AMY YOFFE HAS ALWAYS KNOWN that cancer runs in her family and is acutely aware of the loss that comes with it. Growing up in the 1970s, she often heard that her father’s mother was orphaned as a little girl after her mother—Yoffe’s great-grandmother—died of breast cancer at age 35. The children moved from home to home, relative to relative. “It’s a sad story in our family,” says Yoffe.
She heard stories about other cancer diagnoses as well. One of Yoffe’s great-aunts died of ovarian cancer, and one of her great-uncles died of stomach cancer. Her grandmother was diagnosed with ovarian cancer at age 24, and then with breast cancer in her 60s.
In the early 2000s, Yoffe was living in Southern California and pregnant with her second daughter when she began wondering how the legacy of cancer diagnoses in her family might affect her and her two daughters. She asked her obstetrician about the risks she might have inherited and about genetic tests that could identify inherited genetic variants, or mutations, linked to an increased cancer risk. The physician dismissed her concerns.
“He said, ‘Oh, the cancer is on your father’s side of the family, it’s not relevant,’” Yoffe recalls.
The obstetrician was wrong: DNA changes associated with an increased likelihood of cancer can be inherited from either parent. Nearly a decade later, when she had two young daughters, Yoffe met someone who had inherited a variant in a BRCA (BReast CAncer) gene from her father. When functioning normally, BRCA genes carry instructions for making proteins that suppress tumor growth; when altered, that protective role is lost. Changes in the gene were first linked to an increased risk of breast cancer in women and men in 1994, but more recently they have been associated with a higher risk of ovarian, pancreatic and prostate cancer, and melanoma.
Yoffe was worried. Was she at risk? Were her daughters? As a licensed clinical social worker who specializes in hospice care, she often saw how cancer could devastate families. She sought out a genetic counselor who helped her map out as much of the family cancer history as she knew.
“I could see right before my eyes how you could trace the line of cancer in my family,” she says.
In 2009, a genetic test revealed that Yoffe harbored a harmful variant in the BRCA1 gene. Between half and three-quarters of women with such a variant go on to develop breast cancer, compared with about 13% of women in the general public. Between 39% and 44% of women with BRCA1 variants develop ovarian cancer, compared with just 1.2% of women in the general population. Now she had the knowledge and knew her risk.
But that led to an even bigger question, one that researchers and patients continue to explore: What is the best way to use information about inherited cancer risk?
Inherited Versus Acquired Risk
All cancers arise from changes to a cell’s DNA, but the vast majority of those changes are somatic, meaning they occur after a person is born. (Any cell in the body that’s not a sperm or an egg is a somatic cell.) Any somatic cell can develop variants due to environmental factors, like exposure to carcinogenic chemicals or ultraviolet radiation. When the mutated somatic cell divides, both daughter cells will have the mutation. In the past few decades, scientists have identified hundreds of somatic mutations linked to the development or growth of cancer, and a study published Oct. 19, 2017, in Cell estimated that only a small number of mutations—between one and 10—are needed to trigger the formation of a tumor. But somatic variants are not passed from parents to children.
Germline variants, on the other hand, are passed down from one generation to the next. Each parent contributes DNA to a child, so a father or mother, or both, can contribute a germline alteration to their offspring, contrary to what Yoffe’s obstetrician told her. Of the 1.8 million new cases of cancer diagnosed in a typical year in the U.S., up to 10%, or 180,000, can be attributed to inherited variants in genes including BRCA1 and BRCA2, according to the National Cancer Institute. Researchers have identified more than 50 hereditary cancers associated with unusually high rates of diagnosis in families.
Doctors’ understanding of why cancer runs in some families has advanced over the centuries, thanks to careful tracking of cases. One of the first documented investigations was published in 1866 by Paul Broca, a French surgeon who recorded the cause of death of 38 members of his wife’s family over five generations. Fifteen women, out of 26 total, had developed cancer. In 1895, American pathologist Aldred Warthin learned from his seamstress that her family was prone to cancer. Warthin documented a high number of cancers of the gastrointestinal tract, leading him to speculate that inherited cancer risk may not be limited to breast cancer. In 1913, he published a collection of family histories, including that of the seamstress, suggesting that some families bore a higher than average risk of many cancers.
