Targeted Therapies in Breast Cancer: Increasingly Promising-and Complicated

Published: Friday, Jun 15, 2012
Dr. Leyland-Jones

Brian Leyland-Jones, MD, PhD

Treatment of breast cancer is becoming “horrendously complicated,” said Brian Leyland-Jones, MD, PhD, director of the Winship Cancer Institute at Emory University in Atlanta, Georgia. According to Leyland-Jones, as research on breast cancer progresses, the disease is seen as a set of many different diseases, each with distinct molecular and clinical features.

In February, Leyland-Jones spoke at the 9th Annual Northern New Jersey Breast Cancer Conference, held at the John Theurer Cancer Center, Hackensack, New Jersey, where he gave a broad overview of the current progress and direction of optimal therapies for breast cancer—individualized treatment based on specific molecular targets. Leyland-Jones noted that research in the field, both clinical trial data and new preclinical studies, is progressing so rapidly that it is almost impossible to remember all of the new, targeted areas. “It is becoming clear that breast cancer has 50 to 80 targetable drivers,” he said. “This is a time of massive knowledge change in the entire field.”

The genetic research is identifying new subpopulations of breast cancer to allow for better treatment options—some of the new subtypes could benefit from existing targeted agents and chemotherapy. This new breast cancer subtype clustering based on genetic and transcription data is also identifying new molecular drivers.

Translational research is using the new genetic data to develop drugs from a range of many newly identified targets. Advances in both basic research and translational research are producing a plethora of new targets, according to Leyland-Jones. “The number of targets is shooting up, but fortunately we are getting the drugs to handle those targets,” he said.

It is becoming clear that breast cancer has 50 to 80 targetable drivers. This is a time of massive knowledge change in the entire field. ”
–Brian Leyland-Jones, MD, PhD
Although identification of driver mutations such as HER2 overexpression in breast tumors has allowed for tailored therapies, many aggressive tumor types have no distinguishing genetic characteristics on which to base treatments. Research in this field is very active. A recent study published in the journal Nature characterized over 2000 breast tumors. The study revealed new breast cancer subgroups based on both genomic and transcription analyses.1 The authors of the study identified three new deletion mutations that correlated with already known breast cancer subtypes. Researchers can now take advantage of this knowledge to identify patients with these mutations and test specific drugs that target specific mutations. These types of genomic breast tumor studies will lead to more precise diagnoses and tailored treatments that target the specific molecular defects of a patient’s tumor.

HER2 Pathway
Click to enlarge.
Members of the human epidermal growth factor receptor family.
Mapping the genetic landscape of a tumor allows for identification of biomarkers, which can be used to predict response to treatment or better predict patients with high-risk disease or recurrence. For example, a research team at the Dana-Farber Cancer Institute in Boston, Massachusetts, has identified a marker of DNA damage in patients with triple-negative breast cancer that may be able to predict whether a patient has the potential to respond to platinum-based chemotherapy agents such as carboplatin and cisplatin.2

Currently, triple-negative breast cancer does not have any targeted therapy options because the subtype is actually a heterogeneous group of tumor types that is characterized by what they lack (no expression of estrogen or progesterone receptor and no HER2 overexpression) rather than distinct and targetable genetic aberrations. Platinum-based chemotherapy is widely used as a treatment, but it exposes the patient to toxicity and does not help all patients. Identifying patients who would benefit would save many patients from the toxic effects of systemic therapies that will not be efficacious—and lower unnecessary costs of treatment.

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