A Prospective Trial to Assess Tumor :Breast Ratio and Patient Satisfaction in Following Lumpectomy Versus Mastectomy With Reconstruction
Conditions: Breast Cancer, LCIS, DCIS
Sponsor: Washington University School of Medicine

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A PROSPECTIVE TRIAL TO ASSESS TUMOR: BREAST RATIO AND PATIENT 
SATISFACTION IN FOLLOWING LUMPECTOMY VERSUS MASTECTOMY WITH 
RECONSTRUCTION 
 
 
Washington University School of Medicine 
Department of Surgery 
660 S. Euclid Ave., Campus Box 8109 
St. Louis, MO 63110 
 
Version date:  09/07/2018 
 
 
 
 
 
 
Principal Investigator:  
Terence M. Myckatyn, MD 
 
Phone:   
 
 
(314) 996-8800 
Email:   
 
 
myckatyn@ wustl.edu 
 
 
Sub-Investigators: 
 
Marissa M. Tenenbaum, MD 
Amy E. Cyr, MD 
Julie A. Margenthaler, MD, FACS 
 
 
 

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A PROSPECTIVE TRIAL TO ASSESS TUMOR: BREAST RATIO AND PATIENT SATISFACTION IN 
FOLLOWING LUMPECTOMY VERSUS MASTECTOMY WITH RECONSTRUCTION 
 
  
 
 

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INDEX 
1.0 
BACKGROUND AND RATIONALE .................................................................................. 4 
2.0 
OBJECTIVES ................................................................................................................. 5 
3.0 
PATIENT SELECTION ..................................................................................................... 6 
4.0 
CONFIRMATION OF PATIENT ELIGIBILITY ..................................................................... 7 
5.0 
REGISTRATION PROCEDURES ....................................................................................... 7 
6.0 
PATIENT VISITS ............................................................................................................ 7 
7.0 
REGULATORY AND REPORTING REQUIREMENTS ........................................................ 11 
8.0 
DATA SUBMISSION SCHEDULE ................................................................................... 14 
9.0 
DATA AND SAFETY MONITORING .............................................................................. 15 
10.0 STATISTICAL CONSIDERATIONS .................................................................................. 15 
11.0 REFERENCES .............................................................................................................. 19 
APPENDIX A: Group A — BCT + XRT ARM STUDY VISIT SCHEDULE ......................................... 25 
APPENDIX B:  Group B — MASTECTOMY + RECONSTRUCTION ARM STUDY VISIT SCHEDULE . 26 
APPENDIX C:  Group C — MASTECTOMY STUDY VISIT SCHEDULE .......................................... 27 
 
 
 

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1.0 
BACKGROUND AND RATIONALE 
 
1.1 
Background 
Patients with localized ductal carcinoma in situ (DCIS) and Stage I-IIIA breast cancers are usually 
candidates for either breast conservation therapy (BCT: lumpectomy with radiation) or 
mastectomy since survival outcomes are comparable.  By its very name, BCT implies superior 
aesthetic outcomes as breast tissue is preserved.  Not surprisingly, when offered, the majority of 
women will choose BCT over mastectomy with reconstruction, (~65% BCT vs. 35% with 
mastectomy of which <30% of those receive a reconstruction).   
 
The degree of tissue loss with BCT however falls on a spectrum that is influenced by tumor size 
and the variable impact of radiation therapy.  Large-breasted women are able to absorb a larger 
absolute tumor resection than smaller breasted women due to the relative size of their breast.  
Further, the majority of women note that the upper-inner pole of their breast is more 
aesthetically relevant than other quadrants.  Therefore, BCT impacting this region may create a 
relatively greater degree of dissatisfaction.  A recent survey performed by the American Society 
of Plastic Surgeons found that ~ 46% of women undergoing BCT were disappointed with their 
results.  In another survey – the Breast Cancer Treatment and Outcomes Survey – increased 
breast asymmetry following BCT was correlated with depressed mood and a feeling of 
stigmatization.  In another study, tumors involving >10% of breast volume, and particularly 
those located in the medial breast, were associated with decreased patient satisfaction.  
Unfortunately, quantification of tumor: breast ratio was imprecisely calculated, and patient 
satisfaction was not determined by a validated, breast-specific patient reported outcomes tool 
in any of these studies.   
 
While the percentage of women undergoing mastectomy with reconstruction is still under 30%, 
and approximately 70% are not even informed of their options, there is increasing evidence that 
successful reconstruction offers a clear biopsychosocial advantage.  Advanced reconstructive 
techniques including nipple-sparing mastectomy, immediate implant reconstruction, 
microvascular perforator flaps and adjunctive imaging and materials technologies have 
significantly improved patient outcomes in terms of pain, function, patient reported satisfaction, 
and lowered complication rates.  Compared to national trends, the rate of reconstruction 
following mastectomy is 59% overall at our institution.  Of the remaining patients who did not 
undergo reconstruction following mastectomy, 60% chose not to have it and 40% had medical 
contraindications that precluded it as an option. 
 
