RDC Development for Breast Cancer

Breast cancer, possessing high incidence and mortality rates, is one of the most commonly diagnosed malignant tumors worldwide and the second most common cause of cancer mortality in women in the United States with 268,670 new breast cancer cases in the United States in 2018. Based on molecular and histological biomarker evidence, breast cancer can be divided into three groups, containing breast cancer expressing hormone receptor (estrogen receptor (ER+) or progesterone receptor (PR+)), breast cancer expressing human epidermal receptor 2 (HER2+), and triple-negative breast cancer (TNBC) (ER−, PR−, HER2−).

Fig.1 Illustration of breast cancer.

Risk Factors of Breast Cancer

• Age
  Considering all the predominant risk factors of breast cancer, age is a key risk factor which is confirmed by the higher incidence of breast cancer at younger ages and the incidence doubling about every 10 years until menopause. Likewise, the risk of breast cancer in women with first birth after the age of 30 is about twice the risk of the age of 20 with the highest risk for women having a first birth after the age of 35.
• Family history
  As an autosomal dominant disease, about 10% of breast cancer in Western countries is due to a genetic predisposition, with a higher incidence among both close family members and first-degree relatives.
• Diet
  Lifestyle is another key factor for breast cancer, including diet, alcohol consumption, and sedentary status leading to obesity.
• Exogenous Factors
  Besides, exposure to radiation and hormone replacement therapy at a young age also contributes to a relatively higher risk.

Traditional Therapies for Breast Cancer

The most widely used traditional therapy for breast cancer is chemotherapy with cytotoxic drugs and immunotherapy by agents promoting immune responses against tumors. Although breast cancer, the one that affects one in seven women worldwide during their lifetime, is one of the most studied cancers, patients still recur at a rate of about 15% within the first 10 years after surgery.

Breast Cancer Treatment with RDC

• Targeted Receptor in Breast Cancer
  The HER2/neu oncogene encodes a transmembrane protein (p185HER2) with extensive homology to the epidermal growth factor receptor which is overexpressed in many human tumors, most notably in breast cancer. Nowadays HER2 is a key oncogene in BC, which is commonly used in systemic therapy, in other words, anti-HER2 therapy, for HER2 positive cases. This advanced anti-HER2 therapy method is based on HER2 overexpression, as a major identified factor whose amplification leads to uncontrolled cell proliferation in breast cancer.

Fig.2 The general concept of therapeutic radiopharmaceuticals. (Vahidfar, N., et al., 2021, International journal of molecular sciences)

• Overview of ¹⁷⁷Lu-trastuzumab
  The most widely used anti-HER2 monoclonal antibody in the treatment of breast cancer is trastuzumab, an approved immunotherapeutic agent used for breast cancer treatment. The novel RDC (Radionuclide Drug Conjugate) drug ¹⁷⁷Lu-trastuzumab, composed of trastuzumab and the α-emitter ¹⁷⁷Lu, is commonly used in the treatment for eradicate breast cancer metastases expressing variable levels of HER2/neu.

Fig.3 Schematic representation of ¹⁷⁷Lu -trastuzumab. (Guleria, M., et al., 2021, RSC medicinal chemistry)

• Treatment Effect of ¹⁷⁷Lu-trastuzumab
  The imaging results of the clinical study show the preferential accumulation of ¹⁷⁷Lu -trastuzumab in the breast lesions and the best tumor to background contrast at 72 h post-administration, indicating the therapeutic potential of the agent.

Fig.4 Imaging results of the same patient administrated with [¹⁷⁷Lu] Lu-trastuzumab. (Guleria, M., et al., 2021, RSC medicinal chemistry)

References

1. Vahidfar, N., Aghanejad, A., Ahmadzadehfar, H., Farzanehfar, S., & Eppard, E. (2021). Theranostic advances in breast cancer in nuclear medicine. International journal of molecular sciences, 22(9), 4597.
2. Guleria, M., Sharma, R., Amirdhanayagam, J., Sarma, H. D., Rangarajan, V., Dash, A., & Das, T. (2021). Formulation and clinical translation of [¹⁷⁷Lu] Lu-trastuzumab for radioimmunotheranostics of metastatic breast cancer. RSC medicinal chemistry, 12(2), 263-277.