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Magnetic resonance imaging (MRI) staging for breast cancer in a diverse population

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Magnetic resonance imaging (MRI) staging for breast cancer in a diverse population

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Magnetic Resonance Imaging (MRI) Staging for Breast
Cancer in a Diverse Population

By

Akshara Singareeka Raghavendra

A Thesis Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements of the Degree
MASTER OF SCIENCE
(CLINICAL AND BIOMEDICAL INVESTIGATIONS)

August 2013

Copyright 2013 Akshara Singareeka Raghavendra

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Dedication

Some see a hopeless end, while others see an endless hope. ~ Anonymous
To my parents, mentor and patients

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Acknowledgements
Dr. Debu Tripathy, professor of medicine and co-leader of women’s cancer program. My mentor
and study chair, gave me the opportunity to work on this project. His loyalty towards his
patients, his optimism, dedication and commitment to his work motivates me to put more effort
and dedication in mine. I owe you immensely for everything, being an inspiration not just
professionally, but in life. Thank you for everything. It has been a privilege.

Dr. Linda Larsen, Director of woman's imaging, associate professor and committee member.
Resolving my questions immediately by sharing her vast knowledge about various disciplines
helped me to understand things more clearly. Thank you for being so patient.

Dr. Pulin Sheth, director of breast imaging, assistant professor and committee member. His
enthusiasm in all disciples combined with his open – door policy to approach him with questions.
Despite the multitude of responsibilities he had, there was never a time he was too busy to meet
with me regardless of how trivial the matter may be that concerned me. Thank you for all your
time.

Dr. Stanley Azen, co-director and advisor of my course, for providing me excellent guidance and
for understanding and encouraging when I was stuck in my path. His calmness and kindness
helps to form a great rapport with his students. Thank you so much for your time in guiding me
in this program.

Lingyun Ji and Dongyun Yang for helping me analyze the data.

Staff, at the radiology and oncology department, for all your help and support throughout my
study.

My family, for their love and endless support.

My friends for their constant encouragement and motivation.

This study would not be complete without the patients who were a part of this study and made
this research possible.

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Table of Contents
ABBREVIATIONS ................................................................................................................................................ VIII
ABSTRACT ................................................................................................................................................................ X
CHAPTER 1: INTRODUCTION............................................................................................................................... 1
1.1 BREAST CANCER – SCOPE OF THE PROBLEM ........................................................................................................ 1
1.2 NATURAL HISTORY OF BREAST CANCER ............................................................................................................. 1
1.3 EPIDEMIOLOGY .................................................................................................................................................... 2
1.4 RISK FACTORS...................................................................................................................................................... 4
1.5 PREVENTION ........................................................................................................................................................ 8
1.6 DIAGNOSIS ......................................................................................................................................................... 10
1.7 DIAGNOSTIC IMAGING EVALUATION OF BREAST CANCER ................................................................................. 11
1.7.1 Mammogram .............................................................................................................................................. 12
1.7.2 Breast Ultrasound ...................................................................................................................................... 15
1.7.3 Magnetic Resonance Imaging (MRI) ......................................................................................................... 15
1.8 LIMITATIONS OF MRI ......................................................................................................................................... 16
1.9 STAGING ............................................................................................................................................................ 18
1.10 PROGNOSIS AND PROGNOSTIC FACTORS .......................................................................................................... 23
1.10.1 Assessing and Managing Risk of Breast Cancer Recurrence .................................................................. 25
CHAPTER 2: MATERIALS AND METHODS ..................................................................................................... 27
2.1 THE CLINICAL PROTOCOL .................................................................................................................................. 27
2.2 CRITERIA ............................................................................................................................................................ 27
2.2.1 Inclusion Criteria ....................................................................................................................................... 27
2.2.2 Exclusion Criteria ...................................................................................................................................... 27
2.3 IMAGING PROTOCOL AND INTERPRETATIONS ..................................................................................................... 28
2.4 DATA COLLECTION ............................................................................................................................................ 29
CHAPTER 3: DETECTION OF NON-INDEX LESIONS AND OCCULT CANCERS IN NEWLY
DIAGNOSED BREAST CANCER IN DIVERSE POPULATION ....................................................................... 31
3.1 OBJECTIVE ......................................................................................................................................................... 31
3.2 INTRODUCTION ................................................................................................................................................... 31
3.3 PATIENTS ........................................................................................................................................................... 33
3.4 STATISTICAL ANALYSIS ..................................................................................................................................... 34
3.5 RESULTS............................................................................................................................................................. 35
3.6 DISCUSSION........................................................................................................................................................ 45
3.7 CONCLUSIONS .................................................................................................................................................... 46
CHAPTER 4: DETECTION OF NON-INDEX LESIONS AND OCCULT CANCERS IN BRCA TESTED IN
NEWLY DIAGNOSED BREAST CANCER PATIENTS ..................................................................................... 47
4.1 OBJECTIVE ......................................................................................................................................................... 47
4.2 INTRODUCTION ................................................................................................................................................... 47
4.3 PATIENTS ........................................................................................................................................................... 48
4.4 STATISTICAL ANALYSIS ..................................................................................................................................... 50
4.5 RESULTS............................................................................................................................................................. 50
4.6 DISCUSSION........................................................................................................................................................ 54

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4.7 CONCLUSIONS .................................................................................................................................................... 58
CONCLUSIONS ........................................................................................................................................................ 60
FUTURE PERSPECTIVES ...................................................................................................................................... 61
PRESENTATIONS RELATED TO THIS THESIS ............................................................................................... 62
REFERENCES .......................................................................................................................................................... 63

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List of Tables
TABLE 1: FACTORS THAT INCREASE THE RISK FOR BREAST CANCER IN WOMEN (AMERICAN CANCER SOCIETY, 2012)7
TABLE 2: BREAST IMAGING REPORTING AND DATABASE SYSTEM (THE AMERICAN COLLEGE OF RADIOLOGY BI-
RADS ATLAS, 2012) ......................................................................................................................................... 11
TABLE 3: AJCC CANCER STAGING. 7TH EDITION (AJCC, 2011) ................................................................................. 20
TABLE 4: ANATOMIC STAGE / PROGNOSTIC GROUPS (AJCC, 2011) ............................................................................. 23
TABLE 5: SCARFF BLOOM RICHARDSON GRADING SYSTEM (ROBERT D. CARDIFF AND ROY A. JENSEN) .................... 24
TABLE 6: NON-INDEX LESIONS: DEMOGRAPHIC / CLINICAL FEATURES ....................................................................... 36
TABLE 7: OCCULT CANCERS DETECTED AMONG NON-INDEX LESIONS ....................................................................... 37
TABLE 8: ODDS RATIOS OF PROBABILITY OF A NON-INDEX LESION BEING AN OCCULT CANCER LESION UNIVARIATE
AND MULTIVARIATE ANALYSIS ........................................................................................................................... 38
TABLE 9: DISTRIBUTION OF BREAST CANCER PATIENTS DIAGNOSED IN 2011 BY ETHNICITY – COMPARED TO THE
HOSPITAL AND LOS ANGELES COUNTY POPULATIONS ........................................................................................ 50
TABLE 10: DEMOGRAPHIC AND CLINICAL FEATURES OF BRCA TESTED PATIENTS WITH NON-INDEX LESIONS AND
OCCULT CANCERS ............................................................................................................................................... 51
TABLE 11: BREAST CANCER AMONG BRCA1/2 MUTATION CARRIERS WITH AND WITHOUT BILATERAL PROPHYLACTIC
MASTECTOMY (BPM) PROSE STUDY GROUP .................................................................................................... 57

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List of Figures
FIGURE 1: NORMAL BREAST TISSUE (AMERICAN CANCER SOCIETY, 2012) ................................................................... 2
FIGURE 2: AGE IS POTENTIAL DISCRIMINATOR FOR BOTH RISKS AND BENEFITS (FISHER, B., ET. AL., 1998) ................. 5
FIGURE 3: LIFESTYLE CHANGES TO LOWER BREAST CANCER RISK ............................................................................. 10
FIGURE 4: MAMMOGRAPHIC DENSITY AND BREAST CANCER RISK (LUSINE YAGHJYAN ET AL, 2011)......................... 13
FIGURE 5: PRIMARY TUMOR 1 (T1) (AJCC, 2011) ....................................................................................................... 18
FIGURE 6: PRIMARY TUMOR 2 AND 3 (T2 AND T3) (AJCC, 2011) ................................................................................ 19
FIGURE 7: PRIMARY TUMOR 4A (T4A) (AJCC, 2011) ................................................................................................... 19
FIGURE 8: REGIONAL LYMPH NODES (N) (AJCC, 2011) .............................................................................................. 20
FIGURE 9: LESION DETECTION ..................................................................................................................................... 28
FIGURE 10: MANAGEMENT OF INDEX-LESION .............................................................................................................. 28
FIGURE 11: CLOCK POSITIONS AND QUADRANTS OF THE BREASTS (SEER, 2012) ....................................................... 32
FIGURE 12: MANAGEMENT OF NON-INDEX LESION ...................................................................................................... 33
FIGURE 13: LATERALITY OF THE BREAST AND NODE LESIONS FOR PATIENTS WITH NON-INDEX LESIONS AND OCCULT
CANCERS ............................................................................................................................................................. 40
FIGURE 14: LATERALITY AND BI-RADS OF THE NON-INDEX LESIONS AND OCCULT CANCER LESIONS ..................... 41
FIGURE 15: % TYPE OF SURGERY DONE FOR NON-INDEX AND OCCULT CANCER LESIONS .......................................... 41
FIGURE 16: BREAST PROCEDURES DONE FOR NON-INDEX AND OCCULT CANCER LESIONS ......................................... 42
FIGURE 17: TYPE OF SURGERY DONE FOR NON-INDEX LESIONS BASED ON THE INSTITUTIONS .................................... 43
FIGURE 18: TYPE OF SURGERY DONE FOR OCCULT CANCER LESIONS BASED ON THE INSTITUTIONS ............................ 43
FIGURE 19: AGE AT DIAGNOSIS FOR PATIENTS WITH NON-INDEX LESIONS AND OCCULT CANCERS ............................ 44
FIGURE 20: BRCA TESTED FOR THE TOTAL COHORT AND PATIENTS WITH NON-INDEX LESIONS ................................ 44
FIGURE 21: BIOMARKERS OF PATIENTS TESTED BRCA POSITIVE ................................................................................. 53
FIGURE 22: BIOMARKERS OF PATIENTS WITH NO BRCA MUTATION ............................................................................ 53
FIGURE 23: CUMULATIVE INCIDENCE OF EARLY-STAGE (0 AND I) BREAST CANCER IN MRI ....................................... 54
FIGURE 24: CUMULATIVE INCIDENCE OF STAGES II TO IV BREAST CANCER IN MRI ................................................... 55
FIGURE 25: BREAST CANCER AMONG BRCA1/2 MUTATION CARRIERS WITH AND WITHOUT BILATERAL
PROPHYLACTIC MASTECTOMY (BPM) PROSE STUDY GROUP ........................................................................... 56

