Low-Dose Tamoxifen to Reduce High Background Parenchymal Uptake on Molecular Breast Imaging
Phase: NA
Conditions: High Background Uptake on MBI
Sponsor: Mayo Clinic

Low-Dose Tamoxifen to Reduce High Background Parenchymal Uptake on 
Molecular Breast Imaging 
 
Protocol version: 3 
Revision date: September 13, 2017 
 
 
1 
BACKGROUND AND RATIONALE 
1.1 
MBI as a Supplemental Screening Test 
Approximately 40-50% of women presenting for screening mammography have 
mammographically dense breasts, a factor that severely limits sensitivity of the test. 
Molecular breast imaging (MBI) is one option offered for supplemental screening of dense 
breasts. As MBI is a functional imaging technique that relies on differences in preferential 
uptake of Tc-99m sestamibi in metabolically-active cells, it is able to reveal cancers hidden 
among dense fibroglandular tissue on a mammogram. Performing MBI after a negative 
mammogram in women with dense breasts detects an additional 7.7 to 8.8 breast cancers 
per 1000 women screened [1-3].  
 
MBI is a nuclear medicine test that uses a high-resolution, semiconductor-based gamma 
camera to image the uptake of a radiotracer, typically Tc-99m sestamibi, in the breast. 
Mayo Clinic investigators have pioneered current MBI techniques and developed a low-
radiation-dose MBI protocol for clinical use [4, 5]. Recently, MBI has been implemented 
across the multi-site Mayo Clinic practice. 
 
1.2 
Background Parenchymal Uptake (BPU) on MBI  
In addition to detecting breast cancer, MBI also depicts the level of Tc-99m sestamibi 
uptake in non-cancerous fibroglandular tissue, termed background parenchymal uptake 
(BPU). BPU is subjectively assessed according to a validated lexicon as one of four 
categories (photopenic, minimal to mild, moderate, and marked) that describe the relative 
intensity of uptake in fibroglandular tissue[6]. A quantitative measure of BPU is also 
currently under development by Dr. Hruska’s team (R21 CA197752). BPU varies among 
women with similar-levels of mammographic density and is associated with hormonal 
factors such as menopausal status and use of postmenopausal hormone therapy (Fig. 1) [7]. 
Importantly, we recently showed BPU associated with breast cancer risk; women with 
moderate or marked BPU have 3.4 to 4.8-fold increased risk compared to women with 
photopenic or minimal-mild BPU [8].  
 
The exact mechanism of uptake of Tc-99m sestamibi in breast tissue is not entirely 
understood, but has been correlated with blood flow, tissue viability, mitochondrial 
activity, and mitotic activity in breast cancers. In an effort to understand histological 
characteristics that may account for variability in BPU, analysis has been performed on 
core biopsy specimens from 48 volunteers with mammographically dense breasts who have 
one of the extreme BPU categories of either photopenic BPU (N = 28) or marked BPU (N 

= 20) on MBI (unpublished data). BPU was associated with differences in tissue 
composition: specimens with marked BPU comprised a higher proportion of epithelial cells 
(22% vs. 2.8%, p<0.0001) and a lower proportion of stroma (47% vs. 75%, p = 0.005).  
 
 
BPU was inversely correlated with lobular involution status and associated with Ki-67 
positivity (8.6% positive in marked BPU vs. 2.6% positive in photopenic BPU, p = 0.006). 
These associations with histologic features further support a relationship between BPU and 
breast cancer risk. 
 
We hypothesize that BPU is positioned to serve as a functional imaging biomarker to 
identify the subset of women with dense breasts who are at greatest breast cancer risk and 
most likely to benefit from tailored screening or preventive options. However, more study 
is needed to understand BPU as a marker of risk. It is yet unclear how BPU changes over 
the course of a woman’s lifetime and whether these changes are related to changes in breast 
cancer risk. Further, it is unknown whether chemopreventive options such as tamoxifen 
would decrease BPU and whether these changes could serve as a surrogate marker for 
decrease in risk. 
 
