Understanding the microenvironment of secondary brain cancers

Improved early detection and systemic therapies have seen breast cancer survival rates increase to 90%, five years post-diagnosis. Despite these vast improvements, between 5-20% of breast cancer survivors go on to develop brain metastasis or secondary brain cancer, a terminal prognosis.

Although existing treatments may slow tumour growth and extend life, clinical decisions on treatment can be impacted by a host of factors, such as the number of metastases, size of tumour, location, and a patient’s overall well-being and health.

Patients often display various neurocognitive decline, such as slurred speech, blurred vision, memory loss, difficulty walking, and an inability to concentrate or drive. Over time, this can severely limit a patient’s independence and often leads to a decline in their quality of life.

Around 3000 Australian women die from breast cancer every year, accounting for approximately 6.2% of all cancer related deaths.

In Australia, patients with a single, or limited number of metastases, are normally treated by a multidisciplinary team of doctors, who can decide to remove the tumour by surgery or radiosurgery. Once a patient undergoes surgery, they are monitored every three months to detect possible progression of the disease.

Other treatment options include chemotherapy, radiotherapy, and a high dose of prescription steroids – most often used to help control swelling in the brain caused by the tumour.

Patients with multiple metastases and uncontrollable tumour outside the brain do not usually benefit from radiosurgery or surgery. Instead, they may be treated with whole brain radiation therapy or referred to specialist palliative care, depending on their needs.

The brain is a unique organ that is normally protected within the bones of the skull and cushioned by a fluid, known as cerebrospinal fluid. Its activities are so crucial for regular functioning of the body that human beings have evolved to protect it from any foreign material. One such, protection is known by biologists as the blood-brain barrier (BBB). Under normal circumstances, the BBB stops toxins and pathogens from entering the brain while still allowing required nutrients through. With cancer, the cells adapt in a variety of ways to cut through the BBB barrier and establish a colony.

Studies conducted under the Molecular Breast Pathology group at The University of Queensland’s Centre for Clinical Research (UQCCR), as well as other researchers around the globe, have shown that cancer cells which reach the brain transform through mutations or mimic the properties of neighbouring normal brain cells, or express molecules that are naturally present within that environment. These cancer cells trick the brain into thinking they are part of the normal process and exploit the environment for nutrients and growth. This unique environment of the brain is known as the tumour-microenvironment. In fact, sometimes changes in the metastatic brain tumour could be unique and different from the primary tumour where it first originated.

As published in Therapeutic Advances in Medical Oncology: SAGE Journals, Dr Kalita-de Croft and her colleagues have identified specific changes in the brain metastasis of breast cancer patients, which was not present in their primary disease. Through the analysis of 462 tumours, 371 breast cancers, along with 41 breast cancer with matching brain metastasis, it was found that brain metastasis exclusively expressed an activated form of a protein, known as Human Epidermal growth factor receptor-4 (HER4) and its other family members; thus making it a promising target.

In line with this, a drug known as Neratinib, which targets multiple HER proteins, has been recently approved by the FDA to be administered in patients with advanced or stage IV breast cancers. In this clinical trial, when Neratinib was administered in combination with chemotherapy, it improved survival of patients including the occurrence of symptomatic brain metastasis significantly. This study provides further evidence that non-reversible inhibition of HER family receptors including HER4 by neratinib improve the survival as well as delay symptomatic brain progression in breast cancers.

Tumour microenvironment in the brain comprises of not only brain resident but also infiltrating immune cells. In depth understanding of the contexture of these cells is crucial in identifying specific changes pertaining to treating these recalcitrant tumours. Dr Kalita-de Croft  from the Molecular Breast Pathology group at UQCCR is leading this work to understand the brain microenvironment in a comprehensive way by using high throughput multiplexing and spatial profiling technologies. By understanding the spatial biology and the immune contexture of these tumours’ Dr Kalita-de Croft hopes to uncover unknown mechanisms of treatment resistance and failure. This can ultimately lead to better outcomes for this devastating condition.


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