Our ability to quantify patient satisfaction has also improved with the advent of the Breast Q.  
This instrument represents the most comprehensive and specific quantitative method for 
patient self-assessment following breast surgery.  Specific modules for breast reconstruction 
and BCT are available.  The Breast Q is superior to other previously validated instruments like 

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the Short Form (SF-36) which provides a generic psychometric overview of patient satisfaction 
on an 8 point scale but lacks items specific to breast surgery.  The European Organization for 
Research and Treatment or Cancer’s Quality of Life Questionnaire Breast Cancer Module (EORTC 
QLQ-30 Br23) does provide a breast cancer-specific module, but evaluates overall function and 
does not differentiate between breast conservation therapy and reconstruction.   We believe 
that for patients who get BCT, the relative size of the tumor and volume of its resection will 
profoundly impact breast symmetry and therefore impact patient reported outcomes on the 
Breast Q. 
 
1.2 
Rationale 
This study will show that many patients currently selected for lumpectomy will have better 
aesthetic outcomes when mastectomy with reconstruction is chosen.  While the absolute 
dimensions of a breast cancer are relevant to staging and treatment, tumor: breast ratio is a key 
factor in determining patient satisfaction with lumpectomy, and in turn should determine when 
a mastectomy with reconstruction should be performed to yield an optimal result.   It is the 
relative size of the tumor and volume of its resection that will profoundly impact breast 
symmetry and therefore impact patient reported outcomes following BCT.  Tumor: breast ratios 
> 0.2 will be associated with progressively poorer patient satisfaction outcomes when treated 
with BCT than would be provided by mastectomy with reconstruction.  Tumors in the 
superomedial breast will be even more sensitive to tumor: breast ratio.  We hypothesize that 
BCT will be particularly sensitive to tumor: breast ratio whereas mastectomy with 
reconstruction will be less dependent.  The results from this study will enable plastic and 
oncologic surgeons to identify a new cohort of patients, previously destined for BCT, to undergo 
a mastectomy with reconstruction to optimize their overall satisfaction with the aesthetic 
outcomes with equivalent treatment of their disease. 
 
2.0 
OBJECTIVES 
 
2.1 
Primary Objective 
• 
At which tumor: breast ratio do patient reported outcomes justify performance of a 
mastectomy with reconstruction versus BCT in stage-matched patients? 
 
2.2 
Secondary Objectives 
• 
Does tumor location impact the influence of tumor: breast ratio on patient reported 
outcomes following mastectomy with reconstruction or BCT? 
• 
 How does the pre and post-op Breast Q for the two groups (mastectomy + recon vs. BCT) 
reflect the tumor: breast ratio as calculated from 3D images rendered from MRI utilizing 
software-based algorithms? 
• 
How does the pre and post-op Breast Q for the two groups (mastectomy + recon vs. BCT) 
reflect the VECTRA 3D generated mammometrics? 

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• 
What is the impact of radiation in BCT on Breast Q (Q-score before and after radiotherapy) 
and VECTRA (breast volume, nipple position, total breast skin surface area before and after 
radiotherapy)? 
• 
How do complications that arise from each scenario (mastectomy + recon) vs. BCT impact 
patient satisfaction?  
• 
What is the impact of tumor location and obesity as independent determinants of patient 
satisfaction in the two groups (mastectomy + recon vs. BCT) relative to tumor: breast ratio? 
 
3.0 
PATIENT SELECTION 
 
3.1 
Inclusion Criteria 
• 
Patient must be scheduled to undergo breast conservation therapy (BCT), mastectomy 
or mastectomy with immediate reconstruction (defined as initiating the reconstructive 
process at time of mastectomy) for ductal carcinoma in situ (DCIS), lobular carcinoma in 
situ (LCIS), and early stage breast cancer (Clinical Stages IA-IIB).   Stage IIB tumors are 2-5 
cm with micrometastases 0.2 to 2.0 cm in lymph nodes; or 2-5 cm tumor with 1-3 
positive axillary or internal mammary lymph nodes, or >5 cm with no lymph node 
involvement. Clinical staging, based on imaging and physical exam will be used for 
enrollment. Patients that are unexpectedly upstaged will be excluded at that time.  For 
staging reference please see 
http://www.cancer.gov/cancertopics/pdq/treatment/breast/patient/page2#keypoint13.   
• 
If multifocal/multicentric disease of the ipsilateral breast is encountered and patients are still 
deemed eligible for BCT or mastectomy per standard of care, then the tumor area will be 
calculated as the total volumes of the identified foci.   
• 
Patient must be between 18-72 years old.  
• 
Patient must be able to understand and willing to sign a written informed consent document. 
 
3.2 
Exclusion Criteria 
• 
Cognitive impairment 
• 
History of radiation to the chest wall or breasts 
• 
Patients unable to undergo MRI due to metallic implant or claustrophobia  
• 
Patients that are pregnant since breast MRI is contraindicated  
• 
History of previous breast surgery other than primary cosmetic augmentation or breast 
reduction 
• 
Identification of a concurrent or synchronous contralateral cancer during the enrollment 
period 
• 
Any patient that would not have been considered for BCT or reconstruction  
• 
BCT patients planning to proceed with reconstruction during their study participation 
timeline. 

