Getting personal in the fight against breast cancer: tools that tailor treatments to patients
By: Alexa Desimone
Breast cancer is the most common malignancy among Canadian women.1 In 2017, there were 26,300 new diagnoses, and approximately 5,000 breast cancer-related deaths. Breast cancer may also occur in men, who represented 230 of the new diagnoses in 2017.2 Treatments for breast cancer include surgical intervention, radiation therapy, hormonal therapy, chemotherapy, and targeted therapy. These can be used alone or in combination depending on the patient’s age and/or genetic factors.1 However, it can be challenging for physicians to narrow down the optimal treatment for each individual patient, and difficult to predict their response to a specific intervention. This means the patient may receive one or more unsuccessful courses of treatment, which are often accompanied by significant side effects. For example, approximately 8,500 Canadian patients receive chemotherapy without benefit each year.3 Delays in finding an effective treatment mean higher costs for the healthcare system and greater risks for the patient.
Dr. Maureen Trudeau is one of Canada’s leading breast cancer researchers who has dedicated her career to enhancing the lives of her patients. Dr. Trudeau is a medical oncologist at Sunnybrook Health Sciences Centre, Odette Cancer Centre, and an associate member of the Institute of Medical Science. She is involved in international and interdisciplinary projects to improve the treatment of patients with breast cancer, from predicting treatment efficacy and designing novel therapies to developing breast cancer treatment guidelines for healthcare systems in Canada and around the world.
“I’m currently a part of three clinical trials, two of which are focussed on developing tests that could allow physicians to accurately predict how effective a particular treatment will be for a patient within a week or two of starting the therapy,” says Dr. Trudeau. “The third trial is developing a novel treatment for brain tumours in patients whose breast cancer has metastasized to their brain.”
No single therapy regimen will result in an identical response for all patients, thus, it is important to develop methods to predict customizable therapeutic regimens. Interest in such “personalized medicine” has grown increasingly within the past few years due to its significant benefits to patients, cost, and time when treating a multitude of diagnoses. It is particularly fitting when identifying ways to develop alternative therapies or reduce chemotherapy exposure among cancer patients.
Dr. Trudeau and colleagues began investigating the role of Taxotere in the treatment of metastatic breast cancer and found a 55% response rate to a first-line therapy with this specific drug.4 Later studies revealed an impressive 70% response rate to a combined treatment using both Taxotere and Epirubicin in women with metastatic breast cancer. This led Dr. Trudeau and her colleagues to investigate its use in neoadjuvant therapy – an add-on therapy given before surgery.5 Ribonucleic acid (RNA) was isolated from tumour core biopsies taken from locally advanced breast cancer (LABC) patients prior to, during, and after this combination chemotherapy. Then, researchers analyzed the biopsies to identify each patients’ RNA integrity number—a measure of how degraded the tumour’s RNA was following treatment. They found that the RNA of tumours that responded well to chemotherapy displayed a unique pattern of bands compared to poor- or non-responders.
RNA degradation analysis was able to identify 20% of patients that were chemotherapy non-responders, substantially more compared to clinical assessment alone which only detected 5%.6 This novel biomarker of chemotherapy response could allow physicians to advise patients accordingly, such that non-responding patients may be spared unnecessary toxicity from chemotherapy and be moved to alternative treatments such as surgery, radiation, or other chemotherapy regimens. Additionally, this finding led to the formation of a biotechnology firm called “Rna Diagnostics.” Dr. Trudeau serves as a clinical advisor for this innovation in personalized medicine for cancer therapy (for more information, visit http://rnadiagnostics.com).7 Currently, Dr. Trudeau and Rna Diagnostics are collaborating on an international study developing this novel biomarker on a global scale.
A second project that Dr. Trudeau is working on is assessing chemotherapy efficacy using quantitative ultrasound (QUS) to predict breast cancer response to neoadjuvant chemotherapy (meaning prior to primary treatment). This project is based on the work of Dr. Gregory Czarnota and colleagues who developed and implemented QUS to determine tumour responses to radiotherapy as early as 24 hours post-treatment.9 Traditional imaging techniques lack the specificity and efficiency to determine tumour size reduction, as they often require several weeks to months of treatment administration before changes to tumours can be seen. Additionally, many chemotherapy cases may result in a cytotoxic response but no mass diminishment, and therefore would be missed with conventional imaging techniques.10 What’s more, there are early microstructural changes that occur due to tumour cell death—taking place hours to days post-treatment—that have previously been difficult to quantify. That is why the research team is testing the utility of low frequency QUS techniques to non-invasively monitor microstructural changes and determine the effects of chemotherapy on LABC patients.10,11
The QUS technique characterizes tissue abnormalities in the frequency content of the radiofrequency backscatter acquired by the ultrasound.8 Tumour cell death initiates significant alterations in nuclear structures shown through cellular changes in elasticity, viscosity, density, and the spatial organization of cell ensembles.10 All these parameters subsequently influence the pattern of ultrasound backscatter characteristics. The results of this study identify a unique sensitivity and specificity to pinpoint patients with poor response to therapy early on in their treatment onset. This study provides a step forward towards personalized cancer therapy, where an inefficient regimen can be changed to a more effective one more quickly than ever before.
