Onye+Okolo

= Joy's Unwanted Inheritance: A Battle With Breast Cancer =

**The Cancer**
Joy Uzoechi is 66 year old woman who was born and raised in the city of Umuahia, capital of Abia state in southern Nigeria. She pursued a career in education and became a secondary school teacher, the equivalent to middle school in the United States. Joy raised three children: two daughters and a son, all of whom were able to make their way to the United States. After successfully getting a visa, Joy moved in with her oldest daughter, Felicity, and helped to raise her two children. One day, Joy took notice of a growing sharp pain around the area of her breasts, a pain which she disregarded assuming it was a symptom of her old age. But her daughter was finally able to convince her to see a doctor in order to identify the cause of the discomfort. Her doctor conducted a mammogram and found a fairly large lump in her breast. The proceeding needle biopsy confirmed that what she believed to be a minor issue revealed itself to a larger problem. Joy had been diagnosed with stage IIIA triple negative breast cancer (TNBC). TNBC, a cancer that originates within the milk ducts of the breasts, is the most common form of breast cancer and accounts for approximately 80% of existing breast cancer cases. What makes the cancer unique is the fact that it is negative for estrogen and progesterone receptors and does not overexpress the HER2 gene. She had one tumor, about 6 cm in diameter in the left breast, with cancer cells located in 4 other lymph nodes in her underarm. The cancer located in the lymph nodes caused them to swell, which is what caused her initial discomfort. If she had been receiving checkups fairly regularly, the cancer could have easily been spotted in its earlier stages, in contrast with a similar cancer, invasive lobular carcinoma (ILS). Originating within the milk producing glands, ILS has a lower detection rate. In terms of severity of the cancer, stage IIIA TNBC has a fairly high survival, with about 77 percent of women living 5 years after their diagnosis, as well as a very low percentage of recurrence or metastasis 5 years after treatment.

Joy’s doctor asked her a few questions of her family's cancer history. She revealed that she had an aunt who had died of breast cancer, and was then screened for mutations in the genes BRCA1 and BRCA2, and a mutation was found in the BRCA1 gene. BRCA1 and 2 are genes that produce tumor suppressing proteins. When these genes are mutated, cells are more likely to develop genetic alterations which lead to cancer later on. Mutations in these genes have been shown to be hereditary and increase the likelihood that an individual would develop breast cancer, with BRCA1 and 2 accounting for 20 to 25 percent of hereditary breast cancers when these genes are mutated and a vast majority of the breast cancers that arise due to this mutation are also triple negative. The mutation in Joy’s BRCA1 gene most likely had nothing to do with her ethnicity, seeing as women of African and non-European descent have been shown to have similar rates of harmful BRCA1/2 mutations as those of European descent. . As a disease of old age, Joy’s likelihood of developing cancer increased as she continued to get older and accumulate more mutations.

Although shaken by the revelation of her disease, Joy did not despair about her situation. She was grateful that the disease was caught before it could progress further and cause complications, and on paper, her condition as it stands was very treatable. Above all she was grateful for the support that she had from her family, both in the US and in Nigeria, and she had faith that God would carry her through.

**Molecular Basis**
Breast cancer, like all cancers, is a multistep process, and as such, discovering the exact etiology of the cancer comes with a lot of difficulty. Most of these ductal carcinomas, however, have a similar sequence of stages that lead them to become invasive. A mutation leads to the development of an atypical ductal hyperplasia, which is just some sort of irregular growth within the ducts of the breast. This proliferative growth eventually develops into a ductal carcinoma in situ, a non-invasive tumor, which grows further before finally invading the surrounding lymph nodes in the breasts and underarms.

Similarly, most breast cancers have a mutation in the p53 gene. P53 is a protein that acts largely as a transcription factor and can trigger a variety of anti-proliferative programs by activating or repressing key effector genes. In the presence of particular extracellular signals, such as those released in response to DNA damage, p53 is phosphorylated by various other kinases. From there the protein “decides” whether to repair the DNA, arrest the cell cycle, render the cell senescent, or trigger a programmed cell death, also called apoptosis. With a mutation in p53, these functions are interrupted, and the cell loses a vital mechanism for handling extracellular stresses. The deactivation of p53 is a method by which the cancer evades growth suppressors in the body.

Unfortunately, Joy’s breast cancer isn’t like a typical case of IDC. Hers was caused by a mutation in the BRCA1 gene, which is a hereditable mutation that increases the likelihood of developing cancer: BRCA1 carriers have a 55-65% chance of developing breast cancer by age 70 and cancers caused by this mutation account for only 10% of all breast cancer cases. BRCA1 is located on chromosome 17, and genetic mutations in the gene vary from individual to individual. However, many of these genetic changes in cancerous BRCA1 tumors are loss-of-function mutations. BRCA1, along with BRCA2, are “caretaker” genes that help in sensing and repairing DNA damage, keeping mutations at bay, as well as other regulatory roles which all aid in the suppression of tumors, such as telomerase metabolism. Mutations in BRCA1, which are commonly loss-of-function mutations, prevent the gene from working correctly.

