Preventive Surgeries May No Longer be Necessary for High Risk Breast Cancer Patients

New therapeutic target may decrease breast cancer risk.

A double mastectomy may no longer be necessary for women who want to decrease their chance of breast cancer by opting for the surgery, according to research published in EBioMedicine. Two new studies evaluating the effect the menstrual cycle has on the development of breast and ovarian cancers may render surgery unnecessary, the study found.

Breast cancer is the most common cancer in women worldwide and ovarian cancer is the deadliest gynecological cancer. Women with either BRCA1 or BRCA2 mutated genes are at higher risk for breast and ovarian cancer. Sometimes, women at high risk will opt for a double mastectomy or remove their fallopian tubes and ovaries as a preventative measure to reduce the risk of these cancers.

However, the mutations also affect organs that control the menstrual cycle, which has a central role in the development of breast and ovarian cancers. Previous studies have shown that hormones involved in the menstrual cycle, particularly progesterone, have an effect on the development of cancer.

Progesterone increases the amount of a protein called RANKL in the breast, which in turn triggers breast cancer.

This means that genetic predisposition to breast and ovarian cancer is a result of the effect the genetic mutations have on hormones that control the menstrual cycle, as well as the effect the mutations have on the cells that develop into tumors.

A new study by researchers at University College London revealed that women who have either mutation BRCA1 or BRCA2 have less of a molecule called OPG in their blood. When OPG is present, it blocks the effects of RANKL, stopping breast cancer in its tracks. RANKL is not found at increased levels in women with either mutation, but OPG is significantly lower in women with BRCA1 or BRCA2.

Researchers suggest that a drug that copies the effects of OPG or decreases the effects of progesterone in the body could help prevent breast and ovarian cancers from developing, but more research is needed to determine whether this is a viable prevention strategy.

“Preventative surgery is quite a drastic measure and we’re unsatisfied with the situation — we are aiming to prevent breast cancer, and findings from our research are a significant step forward in demonstrating the importance of why further research is critical in this arena,” said lead author Professor Martin Widschwendter. “Women who develop breast cancer as a consequence of their mutation develop cancers associated with poor prognoses that are difficult to treat. Prevention without surgery is the ultimate goal and this study is the first proof of principle – we have identified a new target we can now use to decrease breast cancer risk.”

The second study used a mouse model to help researchers understand what is behind the effect of the menstrual cycle on the risk of breast and ovarian cancer. The study was led by Professor Louis Dubeau at Keck School of Medicine.

The model uses genetically engineered mice that carry BRCA1-like gene mutations, not only in tissues corresponding to those at increased risk of cancer in human BRCA1 mutation carriers, but also in the organs that control the menstrual cycle, such as the ovaries and pituitary gland. The model allows scientists to confine the mutation to a single area that is more susceptible to tumor growth or to tissues that control the menstrual cycle separately, giving researchers a tool to understand the effects of the mutations on the menstrual cycle independently from their direct effects on the tissues in which the cancers begin.

The scientists found when developing the mouse model that some ovarian cancers originate in tissues outside the ovaries and fallopian tubes. This suggests that the removal of the fallopian tubes may not be an effective preventive strategy for patients concerned about contracting ovarian cancer.

“We know that the menstrual cycle has an effect on the development of these cancers, but we don’t understand the mechanisms behind it,” Dubeau said. “We wanted to develop a mouse model researchers could use to study ways of preventing breast and ovarian cancer in women with BRCA1 and BRCA2 mutations. We hope this will result in new approaches that will eliminate the need for surgery in the future.”

More research is needed to confirm the findings and develop preventative strategies for patients. Widschwendter’s team wants to test the effectiveness of OPG in preventing breast cancer, but cannot conduct a clinical trial until they are completely sure it works. Instead, the team plans to test the treatment on high risk women who are waiting for preventative surgeries. This way, instead of patients waiting for cancer to develop, the team will monitor biological changes in the tissues at risk of cancer to evaluate the effect of treatment on cancer prevention.

“This research demonstrates why our focus is on supporting leading edge medical research that seeks to understand how women-specific cancers start,” said Athena Lamnisos, Chief Executive of The Eve Appeal. “This is a step towards decoding these cancers and understanding how we can develop effective methods of risk prediction and prevention. As the UK’s only gynecological cancer research charity, we are championing for more research into prevention, so that we can save significantly more lives and see a future where fewer women develop and more women survive women’s cancers.”