Malignant breast cancer — both invasive and non-invasive — was diagnosed in about 291,000 women and 2,350 men in 2015 in the U.S., according to the American Breast Cancer Foundation. It is the second most common type of cancer in women, while it is considered rare among men. Breast cancer is caused by an acquired or inherited DNA mutation that results in an uncontrolled growth of cells in the breast. While the causes for this mutation are not fully understood, there are numerous risk factors that contribute to the development of the disease.

Patients often experience symptoms like a new lump or mass, swelling of all or part of a breast, skin irritation or dimpling, breast or nipple painnipple retraction, redness, scaliness, or thickening of the nipple or breast skin, or a nipple discharge other than breast milk. However, improvements in prevention and diagnosis have resulted in earlier diagnosis and increased survival rates.

Treatment options for patients with breast cancer include surgery, radiation therapy, chemotherapy, hormone therapy, targeted therapy, and bone-directed therapy.

How Ado-Trastuzumab Emtansine (Kadcyla) Works

Ado-trastuzumab emtansine (T-DM1) is used to treat a type of breast cancer that has metastasized to other parts of the body and has not improved, or has worsened, after treatment with other medications. It is a targeted therapy classified as an antibody drug-conjugate, and is a combination of trastuzumab and the chemotherapy drug emtansine.

Ado-trastuzumab emtansine is “an antibody-drug conjugate (ADC) consisting of the recombinant anti-epidermal growth factor receptor 2 (HER2) monoclonal antibody trastuzumab conjugated to the maytansinoid DM1 via a nonreducible thioether linkage (MCC) with potential antineoplastic activity,” according to the National Cancer Institute (NCI) Drug Dictionary. “The trastuzumab moiety of this ADC binds to HER2 on tumor cell surface surfaces; upon internalization, the DM1 moiety is released and binds to tubulin, thereby disrupting microtubule assembly/disassembly dynamics and inhibiting cell division and the proliferation of cancer cells that overexpress HER2.”

Ado-trastuzumab emtansine, which is provided intravenously, is currently only indicated for the treatment of breast cancer, but its use is being studied for other cancers. The combination that results in ado-trastuzumab emtansine is expected to improve the work of the two drugs, since emtansine is not a targeted therapy, which means that it affects both cancer and healthy cells.

Therefore, trastuzumab is added to transport emtansine directly to HER2-positive cancer cells and allows it to act by disrupting the growth of cancer cells. “Linkage of antibody and drug through a nonreducible linker has been reported to contribute to the improved efficacy and reduced toxicity of this ADC compared to similar ADCs constructed with reducible linkers.”

Ado-Trastuzumab Emtansine (Kadcyla) for Breast Cancer

Ado-trastuzumab emtansine was approved by the FDA on Feb. 22, 2013, and it is commercialized by Genentech under the brand name Kadcyla. It is indicated as a single agent in patients who suffer from  HER2-positive metastatic breast cancer and were unsuccessfully treated with trastuzumab and a taxane, either separately or in combination. The drug is also recommended for patients whose cancer re-occured less than six months after receiving adjuvant therapy.

The FDA approval was based on a randomized, multicenter, open-label trial which assessed the safety and efficacy of ado-trastuzumab emtansine in 991 patients with HER2-positive metastatic breast cancer.

“The co-primary endpoints of efficacy were progression-free survival (PFS), which was based on tumor response assessments by an independent review committee, and overall survival (OS). Patients who received ado-trastuzumab emtansine lived statistically significantly longer without their disease getting worse (PFS) compared with those who received lapatinib plus capecitabine [HR of progression 0.65 (95 percent CI: 0.55, 0.77), p < 0.0001]. The median PFS was 9.6 months for patients who received ado-trastuzumab emtansine and 6.4 months for patients who received lapatinib plus capecitabine,” reported the NCI.

The study also found that at least 25 percent of the patients who received ado-trastuzumab emtansine experienced side effects of fatigue, nausea, musculoskeletal pain, thrombocytopenia, headache, elevated transaminase levels, and constipation.

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