Breast cancer is the most common cancer in women the United States and affects nearly 200,000 individuals each year. More than half the cases occur in women aged over 65 years. On a positive note, 5-year survival now hovers around 90%.
While breast cancer is a heterogeneous disease, there are now more sophisticated risk models to identify patients with higher likelihood of developing the disease. Importantly, there are now reasonable interventions for high-risk women to reduce their incidence of breast cancer. Primary care offices should become familiar with risk assessment techniques and the potential value of chemopreventive strategies for high-risk women.
Many factors can increase the relative risk of development of breast cancer. Hormone replacement therapy, consumption of alcohol, menarche before age 12, late menopause, first childbirth after age 35, physical inactivity, and postmenopausal obesity modestly elevate the risk for the disease. Family history can have a substantial impact on risk. Having a first-degree relative with breast cancer increases one’s risk two- to fourfold. Personal histories of atypical hyperplasia or radiation therapy to the chest also elevate risk. Individuals with the BRCA mutation have up to an 80% increased risk of developing breast cancer over their lifetime.
Certain characteristics place patients at high risk for genetic predisposition for breast cancer. This can include a family history of cancer prior to 50 years of age; a family member with either breast cancer or breast and ovarian cancer; two close family members with breast, ovarian, or primary peritoneal cancers; or Ashkenazi Jewish ancestry.
Several mathematical models can calculate the risk for an individual patient and are available online. The Gail model is most widely used, especially for patients aged over 35 years. It can identify patients at high risk, which is defined as a 1.66% chance of developing breast cancer over the next 5 years.
Aside from greater surveillance and consideration of prophylactic mastectomy, chemoprevention is emerging as an important option for patients with higher likelihoods of developing breast cancer.
The National Surgical Adjuvant Breast and Bowel Project (NSABP) enrolled more than 13,000 women identified to be at high risk by the Gail model. Participants received tamoxifen or placebo and were followed for a median of 55 months. Overall, the risk reduction for invasive hormone receptor–positive cancer was 49% in the tamoxifen group. Certain subgroups, including women with atypical hyperplasia, had greater reductions in risk. There were other smaller studies that evaluated the same issue and showed variable (some nonstatistically significant) risk reduction in the tamoxifen groups. Study confounders include variations in use of hormone replacement therapy, in family history, and in prior hysterectomy status of study enrollees.
Overall, the benefit of tamoxifen between the four studies was a 38% reduction in the occurrence of hormone receptor–positive breast cancer (CI 8%-46%; P less than .001). Tamoxifen is used at 20 mg by mouth daily.
Of note, risk reduction was seen only in a hormone receptor–positive breast cancer, but not estrogen receptor–negative cancer. There are only limited data on the benefits of chemoprevention for women with BRCA mutations or a history of chest radiation.
Tamoxifen is a nonsteroidal mixed antagonist–agonist of the estrogen receptor. In breast tissue, tamoxifen blocks the binding of estrogen to tissue receptors. In other tissues such as bone and endometrium, however, tamoxifen is an estrogen agonist. While this is effective in reducing osteoclast activity and development of osteoporosis, it can lead to endometrial hyperplasia and subsequent adenocarcinoma. Other side effects include doubling the risk of deep venous thrombosis and an increased risk of cataract formation. In addition, tamoxifen interacts with SSRIs that can alter metabolism through the CYP2D6 pathway in the liver. This incomplete metabolism can promote increased rates of breast cancer recurrence in patients already receiving tamoxifen for established primary breast cancers. Paroxetine, fluoxetine, and sertraline are most prominently cited for this interaction.
Raloxifene is a selective reuptake estrogen modulator. Like tamoxifen, it can increase the risk for deep venous thrombosis but is associated with a lower risk for endometrial cancer.
Raloxifene trials for osteoporosis and cardiac disease were used to assess this agent for effectiveness in breast cancer chemoprevention. Raloxifene was used at 60 mg by mouth daily. Positive and encouraging findings have led to trials comparing raloxifene to tamoxifen for breast cancer prevention. The Study of Tamoxifen and Raloxifene (STAR) trial of nearly 20,000 postmenopausal women identified by the Gail model to be at high risk, demonstrated equivalence in incidence for invasive cancer. Patients taking raloxifene were noted to have a higher number of noninvasive cancers but fewer hysterectomies and endometrial cancer diagnoses.