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3.3 
Inclusion of Women and Minorities 
Only women will be enrolled due to the anatomical specificity of breast cancer.  Members of all 
races and ethnic groups are eligible for this trial. 
 
4.0 
CONFIRMATION OF PATIENT ELIGIBILITY 
The following information is required to confirm patient eligibility prior to registering patient: 
1. Completed eligibility checklist, signed and dated by a member of the study team 
2. Copy of appropriate source documentation confirming patient eligibility 
3. Signed consent form 
4. Documentation of informed consent process 
5. Patient’s race, sex, and DOB 
6. Assignment of unique study identifier 
7. Registering MD’s name 
8. Planned date of enrollment 
 
5.0 
REGISTRATION PROCEDURES 
Patients must be registered in the Siteman Cancer Center database within one working day of 
enrolling physician signing off on patient eligibility. 
 
6.0 
PATIENT VISITS 
 
6.1 
Visit #1:  Preoperative Evaluation with Surgical Oncologist 
The surgical oncologists will discuss treatment options with patients during their initial 
consultation.  Patients will be evaluated to determine whether their age, planned surgical 
procedure, and medical/surgical history meet the inclusion criteria specified in Section 3.1.  
Patients will also be evaluated to be sure they do not meet any of the exclusion criteria in 
Section 3.2.  Patients meeting all study criteria will be approached about their ability to 
participate in this research trial. 
 
The relevant Breast-Q Module is routinely administered pre-operatively to obtain baseline quality 
of life data on all patients being evaluated for breast cancer surgery. There are 3 distinct BREAST 
Q surveys based on the type of surgery planned. There is a “Breast Conservation Therapy” 
version, a “Mastectomy Only” version and a “Mastectomy with Reconstruction” version. Each 
version has surgery specific pre-operative and postoperative modules. All contain several 
domains that generate a Q-Score (0-100) enabling quantitative and validated comparison 
between groups for a particular domain (patient overall satisfaction, satisfaction with care, 
satisfaction with breasts, etc.). It should take 10-15 minutes for this self-administered 

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questionnaire to be completed. 
  
6.2 
Visit #2:  MRI Visit 
Diagnostic imaging visit with radiology is performed via MRI per standard of care prior to the 
surgical procedure that removes breast tissue via lumpectomy or mastectomy. The 3D 
reconstruction can be performed at any time after image acquisition as image data is stored 
per standard procedure, in the radiology department. The tumor: breast ratio calculation will 
be rendered from these images for the purposes of this study.  It is possible some patients 
may have already had a MRI prior to enrollment into this study.   
  
6.3 
Visit #3:  Plastic Surgeon Visit (Group B Mastectomy + Reconstruction Only)  
The plastic surgeons will discuss reconstructive treatment options with patients.  The plastic 
surgeons may order additional tests and imaging procedures during this evaluation as needed.   
 
 
The Breast Q Reconstruction + Expectations Module will be administered pre-operatively to 
obtain baseline quality of life data if it was not completed at visit #1.  It should take 10-15 minutes 
for this self-administered questionnaire to be completed.  The Breast Q is given to all patients 
seeking breast surgery in the clinical practice and is not a research procedure.  
 
 
6.4 
Surgical Intervention (T=0)   
Standardized operation techniques will be used in all treatment groups.  All surgeries will be 
performed by surgical oncologists experienced with breast oncology and affiliated with the 
Siteman Cancer Center at Washington University.  All reconstructions will be performed by one 
of two plastic surgeons who are also experienced with all forms of breast reconstruction (Drs. 
Tenenbaum and Myckatyn).   
 
Operative notes and pathology reports will be collected. 
 
Postoperative management is standard of care for all patients.  Postoperative complications and 
need for re-excision will be recorded and monitored.  
 
 
6.5 
Visits #4 - 5:  Post-Operative Visits 
All patients will have routine follow up visits after surgery.  Timing of follow-up will be 
variable among the three groups.  
• 
Group A:  The surgical oncologist will see the BCT group.   
o Post-Lumpectomy 1st Post-op Visit before Radiotherapy (1-10 weeks after 
lumpectomy) 
▪ 
Post-Op Breast Q will be administered and routine imaging taken to 
quantify volume and mammometric parameters 

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o Post-Lumpectomy Post-op Visit after Radiotherapy (6- 18 months after 
radiation or the latest follow-up time point within the duration confines of 
our study period.) 
▪ 
Post-Op Breast Q will be administered and routine imaging taken to 
quantify volume and mammometric parameters 
Some patients will require no adjuvant chemotherapy following lumpectomy based 
on their pathology. These patients are typically radiated 4-10 weeks after 
lumpectomy. Other patients will require chemotherapy after lumpectomy but prior 
to radiation. Chemotherapy duration can vary depending on selected treatment 
regimen but can be between 8-18 weeks excluding Herceptin which typically is 
administered every 6 weeks for 1 year. Patients receive Herceptin during radiation 
and reconstruction and so the administration of Herceptin does not independently 
alter any study time points. Patients will not undergo chemotherapy or radiation until 
after re-excision is performed in cases where there is a positive cancer margin after 
lumpectomy per standard of care. 
 
