*Cutting the risk*

A recent Jerusalem scientific symposium focused on reducing the risks of breast and ovarian cancer through genetic testing and personalized treatment.

It was a standard routine throughout the Western world. Women over 40 or 50 received a reminder to get an annual or biennial checkup. They went to a clinic, nervously undressed, thinking about their one-in-eight lifetime risk of having breast cancer. They winced as a female technician squeezed their breasts between glass slabs for four x-ray images and waited hours, days or weeks for an expert assessment of the images.
Those fortunate to be negative relaxed until the next time; those unfortunate women with a suspected lesion went through more tests, invasive procedures and – if confirmed – the malignant tumor or the whole breast was excised, followed by radiation therapy and chemotherapy.
Today, thanks to technological, pharmaceutical, genetic and microbiological advances, this course of action has become very different. Not only are x-rays used, but also ultrasound and MRI. Some cancers are now recognized as being faster growing and more aggressive, with others slower and less dangerous. Biological drugs that change the way cancer cells interact and prevent cancer cells from sending signals that make them divide and grow are additional options.
There are numerous types of breast cancer; patients are regarded as individuals; and their treatments are no longer the same for everybody.
These changes were discussed at the Second Annual Breast Symposium held earlier this month at Jerusalem’s Shaare Zedek Medical Center. Organized by Dr. Shalom Strano of the hospital’s breast imaging department, it was attended by hundreds of physicians and researchers. “Our department has diagnosed over 200 breast cancer cases with mammoography in the last two years since we established it,” said SZMC director-general Prof. Jonathan Halevy.
“Mammography will not go the way of the PSA test did,” he said, referring to the blood test for prostate specific antigen that has been largely abandoned for screening. “One has to choose wisely. Some tests may cause more harm than benefit, but mammography is not one of them.”
Among the speakers at the conference was pathfinding US geneticist Prof. Mary- Claire King – who has just won a prestigious, $250,000 prize from the Lasker Foundation.
“The idea that breast cancer – and ovarian cancer – can be inherited was first suggested by Dr. Paul Broca, a 19th century French neurosurgeon, neurologist, anthropologist and anatomist,” said King, who in 1990 discovered the BRCA1 gene that causes many inherited cases of breast and ovarian cancer.
“The deletion of base pairs means that the mutation can be inherited through mothers or fathers. There can be breast cancer in a family that carries the mutation but not be due to the mutation.”
Women with mutations in BRCA1 or BRCA2 (discovered by another group a few years later), “have done everything right,” said King. “They are intelligent, nearly all took excellent care of their health and exercised. In women with an inherited mutation, one copy of the gene has no effect, but if a second mutation appears this second copy, in the cells that line the milk ducts of breasts or the Fallopian tubes or ovaries, this combination of two mutations leads to cancer,” the acclaimed researcher explained. “There are thousands of individual BRCA mutations; in Jewish populations, there are two mutations in BRCA1 and one in BRCA2,” she said.
“Ten years ago, I was interested in BRCA1 and BRCA2 mutations in Ashkenazi Jewish patients and traced back the families of over 1,000 women to see what happened to carriers of the mutations,” said King, who is not Jewish herself but had a Jewish maternal grandfather.
The risk of developing breast and/or ovarian cancer in women with the mutation is over 80 percent by the age of 80. The risk of breast cancer is higher in carriers of mutations in BRCA1 than in BRCA2. There are also non-genetic factors that have increased the prevalence of breast cancer around the world.
Other studies of women with mutations in BRCA1 or BRCA2 showed that of mutation carriers who decided to have their breasts surgically removed to lower their risk, only two out of 105 women developed breast cancer within 30 years, compared to 184 women who decided not to have a risk-reducing operation, King reported.
“This led to the recommendation in 2004 by the US Preventive Services Task Force that if a woman carried a BRCA mutation, she should go for an annual mammogram or MRI from the age of 25, discuss eventual mastectomy and consider the removal of her ovaries and Fallopian tubes after completing their child bearing. Short-term hormone replacement therapy should also be considered, as the amount of estrogen given in HRT is much lower than the amount natural estrogen they would get if they didn’t have their ovaries removed,” said King. If women get the cancer, PARP inhibitor therapy, she added, could help to prolong their lives. PARP inhibitors are a group of compounds aimed at inhibiting an enzyme that promotes various types of tumors.
Fathers can pass their BRCA mutations to their children, but they almost never get breast cancer themselves; only about one percent of breast cancer are diagnosed in males, but they are usually diagnosed later than in men.
King and colleagues at the University of Washington developed BROCA, a test for evaluating patients with a suspected hereditary cancer predisposition, especially for breast and ovarian cancer. The test uses advanced sequencing to detect mutations in these genes. “We named it to honor Dr. Broca for his discovery nearly 200 years ago. Our first application of BROCA was to study patients with ovarian cancer, whatever their family history or age. They underwent surgery, gave DNA samples, and we evaluated their DNA with the test. In Washington State, there is a mixed American population, mostly of North European ancestry. More than 23% of the ovarian cancer patients carried a BRCA mutation. In Israel, 40% of ovarian cancer has been shown to be due to BRCA mutations,” said King.
A few weeks ago, the head of SZMC’s medical genetics institute, Prof. Ephrat Levy-Lahad, King and colleagues recommended in articles in the PNAS (Proceedings of the [American] Academy of Sciences and JAMA (Journal of the American Medical Association) BRCA screening in Ashkenazi Jewish women from the age of 30 and other populations as well.
