New Insights into Why Breast Cancer Drugs Fail for Some Women

“Breast cancer drugs taken by thousands of women stop working because tumours ‘outsmart’ them,” is the headline in The Sun.

Around 70% of breast cancer cases are what are known as oestrogen receptor-positive breast cancers. This means the cancerous cells use the hormone oestrogen as a type of “fuel” to help them reproduce and spread.

After surgery to remove the tumour, many women with this type of cancer are prescribed hormone treatments – tamoxifen or aromatase inhibitors – that cut off the supply of oestrogen to the cancer in the hope the tumour doesn’t return.

But some women build resistance to the drugs, so researchers set out to understand why. They found a particular gene (CYP19A1) becomes amplified, where more copies of the gene are produced, in about one in five women (21.5%) treated with aromatase inhibitors.

This triggers the increased production of aromatase, the enzyme the drugs were trying to block. This enzyme converts hormones in the body into oestrogen. This allows the cancer cells to make their own oestrogen again, and reproduce and spread.

The researchers weren’t able to understand the mechanism behind drug resistance to tamoxifen, but hope to carry out further research to find out how it occurs.

The team behind this study hope their work will pave the way for further research so they can develop a test able to identify whether a woman’s tumour has already started to increase the production of aromatase. This may allow doctors to prescribe different and more effective forms of treatment.

Where did the story come from?

The study was carried out by researchers from several global institutions, including Imperial College London and the European Institute of Oncology in Milan.

Some of the researchers received support through grants from Cancer Research UK and the Associazione Italiana per la Ricerca sul Cancro. No conflicts of interest were reported.

The study was published in the peer-reviewed journal, Nature Genetics.

Although some of the headlines, such as The Mirror’s, were slightly overoptimistic – “Breast cancer discovery could stop disease killing women and leave them with ‘normal life expectancy’” – the UK media’s reporting was generally well balanced.

However, this research more accurately applies to one in five women with oestrogen receptor-positive breast cancer treated with aromatase inhibitors – usually women who have gone through the menopause – not one in four women with breast cancer, as some headlines state.

What kind of research was this?

This laboratory study used human cell samples to investigate the mechanism behind how breast cancer tumours develop resistance to treatments, effectively making them powerless.

Approximately 70% of breast cancers are classified as oestrogen receptor-positive – where the cancer is fuelled by the hormone oestrogen.

In these cases, women can be offered one of two hormone treatments after surgery to prevent the cancer returning: tamoxifen or aromatase inhibitors.

Aromatase inhibitors are usually only given to women who’ve already been through the menopause, while tamoxifen may be given to pre- or postmenopausal women. The medication is designed to stop the production of oestrogen in the body or block its effects.

However, more than one in five women relapse within 10 years of this treatment, and eventually develop metastatic cancer that spreads to other parts of the body. This has spurred scientists on to explore the cause of tumour resistance.

Laboratory studies like this one are useful early-stage research for understanding complex biological mechanisms. They can pave the way for potential future treatment options, but are also able to identify gaps in research.

What did the research involve?

The researchers used samples of human breast cancer tumours from a database containing data on 26,495 women who had undergone surgery for first primary breast cancer between 1994 and 2014. 

They had data available on the patients’ medical history, concurrent disease, surgery, histology assessments, results of staging procedures, radiotherapy, treatments given after surgery, events occurring during follow-up, and treatments for recurrent metastatic disease.

This study analysed tumour samples from 150 women who had experienced a recurrence of breast cancer with metastatic spread to different parts of the body.

Fifty of the women only received aromatase inhibitors after surgery, and 50 only received tamoxifen.

The researchers used various genetic analysis methods to extract DNA and manipulate the hormones to learn more about the exact mechanism behind the resistance to treatment.

What were the basic results?

Overall, the researchers found the CYP19A1 gene became amplified and triggered the increased production of aromatase in about one in five women prescribed aromatase inhibitors after surgery.

Aromatase is the enzyme that normally converts circulating male hormones in the woman’s body into oestrogen, which the aromatase inhibitors are trying to block.

The gene was essentially allowing the cancer cells to make their own supply of oestrogen hormone again, making the aromatase inhibitors ineffective.

The same mechanism doesn’t seem to be behind tamoxifen resistance. In women taking tamoxifen, almost none of the tumours showed increased amplification of the CYP19A1 gene as seen in those taking aromatase inhibitors, so they weren’t producing their own supply of oestrogen in this way.

The researchers hope to embark on further research to understand how cancer cells build resistance to tamoxifen, as this is clearly through a different mechanism.

How did the researchers interpret the results?

The researchers concluded that, “It is tempting to speculate that CYP19A1 amplification might arise in response to reversible inhibitors but could be antagonised [blocked] by switching to irreversible inhibitors.

“Alternatively, it should be clinically feasible to directly antagonise the low levels of circulating male hormones commonly found in postmenopausal women.

“Considering that aromatase inhibitors normally targets peripheral tissues, our data also warrant aromatase inhibitors pharmacodynamics studies to evaluate the ability of this class of drugs to target tumour cells directly.

They go on to say that, “Taken together, our clinical data demonstrate that the evolution of breast cancer is shaped by clinical intervention and thus advocate the development of treatment and setting-specific biomarkers.”

Conclusion

This laboratory study aimed to investigate the mechanism behind how some oestrogen receptor-positive breast cancer tumours develop resistance to the hormone drugs tamoxifen and aromatase inhibitors.

This resistance effectively makes these drugs powerless, causing the cancer to return.

The researchers seemed to find at least part of the answer as to why resistance to aromatase inhibitors can develop.

In some cases, they found treatment triggered the amplification of the CYP19A1 gene, which increased the production of aromatase, essentially allowing the cells to keep making their own oestrogen.

But this doesn’t seem to tell us why drug resistance to tamoxifen develops. This seems to be the result of another mechanism and not related to the production of aromatase.

The researchers hope to investigate how resistance towards tamoxifen is established. They hope to further this research to work on developing a test that will be able to identify whether a woman’s tumour has started to make its own supply of oestrogen through increased aromatase production.

One of the researchers, Dr Luca Magnani, commented: “In many cases when an aromatase inhibitor stops working in a patient, doctors will try another type of aromatase inhibitor.

“However, our research suggests that if the patient’s cancer has started to make their own aromatase, this second drug would be useless. This is why we need a test to identify these patients.”

The hope is that finding out more about why these drugs don’t work for some women will lead to new drugs that do.  

Links To The Headlines

Breast cancer drugs taken by thousands of women stop working because tumours ‘outsmart’ them. The Sun, January 24 2017

Breast cancer discovery could stop disease killing women and leave them with ‘normal life expectancy’. Daily Mirror, January 23 2017

Why breast cancer drugs fail for one in four: Scientists discover that tumours can create their own supply of fuel. Mail Online, January 24 2017

Links To Science

Magnani L, Frigè G, Gadaleta RM, et al. Acquired CYP19A1 amplification is an early specific mechanism of aromatase inhibitor resistance in ERα metastatic breast cancer. Nature Genetics. Published online January 23 2017