In the mid-1990s, scientists for the first time were able to isolate and clone the BRCA1 and BRCA2 genes, mutations in which were thought to increase susceptibility to early onset breast and ovarian cancers. A new Perspective published last week in Science takes a look back at the last twenty years to show how the identification of these genes set in motion a firestorm of research aimed at exploring how genetic information can be used to create both standards of care and strategies for all patients at a high-risk of developing cancer. Much has been learned over the last twenty years and now, Penn Medicine’s Basser Research Center for BRCA - the first and only comprehensive BRCA-focused center of its kind – is at the forefront of the next generation of research about genetics and cancer risk, methods for risk reduction and prevention, and new cancer treatment therapies.
Autosomal dominant diseases, as in the case of BRCA mutations, means you only need to get the abnormal gene from one parent in order for you to be at risk of inheriting the disease. “Affected,” in the context of BRCA mutations, means a patient is “at risk.” It does not necessarily mean a patient has been diagnosed with cancer.
BRCA: Then and Now
Information gleaned over the last twenty years combined with new details about non-BRCA1/2 genetic variations is arming physicians and researchers with the tools to begin to developing models that will provide personalized care plans for BRCA1/2 mutation carriers based on genetic changes. Two decades ago, studies confirmed the association between BRCA1 and BRCA2 mutations and early-onset breast cancer and ovarian cancer. Since then, more than 1,800 distinct variants of BRCA1 and more than 2,000 of BRCA2 have been reported. Further studies revealed that not only are BRCA1/2 mutations hereditary, but some variations are also common among distinct populations. The best known example is in the Ashkenazi Jewish population, in which nearly three percent of individuals carry a mutated version of the gene. That means they have a 1 in 40 chance of carrying a BRCA1 or BRCA2 gene mutation -- a ten times greater probability than that of the non-Jewish population.
“A woman’s risk of breast cancer is still very much tied to family history, but it’s not just about their mother or grandmother; it’s about their father and his family history, too, and the population groups an individual’s family belongs to,” said Katherine Nathanson, MD, associate professor of Medicine in the Division of Translational Medicine and Human Genetics, co-leader of the Cancer Prevention and Control Program at the Abramson Cancer Center, and a co-author on the new Perspective. “Twenty years of research has provided a lot more information about these risk factors which helps us to more effectively counsel patients about their own cancer risk and possible preventative strategies.”
Today, BRCA1 mutation carriers are generally estimated to have a 57 percent chance of developing breast cancer and a 40 percent chance of developing ovarian cancer by age 70, whereas BRCA2 mutation carriers are estimated to have a 49 percent chance of breast cancer and an 18 percent chance of ovarian cancer.
Over the years, large studies of many women with BRCA1
mutations have allowed researchers to identify both environmental and genetic variations which can cut these individuals’ risk of developing cancer. These studies have laid the foundation for models that allow clinicians to more precisely determine cancer-causing risk by combining information about multiple risk factors including population groups to which patients belong, family history, and tumor pathology.
Managing Risk and Care
As research has evolved over the years, clinicians have identified several strategies that can be used to screen for cancer and reduce cancer risk among women who carry BRCA1/2 mutations. At-risk patients are advised to undergo regular screenings to detect tumors at an early stage, and depending on individual considerations – such as in the case of a young carrier who may not be finished having children – prophylactic mastectomy and/or oophorectomy (removal of the ovaries), or chemoprevention using a combination of drugs may also be advised.
Patients known to be at increased cancer risk due to a mutation in BRCA1 or BRCA2 work with a team of care providers including oncologists and genetic counselors to develop a personalized cancer risk management program. For example, research published in 2011 and led by Kathryn Schmitz, PhD, MPH, associate professor of Epidemiology and Biostatistics and a member of the Abramson Cancer Center, revealed that some exercise and weightlifting may reduce the risk of lymphedema for BRCA carriers.
Ongoing studies are looking at how oral contraceptives, antiestrogens and environmental factors may reduce the risk of breast cancer in BRCA1/2 mutation carriers. Clinical trials are also in progress to investigate the efficacy of drugs known as PARP inhibitors which were found in early studies to be especially effective against BRCA-related cancers including breast, ovarian, pancreatic, and prostate. Specifically, last year results were revealed for the largest clinical trial to date that examined the efficacy of PARP inhibitor therapy in BRCA 1/2 carriers with diseases other than breast and ovarian cancer. In that study, led by Penn researchers, the oral drug olaparib was found to be effective against advanced pancreatic and prostate cancers. These and other promising results seen in phase I trials of PARP inhibitors have led many investigators to believe that one of the drugs will soon be approved for widespread use.
2014 and Beyond
Today, testing for mutations is a standard part of care for patients with a personal or family history that may predispose them to future diagnoses. With the advent of new testing procedures and an increasing number of genes identified in familial breast cancer, simultaneous screening of “predisposition” genes is now widely available. However, the authors of the new Science paper note that guidelines for managing the care of individuals found to carry these mutations have not been developed. Additionally, because the associated risk for breast and other cancers is still unknown for some mutations, even a positive result may cause anxiety for both the patient and the physician as there are no current guidelines to guide recommendations for these patients.
“Combined, methods of testing for BRCA1/2 mutations and preventative strategies that have been developed over the last twenty years provide some of the earliest examples of ‘personalized’ prevention through genetics,” said Nathanson. “Now two decades after the first successful cloning of the BRCA genes, breast cancer genetic research continues to be a driving force in developing new models for personalized, precision medicine.”