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Why the breast cancer gene you may never have heard of could matter

Beyond BRCA, medicine is finding more genetic anomalies connected with a greater likelihood of cancer. PALB2 is most strongly linked with breast and pancreatic cancers.

Cancer survivors Maria Shroy and her daughters Kristin McHugh and Tracy Brown.
Cancer survivors Maria Shroy and her daughters Kristin McHugh and Tracy Brown.Read moreSTEVEN M. FALK / Staff Photographer

In the four years since actress Angelina Jolie went public with her decision to have mastectomies to prevent breast cancer, the BRCA tumor-suppressor genes have achieved a level of popular fame rarely seen in the world of genetics.

But though BRCA abnormalities are the best-known mutations linked to breast cancer, they are not the only ones.

As many as 20 additional mutations also pose significant risks for the development of the disease, said Julia Tchou, codirector of the Rena Rowan Breast Center at Penn's Abramson Cancer Center.

One of these is PALB2, a gene that works to repair broken strands of DNA. Without PALB2, unrepaired DNA accumulates, potentially leading to uncontrolled growth and proliferation of abnormal cells and an increased risk of cancer.

"Those who have a change or bad copy of PALB2 may have a predisposition to breast cancer," said Tchou.

And, as with the BRCA mutations, defects in PALB2 can mean cancer potential that extends beyond the breast, as Tracy Brown's family has learned.

The Elkins Park woman, 45, was diagnosed with stage 0 breast cancer (also known as ductal carcinoma in situ, or DCIS, because it is confined to the milk ducts)  this year. Her sister, Kristin McHugh, 51, had Stage 2A breast cancer. Her mother, Maria Shroy, 73, developed thyroid cancer. All carry the mutation.

In addition, relatives who developed cancer before genetic testing became available include Brown's father's two sisters, both of whom had breast cancer, and her maternal grandmother, who had pancreatic and cervical cancer.

The strongest evidence regarding an abnormal PALB2 gene points toward a susceptibility for breast and pancreatic cancers.

"BRCA1 and BRCA2 are the tip of the iceberg," said Angela Bradbury, assistant professor of medicine at Penn Medicine. "There are many other mutations, and if you have a strong family history, you might want to seek genetic testing. Finding out can help guide treatment management, help explain family history, and see who in the family might be at risk."

Weighing the risk

A 2014 study published in the New England Journal of Medicine looked at 362 participants from 154 families with an abnormal PALB2 gene. It found that women with the mutation had a 14 percent risk of developing breast cancer by age 50 and a 35 percent risk of developing breast cancer by age 70. But the risk increased to 58 percent if there was a strong family history, with two or more first-degree relatives with breast cancer.

In comparison, women with an abnormal BRCA1 gene have a 50 percent to 70 percent risk of developing cancer by age 70, and those with an abnormal BRCA2 gene have a 40 percent to 60 percent risk of developing cancer by age 70.

The average lifetime risk of breast cancer is about 12 percent.

Despite her  family history, Brown, an  executive coach and consultant, initially didn't see the point in having genetic testing when her gynecologist suggested it two years ago.

For one thing, the technology remained new, and for another, it cost $1,000. But when a close friend confided that she had been identified as having an autoimmune disease after genetic testing, Brown changed her mind.

Accompanied by her mother, Brown went to Bradbury, who found that although the women didn't have BRCA1 or BRCA2 gene mutations, they did have the abnormal PALB2 gene. Her sister, who had not received genetic testing when she was diagnosed with stage 2A cancer in 2007, had the mutation, as well.

"I didn't panic," said Brown. "But my awareness was heightened and I knew there was no missing mammograms after that."

After her sister's breast cancer diagnosis, Brown had adhered to a six-month regimen of alternating MRIs and mammograms. After the genetic testing found the PALB2 mutation, Bradbury suggested Brown also take tamoxifen, an estrogen-modulating medication used both to treat and reduce the risk of breast cancer.

A radical response

Even with these precautions, earlier this year, a technologist took a second look at Brown's left breast during a mammogram and identified signs of stage 0 cancer close to Brown's chest wall and underarm. For most women, physicians recommend conservative treatment for DCIS, such as a lumpectomy, or in some cases, close monitoring with endocrine therapy and breast imaging including MRI to watch for changes.

But given her genetics and family history, Brown and her physician decided on a more radical course.

After witnessing her sister's treatment, which included intensive chemotherapy and a bilateral mastectomy, Brown chose a double mastectomy to prevent invasive cancer from developing.

"For Tracy, who was very young, with stage 0 breast cancer and the PALB2 gene, a prophylactic mastectomy made sense," Tchou said.

"With the double mastectomy and the early-stage cancer, I don't have the fears that my sister had to live with," said Brown. "I'm in a place where there's a 95 to 99 percent chance the cancer might not come back. The mastectomy is not fun, nor would I wish it on anyone, but I don't need chemo or radiation, so I think of myself as lucky."

Since the women's genetic tests, Shroy's brother found that he also carries the PALB2 mutation. Some family members want to know whether they have the mutation; others do not.

McHugh, who has two daughters and a son, is uncertain whether she'll recommend they receive the genetic testing when they turn 25. Although someone can pursue genetic testing for BRCA mutations at age 18, cancer risks associated with the gene mutations rarely manifest before the late 20s.

"I know I'll need to help educate my daughters so they'll be watched closely. And they'll have to decide at some point if they want to know if they have the mutation," McHugh said.

"But even if my children were 25 now, I don't know if I would want them to be tested, because the risk is uncertain. Do I want them to be seen with a preexisting condition? Do I want them to have that worry?"

Knowing she may have passed along a cancer mutation leaves McHugh angry and apprehensive.

"I'm grateful that Tracy's OK, but I'm really mad that we both had to go through this. I do worry if, God forbid, one of my daughters gets cancer. I don't know how I'll deal with that. I was finally getting over my cancer, and then this whole darn thing comes back."

Compounding the strain is the fact that scientists still are learning just how much of a danger various mutations may pose.

"The risk involved with PALB2 is not that of BRCA1 or BRCA2," said Bradbury. To learn more specifics about the extent of risk  presented by mutations, a large study named Prospective Registry of Multi-Plex Testing (PROMPT) led by Penn and Memorial Sloan Kettering Cancer Center is collecting data.

"Only when we have data from thousands of people can we gauge the risks," said Bradbury.

Meanwhile, who should get tested for genetic mutations?

"Any woman who has a history of early-onset breast or ovarian cancer," said Bradbury. "Anyone with a family history of cancer — particularly with multiple relatives at younger ages — should be assessed by a physician or genetic counselor to see if they are candidates to make decisions like Tracy's in advance of getting cancer."

Though Bradbury understands the burden of discovering a genetic mutation, she also views it as a way to change a family's cancer story.

"I think it can be very powerful," she says. "It doesn't mean it's an easy decision, because it often presents hard health decisions for people. But sometimes they can really take significant steps in reducing risk for cancer in individuals."