Fig. 1 
Examples of background 
parenchymal uptake categories. 
Molecular breast imaging (MBI) 
examinations and corresponding 
full-field digital mammograms 
from four different women are 
shown. All images were acquired 
in the mediolateral oblique 
projection. MBI with photopenic 
background parenchymal uptake 
(BPU) (a) and corresponding 
mammogram (b). MBI with 
minimal to mild BPU (c) and 
corresponding mammogram (d). 
MBI with moderate BPU (e) and 
corresponding mammogram (f). 
MBI with marked BPU (g) and 
corresponding mammogram (h) 
 

1.3 
Low-dose Tamoxifen 
Tamoxifen is a selective estrogen receptor modulator (SERM) that blocks the effects of 
estrogen on breast tissue. Tamoxifen is FDA-approved as a chemopreventive option for 
both premenopausal and postmenopausal women. Studies have shown that preventive 
tamoxifen, when taken daily for five years, can reduce risk of developing breast cancer by 
at least one-third. Results from the National Surgical Adjuvant Breast and Bowel Project 
showed that in women considered at increased risk for breast cancer, preventive tamoxifen 
reduced breast cancer risk by approximately one-half [9]. However, at the standard clinical 
dose of 20 mg per day, tamoxifen can produce side effects such as menopausal symptoms, 
and also carries a small risk (<1% of participants) of serious adverse events, including 
uterine cancer and blood clots in legs or lungs. Concerns about the risk of these adverse 
events accounts for overall low utilization of tamoxifen for chemoprevention. In patients 
who do start tamoxifen, side effects of the drug can lead to non-compliance with long-term 
use.  
 
Because of these concerns, multiple investigations have been done to determine efficacy of 
tamoxifen at lower doses. Tamoxifen taken at 5 mg per day has been proposed as an 
optimal dosage that is associated with decreasing biomarkers of breast disease (including 
mammographic density), and reduced breast cancer risk while potentially mitigating the 
adverse events and side effects seen at the 20 mg/day dose [10-12]. Other studies have 
evaluated efficacy of tamoxifen at 10 mg/day [13-15]. In one study conducted among 
women being treated for breast cancer, tamoxifen at 10 mg per day over a short period of 
14 days resulted in clinically and statistically meaningful declines in molecular markers of 
estrogen receptor positivity, progesterone receptor positivity and Ki-67 (a marker of 
cellular proliferation) [15]. 
 
1.4 
Study Purpose 
In this study, we aim to determine whether short-term intervention with low-dose 
tamoxifen can induce a decline in BPU. Results from this study will provide critical 
knowledge on factors that influence changes in BPU and inform future study of BPU as a 
modifiable risk factor. 
 
2 
STUDY OBJECTIVE 
To assess changes in background parenchymal uptake (BPU) on MBI before and after low-
dose tamoxifen intervention (5 mg per day for 30 days or 10 mg per day for 30 days), 
among women with a history of high BPU. It is hypothesized that both subjective 
categorical and quantitative measures of BPU will decline with low-dose tamoxifen 
intervention. 
 
3 
STUDY DESIGN 
We propose a prospective clinical trial to be conducted within our cohort of women who 
have previously had an MBI test performed at Mayo Clinic. In this study, women with high 

BPU on MBI will be invited to participate in a short-term intervention of low-dose 
tamoxifen (5 mg per day for 30 days or 10 mg per day for 30 days). MBI will be repeated 
at the end of the intervention. Change in BPU before and after the intervention will be 
assessed with both subjective and quantitative measures. 
 
4 
SELECTION AND ENROLLMENT OF PARTICIPANTS 
The study population will include women who have no history of breast cancer and have 
previously had an MBI showing high BPU.  
4.1 
Inclusion Criteria 
The following are requirements for entry into the study: 
1) Female, age 40 or older at the time of enrollment 
2) Most recent MBI examination, performed within 3 years of enrollment, showed 
moderate or marked background parenchymal uptake 
3) Mammogram performed within 24 months prior to enrollment that is available for 
comparison 
4) Willing and able to return for MBI following 30 days of  low-dose tamoxifen 
5) If able to become pregnant 
a. Negative pregnancy test within 48 hours prior to study MBI exam(s) 
b. Agrees to avoid pregnancy during the study and for at least 2 months after 
study participation ends, by abstinence, barrier method, or nonhormonal 
contraception. 
6) Understands and signs the consent form 
4.2 
 Exclusion Criteria 
Subjects will be excluded if any of the following characteristics are present: 
1) Evidence of suspected breast disease as defined by positive findings or 
recommendation for short-interval follow-up on most recent breast imaging 
(including mammography, MBI, MRI, ultrasound, etc.) not yet resolved prior to 
enrollment 
2) Breast biopsy or breast surgery performed within 6 months prior to enrollment 
3) Bilateral breast implants or status post-bilateral prophylactic mastectomy 
4) Pregnant or lactating 
5) Current or recent use (within 6 months prior to enrollment) of any of the 
following drugs: 
a. Systemic hormonal therapy (oral or transdermal patch formulations) 
b. Hormonal contraception (oral, transdermal, implanted, or injected 
formulations not allowed, however hormonal IUDs are acceptable) 
c. Selective estrogen receptor modulators (tamoxifen,  raloxifene, or 
toremifene) 
d. Aromatase inhibitors (anastrazole, letrozole, or exemestane) 
e. GnRH analogs  
f. Prolactin inhibitors 
g. Androgens or antiandrogens 

