Why Men Need to Be Screened for Breast Cancer Mutations

Plenty of people without a family history of breast cancer turn out to have BRCA mutations. Not just Ashkenazis but everybody should be screened, says U.S.-Israeli forum of doctors.

Breast cancer is usually treated with surgery; Cryoablation can replace that.
Breast cancer is usually treated with surgery; Cryoablation can replace that. teyr Dietrich Johannes

Until a cure for cancer is found, early detection can save your life. Testing for "breast cancer gene" mutations offers the option of preempting potential disease – not only for women, but for men too, and everybody should get tested, a panel of experts urges.

Men can develop breast cancer too, albeit at a hundredth the frequency of women. But the "bad" BRCA (breast cancer) genes are also associated with colon cancer in both sexes, and with aggressive prostate cancer in men.

Israel could theoretically test everybody because it has universal healthcare, though it doesn't have the resources. The fragmented American healthcare system couldn't even theoretically do it, agreed the doctors and administrators at the Jerusalem symposium organized by the Israel Healthcare Foundation and Soroka Medical Center in Be'er Sheva. Yet both countries need universal screening, they insist.

A woman has a 1-in-8 chance of developing breast cancer over an 80-year lifespan. The incidence of breast cancer in American men is 1 in about 1,000.

Ovarian cancer is rarer: the lifetime risk is about 1 in 75. But it is deadly, mainly because it is so rarely detected in time. The lifetime risk of prostate cancer in men is about the same – approximately 1-in-7.

Why are women screened? If genetic testing shows they possess certain "cancer genes," though perfectly healthy, some women elect for prophylactic mastectomy and oophorectomy - removal of breast and ovarian tissue. A positive result can also change the manner of treating the disease, the doctors explain. But why should men be screened?

Mutation predating Babylonian exile

"Cancer genes" are a misnomer. They are normal genes that become associated with cancers when they mutate. Otherwise these genes just do what they were supposed to do.

The two BRCA genes for instance actually code for proteins that can curb tumor formation by repairing DNA. Oh, the irony.

So when discussing "breast cancer genes" that cause disease, what we're really talking about is harmful variants of these genes.

Everybody has the notorious genes BRCA1 and BRCA2, which are just two of the many genes associated with breast cancer. But to be clear: it is mutation in BRCA1 and BRCA2 that is implicated in breast and colon cancer in both sexes, ovarian cancer in women and (in the case of BRCA2) aggressive prostate cancer in men.

Mutation can appear anywhere along the DNA chains making up "cancer genes" such as BRCA1 or BRCA2, explains Amnon Lahad, chairman of Family Medicine at Clalit Health Services, elaborating that hundreds of mutations have been identified and described in the literature.

Amnon Lahad, chairman of Family Medicine at Clalit Health Services: Mutations can appear anywhere in the BRCA genes, but only a few types out of hundreds known are common in Ashkenazim.
Emil Salman

Just three of those hundreds commonly appear among Ashkenazi Jews with mutations. The most commonly found variant in Jewish BRCA1 is called 185DelAG, which is believed to be a founder mutation among Ashkenazim.

Fascinatingly, Iraqi Jewry, who split from the Ashkenazim before the great exile, also have high rates of the 185delAG variant. That indicates that the mutation predated the Babylonian captivity, says Lahad.

When genes go rogue

The question the symposium, chaired by Dr. Larry Norton of Memorial Sloan Kettering Medical Center in New York, gathered to explore: Who should be screened for predisposition to breast cancer? Should the general population?

Among Ashkenazi Jews, the known incidence of BRCA1 and 2 mutation is about 1 in 40. Scandinavians – Norwegians, Dutch and Icelanders – also have relatively high incidence.

A model of the protein produced from the BRCA1 gene. The doctors participating in the Clalit-Sloan Kettering-Soroka forum agree: General screening, though not feasible, would be best because family history is no gauge of whether one has a mutant form of BRCA, or not.

So it's a no-brainer to test people of Ashkenazi origin and Nordics. Why test everyone else? (except children – no point in that. Breast cancer doesn't begin before age 25 or so.)

Because the BRCA mutations seem to be more common in general than had been thought. Because the mutations are prevalent chiefly in people of Eastern Europe ancestry, including Ashkenazim, but can appear in anybody.

Because the model of picking women for testing based on a family history of breast cancer is bankrupt.

Because, crucially, a significant proportion of people discovered to carry BRCA mutations, who are therefore at high risk, have no family history of cancer, it turns out based on data from Soroka and other studies, including in northern England.

"It has been shown in Israel, in studies of the Jewish population, that half the mutations found in a series were in people who had no risk factors in family history," says Dr. Judy Garber, the director of the Center for Cancer Genetic and Prevention at Harvard Medical School.

"We talked about the fact that cancer genes run in families. But people don't recognize the risk if they have no family history of cancer, or the history is unknown," Garber says.

