Team:ZJU-China/Background

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Background

Overview

Breast cancer is the main malignant tumor that threatens women's health. In an effort to overcome the non-specificity and side effect of the current contrast agent used for MRI, we reconstruct the magnetosomes from magnetotactic bacteria Magnetospirillum gryphiswaldense to produce a contrast agent with high bio-compatibility that specifically targets HER2-positive breast cancer cells. With biological modifications, magnetosomes can link with anti-HER2 antibodies. By antigen-antibody interaction, engineering magnetosomes can conjugated with HER2 positive breast cancer cells, demonstrating a special pattern on the image under magnetic field. Armed with our engineered contrast agent MagHER2some, the efficiency of evaluating the response of the treatment of HER2-postive breast cancer treatment can be optimized, thus assisting the progress of therapy process. Further application can be made through establishment of a platform with biomarkers targeting various diseases as inputs, paving avenue for precise evaluation of other diseases.

Breast Cancer

Breast cancer is a leading cause of death for women worldwide, with incidence and mortality increasing in lower-income countries^[1]. According to the statistics on the Globocon by International Agency for Research on Cancer, the incidence and mortality rate of breast cancer among women rank the first among all the cancers types worldwide in 2018, which is 24.2% and 15.0% (Figure 1A); the number of countries with breast cancer as the top common cancer is 154, ranking the first in the legend (Figure 1B)^[2].

Figure 1. (A) Pie Charts Present the Distribution of Cases and Deaths for the 10 Most Common Cancers in 2018 forFemales. For each sex, the area of the pie chart reflects the proportion of the total number of cases or deaths. (B) Global Maps Presenting the Most Common Type of Cancer Incidence in 2018 in Each Country Among women.
The number of countries with breast cancer as the top common cancer is 154, ranking the first in the legend (colored in pink).
Source: GLOBOCAN 2018.

In China, breast cancer is one of the most common malignant tumors threatening to female health due to the increasing stress and accelerating pace of life. In the global cancer report released by the international agency for research on cancer (IARC), the cases number of breast cancer in China accounts for 11.19% of the world’s, second to United States. In the past few years, both the incidence rate and mortality rate see a remarkable increase，which speaks of the significance of comprehensive prevention and control strategies (Figure 2)^[3][4].

Figure 2. Trends in (A) Incidence Rates and （B）Mortality Rates (Age‐Standardized to the Segi Standard Population) for Selected
Cancers for Females: China, 2000 to 2011.
Data source: 22 population‐based Chinese cancer registries.

A palpable breast mass is evident in about 30% of women with breast cancer; visible signs associated with breast cancer include dimpling, an orange-peel appearance, erythema, edema, blistering, excoriations, sanguineous nipple discharge, and nipple retraction^[5]. Apart from the painstaking treatment in advanced disease, patients are at an increased risk of anxiety, depression and suicide, and neurocognitive and sexual dysfunctions even after survive the cancer (Figure 3).

Figure 3. Breast cancer patients are suffer both physical and psychological pain. (Figures were from public source)

Current Approaches for Breast Cancer Examination

At present, examination methods of breast cancer can be basically divided into imaging and tissue biopsy. Mammography and ultrasonography are used as initial imaging modalities, while tissue biopsy is to confirm the disease by obtain the information of tumor grade and immunohistology. In combination of the examination method above, diagnosis, presurgical planning and the evaluation of post-treatment response can be carried out to assist management of the disease^[5][6].

Compared with conventional imaging methods, breast magnetic resonance imaging (MRI) shows its superiority as follows:

1. The most sensitive modality in the breast cancer imaging.

With higher resolution and multi-dimensional imaging, MRI outperforms mammography in assessing tumor size, examining the soft tissue and detecting additional lesions in 16% to 20% of patients.

2. Free of ionizing radiation.

Compare to computed tomography (CT), which is another routine screening for breast cancer, MRI is free of ionizing radiation and will not trigger gene mutation.

3. Used in specific circumstances.

Compared with mammography and ultrasonography, MRI can be used in patients with dense breasts, those with a history of breast cancer, and those at high risk for breast cancer; it can more accurately identify skin changes common in inflammatory breast cancer, such as skin invasion.

What it the most effective, MRI also can be used in the presurgical staging and planning or in the evaluation of treatment response. However, some flaws still exist in the current MRI examination, hindering the further development of breast cancer screening.

Current Issues

Breast cancer is a heterogeneous disease with different biological patterns of aggressiveness and clinical manifestations. Consequently, adjunct imaging method that can accurately stage breast cancer and determine its local extent are needed to guide the choice of surgical approach and systemic therapy. To assess the response in patients undergoing neoadjuvant chemotherapy, breast MRI is undoubtedly a powerful modality with its high sensitivity and resolution. However, limitations do exist in current MRI examination, making it difficult to maximize the best effectiveness of assisting the treatment.