h. Anticoagulants or “blood thinners” (warfarin, heparin, rivaroxaban and other 
novel anticoagulants) 
i. Drugs known to be strong inhibitors of CYP2D6, the major P450 enzyme that 
metabolizes tamoxifen, including: 
• bupropion (Wellbutrin) 
• fluoxetine (Prozac) 
• paroxetine (Paxil) 
• quinidine (Quinidex) 
6) Personal history of any type of malignancy, with the exclusion of non-melanoma 
skin cancer, diagnosed prior to enrollment 
7) Personal history or strong family history of blood clots in legs or lungs (also known 
as deep vein thrombosis or pulmonary embolism) 
8) Personal history of transient ischemic attack (TIA)  or cerebrovascular accident 
(CVA) 
9) Active proliferative disorders of the endometrium such as atypical hyperplasia, 
history of active endometriosis, unresected polyps 
10) Any type of retinal disorders or severe cataract 
11) Current smoker 
12) Known carrier of BRCA1 or BRCA2 genetic mutation or known DNA repair defect.  
13) Blood pressure above 140/90 
4.3 Enrollment Procedures  
Our Mayo Clinic MBI databases will be reviewed to identify potential candidates for this 
study. Women who have had high (moderate or marked BPU) on a prior MBI study, 
performed within 3 years of enrollment in the current study, with no apparent conflict with 
inclusion and exclusion criteria will be contacted by invitation letter. This letter informs 
patients of our new research findings showing the association between high BPU and breast 
cancer risk and offers study participation. Patients may contact the study team by phone or 
email. The study coordinator will assess patient eligibility, discuss study procedures with 
the patient, and schedule an in-person enrollment visit at which informed written consent 
will be obtained. The physician co-principal investigator of the study will be available for 
consultation during the consent process. 
5 
STUDY PROCEDURES 
5.1 
Schedule of Evaluations 
Potential participants will be screened for eligibility and undergo informed written consent 
with the study coordinator at the time of enrollment. At Study Visit 1, the participant will 
be asked to complete a study questionnaire and undergo MBI (after a negative pregnancy 
test as necessary). Participants will then undergo 30 days of low-dose tamoxifen 
medication followed by Study Visit 2, at which time a repeat MBI test will be performed.  
 

5.2 
Pregnancy test 
All participants who can become pregnant will be required to have a urine pregnancy test 
performed with negative results within 48 hours prior to each MBI injection. The study 
coordinator will administer this test. 
5.3 
Blood pressure test 
Participants will undergo a blood pressure test prior to starting low-dose tamoxifen. The 
study coordinator will administer this test with an automated machine. If a participant has 
blood pressure over 140/90, she will not proceed with the study. 
5.4 
Molecular breast imaging (MBI) 
MBI testing will be performed at Mayo Clinic Rochester within the Division of Breast 
Imaging and Intervention. MBI procedures will be done as per clinical standard of care 
(described below). 
5.4.1 Equipment – MBI examinations will be performed on an FDA-approved dual-head gamma 
camera system comprised of cadmium zinc telluride detectors and collimation optimized 
for low-dose breast imaging (LumaGem, Gamma Medica, Salem, NH). 
5.4.2 Technologists – Radiotracer injection and MBI image acquisition shall be performed by 
female nuclear medicine technologists who have received training in mammographic 
positioning techniques. 
5.4.3 Patient preparation - Patients will be asked to fast for a minimum of 3 hours prior to the 
MBI examination, when possible, as prior studies have shown fasting to improve uptake 
of Tc-99m sestamibi in breast tissue by reducing splanchnic and hepatic blood flow.[16] 
Patients may take fluids, including black coffee, tea, diet soda and water.  
Patients will remove all clothing and jewelry above the waist and put on a patient gown. 
Patients may be given a warm blanket to wrap around their shoulders and chest prior to 
 