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Abbreviations
AJCC: American Joint Committee on Cancer
ALND: Axillary Lymph Node Dissection
BCS: Breast Conserving Surgery
BI-RADS: Breast Imaging Reporting and Database System
CIS: Carcinoma In-Situ
CLIA: Clinical Laboratory Improvement Amendments approved laboratory
CLTR: Cumulative Life Time Risk
CTC: Circulating Tumor Cells
DCIS: Ductal Carcinoma In-Situ
ER: Estrogen Receptor
HER2: Human Epidermal Growth Factor Receptor 2
HIPAA: Health Insurance Portability and Accountability Act
ID: Identification
IDC: Invasive Ductal Carcinoma
IRB: Institutional Review Board
LAC: Los Angeles County
LAC+USC: Los Angeles County + University of Southern California
LCIS: Lobular Carcinoma In-Situ
LN: Lymph Node
MRI: Magnetic Resonance Imaging
NIL: Non-Index Lesion
No.: Number

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Norris: Norris Comprehensive Cancer Center
NSABP: National Surgical Adjuvant breast and Bowel Project
OC: Occult Cancer
PR: Progesterone Receptor
S.D.: Standard Deviation
SEER: Surveillance Epidemiology and End Results
SERM: Selective estrogen receptor modulator
SLN: Sentinel Lymph Node
STATA: Data Analysis and Statistical Software
TNM: Tumor, Nodes, Metastasis
US: Ultrasound
USC: University of Southern California

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Abstract
Breast magnetic resonance imaging (MRI) offers information about many breast conditions that
cannot be obtained by other imaging modalities such as mammography or ultrasound,
particularly in higher risk situations such as genetic susceptibility. For patients diagnosed with
breast cancer, case series have shown that staging MRI can detect occult breast cancers in other
areas of the breast in 1-10% of newly diagnosed patients. The specificity of MRI, relationship to
demographic and clinical factors, and the impact on surgical management in underserved and
diverse populations has not been well studied. We sought to conduct an analysis in two distinct
populations – an academic practice, involving mostly an insured population, and an underserved,
underinsured minority population, over the same time period using similar diagnostic
procedures.

The Aims of this thesis are:
1. To determine the sensitivity, specificity and overall accuracy of MRI staging to detect occult
malignant lesions not seen on physical examination, mammogram, or ultrasound.
2. To determine subsequent studies that lead to biopsy or additional surgery and the
pathological findings (in-situ, invasive, or benign findings) that result from MRI staging.

The overall research question is whether the use of MRI leads to the additional diagnosis of
occult malignancy in the involved or contralateral breast. Also, the influence of MRI on
additional imaging tests, biopsies, and surgical procedures as well as postoperative medical
therapy and radiation therapy.

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We performed a retrospective analysis of consecutive patients with newly diagnosed in-situ or
invasive breast cancer who had a preoperative MRI staging seen at our centers that care for an
underserved and minority population. Institutional review board (IRB) approval was obtained to
extract demographic and clinic pathological data, imaging studies, and surgical treatment. Non-
index lesions (NIL) are defined as those in breast or axillary nodes not known to be malignant,
and not presenting with suspicious clinical findings, or with mammographic or ultrasound
findings defined as BI-RADS score of 4 or 5. Additionally, a non-index lesion must be in a
different quadrant and at least 5cm away in relation to an index lesion. Occult cancers (OC) are
those lesions found by biopsy or surgery to be invasive or in-situ cancer. Logistic regression was
used to examine the association between the probability of a NIL or occult cancers and patient’s
characteristics. Statistical computation was performed using STATA.
Among 678 patients,144 (21%) had a total of 171 NILs identified by MRI; 67 (9.8%)
were ipsilateral, 44 (6.5%) contralateral and 24(3.5%) axillary nodes, with 57 patients (8.4%)
having a total of 62 occult cancers detected - 34 (5%) ipsilateral, 8 (1.2%) contralateral and 9
(1.3%) axillary nodes of which 49 (7.2%) were invasive and 8 (1.2%) in-situ. 40% of patients
with NILs were confirmed as occult cancers.
In this diverse population, staging MRI detected non-index lesions and occult cancers in
21% and 8.4% of patients, respectively. Ipsilateral lesions and age seemed to be associated with
probability of occult cancers. Interestingly, only one of the occult cancers detected were among
the known 34 mutation carriers. MRI staging appears to identify occult cancers to an equal extent
in a largely Hispanic and younger underserved population as reported in the literature for
populations of mostly insured and Caucasian patients.

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Chapter 1: Introduction
Breast cancer is the most common malignancy in women worldwide. Though there has been a
trend towards a decrease in mortality due to early diagnosis, including screening mammograms
and better adjuvant therapies (Berry, Donald A; et al., 2005), there has been more effort to
improve the methods for earlier detection.
1.1 Breast Cancer – Scope of the Problem
Breast cancer usually produces no symptoms when the tumor is small and most treatable.
Therefore, it is important for women to follow the recommended screening guidelines for
detecting breast cancer at an early stage, before the start of the symptoms. When breast cancer
has grown to a size that can be palpable, the most common physical sign is a painless lump.
Sometimes it can spread to axillary lymph nodes and cause a lump, even before the original
breast tumor is palpable. Less common symptoms of breast cancer include breast pain or
heaviness, skin changes (swelling, thickening, or redness), and nipple abnormalities
(spontaneous discharge, erosion, inversion, or tenderness).
Breast cancer is the most common cancer among American women, except for skin
cancers. About 1 in 8 (12%) women in the US will develop invasive breast cancer during their
lifetime (American Cancer Society, 2012).
1.2 Natural History of Breast Cancer
The breast has 2 main types of tissues: glandular tissues and stromal tissues. The glandular part
of the breast includes the ducts and lobules (Figure 1). In breastfeeding the cells of the lobule
make milk. The support tissue of the breast includes fatty tissue and fibrous connective tissue
that give the breast its size and shape (American Cancer Society, 2012) .

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Cancer is a group of diseases that cause cells in the body to change and grow out of
control. Most types of cancer cells eventually form a lump/tumor, and are named according to
where the tumor originates.

Figure 1: Normal Breast Tissue (American Cancer Society, 2012)

1.3 Epidemiology
The American Cancer Society's (ACS) and cancer statistics estimates for breast cancer in the
United States for 2013 (American Cancer Society, 2012) (Siegel, R., Naishadham, D., and Jemal,
A., 2013).
• About 232,340 new cases of invasive breast cancer will be diagnosed in women.

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• About 64,640 new cases of carcinoma in-situ (CIS) will be diagnosed (CIS is non-invasive
and is the earliest form of breast cancer).
• About 39,620 women will die from breast cancer

After increasing for more than 2 decades, female breast cancer incidence rates began decreasing
in 2000, then dropped by about 7% from 2002 to 2003. This decrease was thought to be due to
the decline in use of hormone therapy after menopause that occurred after the results of the
Women's Health Initiative were published in 2002. Incidence rates have been stable in the recent
years (American Cancer Society, 2012).
Breast cancer is the second leading cause of cancer death in women, first being lung
cancer. The chance that breast cancer will be responsible for a woman's death is about 1 in 36
(about 3%). Death rates from breast cancer have been declining since about 1989, with larger
decreases in women younger than 50 (American Cancer Society, 2012).
At this time there are more than 2.9 million breast cancer survivors in the United States
(this includes women still being treated and those who have completed treatment) (American
Cancer Society, 2012).

Incidence and death rate by race and ethnicity in the United States 2005 to 2009.
Incidence:
• White: 123.3
• African American: 118.0
• Asian American and Pacific Islander: 85.9
• American Indian and Alaska native: 89.1

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• Hispanic/Latino: 93.0

Mortality:
• White: 22.4
• African American: 31.6
• Asian American and Pacific Islander: 11.9
• American Indian and Alaska native: 16.6
• Hispanic/Latino: 14.9
1.4 Risk Factors
Various factors have been found to be predictors of the relative risk of breast cancer.
Age and gender: Women account for majority of the cases in breast cancer. After gender, age is
the most influential risk factor for developing breast cancer. The probability (%) of developing
invasive cancers within selected age intervals, United States, 2007 to 2009 (Siegel, R.,
Naishadham, D., and Jemal, A., 2013) is:
• Birth to 39: 0.50 (1 in 202)
• 40 to 59: 3.78 (1 in 26)
• 60 to 69: 3.56 (1 in 28)
• 70 and older: 6.65 (1 in 15)
• Overall birth to death: 12.38 (1 in 8)
Age is a potential discriminator for both risks and benefits: The distributions of 13207 patients
included in analysis showed 39% of women were aged 35-49 years, 31% were aged 50-59 years,
and 30% were aged 60 years or older (Fisher, B., et. al., 1998) .

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Figure 2 below shows similar decreases in invasive and non-invasive breast cancer and a
similar increase in endometrial cancer and thromboembolic events associated with tamoxifen
administration.

Figure 2: Age is Potential Discriminator for both Risks and Benefits (Fisher, B., et. al.,
1998)

Family history of breast cancer: Women with a genetic predisposition for breast cancer face a
cumulative lifetime risk (CLTR) of breast cancer varying between 15% and 85% (Adriana J.
Rijnsburger, Reinoutje Kaas, , 2010). If there are close relatives who has had breast, uterine,
ovarian, or colon cancer, there is a higher risk of breast cancer. About 20-30% of women with
breast cancer have a family history of the disease (K. McPherson, C. M. Steel, and J. M. Dixon,
1994).
Genetic Predispositions: Certain genetic mutations can lead to breast cancer. The most common
gene defects are found in the BRCA1 and BRCA2 genes. These genes normally produce proteins

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that protect from cancer. If a defective gene is transmitted, you have an increased risk of breast
cancer. Women with one of these defects have up to an 80% lifetime risk of breast cancer and up
to 40% chance of ovarian cancer sometime during their life. US Preventive Services Task Force
recommendations for genetic testing for BRCA mutations (American Cancer Society, 2012) for:
1. Women who are not of Ashkenazi (Eastern European) Jewish heritage should be referred for
genetic evaluation if they have any of the following:
• Two first-degree relatives (mother, sisters, daughters), one of whom was diagnosed when
they were younger than 50.
• Three or more first- or second-degree relatives (includes grandmothers, aunts) diagnosed
with breast cancer.
• Both breast and ovarian cancer among first- and second degree relatives.
• A first-degree relative diagnosed with cancer in both breasts.
• Two or more first- or second-degree relatives diagnosed with ovarian cancer
• A male relative with breast cancer

2. Women of Ashkenazi (Eastern European) Jewish heritage should be referred for genetic
evaluation, if they have:
• A first-degree relative with breast or ovarian cancer.
• Two second-degree relatives on the same side of the family with breast or ovarian cancer.

