by ecancer reporter Janet Fricker

Two independent studies published online in Nature Genetics identify new mutations in genes encoding the oestrogen receptor (ER) in patients with metastatic breast cancer.

Both studies implicate mutations in the ESR1 binding domain and provide new insights into approaches to tackle hormone resistant breast cancer.

It is known that over two thirds of breast cancers express oestrogen receptors (ER) and that most of these are sensitive to ER inhibition.

Drugs such as tamoxifen and fulvestrant work by directly antagonizing ER, while aromatase inhibitors, such as letrozole and exemestane, block the peripheral conversion of androgens into oestrogen.

In the metastatic setting, however, many tumours become refractory to drugs. It is thought, however, that different mechanisms of resistance exist since breast cancer patients developing resistance to aromatase inhibitors often still respond to therapies like tamoxifen.

Both research groups recognise that gaining a better understanding of acquired resistance to hormone antagonists is essential for the development of more durable and effective therapies.

In the first study Sarat Chandarlapaty and colleagues, from Memorial Sloan-Kettering Cancer Center, New York, conducted a comprehensive analysis of two independent cohorts of metastatic ER-positive breast cancer tumours, using normal DNA extracted from white blood cells as the comparator¹.

The investigators identified mutations in ESR1 affecting the ligand-binding domain (LBD) in 14 out of 80 cases. The mutations included recurrent mutations encoding p.Tyr537Ser, p.Tyr537Asn and p.Asp583Gly alterations.

Molecular dynamics simulation studies undertaken by the team suggest that the Tyr537Ser and Asp583Glyc mutations promote the agonist confirmation of the ER in the absence of the ligand.

This, suggest the authors, is likely to represent one of the major causes of acquired resistance to oestrogen depletion therapies, such as aromatase inhibitors.

To validate their observations, the team analyzed tumours collected from 44 patients enrolled in the BOLERO-2 clinical trial, which studied patients with ER-positive metastatic breast cancers that had progressed during treatment on an aromatase inhibitor. Here ESR1 mutations were observed in five patients (11%).

During invitro studies the team went on to show that higher doses of fulvestrant and tamoxifen could fully antagonize ER α.

‘These data and structural modelling results suggest that more potent or specific antagonists of the mutant forms may be effective at blocking ER signalling and may benefit patients where hormonal therapies can have a very high therapeutic index,’ write the authors.

‘Given the widespread use of hormone antagonists as adjuvants to prevent metastatic recurrence, it will be important to determine whether the identified mutations can be implicated in such recurrences and, then, whether newer SERMs or SERDs that more potently block mutant function can be curative when given as adjuvants.’

In the second study, Arul Chinnaiyan and colleagues, from University of Michigan, Ann Arbor, sequenced the exomes of 11 patients with metastatic ER positive breast cancers².

The study was part of the MI-ONCOSEQ program - since April 2011 the group have been undertaking mutational analysis of coding genes to compare current tumour biopsies with matched normal samples obtained from blood or buccal swabs.

The investigators reveal that six patients had mutations in ESR1 affecting the LBD, all of whom had been treated with anti-oestrogen and oestrogen deprivation therapies.

Invitro studies showed that the five new LBD-localised ESR1 mutations identified (encoding p.Leu536Gln, p.Tyr537Ser, p.Tyr537Cys, p.Tyr537Asn and p.Asp538Glyn) resulted in continued responsiveness of the oestrogen receptor in the presence of anti oestrogen therapies.

‘The focused nature of these mutations and their role in aromatase inhibitor resistance suggest the possibility of monitoring patients undergoing treatment using circulating tumor DNA methods.

In this manner treatment could be shifted to head off evolving tumour resistance,’ write the authors.

Reference

1. W Toy, Y Shen, H Won, et al. ESR1 ligand-binding domain mutations in hormone-resistant breast cancer. doi:10.1038/ng.2822

2. D R Robinson, Y Wu, P Vats, et al. Activating ESR1 mutations in hormone-resistant metastatic breast cancer. Nature Genetics. doi:10.1038/ng.2823