BRCA+Breast+Cancer

Eliana Kemper was diagnosed with breast cancer at the age of 37. Although she was devastated and scared, the diagnosis did not come as a total surprise to her, even at such a relatively young age. Eliana comes from a large Ashkenazi Jewish family, and she knew after watching her aunt and mother struggle with breast cancer that she might also be at risk. In 2006, she decided it was time to discuss her family history with a genetic counselor who encouraged her to get tested for possible //BRCA1// or //BRCA2// gene mutations. Her doctor told her that these genetic mutations are heritable and are more common in women with Ashkenazi Jewish ancestry than the general public, and that having either of these mutations greatly increases the risk of developing breast cancer.  When the DNA results came pack positive for the //BRCA1// gene mutation, Eliana took her chances and decided that all she could do was wait. Six years later, she was faced with the reality of taking on the same disease that had destroyed two of the most important women in her life.
 * I. An Ethnic Disease **

Depending on a woman’s age, different screening methods are used to monitor the effects of BRCA gene mutations and the potential development of a tumor in the breast. For example, it is recommended that women under the age of 25 with a //BRCA// mutation have annual clinical breast exams, women between 25 and 29 years old should have clinical breast exams every six to twelve months in addition to a yearly breast MRI, and women over the age of 30 should have supplemental mammograms once a year. All of these methods are very effective in screening for breast cancers, especially when a woman is aware of a hereditary condition that makes her predisposed to developing cancer.

 Her doctor explained to her that a normal functioning //BRCA1// gene is a tumor-suppressing gene that helps repress the cell cycle and can promote cell death if necessary. In the case of a potentially cancerous cell, the normal //BRCA1// gene would develop proteins that help prevent that cell from proliferating and developing a tumor. Although the //BRCA// genes are not the only biological measures in place to detect and prevent cancers in the human body, the suppressive nature of the subsequent proteins contributes to the effectiveness of their function. In Eliana’s case, however, this gene does not function properly and the cancerous cell is more likely to proliferate. The uncontrolled growth – due to the lack of suppressor proteins from the //BRCA1// mutation – of a mutated cell in her breast is what led to the development of the golf ball sized tumor that would now have to be dealt with.

 Breast cancer in general is the most commonly diagnosed cancer among women in the United States, with about 1 in 8 American women developing breast cancer over the course of her lifetime, and it is the second leading cause of cancer death in women.If those odds are not bad enough, around 55 to 65 percent of women who inherit a harmful //BRCA1// mutation will develop breast cancer by age 70.Together, //BRCA1// and //BRCA2// mutations account for about 20 to 25 percent of hereditary breast cancers and about 5 to 10 percent of all breast cancers. The stage of breast cancers are based on the size of the tumor, whether the cancer is invasive or non-invasive, whether the cancer is in the lymph nodes, and whether the cancer has spread to other parts of the body beyond the breast. Stage is usually expressed as a number on a scale of 0 through IV — with stage 0 describing non-invasive cancers that remain within their original location and stage IV describing invasive cancers that have spread outside the breast to other parts of the body.

 There is no known cure for breast cancer; however, treatment success has greatly improved in the last few decades. Death rates from breast cancer have consequently been declining (falling to about 3 percent), with larger decreases in the rates for women younger than 50, like Eliana. These decreases are believed to be the result of earlier detection through screening and increased awareness, as well as the improved treatment and technologies. Usually, especially if the lump is caught early, women with breast cancer go on to live full, healthy lives after treatment. However, breast cancer is not always caught early enough for women to have this chance at recovery. Even though //BRCA// gene mutation breast cancers are not necessarily more aggressive than other types of breast cancers, there must still be an immediate response and plan of attack. Luckily in Eliana’s case, the cancer was caught relatively early and immediate action could take place.

