Why Some Cancer Drugs Stop Working

A type of breast cancer drug stops working in some patients and the reason has been discovered by some scientists. An international team led by Imperial College London and the European Institute of Oncology in Milan reveal some breast tumors evolve to make their own fuel supply that renders treatments powerless.

The findings from this team are published in the journal Nature Genetics. They hope that their work will increase treatment options for patients whose cancer has returned. This is the most common cancer in the U.K. and causes 55,200 new cases every year. The so-called ER-positive breast cancers account for about 70% of all breast cancers. These cancer cells contain a receptor for the hormone estrogen and this hormone is what fuels the tumors.

This type of cancer offers one of two drugs to these patients after surgery to prevent the cancer from coming back. One drug, tamoxifen, prevents the estrogen from binding to DNA in cancer cells while the second type called aromatase inhibitors prevents residual estrogen from being produced in other tissues. This last drug is usually used in those who have gone through the menopause. The ovaries of these women have stopped producing estrogen, but some hormone is still made in several other tissues by an enzyme called aromatase. The enzyme is prevented in making estrogen by this medication.

These two inhibitors stop working in about 1 in 3 patients. It is assumed by the scientists that the tumors developed resistance in some way, but didn’t really know how. It was discovered, however, that in the latest study one in four patients taking aromatase inhibitors were showing the tumors had an increased production of this inhibitor in the cancer cells. They do this by increasing the number of aromatase genes in a process called amplification.

The cancer cells will be allowed to effectively make their own estrogen without relying on external sources of the hormone, as explained by Dr. Luca Magnani, co-lead author of the research from the Department of Surgery and Cancer at Imperial. This is the first time they have seen how the breast cancer tumors become resistant to aromatase inhibitors. By cutting off the tumors fuel supply (estrogen) the cancer adapts to this by making its own fuel supply. The tumors also become resistant in different ways, depending on whether tamoxifen or aromatase inhibitors are used.

They are currently working on a test to identify if a patient’s tumor has started to increase aromatase production, and make its own estrogen. When an aromatase inhibitor stops working for a patient the doctors will then try another type of aromatase inhibitor. Research shows that if the patient’s cancer has started to make their own aromatase, the second drug would be useless and that is why a test to identify these patients is needed. It is suggested that doctors take a second sample of the tumor when the cancer returns. Currently, a patient can only have one biopsy when first diagnosed, but if they had a second biopsy when the cancer returns, this would give vital information about how the cancer has evolved and the treatment options that are available. Once a cancer spreads, the disease is incurable.

This work was funded by an Imperial College Junior Research Fellowship, Cancer Research UK and AIRC.

Dr Fredda Branyon