Approximately 12% of women will develop breast cancer over the course of their lifetimes with more than 200,000 expected to be newly diagnosed in 2010. Given the prevalence of breast cancer in the general population, identifying those patients who likely represent a sporadic occurrence vs. those with a significant inherited or genetic component poses a significant challenge for the busy primary care physician.
Dr. Peter Hulick
Many aspects in medicine require the recognition of patterns, whether they relate to symptoms and physical exam findings, or in the setting of genetics, patterns of disease within the family history and then following through on one’s differential diagnosis by ordering confirmatory testing. The specialty of medical genetics is rooted in recognizing patterns and only recently has there been an explosion in molecular data available to assist in establishing a diagnosis and better categorizing a patient’s genetic risk for disease.
Individually, highly penetrant Mendelian inherited single genes that increase risk for breast cancer (for example, BRCA1, BRCA2, PTEN and TP53) might seem rare, but collectively they are involved in 5%-10% of breast cancers. Identifying the hereditary factors can affect the patient’s management and naturally has implications for family members. The lifetime risk for developing breast cancer is 25%-80% depending on the affected gene. This is substantially higher than the general population’s risk.
Identifying patients who should be counseled on potential genetic risk is critical and relies on recognizing “warning signs” and specific patterns. One’s suspicion should increase if breast cancer is diagnosed in two or more close relatives at an early age, if there are multiple or bilateral primary tumors, and if there is evidence of autosomal dominant transmission (multiple generations affected).
Certain patient populations might have a higher baseline risk for harboring a mutation – so called “founder mutations.” For example on average, a woman diagnosed with breast cancer has a 5% chance of harboring a BRCA1 or BRCA2. This chance is modified based on the age of the patient at the time of diagnosis. For a woman diagnosed by 45 years of age, the risk increases to 10%. If she is older than 45 years, the risk decreases to 2%. If the woman is of Ashkenazi Jewish ancestry (which has a carrier rate for a BRCA1/2 mutations of 1:40) and is diagnosed with breast cancer, her baseline risk for detecting a mutation is 10%. If the breast cancer occurred by age 45 years, her risk of having a mutation increases to 25%. These numbers can be further modified based on family structure and history and provide a quick benchmark for assessing risk during a primary care visit.
The combination of cancers in a family also contributes to the risk assessment. Proper assessment requires a three-generation family history, which is time intensive in a busy medical practice. Fortunately, there are online tools such as My Family Health Portrait that patients can utilize prior to their visit.
Combinations of cancers in a family history can serve as warning sign that further investigation into the family history is warranted. For example, breast cancer is the most common cancer in females with Li-Fraumeni syndrome, which is caused by a mutation in TP53. Early diagnosis of breast cancer in the setting of a family or personal history of childhood leukemia, sarcoma, or brain tumor should raise suspicion.
Our “recognized” patterns continue to evolve. Most physicians recognize the association of BRCA1 and BRCA2 mutations with breast and ovarian cancer, but there is more to the pattern. For example, males with BRCA1/2 mutations have a higher risk for prostate cancer (30-40% lifetime risk), which can occur at an earlier age and is often more aggressive. Pancreatic cancer also is included in the spectrum of BRCA1/2–associated tumors. In fact, BRCA2 mutations have been identified in 5%-7% of unselected pancreatic cancer patients. Recognizing these associations is not only paramount to identifying future cancer risk, it may also open the door to novel therapeutics (PARP inhibitors) that impair the ability of BRCA-related tumors to repair DNA damage.
The reality is that we often are confronted with a family history in which several members are affected with breast cancer, but a specific genetic cause cannot be identified. Intuitively, we think there must be a “genetic component,” however assessing the magnitude of risk represents a challenge. An estimated 20% of breast cancer occurs in such familial clusters and it is important to recognize these families, as there are implications for breast cancer screening recommendations.
In families that exhibit a clustering of breast cancer, women who are unaffected may meet recently established criteria by the American Cancer Society (ACS) to have breast MRI as an adjunct to routine mammography as part of their annual screening regimen. If a woman’s lifetime risk for developing breast cancer surpasses 20%-25%, the addition of MRI screening should be considered as per the ACS guideline. This risk estimate is calculated using models that are dependent on family history in addition to personal risk factors. Common examples include BRCAPRO and the Tyrer-Cuzick models that are used by many high-risk cancer assessment/genetics clinics. The Gail model is another popular model. While it is limited in assessing the family history, it has a prominent role in predicting a woman’s 5-year risk of developing breast cancer and in determining whether she may benefit taking tamoxifen for the prevention of breast cancer.
Time constraints on primary care physicians can be a significant barrier to obtaining an adequate family history for assessing risk. By having a patient complete the family history via online tools and remembering some key associations, we can better assess for genetic risk and, ultimately, improve the care we provide to our patients.
Following are the combination of cancers that might suggest recommending a risk assessment:
BRCA1/2
Breast, ovarian, pancreatic, stomach, and prostate cancer
CDH1
Lobular breast and diffuse gastric cancer
PTEN
Thyroid and endometrial cancer
TP53
Sarcoma, childhood leukemia/lymphoma, brain cancer
STK11
Colorectal (Peutz-Jeghers–type hamartomatous polyps), gastric, pancreatic, breast, and ovarian cancers
Dr. Hulick is a medical geneticist at NorthShore University HealthSystem, Evanston, Ill., and a clinical assistant professor at the University of Chicago Pritzker School of Medicine.