What Are ADC Drugs? Which Breast Cancer Patients Can Receive ADC Treatment?

Breast cancer, regarded as the “killer of beauty,” is a malignant tumor that severely threatens women’s health, with an increasing incidence year by year. Antibody-drug conjugates (ADC), as a new type of therapeutic drug, have become a hot research topic in the field of breast cancer due to their advantages of “high efficacy and low toxicity.” In recent years, more than 100 ADC drugs have been undergoing clinical trials globally, with 14 approved for market, and currently, 3 ADC drugs have been approved for the treatment of breast cancer in China, significantly impacting the treatment landscape of breast cancer. So, what are ADC drugs? What advantages do ADC drugs have? Which patients can use ADC drugs?

What Are ADC Drugs? Which Breast Cancer Patients Can Receive ADC Treatment?

1

What Are ADC Drugs?

ADC drugs, fully known as antibody-drug conjugates, are a class of targeted biological agents that connect cytotoxic drugs to monoclonal antibodies through linkers, using monoclonal antibodies as carriers to efficiently deliver small-molecule cytotoxic drugs to target tumor cells in a targeted manner[1].
ADC drugs consist of three main components: antibodies, linkers, and cytotoxins[2]. They serve the following functions:

  • The antibody is the main component of ADC drugs, which has high specificity and can specifically bind to antigens on the surface of tumor cells.

  • The linker is the molecule that connects the antibody and the cytotoxin. Its main function is to maintain the stability of the ADC and release the cytotoxin after the antibody binds to the tumor cell.

  • The cytotoxin is the pharmacological component of ADC drugs, which has high cytotoxicity and can kill cancer cells. The cytotoxin can be a chemical drug, a radioactive nuclide, or other cytotoxic substances.

What Are ADC Drugs? Which Breast Cancer Patients Can Receive ADC Treatment?
Figure 1. Schematic Diagram of ADC Drug Structure[3]
Among the ADC drugs used for breast cancer treatment, the most common monoclonal antibody target is the human epidermal growth factor receptor-2 (HER-2). Trastuzumab emtansine (T-DM1) is the first ADC drug approved for the treatment of breast cancer. In January 2023, it was officially included in the national medical insurance catalog for all indications, and the national medical insurance payment standard was determined simultaneously, making ADC drugs a class of drugs that can be widely used by HER-2 positive breast cancer patients in China. In addition to T-DM1, the ADC drugs currently approved in the field of breast cancer also include trastuzumab deruxtecan (T-DXd) and sacituzumab govitecan (SG)[1], with SG being an ADC drug targeting the Trop-2 protein.

2

What Are the Advantages of ADC Drugs?

Tumor-specific antibodies allow ADC drugs to selectively deliver small-molecule cytotoxic drugs, reducing the off-target effects of small-molecule cytotoxic drugs while retaining their anti-tumor properties, effectively improving the benefit-risk ratio of anti-tumor therapy. Therefore, ADC drugs are also referred to as “magic bullets.” So, what specific advantages do ADC drugs have?
The design and mechanism of ADC drugs enable them to overcome some limitations of traditional chemotherapy and targeted therapy, mainly reflected in the following aspects[3]:
1) Highly Specific Targeted Therapy
ADC drugs utilize the high specificity of antibodies to selectively bind to antigens on the surface of tumor cells. Compared to traditional chemotherapy drugs, ADC drugs can more accurately target cancer cells, reducing damage to normal cells and thus decreasing some common chemotherapy side effects.
2) Local Release of Cytotoxins
ADC drugs achieve local release of cytotoxins through linkers connecting the cytotoxin to the antibody. This method allows the cytotoxin to be concentrated primarily near the tumor cells bound to the antibody, minimizing toxicity to normal cells.
3) Overcoming Drug Resistance
Due to the specific targeting of ADC drugs, their mechanism of action can bypass some common drug resistance mechanisms. Additionally, ADC drugs typically consist of multiple components, including different antibodies, linkers, and cytotoxins. This multi-component combination can reduce tumor cell resistance to a single target and improve therapeutic efficacy.

