LOS ANGELES--A monoclonal antibody directed at the HER2 receptor greatly enhances the effect of chemotherapy for women whose breast cancer overexpresses the HER2 gene. This encouraging finding comes as experts are beginning to suspect that increasing dose intensity of conventional chemotherapy may have "gone about as far as it can go," said Dennis Slamon, MD, PhD, chief, Division of Hematology-Oncology, UCLA School of Medicine.
At an ASCO symposium on HER2 research, Dr. Slamon reported that combining conventional chemotherapy with the anti-HER2 antibody trastuzumab(Drug information on trastuzumab) (Herceptin) improved response rates by 50%, response duration by 57%, and time to progression by 67% in women with metastatic breast cancers that overexpressed HER2.
Based on these results, trastuzumab has been "fast-tracked" by the FDA. Dr. Slamon predicted that the drug, developed by Genentech, Inc, will be approved before the end of 1998.
The Slamon study was a randomized, double-blind, multicenter trial in 469 women with metastatic breast cancers overexpressing HER2 (also referred to as HER2/neu)."We dont think this antibody is going to be effective for non-overexpressing tumors," Dr. Slamon said.
HER2 overexpression is a non-inherited alteration found in 25% to 30% of breast cancers. It is associated with swifter disease progression and poorer response to chemotherapy. "Patients who have HER2 overexpressing tumors really do have a different type of breast cancer and should be considered accordingly," Dr. Slamon said.
The results of his study also suggest that all breast cancer patients should be routinely examined for HER2 overexpression, a test that is widely available but not routinely done. "Overexpression" was defined in this study as more than 15% to 20% of cells positive for HER2 using immunostaining (see Figure).
None of the women in Dr. Slamons study had been treated with cytotoxic chemotherapy for metastatic disease, although many had received either paclitaxel (Taxol) or anthracycline-based chemotherapy for their primary disease.
Patients who had received previous doxorubicin(Drug information on doxorubicin) were assigned to treatment with paclitaxel(Drug information on paclitaxel), with or without trastuzumab. Those with no previous exposure to doxorubicin received either doxorubicin (Adriamycin)/cyclophosphamide (AC), epirubicin(Drug information on epirubicin)/cyclophosphamide, or paclitaxel. Half the patients in each group were then randomized to also receive the anti-HER2 antibody.
Median time to progression was 7.6 months for chemotherapy with antibody vs 4.6 months for chemotherapy alone (P = .0001). For patients who received AC, median time to progression was 8.1 months with antibody vs 6.1 months without. For those on paclitaxel, median time to progression was 6.9 months with antibody vs 3.0 months without (P = .0001).
One-year survival was 78% for chemotherapy plus antibody vs 67% without antibody. (However, these figures are complicated by the fact that patients on chemotherapy alone whose disease progressed were crossed over to chemotherapy plus antibody.)
The overall response rate was 32% for chemotherapy alone vs 49% for chemotherapy plus antibody. Among the patients who received AC, the overall response rate was 52% with antibody vs 43% without. These improvements were achieved without an increase in adverse events.
Dr. Slamon reported that a syndrome of myocardial dysfunction similar to that observed with anthracyclines was reported more commonly with AC plus antibody than with AC alone, paclitaxel plus antibody, or paclitaxel alone.
In an interview, Dr. Slamon said that most patients with this cardiomyopathy were treated successfully with ACE inhibitors, diuretics, or digoxin(Drug information on digoxin), and were able to continue the antibody. He advised clinicians treating patients with trastuzumab to monitor cardiac function with echocardiography every 12 weeks.
From Discovery to Phase III
Dr. Slamon, who is perhaps more closely associated with HER2 than any other researcher, began searching for a way to use HER2 to fight breast and other cancers more than a decade ago when he first discovered that the gene is overproduced in many breast cancers and that these cancers are more aggressive. Women whose cancer overexpress HER2 have a median survival of 3 years vs 6 to 7 years for women without HER2 overexpression.
Funding From Revlon Accelerated HER2 Research
Revlon Inc. has provided more than $13 million to the Revlon/UCLA Womens Cancer Research Program since 1990, with half of that amount going directly to work on the HER2 gene. Dr. Slamon estimates that the unrestricted grants from the cosmetic company accelerated his research by as much as 10 years. "The science that ultimately led to the development of Herceptin would not have happened when it did without the support of Revlon," he said.
Dr. Slamon explored this finding in the laboratory by transferring additional HER2 genes into cultured breast cancer cells that did not overexpress the gene, to see if this would change these tumor cells into the more virulent variety. He found that increasing HER2 expression increased DNA synthesis, cell growth, tumorigenicity, metastatic potential, and growth in soft agar.
"Our goal was to discover what is involved in converting a normal cell into a malignant cell," Dr. Slamon said. If we could find something that was broken and might be potentially targeted, we might be able to develop therapeutics around that." HER2 overexpression clearly fit that role and in addition is easily detected using immunostaining.
Trastuzumab inhibits HER2 overexpressing breast cancer cells in vitro but apparently does not affect normal cells or breast cancer cells that lack HER2 overexpression. Once it was shown that the antibody alone has efficacy, Dr. Slamon moved forward with this phase III trial.
"Throwing bigger and better bombs at the disease isnt necessarily going to get us a lot further," Dr. Slamon said. "Our data prove the paradigm for development of targeted therapy with less toxicity in breast cancer." He also suggested that the most logical place to use trastuzumab is likely to be "earlier and up front."