Mutations can reduce the effect of anti-oestrogen treatment

A small proportion of women who receive anti-oestrogen treatment after breast cancer surgery have worse outcomes, as a result of mutations in the oestrogen receptor gene. This is according to a new study — said to be the largest of its kind on resistance mutations in the oestrogen receptor in primary breast cancer — led by Lund University and published in JNCI Cancer Spectrum.

Breast cancer is the most common type of cancer in women. The majority of breast tumours have high levels of the oestrogen receptor (encoded by the gene ESR1); and after surgical removal of the cancer, the most important treatment for these women is anti-hormonal drugs that reduce the activity of the oestrogen receptor and thereby reduce the risk of relapse.

The researchers focused on the mutations in the oestrogen receptor ESR1 gene, which had been previously discovered to be common in relapsed breast cancer in women who had received prior anti-oestrogen cancer treatment. The mutations made the tumour resistant to the hormonal treatment. Recent studies, however, have shown that the incidence of these resistance mutations was very low in patients at the first diagnosis of cancer, and no studies explored how such pre-existing mutations might be related to response to anti-hormonal treatments.

The Lund researchers analysed RNA sequencing data from more than 3000 breast tumours from within the large SCAN-B research project, samples taken before treatment with drugs. Among the 2720 tumours positive for the oestrogen receptor and therefore eligible for hormonal treatment, they found 29 tumours with an ESR1 resistance mutation. All mutations were found in patients older than 50 years.

“We investigated whether the resistance mutations, which occurred before cancer treatment, affected the patients’ survival and saw that patients with a mutation in their primary tumour had three times higher risk of recurrence and 2.5 times higher risk of dying,” said Lund doctoral student Malin Dahlgren. “The link between the mutations and poor survival was also seen after statistical corrections for age or for other factors that may affect the outcome for the patient.”

“This not only confirms what previous studies have shown — that the mutations are relatively rare — but we now show that these resistant mutations occur in about 1% of breast cancer cases already at initial diagnosis and we are the first to show that these patients seem to respond less well to hormonal treatment,” said study leader Lao Saal.

“If our results are confirmed in further studies, it would be relevant to screen for these resistance mutations already at diagnosis, and then consider other treatment options that could work better for patients with mutated tumours.”

Image credit: ©stock.adobe.com/au/Voyagerix

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