Drugs for ovarian tumor can treat breast cancer
The most comprehensive analysis yet of breast cancer has revealed that one of the most deadly subtypes is genetically more similar to ovarian tumors than to other breast cancers.
The findings suggest that most basal-like breast tumors and ovarian tumors have similar genetic origins and potentially could be treated with the same drugs, said the study’s co-leader Matthew J. Ellis, MD, PhD, the Anheuser-Busch Chair in Medical Oncology at Washington University School of Medicine in St. Louis.
Basal-like tumors account for about 10 per cent of all breast cancers and disproportionately affect younger women and those who are African-American.
The new research is part of The Cancer Genome Atlas project, which brings together leading genetic sequencing centers, including The Genome Institute at Washington University, to identify and catalog mutations involved in many common cancers. The effort is funded by the National Institutes of Health (NIH).
“With this study, we’re one giant step closer to understanding the genetic origins of the four major subtypes of breast cancer,” said Ellis, who treats breast cancer patients at the Siteman Cancer Center at Barnes-Jewish Hospital and Washington University.
“Now, we can investigate which drugs work best for patients based on the genetic profiles of their tumors. For basal-like breast tumors, it’s clear they are genetically more similar to ovarian tumors than to other breast cancers. Whether they can be treated the same way is an intriguing possibility that needs to be explored,” he added.
Hormone therapy for ovarian cancer
Hormone therapy is the use of hormones or hormone-blocking drugs to fight cancer. This type of systemic therapy is rarely used to treat epithelial ovarian cancer, but is more often used to treat ovarian stromal tumors.
Gonadotropin-releasing hormone (GNRH) agonists switch off estrogen production by the ovaries. These drugs are useful in lowering estrogen levels in women who are premenopausal. Examples of GNRH agonists include goserelin (Zoladex®) and leuprolide (Lupron®). These drugs are injected every 1 to 3 months. Side effects can include any of the symptoms of menopause, such as hot flashes and vaginal dryness. If they are taken for a long time (years), these drugs can weaken bones (sometimes leading to osteoporosis).
Tamoxifen is an anti-estrogen drug that is often used to treat breast cancer. It can also be used to treat ovarian stromal tumors and is rarely used to treat advanced epithelial ovarian cancer. The goal of tamoxifen therapy is to prevent any estrogens circulating in the woman’s body from stimulating growth of the cancer cells. Even though tamoxifen may prevent estrogen from nourishing the cancer cells, it acts like a weak estrogen in other areas of the body. It does not cause bone loss, but can cause hot flashes and vaginal dryness. People taking tamoxifen also have an increased risk of serious blood clots in the legs.
Aromatase inhibitors are drugs that block an enzyme (called aromatase) that turns other hormones into estrogen in post-menopausal women. They don’t stop the ovaries from making estrogen, so they are only helpful in lowering estrogen levels in women after menopause. These drugs are mainly used to treat breast cancer, but can also be used to treat some ovarian stromal tumors that have come back after treatment. They include letrozole (Femara®), anastrozole (Arimidex®), and exemestane (Aromasin®). These drugs are pills that are taken once a day.
Common side effects of aromatase inhibitors include hot flashes, joint and muscle pain, and bone thinning. The bone thinning can lead to osteoporosis and bone that break easily.
Currently, for example, basal-like breast tumors often are treated like many other breast cancers, using anthracycline-based chemotherapy. But another of Ellis’s studies recently showed that women with basal-like tumors don’t benefit from these drugs, which also have severe side effects.
At the very least, he said, the new data indicates that clinical trials should be designed to avoid the use of these drugs in basal-like tumors.
The study confirmed the existence of four main subtypes of breast cancer: Luminal A, luminal B, HER2 and basal-like. The latter includes most triple-negative breast tumors, so-named because they lack receptors for the hormones estrogen, progesterone or human epidermal growth factor 2 (HER2). These tumors often are aggressive and do not respond to therapies that target hormone receptors or to standard chemotherapies.
A recent controlled study has indicated that prolonged use of fertility drugs may increase the risk of ovarian tumors. Researchers at the University of Washington and Fred Hutchinson Cancer Center in Seattle decided to look into the matter after case reports suggested that women who undergo fertility treatment may develop tumors at higher than average rates. The scientists wanted to learn whether increased risk was the result of conditions responsible for infertility or by the drugs taken to increase fertility.
The research team examined the records of 3837 women who visited fertility clinics between 1974 and 1986. When they cross-checked the women’s names against those in a tumor registry, they discovered that by the end of 1991 four of the women had been diagnosed with ovarian cancer and an additional seven with borderline malignant tumors. The overall risk of ovarian tumors for women who had fertility treatments was 2 1/2 times that of women in general.
The Seattle scientists found that the women who developed ovarian tumors were more likely to have taken one particular fertility drug, clomiphene (Clomid), than were other infertile women. They calculated that although infertility itself did not appear to increase ovarian-tumor risk, taking clomiphene for longer than 12 months increased that risk substantially. Even so, the lifetime risk of ovarian cancer, which increased from about 2% to 4-5% for women in the study, was still relatively slight. Moreover, undergoing clomiphene treatment for less than a year appeared to have no effect on risk whatsoever. The study appeared in the September 22, 1994, issue of the New England Journal of Medicine.
Across the four subtypes, mutations in only three genes - TP53, PIK3CA and GATA3 - occurred in more than 10 percent of patients’ tumors. But, the scientists found unique genetic and molecular signatures within each of the subtypes.
Their findings add to the growing body of evidence suggesting that tumors should be cataloged and treated based on the genes that are disrupted rather than the location in the body.
In general, compared to the other subtypes, basal-like and HER2 tumors had the highest mutation rates but the shortest list of significantly mutated genes. These genes are thought to be major drivers of cancer progression. For example, 80 percent of basal-like tumors had mutations in the TP53 gene, which have been linked to poor outcomes. About 20 percent of the tumors also had inherited mutations in BRCA1 or BRCA2 genes, which are known to increase the risk of breast and ovarian cancer.
“This suggests that it only takes a few hits to key genes that drive cancer growth,” Mardis explains.
A high frequency of TP53 mutations also occurs in ovarian cancer, the researchers noted. Overall, the genetic profiles of basal-like and ovarian tumors were strikingly similar, with widespread genomic instability and mutations occurring at similar frequencies and in similar genes.
Finding new drug targets for basal-like breast tumors is critical, and the research suggests that patients with mutations in the BRCA genes may benefit from PARP inhibitors or platinum-based chemotherapy, which are already used to treat ovarian cancer.
The findings have been published online in Nature.
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