• 
Group B:  Mastectomy with reconstruction patients will be seen in follow up with 
plastic surgery.  
o Post-mastectomy 1st Post-op Visit before Completion of Reconstruction (1-10 
weeks after mastectomy) 
▪ 
Post-Op Breast Q will be administered and routine imaging taken to 
quantify volume and mammometric parameters 
o Post-mastectomy Post-op Visit after Final Reconstruction (3-8months after 
final reconstructive procedure or the latest follow-up time point within the 
duration confines of our study period.) 
▪ 
Post-Op Breast Q will be administered and routine imaging taken to 
quantify volume and mammometric parameters 
 
• 
Group C:  The surgical oncologist will see the mastectomy only group.   
o Post-mastectomy 1st Post-op Visit (1-10 weeks after mastectomy) 
▪ 
Post-Op Breast Q will be administered and routine imaging taken to 
quantify volume and mammometric parameters 
o Post-mastectomy Post-op Visit (6- 18 months after mastectomy or the latest 
follow-up time point within the duration confines of our study period.) 
▪ 
Post-Op Breast Q will be administered and routine imaging taken to 
quantify volume and mammometric parameters 
 
 
6.6 
Variable Duration of Study Observation 
Some patients may receive neoadjuvant chemotherapy prior to either lumpectomy or 
mastectomy.  Adjuvant chemotherapy may also be required based on pathologic findings.  If 
required, chemotherapy may begin approximately 6 weeks following surgery. Chemotherapy 

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duration can vary depending on selected agents but can be between 8-18 weeks.   Radiotherapy 
if needed is usually scheduled for 6 weeks after the final chemotherapy and can last 
approximately 6 weeks.  Treatment time may be lengthened for complications.  Reconstruction 
procedures can happen in multiple stages, therefor extending the time to final completion. This 
variability in adjuvant treatment will affect the timelines for follow-up and will be recorded for 
study purposes.   
 
Fig. 1. Study Arms and Duration 
 
 
6.7 
Criteria for Removal from Study   
If the patient, at any time wishes to be removed from the study, they will be.  This study does 
not propose any new interventions – it is an observational study of patients receiving normal, 
uninfluenced care for the treatment of breast cancer. 
 
 
Group A
BCT Group:  
Lumpectomy with XRT 
(n=83)
May receive chemo if medically 
indicated, but none can undergo 
reconstruction during study 
enrollment
Final Study Follow Up Visit: 6-
18 months AFTER radiation 
concludes OR the latest follow-
up time point within the 
duration of our study period
Follow-up with surgical 
oncologist.
Group B
Mastectomy + 
Reconstruction
(n=83)
Reconstruction may be 
immediate implant, expander, 
any flap, bilateral procedures to 
improve symmetry including 
contalateral prophylactic 
mastectomy + reconstruction
May receive chemo and/or XRT if 
medically indicated
Final Study Follow Up Visit: 3-8 
months AFTER final 
reconstruction procedure OR 
the latest follow-up time point 
within the duration of our study 
period
Follow-up with plastic surgeon.
Group C
Mastectomy Only
(n= up to 20)
Patients eligible for 
reconstruction but declined.
May receive chemo and/or XRT if 
medically indicated
Final Study Follow Up Visit: 6-
18 months AFTER mastectomy 
procedure OR the latest follow-
up time point within the 
duration of our study period
Follow-up with surgical 
oncologist.

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6.8 
Anticipated Time Duration of Study 
RECRUITMENT:  41 Months to recruit  
FOLLOW-UP:  MONTHS:  Variable with minimum 12 months and maximum  4.5 years 
TOTAL TIME TO CLOSURE:  58 MONTHS  
  
7.0 
REGULATORY AND REPORTING REQUIREMENTS 
 
7.1 
 Adverse Events (AEs) 
Definition: any unfavorable medical occurrence in a human subject including any abnormal sign, 
symptom, or disease. 
This is an observational study where diagnostic imaging and patient reported outcomes are 
measured in the context of routine breast cancer care. There will be no intervention that is unique 
to this study that does not normally occur with standard patient care. As such, there are no 
adverse events that are unique to this study.  
 
Common complications associated with breast oncologic and reconstructive surgery will be 
tracked since we suspect that complications will be an independent risk for adversely affecting 
patient reported outcomes independent of tumor: breast ratio. Common complications will be 
obtained by reviewing the inpatient and outpatient electronic medical records in Clinical Desktop 
and Allscripts of all enrolled patients. We will therefore record anticipated morbidities such as 
anesthetic complications, bleeding, infection requiring readmission or surgery, wound healing 
problems requiring surgical intervention, need for re-excision in lumpectomy due to positive 
margins, and reconstructive failures due to flap loss or breast prosthesis explant for the purposes 
of this study. However, none of these are expected to be related to the performance of this study 
Initial HRPO 
Submission
Dec 2013
Patient Recruitment 
April 2014- Sept 30, 2017
(41 months)
Conclude Follow Up
October 31, 2018
Total = 58 Months

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and will not be summarized, graded or reported as traditional adverse event reporting in an 
interventional oncology trial. 
 
