Joon Kim

Background: Breast cancer is the most common cancer among women, about 42,000 women dying every year worldwide.¹ It is known to develop from breast cancer stem cells (BCSCs). BCSCs have different types that develop into different types of breast cancer cells.² Due to the heterogeneity of breast cancer cells, drugs may kill some types of cancer cells but not others, leading to cancer drug resistance.³ So, it is important to overcome the drug resistance due to tumor heterogeneity to treat breast cancer. It is proposed that antibody-drug conjugates (ADCs), which are complexes in which drugs are crosslinked to antibodies, can specifically recognize proteins overexpressed by cancer cells, such as HER2, and overcome the heterogeneity of cancer cells expressing variable levels of HER2.⁴

Objective: How scientists studied ADCs and their potential to overcome the drug resistance of breast cancer have been explored.

Search Methods: An online search in PubMed was done from 2019 to 2024 using the following keywords: “breast cancer”, “tumor heterogeneity”, “antibody-drug conjugates”, “breast cancer drug resistance”.

Results: A study compared the cytotoxic effect of MMAE to other conventional anticancer drugs such as cisplatin and paclitaxel and found that MMAE was the most cytotoxic drug and can be used as the anticancer drug for ADCs.⁵ Also, a study found that thermally stable ADCs can be synthesized by using transglutaminase-mediated conjugation and azide-alkyne click reaction to crosslink the drug to an antibody.⁴ Then, it was found that ADCs exhibit significantly higher cytotoxicity rates in vitro MTT assays compared to trastuzumab, a HER2-recognizing antibody drug.⁶ Also, two different types of drugs were crosslinked to an antibody to synthesize dual-payload ADCs.⁷ The study found that dual-payload ADCs inhibited breast cancer cell growth better than trastuzumab in vitro MTT assays.⁷ Furthermore, a study synthesized a heterogenous tumor by mixing HER2⁺ and HER2^– cells and injecting it into mice.⁸ Then, the study administered each mouse with either MMAE ADCs, MMAF ADCs, 1:1 mixture of the ADCs, or dual-payload MMAE-MMAF ADCs.⁸ The mice treated with dual-payload ADCs had the lowest tumor volume and highest probability of survival, showing that administering two different types of drugs likely have a synergistic effect and lead to better growth inhibition of cancer cells in vivo.⁸ Finally, a study treated 557 patients diagnosed with metastatic breast cancer with either the ADC treatment or the traditional chemotherapy, and they found that patients who received the ADC treatment had longer average overall survival length, longer progression-free survival lengths, and lower occurrence of adverse events of Grade 3 or higher.⁹

Conclusions: Studies have found that ADCs are more cytotoxic against breast cancer cells in vitro than anticancer drugs, showing that the antibody-protein interaction could potentially overcome the drug resistance. Also, they found that dual-payload ADCs are more cytotoxic than single-payload ADCs and that there is likely a synergistic effect between different drugs. Finally, studies found that ADCs could lead to better clinical outcomes than traditional treatment methods. ADCs show great potential to be an effective treatment against breast cancer and overcome drug resistance.

Works Cited:

1. Ben-Dror J, Shalamov M, Sonnenblick A. The history of early breast cancer treatment. Genes. 2022;13(6):960. doi:10.3390/genes13060960
2. Barzaman K, Karami J, Zarei Z, et al. Breast cancer: Biology, biomarkers, and treatments. International Immunopharmacology. 2020;84:106535. doi:10.1016/j.intimp.2020.106535
3. Zhang A, Miao K, Sun H, Deng C-X. Tumor heterogeneity reshapes the tumor microenvironment to influence drug resistance. International Journal of Biological Sciences. 2022;18(7):3019-3033. doi:10.7150/ijbs.72534
4. Anami Y, Deng M, Gui X, et al. Lilrb4-targeting antibody–drug conjugates for the treatment of acute myeloid leukemia. Molecular Cancer Therapeutics. 2020;19(11):2330-2339. doi:10.1158/1535-7163.mct-20-0407
5. Hingorani DV, Allevato MM, Camargo MF, et al. Monomethyl auristatin antibody and peptide drug conjugates for Trimodal Cancer Chemo-Radio-Immunotherapy. Nature Communications. 2022;13(1). doi:10.1038/s41467-022-31601-z
6. Yaghoubi S, Gharibi T, karimi MH, et al. Development and biological assessment of MMAE-trastuzumab antibody–drug conjugates (adcs). Breast Cancer. 2020;28(1):216-225. doi:10.1007/s12282-020-01153-5
7. Mckertish CM, Kayser V. A novel dual-payload ADC for the treatment of her2+ breast and colon cancer. Pharmaceutics. 2023;15(8):2020. doi:10.3390/pharmaceutics15082020
8. Yamazaki CM, Yamaguchi A, Anami Y, et al. Antibody-drug conjugates with dual payloads for Combating Breast Tumor Heterogeneity and drug resistance. Nature Communications. 2021;12(1). doi:10.1038/s41467-021-23793-7
9. Modi S, Jacot W, Yamashita T, et al. Trastuzumab Deruxtecan in previously treated HER2-low advanced breast cancer. New England Journal of Medicine. 2022;387(1):9-20. doi:10.1056/nejmoa2203690