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BRCA Mutation Carriers: Breast and Ovarian Cancer Screening

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BRCA Mutation Carriers: Breast and Ovarian Cancer Screening ello. This is Dr. David Bluemke in Madison, Wisconsin. I’m the Editor of the journal Radiology. This is part one of our June, 2019 podcast. The goal of these podcasts is to present a brief summary of key research in our field to keep you up-to-date. Today we will have one review article and three research Harticles. So let’s proceed to today’s topics. BRCA Mutation Carriers: Breast and Ovarian Cancer Screening Guidelines and Imaging Considerations Radiology 2019; 291:554–569 Mai Elezaby, MD • Brittany Lees, MD • Katherine E. Maturen, MD, MS • Lisa Barroilhet, MD • Kari B. Wisinski, MD • Sarina Schrager, MD • Lee G. Wilke, MD • Elizabeth Sadowski, MD e will start with an article about genetically determined cancer. BRCA3 gene as well, but the genetic location has not been determined. A few The title is BRCA Mutation Carriers: Breast and Ovarian Cancer other facts: these gene mutations are autosomal dominant. Children have a 50 WScreening Guidelines and Imaging Considerations. The first author percent chance of receiving the same gene mutation from their parents. The is Dr. Mai Elezaby. The senior author is Dr. Elizabeth Sadowski from the gene mutation abnormality in the general population is relatively low, about University of Wisconsin. Background: Let’s start with the background on one in four hundred. But it is one in forty individuals with Ashkenazi Jewish genetic abnormalities associated with breast and ovarian cancer. There are ancestry. There are other founder mutations with these same gene abnormali- two genes that we associate with breast cancer. These genes are BRCA1 and ties in a range of populations including those of Dutch, Spanish, and German BRCA2. The abbreviation BRCA stands for breast cancer. Radiologists are heritage. Next: How do we screen for cancer for patients with these gene mu- not geneticists but still know that genes are there for a reason. Genes do tations? What are the current screening guidelines? Patients who test positive not normally cause cancer. There are more than 30,000 human genes and for BRCA1 or 2 mutation are recommended to have imaging with MRI and the BRCA1 gene is supposed to encode a normal protein just like our other mammography every twelve months starting as early as age 25. Bilateral pro- 30,000 genes. Normally, BRCA1 and 2 genes each produce a different pro- phylactic mastectomy may be offered to reduce the risk of breast cancer by 95 tein that is involved in repairing damaged DNA. Or, if the DNA cannot be percent. Two national societies also recommend that women have prophylactic repaired properly, the protein participates in destroying the damaged cell. Ei- bilateral ovarian removal after child bearing or after about age 35. Patients ther one or both strands of the double stranded helix of DNA are constantly who have not had ovarian resection are screened regularly for serum CA125 being broken so repair is essential. If both DNA strands are broken, the repair levels and with pelvic ultrasound. A little detail about breast cancer expres- process is difficult. This is when the BRCA protein is especially needed. So sion; in BRCA1 mutation the most common cancer is poorly differentiated we need the BRCA protein, but if there is a mutation in the BRCA gene so infiltrating ductal carcinoma. Many tumors are triple negative, estrogen re- that a damaged BRCA protein is made then double stranded DNA will not ceptor and progesterone receptor negative with low HER2 overexpression. be repaired. This results in increased risk for breast cancer. Of course we have These types are the most resistant to treatment. For BRCA2 breast cancer, two copies of every gene, but having only one damaged gene is enough to be those do not have a specific subtype but appear more like tumor types in the associated with cancer. As of 2015, there were only two living adults known general population. DCIS is also more common with BRCA2, but not with to have both BRCA genes that were damaged. Both of those adults had con- BRCA1. Breast MRI is the most effective screening method. At a young age, genital or developmental problems as well as cancer. Even though we are not 25 or 30 years, breast density may be high and tumors difficult to identify genetics experts we still have to use the correct terms. We do not say that a by mammography. But the sensitivity for MRI for tumors in these patients patient has a BRCA gene. Everyone has BRCA1 and BRCA2 genes. Instead, is greater than 90 percent. I was a researcher in a breast cancer screening trial we should say that a patient has a BRCA1 or 2 gene mutation, but there is no with MRI that we published in this journal in 2007 involving about 200 single mutation in the BRCA1 gene that causes cancer. The DNA for BRCA1 patients. The sensitivity of MRI in our study was 100 percent. One feature has about 80,000 base pairs. More than 1800 different mutations of that gene I recall when doing research about MRI in breast cancer, these were the only have been identified. Hundreds of those mutations are known to cause cancer research studies I ever did where recruitment finished earlier than expected. in both men and women. The gene that encodes for the BRCA protein to Normally, recruiting patients took forever and took tremendous effort and repair damaged DNA was discovered at UC Berkley in 1990. BRCA is located advertising. Not for breast cancer in MRI. Patients wanted to and needed on chromosome 17. Besides breast cancer, BRCA1 and 2 are also famous genes to participate. For BRCA1 and 2, the sensitivity of mammography is only because a company called Myriad Genetics patented the methods for detecting about 30 or 40 percent. But the combination of MRI and mammography mutations in these genes in 1994. However, the United States Supreme Court identifies the majority of tumors. One approach is to alternate screening with invalidated the patents in 2013 indicating that a naturally occurring DNA mammography followed by MRI six months later. Now what do these tu- segment is a product of nature and not patent eligible merely because it has mors look like? BRCA associated breast cancers can be overlooked because been isolated. Now what about breast cancer and ovarian cancer? In round they more often look round or oval versus the spiculated irregular appearance numbers about five percent of all women with breast cancer have a mutation of invasive breast cancer. A first year resident could mistake the tumor for a in BRCA1 or BRCA2. For ovarian cancer, BRCA1 mutations are present in fibroadenoma. However on MRI, fibroadenoma has non-enhancing septa- about 18 percent of individuals. People with these genes have an accumulation tions, but BRCA associated tumors do not have those septations. Regarding of damaged DNA. If an individual has a BRCA1 mutation the risk of breast ultrasound; ultrasound is not recommended as a screening modality for these cancer is 90 percent and 50 percent for ovarian cancer over their lifetime. For patients. Ultrasound is not as effective as MRI. What about ovarian cancer? BRCA2 the risk of breast cancer is about 50 percent and 20 percent for ovarian The most common pathologic type is high-grade serous carcinoma for both cancer. The risk is highest at young age, less than 50 years old. There are other BRCA1 and 2 mutations. This is also the most common type of epithelial cancers that cluster with these gene mutations. These are pancreatic cancer, ovarian cancer in the general population. The tumors are high grade with melanoma, and prostate cancer in men. Finally, researchers believe there is a short doubling times and are aggressive with poor survival rates. Can we find .
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