7.2 
Unanticipated Problems 
Definition: 
 
• 
unexpected (in terms of nature, severity, or frequency) given (a) the research procedures 
that are described in the protocol-related documents, such as the IRB-approved research 
protocol and informed consent document; and (b) the characteristics of the subject 
population being studied; 
• 
related or possibly related to participation in the research (“possibly related” means there 
is a reasonable possibility that the incident, experience, or outcome may have been 
caused by the procedures involved in the research); and 
• 
suggests that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized. 
 
7.3 
Noncompliance 
Definition: failure to follow any applicable regulation or institutional policies that govern human 
subject’s research or failure to follow the determinations of the IRB.  Noncompliance may occur 
due to lack of knowledge or due to deliberate choice to ignore regulations, institutional policies, 
or determinations of the IRB. 
 
7.4 
Serious Noncompliance 
Definition: noncompliance that materially increases risks, which result in substantial harm to 
subjects or others, or that materially, compromises the rights or welfare of participants. 
 
7.5 
Protocol Exceptions 
Definition: A planned deviation from the approved protocol that are under the research team’s 
control. Exceptions apply only to a single participant or a singular situation. 
Pre-approval of all protocol exceptions must be obtained from the Human Research Protection 
Office prior to the event.   
 
7.6 
Reporting to the Human Research Protection Office (HRPO) and the Quality 
Assurance and Safety Monitoring Committee (QASMC) at Washington University 
The PI is required to promptly notify the IRB of the following events: 
• 
Any unanticipated problems involving risks to participants or others which occur at WU, 
any BJH or SLCH institution, or that impacts participants or the conduct of the study. 

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• 
Noncompliance with federal regulations or the requirements or determinations of the 
IRB. 
• 
Receipt of new information that may impact the willingness of participants to participate 
or continue participation in the research study. 
 
These events must be reported to the IRB within 10 working days of the occurrence of the event 
or notification to the PI of the event.   
7.7 
Timeframe for Reporting Required Events  
 
 
 
Unanticipated Problems 
Any unanticipated events as described in Section  7.2  
Immediately, within 24 hours to 
PI and within 10 working days to 
the IRB  
Noncompliance and Serious Noncompliance 
All noncompliance and serious noncompliance  
Immediately, within 24 hours, to 
PI and within 10 working days to 
the IRB 
 
 
7.8 
Anticipated Risks 
There are no additional risks that this study poses to study participants relative to not 
participating. All enrolled patients are subject to the same risks as any other patient undergoing 
standard of care breast oncologic and reconstructive care. 
 
 

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8.0 
DATA SUBMISSION SCHEDULE 
 
Case Report Form 
Submission Schedule 
Original Consent Form 
Prior to registration 
Eligibility Checklist RedCap 
Enrollment, Visit 1, Visit 2 MRI, 
and Visit 3 Plastics (if applicable) 
 
Prior to surgery 
RedCap Surgical Intervention 
Following receipt of final operative and 
pathology reports 
RedCap Follow-Up Forms Post-Operative Visit 
1, Oncology Course, and Post-Operative Visit 2 
Group A:  
o Post-Lumpectomy 1st post-op visit 
before Radiotherapy (1-10 weeks 
after lumpectomy) 
o Post-Lumpectomy post-op visit after 
radiotherapy (6-18 months after 
radiation or the latest follow-up time 
point within the duration confines of 
our study period.) 
Group B:  
o Post-mastectomy 1st post-op visit 
before completion of reconstruction 
(1-10 weeks after mastectomy) 
o Post-mastectomy Post-op Visit after 
final reconstruction (3-8 months 
after final reconstructive procedure 
or the latest follow-up time point 
within the duration confines of our 
study period.) 
Group C:   
o Post-mastectomy 1st post-op visit (1-
10 weeks after mastectomy) 
Post-mastectomy post-op visit (6-18 
months after mastectomy or the latest 
follow-up time point within the 

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duration confines of our study period.) 
Unanticipated Event via HRPO 
At the time of any unanticipated event 
MRI T:B ratio, Breast Q-Scores, and Vectra 
Mammometrics 
The coordinators will ensure MRI performed, 
Breast-Q’s completed and Vectra images 
captured during active patient phase.  MRI T:B 
ratio will be performed late in the active study 
phase to allow for a limited number of staff to 
perform bulk of measurements to optimize 
standardization. There is also a possibility the 
software will be upgraded to automate the T:B 
ratio later in the study period.  Breast-Q scores 
and Vectra mammometrics will be also 
evaluated in bulk late in the active study phase 
using SAS, SPSS, or another similar statistical 
program. 
 