 Breast cancers in women with a harmful //BRCA1// mutation are more likely to be triple-negative cancers, meaning that the breast cancer cells do not have estrogen receptors, progesterone receptors, or large amounts of the HER2/neu protein from the epidermal growth factor receptor oncogene. These triple-negative cancers generally have a poorer prognosis than other breast cancers because they are more difficult to treat. Because the products of the //BRCA1// and //BRCA2// genes are involved in DNA repair, some researchers have hypothesized that cancer cells with a harmful mutation in either of the //BRCA// genes may be more sensitive to anticancer treatment options, such as the drug Cisplatin, that act by damaging DNA. In preclinical studies, drugs called poly ADP ribose polymerase (PARP) inhibitors, which block the repair of DNA damage, have been found to arrest the growth of cancer cells that have //BRCA// mutations. These drugs have also shown some activity in cancer patients who carry //BRCA// mutations, and researchers are continuing to develop and test these drugs.

 Optimistically, Eliana will be able to make a recovery with the available treatment options. Hopefully in the near future more successful anticancer treatments will be made available for women with the harmful //BRCA1// and //BRCA2// gene mutations.

 **II. Treatment **

Diagnosing the stage of breast cancer can help determine the most effective treatment options available. After Eliana’s diagnosis of stage IIB breast cancer at age 37 caused by a hereditary //BRCA1// gene mutation, treatment options were immediately discussed with her physician. Stage IIB breast cancers are categorized as a tumor in the breast that either greater than 5 centimeters but no lymph nodes involved, or a tumor between 2 and 5 centimeters with lymph nodes involved. Since her specific cancer was caused by a mutation in the //BRCA1// gene, the cancer’s growth is not fueled by the hormone estrogen and has a “high-grade” cell growth. High-grade cells look very different from normal cells and grow quickly in disorganized, irregular patterns, with many dividing to make new cancer cells. These characteristics mean that chemotherapy would be more effective than hormonal (anti-estrogen) therapy in treating her cancer.

Women with a //BRCA// gene mutations also have to be aware of the possibility of developing a new, second breast cancer or ovarian cancer. This is because women with breast cancer and a //BRCA// gene abnormality have a significantly higher risk of developing an additional cancer in their breast or ovaries. Studies have shown that the 10-year survival rate among women with breast cancer due to a //BRCA1// mutation is similar to that of breast cancer patients without a //BRCA1// mutation. According to these studies, survival rates of women with a //BRCA1// mutation can be greatly improved after an oophorectomy, or surgical removal of the ovaries.

Due to the specific nature of Eliana’s cancer, a more specific route of treatment will significantly increase her chances of survival and recovery. Her triple-negative breast cancer (estrogen receptor-negative, progesterone receptor-negative, and HER2/neu-negative) means that the options of hormonal therapy and the drug Herceptin are out of the question. In the case of an estrogen receptor-positive breast cancer, hormonal therapies including reducing the amount of estrogen or blocking its action would be more effective because the estrogen is the reason the breast cancer is growing. In estrogen receptor-negative breast cancers (like triple-negative types), blocking or decreasing the amount of estrogen is not effective because estrogen does not play a role in the growing cancer. Therefore women with triple-negative breast cancers, like Eliana, are usually treated with some combination of surgery in the form of a mastectomy or lumpectomy, radiation therapy, and chemotherapy. Additionally, her stage IIB cancer would have to be treated with a lymph node biopsy and radiation to supraclavicular and internal mammary lymph nodes. These treatment options can be very successful for breast cancer patients diagnosed with stage II cancer, with a five-year survival rate of 93% after treatment.

 The genes linked to triple-negative tumors are not well understood at this time and thus, targeted therapies do not yet exist. However, potential targets for future therapies include the EGF receptor, Alpha B-crystallin protein, and cyclin E. A study found that more than 25% of people with an abnormal //BRCA// gene being treated for advanced-stage breast, ovarian, pancreatic, or prostate cancer got some benefit from Olaparib, an experimental targeted therapy medicine that inhibits the poly ADP ribose polymerase (PARP) enzyme, a protein involved with DNA repair and programmed cell death. Research in the lab on cancer cells with an abnormal //BRCA// gene showed that the cells were 1,000 times more sensitive to PARP inhibition than cancer cells that did not have an abnormal //BRCA// gene. A PARP inhibiting drug like Olaparib would be useful in causing rapidly dividing cancer cells to undergo cell death due to mutagenic breaks in the double stranded DNA. Based on those results, the researchers felt that treating cancers in people with an abnormal //BRCA// gene with Olaparib would probably be effective.