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Table 1: Factors that Increase the Risk for Breast Cancer in Women (American Cancer
Society, 2012)
Relative Risk Factor
> 4.0 Age (65+ vs. <65 years, although risk increases across all ages until age 80)
Biopsy-confirmed atypical hyperplasia
Certain inherited genetic mutations for breast cancer (BRCA1 and/or BRCA2)
Mammographically dense breasts
Personal history of breast cancer
2.1 - 4.0 High endogenous estrogen or testosterone levels
High bone density (postmenopausal)
High-dose radiation to chest
Two first-degree relatives with breast cancer
1.1 - 2.0 Alcohol consumption
Ashkenazi Jewish heritage
Early menarche (<12 years)
Height (tall)
High socioeconomic status
Late age at first full-term pregnancy (>30 years)
Late menopause (>55 years)
Never breastfed a child
No full-term pregnancies
Obesity (postmenopausal)/adult weight gain
One first-degree relative with breast cancer
Personal history of endometrium, ovary, or colon cancer
Recent and long-term use of menopausal hormone therapy containing estrogen
and progestin
Recent oral contraceptive use

Menstrual cycle: Women with early menarche (before age 12) and late menopause (after age
55) have an increased risk of breast cancer.
Previous breast biopsy benign: Women you have previously had a breast biopsy as benign
have an increased risk of breast cancer since these biopsies reflect histologically, changes which
are physiological to approximating in-situ lesions (WD Dupont, 1985).

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1.5 Prevention
While genetic predisposition and strong family history of breast cancer cannot be prevented,
certain other lifestyle modifications can be done to reduce the susceptibility. The ACS guidelines
for nutrition and physical activity for cancer prevention (American Cancer Society, 2012) are as
follows:
• Maintain a healthy weight throughout life if overweight or obese. The results from a pooled
analysis studies by (Piet A. van den Brand,Donna Spiegelman, 1999) compared the
premenopausal women with a BMI of less than 21 kg/m2, women with a BMI exceeding 31
kg/m2 had an RR of 0.54 (95% CI: 0.34, 0.85). In postmenopausal women, the RRs did not
increase further when BMI exceeded 28 kg/m2; the RR for these women was 1.26 (95% CI:
1.09, 1.46).
• Balance calorie intake with physical activity. According to (Inger Thune, M.D., Tormod
Brenn, M.Sc., , 1997), greater leisure-time activity was associated with a reduced risk of
breast cancer, after adjustments for age, body-mass index (the weight in kilograms divided
by the square of the height in meters), height, parity, and county of residence (relative risk,
0.63; 95 percent confidence interval, 0.42 to 0.95), among women who exercised regularly,
as compared with sedentary women (P for trend = 0.04).
• Adults should engage in at least 30 minutes of moderate to vigorous physical activity, above
usual activities, on 5 or more days of the week; 45 to 60 minutes of intentional physical
activity is preferable.
• Children and adolescents should engage in at least 60 minutes per day of moderate to
vigorous physical activity at least 5 days per week. Eat a healthy diet, with an emphasis on
plant sources.

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• Choose foods and drinks in amounts that help achieve and maintain a healthy weight.
• Eat 5 or more servings of a variety of vegetables and fruits each day.
• Choose whole grains over processed (refined) grains.
• Limit intake of processed and red meats. If you drink alcoholic beverages, limit your intake.
• Women should drink no more than 1 drink per day (or 2 per day for men)
• The selective estrogen-recptor modulator (SERM) tamoxifen has been considered to reduce
the risk of estrogen receptor positive tumors and in osteoporotic women with an increased
risk of breast cancer. Through 7 years of follow-up, the rate of invasive breast cancer reduced
from 42.5 per 1000 women in placebo group to 24.8 per 1000 women in the tamoxifen group
(P < 0.001) (Fisher, B., et. al., 1998).
In spite of its preventive efforts, tamoxifen has increased risk of endometrial cancer and
thromboembolic events associated with its use (Vogel, V. G., et. al., 2010).
The National Surgical Adjuvant breast and Bowel Project (NSABP) protocol,the study of
tomoxifen and raloxifen (STAR) which directly compared tamoxifen and raloxifene in
19,747 healthy postmenopausal women at an increased risk of development of breast cancer.
With 47 months of follow-up, the initial STAR results demonstrated no difference between
the two trails in the incidence of invasive breast cancer, both with an estimated decreased
incidence of approximately 50% (Vogel, V. G., et. al., 2010).

Figure 3 summarizes the lifestyle changes to lower breast cancer risk:

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Figure 3: Lifestyle Changes to Lower Breast Cancer Risk
1.6 Diagnosis
Early detection of cancer due to awareness and routine screening mammograms has helped in
better approach of managing the disease. The ACS guidelines for the early detection of breast
cancer in average risk, asymptomatic women (American Cancer Society, 2012):
Age 20-39:
• Clinical breast examination at least every 3 years
• Breast self-examination (optional)
Age 40 and over:
• Annual mammogram
• Annual clinical breast examination (preferably prior to Mammogram)
• Breast self-examination (optional)

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1.7 Diagnostic Imaging Evaluation of Breast Cancer
The radiology imaging reports use a quality assurance tool to assess a patient's risk of developing
breast cancer. In Table 2 the distribution of categories is presented, assessing each of them with a
recommended follow-up imaging.

Table 2: Breast Imaging Reporting and Database System (The American College of
Radiology BI-RADS ATLAS, 2012)
Category Assessment Follow-up Recommendations
0
Need Additional Imaging Evaluation
and/or Prior Mammograms for
Comparison
Additional imaging and/or prior images
are needed before a final assessment can
be assigned
1 Negative
Routine annual screening mammography
(for women over age 40)
2 Benign Finding(s)
Routine annual screening mammography
(for women over age 40)
3
Probably Benign Finding – Initial Short-
Interval Follow-Up Suggested
Initial short-term follow up (usually 6-
month) examination
4
Suspicious Abnormality – Biopsy Should
Be Considered
Optional subdivisions:
4A: Finding needing intervention with a
low suspicion for malignancy
4B: Lesions with an intermediate
suspicion of malignancy
4C: Findings of moderate concern, but
not classic for malignancy
Usually requires biopsy
5
Highly Suggestive of Malignancy –
Appropriate Action Should Be Taken
Requires biopsy or surgical treatment
6
Known Biopsy-Proven Malignancy –
Appropriate Action Should Be Taken
Category reserved for lesions identified
on imaging study with biopsy proof of
malignancy prior to definitive therapy

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1.7.1 Mammogram
A mammogram is an x-ray of the breast. When a mammogram is performed in women without
breast symptoms, it is called as a screening mammogram. When it is performed in women with
symptoms, such as a breast mass, or after an abnormal screening, a diagnostic mammogram is
obtained that includes additional magnification views and often will include a focused
ultrasound. Common findings on a mammogram are:
Calcifications: Calcifications are tiny mineral deposits within the breast tissue. They may or
may not be caused by cancer. There are 2 types of calcifications:
1. Macrocalcifications: Coarse (larger) calcium deposits that are most likely changes in the
breasts caused by aging of the breast arteries, old injuries, or inflammation. These deposits
are usually non-cancerous conditions and do not require a biopsy. About half of women over
50, and 1 in 10 women under 50 have macrocalcifications (The American College of
Radiology BI-RADS ATLAS, 2012).
2. Microcalcifications: Tiny specks of calcium in the breast. They may be solitary or in clusters.
The shape and layout of microcalcifications helps to analyze how likely it is that cancer is
present. If they are suspicious, a biopsy will be needed.
Masses: Masses, which may or may not have calcifications, are another important finding seen
on mammograms. Masses could be cysts (non-cancerous, fluid-filled sacs) and non-cancerous
solid tumors (such as fibroadenomas), but they could also be cancer. Sometime, findings other
than masses such as architectural distortion of the breast, skin or nipple may require further
evaluation.

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Breast Density: Another measure seen on a mammogram is breast density, which describes the
proportion of fat (non-dense) to connective tissue (dense) in a women’s breasts. There are at least
four categories for breast density (Dr Garth Kruger and Radswiki et al):
1. Entirely fat : < 25% fibro-glandular tissue
2. Scattered fibro-glandular dense tissue: 25 - 50% fibroglandular tissue
3. Heterogeneously dense: 51 - 75% fibroglandular tissue
4. Extremely dense: > 75% fibroglandular tissue

To investigate, researchers at Harvard Medical School and Brigham and Women's Hospital in
Boston compared breast density in 1,042 postmenopausal women who had breast cancer and
1,794 age-matched women who did not have breast cancer. As expected, the risk of breast cancer
was higher for women with higher breast densities. Women with 50% or higher breast density on
a mammogram were three times more likely to be diagnosed with breast cancer over a 15-year
period than women with less than 10% breast density (Lusine Yaghjyan et al, 2011).

Figure 4: Mammographic Density and Breast Cancer Risk (Lusine Yaghjyan et al, 2011)

14

The incidence of invasive ductal carcinoma (IDC) is higher in the extremely dense group than in
other groups of breast density, likely as a combination of the amount of glandular tissue present
as well as possible observation error. It is in this group where screening ultrasound or MRI may
be potentially beneficial. Factors that can increase breast density as stated by (Dr Garth Kruger
and Radswiki et al) are:
• Hormone replacement therapy: the effect is greater with combination hormone therapy than
with estrogen therapy alone
• Pregnancy
• Lactation
• Weight loss: from reduction of breast fat
• Breast cancer: especially inflammatory breast cancer
• Inflammation: mastitis
Factors that can decrease breast density as stated by (Dr Garth Kruger and Radswiki et al) are:
• Medications: e.g. Danazol
• Vitamin D and calcium intake in pre-menopausal women
• Increasing age
• Weight gain
• Acromegaly
However, as mentioned in (American Cancer Society, 2012) mammography does have
limitations. Not all breast cancers will be detected by a mammogram, and some of the cancers
which are detected, have a poor prognosis. A small percentage of breast cancers identified by
screening would not have progressed, and thus, may be treated unnecessarily. However,
researchers have not yet discovered which tumors will progress and need treatment. Also,

15

mammography can lead to many follow-up examinations, including more mammograms,
ultrasounds, and even breast biopsies that demonstrate non-cancerous lesions. These are referred
to as false-positive test results.
Despite these limitations, mammography is the single most effective method (Leitch, A.
M., et al., 1997) of early detection since it can identify cancer several years before physical
symptoms develop.
1.7.2 Breast Ultrasound
Ultrasound (US) is non-invasive study that uses the echoes from the sound waves that are
detected and analyzed by a computer into a black and white image on a computer screen.
Ultrasound is useful for evaluating breast masses that are found on a mammogram or with a
physical exam. It has become a valuable tool because it is widely available, non-invasive, and
costs less than other options. This test helps distinguish between cysts (fluid-filled sacs) and
solid masses and sometimes can help tell the difference between benign and cancerous tumors. It
is also used to help guide a biopsy needle into some breast and axillary lesions. Still, ultrasound
cannot replace mammograms for breast cancer screening.
1.7.3 Magnetic Resonance Imaging (MRI)
MRI scans use radio waves and strong magnets instead of x-rays. The energy from the radio
waves is absorbed and then released in a pattern formed by the type of tissue and by certain
diseases. A computer translates the pattern of radio waves given off by the tissues into a very
detailed image of parts of the body. Contrast material (commonly gadolinium) is used for better
visualization. Breast MRI can be used along with mammography for screening some women at
very high risk of breast cancer. It can also be used to better look at suspicious areas seen on a
mammogram, especially if ultrasound is not helpful.