Enrollment 
Study 
Visit 1 
30 days 
between visits 
Study 
Visit 2 
Eligibility Checklist 
X 
 
 
 
Informed Consent 
X 
 
 
 
Questionnaire: Breast Health and History 
 
X 
 
 
Blood pressure measurement 
 
X 
 
 
Urine pregnancy test (if necessary)  
 
X 
 
X 
MBI 
 
X 
 
X 
Tamoxifen (5 mg/day for 30 days  
or 10 mg/day for 30 days) 
 
 
X 
 
Check-in phone calls at day 5 and 20  
 
 
X 
 
Study close-out 
 
 
 
X 

the MBI examination, in order to increase peripheral blood flow to breast tissue and thus 
improve Tc-99m sestamibi uptake. 
5.4.4 Tc-99m sestamibi injection - The technologist should verify that the patient is not pregnant 
or breast feeding prior to injection of Tc-99m sestamibi. 
MBI examinations will be performed with a dispensed dose of 8 mCi (300 MBq) Tc-99m 
sestamibi (range 7.2 – 8.8 mCi). A nuclear medicine technologist will deliver an 
intravenous injection of the Tc-99m sestamibi dose in an antecubital vein of either arm. 
Flushing of the syringe with saline and use of syringes that provide low sestamibi 
adhesion is recommended to minimize residual activity.  
Infiltration, or extravasation of the injected dose into the soft tissue rarely occurs (~1-2% 
of studies). If infiltration is suspected, the technologist will observe the count rate obtained 
on a persistence view prior to beginning imaging. If the count rate is lower than typical 
(defined as less than 0.2 kcts/minute in the craniocaudal [CC] view and less than 0.3 
kCts/minute in the mediolateral oblique [MLO] view for an average-sized breast) the 
technologist will image the injection site to evaluate.  
If there is no evidence of infiltration on imaging of the injection site, the technologist will 
proceed with the breast images.  If infiltration is confirmed by both low count rates and 
high uptake at the injection site, the technologist will ask for the patient’s consent to 
proceed with a second injection of 8 mCi Tc-99m sestamibi. The patient will be given the 
option to refuse a second dose and continue with the study, although poor image quality 
may be obtained, or to discontinue MBI imaging and thus end study participation. 
5.4.5 Image acquisition - MBI imaging will commence immediately after injection. Two views 
of each breast will be acquired in the CC and MLO projections. Acquisition duration will 
be 10 minutes per view. Images will be acquired in static mode using an energy 
acceptance window of 110-154 keV. 
For each view, patients will be seated with the breast positioned between the two 
detectors. The persistence-scope should be used to validate correct breast positioning. If 
available, the recent mammogram can be viewed to replicate positioning on the MBI. 
Light compression is applied to stabilize the breast and to limit motion artifact. Placement 
of pillows behind the patient’s back is recommended to reduce motion and increase 
comfort. Verification of the patient’s comfort level and ability to complete 10 minutes of 
imaging in the position should be done before acquisition begins. Compression thickness 
for each MBI view will be recorded. At Study visit 2, the compression thickness for each 
view will be adjusted to match that recorded from the Study visit 1. 
In participants with breasts larger than the detector field of view, the technologist may opt 
to acquire two 10-minute tiled MLO views of each breast, in place of a CC and MLO 
view, in order to ensure that the entire breast is included in the image set. 
During the acquisition of each view, the technologist will briefly place the appropriate Co-
57 laterality markers (R for right and L for left) in the field of view until well seen on the 
persistence screen.   

The patient will be visually monitored by the nuclear medicine technologist from the time 
of injection of the radionuclide until image acquisition is completed.  
5.4.6 Post-acquisition processing - Following completion of the acquisition, the technologist 
will format the acquired images in the standard format used for MBI display and 
interpretation.  
5.5 
MBI Interpretation 
MBI interpretation will be performed by study radiologists. The radiologists will 
subjectively assess BPU on a 5-category scale as 1 – photopenic, 2 – minimal, 3 – mild, 4 
– moderate, or 5 – marked. Changes in BPU between pre-tamoxifen and post-tamoxifen 
MBI will be assessed, with blinding to the order of the studies.  
 