Although Olaparib warrants further investigation in confirmatory studies, it seems to be very promising in clinical trials with a focus on treating breast and ovarian cancers caused by //BRCA// mutation. These types of studies suggest that adding the experimental targeted therapy Olaparib to a taxane chemotherapy drug such as Taxol or Abraxane may be very effective against triple-negative breast cancers. Since this drug had not yet been proven to be effective and safe, Eliana’s doctor recommended that she stick with the common and relatively safe treatment of mastectomy, radiation therapy, and chemotherapy to tackle her //BRCA1// mutation breast cancer, even though she qualified for the clinical trials based on her cancer type and stage, as well as her age and genetics. If the cancer came back after the standard treatment, or if she were to develop ovarian cancer as a result of the //BRCA// mutation, the drug Olaparib might become an important element in her continued treatment.

** III. The Molecular Basis **

The particular molecular basis of the BRCA1 gene and the function of the protein that it codes for directly effect the development of the cancer as well as treatment success. BRCA1 is a human tumor suppressor caretaker gene found in all humans. Caretaker genes encode products that stabilize the genome. Mutations in ca retaker genes, like the //BRCA1// gene, can lead to genomic instability and the growth of tumor cells. The protein that the //BRCA1// gene codes for, the BRCA1 protein, is responsible for repairing DNA when it has become damaged due to a mutation or for destroying cells if the DNA cannot be repaired. They are involved in the repair of chromosomal damage with an important role in the error-free repair of DNA double-strand breaks. If the protein itself is nonfunctional, damaged DNA cannot be repaired properly due to the mutation in //BRCA1//, therefore increasing the risk for developing breast cancer. In addition to repairing damaged or broken DNA, the BRCA1 protein also plays a role in enzymatic processes, transcriptional regulation, and other molecular functions. The strands of the DNA double helix are continuously breaking as they incur damage. Sometimes one strand is broken, and sometimes both strands are broken simultaneously. DNA cross-linking agents are an important source of chromosomal or DNA damage, of which the BRCA1 protein acts as a repair mechanism. When both strands of DNA are broken, it is difficult for the repair mechanism to know how to replace the correct DNA sequence, and there are multiple ways to attempt the repair. One double-strand repair mechanism that the BRCA1 protein participates in is homologous recombination. Through this mechanism, the repair proteins utilize an intact sequence from a sister chromatid, from a homologous chromosome, or from the same chromosome – depending on cell cycle phase – as a template for repair and recoding. The normal functioning protein is also involved in another type of DNA repair, called the mismatch repair mechanism. The BRCA1 protein interacts with the DNA mismatch repair protein MSH2, another tumor suppressor protein, to recognize and repair erroneous insertions, deletions, and wrongful incorporation of bases that can arise during DNA replication and recombination.

Certain variations of the //BRCA1// gene lead to an increased risk for breast cancer as part of the hereditary breast-ovarian cancer syndrome that Ms. Kemper was diagnosed with. Researchers have identified hundreds of mutations in the //BRCA1// gene, many of which are associated with an increased risk of cancer. A mutated //BRCA1// gene usually makes a protein that does not function properly. Researchers believe that a defective BRCA1 protein is unable to help fix DNA damages leading to mutations in other genes. These mutations can accumulate and may allow cells to grow and divide uncontrollably to form a tumor, the first hallmark of cancer. Due to the uncontrolled cell growth and proliferation, the size of the tumor continues to grow. In this particular case, Ms. Kemper's stage IIB tumor can be treated with chemotherapy and targeted radiation and removed through a surgical double mastectomy.  Because of the nature of this BRCA1 cancer, her doctor recommended a double mastectomy due to the increased likelihood of developing a secondary cancer in her other breast.