16

Role of MRI in Breast Cancer: Breast MRI offers information about many breast conditions
that cannot be obtained from mammography or ultrasound, particularly in higher risk patients
such as those that carry genetic susceptibility. Breast MRI is frequently performed at the time of
diagnosis of all early breast cancer to identify contralateral and additional ipsilateral disease.
Case series have shown that MRI staging in patients with known breast cancer leads to occult
malignant findings in the ipsilateral (3.5%) and contralateral (2.9%) breast. The routine use of
preoperative breast MRI following a diagnosis of breast cancer remains controversial because the
ultimate impact on patient outcome has not been defined. Two randomized trial have been
carried out to assess the impact of MRI staging on re-excision rate and no differences was found
(Turnbull, L., S. Brown, et al., 2010) (Peters, N. H. G. M., et al., 2011). Nevertheless, MRI is a
sensitive method of breast imaging, with many studies showing that MRI can improve the
preoperative staging of breast cancer and has become a popular tool to help with surgical
planning and for the detection of occult cancers (Morrow, M., Waters, J., and Morris, E, 2011).
1.8 Limitations of MRI
Some of the challenges with interpretation of breast MRI include (Anil Kumar Swayampakula,
Charlotte Dillis, Jame Abraham, 2008):
• Enhancement of normal fibro-glandular tissue in the proliferative phase of menstrual cycle.
• Benign breast disease and post irradiation and postsurgical scar formation, which make it
difficult to differentiate possible recurrence and local granulation tissue formation.
• MRI may not be able to correctly differentiate between inflammatory carcinoma and mastitis.

17

• MRI is useful in assessing the response to neo-adjuvant chemotherapy; however, it may
underestimate the residual tumor due to decreased vascularity and permeability after
chemotherapy.
• Studies that reported on surgical impact of MRI detected findings showed more extensive
surgery. In women with (histological proven) additional foci of cancer detected by MRI,
meta-analysis showed that conversion from wide local excision to more extensive surgery
occurred in 11.3% of instances, and this was largely conversion to mastectomy (Houssami,
N., et. al., 2008).
• The false-positive rate of MRI is usually around 5% (Lehman, C. D., et al., 2005) and
additional biopsies are frequently needed.
• Targeted “second-look” ultrasonography of MRI-detected lesions does not always visualize
these lesions to allow biopsy (LaTrenta, L. R., J. H. Menell, et al., 2003). Additionally, MRI-
compatible biopsy devices are not available at all imaging centers and small lesions (< 1 cm)
may be difficult to biopsy under MRI-guidance. Consequently, benign lesions may prompt
larger excision volumes or the decision of mastectomy and prophylactic contralateral
mastectomy (Bilimoria, K. Y., A. Cambic, et al., 2007). The only randomized trial assessing
staging MRI used repeat operation or further mastectomy within 6 months as the primary
endpoint and found no difference (Turnbull, L., S. Brown, et al., 2010) .
• The cost of MRI is more than $1000 compared with about $100 for mammography.

Most of the series and trials of staging MRI have been conducted in an insured and primarily
Caucasian population. Patient who are uninsured tend to also be over-represented by individuals
of ethnic minority (African American or Hispanic in the U.S.) and tend to be younger and

18

therefore at higher risk for familial cancers. At out institution, we care for a significant
proportion of such patients have instituted MRI screening on a majority of newly diagnosed
breast cancer patients beginning in 2006.
1.9 Staging
Staging is a process used to determine the extent of the disease and whether the cancer has
spread within the breast or to other parts of the body. The information gathered from the staging
process including tumor size, extent of nodal involvement and distant metastasis determines the
stage of the disease. It is important to know the stage in order to plan treatment. Seen below in
Figure 5, Figure 6, Figure 7, and Figure 8 are the different sizes of tumor and node representing
the different stages as per the (AJCC, 2011) guidelines.

Figure 5: Primary Tumor 1 (T1) (AJCC, 2011)

19

Figure 6: Primary Tumor 2 and 3 (T2 and T3) (AJCC, 2011)

Figure 7: Primary Tumor 4a (T4a) (AJCC, 2011)

20

Figure 8: Regional Lymph Nodes (N) (AJCC, 2011)
Table 3: AJCC Cancer Staging. 7th Edition (AJCC, 2011)
Primary tumor (T)
TX Primary tumor cannot be assessed
T0 No evidence of primary tumor
Tis Intraductal carcinoma, lobular carcinoma in-situ, or Paget disease of the
nipple with no associated invasion of normal breast tissue
Tis DCIS
Tis LCIS
Tis Paget disease of the nipple with no tumor.
T1 Tumor not larger than 2.0 cm in greatest dimension
T1mic Microinvasion not larger than 0.1 cm in greatest dimension
T1a Tumor larger than 0.1 cm but not larger than 0.5 cm in greatest
dimension
T1b Tumor larger than 0.5 cm but not larger than 1.0 cm in greatest
dimension
T1c Tumor larger than 1.0 cm but not larger than 2.0 cm in greatest
dimension
T2 Tumor larger than 2.0 cm but not larger than 5.0 cm in greatest
dimension

21

T3 Tumor larger than 5.0 cm in greatest dimension
T4 Tumor of any size with direct extension to (a) chest wall or (b) skin,
only as described below
T4a Extension to chest wall, not including pectoralis muscle
T4b Edema or ulceration of the skin of the breast, or satellite skin nodules
confined to the same breast
T4c Both T4a and T4b
T4d Inflammatory carcinoma

Regional lymph nodes (N)
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Metastasis to movable ipsilateral axillary lymph node(s)
N2 Metastasis to ipsilateral axillary lymph node(s) fixed or matted, or in
clinically apparent ipsilateral internal mammary nodes in the absence of
clinically evident lymph node metastasis
N2a Metastasis in ipsilateral axillary lymph nodes fixed to one another
(matted) or to other structures
N2b Metastasis only in clinically apparent ipsilateral internal mammary
nodes and in the absence of clinically evident axillary lymph node
metastasis
N3 Metastasis in ipsilateral infraclavicular lymph node(s) with or without
axillary lymph node involvement, or in clinically apparent ipsilateral
internal mammary lymph node(s) and in the presence of clinically
evident axillary lymph node metastasis; or, metastasis in ipsilateral
supraclavicular lymph node(s) with or without axillary or internal
mammary lymph node involvement
N3a Metastasis in ipsilateral infraclavicular lymph node(s)
N3b Metastasis in ipsilateral internal mammary lymph node(s) and axillary
lymph node(s)
N3c Metastasis in ipsilateral supraclavicular lymph node(s)

Pathologic classification (pN)
pNX Regional lymph nodes cannot be assessed
pN0 No regional lymph node metastasis histologically, and no additional
examination for isolated tumor cells
pN0(i-) No regional lymph node metastasis histologically, negative IHC
pN0(i+) No regional lymph node metastasis histologically, positive IHC, and no
IHC cluster larger than 0.2 mm
pN0(mol-) No regional lymph node metastasis histologically, and negative
molecular findings

22

pN0(mol+) No regionally lymph node metastasis histologically, and positive
molecular findings
pN1 Metastasis in one to three axillary lymph nodes, and/or in internal
mammary nodes with microscopic disease detected by SLN dissection
but not clinically apparent
pN1mi Micrometastasis (larger than 0.2 mm but not larger than 2.0 mm)
pN1a Metastasis in one to three axillary lymph nodes
pN1b Metastasis in internal mammary nodes with microscopic disease
detected by SLN dissection but not clinically apparent
pN1c Metastasis in one to three axillary lymph nodes and in internal mammary
lymph nodes with microscopic disease detected by SLN dissection but
not clinically apparent
pN2 Metastasis in four to nine axillary lymph nodes, or in clinically apparent
internal mammary lymph nodes in the absence of axillary lymph node
metastasis to ipsilateral axillary lymph node(s) fixed to each other or to
other structures
pN2a Metastasis in four to nine axillary lymph nodes (at least one tumor
deposit larger than 2.0 mm)
pN2b Metastasis in clinically apparent internal mammary lymph nodes in the
absence of axillary lymph node metastasis
pN3 Metastasis in ten or more axillary lymph nodes, or in infraclavicular
lymph nodes, or in clinically apparent ipsilateral internal mammary
lymph node(s) in the presence of one or more positive axillary lymph
node(s); or, in more than three axillary lymph nodes with clinically
negative microscopic metastasis in internal mammary lymph nodes; or,
in ipsilateral supraclavicular lymph nodes
pN3a Metastasis in ten or more axillary lymph nodes (at least one tumor
deposit larger than 2.0 mm); or, metastasis to the infraclavicular lymph
nodes
pN3b Metastasis in clinically apparent ipsilateral internal mammary lymph
nodes in the presence of one or more positive axillary lymph node(s); or,
in more than three axillary lymph nodes and in internal mammary lymph
nodes with microscopic disease detected by sentinel lymph node
dissection but not clinically apparent
pN3c Metastasis in ipsilateral supraclavicular lymph nodes

Distant metastasis (M)
MX Presence of distant metastasis cannot be assessed
M0 No distant metastasis
M1 Distant metastasis

23

Table 4: Anatomic Stage / Prognostic Groups (AJCC, 2011)
Stage 0 Tis N0 M0
Stage IA T1 N0 M0
Stage IB T0 N1mi M0
T1 N1mi M0
Stage IIA T0 N1 M0
T1 N1 M0
T2 N0 M0
Stage IIB T2 N1 M0
T3 N0 M0
Stage IIIA T0 N2 M0
T1 N2 M0
T2 N2 M0
T3 N1 M0
T3 N2 M0
Stage IIIB T4 N0 M0
T4 N1 M0
T4 N2 M0
Stage IIIC Any T N3 M0
Stage IV Any T Any N M1
1.10 Prognosis and Prognostic Factors
Due to various treatment modalities and clinical trials, it is critical to define certain prognostic
factors to balance improvements in survival and decrease recurrence against side effects of
therapy. The common prognostic factors used are:
Axillary Node Status: The presence and degree of involvement predict the survival or
recurrence of the cancer. According to (RUBEN A. SAE, MB, 1989) the National surgical
adjuvant breast and bowel project (NSABP) showed a relapse rate with increasing numbers of
involved axillary nodes.
Grading: Refers to how the cancer cells look under the microscope compared with normal breast
cells. In the Nottingham/Tenovus Primary Breast Cancer study the most commonly used method,