The interpreting study radiologist will issue a report in the patient’s medical record to state 
that the MBI was performed for research purposes under IRB #16-008736. The report will 
either state that no suspicious findings were noted, or will describe any incidental findings 
seen on MBI for which diagnostic workup is recommended. Any necessary diagnostic 
workup of MBI findings will be performed according to the established standard of care 
[17].  
 
5.6 
Low-dose tamoxifen intervention 
Subjects will be enrolled to one of two arms of the study. The study arms will be identical, 
except for the dose of tamoxifen. For Arm 1, the dose of tamoxifen will be 5 mg per day 
for 30 days. For Arm 2, the dose of tamoxifen will be 10 mg per day for 30 days. 
Participants will receive a prescription for tamoxifen. A physician co-principal 
investigator will order participant prescriptions, which will be filled through the Mayo 
Clinic Outpatient Research Pharmacy.  For subjects in Arm 1, the research pharmacy will 
perform splitting of the standard tamoxifen tablets (available in either 10 mg or 20 mg 
doses) and over-encapsulation to arrive at 5 mg tablets. 
Participant instructions for the tamoxifen medication will be as follows: 
• Take one capsule per day for 30 days 
• Take each dose at approximately the same time each day 
• Capsules should be taken with water or a non-alcoholic beverage. Capsules can be 
taken with or without food. 
• If you miss a dose, take the missed dose as soon as you remember it. However, if it 
is almost time for the next dose, skip the missed dose and continue your regular 
dosing schedule. Do not take a double dose to make up for a missed one. 
Participants will also be given a “Drug Diary” log and asked to make notes of when each 
dose is taken and to record any symptoms experienced. Participants will be asked to return 

Drug Diary logs and pill bottles at the Study Visit 2. Any remaining pills will be returned 
to the Outpatient Research Pharmacy for disposal. 
 
Participants will be advised that they may elect to stop the tamoxifen medication at any 
time, should they experience unwanted side effects. Patients will be asked to contact study 
staff if they do choose to stop. Patients who start tamoxifen but choose to stop earlier than 
30 days will be asked to return for their post-tamoxifen MBI test (Study Visit 2) at that 
time. 
5.7 
Image Analysis 
Quantitative assessments of BPU on all MBI studies will be performed by study staff 
using region of interest analysis. Counts within breast fibroglandular tissue and areas of 
fat in the breast will be obtained to calculate the ratio of counts per pixel in fibroglandular 
tissue vs. fat. Change in this ratio across MBI studies performed within patients will be 
determined. 
6 
STUDY RISKS 
6.1 
Discomfort during MBI 
An MBI exam involves an intravenous injection in the arm, which may cause minor 
discomfort. Following each injection, the subject is required to sit on a chair for ~40 
minutes for the MBI with either breast placed in light compression during the image 
acquisitions. This procedure should cause little to no discomfort to the subject. 
6.2 
Tc-99m sestamibi 
Tc-99m sestamibi is an FDA-approved drug with an excellent safety profile. This drug has 
been safely used in clinical practice for over 30 years. Very rarely, patients receiving 
sestamibi experience mild symptoms such as flushing, a rash, or a brief metallic taste after 
injection. 
6.3 
Radiation 
The radiation dose from a total administered dose of 8 mCi Tc-99m sestamibi has an 
effective (whole-body) dose of ~2.1 mSv. Subjects will undergo two MBI examinations for 
a total effective dose of about 4.2 mSv. This radiation dose has a very low risk of harmful 
effects.  Pregnant women and women who are nursing will not be permitted to participate 
in this study. 
6.4 
Incidental findings on MBI 
Based on prior studies of screening MBI in women with dense breasts, we expect that 
about 5% of study participants will have an abnormality found on the MBI test. Finding an 
abnormality on the study testing can be emotionally distressing to participants. Participants 
with concerning findings on MBI will be recommended to return for additional diagnostic 

workup, as per routine clinical standard of care. Participants will be informed that any 
additional testing beyond the MBI test is not part of this research study and financial costs 
will need to be covered by the patient and their insurance. 
6.5 
Risks of Tamoxifen 
Tamoxifen has been used for over 40 years to treat hormone-receptor positive breast 
cancer. Side effects of tamoxifen taken at the standard 20 mg dose, ranging from mild to 
serious, have been reported. We expect side effects at the 5 mg or 10 mg dose to occur less 
frequently, if at all, especially over the short time frame of 30 days. 
 