The process of DNA replication inherently places cells at risk of acquiring mutations. Thus, caretaker genes are vitally important to cellular health. Rounds of cell replication allow fixation of mutated genes into the genome. Caretaker genes provide genome stability by preventing the accumulation of these mutations. Factors that contribute to genome stabilization include proper cell-cycle checkpoints, DNA repair pathways, and other actions that ensure cell survival following DNA damage. Specific DNA maintenance operations encoded by caretaker genes, like //BRCA1//, include nucleotide excision repair, base excision repair, non-homologous end joining recombination pathways, mismatch repair pathways, and telomere metabolism. All of these functions are essential to normal cell development and replication. When the BRCA1 protein does not operate properly due to a mutation, it may not be able to perform all of its caretaker properties and can lead to the progression of various forms of the breast cancer. In most cases, including Ms. Kemper’s cancer, it is often unclear which of these functions are not working properly or are overactive due to the mutation, therefore making it more difficult to treat.

<span style="color: #403838; font-family: Arial,Helvetica,sans-serif; font-size: 10pt;">BRCA1 mutant breast tumors are typically estrogen receptor negative, whereas most sporadic tumors express wild-type BRCA1 and are estrogen receptor positive, which is why hormonal therapies are not appropriate for treating those kinds of cancers, including Ms. Kemper’s triple-negative (ER-, PR-, HER2-) breast cancer. There are several mechanisms that cause the observed estrogen receptor-negative phenotype of BRCA1 mutant tumors (Figure 1). Studies suggest that mutant BRCA1 tumors fail to express estrogen receptors due to the loss of BRCA1-mediated transcriptional activation of estrogen receptor 1 (ESR1). The reduced BRCA1 expression in these types of cancer is also associated with estrogen receptor negativity. It is hypothesized that the loss of the wild-type BRCA1 allele, which occurs during neoplastic development in BRCA1 mutation carriers, has a direct effect on ESR1 transactivation, resulting in the loss of estrogen receptors and protein expression. Ms. Kemper’s triple negative breast cancer made the tumor slightly more difficult to treat due to the fact that hormone therapies are ineffective, but the proper surgical procedure, radiation, and chemotherapy should successfully remove it and prevent it from returning. <span style="font-family: Arial,Helvetica,sans-serif; font-size: 9pt;">Figure 1: A model of the sequence of events leading to estrogen receptor alpha (ERα) deficiency in BRCA1 mutated tumors and sporadic tumors. A complete loss of BRCA1 function in sporadic breast cancers would result in tumors that are ERα negative.

<span style="color: #403838; display: block; font-family: Arial,Helvetica,sans-serif; font-size: 13.3333330154419px; text-align: justify;"> <span style="color: #403838; font-family: Arial,Helvetica,sans-serif; font-size: 10pt;">After months of dealing with the side effects and grueling aspects of disease, the prescribed treatment regimen proved successful for Eliana. She fortunately remains cancer free to this day. Although BRCA1 breast cancer is a rare heritable form of breast cancer that only affects a small percentage of women, it is still important to continue research and clinical trials. Further development in treating hereditary cancers will make options more accessible and appropriate for patients like Ms. Kemper. Better genetic testing and more effective treatment methods in the near future might be useful for treating other cancers, including breast and ovarian cancers, that affect a much larger percentage of the population. Like in Eliana’s case, there are many treatment and support options for women with BRCA mutations and breast cancers. It is essential to remember that not all cancers or patients are the same, and that ultimately the patient’s life lies in their own hands. _____________________________________________________________________________________________________________

Breast cancer is a difficult disease that does not have just one cause. With that in mind, there are many successful preventative measures and treatment options that save lives every day.