New research has shown that it may be possible to predict whether women with breast cancer will ... [+]
Researchers from Stanford University in California have developed a new genetic fingerprint test which aims to identify women with breast cancer who are more or less likely to respond to a class of often-useful, but toxic chemotherapy agents.
The work was published today in Nature Medicine and looks at drugs called anthracyclines, used in the treatment of several types of cancer including breast and some childhood cancers.
“Anthracyclines are a mainstay of chemotherapy and have been important for the treatment of early stage breast cancer for nearly thirty years,” said Christina Curtis, PhD, an assistant professor of medicine and of genetics at Stanford and one of the senior authors of the paper along with Gerald Crabtree, MD, professor of pathology and of developmental biology at Stanford and investigator at the Howard Hughes Medical Institute.
Anthracyclines are effective for many people, but despite this, they can be quite toxic, particularly affecting the heart and increasing the risk of secondary cancers. However, some breast tumors don’t really respond to the drugs at all, meaning that women are still exposed to toxic drugs and risk of serious side effects, with little or no benefit.
One of these, doxorubicin (also called adriamycin) is so notoriously known for causing side effects, that it is often referred to as “the red devil” by breast cancer patients and survivors, thanks to its bright red hue. The use of the drugs has declined in recent years and there have been some suggestions that now other, less toxic drugs for many breast cancer types are available, that anthracyclines use should reduce further.
“If we knew that a woman was at a high risk of recurrence, and that her tumor was likely to be responsive to anthracyclines, thereby lowering that risk, this may tip the balance towards a treatment that includes anthracyclines, despite the potential side effects,” said Curtis. “In contrast, we would avoid these drugs if we knew a patient was unlikely to benefit from their use,” she added.
The researchers began by looking at proteins in the cell called topoisomerases, which control unwinding and winding of DNA which happens when cells divide. Anthracyclines work by poisoning these proteins, stopping cells from dividing and ultimately leading to cell death.
“Topoisomerases are proteins that help to untangle and repackage the nearly two meters of DNA within the nucleus of each cell in our body – a space nearly a million times smaller,” said Curtis.
These topoisomerases are, in turn, controlled by a host of other proteins which help fold and unfold DNA into tiny chunks in the nucleus called chromatin regulatory proteins. Curtis and her colleagues constructed a network of approximately 400 of these chromatin regulators using computer analyses to figure out how these genes interact.
“It was akin to determining the connectivity in a social network like Facebook. Right away we observed that expression of these genes was completely rewired in breast cancer, compared to normal breast tissue,” said Curtis.
Next, they looked at chromatin genes in samples from over 1000 early-stage breast cancer patients and correlated the expression of these chromatin genes with response to anthracyclines. The scientists were able to narrow down their lens to 54 chromatin genes associated with anthracycline response.
“We found that in chromatin regulatory genes determined a breast tumor’s sensitivity to doxorubicin or etoposide, both of which are anthracyclines,” said Curtis.
They also tested another common breast cancer drug, paclitaxel which does not interact with topoisomerases, finding that there was no relationship between chromatin gene expression and response to this drug.
“These initial data are very promising indeed,” said Michael Melner, PhD, Senior scientific director, molecular genetics of cancer at the American Cancer Society. “This work as an initial step, its going to need much more evidence before it can be verified to be an important part of the treatment regimen. What’s exciting is its potential to do this,” he added.
There are several different types of breast cancer which behave differently and respond dramatically differently to treatments. Importantly, Curtis and the team found that this “abnormal wiring” of chromatin genes was found in all types of early-stage disease, raising the possibility that a universal test to predict response to anthracyclines could eventually be given to all breast cancer patients.
“This is a window into the future for potentially reducing the number of patients that may experience toxicity who may not receive much clinical benefit from the drugs. But it’s way too early to make clinical decisions, saying we will or won’t treat based on this data. Certainly this is really very interesting and has tremendous potential,” said Melner.
Anthracyclines, despite their potential toxicity are still a vital part of lifesaving treatment regimens for many women with breast cancer, so it is critical that any test to predict who will get benefit from the drugs is highly accurate.
So what is being done to translate these early, but incredibly impressive results into a test that can help women with breast cancer? Firstly, the researchers are looking at more patients with breast cancer to further test their findings.
“Ultimately, we would like to have a routine diagnostic test that indicates whether or not a patient is likely to benefit from these drugs so that an informed decision about the risks and benefits of different treatment options can be weighed by the physician and patient in conjunction with other clinical information,” said Curtis.