The only way to locate people at high risk without helpful prodding by aunties is general screening, the team concluded.

left to right: Dr. Kenneth Offit (Memorial Sloan Kettering), Dr. Judy Garber (Harvard Medical School), Andrew Abramson (Cure Breast Cancer Foundation), Dr. Ehud Davidson (Soroka), Dr. Larry Norton (Memorial Sloan Kettering), Dr. David Geffen (Soroka), Dr. Amnon Lahad (Clalit) and Dr. Perry Davis (Israel Healthcare Foundation).
Soroka Medical Center

The Israeli part of the study that found "cancer gene" mutations to be unexpectedly common was done at Soroka. The hospital is in the process of building a huge cancer center costing over $50 million (Clalit is footing most of the bill) that should be ready to roll within a year. Norton chose Soroka to study the prevalence of BRCA mutations in the general population, because it has a vast, genetically and culturally diverse "captive audience" of over a million people. It's the only hospital serving the entire Negev population - Jews, Arabs, and Bedouins.

Also, all Israelis have health insurance, so no biases are created because of access to care, Norton points out, adding that Soroka's medical records are "immaculate." (Whew.)

The study tested 8,000 healthy Israeli men for BRCA 1-2 mutations, found 175 "mutant" men; then looked at their family histories.

Of the BRCA1-2 mutation carriers, a stunning two-thirds had no family history of breast cancer, Lahad said. 

"Only recommending testing for people with a family history of breast cancer is clearly a mistake," he spells out, especially as mutation carriers tend to develop breast cancer earlier than non-carriers.

The location of the BRCA1 gene on the long arm of Chromosome 17. Most mammals whose genomes have been sequenced turn out to have some form of BRCA1 gene, which has also been implicated in Alzheimer's, because the gene critically contributes to repair of double-strand-breaks in the DNA of nerve cells as well.
Armin Kübelbeck, Wikimedia Commons

Pogrom genetics

Why do certain groups have more mutations, and others less? Lahad fields the question.

In Eastern Europe, pogroms over centuries decimated the Ashkenazi Jewish population, killing off mainly the men. Unrelated studies estimate that today's Ashkenazi population derived from just 350 founders who survived the massacres – and somebody there evidently had a founder mutation.

"Because of population isolation, the frequency of the mutation in that small group increased over time. It was historic bad luck," Lahad explains. Sephardic Jews have no such history of historical or geographical confinement.

Population screening could spare Israelis about 260 cases of breast or ovarian cancer a year among Ashkenazis, Lahad estimates. That number would increase if the general population was tested, especially if the tests are widened beyond BRCA.

Sounds expensive. "The effects of this would be bigger than a lot of other stuff we do on a regular basis," Lahad points out. "As a preventative for cancer, it's secondary to getting people to stop smoking, but it should rank higher than many other preventative things we do."

Breast cancer is curable

What would the point of mass testing be? Mainly, to improve the quality of life, not necessarily survival. 

"Prophylactic mastectomy has not been shown to improve survival rates," Norton says, to Haaretz's surprise. He explains: "In a screened population, most cases of breast cancer are cured nowadays."

What does "cured" mean, in this context? Haaretz inquired. "You die of something else," Norton smiles.

Dr. Larry Norton, Memorial Sloan Kettering Cancer Center. Dr. Norton, wearing a dark suit, light colored striped shirt, yellow tie with square patterns and glasses, is balding on top and smiling.
Memorial Sloan Kettering Cancer Center

Uh huh. If breast cancer is curable, why would women elect for preventative mastectomies and oophorectomies?

One: Because the cure can be horrible. "To be cured, if you have breast cancer, you may have to go through chemotherapy, taking noxious things, plus there is the trauma of being screened on a regular basis," Norton points out. Yes, women are electing for bilateral mastectomies to avoid the horror of cancer therapy.

Two: Preventative breast and ovary removal is generally done after the women have had their children, or after 40.

Three: Not a few women are happier with their reconstructed breasts than they had been with the original ones, says the doctor. The statistics for voluntary plastic surgery suggest that to be a widespread truism.

The story for prophylactic oophorectomy, removal of the ovaries, is something else entirely. That is about not dying of ovarian cancer, which in contrast to breast cancer, is almost always fatal. That's because ovarian cancer is almost always diagnosed by complete coincidence and seldom caught in time to be treatable, says the doctor.

Other non-genetic risks for breast cancer, by the way, include obesity, lack of exercise, HRT and exposure to toxins like radioactive substances.

"Prophylactic mastectomy does reduce the incidence of breast cancer. It has not been found to reduce mortality. But if we had a bigger test sample – much bigger – we might find effect of reduced mortality," surmises Lahad.

The bottom lines are then that in a perfect world, everybody would be tested for the more common cancer mutations; that family histories are lousy gauge of cancer probability; and that prophylactic mastectomies and oophorectomies can save women's lives and/or spare them onerous treatments.

While the prophylactic practice is becoming increasingly common in America, Israeli women are having none of it. Even if urged to the scalpel by their doctors, they'd rather opt for closer monitoring, even though mammograms suck, the Israeli doctors agree.  Why? Who knows. "Cultural differences?" shrugs one of the doctors.