24

described by Bloom & Richardson, has been modified to make the criteria more objective. The
revised technique involves evaluating the following three morphological features:
1. Percentage of tubule formation
2. Degree of nuclear pleomorphism
3. Mitotic count using a defined field area
Below in Table 5 are the scoring system based on the features. A numerical scoring system is
used and the overall grade is derived from a summation of individual scores for the three
variables; three grades of differentiation are used (Elston CW, Ellis IO., 1991):
• Grade 1 (low-grade): The cancer cells look similar to normal cells and are slow in growth
• Grade 2 (moderate- or intermediate-grade): The cancer cells look more abnormal and are
slightly faster growing
• Grade 3 (high-grade): The cancer cells look very different from normal cells and tend to
grow quickly
Table 5: Scarff Bloom Richardson Grading System (Robert D. Cardiff and Roy A. Jensen)
Tubule Formation
Majority of Tumor (>75%) 1
Moderate Degree (10-75%) 2
Little or None (<10%) 3
Mitotic Count
0-9 Mitoses / 10hpf 1
10-19 Mitoses / 10hpf 2
20 or > Mitoses / 10pf 3
Nuclear Pleomorphism
Small Regular Uniform Cells 1
Moderate Nuclear Size and
Variation
2
Marked Nuclear Variation 3
Combined Histologic Grade
Low Grade (I) 3 - 5
Intermediate Grade (II) 6 - 7
High Grade (III) 8 - 9

25

Hormone and Growth Factor Receptors: The hormone receptor status helps in making
treatment decisions for tumors positive for estrogen receptor (ER) and progesterone receptor
(PR). Hormonal therapy is usually offered when these steroid receptors are positive and as such,
these patients have a higher cure rate and longer disease free interval than compared to hormone
receptor negative tumors.
Her2/neu: The Human Epidermal Growth Factor Receptor 2 (HER2) oncogene encodes a
transmembrane tyrosine kinase receptor and has been widely tested along with the hormone
receptor for all primary cancer tumors. If the HER gene is amplified or the protein is
overexpressed, it is considered more aggressive, though treatment with trastuzumab (Herceptin)
significantly improves the outcome.
1.10.1 Assessing and Managing Risk of Breast Cancer Recurrence
New and improved treatments are helping patients with breast cancer to live longer. Even with
treatment, though, breast cancer can spread to other parts of the body. Sometimes, cancer returns
even after the entire tumor has been removed and nearby lymph nodes is found to be cancer-free.
The more advanced the cancer, the higher the risk of recurrence, particularly distant recurrence,
or metastasis, which is associated with poorer outcome. Other factors used to determine the risk
of recurrence and the likelihood of successful treatment include:
• Tumor size and involvement of skin or chest wall (T stage)
• Number and location of involved lymph nodes (N stage)
• Presence of distant metastases (M stage)
• Tumor grade and other measures of the rate of cell division
• ER, PR and HER2 receptor status

26

• More recently, gene expression profiling has also been instrumental in developing the
molecular classification of breast cancer. The 21-gene recurrence score can be used to predict
the risk of recurrence in patients with newly diagnosed, node-negative, estrogen receptor
(ER)-positive disease and to identify patients who are likely to benefit from chemotherapy
added to adjuvant endocrine therapy (Daniel F Hayes, MD, 2013).

27

Chapter 2: Materials and Methods
2.1 The Clinical Protocol
The HIPAA- compliant retrospective study is being performed with approval from the University
of Southern California institutional review board (IRB). This study will contribute to existing
knowledge since it would be conducted in 2 populations, academic, involving mostly an insured
population and in an under-served minority population. We obtained records for the last 5 years
(Jan 1 2006 until December, 2011) 678 cases were abstracted for patients who underwent staging
MRI studies for a new diagnosis of breast cancer and who had follow-up records available for
analysis. Data sources included electronic radiology records, electronic medical records (Cerner
and Affinity) and paper records as well as billing records when necessary. In addition, we used
data from the Cancer Surveillance program and Cancer Registries of LAC+USC, Norris and
University Hospital for longer term follow-up.
2.2 Criteria
2.2.1 Inclusion Criteria
1. Newly diagnosed breast cancer
2. Preoperative MRI imaging performed for these newly diagnosed cancers
3. Prior to any medical, radiation or surgical therapy (other than biopsy)
2.2.2 Exclusion Criteria
1. Previously diagnosed and treated cancer
2. Recurrence of breast cancer
3. Prior surgical, medical or radiation therapy for breast cancer

28

2.3 Imaging Protocol and Interpretations
Index lesion is confirmed to be either ductal carcinoma in-situ or invasive carcinoma and initially
detected by physical examination, mammogram, or ultrasound. Below is the flowchart (Figure 9)
which explains the method of detecting a lesion, both at Norris and LAC+USC.

Figure 9: Lesion Detection

Figure 10: Management of Index-Lesion

29

2.4 Data Collection
We proposed to evaluate the MRI and pathology findings in all patients we had treated over the
past 5 years for breast cancer who had undergone MRI staging. Imaging study reports (MRI,
mammograms, ultrasounds of the breast), pathology reports and medical records including
treatments received and long-term outcome including recurrence of all such patients were
gathered.
Patient records were obtained who have had breast MRIs for a known diagnosis of cancer
from the radiology records, Cerner, Affinity and from the radiology database. Forms for clinical
and radiological data did not have the patients name but coded with an ID number. The study
involved abstraction of clinical information and archived MRI scans from medical record sources
and the radiology department. All the information was coded to protect the privacy of research
subjects.
We were interested in determining what additional procedures, alternations in treatment
and long term outcomes are associated with MRI staging. Breast MRI is frequently performed at
the time of diagnosis of early breast cancer to identify contralateral and additional ipsilateral
disease. The reported incidence of unexpected contralateral cancer is about 2-5%, but many of
these lesions are pre-invasive and the extent to which they influence treatment and affect long-
term outcome is unknown, especially in minority populations. Specific metrics of interest was
the number of abnormal finding on MRI and their concordance to findings on mammography
and ultrasound, although with the follow-up procedures and results of any biopsy and surgical
procedures in order to estimate the sensitivity, specificity and positive predictive value of
abnormal MRI findings (specifically BIRADs score 4 and 5 for which further evaluation is
recommended).Standard definitions of sensitivity and specificity was used with histologic

30

diagnosis of invasive cancer or ductal carcinoma in-situ as the gold standard. Descriptive
statistics was used to calculate other measures of outcome and exploratory statistics (e.g.
pairwise comparisons and log-rank analysis adjusted for multiple variables) to be carried out on
demographic and clinicopathological variables.

31

Chapter 3: Detection of Non-Index Lesions and Occult Cancers in
Newly Diagnosed Breast Cancer in Diverse Population
3.1 Objective
Breast MRI is a more sensitive imaging modality compared to mammography or ultrasound,
particularly in higher risk situations such as genetic susceptibility. For patients newly diagnosed
with breast cancer, case series have shown that staging MRI can detect occult breast cancers in
1-10% of cases. MRI staging is also being increasingly used for preoperative evaluation in
patients with a diagnosis of operable breast cancer. Several studies have demonstrated a
detection rate for non-index ipsilateral occult malignant foci of 6-27%, with contralateral occult
malignancies found in 3-9% of patients (Lee, S. G., S. G. Orel, et al. , 2003).
However, the number of false positives, false negatives and the consequences of
abnormal findings on performance of additional imaging tests, biopsies, surgical procedures and
post-operative, systemic and radiation therapy remains to be determined from larger scale
studies. The prevalence and predictors of occult cancers detected by MRI in underserved
populations is unstudied. As such, the overall utility and outcomes of routine preoperative MRI
on surgical management remains unproven and outcomes associated with the use of staging MRI
in underserved and minority populations has not been previously described (Brennan, M. E., N.
Houssami, et al., 2009). We sought out to study more about the predictors and outcome of this
staging MRI.
3.2 Introduction
We sought to conduct an analysis of staging MRI in two distinct populations – an academic
practice, involving mostly an insured population and an underserved minority population over
the same time period using similar diagnostic procedures.

32

A retrospective analysis was conducted of consecutive patients with newly diagnosed in-
situ or invasive breast cancer who had a preoperative staging MRI seen at USC Norris
Comprehensive Cancer Center and Los Angeles County Medical Center (LAC+USC), that cares
for an underserved and minority population, from 2006 to 2011. IRB approval was obtained to
extract demographic and clinicopathological data, MRI, mammography and additional imaging
results, biopsy and surgical procedures through the review of electronic medical records and
clinic charts.

Figure 11: Clock Positions and Quadrants of the Breasts (SEER, 2012)

Non-index lesions (NIL) are defined as those in breast or axillary nodes not known to be
malignant, and not presenting with suspicious clinical findings, or with mammographic or
ultrasound findings defined as BI-RADS score of 4 or 5. Additionally, a non-index lesion must
be in a different quadrant and at least 5cm away in relation to an index lesion.
Occult cancers are those lesions found by biopsy or surgery to be invasive or in-situ
cancer. The proportion of occult cancer lesions among the non-index lesions was calculated and
presented for lesions with different characteristics. Analyses were performed to examine the

33

association between the probability of a non-index lesion being an occult cancer lesion and
patients demographic or disease characteristics as well as lesion characteristics.

Figure 12: Management of Non-Index Lesion
3.3 Patients
Los Angeles County Medical Center affiliated with University of Southern California
(LAC+USC) and the Norris Cancer Center cares for an ethnically diverse patient population.
While LAC+USC is more of underserved/uninsured populations, Norris has the insured
population. Amongst newly diagnosed breast cancer patients at LAC+USC, 80% are Hispanic
and 15% Asian, while there is more equal distribution at the Norris Cancer Center. In this study,

34

of the total 678 patients, 349 were from LAC+USC and 329 were seen at the Norris Cancer
Center.
Staging was based on clinical staging for patients who received pre-operative systemic
therapy, and on pathological staging for all other cases. Pathological staging is determined using
American Joint Committee on Cancer (AJCC) staging system, 7
th
edition (AJCC, 2011). ER and
PR positive are defined as greater than or equal to 1% positive. HER 2 positive is defined by
HER2/centromere chromosome 17 ratios are greater than or equal to 2.
3.4 Statistical Analysis
In the main analyses, lesions that did not have a surgical diagnostic evaluation but were negative
on targeted ultrasound studies were considered as not having occult cancer. To examine how
much the inclusion of these lesions as negative lesions would influence the results on the
association between the probability of being an occult cancer lesion and different variables,
analyses were also performed by excluding the lesions without a surgical diagnostic evaluation.
These secondary analyses gave equivalent results to the main analyses. Results from the main
analyses are reported.
Logistic regression was used to examine the association between the probability of a non-
index lesion being an occult cancer lesion and patients demographic, clinical or disease
characteristics as well as lesion characteristics (including lesion type and surgery type, etc.). In
our cohort, each patient could have 1, 2 or 3 non-index lesions. In the logistic regression
analyses, accounting for this intra-patient correlation gave equivalent results to analyses that
ignored this correlation. Lesions that were lost to follow-up were excluded from all analyses that
evaluated associations.