Evidence continued to accumulate through the 20th century. In 1994, researchers connected mutations in the BRCA1 gene to increased risk of breast and ovarian cancer, and in 1995, they linked mutations in BRCA2 to breast cancer risk in men and women. Also in 1995, studies reported a link between breast cancer risk and variants in another gene called ATM; since then, other genetic mutations have been similarly implicated, but they usually confer only a small increase in risk.
The mere presence of a harmful alteration in BRCA1, BRCA2 or one of the other genes associated with a cancer type doesn’t guarantee an unwelcome diagnosis, says epidemiologist Douglas Easton, who directs the Centre for Cancer Genetic Epidemiology at the University of Cambridge in England. Easton worked on the team that helped identify the first harmful variants in BRCA2.
Researchers are now working on ways to determine how genetic variants mix with other exposures to affect a person’s risk. Ideally, “you really want to consider all your risk factors together,” he says.
Recent studies suggest that inherited variants increase the risk of cancer in a variety of ways. Since many genes associated with cancer risk are involved in DNA repair, variants can increase cancer risk by hindering this process, which may allow mutations in somatic cells to accumulate faster. But the science behind that mechanism remains uncertain for now, says Easton.
“If you have an inherited mutation, your risk is changed by other factors including genetic factors and lifestyle factors, even your reproductive history and BMI. That picture is becoming clearer, and now we have models that consider all known factors together,” says Easton. “But it’s still ongoing.” Even now, he adds, genetic counselors and researchers have proven strategies and approaches for assessing risk that can inform decisions about what to do next.
Empowered by Knowledge
Broadly speaking, Easton says three groups of genetic alterations may influence a person’s inherited cancer risk.
The first includes the BRCA1 and BRCA2 genes. Since they were first implicated more than 25 years ago, researchers have identified tens of thousands of potential mutations that might show up on the genes, but not all of them have been linked to increased risk of cancer. Recent studies have investigated which ones may be harmful—and for which conditions—and which ones are benign. Knowing the difference is important. The 23andMe home genetics test, for example, can only identify three known variants—and misses at least 90%, according to a 2019 study. According to a mutation database maintained by pathologists at the University of Utah, about 85% of identified variants in BRCA1 or BRCA2 are classified as “definitely pathogenic.”
The second group includes rare mutations in other genes like ATM, TP53 or PTEN that have been linked to cancer. Like BRCA, TP53 is a tumor suppressor, and mutations in the gene may be inherited or acquired. Around 70% of people with Li-Fraumeni syndrome—which is associated with a high lifelong risk of many cancers, including leukemia, sarcomas, breast cancer and bone cancer—have an inherited mutation in TP53, for example.
The third group includes hundreds of common genetic variants, which do not alter the risk of cancer as much as the first two groups. These DNA changes don’t occur in genes, but they can be identified by a genomic test, and information about them can be combined together to estimate an overall risk, called a polygenic risk score. When combined, they can be used to predict risk in the general population and may shape future guidelines for screening. “However, they also predict risk in individuals with a strong family history, or even in someone who carries a high-risk gene variant,” Easton says. “So, the common variants can also be important for guiding screening and management decisions [for those patients] as well.”
All this research has contributed to an increasingly sophisticated body of knowledge that can inform decision-making in cancer.
“I think awareness of hereditary genetics in cancer has improved tremendously, thanks to doctors being more aware, patients being more aware, and [the work of] advocacy groups,” says oncologist and clinical geneticist Michael Hall at Fox Chase Cancer Center in Philadelphia.
