Established therapy could bring new hope to patients with triple negative breast cancer

Researchers have identified a change in some instances of the disease which could be used as potential targets for an existing treatment, Peter Doyle reports

A drug used in the treatment of oestrogen receptor positive (ER+) secondary breast cancer could also be used to treat some women diagnosed with triple negative breast cancer, a new study is reporting.

Triple-negative breast cancer (TNBC) refers to a diverse group of breast cancers which lacks the oestrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2).

The absence of the ER, PR and HER2 molecules in TNBC has meant there was a lack of variety in treatment options for this group of breast cancers and as a result the disease was usually treated with a combination of surgery, chemotherapy, and radiotherapy.

Researchers have now suggested that the drug palbociclib – the first CDK4/6 inhibitor to be approved as a cancer therapy and which is currently used to treat other metastatic breast cancers – has the potential to be used to treat about a fifth of people living with TNBC.

Investigators at the Institute of Cancer Research (ICR), London – which is funded by United Kingdom (UK) charity Breast Cancer Now – said the research provided the basis for a clinical trial of a new treatment for the disease which accounts for approximately 10-15 per cent of all breast cancers.

Commenting on the findings, Dr Simon Vincent, Director of Research, Support and Influencing at Breast Cancer Now, said new, effective ways to treat women diagnosed with TNBC were “desperately needed”.

Dr Simon Nugent

“It’s hugely exciting that this research has uncovered a new possible use for palbociclib as a targeted treatment for some women living with triple negative breast cancer,” he continued.

“We hope that if clinical trials confirm that palbociclib is beneficial for some of these women, it will be advanced through the approval process and made available for those who need it as quickly as possible.”

The research, led by Dr Rachael Natrajan, who heads the ICR’s Functional Genomics team, found a change in some TBNCs which was helping the growth of cancer cells.

“Our study shows what drives the growth of some triple negative breast cancers and suggests the exciting possibility that an already-approved breast cancer drug could be used to help women with triple negative breast cancer,” Dr Natrajan added.

“Our findings were only possible because we used an innovative model, involving the growth of 3D ‘mini tumours’ in the lab, to more closely reflect how tumours develop in the body.”

Her team had looked at the most frequently altered genes in breast cancer to investigate how changes in these genes affected the cancer’s ability to grow.

By growing ‘mini-tumours’ in the lab which mimicked tumour growth in a human body, they found that TNBC cells with alterations that caused a decrease in the levels of the CREBBP protein could grow faster and more aggressively.

Dr Natrajan’s team also found that when CREBBP levels were low, breast cancer cells start to rely on the CDK4 and CD6 proteins to grow.

But these proteins could be blocked with CDK4/6 inhibitors.

Researchers later tested the effectiveness of palbociclib on cancer cells with CREBBP alterations and found the drug was effective even when tested on standard chemotherapy-resistant TNBC cells that lacked CREBBP.

While not all TNBC tumours have low CREBBP levels, they added it was the case in about a fifth of patients.

This meant that measuring CREBBP protein levels in tumours could help to identify thousands of patients that could benefit from a treatment that is already approved for use in most countries.

The results were published in the January 2021 edition of the Journal of the American Association of Cancer Research (AACR).

In the paper, Natrajan et al said that TNBCs were resistant to standard-of-care chemotherapy and lack known targetable driver gene alteration, (‘3D Functional Genomics Screens Identify CREBBP as a Targetable Driver in Aggressive Triple-Negative Breast Cancer’; AACR; doi: 10.1158/0008-5472.CAN-20-1822).

“Identification of novel drivers could aid the discovery of new treatment strategies for this hard-to-treat patient population, yet studies using high-throughput and accurate models to define the functions of driver genes in TNBC to date have been limited,” they wrote.

Noting that the genetic landscape of human cancers has been “comprehensively mapped by large sequencing efforts such as The Cancer Genome Atlas which have revealed many of the recurrent mutation events that are present in different tumour types”, they said that most of these mutations have not as yet been established as bona fide ‘drivers’ or exploited therapeutically.

“It remains a formidable challenge to investigate the ‘long tail’ of driver mutations in relevant cancer models, however, the identification of novel cancer genes and resultant cancer-specific vulnerabilities is needed, in particular for aggressive tumour types that are resistant to current treatment options,” researchers added.

The aim of their study, they said was three-fold: first, to establish the functional impact of recurrently mutated genes in TNBC; second, to identify how to target these through synthetic lethal approaches; and third, to assess whether these findings could be extended to other hard-to-treat aggressive cancers.

“Using a functional genomics approach under conditions more similar to those encountered in the unfavourable tumour microenvironment, multicellular spheroid cultures, we silenced the 200 most frequently mutated genes in breast cancer, and identified that inactivation of the histone acetyltransferase CREBBP significantly increased cell growth in cancer cells that experienced nutrient stress, such as hypoxia,” they wrote.

The use of 3D functional genomics screening of the 200 most frequently mutated genes in breast cancer allowed for high-throughput assessment of novel genetic dependencies involved in cancer progression.

“It is now appreciated that more complex models of cancer are required to fully appreciate the contributing factors that drive tumorigenesis in vivo and increase the efficacy of novel therapies that make the transition from preclinical models to clinical trials,” they observed.

To investigate the clinical implications of CREBBP alterations in TNBC, investigators evaluated patient data from The Cancer Genome Atlas (TCGA) and the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) cohorts.

“CREBBP protein expression in patient tumour samples was absent in 8 per cent of TNBCs and at a high frequency in other tumours, including squamous lung cancer, where CREBBP-inactivating mutations are common,” they wrote.

“In TNBC, CREBBP alterations were associated with higher genomic heterogeneity and poorer patient survival and resulted in upregulation and dependency on a FOXM1 proliferative programme.”

Their results, they said, matched a recent pan-cancer analysis study that had highlighted CREBBP mutations “to be one of the most highly correlated mutated genes in tumours with elevated hypoxic signatures”, (‘Bhandari V, Li CH, Bristow RG, Boutros PC, Consortium P. Divergent mutational processes distinguish hypoxic and normoxic tumours. Nat Commun 2020; 11:737’).

Proposing a model whereby CREBBP loss imparted a more aggressive disease trajectory in TNBC as a result of increased transcriptomic diversity, they said this was in agreement with the clinical observations that CREBBP-altered tumours were less sensitive to established anti-cancer therapies and patients were more likely to relapse.

The significance of their own study was, they concluded, it demonstrated that CREBBP genomic alterations drive aggressive TNBC, lung cancer, and lymphomas and these could be selectively treated with clinical CDK4/6 inhibitors.

However, they cautioned that although it was tempting to speculate that CREBBP altered tumours might respond well to combinations of immune checkpoint blockade and CDK4/6 inhibitors, this needed to be tested in the clinical trial setting.

But any such trial could be progressed quickly not only because palbociclib was an already licensed drug, proven to be safe, but also because the new data, researchers said, provided the rationale for a molecularly stratified clinical trial.

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