35

Variables that were associated with the probability of a non-index lesion being an occult
cancer lesion at p≤0.30 in univariate analyses were then included in a multivariable logistic
regression model, and a backward stepwise model selection method was used to select a final
model by successively dropping non-significant variables from the model and re-fitting reduced
models until all remaining variables were statistically significant at 0.10. Statistical computation
was performed using the STATA software.
3.5 Results
• Of 678 total patients, 144 (21%) had a total of 171 non-index lesions identified by MRI;
73 (10.8%) patients have ipsilateral breast lesions
53 (7.8%) patients have contralateral breast lesions
31 (4.6%) patients have axillary nodes
• 57 patients (8.4%) had a total of 62 occult cancers detected
40 (5.9%) patients have ipsilateral breast lesions
9 (1.3%) patients have contralateral breast lesions
9 (1.3%) patients have axillary nodes
• Of 57 patients with occult cancers 49 (7.2%) were invasive and 8 (1.2%) were in-situ

Table 6 presents the demographic and clinical features of total cohort (N=678) and patients with
non-index lesions (N=144). Followed by Table 7, containing statistics of occult cancers detected
in non-index lesions (per lesion as well as per patient). Finally, Table 8 presents the univariate
and multivariate analysis of non-index lesion being an occult cancer lesion.

36

Table 6: Non-Index Lesions: Demographic / Clinical Features
Variables All Patients (N=678)
Patients with Non-
Index Lesions (N=144)
# % # %
Institution
LAC+USC 349 51.5 72 50
Norris 329 48.5 72 50
Race / Ethnicity
Hispanic 280 41.3 53 36.8
Asian 66 9.7 11 7.6
Caucasian 195 28.8 44 30.6
African American 45 6.6 11 7.6
Others 16 2.4 4 2.8
Unknown 76 11.2 21 14.6
Age in Years at Diagnosis
< 40 100 14.8 19 13.2
40 – 49 161 23.8 41 28.5
50 – 64 283 41.7 63 43.8
>= 65 134 19.8 21 14.6
Biomarkers on Primary Tumor
HER2-negative, ER or PR + 300 44.3 66 45.8
Triple Negative 76 11.2 9 6.3
HER2 + 106 15.6 28 19.4
HER2 missing, ER or PR + 107 15.8 21 14.6
HER2 missing, ER/PR missing/- 89 13.1 20 13.9
BRCA Status
BRCA1 18 2.7 -- --
BRCA2 14 2.1 -- --
No Mutation 173 25.5 34 23.6
Untested or Unknown 473 69.8 110 76.4
Mammographic Density
Fatty 24 3.5 4 2.8
Scattered Fibroglandular 246 36.3 52 36.1
Heterogeneously Dense 338 49.9 75 52.1
Extremely Dense 18 2.7 5 3.5
Unknown 52 7.7 8 5.6
Patients with Non-index Lesions
No 534 78.8 -- --
Yes 144 21.2 144 100
Number of Non-Index Lesions
0 534 78.8 -- --
1 118 17.4 118 81.9
2 25 3.7 25 17.4

37

3 1 0.2 1 0.7
Follow-up Evaluation
Surgery / Biopsy 652 96.2 123 85.4
Loss to Follow-up 14 2.1 12 8.3
Follow-up Imaging with
Ultrasound/MRI
12 1.8 9 6.3
*Note: HER2 not performed on in-situ lesions (N =59)

Table 7: Occult Cancers Detected Among Non-Index Lesions
Variables By Lesion By Patient
Total
Occult
Cancer
Total
Occult
Cancer
# # % # # %
Overall
N 157 62 39.5 132 57 43.2
Institution
LAC+USC 81 31 38.3 68 25 36.8
Norris 76 31 40.8 64 25 39.1
Race/Ethnicity Group
Hispanic 61 22 36.1 51 17 33.3
Asian 11 3 27.3 8 2 25
Caucasian 46 18 39.1 41 17 41.5
African American 13 6 46.2 11 5 45.5
Others/Unknown 26 13 50 21 9 42.9
Age in Years at Diagnosis
< 40 22 6 27.3 19 4 21.1
40 – 49 45 17 37.8 36 16 44.4
50 – 64 69 27 39.1 60 21 35
>= 65 21 12 57.1 17 9 52.9
Biomarkers
HER2 -, ER or PR + 73 32 43.8 62 28 45.2
Triple Negative 11 5 45.5 9 3 33.3
HER2 + 33 13 39.4 28 9 32.1
HER2 missing, ER or PR + 22 8 36.4 18 6 33.3
HER2 missing, ER/PR
missing/-
18 4 22.2 15 4 26.7
Mammogram Density
Fatty 5 1 20 4 1 25
Scattered Fibroglandular 54 23 42.6 47 18 38.3
Heterogeneously Dense 84 33 39.3 70 27 38.6
Extremely Dense 5 3 60 4 2 50
Unknown 9 2 22.2 7 2 28.6

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Location of NIL
Contralateral Breast 54 9 16.7
Contralateral Node 3 1 33.3
Ipsilateral Breast 74 44 59.5
Ipsilateral Node 26 8 30.8
Bi-RADS
Bi-RADS 4 130 47 36.2
Bi-RADS 5 27 15 55.6
Type of Surgery
Biopsy 59 6 10.2
Lumpectomy 10 6 60
Mastectomy 24 20 83.3
Biopsy followed by
Lumpectomy
11 6 54.5
Biopsy followed by
Mastectomy
15 12 80
None 38 12 31.6
Type of Node Surgery
SLN 14 2 14.3
ALND 8 6 75
SLN and ALND 7 4 57.1
None 128 50 39.1

1
A patient is considered as having occult cancer if any of the non-index lesions of the patient had occult
cancer.
Note: Of all 171 non-index lesions, 23 did not have a surgical diagnostic evaluation. Of these lesions, 9
were negative on targeted ultrasound and were considered as not having occult cancer. The remaining 14
were lost to follow-up and did not have a final diagnostic evaluation, and were therefore excluded from
this table.

Table 8: Odds Ratios of Probability of a Non-index Lesion being an Occult Cancer Lesion
Univariate and Multivariate Analysis
Variables Univariate Multivariate
3

OR (95%CI) p OR (95%CI) p
Institution 0.75
LAC+USC ref Excluded from the model
Norris 1.11 (0.59, 2.11)
Race/Ethnicity Group 0.66
1

Hispanic ref Excluded from the model
Asian 0.66 (0.16, 2.77)
Caucasian 1.14 (0.52, 2.51)
African American 1.52 (0.45, 5.09)
Others/Unknown 1.77 (0.70, 4.49)

39

Age in Years at Diagnosis 0.069
2

<40 ref Excluded from the model
40-49 1.62 (0.53, 4.94)
50-64 1.71 (0.60, 4.93)
>=65 3.56 (0.99, 12.7)
Biomarkers 0.52
1

Her2 -, ER or PR + Ref Excluded from the model
Triple Negative 1.07 (0.30, 3.82)
Her2 + 0.83 (0.36, 1.92)
Her2 missing, ER or PR + 0.73 (0.27, 1.96)
Her2 missing, ER or PR missing or - 0.37 (0.11, 1.22)
Mammogram Density 0.53
Fatty/ Scattered Fibroglandular ref Excluded from the model
Heterogeneously Dense/ Extremely Dense 0.99 (0.51, 1.94)
Laterality <0.001 0.005
Contralateral ref ref
Ipsilateral 5.09 (2.32, 11.2) 4.24 (1.50, 12.0)
Bi-RADS 0.063
Bi-RADS 4 ref Excluded from the model
Bi-RADS 5 or 6 2.21 (0.95, 5.11)
Type of Diagnostic Surgery <0.001
1
<0.001
1

Biopsy ref ref
Mastectomy 40.4 (12.5, 131) 32.2 (9.57, 108)
Excision 11.8 (3.52, 39.4) 9.82 (2.79, 34.6)
SLN and/or ALND 6.23 (2.03, 19.1) 3.29 (1.01, 10.8)

1
Overall p value
2
p value from trend test
3
Variables that were significantly associated with the outcome at p≤0.30 in the Univariate analyses were
included in a multivariable logistic regression model, and the stepwise backward selection procedure
was used to eliminate any variable that was not significant at p≤0.10.
Abbreviations: OR – Odds Ratio; CI – Confidence Interval
Note: 14 non-index lesions were lost to follow-up and did not have a final diagnostic evaluation. They
were excluded from these analyses.

Figure 13 shows the laterality of the lesions for patients with the non-index and occult cancers.
Figure 14 represents the Bi-RADS and the laterality of the non-index lesions in percentage.

40

Figure 13: Laterality of the Breast and Node Lesions for Patients with Non-Index Lesions
and Occult Cancers

41

Figure 14: Laterality and BI-RADS of the Non-Index Lesions and Occult Cancer Lesions

Figure 15: % Type of Surgery done for Non-Index and Occult Cancer Lesions

42

Figure 15 and Figure 16 show the type of surgery for non-index lesions and occult cancers.
Figure 17 and Figure 18 show the surgical procedure distribution based on the type of institution,
LAC+USC and Norris.

Figure 16: Breast Procedures done for Non-Index and Occult Cancer Lesions

43

Figure 17: Type of Surgery done for Non-Index Lesions based on the Institutions

Figure 18: Type of Surgery done for Occult Cancer Lesions based on the Institutions

44

Figure 19 shows the age at diagnosis of breast cancer among the non-index and occult cancer
lesions. Figure 20 shows the BRCA tested population from the total cohort and the total non-
index lesions from the same cohort.