One in 40 Ashkenazi women – and men – are carriers. There are 18 other genes for breast and ovarian cancer besides BRCA1 and BRCA2. In the US, more than 10% of breast cancer and more than 20% of ovarian cancer come from mutated genes, said King. “Cancer can be prevented in women with mutations,” King declared. “Genetic testing is technically accurate and the cost is dropping. One needs only a blood sample. I believe it will eventually happen, because the cost of saving women is far less than that of treating the women’s cancer. In principle, one could even test newborn baby girls, but there is no reason to do so. Testing women at about age 30 makes sense, because at this age those with mutations can mae a plan about their lives. We would like to see population-wide testing offered sooner rather than later. Women who discover they have BRCA mutations can be examined regularly, and some will chose to undergo surgery to almost eliminate their risk. There shouldn’t be any women dying of cancer due to BRCA1 or BRCA2 mutations.”
PROF. LAURA Esserman, a leading breast surgeon and director of the Buck Breast Care Center at the University of California at San Francisco, noted that screening policies vary widely depending on the country.
“In the US, women are invited for screening annually from the age of 40 through their whole lifetime. In Sweden, it is between 50 and 70 and biennially. In Israel, it is from 50 (except for women with a family history or a known mutation, who are tested annually from age 40) every two years through age 74,” said Esserman.
“But in Switzerland, health authorities are thinking of stopping mammography altogether because they claim it is ‘not proven.’ I think the Israeli policy is very sensible. But women everywhere are confused, and they don’t have proper guidance. Some are underscreened, and others are overscreened. Women are caught in the middle.” Esserman advocated an individualized mammography screening program depending on risk and biology. Mammography screening would cost $10 billion annually in the US if all relevant women agreed to do it; the actual current cost is $8 billion a year. But if it were done according to scientific evidence, we would save $6.5 billion a year.”
Before more advanced biological and other treatment was available, the UCSF physician said, “screening policy had been based on clinical trials from 1980s. There were a lot of false-positive results, and 75% of biopsies were benign. There was overdiagnosis and overtreatment. We owe it to women to find a better way. I agree with Mary-Claire that screening should be done according to risk assessment and biology. Make it more cost effective and integrate it with prevention. It must be evidence based, adaptive and be more effective at finding relevant cancers. One size does not fit all. Check the woman’s biology, conduct genetic tests. Today, we too often make a mistake by screening all women the same way. Let’s stop arguing whether mammography works or not. Instead, we need a modern screening trial that compares annual or biennial screening versus personalized screening,” said Esserman.
“We can’t afford to wait another 10 years.”
She is among the founders of the Athena Breast Health Network, involving all five University of California medical centers and their affiliates.
The program brings together 150,000 women, their doctors, specialists and researchers in pursuit of the common goal of better breast health for every woman. Women fill out a health questionnaire, get a risk report based on their personal information and a personalized plan for screening by their health insurance provider.
Esserman’s UCSF young colleague, Dr. Martin Ekund, who also works at Sweden’s Karolinska Institute, added: “It’s important to focus resources and effort properly. One can predict risks from age, breast density and mutations. Personalized screening is needed. But without getting genetic data, we can’t do it. We would like to collaborate with Israelis.”
PROF. UZI Beller, head of SZMC’s gynecology department and a wellknown expert on ovarian and other gynecological cancers, said that ever year, about 235,000 women are diagnosed with ovarian cancer around the world. It also is responsible for the deaths of 140,000 women annually. Statistics show that just 45% of women with the tumor are likely to survive for five years compared to up to 89% of women with breast cancer, as it usually is diagnosed much later, and there is no good screening for it that reduces the mortality rate.
“When actress Angelina Jolie announced that she was a BRCA carrier and was going to undergo risk-reducing surgery, twice as many women went to their doctors to be tested.”
Beller added that thanks to the discovery of BRCA, there has been a “dramatic improvement in the understanding of ovarian cancer. There are two kinds, one from the ovaries and the other from the Fallopian tubes. Using oral contraception can reduce the risk, including BRCA carriers. If ovaries are removed, the risk is almost eliminated. There is no evidence yet that removing the Fallopian tubes alone can prevent cancer in the nearby ovaries. Taking aspirin daily, however, could reduce the danger of ovarian cancer in high-risk women.”
Levy-Lahad announced at the symposium the launching of the Prevention GENEration program (known as Hasikui She’basikun) “to increase awareness and testing of carriers. “Israeli families don’t talk so much when cancer strikes, so they don’t know all of their relatives’ history of the disease,” she said. “Screening of carriers is technically feasible now, and after the test, there is high satisfaction and minimal psychological damage. Even many family physicians don’t refer their patients for screening even if there is a family history.”
The program, offered in cooperation with the Israel Cancer Association (ICA), is supported financially by the Northern Charitable Foundation based in the US, said Rosa Dembitzer, who heads it, came on aliya four years ago with husband and lives in Herzliya.
They have two children aged 22 and 19.
“I had a routine mammogram in New York at the age of 45. By pure chance, a friend asked if I got tested for BRCA. I said that no one in my family had either breast or ovarian cancer, but I went for a test and found out I was positive for it.” She underwent a risk-reducing double mastectomy and also had her Fallopian tubes and ovaries removed. Doctors also found she had ovarian cancer. “I had chemotherapy and am well.”
Dembitzer was introduced to Levy-Lahad and cancer association director-general Miri Ziv. “Now we have an interactive questionnaire on the ICA website,” said Dembitzer.
“We want to raise awareness of genetic testing and early diagnosis. I want to help other carriers so they won’t have to go through the whole ordeal I went through,” she said.