BRCA1 and BRCA2

The average lifetime risk of breast cancer for women is about 10 – 12%. For women who have a BRCA1 or BRCA2 pathogenic (cancer-causing) variant, the risk of developing breast cancer in your lifetime, up to the age of 80 years, is between 38% and 87%. Your lifetime risk of ovarian cancer is also much higher at 17% to 63% (in comparison to the usual risk of less than 2%). Men can also carry a faulty BRCA gene  and are at a slight increased risk of developing male breast cancer. The lifetime risk for men with a faulty BRCA2 gene can be as high as 9%. Men are also at an increased risk of prostate cancer of between 16% and 27% (usual risk is 12%). The BRCA genes are also associated with a slight increased risk for pancreatic cancer and BRCA2 with a melanoma risk.

PALB2

Women with pathogenic variants in the PALB2 gene have a 33% to 58% lifetime risk, up to the age of 70 years, of developing breast cancer. The full effect of PALB2 gene variants is still being investigated. Male breast, pancreatic, and ovarian cancers are thought to be increased, but the exact degree of increase remains under investigation. The cancer risks are very much dependent on the family history of the individual who carries a faulty PALB2 gene.

ATM

The ATM gene has more recently been found to be associated with an increased risk for breast cancer. Women who carry a pathogenic ATM variant are believed to be at 17% to 60% lifetime risk of developing breast cancer. Prostate (in men) and pancreatic cancer has also been strongly associated with a faulty ATM gene; however, the exact risk figures are still being determined. Preliminary evidence suggests a possible link with ovarian (in women) and colorectal cancer.

CHEK2

Pathogenic variants in the CHEK2 gene are associated with an increased risk for female and male breast, colon, thyroid, prostate (in men) and possibly other cancers. The exact risks are still under investigation. When calculating the cancer risks, the exact familial pathogenic variant as well as the family history needs to be considered. The lifetime risk for female breast cancer, mainly associated with the 1100delC variant, have been estimated to be 25% to 39%. This risk is believed to be lower in other variants.

Passing it on

Men and woman who carry a faulty BRCA1, BRCA2, PALB2, ATM or CHEK2 gene can pass it on to their children. The risk of passing the specific pathogenic variant on to each of their children is 50%. If the child carries the variant, they will also be at an increased risk for the associated cancers. While rare, it is possible for a person to have more than one cancer-causing gene variant in different genes, for example one in the BRCA1 gene and the other in BRCA2. Management options remain the same as for single gene carriers, but the risk of passing it on to their children is higher.

How does being a BRCA1 and BRCA2 carrier, effect the type of breast cancer?

Cancers in women with BRCA pathogenic variants may differ from other breast cancers. Some of the differences are:

• Breast cancers in women with a faulty BRCA1 gene are more likely to be estrogen-receptor-negative, meaning that the cancer’s growth is not fueled by the estrogen hormone. The cancer is also more likely to have high-grade cell growth, which means that chemotherapy will be required.
• BRCA1- and BRCA2-related cancers are less inclined to overexpress HER2/neu.

What if I already had breast cancer?

All patients with invasive breast cancer or In-situ breast cancer (DCIS) should be evaluated so see if a pathogenic gene variant might have contributed to the development of the breast cancer. Not everyone will require a genetic test, but having a session with a genetic counsellor is very important to assist in assessing your risk of developing another cancer. As time passes, the risk of your initial cancer gets less and the risk of getting a second or third cancer increases.  This cancer might be different from your first cancer, and at times even more aggressive, requiring more intense treatment. You’ll also want to talk with your doctor about reducing the risk of a new, second breast cancer or other cancers (e.g. ovarian).

How can we lower your risk of a future breast cancer or other cancer, specifically ovarian cancer?

Whether or not you’ve ever had breast cancer, knowing that you have a cancer-causing gene variant means that you are at much greater risk of developing breast and possibly other cancer in the future. For the BRCA1 and BRCA2 genes, the risk for ovarian cancer is of concern. The latest research offers these insights about strategies for lowering those risks:

• Preventive or “prophylactic” mastectomy, or removal of both breasts, has been found to reduce the risk of breast cancer in high-risk women by about 90%. After a diagnosis of one breast cancer in a woman with a faulty gene, the risk of her getting a new breast cancer is approximately 3% every year (for example, 15% over 5 years). Without a BRCA1 or BRCA2 variant, this risk is only 1% per year.
• Preventive or prophylactic salpingo-oophorectomy (the removal of both ovaries and fallopian tubes) can reduce the breast cancer risk by as much as 50% when it is done before menopause. This is because it takes away the body’s main source of the hormone estrogen. This surgery also greatly reduces the ovarian cancer risk. The timing of removing the ovaries differs depending on whether a person has a BRCA1 or BRCA2 pathogenic variant. For those with a faulty BRCA1 gene, the recommended timing of removing both ovaries and fallopian tubes are between the ages of 35 and 40 years. For those with a faulty BRCA2 gene, the surgery can be considered between ages 40 and 45 years.
• Hormonal therapy medicines: Two SERMs (selective estrogen receptor modulators) and two aromatase inhibitors have been shown to reduce the risk of developing hormone-receptor-positive breast cancer in women at high risk.
  • Tamoxifen has been shown to reduce the risk of first-time hormone-receptor-positive breast cancer in both postmenopausal and premenopausal women at high risk.
  • Evista (chemical name: raloxifene) has been shown to reduce the risk of first-time hormone-receptor-positive breast cancer in postmenopausal women.
  • Aromatase inhibitors (AI’s), have been shown to reduce the risk of first-time hormone-receptor-positive breast cancer in postmenopausal women at high risk.

It is important to note that hormonal therapy medicines do not reduce the risk of hormone-receptor-negative breast cancer. Researchers believe that hormonal therapy medicines will likely lower breast cancer risk in women with a faulty PALB2 gene, but no specific studies have been done to date.

What can you do to try to increase the odds of early cancer detection?

Another option besides preventive surgery is to undergo more frequent cancer screenings in an effort to catch cancer early, should it ever develop. Although more frequent screenings do not guarantee early detection, they are generally recommended for women who do not wish to have surgery. You are encouraged to work with your genetic counsellor and doctor to come up with a screening schedule that is right for you. For example, you might take the following steps: Breast cancer:

• Have a clinical breast exam every 6 months and monthly self-examinations.
• Begin annual breast MRI at age 25 or mammogram if breast MRI is unavailable. Screening may start sooner if a family member has been diagnosed under the age of 30.
• Between ages 30 and 75, begin annual mammogram and breast MRI.
• For women over the age of 75, screening should be considered on an individual basis with their physicians.
• Men should receive yearly clinical breast exam starting at age 35, and they should start performing breast self-examinations at age 35.
• Consider participating in a clinical trial evaluating newer methods of early detection.

• Begin annual screening with pelvic exam by a gynecologist by age 25. 
• Between ages 30 and 35, consider ovarian cancer screening with annual pelvic ultrasound with an intravaginal probe and blood tests for a special protein called CA-125.