Genetic Alterations in MRI Screen-Detected Breast Lesions

Institution: Stanford University
Investigator(s): James Ford, M.D. - Sylvia Plevritis, Ph.D. -
Award Cycle: 2002 (Cycle VIII) Grant #: 8DB-0153 Award: $145,649
Award Type: TRC Pilot Award
Research Priorities
Biology of the Breast Cell>Biology of the Normal Breast: the starting point



Initial Award Abstract (2002)
The genetic events that underlie the progression of normal breast tissue to that of increasingly malignant potential remain poorly understood. In our laboratory, we recently discovered that the tumor suppressor gene BRCA1 may be critical to this process by regulating DNA repair and genomic stability. We now propose a research project to translate our laboratory findings to the clinic. We propose to examine specific genetic events that may be critical to the development and progression of malignancy in women at high risk for breast cancer due to inherited BRCA1 mutations. We are particularly concerned about the malignant potential of breast lesions that are detected on an MRI screening examination and shown to be histopathologically benign. We suspect that these lesions may have undergone premalignant genetic changes. To address this concern, we propose collaborative program that brings together clinical investigators with expertise in MRI breast screening and basic science investigators with expertise in the DNA repair genes and genomic stability.

In this pilot study, we propose to test the central hypothesis that benign breast lesions that are screen-detected on MRI have already undergone specific genetic alternations that may be associated with breast carcinogenesis. If we find evidence of this effect, we will pursue a longer-term follow-up study where we hope use these preliminary results to identify the specific multi-step genetic alternations that underlie the progression of normal breast tissue to premalignant and malignant breast disease.

Women will be recruited from Stanford's Breast Cancer Genetics Clinic which draws patient from the culturally diverse San Francisco Bay Area. Women who test positive for the BRCA1 mutation will be invited to our study. To test our central hypothesis, we will analyze benign breast lesions, premalignant and malignant lesions that are screen-detected by MRI and determine if these lesions contain mutations in the tumor suppressor genes BRCA1 and p53. Among lesions that have undergone these additional genetic mutations, we will analyze them for changes in the expression levels of DNA repair genes that are regulated by the BRCA1 and p53 genes.

We aim to be the first to analyze the DNA repair genes of benign breast lesions screen-detected by MRI. Demonstrating these premalignant events may have two significant long-term outcomes. First, our work could become the basis that makes MRI screening for premalignant disease more clinically relevant. Second, our work may reveal specific genetic events in breast carcinogenesis that may be critical in breast cancer risk reduction and prognosis.


Final Report (2003)
The genetic events that underlie the progression of normal breast tissue to cancer remain poorly understood. Inherited mutations in the BRCA1 tumor suppressor confer a 50-85% lifetime risk of developing breast cancer. Cancers that have mutations in the BRCA1 gene frequently have alterations in the p53 gene, another tumor suppressor gene that is critical in maintaining healthy, non-cancerous cells. In our laboratory, we recently discovered that the BRCA1 gene regulates a specific kind of DNA repair, called nucleotide excision repair, that when not functioning properly may cause breast cancer. This pathway repairs DNA that has been damaged by environmental insults such as tobacco smoke, ultraviolet-irradiation, and by-products from combustible gasoline.

We performed a pilot research project to translate our laboratory findings to the clinic by examining specific genetic events that may be critical to the development and progression of malignancy in women at high risk for breast cancer due to inherited BRCA1 mutations. We laid the groundwork to study the potential of pathologically benign breast lesions that were detected on an MRI screening examination to become cancer, by examining them for specific genetic alternations in the nucleotide excision repair pathway. MRI is a highly sensitive technique to detect early high-risk lesions in women at elevated risk for breast cancer.

Forty-six women were recruited from Stanfordís Breast Cancer Genetics Clinic to this study. Twenty-four have tested positive for BRCA1 mutations, and the others have a calculated risk of developing breast cancer based upon their family history of greater than 10%. All women have undergone biannual clinical breast exams, annual mammograms and breast MRI. Of this group, 13 patients had biopsies of suspicious lesions. One proved to be high-grade DCIS missed on mammography, and the patient subsequently underwent bilateral mastectomy. Two other biopsies were consistent with radial scars, and 3 biopsies showed atypical lobular hyperplasia. Normal and malignant portions of these tissues have been frozen for future molecular studies. We have developed improved methods in the laboratory toward analysis of DNA repair.