1. Limited specificity.

The discovery that breast cancer is a genetic disease contribute to implications on how to treat it. Although established MRI factors (histological type, tumor size, grade, etc.) are of great prognostic importance, these cannot fully cover the heterogeneity of breast cancer. Therefore, it is crucial to introduce the classification concept of molecular subtypes, which can be achieved by the revolutionary method of gene-expression profiling. Classification of molecular subtypes are based on the evolving field of genomics analysis, a novel non-invasive approach that aims to associate imaging findings with molecular subtypes, gene mutations, and other genome-related features of cancers (Figure 4)^[6]. To date, this field in breast imaging is dominated by MRI with both great potential and challenges.

Figure 4. The Cancer Genome Atlas (TCGA) Network has defined four intrinsic molecular subtypes for the classification of breast cancer. luminal A (ER- or progesterone [PR]-positive and HER2-negative), luminal B (ER- or PR-positive and HER2-positive), HER2-enriched (ER- and PR-negative and HER2-positive), and TN/basal-like (ER-, PR-, and HER2-negative).

Unfortunately, subtype classification based on existing MRI is limited, as there is no specific genetic testing readily available—different signals from the tumor areas and normal tissues under the magnetic field result in the strong contrast in the image, showing no specific in molecular subtypes.

2. Existing side effect of MRI contrast agent.

MRI contrast agents typically function by detectably altering the longitudinal (T1) or transverse (T2) relaxation times of nearby hydrogen nuclei^[7]. Gadolinium-based contrast agent, a sort of T1 contrast agent, has been widely used for MRI. However, gadolinium is not always desired due to its inherent enhancement properties and potential side effects (e.g. nephrogenic systemic fibrosis)^[8]. Therefore, it is imperative to develop the ideal contrast agent that meet the demand of both contrast effect and clinical safety.

To solve the problems above, Team ZJU-China 2020 is working on the specific magnetosome contrast agent for molecular MRI. To be specific, we will:

● Create a new kind of contrast agent which have the ability to specifically target breast base on different molecular subtype. Currently, we are focusing on the subtype of HER2 positive, and ER positive, PR positive can be solved in the same way.

● Use magnetosomes as our contrast agent. Magnetosome is a kind of Fe₃O₄ particles wrapped in bilevel phospholipid, has excellent biocompatibility, and non-toxic side effects on mammals.

In the long run, future prognosis and evaluation mode will be revolutionized when this magnetic contrast agent is applied into some other target molecules. We are fully convinced that under the gudiance of synthetic biology, a novel non-invasive imaging method, precise post-treatment evaluation and therapy adjunct will be achieved. Armed with our engineering MagHER2some contrast agent, the best of the evaluation effects can be made to minimize the empirical judgement during the image analysis by doctors and facilitates the ongoing breast cancer management. Click to know more about our solutions.

References

[1]. Jerusalem, G., Lancellotti, P., & Kim, S. B. (2019). HER2+ breast cancer treatment and cardiotoxicity: monitoring and management. Breast cancer research and treatment, 177(2), 237–250.
https://doi.org/10.1007/s10549-019-05303-y

[2]. Bray, F., Ferlay, J., Soerjomataram, I., Siegel, R. L., Torre, L. A., & Jemal, A. (2018). Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: a cancer journal for clinicians, 68(6), 394–424.
https://doi.org/10.3322/caac.21492

[3]. He Li, Rongshou Zheng, Siwei Zhang, Hongmei Zeng, Kexin Zhang, & Changfa Xia, et al. (2018). Analysis on the incidence and death of breast cancer in Chinese women in 2014. Chinese Journal of Oncology, 40(003), 166-171.

[4]. Chen, W., Zheng, R., Baade, P. D., Zhang, S., Zeng, H., Bray, F., Jemal, A., Yu, X. Q., & He, J. (2016). Cancer statistics in China, 2015. CA: a cancer journal for clinicians, 66(2), 115–132.
https://doi.org/10.3322/caac.21338

[5]. Watkins, E. J. (2019). Overview of breast cancer. Journal of the American Academy of PAs, 32(10), 13-17.
https://doi.org/10.1097/01.JAA.0000580524.95733.3d [6]. Adrada, B. E., Candelaria, R., & Rauch, G. M. (2017). MRI for the staging and evaluation of response to therapy in breast cancer. Topics in Magnetic Resonance Imaging, 26(5), 211-218.
https://doi.org/10.1097/RMR.0000000000000147

[7]. Zhang, F., Li, F., Lu, G. H., Nie, W., Zhang, L., Lv, Y., ... & Xie, H. Y. (2019). Engineering magnetosomes for ferroptosis/immunomodulation synergism in cancer. ACS nano, 13(5), 5662-5673.
https://doi.org/10.1021/acsnano.9b00892

[8]. Wesolowski, J. R., & Kaiser, A. (2016). Alternatives to GBCA: are we there yet?. Topics in Magnetic Resonance Imaging, 25(4), 171-175.
https://doi.org/10.1097/RMR.0000000000000096

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