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Breast Cancer Genetic Testing for All Women?

“I have no family history of breast cancer,” says the woman in a public service announcement stressing the importance of mammograms for all women.

“No one in my family had breast cancer. Not one. But I start chemo next week,” says the woman in another PSA.

Unfortunately, people paying only partial attention, as we tend to do these days, might come away with the earworm “family history – cancer,” and perpetuate the misunderstanding that breast cancer only happens to people with a family history of it. That’s simply not true, but the health care community apparently hasn’t caught up.

A recently-published study in JAMA Oncology reports the number of lives saved among a large group of women diagnosed with breast cancer who had testing for three genetic risk (susceptibility) genes, even if they have no affected relatives. Might testing all women – not just those who already have breast cancer or have relatives with it – save lives as well? I think so.

Widening the Testing Net

Current policy in the U.S., from the National Comprehensive Cancer Network, is complicated. The guidelines advise genetic testing for people who:

  • have breast, ovarian, or pancreatic cancer
  • don’t have cancer but have at least 3 relatives with any of 15 specific types of cancer
  • have a close relative with a cancer risk mutation
  • have two or more close relatives with breast cancer
  • have more distant relatives who have early-onset breast cancer

“The current policy misses a large number of women. Individuals have to jump through hoops to fulfill the criteria and try to see a genetic counselor. What if we offered genetic tests to everyone diagnosed with breast cancer?” said Ranjit Manchanda, MD, PhD, of Barts Cancer Institute at Queen Mary University of London, senior author of the new paper in an interview with the journal’s editor.

Actress and activist Angelina Jolie had prophylactic surgeries after discovering that she has a BRCA1 risk mutation. Mutations in several dozen other genes raise risk too.

But Mary-Claire King, PhD, the American Cancer Society Professor of Genome Sciences at the University of Washington, has suggested that all women over 30 be offered testing for mutations that increase risk of breast and ovarian cancer – and those genes number many more than the two she discovered, BRCA1 and BRCA2.

“Many women with mutations in these genes are identified as carriers only after their first cancer diagnosis because their family history of cancer was not sufficient to suggest genetic testing. To identify a woman as a carrier only after she develops cancer is a failure of cancer prevention,” she said upon winning the Lasker Award in 2014. She began her work with families with cancer-predisposing mutations in 1974.

What Cancer Risk Genes Do

Inherited mutations that raise cancer risk, like the BRCA genes, account for only 5 percent or so of cancers. They pass to every cell from the fertilized ovum, blossoming into cancer when a second mutation occurs in a cell decades later, such as in a breast. The other 95 percent of cancers arise from two (somatic) mutations in cells of the affected body part, usually later in life.

Even though the inherited (aka “germinal”) mutations like the BRCAs are relatively rare, testing for them is important for two reasons: to help a newly-diagnosed woman choose the aggressiveness of treatment (such as a double mastectomy because of the lifelong elevated risk), and to alert relatives who might already have cancer and not know it, or wish to take action to prevent it.

Cancer risk genes control natural DNA repair, and they interact in complex ways. Because people have different combinations of genes, a mutation that increases risk of cancer in one person might not in another.

A breast cancer cell dividing (National Cancer Institute)

The New Findings

The research team looked at the value of testing for three cancer risk genes (BRCA1, BRCA2, and PALB2) in nearly 12,000 patients with breast cancer who were enrolled in four large studies in the UK or the US.

The researchers teased out valuable info by considering the breast cancer patients in two ways. First they did calculations (“microsimulation modeling”) for all of them, and then again for only patients who either had a family history of breast cancer or met clinical criteria of higher risk (under age 50 at diagnosis or having triple negative breast cancer).

Restricting the pool to women with breast cancer who had affected relatives or who met the clinical criteria about doubled the number of additional cases found. But widening the pool to all the women with breast cancer also saved lives, perhaps enough to support the population-level screening (all women) that Dr. King suggests.

The metrics: Testing all women diagnosed with breast cancer for the three risk genes would prevent 2,101 other cases of breast or ovarian cancer and 633 deaths in the United Kingdom and 9,733 cases of either cancer and 2,406 deaths in the United States – A YEAR. Testing also cut costs. “These findings support changing current policy to expand genetic testing to all women with breast cancer,” the researchers conclude.

