Each October, the color pink seems to take over as breast cancer awareness month moves into full swing. Everything from nonprofit fundraisers to big time sporting events get a fresh pop of color as a visual reminder of the need for more education and increased awareness, the hope for new cancer treatments, and as a tribute to those who have been affected by, or who have lost their lives, to the disease.
But 2019 represents a specific milestone in the fight. It’s been 25 years since the BRCA1 gene was first cloned — a discovery that accelerated cancer research and opened a new path for exploration in cancer prevention and treatment. To mark the occasion, members of the Basser Center for BRCA at the Abramson Cancer Center of the University of Pennsylvania – a center which owes its entire existence to the genetic discovery – shared their perspectives on how the landmark discovery has affected their work, where the field still needs to improve, and how the science has moved beyond breast cancer.
Paving a Path to New Treatments
“The tremendous amount of research, innovation, and collaboration over the past 25 years has led us to a better understanding of the steps we can take to detect cancers early or prevent them altogether,” said Susan Domchek, MD, executive director of the Basser Center.
Domchek pointed to one particularly exciting example, the discovery that individuals who have BRCA1/2 mutations and advanced cancer may benefit from specific medications called PARP inhibitors – several of which have been approved by the FDA in just the past few years – to help treat their disease. The approvals allow for new treatment approaches for many patients who, even as little as five years ago, had few options.
While BRCA is most closely associated with breast cancer, it also leads to an increased risk for ovarian, prostate, and pancreatic cancer. The discovery of these relationships is already improving outcomes for affected patients. Kim Reiss Binder, MD, an assistant professor of Hematology-Oncology, is studying the use of PARP inhibitors for pancreatic cancer patients who are BRCA-positive. Her recent trial showed it can shrink tumors in many of these cases.
“In recent years, we discovered in the lab that platinum chemotherapies and PARP inhibitors are particularly effective against BRCA-related pancreatic cancer,” Reiss Binder said. “Now, we’re bringing that knowledge into the clinic to make a difference for patients battling one of the most difficult-to-treat cancer types.”
Roger Greenberg, MD, PhD, a professor of Cancer Biology, credited the discovery of the BRCA genes with enabling all laboratory and clinical advances in hereditary breast and ovarian cancer.
“By serving as a focal point for laboratory investigation, this discovery has allowed us to understand the central importance of homologous recombination DNA repair mechanisms to both the causes and therapeutic responses to these cancers,” he said.
Ultimately, this understanding has sparked a new wave of cancer research, diving deeper into the genetic factors that underlie disease risk and treatment response.
In other cancer types, the discovery has led to the development of entirely new fields of study, with researchers focused on the link between genetics and cancer when it comes to assessing risk, improving diagnoses, and even changing the way surgeons approach procedures related to these diseases.
“We’re able to study how genetics impacts cancer development in men with prostate cancer and women with breast cancer because the discovery of BRCA1 demonstrated that cancer risk can be inherited as a single gene,” said Kara Maxwell, MD, PhD, an assistant professor of Hematology-Oncology. “Prior to the BRCA1 discovery, it was known that cancer is a genetic disease, but it was thought that an individual’s genes only affected the specific type of cancer, and not the risk of developing the disease itself.”
Genetic Impact on Clinical and Surgical Care
In the decades since the discovery, the deeper understanding of the link between cancer and genetics has had profound impacts the treatment approaches for multiple disease types, including ovarian cancer, which has long been a particularly difficult type of cancer to detect before it reaches an advanced, life-threatening stage. Ronny Drapkin, MD, PhD, a professor of Pathology in Obstetrics & Gynecology, noted that since the first BRCA1 cloning, research has revealed underlying factors about tumor growth patterns which has allowed for the development of prophylactic risk-reducing surgeries – such as preventive removal of one or both ovaries, or the breasts – for patients who carry a mutation.
“By studying tissue samples, we came to realize that ovarian cancers actually arise from the fallopian tubes, rather than in the ovaries,” Drapkin said. “This discovery was a paradigm shift in the field and has allowed for the development of a number of clinical studies to test whether removal of the Fallopian tubes alone is an effective way to reduce cancer risk.”
Leaving the ovaries intact and removing only the tubes, he said, could spare patients from early onset menopause and loss of fertility. The mounting evidence showing the effectiveness and benefits of tube-only removal is now making it the standard recommendation for at-risk, premenopausal women with a BRCA mutation. The developments of treatment options – both prophylactic and after diagnosis – come from the hard work and dedication of scientists who spend their time in the lab, making breakthroughs in animal models that hopefully translate to helping patients down the road.
Since 1994, researchers have also been able to deepen their knowledge around these discoveries and build on them to expand their potential benefits.
“The identification of BRCA1 was a huge step forward in confirming the existence of inherited genetic causes for cancer, and we’ve been able to use that knowledge to better understand the genetic basis for other cancer types,” said Katherine Nathanson, MD, deputy director of the Abramson Cancer Center and director of Genetics at the Basser Center for BRCA. Nathanson—who recently received a $3 million research grant from the Gray Foundation—and her team are currently studying new approaches to understanding immune function both in healthy BRCA mutation carriers and BRCA-related cancers.
Assessing Risk and Making Informed Decisions
Despite all of the progress in the lab, identifying people with BRCA1/2 mutations through genetic testing remains a challenge. As many as 90 percent of mutation carriers do not know their status, and that’s especially concentrated in minority populations, who can be both more likely to carry the mutation and less likely to seek genetic counseling.
“Eliminating this disparity in genetic counseling will require enlisting the help of multi-lingual genetic counselors and culturally sensitive educational materials to spark interest,” said Dana Clark, MS, LCGC, a senior genetic counselor.
Clark cautioned that while direct-to-consumer genetic testing like those sold by 23andme may seem like a possible solution, interpreting those results is not so easy. With only 5,171 genetic counselors currently practicing worldwide, every genetic counselor would have to see 1,934 customers each year, just to access results from 23andMe. She says increasing accessibility to genetic counselors will allow consumers to get responsibly ordered genetic testing, pre-test education, and sound discussion of the results.
Recognizing the disparity in access to counseling and education about disease risk allows Clark and colleagues to focus outreach efforts on populations who stand to benefit the most. Latinas, for example, have the second highest prevalence of BRCA1/2 mutations after Ashkenazi Jews. By knowing their status and being proactive about their care, these communities can rely on their genetic information to stay one step ahead of cancer.
From prevention to detection, and from better understanding and better treatments, the last 25 years have seen remarkable progress. And while there’s still plenty of work left to do, Domchek says the advances we’ve already seen are a reason for optimism.
“Because of the immense amount of progress of these last 25 years, I am incredibly hopefully about the next 25.”