Ashkenazi Jews have a 2.5% chance of having a BRCA mutation

Women with breast cancer genetic marker hope osteoporosis drug could halt disease

Shaare Zedek Medical Center participates in international long-term clinical trial of Denosumab, which investigators say may offer medical alternative to preventive mastectomy

Renee Ghert-Zand is the health reporter and a feature writer for The Times of Israel.

Illustrative image: a doctor holds up a pink ribbon for breast cancer awareness. (dragana991 via iStock by Getty Images)
Illustrative image: a doctor holds up a pink ribbon for breast cancer awareness. (dragana991 via iStock by Getty Images)

Providing hope for women carrying the BRCA1 genetic mutation, a clinical trial at Shaare Zedek Medical Center in Jerusalem is investigating whether a drug used to treat osteoporosis can prevent breast cancer.

Recruitment for the trial began a year ago and will continue until at least September. Israel is one of eight countries participating in the phase 3 trial, which is based on recent peer-reviewed international research showing that the RANKL molecular pathway that causes bone breakdown is also found in breast tissue and causes tumor formation and progression.

The 10-year trial is meant to determine whether Denosumab — an injectable human monoclonal antibody known by the brand names Prolia or Xgeva — is as effective in blocking the RANKL pathway in breast tissue as it is in bones. Earlier-stage trials showed a 35-40 percent success rate.

The study in Israel was initiated by Dr. Shani Paluch-Shimon, who now heads the breast cancer unit at Hadassah Medical Center. The current primary investigator is Dr. Rachel Michaelson-Cohen, a gynecologist and the director of the prenatal genetics unit at Shaare Zedek. She told The Times of Israel that she hopes a positive outcome will result in women with BRCA1 eventually having a medical treatment option to reduce their breast cancer risk.

“BRCA1 is more aggressive than the BRCA2 mutation. BRCA1 carriers have an 80% risk of developing breast cancer. Right now, their only options are a preventive mastectomy — which is the sole way to provide full protection — or close monitoring for early detection. In Israel, this means a mammogram once a year and an MRI once a year,” Michaelson-Cohen said.

Unlike many women at high risk for developing breast cancer in other countries who opt for mastectomies, Israeli women are more hesitant to undergo the major surgery. Israel was chosen to participate in the trial for this reason, along with the fact that there are many BRCA1 carriers among the country’s population.

Dr. Rachel Michaelson-Cohen, director of the prenatal genetics unit at at Shaare Zedek Medical Center in Jerusalem. (Courtesy of Shaare Zedek)

Ashkenazi Jews — men and women — have a 2.5% chance of having a BRCA mutation. Genetic testing for anyone with one Ashkenazi grandparent was added to Israel’s health basket two years ago after studies showed its cost effectiveness.

Ruchama Schmulewitz, a Jerusalem architect and mother of four, is a BRCA1 carrier followed at Shaare Zedek’s Noga multidisciplinary clinic for women who were diagnosed with a BRCA1 or BRCA2 mutation. Now 40, she learned of her BRCA1 carrier status when she was tested 14 years ago. Her father had just died of pancreatic cancer, and she was told that his cousins had passed away from breast and ovarian cancer.

“My siblings decided we should do genetic testing. I was the first to do it, and it turned out that I had BRCA1,” Schmulewitz said.

She was seriously considering having a preventive mastectomy when she heard about the Denosumab trial from Michaelson-Cohen at one of her regular checkups at the Noga clinic. She decided it was worth holding off on the surgery to sign up for the trial.

“When you have the mutation you think about how you can keep yourself safe for you own sake and for that of your family. I always like to hear if there is new research. I always hope there will be new developments,” Schmulewitz said.

Illustrative: A surgeon operates on a patient with breast cancer, on June 10, 2021 at the University-affiliated hospital (CHU) in Angers, western France. (LOIC VENANCE / AFP)

“I heard that so far there have been good results [with Denosumab], so it gave me hope and another reason to trust the follow-up [yearly MRIs and mammograms]. The other choice is major surgery, and that affects your body and your body image,” she said.

Michaelson-Cohen emphasized that the thousands of trial participants worldwide must meet criteria beyond being BRCA1 carriers. This is especially important for the first of the trial’s two five-year stages.

“The first stage is the treatment phase, and the second is for follow-up. During the first stage, participants must commit to preventing pregnancy, because the drug cannot be taken while pregnant or breastfeeding,” she said. The age limit for participation is 55.

In addition, the trial is not for women who have had a mastectomy or are planning to have one. Women who change their minds about any of those criteria are free to leave the trial.

With her childbearing years behind her, BRCA1 carrier Haggit Russo, 49, decided to join the trial. Russo’s mother developed breast cancer before the age of 50, and her grandmother died from the disease.

“When Dr. Michaelson informed me about the study when I came to one of my appointments at the Noga clinic, I figured I had nothing to lose by joining it,” said Russo, who works in high-tech finance and lives with her family on a kibbutz north of Netanya.

Russo has early signs of osteoporosis, so she figured there was no downside to taking the twice-yearly Denosumab shots.

“I just hope I’m not in the placebo group,” she remarked.

Illustrative: A woman undergoes a digital mammogram (Bizuayehu Tesfaye/AP Images for College of American Pathologists)

Michaelson said she assures patients that the since Denosumab was approved by the US Food and Drug Administration more than a decade ago and has been in wide use, the drug is known to be safe. However, if a patient experiences concerning side effects, they will go away if the shots are discontinued.

While the trial focuses on breast cancer, BRCA1 carriers must also worry about their high risk of ovarian cancer. Whereas the average American woman faces a 2% risk of developing the disease in her lifetime, a woman with BRCA1 has an estimated 39-46% risk of developing ovarian cancer by age 70.

Russo spoke to The Times of Israel as she recuperated from an oophorectomy, or surgery to remove her ovaries.

According to Michaelson-Cohen, “There is rarely an early diagnosis of ovarian cancer. A woman can have an ultrasound and the disease will not be detected. The only way to prevent ovarian cancer is to remove the ovaries. We strongly encourage women with BRCA1 to have an oophorectomy after they have finished having children.”

Only in a decade from now will she and her international colleagues know the extent of the trial’s success, but the fact that it is happening holds out hope for BRCA1 carriers.

“We have so many women in Israel opting to do breast imaging rather than a mastectomy. They live in fear every time they come in to do their MRI,” Michaelson-Cohen said.

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