Current and future targeted treatments

This article reviewed the current standard of care in the treatment of metastatic breast cancer, as well as recent therapy advances and possible future directions.

Breast cancer is the most common form of female cancer. Recent knowledge of the different molecular activities within different types of breast cancer has led to more targeted treatments, dramatically increasing survival rates. The current review discusses the state of current targeted treatments and recent treatment advances for each subtype of breast cancer.

Subtypes of breast cancer are currently defined based on the different receptors (complexes on the surface of the cells) expressed by the cancer. For example, some breast cancers are caused by overproduction of human epidermal growth factor receptor 2 (HER2), which promotes the uncontrolled growth of cancer cells. Therefore breast cancers are often differentiated into HER2-positive or HER2-negative cancers. Similarly, estrogen receptor positive (ER+) breast cancers are highly dependent on the hormone estrogen for continued growth. Breast cancers not responsive to estrogen are thus termed estrogen receptor negative (ER-) cancers.

The most common subtype of breast cancer is ER+/HER2-, accounting for about 60% of all breast cancers. 20% to 40% of women with metastatic ER+ breast cancer will respond to endocrine therapy (also called hormonal therapy), in which estrogen production is suppressed, or the stimulating effect of estrogen on the cancer cells is blocked.

In post-menopausal women, aromatase inhibitors are used to block estrogen production. A review of 25 studies including more than nine-thousand patients found that aromatase inhibitors led to a 10% reduction in the risk of death compared to all other forms of hormonal treatment. For patients who become resistant to endocrine therapy with aromatase inhibitors, a combination of tamoxifen and everolimus (Afinitor) was found in one trial to increase the time until disease progression by 4.1 months compared to treatment with tamoxifen alone.

Endocrine therapy for pre-menopausal women often includes tamoxifen (which blocks the estrogen receptors). Recent studies have suggested that when tamoxifen is given in combination with gonadotropin-releasing hormone (GnRH) agonists (which suppress the production of estrogen), it is more effective at delaying disease progression among metastatic patients.

25% to 50% of ER+ patients become resistant to hormonal treatments. A recent phase III trial included 1286 patients with ER+ metastatic breast cancer which progressed despite treatment. Women receiving letrozole (an aromatase inhibitor) in combination with lapatinib (Tykerb) showed a trend towards prolonged survival. New treatment directions currently under investigation include a new cyclin-dependent kinase (CDK) 4/6 inhibitor (PD0332991). In an early phase II trial an impressive prolongation in the time until disease progression was seen among patients receiving PD0332991, from 5.7 to 18.2 months.

HER2-positive breast cancer is commonly treated with trastuzumab (Herceptin), which blocks the stimulating action of HER2 on cancer growth. Trastuzumab is often combined with chemotherapy, and recent research has shown taxane based chemotherapy drugs to be most effective and least toxic when combined with trastuzumab. Whether or not trastuzumab should be continued after cancer progression (supposedly indicating failure of treatment) is still a matter of some debate. A recent phase III trial has shown that continuation of trastuzumab even after disease progression results in increased respone rates to chemotherapy (48.9% vs. 24.6%) and a 29% reduction in the risk of disease progression.

Lapatinib (Tykerb) is a relatively new drug which also blocks the actions of the HER2 receptor. While several trial have shown that trastuzumab is superior to lapatinib, dual HER2 blockade with a combination of trastuzumab and lapatinib has been shown to reduce the risk of cancer progression by 26% and prolong survival by an average of 4.5 months compared to treatment with lapatinib alone. A phase III trial evaluated the addition of pertuzumab (Perjeta), another type of HER2 blocker, to trastuzumab and chemotherapy. Dual HER2 blockade with a combination of trastuzumab and pertuzumab, combined with chemotherapy, demonstrated a 38% reduction in the risk of disease progression within 6 months, and a 34% reduced mortality risk.

Trastuzumab emtansine (T-DM1) is a newly developed form of trastuzumab, directly attached to a chemotherapy agent. T-DM1 allows for targeted delivery of the toxic chemotherapy drug only into HER+ cancer cells. In a recent phase III trial, T-DM1 led to an average prolongation of 3.8 months before disease progression, and a 32% reduced mortality risk, without significant toxic side-effects.

Triple negative breast cancer (ER-/HER2-) is considered an aggressive form of cancer, with limited treatment options. In contrast to ER+ or HER2+ cancers, no specifically targeted therapies exist for the treatment of triple negative breast cancer. Patients initially respond well to chemotherapy, but response to treatment is generally short-lived. Current research is focused on determining the genetic basis of triple negative breast cancers in an attempt to develop new targeted molecular therapies.

This review concludes that treatments targeted to specific subtypes of breast cancer are currently the most effective, and the future treatments should depend on further development of these, as well as an increased concentration on patient quality of life.