Breast Cancer

GENETIC TESTING: Gene sequencing and deletion/duplication analysis reveals for example the c.4357+1G>A mutation in the BRCA1 gene. This test result is positive predisposing the patient to cancers associated with hereditary breast and ovarian cancer syndrome (HBOC).

HEREDITARY BREAST AND OVARIAN CANCER SYNDROME CANCER RISKS: Although the exact risk of cancer conferred by specific mutation has not been determined, studies indicate that deleterious mutations in the BRCA genes may confer the following lifetime cancer risks:

MANAGEMENT FOR HEREDITARY BREAST AND OVARIAN CANCER SYNDROME: Knowing one’s genetic status and hence one’s cancer risk may help to guide important health care decisions for them and their family. Therefore, we reviewed the current recommendations for individuals who have a BRCA mutation. There are currently three modalities for the management of mutation carriers including, enhanced surveillance, prophylactic surgery, and chemoprevention. The decision of which modality is more suitable is a very personal choice and may be dependent upon age, childbearing, and ones’ experience with cancer.

Screening:

Female Breast Cancer:

Breast self-examinations monthly beginning at age 18,

Clinical breast examinations (CBE) every 6-12 months beginning at age 25, and

Mammography and breast MRI screening annually, alternating each every 6 months, beginning at age 25 or earlier based on the earliest breast cancer in the family.

Ovarian Cancer: Ovarian cancer is much more difficult to detect through routine screening than breast cancer. Unfortunately, there is no data demonstrating that the recommended screening measures can reduce death from ovarian cancer. For mutation positive women who have not yet undergone risk reducing surgery to remove their ovaries and fallopian tubes, the recommended screening for ovarian cancer includes:

Transvaginal ultrasound and measurement of CA-125 levels every 6 months beginning at the age of 30 (or 5-10 years prior to earliest diagnosis in the family).

It is recommended that these tests be performed preferably on day 1-10 of the menstrual cycle in premenopausal women. CA-125 testing detects 80 percent of epithelial ovarian cancers; however, CA-125 is elevated in fewer than 50 percent of stage I tumors and only 21 percent of cases limited to microscopic involvement. In addition, pregnancy, uterine fibroids, benign ovarian cysts, endometriosis, and even menstruation can elevate levels of CA-125 in women during their reproductive years. Hence, CA-125 testing has serious limitations when used to detect early stage ovarian cancer.

Male Breast Cancer: Although the risk of breast cancer in males is different depending upon whether he has a BRCA1 or BRCA2 mutation, males who carry mutations in either gene are encouraged to have:

Chest wall self examinations monthly beginning at age 35 and talk to their doctor if any suspicious lump or change is found,

Clinical chest wall examinations every 6-12 months beginning at age 35, and

A baseline mammogram at age 40.

Prostate Cancer: While the risk of prostate cancer in males differs depending upon whether he has a BRCA1 or BRCA2 mutation, males who carry mutations in either gene are encouraged to have:

Digital rectal examination (DRE) and measurement of serum prostate-specific antigen (PSA) annually beginning at age 40.

Pancreatic Cancer: There is currently no effective screening for pancreatic cancer; however endoscopic ultrasound (EUS) is a technique that can be used to try and diagnose cancer of the pancreas and should be discussed in more detail with your doctor. Mutation carriers are also encouraged to consider enrollment in investigational protocols for pancreatic cancer. For a list of available pancreatic cancer screening trials, visit the National Institutes of Health website at http://clinicaltrials.gov/.

Melanoma: Men and women who carry BRCA2 mutations are known to be at an increased risk to develop both cutaneous (skin) and ocular (eye) melanomas, while BRCA1 mutation carriers may be at an elevated risk as well. Therefore, BRCA1/2 mutation carriers should undergo:

Clinical examinations of the skin annually, and

Eye examinations by a specialist.

Prophylactic Surgery

Additional options for cancer risk reduction include preventive surgery. This kind of surgery is called prophylactic, because the goal is to prevent the development of cancer. However, a risk of cancer remains even when prophylactic surgery is performed.