But it can also be frustrating and overwhelming, says Yoffe, whose own experience prompted her to start a local branch of FORCE, Facing Our Risk of Cancer Empowered, an organization dedicated to improving the lives of people with inherited cancer risk. Because of the complexity of the field, experts recommend that anyone with questions about their family history of cancer start by meeting with a certified genetic counselor.
“The field is growing so rapidly that it’s hard for anyone—even oncologists, even surgeons—to keep up with what the most up-to-date tests are,” Yoffe says. “But genetic counselors are very focused on that. The medical community at large really emphasizes the importance of seeing a genetic counselor.”
To Do or Not to Do
In 2009, after Yoffe underwent genetic testing and found out she had a harmful BRCA variant, she discussed her options with her genetic counselor, her family and a gynecologic oncologist. She didn’t have a cancer diagnosis, but she knew her family history and understood her risk. “I was very laser focused on doing whatever I could to reduce my risk of cancer,” she says. “I didn’t want to die and leave my children the way my great-grandmother left my grandmother.”
Acting on findings from genetic tests can be stressful. Some people need to consider how their decisions will impact a desire to have or grow a family, says Yoffe, but when she was tested she had already decided not to have any more children. She had her ovaries removed immediately, in 2009, and the following summer had a prophylactic double mastectomy with reconstruction.
“I acted very quickly,” she says, “and the double mastectomy was a pretty challenging surgery and recovery.”
Yoffe says she felt empowered by choosing prophylactic surgery, but not everyone has the same option to reduce their risk, and not everyone chooses it. Some people feel more comfortable choosing surveillance. People with an inherited and elevated risk of melanoma or pancreatic cancer, for example, don’t have surgical options to reduce risk, but they can start screening for these diseases. Other people may not choose surgery, even if it is an option.
People already diagnosed with cancer may have decisions to make as well. A growing chorus of experts advises that anyone diagnosed with cancer get tested for germline mutations, in part because some drugs exist to treat inherited cancers. (See “Universal Testing for Inherited Risk?” above.) Lynparza (olaparib) is a PARP inhibitor approved by the Food and Drug Administration to treat people with certain inherited cancers in the breast, ovaries, pancreas and prostate. Clinical trials also suggest it can extend progression-free survival.
Through her work with FORCE, which hosts meetings for people with inherited cancer risk, Yoffe has seen a spectrum of responses to genetic tests. She’s worked with a woman whose relatives have tested positive for the BRCA variants but who doesn’t have a family history of cancer. “She’s chosen surveillance because she’s not ready to make a decision about a mastectomy,” she says. “Our decisions can be influenced by our personal life story and family history.”
The important thing, says oncologist and clinical geneticist Kristen Whitaker, also at Fox Chase, is that people make informed decisions. “While knowing that one carries a mutation that increases the chance of developing cancer can be anxiety-provoking, I tend to think the benefits that come from that information—in terms of early detection through enhanced screening and cancer prevention through preventative surgeries—outweigh the downsides,” she says.
On the flip side, says Hall, “germline genetic testing is useless and a waste of money if patients don’t understand the result and don’t act based on the result, or worse, if they take the wrong actions based on misunderstanding the result.”
Hall also worries that not everyone who can benefit from genetic testing has access to it. “We see rates of referral to genetics and genetic testing are lower among nonwhite, less educated and generally underserved populations,” he says. “We need to address this immediately. Genetic testing to support cancer prevention is inexpensive and should be available to everyone, not just the wealthiest Americans with the best health care.”
Yoffe, now 50, says she’s become aware of stark racial and socioeconomic imbalances in the people she talks with about genetic testing and counseling. She’s also learned how the field of genetic testing for cancer continually changes.
But it’s always personal. Her oldest daughter is now 22 years old, just two years younger than the age when her grandmother was first diagnosed with ovarian cancer. Her other daughter is 19. “Now my concern has switched to them, and my eldest daughter has her first genetic counseling appointment and is planning to get tested at that time,” she says. “This legacy of cancer has a lasting impact on families.”
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