Combining Conventional and Biologic Therapies

BARCELONA—Clinical and scientific rationale increasingly supports the use of cytotoxic and bio-logic agents in combination to treat breast cancer, a Spanish oncologist asserted during a satellite meeting at the San Antonio Breast Cancer Symposium, sponsored by Bristol-Myers Squibb Oncology.

“I think it is clear that the combination of conventional agents with biologics is more than a promising approach,” said Jose Baselga, MD, chairman of oncology, Vall d’Hebron General Hospital, Barcelona. “In particular, Herceptin [trastuzumab] given with chemotherapy does enhance clinical benefit in patients who have HER-2-expressing tumors.”

There is also a rationale for combining biologic agents and then adding those combinations to chemotherapy, he said.

“We are facing a very interesting situation in which we will have to do studies to prove that the new combinations are of use and that biologic agents are of use in earlier disease. A whole series of adjuvant trials is planned.”

Dr. Baselga is among investigators worldwide who are evaluating a wide range of new biologic compounds, such as inhibitors of epidermal growth factor receptor (EGFR) and tyrosine kinase.

“Tyrosine kinase inhibitors are very small molecules,” he said. “We have found we can prevent receptor phosphorylation completely with small doses of the inhibitor. There appears to be a relationship between the number of receptors and sensitivity to the compound in breast cancer models.”

Arguably, the synergy between biologic and cytotoxic agents has been demonstrated most clearly with paclitaxel (Taxol) and Herceptin (see box for a possible explanation of this synergism).

Possible Mechanism of Herceptin/Taxol Synergy

Recent laboratory investigations have provided insight into the means by which trastuzumab (Herceptin) and paclitaxel (Taxol) might have synergy. In particular, the evidence suggests that effects on cell cycle proteins might account for the increased antitumor activ-ity seen with the combination, Dr. Jose Baselga said in his San Antonio presentation.

Paclitaxel activates p34, which plays a role in regulating apoptosis. Overexpression of HER-2 is associated with activation of p21, which appears to interact with p34 in ways that inhibit paclitaxel’s antitumor activity.

“If this, in fact, is what is happening, it would be a good idea to use a compound that decreases the amount of HER-2 in cells, and that is what happens with Herceptin,” he said.

In a series of preclinical studies, Dr. Baselga and his colleagues evaluated single-agent treatment with Herceptin, doxorubicin, or paclitaxel. They then combined each chemotherapeutic agent with Herceptin.

Enhanced Antitumor Response

Combining Herceptin with either chemotherapeutic agent resulted in enhanced antitumor response, compared to treatment with individual agents. However, the greatest inhibitory effect occurred when paclitaxel and Herceptin were combined (Cancer Research 58:2825-2831, 1998).

“The combination of Taxol and Herceptin resulted in complete elimination of tumors in a much higher percentage of cases than with either agent alone,” Dr. Baselga said. “The model was biased against responses because the therapy was not started until the tumors were of an important size. We observed the effects with three different dose levels and two different dose schedules of Taxol.”

He added that there has been no risk of severe adverse events with Herceptin used in combination, “other than the cardiac risk that has been observed when Herceptin is given ith anthracyclines. The cardiac risk is not observed when Herceptin is given with paclitaxel.”

Dr. Baselga said a next logical step will be to evaluate biologic combinations for additive or synergistic effects. Some evidence already suggests that anti-EGFR antibodies and HER-2 antibodies are synergistic in combination, he added.