Mastectomy: Removal of the breasts (mastectomy) reduces the risk of developing breast cancer by more than 90 percent. This surgery cannot, however, eliminate cancer risk due to the possibility of residual breast tissue, which may remain following surgery. A total mastectomy is the preferred surgery as opposed to a subcutaneous mastectomy, which leaves the nipple and areola complex intact.

Bilateral Salpingo Oophorectomy: The risk for ovarian cancer is reduced by as much as 96 percent following the removal of the ovaries and fallopian tubes (bilateral salpingo oophorectomy). This risk, however, is also not reduced to zero. Ovarian-like cancers have been reported to develop in the peritoneal lining of the abdomen. Recent data indicate that a prophylactic bilateral salpingo oophorectomy not only reduces the risk of ovarian cancer, but also reduces the risk of breast cancer in premenopausal BRCA1/2 mutation carriers by as much as 53 percent. Since screening for ovarian cancer remains problematic, it is recommended that BRCA1/2 mutations carriers undergo a prophylactic bilateral salpingo oophorectomy between the ages of 35-40 and after childbearing, or earlier depending upon the earliest age of onset of ovarian cancer in the family.

Chemoprevention

Tamoxifen: Tamoxifen is a selective estrogen receptor modulator (SERM) that has been used for many years to treat breast cancer. In breast cancer patients, Tamoxifen suppresses the development of new primary cancers in the opposite breast. An evaluation of a subset of unaffected patients with BRCA1/2 mutations taking Tamoxifen revealed that breast cancer risk was reduced by 62 percent in patients with BRCA2 mutations, but not BRCA1 mutations. This is most likely due to the fact that BRCA2 breast cancers tend to be hormone receptor positive, while BRCA1 breast cancers tend to be hormone receptor negative. Tamoxifen has also been shown to be effective in reducing the risk of a second, independent breast cancer in both groups of patients. An additional benefit of Tamoxifen was a decrease in bony fractures.

Some of the side effects of Tamoxifen include hot flashes and vaginal dryness. More serious potential side effects include an increased risk of blood clots in the legs and lungs, cataracts, and endometrial cancer (risk goes from 1 in 1,000 women to 2-3 in 1,000). Any woman considering Tamoxifen should inform her physician of any history of blood clots as this history would be contraindicated to taking Tamoxifen. Women who have undergone a hysterectomy would not be at risk for endometrial cancer. However, women who still have their uterus should discuss the risk of endometrial cancer and symptoms of the disease such as bleeding, pelvic pain, and weight loss with their physician before beginning Tamoxifen.

Raloxifene: Raloxifene is a second generation SERM that is chemically different from Tamoxifen and appears to have similar benefits with no increase in the risk of endometrial cancer. There is no data currently available regarding the efficacy of Raloxifene in BRCA1/2 mutation carriers.

Oral Contraceptives: Premenopausal women may also benefit from the use of oral contraceptives as chemoprevention for ovarian cancer. The protective effect of oral contraceptives has been well documented in the general population, but remains somewhat controversial in women who carry BRCA mutations due to contradictory evidence about oral contraceptives increasing breast cancer risk. One study however, found a 14 percent reduction in ovarian cancer risk in ever users and a 38 percent reduction in long-term users among BRCA carriers. Additionally, another study found no evidence that the use of current formulations of low-dose oral contraceptives (available after 1975) increases the risk of early-onset breast cancer for BRCA mutation carriers.

Lifestyle

In addition to management choices, a healthy life-style may also play an important role in the development of cancer. A low fat diet, adequate physical activity, and smoking cessation may help to reduce the risk of many cancers.

Women who are BRCA mutation carriers are considered high risk and are candidates for all of the screening and management options listed above. Women who are not found to be BRCA mutation carriers but have a significant family history of breast and/or ovarian cancer are still considered at high risk, and may be eligible for some of the screening and management options based upon their own family history and personal medical history.

Reproductive Options

For individuals with a hereditary cancer syndrome, who are concerned about passing the familial genetic mutation to their offspring, alternative reproductive planning options may be available. These options include: prenatal diagnosis (PND), pre-implantation genetic diagnosis (PGD), and adoption.

