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Thesis Format

Integrated Article

Degree

Doctor of Philosophy

Program

Biomedical Engineering

Supervisor

Samani, Abbas

2nd Supervisor

Sadeghi-Naini, Ali

Affiliation

York University, Toronto, ON, Canada

Joint Supervisor

Abstract

Breast cancer is the second most diagnosed cancer in women, estimated to affect 1 in 8 women during their lifetime. About 10% to 20% of new breast cancer cases are diagnosed with locally advanced breast cancer (LABC). LABC tumors are usually larger than 5 cm and/or attached to the skin or chest wall. It has been reported that when such cases are treated with surgery alone, metastasis and mortality rates are high, especially where skin involvement or attachment to the chest wall is extensive. As such, efficient treatment for this kind of breast cancer includes neoadjuvant chemotherapy (NAC) to shrink the tumor and detach it from the chest wall followed by surgery. Several studies have shown that there is a strong correlation between response to NAC and improved treatment outcomes, including survival rate. Unfortunately, 30% to 40% of patients do not respond to chemotherapy, hence losing critical treatment time and resources. Predicting a patient’s response at the early stages of treatment can help physicians make informed decisions about whether to continue the treatment or use an alternative treatment if a poor response is predicted. Such early and accurate response prediction can shorten the wasted time and reduce resources dedicated to patients while they endure significant side effects. Therefore, it is important to identify this group of non-responder patients as early as possible so that they can be prescribed alternative treatments. Current methods for evaluating LABC response to NAC are based on changes in tumor dimensions using physical examinations or standard anatomical imaging. Such changes may take several months to be detectable. Studies have shown that there is a correlation between LABC response to NAC and tumor softening. In other words, in contrast to responder patients where tumor stiffness generally decreases in response to NAC, in non-responder patients the stiffness of the tumor increases or does not change significantly. As such, a reliable and widely available breast elastography technique can have a major impact on the effective treatment of LABC patients. In this study, we first develop a tissue-mechanics-based method for improving the accuracy of ultrasound elastography. This method consists of 3 steps that are applied to the displacement fields generated from conventional motion-tracking methods. These three steps include: smoothing the displacement fields using Laplacian filtering, enforcing tissue incompressibility equation to refine the displacement fields, and finally enforcing tissue compatibility equation to refine the strain fields. The method was promising through validation using in silico, phantom, and in vivo studies. A huge improvement of this method compared to other motion-tracking methods is its ability in generating lateral displacement with high accuracy. This becomes especially important when the displacement and strain fields are used as inputs to an inverse-problem framework for calculating the stiffness characteristics of tissue, for example, Young’s modulus. We then use this enhanced ultrasound elastography technique to assess the response of LABC patients to NAC based on monitoring the stiffness of their tumors throughout the chemotherapy course. Our results show that this method is effective in predicting patients’ responses accurately as early as 1 week after NAC initiation.

Summary for Lay Audience

Breast cancer is the most diagnosed type of cancer and the second leading cause of cancer-related deaths in women. In 2020, it was estimated that more than 27,000 new invasive breast cancer cases to be diagnosed in women while 5100 women were predicted to die from this disease in Canada. Breast cancer tumor development is associated with considerable interaction with stromal cells, extracellular matrix, and connective tissue. As such, breast cancer is associated with significant changes in tissue biomechanical properties.

Out of patients struck with breast cancer, 10% to 20% are diagnosed with locally advanced breast cancer (LABC). Current treatments for LABC include neoadjuvant chemotherapy (NAC), followed by mastectomy or lumpectomy. The NAC is administrated to shrink the tumor and detach it from the chest wall so that it becomes operable. While the response to chemotherapy has demonstrated a strong correlation with overall treatment outcomes and patients’ survival, unfortunately, 30% to 40% of patients do not respond to chemotherapy. Therefore, it is important to identify this group of non-responder patients as early as possible so that they can be prescribed alternative treatments. The current methods for evaluating LABC response to NAC is based on changes in tumor dimensions using physical examinations or standard anatomical imaging. However, changes in tumor size after NAC may take several months to be detectable, and in some cases, they do not become apparent despite a positive histological outcome. Studies have shown that, generally, there is a correlation between LABC response to NAC and tumor softening. In other words, in contrast to responder patients where tumor stiffness generally decreases in response to NAC, in non-responder patients the stiffness of tumor increases or does not change significantly.

Ultrasound (US) Elastography is a non-invasive imaging modality developed for tissue stiffness mapping. This imaging modality can potentially be used as a clinically viable diagnostic tool to detect and characterize mechanical properties of breast cancer tumors including stiffness changes over time. The primary purpose of our long-term study is to develop novel methods for US elastography to improve its accuracy and reliability in the clinical setting. Once developed, we applied the methods using clinical data acquired through an observational study on LABC patients who underwent NAC. Results obtained from this study are used to assess the efficacy of our enhanced US elastography technique in evaluating LABC patient response soon after the start of NAC. According to these results, our method is successful in assessing this response as soon as 1 week after the start of NAC.

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