In patients taking standard 20 mg dose tamoxifen, vasomotor symptoms (hot flashes and 
night sweats) and vaginal discharge are the most likely side effects. However, in studies of 
women taking low-dose (5 mg or 10 mg) tamoxifen, hot flashes and vaginal discharge were 
not increased compared to women taking placebo.  
 
Among women taking 20 mg tamoxifen for 5 years, there is a small increased risk of 
uterine cancer, abnormal blood clots, or vision changes. Other less serious side effects 
reported from 20 mg tamoxifen treatment include changes in menstrual cycle (among 
premenopausal women), weight gain, depression, insomnia, and urinary incontinence. 
These side effects are not expected to occur for short-term, low-dose tamoxifen used in this 
study. 
 
Tamoxifen can cause birth defects. Participants who can become pregnant will undergo a 
pregnancy test prior to MBI, which must be negative. Participants will be instructed to 
avoid pregnancy during the study and for at least 2 months after study participation ends, 
by abstinence, barrier method, or nonhormonal contraception. If a participant should 
become pregnant, she will be instructed to stop using tamoxifen immediately. 
7 
ADVERSE EVENTS 
Participants will be asked to report any adverse events or side effects, should they occur, by 
contacting study staff. At approximately days 5 and 20 of the tamoxifen intervention, the 
study coordinator will contact participants by phone to assess medication compliance and 
inquire about any adverse events. Adverse events will also be assessed at the study closeout 
during Study Visit 2. The duration and severity of adverse events will be recorded. 
Although we do not expect serious side effects to occur with 5 mg tamoxifen over a 30-day 
period, patients will be advised to stop taking tamoxifen medication immediately if any of 
the following should occur:  
• vision problems 
• loss of appetite 
• yellowing of skin or eyes 
• unusual bruising or bleeding 
• fever 
• blisters 

• rash 
• swelling of eyes, face, lips, tongue, throat, hands, arms, feet, ankles, or lower legs 
• thirst 
• muscle weakness 
• restlessness 
• vaginal bleeding or spotting 
8 
REMUNERATION 
Participants will receive a total of $200 to compensate for their time spent in the study. If 
participants start the study but do not finish, they will receive part of the money. The 
breakdown of remuneration payments will be as follows: 
Study Visit 1: $50 
Completion of 30 days tamoxifen: $100 
Study Visit 2: $50 
9 
SAMPLE SIZE CONSIDERATIONS 
There have yet to be any studies examining BPU response to tamoxifen. Thus, this study is 
a pilot design that will aim to enroll 30 patients who complete pre- and post-tamoxifen 
MBI. A sample size of 30 will have 80% power to detect a means change of 1 BPU 
quantitative unit (e.g. overall mean of 4.5  pre low-dose tamoxifen intervention, and post 
tamoxifen mean of 3.5), assuming a standard deviation of differences of 1.89 (effect size = 
0.53), using a paired t-test with an α=0.05 two-sided significance level. 
 
Allowing for potential study withdrawals, we will allow for a total of 50 patients to begin 
the low-dose tamoxifen intervention. In addition, women who are invited to participate 
may not have persistent BPU on their MBI performed at Study Visit 1. Prior pilot data 
showed that approximately half of women with prior high BPU had persistent high BPU on 
a current MBI. Therefore, up to 100 women will be screened with MBI to assess potential 
enrollment in the low-dose tamoxifen intervention. We will aim to balance enrollment of 
premenopausal and postmenopausal subjects. 
 
10 
CONFLICT OF INTEREST 
Mayo Foundation and two of the co-investigators (M.K. O’Connor, C.B. Hruska) on this 
protocol have a conflict of interest, due to licensing arrangements between Mayo 
Foundation and the manufacturer of the CZT detectors, Gamma Medica – Ideas, for rights 
to the hardware and software technology developed for low dose MBI. This conflict is 
noted in all the consent forms. Neither Dr. O’Connor nor Dr. Hruska will be permitted to 
consent subjects for the study. None of the other investigators have a conflict of interest. 
 