Figure 19: Age at Diagnosis for Patients with Non-Index Lesions and Occult Cancers

Figure 20: BRCA Tested for the Total Cohort and Patients with Non-Index Lesions

45

3.6 Discussion
Preoperative MRI has been in great use for early stage breast cancer without much evidence of
improved outcomes compare to the standard assessments. Especially the sensitivity of
mammography is lower in young women, women with dense breast tissue and who carry BRCA
mutations (Morrow, M., Waters, J., and Morris, E, 2011). In a meta-analysis of 19 studies, this
included 2610 patients with breast cancer, the prevalence of detection of additional foci
(multifocal or multicentric) in the affected breast ranged from 6% to 34% across studies with a
median of 16% (interquartile range, 11% to 24%) (Houssami, N., et. al., 2008).
The role of MRI in identification of the primary tumor has been studied in a series of
retrospective studies, most with fewer than 20 patients, and in a meta-analysis of 8 studies
including 220 patients. The pooled sensitivity for detection of cancer was 90% and the
specificity was 31% (Morrow, M., Waters, J., and Morris, E, 2011).
Analyses showed that age was marginally significantly associated with the probability of
having occult cancers (OR=1.5 for each 10 years increase, p=0.080). Patients with no BRCA
mutation had significantly higher chance of having non-index lesions tested with MRI (p=0.003),
but the probability of having occult cancers did not significantly differ between those tested.
Ipsilateral compared to contralateral non-index lesions had a 4-fold higher chance of being occult
cancers (p<0.001). For non-index lesions (n=157), 59 (37.6%) underwent biopsy, 11 (7%) biopsy
followed by lumpectomy, 10(6.4%) had lumpectomy, 24 (15.3%) mastectomy, 15 (9.6%) biopsy
followed by mastectomy and (15) 9.6% node dissection. Amongst occult cancers (n=62), 6
(3.8%) underwent biopsy, 6 (3.8%) biopsy followed by lumpectomy, 6 (3.8%) lumpectomy, 20
(12.7%) mastectomy, 12 (7.6%) had biopsy followed by mastectomy and 10 (6.4%) node
dissection.

46

In a study by Lehman et al. MRI of the contralateral breast in women recently diagnosed
with breast cancer detected a second breast lesion in 30 of 969 women (3.1%) (Patricia Young,
Benjamin Kim, and Jennifer Malin, 2012).
3.7 Conclusions
In this ethnically diverse underserved population of patients with newly diagnosed breast cancer,
MRI detected non-index lesions and occult cancer in 21% and 8.4% of patients, respectively.
There were no factors that predicted a higher prevalence of non-index lesions or occult cancers
other than laterality (ipsilateral non-index lesions with a 4-fold higher chance of being an occult
cancer). About 40% of patients with lesions classified by MRI as suspicious were confirmed as
invasive or in-situ cancer. Interestingly, none of the occult cancers detected were among the
known 32 BRCA mutation carriers. MRI staging appears to identify occult cancer to an equal
extent in a largely Hispanic and younger underserved population as reported in the literature for
populations of mostly insured Caucasian patients.

47

Chapter 4: Detection of Non-Index Lesions and Occult Cancers in
BRCA Tested in Newly Diagnosed Breast Cancer Patients
4.1 Objective
This sub-study is to ascertain the non-index lesions in a group of hereditary predisposed patients
seen on MRI with breast cancer who have undergone BRCA testing and correlate the findings
with pathology. Annual MRI breast screening is recommended for women with BRCA mutations
on the basis of improved sensitivity and earlier detection but without a proven long-term
outcome benefit (Saslow, D., C. Boetes, et al. , 2007).
Mutations in BRCA 1 and 2 are associated with very substantial increased risk of breast
cancer and increase the likelihood of contralateral disease. Breast MRI is frequently performed at
the time of diagnosis of all early breast cancer to identify contralateral and additional ipsilateral
disease. We have performed BRCA testing in approximately 287 patients with breast cancer at
the LAC+USC Medical Center and Norris Cancer center. This will provide a unique opportunity
to evaluate MRI results in a series of patients with breast cancer who have been identified as
high risk for carrying mutations in BRCA 1 or 2.
The purpose of this study was to evaluate the effectiveness of preoperative breast MRI on
the diagnosis of non-index breast malignancies and the outcomes related to the MRI staging in
an underserved and primarily Hispanic breast cancer population at risk for familial breast cancer
and screened with BRCA testing.
4.2 Introduction
As mentioned in section-1.4 mutations in BRCA 1 and 2 are associated with an increased risk of
breast cancer and possibility of a contralateral disease. In this retrospective study we propose to
evaluate the MRI and pathology findings in all patients we have treated over the past 5 years for

48

breast cancer who have undergone clinically indicated genetic testing for BRCA 1 and 2. The
BRCA test results will then be correlated with abstracted data looking at the MRI findings and
pathology results in BRCA 1, 2 mutation carriers and non-carriers. Patients with breast cancer
and a positive family history of breast cancer and/or BRCA 1 or 2 mutations have an elevated
risk of second contralateral and/or ipsilateral breast cancers (Weitzel, J. N., V. Lagos, et al. ,
2005) .
MRI screening is proved to be cost-effective for very high-risk women, such as BRCA
carriers, and others at 20% or greater lifetime risk, by the cost per year of life saved (Feig, S. ,
2011). This population tends to be younger and enriched in minorities. Both of these factors are
associated with hereditary predisposition and aggressiveness of cancer.
4.3 Patients
Los Angeles County Medical Center, affiliated with University of Southern California
(LAC+USC) cares for a medically underserved and an ethnically diverse patient population.
Since 2008, genetic counseling and testing of breast cancer patients has been integrated into
routine care of newly diagnosed breast cancer patients. Approximately 16.3% of the U.S.
population is Hispanic with the majority residing in urban centers such as Los Angeles by United
States Census Data 2010 (Census , 2010). Norris Cancer Center cares for patients with insurance
and has diverse patient populations in the country. The aim of our study was to assess the
incidence of and outcomes of the non-index lesions(as defined in Chapter 3.2 from breast MRI
in high risk an underserved breast cancer patient’s population primarily screened with BRCA
testing due to the personal and familial cancer history in a diverse population.
We undertook a retrospective evaluation of all patients with recently diagnosed invasive
or in-situ breast cancer who underwent genetic counseling and BRCA 1 and 2 testing as well as

49

pre-operative bilateral breast MRI at LAC+USC and Norris Cancer Center from March 2008 to
December, 2012. IRB approval was obtained to extract data for this analysis. The demographic,
clinical, pathology, staging, genetic testing data, imaging and cancer treatments rendered were
collected by the study team’s medical oncologists, radiologists, and genetic counselor.
The patients were referred for genetic counseling based on the personal and familial
cancer history, including a personal history of early onset breast cancer and personal and /or
family history of BRCA-related cancers. Analysis of the BRCA genes was performed in women
diagnosed with breast cancer (either invasive or in-situ) at or under age 45, regardless of family
history, and women with breast cancer diagnosed over age 45 reporting a family history of breast
cancer diagnosed under age 50, multiple breast cancers in the family, male breast cancer at any
age, ovarian cancer diagnosed at any age (Clinical and NCCN Practical Guidelines: Genetic
Familial/High-Risk Assessment: Breast and Ovarian, 2009) . Analysis of the BRCA1 and BRCA2
genes was performed in a Clinical Laboratory Improvement Amendments (CLIA) approved
laboratory (Myriad Genetics). Demographic information along with clinical and pathological
stage at presentation, family cancer risks, BRCA testing results, pathology, surgical treatment,
MRI and mammography results and follow up studies for occult lesions were obtained through
the review of electronic medical and imaging records.
The Table 9 below shows the distribution of breast cancer at the LAC-USC and Norris
cancer center by ethnicity in 2009.

50

Table 9: Distribution of Breast Cancer Patients Diagnosed in 2011 by Ethnicity –
Compared to the Hospital and Los Angeles County Populations

4.4 Statistical Analysis
The descriptive statistics were used for patient demographic, tumor, and clinical characteristics.
The associations between BRCA status, NIL, NIL cancer, and patient characteristics were
examined using Fisher’s exact test, Chi-square tests or logistic regression whenever appropriate.
All analyses were performed using SAS 9.3 (SAS Institute Inc. NC, USA). P values were two-
sided.
4.5 Results
A total 287 patients were included in the study. Of which, 237 patients are from the indigent
population of the Los Angeles county hospital, 50 patients are from the Norris cancer center.
67% were Hispanic, 17% Non-Hispanic White, 9%Asian, 5% African American, and 2% other
ethnicities. A total 34 (12%) patients were found to have a known deleterious BRCA1/2

51

mutation, 20 (7%) in BRCA1 and 14(5%) in BRCA2. 24 (8.4%) patients with BRCA1/2 mutations
were in Hispanic patients, similar proportion of all patients in this overall study population.
Median age at diagnosis of all patients was 42 years. There was no difference in median
age or stage at diagnosis based on BRCA mutation status.
There were 73 non-index lesions detected among which 38 were ipsilateral and 35 were
contralateral. Of the 38 ipsilateral lesions, 6 had only biopsy with no surgery and 28 underwent
surgery. 4 did not have any surgical procedure.13 of these ipsilateral lesions were found to be
occult cancers.
Among the contralateral lesions, 18 underwent only biopsy and 9 underwent surgery. 8
did not have any surgical procedure. 3 of these contralateral lesions were found to be occult
cancers.
Table 10: Demographic and Clinical Features of BRCA Tested Patients with Non-Index
Lesions and Occult Cancers
All BRCA 1 BRCA 2
Patients
with NILs
Patients
with OCs
N % N % N % N % N %
N 287 20 14 61 16
Age (Years)
Median (range) 42 43 45 42 41
19-34 43 15 5 25 1 7 11 18 4 25
35-39 64 22 2 10 3 21 12 20 2 13
40-44 80 28 5 25 3 21 16 26 5 31
45-54 61 21 7 35 2 14 15 25 3 19
55-77 39 14 1 5 5 36 7 11 2 13
Race/Ethnicity
White 50 17 3 15 1 7 8 13 1 6
Hispanic 193 67 14 70 10 71 42 69 13 81
Asian 25 9 3 15 3 21 8 13 1 6
African American 14 5 0 0 0 0 3 5 1 6
Others 5 2 0 0 0 0 0 0 0 0
Mammographic Density
Fatty 8 3 0 0 0 0 1 2 1 6
Scattered Fibroglandular 82 29 6 30 5 36 11 18 3 19
Heterogeneously Dense 183 64 13 65 9 64 44 72 12 75

52

Extremely Dense 14 5 1 5 0 0 5 8 0 0
Hormone Receptor
Positive 198 69 6 30 14 100 46 75 12 75
Negative 88 31 14 70 0 0 15 25 4 25
Unknown 1 0 0 0 0 0 0 0 0 0
Her-2 Status
Positive 58 20 2 10 0 0 11 18 2 13
Negative 200 70 16 80 13 93 42 69 11 69
Unknown 2 1 0 0 0 0 0 0 0 0
DCIS / N.A. 27 9 2 10 1 7 8 13 3 19
Triple Negative
Yes 56 20 13 65 0 0 10 16 3 19
No 226 79 7 35 14 100 50 82 12 75
Unknown 5 2 0 0 0 0 1 2 1 6
1st Relative Cancer
0 199 69 6 30 6 43 49 80 14 88
1 71 25 12 60 7 50 11 18 2 13
2 and 3 17 6 2 10 1 7 1 2 0 0
2nd Relative Cancer
0 211 74 10 50 7 50 42 69 11 69
1 61 21 7 35 6 43 15 25 4 25
2 and 3 15 5 3 15 1 7 4 7 1 6
Breast Surgery 252 11 9 52 14
Biopsy 27 11 1 9 2 22 6 12 1 7
Excision 96 38 2 18 3 33 15 29 3 21
Bilateral Excision 4 2 0 0 0 0 2 4 1 7
Mastectomy 118 47 8 73 3 33 26 50 7 50
Bilateral Mastectomy 7 3 0 0 1 11 3 6 2 14
Node Surgery 118 8 2 24 7
Node Surgery 116 98 7 88 2 100 24 100 7 100
Bilateral Node Surgery 2 2 1 13 0 0 0 0 0 0
Prophylactic Surgery 33 9 5 9 2
Excision 6 18 1 11 0 0 4 44 2 100
Mastectomy 27 82 8 89 5 100 5 56 0 0
Staging* 287 20 14 61 16
0 (DCIS) 26 9 0 0 1 7 7 11 0 0
I 66 23 3 15 4 29 14 23 3 19
II 108 38 11 55 6 43 27 44 9 56
III 79 28 5 25 2 14 12 20 4 25
IV 6 2 1 5 1 7 0 0 0 0
Unknown 2 1 0 0 0 0 1 2 0 0
* Neo-Adjuvant: Clinical Staging (N) 82 8 3 18 5
Lost to Follow-up: Clinical Staging (N) 10 1 1 3 0
Others: Pathological Staging (N) 195 11 10 40 11

53

The following pie charts, Figure 21 and Figure 22, show the distribution of biomarkers for
patients tested BRCA positive and negative (no mutation), respectively. Interestingly, most of the
patients (about 94%) tested BRCA positive have HER2 not amplified.