9.0 
DATA AND SAFETY MONITORING 
In compliance with the Washington University Institutional Data and Safety Monitoring Plan, the Principal 
Investigator will provide a Data and Safety Monitoring (DSM) report to the Washington University Quality 
Assurance and Safety Monitoring Committee (QASMC). 
 
The Principal Investigator will review all patient data at least monthly and provide a semi-annual report 
to the Quality Assurance and Safety Monitoring (QASM) Committee.  This report will include: 
 
1. the protocol title, IRB protocol number, and the activation date of the study. 
2. the number of patients enrolled to date 
3. the date of first and most recent patient enrollment 
4. a summary of all unexpected events 
5. a response evaluation for evaluable patients 
6. a summary of any recent literature that may affect the ethics of the study. 
 
The study principal investigator and Research Patient Coordinator will monitor for unexpected events on 
an ongoing basis. Once the principal investigator or Research Patient Coordinator becomes aware of a 
research related and unanticipated adverse event, it will be reported to the HRPO according to 
institutional guidelines.  
 
10.0 
STATISTICAL CONSIDERATIONS 
 

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10.1 
Outcome Measures 
• 
Tumor: breast ratio generated from MRI  
• 
The Breast Q (pre and post op) outcome measurements 
• 
Breast mammometrics generated from 3D imaging 
 
10.2 
Data Fields Recorded 
• 
PATIENT VARIABLES :  BMI, smoking history, patient age, race, previous history breast 
augmentation,  
• 
CANCER VARIABLES:  cancer stage, presence or absence of sentinel lymph node biopsy, 
receptor status, tumor location, multifocal 
• 
RADIATION & CHEMOTHERAPY VARIABLES:  radiation received, length of treatment, 
chemotherapy selected, complications causing radiation or chemotherapy delay or dose 
reduction 
• 
BREAST VARIABLES :, standardized breast measurements (sternal notch to nipple, IMF to 
nipple, maximum areolar diameter, ptosis) 
• 
SURGICAL VARIABLES: patients undergoing mastectomy with reconstruction as per routine 
will be recorded as immediate implant, expander-reconstruction, use of acellular dermal 
matrix, or flap including predominantly DIEP, but also free TRAM, latissimus, PAP, SIEA, TUG, 
or SGAP. Also balancing procedures will be considered like breast 
reduction/lift/augmentation/augmentation with lift, fat grafting, adjacent tissue transfer, 
pseudohernia repair, correction of malposition, implant exchange, capsulectomy, 
capsulorrhaphy, Ryan procedure,  
• 
IMAGING VARIABLES: tumor: breast ratio, mammometrics (breast volumes, surface area, 
nipple position, chest wall morphology, vectors, anatomic landmarks) 
• 
COMPLICATION VARIABLES: complications related to breast surgery will be recorded 
(anesthetic complications, bleeding, infection requiring readmission or surgery, wound 
healing problems requiring surgical intervention, need for re-excision in lumpectomy due to 
positive margins, and reconstructive failures due to flap loss or breast prosthesis explant). 
Patients with complications will be included as this is a key determinant of patient reported 
outcomes. 
 
10.3 
Study Design 
All DCIS, LCIS and Stage IA-IIB breast cancers that are reasonably treated with mastectomy or 
BCT will be screened for eligibility for participation in this study.  There will be significant 
heterogeneity within each group in terms of presence/absence, type, timing 
(adjuvant/neoadjuvant) and duration of chemoradiation administered.  To standardize the 
timing of our outcome measurement, t=0 will always be in relation to the tumor surgery 
(lumpectomy or mastectomy).  We will also obtain a late time point for last follow-up at least 
6 months after the final intervention whether therapeutic or reconstructive, whichever is last.  
Data collected at this late time point – relative to the initial cancer resection at t=0 – is expected 

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to vary substantially (months-year) between subjects.  We have carefully selected IIB patients 
as the most advanced stage of breast cancer included.  This enables us to evaluate patients 
with large (>5 cm) tumors that are candidates for mastectomy or BCT which will be important 
since it is in the larger tumors we hypothesize that patient satisfaction and mammometric data 
would favor mastectomy + reconstruction over BCT.   
 
Patients that meet the  inclusion criteria but who opt for mastectomy without reconstruction 
are included as a control group to further evaluate the impact of post-mastectomy 
reconstruction.   
 
10.4 
Sample Size 
Mammometrics will be converted to comparable data and then related to Q-Score as these are 
expected to be complex relationships.  
 
We anticipate enrolling 83 subjects per study arm (166 total) with up to an additional 20 subjects 
undergoing mastectomy without reconstruction as a negative control for a total of 186 patients.  
 
 
Initial plan is to use G*Power v 3.1, or a comparable statistical package. Based on an effect size 
d=of 0.45, Type I error a=0.05, and power (1-ß) =0.8, normal distribution, and 2-tails, we will 
require 83 subjects per arm (166 total).  Assumptions: A difference in mean scores of 10 on a 100-
point scale (Q-Score generated from Breast Q) was assumed to be significant. This is determined 
by assuming an SD of 20, with one-half of an SD being the threshold of discrimination for change 
in health-related quality of life. 
Sample size calculations are based on 1) previously reported sample size calculations where data 
from the Breast Q for Breast Reconstruction was used with 2) the open-source statistical 
package G*Power 3.1. 
 