But as Dr. King has repeatedly pointed out, testing all women would be even better, because mutations in the BRCA genes and the dozens of others that predispose to cancer can run through a family silently. This can happen if a family is small, members are all young, or most members are male.

Origin of the Family History Idea

The idea that only women whose relatives have breast cancer can also get it may have arisen from the way that genetic research was once done. Before DNA sequencing became routine, family studies were crucial to identifying the genes behind illnesses.

In the 1980s and 1990s, geneticists traced the co-occurrence of an illness with specific mutations through extended families in which several members have the same disease. Searching among such “kindreds” was like enlarging the needle in a haystack to the size of a harpoon.

Early studies on the BRCA genes used families with many affected members, narrowing the gene search, like a large needle in a haystack.

I looked at the papers leading to the initial descriptions of the BRCA genes, the first in 1994 and the second a year later. Those took me to a study from 1988 that traced what would be dubbed BRCA1 in 1,579 families that had many breast cancers. But even the 1988 paper found, in family trees, that mutations in the gene are prevalent enough that they can appear in a family more than once from different lineages. Coincidence and inheritance from a shared ancestor aren’t the same, by definition and in terms of associated health risks.

BRCA mutations, it turns out, are both common and complicated.

The idea of breast cancer running in families picked up speed as researchers discovered more cancer risk genes. And as more people were tested and data accrued, the proportion of breast cancer cases among women without family history increased, from slightly more than 50% in a report from 2007 to more than 70% in a study a decade later. It’s now more than 75 percent. (This DNA Science post from 2015 links to individualized risk calculators.)

Population Screening is the Way to Go

Dr. King cited World Health Organization criteria for population (meaning everyone) screening for genetic predisposition to a disease:

  • importance to the public health burden in the population
  • known risk from specific mutations
  • interventions available to prevent or treat the condition.

Population-wide screening of all women for breast cancer risk genes would save lives. (NHGRI)

I’d go farther: BRCA1, BRCA2, and even PALB2 are only a trio of dozens of cancer risk genes, for which some labs, like Invitae and Myriad Genetics, now test. I was tested for 104 genes.

Plus, for a test to be fully informative, the genes must be entirely sequenced to detect all possible mutations as well as missing, extra, and rearranged parts. Consumer DNA testing companies like 23andMe only test for the three most common mutations in the BRCA genes. These giant genes can mutate in many ways, just like a long book would have more typos than a short one.

Women with Breast Cancer: We Help Ourselves

Dr. Manchanda suggested in the interview, and the article advises, that because of the shortage of genetic counselors in cancer centers, that surgeons, oncologists, and clinical nurse specialists be trained to provide the genetic counseling necessary for cancer risk genetic testing. He spoke about health care infrastructure, about academic studies, and “context-specific delivery models,” involving math.

All that is necessary. When I asked my breast surgeon about testing genes other than BRCA, her response was a deer-in-the-headlights confusion. Ditto my oncologist. But my genetic counselor gave me half a dozen lab choices, each testing for many more than the BRCA genes.

The new research paper may be somewhat out of touch because it doesn’t mention the vast online communities of women who help each other in practical ways, by providing information gleaned from direct experience, often something that a clinician who has never personally experienced the terror of breast cancer can do.

A woman asks a question:

  • How long will I miss work following a lumpectomy?
  • What does radiation feel like?
  • How does an oncoscore differ from receptor status?
  • Which implants are being recalled?
  • Is a hormone blocker necessary past a certain age?
  • How long must a woman who goes flat wait before getting chest tattoos?
  • Why does so little funding go to metastatic disease?

Dozens of answers flood in within minutes, often with specific information. We’re from all over the world, and we keep each other going.

The online breast cancer communities, such as and many closed Facebook groups like Breast Cancer Straight Talk, are wonderful. The October pink campaign, not so much. Some of us dread it.

On October 1, I awoke and didn’t immediately think about breast cancer, my diagnosis now two years behind me. Then I stopped at the bank and saw the desks festooned in pink ribbons and flowers. At zumba, the cheery pink-clad instructor announced that we should all wear the iconic color.

And the terror flashed back. Instantly. I relived my experiences throughout that zumba class. The next morning, the monster was, once again, the first thing I thought about.

Making genetic risk testing available to all women, as Mary Claire King advises, will bring more women into our club that no one wants to join. But the earlier treatments that more widespread testing will foster can go a long way towards making breast cancer more often a chronic disease, and less often a killer.









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