3

Which Breast Cancer Patients Can Receive ADC Drug Treatment?

Given that ADC drugs have so many advantages, which patients can use ADC drugs?
We know that in the field of breast cancer, the main target of currently marketed ADC drugs is HER-2. Guidelines generally recommend that HER-2 positive breast cancer patients, especially those with advanced or second-line treatment, can consider ADC drugs after progression on trastuzumab therapy. Among the treatment options for advanced breast cancer against HER-2, ADC drugs can also be prioritized for patients with brain metastases[4].
So, is it only recommended for advanced breast cancer patients to use ADC drugs? Actually, that’s not the case. Taking T-DM1 as an example, the currently approved indications include both advanced breast cancer patients and early-stage patients.
In HER-2 positive advanced breast cancer patients, T-DM1 can be used for patients who have previously received trastuzumab and taxanes alone or in combination and meet one of the following conditions[1]:
1) Previously received treatment for metastatic disease
2) Recurrence during adjuvant therapy
3) Recurrence within 6 months after completing adjuvant therapy
As for HER-2 positive early breast cancer patients, it can be used for adjuvant therapy in patients with residual invasive disease after neoadjuvant therapy with taxanes and trastuzumab[1].
Therefore, ADC drugs are not limited to advanced patients; both advanced and early patients may benefit from ADC drugs as long as they meet the treatment criteria after evaluation by a physician.
So, for triple-negative breast cancer that does not express HER-2, progesterone receptor, and estrogen receptor, can these patients also use ADC drugs? Research shows that using ADC drugs can significantly improve survival rates for triple-negative breast cancer patients with limited treatment options[5]. Currently, ADC drugs have been approved for the treatment of unresectable locally advanced or metastatic triple-negative breast cancer patients.
Of course, like all drugs, ADC drugs also have adverse reactions. Due to the differences between antibodies and cytotoxic drugs, the adverse reactions of different ADC drugs also vary, so adverse reactions should be closely monitored during treatment, and timely medical attention should be sought if necessary, to reduce the impact of adverse reactions on patient prognosis and quality of life[1].

Conclusion

ADC drugs combine antibodies, linkers, and cytotoxins to achieve the advantages of targeted therapy, and through precise targeting and local release of cytotoxins, overcome some limitations of traditional chemotherapy and targeted therapy. This gives ADC drugs broad prospects in the treatment of breast cancer and provides patients with more effective and personalized treatment options. In the future, with the continuous emergence of more new drugs, breast cancer will gradually become a “chronic disease,” and we believe that in the near future, we will conquer this mountain of breast cancer and move towards a cure.

References

[1] Chinese Anti-Cancer Association Clinical Research Committee of Anticancer Drugs, National Expert Committee for Monitoring Clinical Application of Anticancer Drugs, National Quality Control Center for Breast Cancer Experts, et al. Clinical Application of Antibody-Drug Conjugates in the Treatment of Malignant Tumors: Chinese Expert Consensus (2023 Edition) [J]. Chinese Journal of Oncology, 2023, 45(9):741-762.

[2] Yang Huixin, Qian Yingying, Huang Xu, et al. Research Progress of Anti-HER2 Breast Cancer ADC Drugs [J]. Chinese Journal of Geriatrics, 2023, 43(2):500-506.

[3] Zhuang Ming. “Magic Bullet” ADC Drugs—The Nemesis of Breast Cancer [J]. Science and Technology Vision, 2023, 7:25-28.

[4] Expert Group of “Chinese Breast Cancer Neoadjuvant Therapy Consensus (2022 Edition).” Chinese Breast Cancer Neoadjuvant Therapy Consensus (2022 Edition) [J]. Chinese Journal of Cancer, 2022, 32(1):80-89.

[5] Bardia, A., Hurvitz, S. A., Tolaney, S. M., Loirat, D., Punie, K., Oliveira, M., … & Rugo, H. S. (2021). Sacituzumab govitecan in metastatic triple-negative breast cancer. New England Journal of Medicine, 384(16), 1529-1541.

Editor: Yan Xiaoqian

Layout Editor: Awa

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