 
10.5 
Data Analysis 
 
This is a longitudinal observational study to compare effects of two treatment groups on the 
quality of life and to explore how the treatment effects are modified by T:B ratio. For each study 
patient, we have a data vector D=(group, T:B ratio, location, Q(t), 3D(t), W), where group is a 
binary indicator for two comparison groups. T:B ratio is the tumor: breast ratio measured at a 
continuous scale, and location is a binary indicator of tumor location. Q(t) and 3D(t) are Q score 
and the VECTRA 3D generated mammometrics respectively, measured as continuous variables 
at t=(0,1,2), where t=0 is the pre-treatment baseline measurement. W is a set of patient 
characteristics – e.g., age, obesity, stage, etc. A longitudinal study generates correlations among 
the repeated measurements within the same individual, and observational study often comes 
with a biased estimate of the treatment comparison due to confounding. These two issues, the 
correlation of repeated measurements and confounding, must be taken into account in the data 

Version  7.0, 09.07.18 
 
page 18 of 27 
analysis. Regression analyses of correlated data can simultaneously address these two issues. 
There are two families of statistical methods for regression analyses of correlated data – mixed 
effect model and generalized estimating equation (GEE).  Both are appropriate for our study, 
even though the interpretations are different – population average vs subject specific. Data 
analyses for our study will be performed within this framework to adjust for the patient 
characteristics for unbiased comparison of treatment effect and to take into account the 
correlations. 
 
10.5.1 Primary objectives: 
For main effect of treatment group on Q-score: fit and test a model with Q score as the 
dependent variable and group as the independent variable, controlling for W in the 
model – (Model 1). 
For the difference in Q score between two treatment groups modified by T:B ratio:  fit  
and test a model with Q score as the dependent variable, and group, T:B ratio, and group-
by-T:B ratio interaction as the independent variables, controlling for  W in the model – 
(Model 2).  The results can be better presented as a graph with two lines – Q score as a 
function of T:B ratio for these treated with BCT, and for those treated with 
Mastectomy+reconstruction. 
10.5.2 Secondary objectives: 
Does tumor location impact the influence of tumor: breast ratio on patient reported 
outcomes following mastectomy with reconstruction or BCT? 
• 
Add location and three way interaction term –group-by-T:B ratio-by-location 
into Model 2 – (Model 3).  The results can be better presented as two graphs – 
one for each location. See Model 2 for the graph. 
How does the pre and post-op Breast Q for the two groups (mastectomy + recon vs. BCT) 
reflect the tumor: breast ratio as calculated from 3D images rendered from MRI utilizing 
software-based algorithms? 
●    Fit and test a model with Q-score as the dependent variable and 3D image data 
as the independent variable with appropriate non-linear terms for 3D (e.g. 
spline functions), with group and possible interaction of group-by-3D (Model 4). 
How does the pre and post-op Breast Q for the two groups (mastectomy + recon vs.  BCT) 
reflect the VECTRA 3D generated mammometrics? 
• 
Both the Breast Q and the VECTRA 3 D generated mammometrics are 
continuous variables. The correlation between them will be quantified by 
Pearson or Spearman correlation coefficient with one sample t test for 
population correlation coefficient =0, and with Fisher Z transformation to test 
the population correlation coefficient not equal to zero. 
What is the impact of radiation in BCT on Breast Q (Q-score before and after 

Version  7.0, 09.07.18 
 
page 19 of 27 
radiotherapy) and VECTRA (breast volume, nipple position, total breast skin surface area 
before and after radiotherapy)? 
• 
Perform the subgroup analyses of BCT patients comparing change in outcomes 
of interest before and after radiation.  
How do complications that arise from each scenario (mastectomy + recon) vs. BCT 
impact patient satisfaction?  
• 
Fit and test a model with Q-score as the dependent variable and complication 
and group, and possible group-by-complication interaction as independent 
variables controlling for W in the model. 
What is the impact of tumor location and obesity as independent determinants of 
patient satisfaction in the two groups (mastectomy + recon vs. BCT) relative to tumor: 
breast ratio? 
• 
Fit and test a model with Q-score as the dependent variable and group, T:B 
ratio, location, and obesity as the independent variables, controlling for W in 
the model.  Obtain the standardized regression coefficients for location, obesity, 
and T:B ratio, and compare each other to determine their relative importance.  
 
