Clinical research

BoNSAI - Improving treatments for brain metastases through advanced imaging

Oncology R&D is flourishing at the moment, yet molecular-targeted agents are still not routinely used to manage metastatic brain disease. Historically, a heavy co-morbidity burden and misconceptions about added risk of toxicity restricted their participation in clinical trials, but this trend is beginning to change. An increasing number of clinical trials assessing the intracranial efficacy of molecular-targeted agents are being registered. Many are testing monoclonal antibodies (mAbs) that target human epidermal growth factor receptors (HERs), which have been strongly implicated in the risk of metastatic outgrowth in neuregulin-rich brain tissue. This reflects the urgency of the public health problem and is a promising sign of healthcare reform. 

Brain metastases are highly vascular, so their recalcitrance to circulating therapeutics (particularly larger drugs like mAbs) has been mainly attributed to intrinsic resistance and restricted uptake across the blood-brain-barrier. But emerging data suggest a more complex scenario in which drug bioavailability is also restricted by oedema, chaotic vascular perfusion and abnormal interstitial fluid dynamics. Paradoxically, these factors can create areas of sluggish blood flow and hypoxia in an otherwise hypervascular tumour. 

BoNSAI is a cross-sectional, observational clinical trial. Patients participating in this study will be administered with a small dose of 89Zr-pertuzumab tracer, then imaged several times over the following week to determine the uptake and retention of the tracer in brain tumours over time. The study aims to establish guidelines to predict which patients will benefit from HER2-targeted therapy, and around mAb dosing schedules for treatment of metastatic brain disease.

Team members: Malcolm Lim and Colleen Niland

For more information please contact Malcolm Lim.

For more information about clinical intervention trials for brain metastases visit BRAINMETSBC.org

New prognostic and predictive  breast cancer biomarkers

We now know that breast cancer is not a single disease, but a collection of entities that vary widely in their appearance under the microscope, genetic makeup, cellular composition and clinical presentation. This variability, or heterogeneity, exists not only between cancers, but also within each cancer. For example, there may be patchy areas of very tightly packed cancer cells and necrosis (dead or dying tissue that is hypoxic), which can alter the uptake of drugs or immune cells into those areas; and certain genetic alterations may be present in some parts of a tumour but not others. This immense heterogeneity can make it very difficult to predict how an individual cancer will respond to particular therapies.

Ideally, each patient’s treatment should be personalised according to accurate predictions about the risk of relapse, and which therapies are likely to achieve the best results.

The MBP group is part of an international research effort focused on bringing this personalised model of cancer care into clinical practice. Together with traditional histopathology assessment and immunohistochemistry, we also apply cutting-edge molecular profiling technologies and try to correlate molecular tumour features with patient outcomes. A lot of our work involves extracting DNA and RNA from patient tissues, and applying technologies like next-generation sequencing and DNA copy-number analysis.

We are excited about our work in this area with our collaborators from QIMR Berghofer, which is focused on accurately measuring tumour expression of multiple genes associated with aggressive clinical behaviour at the same time to predict the most optimal chemotherapy regimen for each patient. We hope that this work will lead to a new diagnostic test to inform clinical management.

Team members: Amy McCart Reed, Jamie Kutasovic, Peter Simpson, Margaret Cummings.

For more information please contact Amy McCart Reed. 

Invasive Lobular Cancer (ILC) is the most common ‘special type’ of breast cancer, accounting for up to 15% of all cases. ILCs have a characteristic diffuse morphology and routinely lose expression of the adhesion molecule, E-cadherin.

ILCs are mostly oestrogen receptor positive, which allows treatment of these patients with anti-oestrogen therapies, for example, Tamoxifen. An ILC diagnosis is generally associated with a good short term prognosis, however over the longer term (~20 years) there is increasing evidence to suggest that ILC patients have a worse outcome than patients with the more common subtype of breast cancer (Invasive Carcinoma, no special type). 

There are special morphological subtypes of ILC (including those of mixed phenotypes) and the team is also working toward understanding the molecular heterogeneity of these tumours. ILC show a unique pattern of metastatic progression, and our genomics studies will also elucidate the mechanistic drivers of this so called ‘organotropism’. 

Team members: Dr Peter Simpson, Dr Amy McCart Reed, Dr Jamie Kutasovic, Dr Lauren Kalinowski

For more information please contact Dr Peter Simpson. 

Metaplastic breast carcinomas (MBC) are named from the Greek word ‘metaplasia’, meaning change in form, and typically these tumours present with a mix of malignant cell types (mesenchymal and epithelial elements).

MBC account for <5% of all invasive breast cancers; in other words, they are very rare. However, these tumours can be very aggressive and contribute significantly to global mortality from breast cancer. Current clinical diagnostic criteria are regarded as inadequate for this subtype. A better understanding of Metaplastic breast cancer (and indeed other triple-negative, basal-like breast cancers) will help us to develop more effective therapies.

We have established the Asia-Pacific Metaplastic Breast Cancer Consortium (APMBCC) to facilitate the assembly of a large cohort of these rare tumour samples for research.