One of Dr. Trudeau’s more recent projects focuses on breast cancer patients whose tumours are positive for human epidermal growth factor receptor 2 (HER2+). A tyrosine kinase receptor, HER2 is associated with a poor prognosis, aggressive tumour proliferation, and poor response to chemotherapy.12 This molecular abnormality amongst breast cancer patients prompted HER2 testing guideline in Canada to determine the appropriate treatment and sequence of treatments. Currently, targeted therapy with the agent trastuzumab, which specifically targets those HER2+ tumour cells, significantly improves disease-free survival and mortality in patients with HER2 overexpression. However, HER2+ breast cancer patients are highly susceptible to develop brain metastases, and trastuzumab therapy is unable to cross the blood brain barrier (BBB).13
“The HER2-positive breast cancer patients are at a higher risk of developing brain metastases, so the question is how do you treat them?” explains Dr. Trudeau. “If the systemic disease is under control but you cannot access the brain, what else can you do?”
Surgery, whole brain radiation, and stereotactic radiosurgery are the traditional treatment options for these brain metastases. Dr. Trudeau, Dr Nir Lipsman, Dr Arjun Saghal and their team set out to develop less invasive and more effective therapies for these patients. The utility of focused ultrasound (FUS) after a primary treatment is a promising technique aimed at inducing controlled BBB permeability in order to further treat HER2+ brain metastases. The FUS technique, originally pioneered by Dr. Kullervo Hynynen at the Sunnybrook Research Institute, is a non-invasive technique where ultrasound is used to promote movement of drugs across the BBB and into certain areas of the brain.14 Many factors, including tumour location, number of lesions, risk of bleed, and skull thickness will influence the optimization of this treatment. In the current study, patients will receive a loading dose of trastuzumab (if they haven’t been on trastuzumab already) and then receive FUS in hopes of opening the BBB to allow the drug to reach the brain tumour. In order to confirm the BBB permeability, a contrast dye will be administered. Additional amendments will be added to the clinical study to include radiolabelling on trastuzumab in order to track drug delivery to the brain and confirm its efficacy. Although this clinical study is in the beginning stages of optimization, Dr. Trudeau and her colleagues are optimistic.
As a healthcare provider, Dr. Trudeau is involved in several committees focused on healthcare delivery and guideline development. As a member of the pan-Canadian Oncology Drug Review (pCODR) and Chair of the Expert Review Committee (pERC), she is responsible for assessing cancer drugs and guiding funding decisions based on clinical and economic evidence, patient values, and adoption feasibility. Additionally, Dr. Trudeau is interested in the Ontario Cancer Data Linkage Project (cd-link), a collaboration between Cancer Care Ontario and the Institute for Clinical Evaluative Sciences. Cd-link is a data release program that provides direct access to de-identified healthcare data through a comprehensive Data Use Agreement to all researchers. Specifically, Dr. Trudeau is looking into specific chemotherapy regimens from previous clinical trials and comparing whether the real-world data is corresponding to the results of the original clinical trial. This is an important initiative to further assess the efficiency of drug allocation, and to ensure patients are receiving equitable resources in a timely fashion.
- Government of Canada (2017). Breast Cancer. https://www.canada.ca/en/public-health/services/chronic-diseases/cancer/breast-cancer.html
- Canadian Cancer Society (2019). Breast cancer statistics. https://www.cancer.ca/en/cancer-information/cancer-type/breast/statistics/?region=on
- Bombard, Y., et al. (2014). Patients’ perceptions of gene expression profiling in breast cancer treatment decisions. Current Oncology, 11(2), e203-211.
- Trudeau, M.E., et al. (1996). Docetaxel in patients with metastatic breast cancer: a phase II study of the National Cancer Institute of Canada-Clinical Trials Group. Journal of Clinical Oncology, 14(2), 422-428.
- Pritchard, K. and Whelan, T. (2005). Clinical trial update: National Cancer Institute of Canada. Breast Cancer Research, 7(2), 48-51.
- Parissenti, A.M., et al. (2015). Tumor RNA disruption predicts survival benefit from breast cancer chemotherapy. Breast Cancer Research and Treatment, 153, 135-144.
- Rna Diagnostics (2017). Meet the Rna Diagnostics Team. http://rnadiagnostics.com/about/
- Tadayyon, H., et al. (2016). Quantitative ultrasound assessment of breast tumor response to chemotherapy using a mutli-parameter approach. Oncotarget, 7(29), 45094-45111.
- Vlad, R.M., et al. (2009). Quantitative Ultrasound Characterization of Responses to Radiotherapy in Cancer Mouse Models. Clinical Cancer Research, 15(6), 2067-2075.
- Sadeghi-Naini, A., et al. (2013). Quantitative Ultrasound Evaluation of Tumour Cell Death Response in Locally Advanced Breast Cancer Patients Receiving Chemotherapy. Clinical Cancer Research, 19(8), 2163–74.
- Sadeghi-Naini, A., et al. (2013). Low-frequency quantitative ultrasound imaging of cell death in vivo. Med Phys, 40(8), 082901 (13 pp).
- Marshall, D.A., et al. (2019). Adherence to human epidermal growth factor receptor-2 testing and adjuvant trastuzumab treatment guideline in Ontario. Journal of Oncology Pharmacy Practice, 0(0), 1-7.
- Maurer, C., et al. (2018). Risk factors for the development of brain metastases in patients with HER2-positive breast cancer. ESMO Open, 3, e000440.
- Burgess, A., et al. (2015). Focused ultrasound-mediated drug delivery through the blood-brain barrier. Expert Review of Neurotherapeutics, 15(5), 477-491.