An Indian team of researchers has identified a key genetic reason why patients with the most common type of breast cancer in India become resistant to standard hormone therapies used for treatment.
Researchers from University of Delhi, South Campus, and Tata Memorial Hospital, Mumbai, have found that loss or damage to a gene called CDKN1B could be one of the reasons why standard drugs used to treat what is known as hormone receptor–positive (HR+) breast cancer do not work effectively in some patients.
The HR+ type breast cancer accounts for nearly 70 per cent of all cases in India, and is treated with routine hormonal therapy using drugs like tamoxifen that block or reduce the effect of hormones like estrogen which drive the growth of breast cancer cells.
However, in about 40 per cent of the cases, the drugs lose their effectiveness within months to a few years, resulting in a relapse, and regrowth of cancerous cells. Why this happens was not very well understood.
The Indian group of researchers, led by Amit Dutt at the Integrated Cancer Genomics Laboratory, University of Delhi South Campus, and Sudeep Gupta at the Tata Memorial Hospital, have now zeroed in on the CDKN1B gene as the possible reason. This gene is responsible for the production of a protein called p27 which slows down the growth of breast cancer cells. The p27 protein is important for a drug like tamoxifen to work effectively. When the CDKN1B gene is missing, or damaged, or not performing optimally for some reason, the production of p27 protein is affected.
The researchers studied 186 breast cancer patients, of which 98 had developed resistance to the hormonal therapy. They found that the CDKN1B gene was missing or heavily mutated in the patients who had developed resistance. To establish causation, the team was also able to show that if the CDKN1B gene was restored, the drug began to show its intended effect once again.
The researchers have published their findings in the British Journal of Cancer.
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Boost to treatment
India reports about 200,000 cases of breast cancer every year. Hormonal therapy, in cases where it is applicable, is the most common and cost-effective treatment, involving just oral medication. The discovery by the researchers is likely to make this line of treatment work better by addressing the present weaknesses.
“We found that loss-of-function mutations or deletions in CDKN1B were dramatically enriched in resistant tumors,” said Suhail Ahmad, first author of the study.
They also found that another class of drugs called CDK4/6 inhibitors (CDK4/6 are enzymes that drive cell division), like palbociclib, which is used in advanced cases of breast cancer, work effectively even in the absence of the p27 protein. Working on mice models, the researchers showed that a combination of both kinds of drugs, tamoxifen as well as palbociclib, was more effective at killing the cancerous cells.
The discovery by the researchers presents a practical biomarker to identify patients at high risk of developing resistance to hormonal therapy. By measuring p27 levels in laboratory testing, patients can be assessed for their vulnerability to drug resistance even before the start of the hormonal treatment. Patients with low p27 levels may benefit from addition of drugs like palbociclib at the early stage of the cancer itself.
“For the first time, we have a functional, clinically actionable driver that explains resistance in a substantial subset of breast cancer patients,” said Dr Dutt.
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“It opens the door to precision medicine: test for p27, escalate to CDK4/6 inhibition (through drugs like palbociclib) early, and potentially spare thousands of women from futile hormone therapy and rapid progression,” he said.
India reports about 200,000 cases of breast cancer every year. Hormonal therapy, in cases where it is applicable, is the most common and cost-effective treatment, involving just oral medication. The discovery by the researchers is likely to make this line of treatment work better by addressing the present weaknesses.