PND enables the diagnosis of a genetic condition during a pregnancy. The two most common forms of PND include chorionic villus sampling (CVS) which is performed at 10-12 weeks gestation, and amniocentesis which is performed after 15 weeks gestation. PND gives parents the option to know if their unborn baby carries a genetic mutation to aid in future planning, or in some cases parents may opt to terminate a pregnancy.

PGD enables the diagnosis of a genetic condition before pregnancy. This modality is used in conjunction with an assisted reproductive technology, most commonly in vitro fertilization (IVF). PGD involves testing the embryos at a very early stage—the eight cell stage which is called a blastocyst—for certain genetic mutations (changes), and only transferring the embryos without the genetic mutation.

It is important to note that both PND and PGD may not be available for all hereditary cancer syndromes, and these options still remain controversial for some hereditary cancer syndromes.

MANAGEMENT: Recommend annual mammograms alternating every six months with MRI breast screening. However, you indicated that you will most likely choose to go forward with a bilateral mastectomy, so this screening will not be necessary. In terms of ovarian cancer risk, we recommend that you consider removal of your ovaries as soon as possible, once child bearing is complete. If you do not have the ovaries removed at this time, we recommend that you undergo screening every six months by transvaginal ultrasound and CA-125 blood test, until the time that you pursue surgery. We also recommend that you receive annual skin and eye examinations by a specialist to screen for melanoma.

RISKS TO FAMILY MEMBERS: The c.4357+1G>A BRCA1 mutation is inherited in an autosomal dominant fashion meaning that both males and females have an equal chance to carry and transmit this mutation to their children. An individual who carries this mutation has a 50 percent chance of passing the mutation to each of his or her children, meaning each of your children have a 50 percent chance of having this mutation. It also means that if a person carries a mutation, his or her siblings may also have a 50 percent chance of carrying the same mutation, meaning your siblings have a 50 percent chance of carrying this mutation as well.

In reviewing your family history, it is unclear from which side of the family you inherited this mutation. Therefore, we recommend that one of your parents undergo testing to determine which of your extended family members are at risk.

The decision of when and how to disclose to your relatives can be a very difficult one. The benefit of testing for the family is that those relatives who test negative for the mutation identified in you can be spared any unnecessary screening and/or surgery because their risk of developing the associated cancers would be reduced to that of the general population. For many men, the primary reason to be tested for mutations in the BRCA1/2 genes is to learn if they have a gene mutation that could be passed on to their children, in particular their daughters.

For those that test positive for the familial mutation, he or she would follow the recommended guidelines mentioned above. You are welcome and encouraged to share this letter with your relatives to help them understand the implications of your genetic test result. Genetic testing is available for any family member who is 18 years of age or older. We would be happy to see any of your relatives for genetic counseling or refer them to a Genetics Center in their area.

IMPLICATIONS OF TESTING: Finally, genetic testing for cancer may have some psychological implications. For some individuals, learning of a positive test result is actually a relief because this information helps to resolve uncertainty about cancer risk. For others, news of a positive result may trigger feelings of sadness, depression, or doubts about the future, both for themselves and their families. All of these emotional responses are normal and understandable. We have a professional support person in place for any of our patients who need an additional source of support during this process. Please let us know if we can be of help in this regard. During today’s visit, you were provided with information regarding Facing Our Risk of Cancer Empowered (FORCE), an online support organization for individuals with a BRCA mutation.

DISPOSITION:

Ms. Clark’s BRCA1/2 sequencing and deletion duplication analysis results revealed that she is positive for the BRCA1 mutation, c.4357+1G>A.

Screening and management recommendations were discussed.

Implications for other family members were reviewed.

Given that family history is dynamic and constantly changing, it is recommended that a family history of cancer be updated at least every 5-10 years by a health care provider. Should a new cancer develop in Ms. Clark or her family, we ask that she be referred back to our clinic to update their risk assessment and if necessary alter our management and screening recommendations.

Finally, due to the dynamics of the field of cancer genetics, we ask that Ms. Clark contact us on a regular basis to let us know of any changes in her family history as well as to learn of any new testing or management options.