BRCA1 tumors usually tend to also be negative for estrogen receptor alpha, while many sporadic tumors with wild type BRCA1 genes contain the estrogen receptor. Estrogen receptors as well as progesterone receptors on breast cancer tumors signify its need of these hormones to grow, which makes them common targets for breast cancer drugs, such as tamoxifen and aromatase inhibitors. These drugs work by disrupting various estrogen pathways: tamoxifen selectively binds to estrogen receptors while aromatase inhibitors block the activity of the enzyme aromatase, which the body uses to make estrogen. A recent study has shown that the lack of estrogen receptors might be caused directly by the BRCA1 mutation in the cells, which might be due to the fact that BRCA1 has some regulatory control over the presence of these receptors. This hypothesis is further solidified by the fact that estrogen receptor expression levels increased significantly after BRCA1 expression was reconstituted in the cells by transfecting the defective cell with a cell with wild-type BRCA1 gene. Unfortunately, the lack of those receptors makes the cancer more difficult to target. It is a fairly common occurrence to see a BRCA1 breast cancer that is negative for the usual receptor targets; estrogen, progesterone, and HER2, also known as triple negative breast cancers.

**Treatment**
Cancer treatment can oftentimes be akin to stumbling through the dark, oftentimes with only a slight idea of the intended target. Unfortunately for Joy, the nature of her cancer makes the target even less obscure. Due to the nature of her triple negative breast cancer Joy has a more limited set of treatment options than other breast cancer subtypes. Joy would not benefit from any sort of hormone therapy, because the tumors are negative for any of the usual hormonal targets. The best treatment method for her specific stage of cancer requires either a mastectomy (removal of the breast) or a lumpectomy (removal of the tumor and some surrounding tissue). Along with the removal of the tumor, the removal of axillary lymph nodes will be required, since the cancer was able to spread to a few of her lymph nodes. Chemotherapy can be administered before or after surgery, and many cases will be a combination of different drugs. A common chemotherapy for breast cancer is a combination of doxorubicin and cyclophosphamide followed by paclitaxel. Joy would also undergo radiation therapy as well, due to the size of her tumor and the spread of the cancer to lymph nodes around her breast. Women with a BRCA gene mutation are also much more likely to develop a recurring breast or ovarian cancer, so patients can opt for a double mastectomy and/or oophorectomy, removal of the ovaries, to further reduces the chances of a recurring cancer.

In terms of efficacy, I believe that the safest bet would be proceeding with the double mastectomy over a lumpectomy, because at this point Joy’s cancer is approaching a fairly advanced stage, and removing as much of the susceptible tissue as possible would be the best method to prevent a recurring breast cancer. Overall, the current standard of care results in fairly high five-year survival rates, with about 77% of patients diagnosed with triple negative breast cancer surviving at least five years after diagnosis. Patients who live five years after diagnosis also have a significantly low mortality rate due to a recurring cancer. The success of these treatments are not without consequence, however. Side effects to breast cancer drugs like doxorubicin include nausea, vomiting, low blood counts, and hair loss. In younger women, the drug can also cause infertility in rare cases. Another major issue is also the aggressiveness of hereditary breast cancers, as the cancer could still recur even after removing the breast tissue. While this realization may be crippling to some, it is also very important to consider the significant decrease in risk that occurs with the removal of susceptible tissue as well as the importance of the chemotherapy in assuring that all the cancer cells have been killed. Overall, the prospect of making a full recovery makes all the drawbacks completely worth it.

Due to the lack of information on the specific mechanisms that drive cancers caused by BRCA1 mutations, there are no current targeted therapies. However, a recent clinical trial revealed a new treatment method that utilizes platinum based drugs, such as carboplatin and cisplatin, in order to combat the cancer. These drugs work by creating interstrand cross-links that can only be repaired through homologous recombination; Wild-type BRCA1 proteins would be able to repair such damage but the mutant would not. According to these trials, platinum based drugs can be used as a form of neoadjuvant therapy. These trials have a fairly high success rate, with the chance of creating a new standard of care for this specific subtype of breast cancer: the therapy saw a positive response rate of about 80% in a sample primarily composed of patients with basal like triple negative breast cancers. As a patient who fits all the requirements for the test due to her specific cancer type, Joy can participate in this study, and because of the fact that the drug is being tested as a neoadjuvant therapy, Joy could still go through with the current standard of care and supplement it with the drugs from the trial. For all these reasons I would recommend to her to go along with the clinical trial.

Aperçu
Triple negative breast cancer is one of the rarest forms of breast cancers. Joy inherited the struggle for no other reason than her family history. However that same family will be the very one that pulls her through her hardest times.

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