11 
REFERENCES 
1. 
Rhodes DJ, Hruska CB, Conners AL, et al. Journal Club: Molecular Breast Imaging at 
Reduced Radiation Dose for Supplemental Screening in Mammographically Dense 
Breasts. American Journal of Roentgenology 2015; 204:241-251 
2. 
Rhodes DJ, Hruska CB, Phillips SW, Whaley DH, O'Connor MK. Dedicated dual-head 
gamma imaging for breast cancer screening in women with mammographically dense 
breasts. Radiology 2011; 258:106-118 
3. 
Shermis RB, Wilson KD, Doyle MT, et al. Supplemental Breast Cancer Screening With 
Molecular Breast Imaging for Women With Dense Breast Tissue. American Journal of 
Roentgenology 2016:1-8 
4. 
Hruska CB, Weinmann AL, O'Connor MK. Proof of concept for low-dose molecular 
breast imaging with a dual-head CZT gamma camera. Part I. Evaluation in phantoms. 
Med Phys 2012; 39:3466-3475 
5. 
Hruska CB, Weinmann AL, Tello Skjerseth CM, et al. Proof of concept for low-dose 
molecular breast imaging with a dual-head CZT gamma camera. Part II. Evaluation in 
patients. Med Phys 2012; 39:3476-3483 
6. 
Conners AL, Hruska CB, Tortorelli CL, et al. Lexicon for standardized interpretation of 
gamma camera molecular breast imaging: observer agreement and diagnostic accuracy. 
Eur J Nucl Med Mol Imaging 2012; 39:971-982 
7. 
Hruska CB, Rhodes DJ, Conners AL, et al. Background parenchymal uptake during 
molecular breast imaging and associated clinical factors. AJR American journal of 
roentgenology 2015; 204:W363-370 
8. 
Hruska CB, Scott CG, Conners AL, et al. Background parenchymal uptake on molecular 
breast imaging as a breast cancer risk factor: a case-control study. Breast Cancer Res 
2016; 18:42 
9. 
Fisher B, Costantino JP, Wickerham DL, et al. Tamoxifen for the Prevention of Breast 
Cancer: Current Status of the National Surgical Adjuvant Breast and Bowel Project P-1 
Study. Journal of the National Cancer Institute 2005; 97:1652-1662 
10. 
Decensi A, Gandini S, Serrano D, et al. Randomized dose-ranging trial of tamoxifen at 
low doses in hormone replacement therapy users. J Clin Oncol 2007; 25:4201-4209 
11. 
Decensi A, Robertson C, Guerrieri-Gonzaga A, et al. Randomized double-blind 2 x 2 trial 
of low-dose tamoxifen and fenretinide for breast cancer prevention in high-risk 
premenopausal women. J Clin Oncol 2009; 27:3749-3756 
12. 
Guerrieri-Gonzaga A, Sestak I, Lazzeroni M, et al. Benefit of low-dose tamoxifen in a 
large observational cohort of high risk ER positive breast DCIS. Int J Cancer 2016; 
139:2127-2134 
13. 
Decensi A, Bonanni B, Guerrieri-Gonzaga A, et al. Biologic activity of tamoxifen at low 
doses in healthy women. J Natl Cancer Inst 1998; 90 
14. 
de Lima GR, Facina G, Shida JY, et al. Effects of low dose tamoxifen on normal breast 
tissue from premenopausal women. Eur J Cancer 2003; 39 
15. 
de Sousa JA, Facina G, da Silva BB, Gebrim LH. Effects of low-dose tamoxifen on 
breast cancer biomarkers Ki-67, estrogen and progesterone receptors. International 
Seminars in Surgical Oncology 2006; 3:29 
16. 
O'Connor MK, Hruska CB, Tran TD, et al. Factors Influencing the Uptake of 99mTc-
Sestamibi in Breast Tissue on Molecular Breast Imaging. J Nucl Med Technol 2015; 
43:13-20 

17. 
Hruska CB, Conners AL, Jones KN, et al. Diagnostic workup and costs of a single 
supplemental molecular breast imaging screen of mammographically dense breasts. AJR 
Am J Roentgenol 2015; 204:1345-1353