Survival shortened when estrogen or progesterone receptor negative breast cancer spreads to the brain

Dec 17 2007

Two studies from Mayo Clinic's site in Jacksonville, Fla., of women whose breast cancer spread to their brain, have found that women whose tumors do not have estrogen or progesterone receptors have the worst overall outcomes.

Because of this, these patients should be treated aggressively after an initial diagnosis to help prevent such a metastasis, say the investigators, who presented their findings at the San Antonio Breast Cancer Symposium.

Those cancers include so-called triple negative tumors — cancer that does not exhibit HER2 growth factors or estrogen (ER) or progesterone receptors (PR) — as well as HER2 positive cancers that are also ER/PR negative, say Mayo investigators.

This research is the first to look at differences in brain metastases and survival by different breast cancer subtypes. In one of the studies led by Stephanie Hines, M.D., investigators found that the median survival from diagnosis to death in women with triple negative tumors with brain metastases was 26 months, compared to 49 months in women with other types of breast cancer brain metastasis.

The second study, led by Laura Vallow, M.D., looked only at HER2+ tumors that had spread to the brain, and concluded that median survival from initial diagnosis to death in patients with ER/PR- tumors was only 17.5 months, compared to 55 months for women with ER/PR+ cancer.

“We need to be aware that this kind of cancer is high risk and we should do all that we can to prevent brain metastasis,” says Dr. Hines. “For women with triple negative breast cancer, improvements in outcome will likely come when new treatments for this type of cancer are successfully developed.”

Targeted therapies are available for cancers that are ER/PR+ or HER2+ before they metastasize to the brain. Herceptin, which treats HER2+ cancer, is theorized to be too large to breach the blood-brain barrier, and patients who have triple negative or HER2+ ER/PR – breast cancer do not have targeted therapies. “What's needed, therefore, are treatments for HER2+ and triple negative tumors that can reach the brain, as well as treatments that are specifically targeted to treat triple negative breast cancer cells,” Dr. Hines says.

Metastatic breast cancer accounts for 20 percent to 30 percent of the 170,000 cases of brain metastases diagnosed annually, and as improvements in systemic therapy prolong survival, brain metastasis in breast cancer patients is becoming more evident, says Dr. Vallow. “These results suggest that more aggressive therapy in ER/PR- tumors may be warranted because patients with ER/PR- disease tend to develop brain metastasis even if the cancer has not spread anywhere else, and this metastasis develops sooner and survival is shorter compared to breast cancer that is ER/PR positive,” she says.

While the outcome looks worse for HER2+/ER/PR- tumors than for triple negative cancers, findings from the two studies cannot be matched against each other because the studies did not directly compare these two groups of patients against each other. “One compared triple negative cancers against all other subtypes, and the other compared HER2+/ER/PR+ cancers against HER2+/ER/PR- cancers,” Dr. Hines says. “We didn't directly compare outcomes from triple negative tumors against HER2+ ER/PR- cancer.”

“For now, what we can say is that both the triple negative group and the HER2 + ER/PR- groups appear to have a poor outcome, which is unfortunate,” she says.

The studies looked at women treated for breast cancer at Mayo Clinic Jacksonville from 1993 to 2007 (Hines study) or from 1996 to 2006 (Vallow study) whose cancer spread to the brain.

Dr. Hines found in a study of 103 patients that those with triple negative tumors developed systemic and brain metastasis sooner than patients with other types of breast cancer, and had significantly shorter survival overall. Specifically, investigators concluded that time from:

• Diagnosis to distant metastasis was a median of 15 months in the triple negative group versus 24 months in the rest of the patients.

• Distant metastasis to brain metastasis was a median of three months for triple negative cancer versus 11 months for other subtypes.

• Brain metastasis to death, on average, was the same in both groups — seven months — presumably because the tumors, once in the brain, were treated alike, with whole brain radiation, stereotactic radiosurgery, and /or surgery, despite their tumor subtype.

• Diagnosis to death was a median of 26 months in the triple negative patients versus 49 months in other patients.

Dr. Vallow and her team of researchers looked at data from 83 women whose HER2+ tumors had spread to their brains. They found that:

• Patients with ER/PR- tumors were more likely to have brain metastasis as the first site of disease progression (73 percent) compared to women with ER/PR+ cancer (27 percent).

• Time from diagnosis to brain metastasis was a median of 45 months in ER/PR+ tumors compared to 14.5 months in ER/PR- cancer.

• Time from brain metastasis to death was a median 10 months in women with ER/PR+ tumors compared to 3 months in patients with ER/PR- cancer.

• Median survival for the ER/PR+ patients was 55 months compared with 17.5 months in patients with ER/PR- cancer.

“This study shows us that the outcome of HER2 patients with brain metastasis tended to be worse for those women with ER/PR negative status, however, because this study was small, more patients need to be studied to confirm this finding,” Dr. Vallow says.