APMBCC members:

• Dr Rin Yamaguchi (Japan)
• Dr David Papadimos (QLD, Australia)
• Dr Gary Tse (Hong Kong)
• Dr Puay Hoon Tan (Singapore)
• Dr Gavin Harris (New Zealand)
• Dr Sandra O’Toole (NSW, Australia)
• Prof Nirmala Pathmanathan (NSW, Australia)
• Prof Sunil Lakhani (QLD, Australia)
• Dr Pathma Rajadurai (Malaysia)
• Dr Amy McCart Reed (QLD, Australia)
• Dr Peter Simpson (QLD, Australia)
• Dr Nic Waddell (QLD, Australia)

For more information please contact Dr Amy McCart Reed. 

The Australian Institute of Health and Welfare (AIHW) predicted there would be 15,740 new cases of breast cancer in 2015. Mortality from breast cancer has decreased over the last few decades, but unfortunately around 10% of patients still succumb to their disease within 5 years. Most of these early breast cancer deaths involve the spread of cancer (metastais) to the brain.

The development of brain metastases is a very serious complication that affects more than 2000 Australian breast cancer patients each year. Many are young women with HER2+ or triple-negative disease. Prognosis depends on whether disease has also spread to other sites in the body and the subtype of the primary tumour, but unfortunately, most patients experience very challenging neurological side effects and succumb to their disease within a few years of diagnosis. Surgery, radiotherapy and sometimes chemotherapy are used to manage brain metastases currently, and while there have been advances in the way they are delivered to improve local control of disease and quality-of-life, morbidity and mortality remain very high.

There is huge energy across the spectrum of basic, translational and clinical research to address this challenging problem in our community, and researchers around the world are working hard to find new options. The MBP Group is working on several projects in this area:

• Development of new theranostic agents using the HIRF (Herston Imaging Research Facility), located next to the UQCCR;
• Identification of miRNA-regulated gene networks involved in the growth of breast cancer cells in the brain;
• Investigating how tumour cell-intrinsic processes enabling the outgrowth of cancer cells in the brain are influenced by the very unique microenvironment in this organ.

Team members: Malcolm Lim, Sunil Lakhani

For more information please contact Malcom Lim. 

The most common sites of breast cancer spread, or metastasis, are the bone, lung, liver and brain; but different types of breast cancer tend to spread in specific patterns – so-called organotropic behaviour.

Invasive Lobular Carcinoma (ILC), the second most common type of breast cancer, is more likely to spread to gynaecological and gastrointestinal sites than other types of breast cancer, particularly in young women. In many cases, by the time gynaecological metastases are symptomatic, the disease has often already spread throughout multiple different organ systems (for example, the ovaries, fallopian tubes, and throughout the peritoneum). This insidious, late-presenting complication can be very challenging clinically, and many patients could benefit from earlier detection of metastatic disease so that surgical and/or oncological interventions can be initiated while cancer deposits are still small, and before they are symptomatic. 

The MBP group has an ongoing program of work to study the molecular similarities and differences between primary and metastatic cancer deposits from patients whose disease involves the gynaecological organs. We think this will improve our understanding of how and why these tumours spread in this pattern. 

The main translational aim of this research is to identify primary tumour biomarkers that can be used to predict which patients are at risk of gyanecological metastasis to identify patients who might benefit from heightened clinical surveillance (e.g. advanced imaging). 

Team members: Dr Peter Simpson, Dr Amy McCart Reed, A/Prof Margaret Cummings, Dr Jamie Kutasovic

For more information please contact Dr Peter Simpson. 

Whole genome sequencing to understand tumour development in familial breast cancer

Family history is a significant risk factor for the development of breast cancer. For some individuals and their families, the genetic component of this risk is well understood and attributed to pathogenic germline variants in moderate-high risk genes (e.g. BRCA1, BRCA2, PALB2, TP53, ATM, CHEK2). For most individuals the underlying genetic risk is unknown. We have been using whole genome sequencing of germline and matched tumour DNA to characterise somatic mutation signatures present in tumours from high risk individuals. These approaches are providing insight into the mechanisms driving tumourigenesis in familial breast cancers and also therapeutic strategies. 

Team members: Dr Peter Simpson, Dr Katia Nones (QIMR Berghofer Medical Research Institute), Dr Nic Waddell (QIMR Berghofer Medical Research Institute), Dr Sriganesh Srihari, kConFab, Xavier Marc De Luca (RHD Student)

Funding: National Health and Medical Research Council

For more information please contact Dr Peter Simpson. 

Streamlining lung cancer diagnosis through genomic testing of cytology smears.

Endobronchial ultrasound transbronchial needle aspiration (EBUS-TBNA) sampling of lymph nodes is an important procedure to make a diagnosis of Lung cancer, particulalry in patients presenting with advanced, inoperable disease. Next generation sequencing is an important component of diagnostic practice and therapeutic decision making for lung cancer patients. Our program of work is focused on optimising sequencing approaches from small diagnostic aspirate samples yielded by EBUS TBNA.

Team members: Dr Peter Simpson, Dr David Fielding (Royal Brisbane & Women’s Hospital, UQCCR), Dr Andrew Dalley, Dr Katia Nones (QIMR Berghofer Medical Research Institute), Dr Nic Waddell (QIMR Berghofer Medical Research Institute), Professor Sunil Lakhani, Dr Mahendra Singh (Pathology Qld), Dr Lakshmy Nandakumar (Pathology Qld)

Funding: Cancer Council Queensland, Cancer Australia, Australian Genomics – Australian Genomics Health Alliance, Pathology Queensland Study Education Research Committee fund.

For more information please contact Dr Peter Simpson.