Australian researchers uncover a promising new way to tackle triple-negative breast cancer

Australian researchers have uncovered a promising new way to tackle one of the most aggressive forms of breast cancer, raising hopes for more effective treatments to stop the disease from spreading.

The study, undertaken by Adelaide University and the Olivia Newton-John Cancer Research Institute, has identified a molecular switch that drives the spread of triple-negative breast cancer (TNBC) – the subtype responsible for some of the poorest outcomes because it lacks the hormone receptors that make many other breast cancers treatable with existing therapies that target these receptors.

The research, published today in EMBO Molecular Medicine, found that patients with low levels of a naturally occurring molecule known as miR-342 and high activity of a cancer-driving pathway called E2F were more likely to develop metastatic disease.

In pre-clinical models, the team demonstrated that restoring miR-342 levels markedly reduced the spread of breast cancer to other organs, including the lungs and bones.

They also showed that the existing breast cancer drug palbociclib – a CDK4/6 inhibitor currently used to treat advanced hormone receptor-positive breast cancer – significantly reduced the growth of metastatic tumors in models with low miR-342.

The findings suggest that measuring miR-342 levels could help identify a subset of women with triple-negative breast cancer who are most likely to benefit from treatment with CDK4/6 inhibitors, potentially allowing an existing therapy to be repurposed for one of the deadliest forms of breast cancer.

Co-senior author Associate Professor Philip Gregory, from Adelaide University's Centre for Cancer Biology and SA Pathology, said metastasis remains the greatest challenge in treating triple-negative breast cancer.

Most deaths from breast cancer occur because the cancer spreads to other parts of the body, rather than being caused by the primary tumor itself.

Triple-negative breast cancer is particularly difficult to treat because it lacks the hormone receptors and HER2 proteins upon which many targeted therapies rely. While immunotherapy is improving outcomes for some patients, treatment options remain very limited once the cancer returns.

Our research identified a subgroup of patients whose tumors appear to rely on a specific molecular pathway to spread. By targeting that pathway, we were able to dramatically reduce metastatic growth in our laboratory models."

Philip Gregory, Associate Professor, Adelaide University's Center for Cancer Biology and SA Pathology

Associate Professor Gregory said the team discovered that miR-342 acts as a master regulator of an entire network of genes involved in cancer progression.

"When miR-342 levels fall, the E2F pathway becomes overactive, allowing dormant cancer cells that have already travelled through the body to grow into dangerous secondary tumors.

"The exciting aspect of this discovery is that drugs targeting this pathway already exist. CDK4/6 inhibitors are routinely used for patients with advanced hormone receptor-positive breast cancer, and our findings suggest they could also benefit a carefully selected group of patients with triple-negative disease."

Co-senior author Professor Robin Anderson, from the Olivia Newton-John Cancer Research Institute, said understanding why cancers spread beyond the primary tumor is essential because metastatic disease is responsible for most breast cancer deaths.

"Primary tumors can often be treated successfully with surgery or local therapies, but once cancer spreads throughout the body it becomes far more difficult to control," Professor Anderson said.

"Triple-negative breast cancer is incredibly diverse, and that's one of the reasons it has been so challenging to develop targeted treatments."

The researchers found that administering palbociclib after cancer cells had already spread was particularly effective in preventing microscopic metastatic tumors from growing.

"Rather than shrinking the primary tumor, this treatment may prove most valuable by stopping tiny metastatic deposits from developing into life-threatening secondary cancers.

"Our study identifies a distinct subgroup of patients whose cancers share a common biological weakness, opening the door to a much more personalized treatment approach."

The researchers say the next step is to validate the findings using patient-derived pre-clinical models before progressing to clinical trials.

Triple-negative breast cancer accounts for around 10–15% of Australia's approximately 21,000 breast cancer diagnoses each year but causes a disproportionate number of breast cancer deaths because of its aggressive nature and tendency to spread rapidly to distant organs.