CTRC-AACR San Antonio Breast Cancer Symposium presents new data on emerging breast cancer therapies

September 18, 2015

The first study to be reported demonstrated a significant progression-free survival benefit in patients with advanced breast cancer who were treated with capecitabine chemotherapy and sorafenib, compared to treatment with capecitabine alone. The other two studies are ongoing.

Sorafenib is an oral agent that has been shown to target members of two classes of kinases involved in cell growth and angiogenesis, the growth of blood vessels to feed tumors. It is approved to treat advanced kidney cancer and liver cancer. Paclitaxel is used to treat a number of different cancers, including both early and advanced breast cancer.

Early research suggested sorafenib may be a promising treatment for breast cancer, and initial clinical studies demonstrated it has a modest activity as a single agent in patients with metastatic disease.

To see if benefit improved when sorafenib was paired with chemotherapy, the researchers randomized 119 patients to the combination therapy and 118 patients to a placebo and paclitaxel.

Results showed median progression-free survival was 6.9 months (combination therapy) vs. 5.6 months (placebo/paclitaxel). Median time-to-progression was 8.1 months vs. 5.6 months for patients receiving sorafenib/paclitaxel compared to placebo/paclitaxel. The overall response rate was 67 percent vs. 54 percent, respectively.

Discontinuation of study treatment due to adverse events occurred in 23 patients in the combination arm compared to five patients in the placebo/paclitaxel arm. With the exception of neuropathy, more grade 3 and 4 toxicities occurred in patients who received sorafenib/paclitaxel. Treatment-related deaths occurred in two patients in the combination treatment arm.

"There were no new toxicities observed with the combination and adverse events were manageable," Gradishar said.

67. Targeting Aldose Reductase: A Novel Strategy in Treating Endocrine Resistance Using Combination Therapy

Treating estrogen receptor-positive breast cancer tumors with a combination of fidarestat (an inhibitor of aldose reductase enzyme) and letrozole (an aromatase inhibitor) could delay or stop tumor resistance to endocrine therapy, according to data presented at the CTRC-AACR San Antonio Breast Cancer Symposium.

"Single agents are less effective," said Rajeshwar Rao Tekmal, Ph.D., professor of obstetrics and gynecology at the University of Texas Health Science Center at San Antonio. "Many tumors develop resistance, so this combination approach could prolong that window when endocrine therapy is effective."

About two-thirds of breast cancer tumors initially are hormone sensitive or estrogen receptor-positive and respond well to endocrine therapy. However, close to half of those tumors develop resistance to endocrine therapy, said Tekmal.

In this preclinical study, researchers treated estrogen receptor-positive tumors already resistant to letrozole with letrozole and fidarestat. As an inhibitor of aldose reductase enzyme, fidarestat blocks the metabolism of glucose in cancer cells.

Together, the combination effectively re-sensitized the cells to letrozole, allowing for effective endocrine therapy and more cell death.

Researchers believe increased glucose metabolism (polyol accumulation) contributes to oxidative stress, which, in turn, could alter intracellular signalling by affecting the regulation of protein kinases that are known to be involved in therapy resistance. Blocking the path of glucose metabolism may help to restore sensitivity to endocrine therapies or it may stop or delay the development resistance endocrine therapies in first place.

While this is a preclinical study, Tekmal believes it could lead to future drug treatments that will make endocrine therapy more effective for longer periods of time.

"This is a very promising study showing that combination treatments seem to work on resistance and re-sensitizing tumors that are resistant to endocrine therapies," he said.

Source: CTRC-AACR San Antonio Breast Cancer Symposium