11.0 
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APPENDIX A: Group A — BCT + XRT ARM STUDY VISIT SCHEDULE 
 
Screening 
Oncology 
Surgeon 
Radiology 
Breast 
Conservation 
Therapy (BCT) 
 
Postop Visit 
Oncology 
Surgeon 
Final Study 
Visit 
Oncology 
Surgeon 
 
Visit #12 
Visit #24 
T=0 
Visit #45 
Visit #56 
Past medical history1,2 
X 
 
 
 
 
Physical Exam2,3 
X 
 
 
X 
X 
Informed Consent2 
X 
 
 
 
 
Discussion of therapeutic 
options (Breast Surgery, 
sentinel node biopsy, XRT 
&/or chemo) 
X 
 
 
X 
 
Breast-Q 2 (BCT vs.) 
X (Preop Vs.) 
 
 
X 
(Post Op Vs.) 
X 
(Post Op Vs.) 
MRI4 
 
X 
 
 
 
Photography2 
3D 
 
 
3D 
3D 
Documentation of 
lumpectomy findings 7 
 
 
X 
 
 
Monitor for Unexpected 
Events 
 
 
X 
X 
X 
1Study-relevant past medical and surgical history 
 
2Screening procedures to be completed within 90 days of surgery. 
3Baseline height, weight, clinical stage, biopsy results from pre-surgical physical examination 
4MRI may be completed prior to Visit #1. 
5This is done 1-10 weeks after lumpectomy where the surgical margins were cleared. 
6Done 6- 18 months after radiation therapy has concluded or the latest follow-up time point within the duration confines of our study period. 
7Final pathological stage, document if re-excision is needed 
Note:  No required Visit #3 for Group A. 

Version  7.0, 09.07.18 
 
page 26 of 27 
APPENDIX B:  Group B — MASTECTOMY + RECONSTRUCTION ARM STUDY VISIT SCHEDULE 
 
Screening 
Oncology 
Surgeon 
Radiology 
Screening/Baseline 
Plastic Surgeon 
Mastectomy + 
Reconstruction 
Postop Visit 
Plastic Surgeon 
Final Study Visit 
Plastic Surgeon 
 
Visit #12 
Visit #24 
Visit #32 
T=0 
Visit #45 
Visit #56 
Past medical history1,2 
X 
 
X 
 
 
 
Physical Exam2,3 
X 
 
X 
 
X 
X 
Informed Consent2 
X 
 
X 
 
 
 
Discussion of therapeutic options 
(Breast Surgery, sentinel node 
biopsy, XRT &/or chemo) 
X 
 
 
 
X 
 
Breast-Q 2 (mastectomy and 
reconstruction vs.) 
X (Preop Vs.) 
 
X (Preop Vs.) 
 
X 
(Post Op Vs.) 
X 
(Post Op Vs.) 
Discussion of reconstruction options 
 
 
X 
 
 
 
MRI4 
 
X 
 
 
 
 
Photography2 
3D 
 
3D 
 
3D 
3D 
Documentation of intraoperative 
findings 7,  
 
 
 
X 
 
 
Monitor for Unexpected Events 
 
 
 
X 
X 
X 
1Study-relevant past medical and surgical history 
2Screening procedures to be completed within 90 days of surgery. May be completed in Group B at Visits #1 and/or #3. 
3Baseline height, weight, clinical stage, biopsy results from pre-surgical physical examination 
4MRI may be completed prior to Visit #1. 
5This is done 1-10 weeks after the first reconstructive intervention, typically at time of mastectomy.  
6This is done 3-8 months after the final reconstructive intervention, or the latest follow-up time point within the duration confines of our study period. 
7Final pathological stage, presence or absence of sentinel lymph node biopsy and the outcome of biopsy  

Version  7.0, 09.07.18 
 
page 27 of 27 
APPENDIX C:  Group C — MASTECTOMY STUDY VISIT SCHEDULE 
 
Screening 
Oncology 
Surgeon 
Radiology 
Mastectomy 
PostOp Visit 
Oncology 
Surgeon 
Final Study 
Oncology 
Surgeon 
 
Visit #12 
Visit #24 
T=0 
 
Visit #45 
Visit #56 
Past medical history1,2 
X 
 
 
 
 
Physical Exam2,3 
X 
 
 
X 
X 
Informed Consent2 
X 
 
 
 
 
Discussion of therapeutic 
options (Breast Surgery, 
sentinel node biopsy, XRT 
&/or chemo) 
X 
 
 
X 
 
Breast-Q 2 
(mastectomy vs.) 
X (Preop Vs.) 
 
 
X 
X 
(Post Op Vs.) 
MRI4 
 
X 
 
 
 
Photography2 
3D 
 
 
3D 
3D 
Documentation of 
intraoperative findings 7, 
 
 
X 
 
 
Monitor for Unexpected 
Events 
 
 
X 
X 
X 
1Study-relevant past medical and surgical history 
2Screening procedures to be completed within 90 days of surgery.  
3Baseline height, weight, clinical stage, biopsy results from pre-surgical physical examination 
4MRI may be completed prior to Visit #1. 
5Visit #4 should occur 1-10 weeks after mastectomy. 
6Visit #5 should occur 6- 18 months after mastectomy or the latest follow-up time point within the duration confines of our study period. 
7Final pathological stage, presence or absence of sentinel lymph node biopsy and the outcome of biopsy  
.   
Note:  No required Visit #3 for Group C.