To test our central hypothesis, we will analyze these tissues for mutations in the tumor suppressor genes BRCA1 and p53. Among lesions that have undergone these additional genetic mutations, we will analyze them for changes in the expression levels of DNA repair genes involved in the nucleotide excision repair pathway that are regulated by the BRCA1 and p53 genes. Our study has already shown that MRI can identify early cancer and high-risk lesions at a higher rate than exam or mammography in this population. During the next phase of this project, we will use a novel method for whole genome LOH analysis, Molecular Inversion Probe, to study the underlying genetic alterations.

We believe that many breast cancers may follow a similar pathway to disease as those in the high-risk population. Analyzing breast lesions from women in our pilot study could lead to a better understanding of the progression of breast cancer in all women.


Symposium Abstract (2005)
Allison W. Kurian M.D., Anne-Renee Hartman M.D.*, Bruce L. Daniel M.D., Meredith A. Mills B.A., Kent W. Nowels M.D., Margo Jaffee B.A.*, Nicolette M. Chun M.S., Kerry E. Kingham M.S., Frederick M. Dirbas M.D., Robert J. Herfkens M.D., Laura C. Collins M.D.*, Judy E. Garber M.D.*, Sylvia K. Plevritis Ph.D., James M. Ford M.D.

Stanford University and *Dana-Farber Cancer Institute

GOAL: To evaluate the combination of two emerging breast cancer screening techniques, breast magnetic resonance imaging (MRI) and ductal lavage (DL), for early detection of breast cancer in high-risk women

BACKGROUND: About 9,000-18,000 breast cancer cases yearly in the United States (U.S.) are attributable to high inherited risk; greater than 500,000 people in the U.S. carry such risk. Screening mammography often performs poorly in high-risk women, and the only proven method of breast cancer prevention is prophylactic mastectomy. There is an urgent need for more effective and tolerable methods of breast cancer screening and prevention in this population; moreover, techniques found to be effective in high-risk women may benefit those at lower risk.

METHODS: 122 women with high inherited breast cancer risk, either because of an inherited mutation in the cancer susceptibility genes BRCA1/2, p53, or CDH1, or because of a strong family history, were enrolled in a protocol of yearly breast MRI, mammogram, and DL, with clinical breast examination (CBE) semi-annually. Women were advised to perform breast self-examination monthly. Follow-up MRI or mammograms were performed at 6 months if abnormal results were found on prior imaging or DL. A questionnaire was administered to assess patient tolerance of this protocol.

RESULTS: 118 women have undergone at least one round of screening, resulting in 35 breast biopsies in 28 women. Five malignant lesions have been found: 3 cases of high-grade ductal carcinoma in situ (DCIS) found by MRI only, and 2 invasive breast cancers, one by mammogram only and one by CBE only. There was a trend toward a lower positive predictive value of MRI in women who underwent treatment likely to reduce breast cancer risk (0% vs. 30%, p=0.07). DL was attempted in 79 women, and succeeded in 64 (81% [71.0- 88.3%]). Atypical cells were found in 18 women (28.1% [18.9-40.3%]), and were more common from ducts which did not produce fluid (72.2% vs. 27.8%, p=0.02). In one woman, atypical cells on DL prompted a follow-up MRI and subsequent breast biopsy, yielding high- grade DCIS. This protocol was well tolerated, with 85.3% (p=0.017) willing to continue after at least one round of screening.

POTENTIAL IMPACT AND FUTURE RESEARCH: Breast MRI screening can find early malignant lesions, including DCIS, in high-risk women; however, it has a high false-positive rate, especially in women whose risk has been somewhat reduced. Longer follow-up is necessary to determine the clinical significance of atypical cells on DL. Future study will include 1) optimization of MRI screening guidelines, incorporating patient preferences, through computer modeling and 2) exploration of breast duct cell analysis for studies of risk assessment and chemoprevention.

Breast magnetic resonance image screening and ductal lavage in women at high genetic risk for breast carcinoma.
Periodical:Cancer
Index Medicus: Cancer
Authors: A Hartman, B Daniel, A Kurian, M Mills, K Nowels, F Dirbas K Kingham N M. Jim Ford
Yr: 2004 Vol: 100 Nbr: 3 Abs: Pg:479-489

Comprehensive screening using breast MRI and ductal lavage in high-risk women. San Antonio Breast Cancer Symposium.
Periodical:Breast Cancer Research and Treatment
Index Medicus: Breast Cancer Res Treat
Authors: Hartman AR, Daniel BL, Ford JM, Chun NM, Kingham KE, et al
Yr: 2002 Vol: 76S1 Nbr: Abs: Pg:618