yyyy): 
 
Please answer the following questions about your symptoms. 
 
 
Not at 
all 
A little 
bit 
Somewhat 
Quite a bit 
Very much 
In the last 7 days, how much did anxiety 
INTERFERE with your usual or daily 
activities: 
 
 
 
 
 
In the last 7 days, how much did insomnia 
including difficulty falling asleep, staying 
asleep, or waking up early INTERFERE 
with your usual or daily activities: 
 
 
 
 
 
In the last 7 days, how much did decreased 
appetite INTERFERE with your usual or 
daily activities: 
 
 
 
 
 
 
Never 
Rarely 
Occasionally Frequently Almost 
Constantly 
In the last 7 days, how OFTEN did you 
have nausea: 
 
 
 
 
 
 
Not at 
all 
A little 
bit 
Somewhat 
Quite a bit 
Very much 
In the last 7 days, how much did shortness 
of breath INTERFERE with your usual or 
daily activities: 
 
 
 
 
 
In the last 7 days, how much did problems 
with concentration INTERFERE with your 
usual or daily activities: 
 
 
 
 
 
In the last 7 days, how much did sad or 
unhappy feelings INTERFERE with your 
usual or daily activities: 
 
 
 
 
 
 
None 
Mild 
Moderate 
Quite a bit 
Very severe 
In the last 7 days, what was the 
SEVERITY of your constipation at its 
WORST: 
 
 
 
 
 
 
Not at 
all 
A little 
bit 
Somewhat 
 Quite a 
bit 
Very much 
In the last 7 days, how much did numbness 
or tingling in your hands or feet 
INTERFERE with your usual or daily 
activities: 
 
 
 
 
 
 
Never 
Rarely 
Occasionally Frequently Almost 
Constantly 
In the last 7 days, how OFTEN did you 
have loose or watery stools (diarrhea): 
 
 
 
 
 
 
 
 
 

 
50  
MC1732 
 
Appendix IV 
Mayo Patient Survey 
 
Survey Date (mm/dd/yyyy): 
 
Please respond to each item by choosing one number per row. 
 
 
Excellent 
Very 
Good 
Good 
Fair 
Poor 
In general, would you say your health is: 
 
5 
 
4 
 
3 
 
2 
 
1 
In general, would you say your quality of life 
is: 
 
5 
 
4 
 
3 
 
2 
 
1 
In general, how would you rate your physical 
health? 
 
5 
 
4 
 
3 
 
2 
 
1 
In general, how would you rate your mental 
health, including your mood and your ability 
to think? 
 
5 
 
4 
 
3 
 
2 
 
1 
In general, how would you rate your satisfaction 
with your social activities and relationships? 
 
5 
 
4 
 
3 
 
2 
 
1 
In general, please rate how well you carry out 
your usual social activities and roles (Includes 
activities at home, work, community, parenting, 
marriage, friends.) 
 
 
5 
 
4 
 
3 
 
2 
 
1 
 
Completely Mostly 
Moderately A 
little 
Not at 
all 
To what extent are you able to carry out your 
everyday physical activities such as walking, 
climbing stairs, carrying groceries, or moving 
a chair? 
 
 
5 
 
4 
 
3 
 
2 
 
1 
 
Never 
Rarely 
Sometimes 
Often 
Always 
In the past 7 days… 
How often have you been bothered by 
emotional problems such as feeling anxious, 
depressed, or irritable? 
 
1 
 
2 
 
3 
 
4 
 
5 
 
 
How would you rate your fatigue on average? 
 
 
 
 
 
How would you rate your fatigue on average? 
 
 
 
1 
 
2 
 
3 
 
4 
 
5 
 
 
 
 
Worst pain 
imaginable 
 
0 
 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
7 
 
8 
 
9 
 
10 
No 
pain 
 
 
 
 
 
 
 
 
 
Worst pain 
imaginable