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Progress in Predicting Invasive Breast Cancer

Researchers Identify Biomarkers That May Help Decide Who Will Need Aggressive Treatment

By Charlene Laino
WebMD Health News

Reviewed By Laura J. Martin, MD

April 28, 2010 -- Doctors are a step closer to being able to predict which women with noninvasive breast tumors will go on to develop invasive breast cancer -- and therefore whether or not they need more aggressive treatment.

Researchers studied nearly 1,200 women with ductal carcinoma in situ (DCIS), a noninvasive and very early form of breast cancer confined to the milk ducts. They found that a combination of three tissue biomarkers was associated with a high risk of developing an invasive breast cancer with the potential to spread eight years later.

Also, DCIS that was diagnosed from a breast lump was linked to a greater risk of subsequent invasive cancer than DCIS that was diagnosed by mammography.
There's still a long way to go before the personalized approach to treatment is ready for prime time.

"But the study gets us closer to our goal of separating women with DCIS into risk groups, so as to avoid overtreatment of women with low-risk breast lesions and undertreatment of women with high-risk lesions," study researcher Karla Kerlikowske, MD, of University of California, San Francisco, tells WebMD.

The study was published online by the Journal of the National Cancer Institute.

Overtreatment of DCIS

Currently, overtreatment of DCIS, which will be diagnosed in over 47,000 women this year, is the big problem, according to Kerlikowske.

"Since there's currently no way to predict which women with DCIS will go on to develop invasive cancer, almost all are offered radiation after the lump is removed [lumpectomy] or mastectomy and sometimes hormone therapy. But our results suggest as many as 44% of women with DCIS may not require any treatment other than removal of the lump and can instead rely on active surveillance, or close monitoring," Kerlikowske says.

The close monitoring offers these women a safety net, she says. "If a tumor comes back, we can always give radiation then."

Radiation therapy not only carries a risk of side effects such as nausea, vomiting, and fatigue but also precludes irradiating the same area of the breast a second time, Kerlikowske says. "So you want to save it for when it is really needed," she says.

Predicting Invasive Breast Tumors

The study involved 1,162 women aged 40 and older who were diagnosed with DCIS and treated with lumpectomy alone between 1983 and 1994.

Overall, their eight-year risks of developing a subsequent DCIS or a subsequent invasive cancer were 11.6% and 11.1%, respectively.

When the researchers looked at women whose DCIS was diagnosed by feeling a lump, the eight-year risk of subsequent invasive cancer was substantially higher than average, 17.8%.

Then they looked at different combinations of biomarkers using tissue that had been stored for 329 of the women when they were first diagnosed with DCIS. These biomarkers include estrogen receptor, progesterone receptor, Ki67 antigen, p53, p16, epidermal growth factor receptor-2, and cyclooxygenase-2.

The study showed that women who express high levels of three biomarkers -- p16, cyclooxygenase-2, and Ki67 -- also had a substantially higher-than-average eight-year risk of developing invasive cancer (27.3%).

The researchers stratified all 1,162 women into four risk groups. A total of 17.3% were in the lowest-risk group, with only a 4.1% chance of developing invasive cancer at eight years; 26.8% were in the next lowest risk group, with a 6.9 chance of developing invasive cancer at eight years. If the findings are validated, it is these two groups that could forgo treatment other than lumpectomy and active surveillance, Kerlikowske says.

A total of 27.6% of the women were in the high-risk group, with a nearly 20% chance of developing invasive cancer at eight years. These are the women who need more aggressive therapy with radiation and perhaps hormone therapy, she says.

Factors associated with a higher risk of having a subsequent ductal carcinoma in situ included having no cancer cells remain within 1 millimeter of the area from which the lump was removed and different combinations of biomarkers.

Unanswered Questions

Still, many questions remain.

For starters, about half of women who developed invasive cancer in the study didn't have the three biomarkers or DCIS diagnosed from a lump, so the researchers have to figure out what other factors are at play, Kerlikowske says.

Also, the approach has not been shown to actually extend lives.

Additionally, the study involved women who had undergone lumpectomy alone, which is no longer the standard of care, says Ramona Swaby, MD, a breast cancer specialist at Fox Chase Cancer Center in Philadelphia.

Recurrence rates are lower in women who also get radiation and if needed, hormone therapy, so it's important to see if the findings hold up in such women, she tells WebMD.

Craig Allred, MD, of Washington University School of Medicine in St. Louis, also calls for further study in an editorial accompanying the study. Still, "if validated, the results could optimize current therapy in certain settings: [withholding] radiation from women with low-risk DCIS, for example," he writes.

Several companies have expressed interest in helping to further develop and eventually market any tissue biomarker test, which will also need FDA approval, according to Kerlikowske.

Since it utilizes the same method and can be done at the same time doctors determine a tumor's hormone-receptor status, she doubts it will cost more than a few hundred dollars.

Funding for the research was provided by the National Cancer Institute and the California Breast Cancer Research Program.

SOURCES: Kerlikowske, K. Journal of the National Cancer Institute, online edition, April 29, 2010.

Allred C. Journal of the National Cancer Institute, online edition, April 29, 2010.

Karla Kerlikowske, MD, professor of medicine, epidemiology and biostatistics, University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center.

Ramona Swaby, MD, Fox Chase Cancer Center, Philadelphia.

Craig Allred, MD, Washington University School of Medicine, St. Louis.

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