Figure 21: Biomarkers of Patients Tested BRCA Positive

Figure 22: Biomarkers of Patients with no BRCA Mutation

54

4.6 Discussion
We described this to be a unique cohort of an underserved and ethnically diverse, primarily
Hispanic population (66%) with preoperative MRI and BRCA testing data available in
LAC+USC and Norris Cancer Center in the past 4 years. Total 287 patient’s data were available.
Previous studies have shown the importance of MRI as a screening in women with BRCA
mutations. A prospective study done by Ellen et al, on 1275 women with BRCA1 or BRCA2 were
followed for a mean of 3.2 years. Of these 1275 patients, 445 were enrolled in an MRI screening
trial in Toronto, Ontario and 830 were in the comparison group (Ellen Warner et al, 2011). The
cumulative incidences of ductal carcinoma in situ (DCIS), early-stage, and late-stage breast
cancers were estimated at 6 years in the cohorts (Ellen Warner et al, 2011).
Below is the cumulative incidence of early-stage (stages 0 to I) breast cancer in magnetic
resonance imaging (MRI) – screened cohort and comparison group.

Figure 23: Cumulative Incidence of Early-Stage (0 and I) Breast Cancer in MRI

55

Figure 24: Cumulative Incidence of Stages II to IV Breast Cancer in MRI
Above is the cumulative incidence of stages II to IV breast cancer in MRI-screened cohort and
comparison group.
The cumulative incidence of DCIS or stage I breast cancer at 6 years was significantly
higher for the MRI-screened cohort (13.8%; 95% CI, 9.1% to 18.5%) than it was for the
comparison group (7.2%; 95% CI, 4.5% to 9.9%; P = .01; Fig x). In contrast, the cumulative
incidence of stages II to IV breast cancers at 6 years was lower for the MRI-screened cohort
(1.9%; 95% CI, 0.2% to 3.7%) than it was for the comparison group (6.6%; 95% CI, 3.8% to
9.3%; P = .02; Fig y) (Ellen Warner et al, 2011). This study shows that there was a decrease in
the incidence of advanced staged breast cancer in BRCA carrier women with breast cancer.
Per SEER report 2011, from 2004-2008, the median age for a breast cancer diagnosis was
61 years of age. Our study population is at relatively younger age. (Median age is 42). In
BRCA1 mutation positive patients, more women had triple negative and ER/PR negative cancer

56

compared to BRCA2 mutation positive patients. The result was consistent with previous study
which showed that there was a trend for ER and PR negativity to correlate with BRCA1
mutation, though not statistically significant (Kim, S., D. Rimm, et al. , 2003).
As mentioned in the (Timothy R. Rebbeck,Tara Friebel,, 2004), bilateral prophylactic
mastectomy reduces the risk of breast cancer in women with BRCA1/2 mutations by
approximately 90%. Among the 287 patients tested for BRCA mutation, there were 27
prophylactic mastectomies done which had 3 non-index lesions and 1 incidental cancer
diagnosed as DCIS. Prophylactic excisions were 6 with 3 non-index lesions. 1 Prophylactic
excision was done due to low BI-RADS on imaging (BI-RADS 3) and the remaining 5 were
biopsy benign. 12 were lost to follow-up and 11 are expected to undergo surgery, 2 of which are
scheduled for a prophylactic mastectomy.

Figure 25: Breast Cancer among BRCA1/2 Mutation Carriers with and without Bilateral
Prophylactic Mastectomy (BPM) PROSE Study Group

57

Table 11: Breast Cancer among BRCA1/2 Mutation Carriers with and without Bilateral
Prophylactic Mastectomy (BPM) PROSE Study Group
N BC cases
No BPM 378 184 (48.7%)
BPM 105 2 (1.9%)
BPM – 95% reduction w/ oophorectomy
BPM – 90% reduction w/ no oophorectomy

From the above Figure 25 and Table 11 we can conclude that bilateral prophylactic mastectomy
significantly reduces the risk of breast cancer in BRCA1/2 mutation carriers (Timothy R.
Rebbeck,Tara Friebel,, 2004).
Indications of prophylactic mastectomy set by the Society of surgical oncologists (2007):

In Patients without a Cancer Diagnosis
• High Risk BRCA mutations or other genetic susceptibility genes
• Strong family history with no demonstrable mutation
• Histological risk factors (ADH, ALH, LCIS)
• Difficult surveillance

ADH, ALH, LCIS are especially significant if present in a patient with a strong family history of
breast cancer. Special circumstances include:
• extremely dense fibronodular tissue that is difficult to evaluate with standard breast
imaging
• several prior breast biopsies for clinical and/or mammographic abnormalities
• strong concern about breast cancer risk

58

Selection Principles of prophylactic mastectomy set by the Society of surgical oncologists
(2007):
• Patient selection must be individualized
• Psychological evaluation critical
• Decision making should not be rushed
• Ultimately only the patient can decide
• Satisfaction over decision is generally very good and improves over time
• Sentinel node not indicated, but is + in 1-3% - might be lower with comprehensive pre-op
imaging.

There were 3 Non-Index lesions discordant for which findings showed negative on imaging and
biopsy was benign which was further excised.
4.7 Conclusions
Previous studies found the non-index ipsilateral additional foci of malignancy in 6-27% of
patients, and contralateral additional lesions in 3-9% of patients. The ipsilateral non-index lesion
rate in our population is 5.6% (38/668), at the lower side which is lower comparing other studies.
The contralateral non-index lesion rate is 5.2 % (35/668), which lower than previous studies. The
reason could be that median age of our patient population is a high risk underserved breast
cancer population with primary Hispanic, is lower than the median age of in general breast
cancer population, 42 vs. 61 years old.

59

Of the 16 occult cancer patients, 15 were BRCA negative while 1 occult cancer was
detected in a patient test with BRCA2. The P value of the association between the BRCA status
and MRI detected non-index lesions by the Fisher’s exact test is 0.12.
Due to the statistical insignificance, we think that MRI staging may be effective at
detecting additional cancers in this underserved diverse, largely Hispanic and high familial risk
population, despite of BRCA status.

60

Conclusions
In this ethnically diverse underserved population of patients with newly diagnosed breast cancer,
MRI detected non-index lesions and occult cancer in 21% and 8.4% of patients, respectively.
There were no factors that predicted a higher prevalence of non-index lesions or occult cancers
other than laterality (ipsilateral non-index lesions with a 4-fold higher chance of being an occult
cancer). About 40% of patients with lesions classified by MRI as suspicious were confirmed as
invasive or in-situ cancer.
Comparing the study in Chapter 4: with the main cohort in Chapter 3: we find that the
screening recommendations using MRI is no different for a BRCA tested population to detect an
occult cancer.
MRI staging appears to identify occult cancer to an equal extent in a largely Hispanic and
younger underserved population as reported in the literature for populations of mostly insured
Caucasian patients. Prospective trials and larger pooled retrospective analyses are needed to
define longer term benefits and specific populations that benefit from MRI staging after a
diagnosis of breast cancer.

61

Future Perspectives
Further studies for outcomes after long term follow up of the local recurrence rates or incidents
of contralateral breast cancer and survival benefits are needed to further evaluate how the
preoperative MRI affect the long term outcomes while the survival benefits may need a very
large patient population.
The present database will be updated regularly for further assessments and to re-analyze
the data with a larger sample size.

62

Presentations Related to This Thesis
Akshara Raghavendra, Charite Nicolette Ricker, Lingyun Ji, Terry Church, Sujie Tang, Linda
Larsen, Pulin Sheth, Debu Tripathy: “Clinical findings and outcomes from MRI staging of breast
cancers in women”, 2012 ASCO Annual Meeting, Chicago, IL, 2012.

Raghavendra A, Ji L1, Ricker C, Tang S ,Church T, Larsen L, Sheth P,Sposto R, Sener, S,
Tripathy D, “Clinical Findings and Outcomes from MRI Staging of Breast Cancer in a Diverse
Population”, San Antonio Breast Conference Symposium.

63

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Asset Metadata

Creator Singareeka Raghavendra, Akshara (author)

Core Title Magnetic resonance imaging (MRI) staging for breast cancer in a diverse population

School Keck School of Medicine

Degree Master of Science

Degree Program Clinical and Biomedical Investigations

Publication Date 07/23/2015

Defense Date 07/23/2013

Publisher University of Southern California (original), University of Southern California. Libraries (digital)

Tag breast cancer,MRI,OAI-PMH Harvest

Format application/pdf (imt)

Language English

Contributor Electronically uploaded by the author (provenance)

Advisor Tripathy, Debu (committee chair), Hovanessian-Larsen, Linda (committee member), Sheth, Pulin (committee member)

Permanent Link (DOI) https://doi.org/10.25549/usctheses-c3-297404

Unique identifier UC11295078

Identifier etd-Singareeka-1832.pdf (filename),usctheses-c3-297404 (legacy record id)

Legacy Identifier etd-Singareeka-1832.pdf

Dmrecord 297404

Document Type Thesis

Format application/pdf (imt)

Rights Singareeka Raghavendra, Akshara

Type texts

Source University of Southern California (contributing entity), University of Southern California Dissertations and Theses (collection)

Access Conditions The author retains rights to his/her dissertation, thesis or other graduate work according to U.S. copyright law. Electronic access is being provided by the USC Libraries in agreement with the a...

Repository Name University of Southern California Digital Library

Repository Location USC Digital Library, University of Southern California, University Park Campus MC 2810, 3434 South Grand Avenue, 2nd Floor, Los Angeles, California 90089-2810, USA