New Agents, Sequential Schedules Hold Promise

VIENNA, Austria—Breast cancer management has booked steady progress thanks to the integration of new chemotherapeutic and biologic agents into standard regimens and the development of sequential and dose-dense schedules of administration, Larry Norton, MD, of Memorial Sloan-Kettering Cancer Center, said at the 10^th European Cancer Conference (ECCO 10).

The Intergroup 0148/CALGB 9344 study showed significant improvements in disease-free and overall survival among women with high-risk breast cancer who were crossed over to paclitaxel (Taxol) after receiving doxorubicin plus cyclophosphamide (AC®T). This study was first reported in Los Angeles at the 1998 annual meeting of the American Society of Clinical Oncology (ASCO).

Dr. Norton reported the updated results from this trial, which confirm that the advantage of adding paclitaxel sequentially is maintained for at least 4 years. The data showed a highly significant 22% reduction in the annual risk of recurrence, compared with doxorubicin and cyclophosphamide alone.

These data were recently presented to the FDA’s Oncologic Drugs Advisory Board, which recommended approval of Taxol for the new indication as adjuvant therapy of node-positive breast cancer given sequentially to standard doxorubicin-based combination therapy (see Oncology News International, Nov. 1999, page 4), and the new indication was recently approved.

Dr. Norton noted that the NSABP is conducting a similar trial using a paclitaxel dose of 225 mg/m². In addition, he said, CALGB has just completed accrual for a study comparing a split AC®T regimen given every 3 weeks with a dose-dense regimen of doxorubicin followed by paclitaxel followed by cyclophosphamide (A ® T®C) given every 2 weeks with growth factor support.

Notwithstanding the disappointing results recently reported for high-dose chemotherapy, an Intergroup/SWOG trial is continuing with its comparison of A ® T®C vs a high-dose regimen with transplant in women with 4 to 10 positive lymph nodes. ECOG is about to start a trial to determine whether weekly injection of either paclitaxel or docetaxel (Taxotere) following AC chemotherapy provides any additional benefit.

“One of the key things we have to do to get beyond where we are now is to add biologic agents to these therapies,” Dr. Norton advised. As an example, he cited recent reports indicating that the addition of Herceptin (trastuzumab) to chemotherapy improves response rate, time to progression, and overall survival in women with advanced breast cancer.

A further analysis of patients who responded to chemotherapy found that, among the responders, patients who received Herceptin along with chemotherapy had an improved response duration (median 9.1 vs 6.1 months, relative to chemotherapy alone) and an improved median survival (37 vs 27 months).

“So Herceptin was not just increasing the percentage of patients showing benefit but actually increasing the cell kill in the individuals who benefited from chemotherapy, which is a very important result,” Dr. Norton said.

Ongoing trials are attempting to build on these results by exploring the role of Herceptin in adjuvant chemotherapy. An Intergroup/NCCTG study of stage II breast cancer is testing AC chemotherapy followed by (1) paclitaxel alone, (2) paclitaxel followed by Herceptin, or (3) paclitaxel with and followed by Herceptin. “This is critical because, if there is synergy between the agents, you’ll see it in the third arm but not in the second arm,” Dr. Norton commented.

For women with HER2-positive stage IIIb disease, the CALGB is conducting a trial of induction chemotherapy with AC followed by paclitaxel with or without Herceptin. After surgery and radiotherapy, participants in the CALGB trial will be randomized to receive Herceptin or no further therapy for 1 year.

Decreasing Mass Dimension

Dr. Norton reminded the audience of the recent discovery that normal human cells can be transformed into malignant cells by the insertion of three genes: the hTERT (telomerase) gene, which de-creases apoptosis; the SV-40 large T antigen, which increases mitosis and decreases apoptosis; and an oncogenic variety of RAS, which increases the cell’s mass dimension, or density.

Mass dimension, he said, may be an important issue in breast cancer, since physicians have long recognized that women with dense breasts and a high degree of branching are more likely to develop cancer.

“If we’re really going to make ad-vances in cancer therapeutics, we’re going to have to stop concentrating on just killing cells, ie, decreasing mitosis or increasing apoptosis, and we’re going to have to start looking at drugs that decrease the mass dimension,” Dr. Norton commented. He suggested that the synergistic effect of Herceptin and chemotherapy may stem from the ability of Herceptin to decrease the tumor cell’s mass dimension.

Other agents that interfere with the HER2 receptor are geldanamycin and its derivatives, which increase apoptosis and induce cell differentiation, leading to decreased mass dimension. “We are very excited about the use of this drug in clinical trials in combination with chemotherapy to try to increase the killing of cells,” Dr. Norton said. “If we can affect things like HER2, we can prevent cells from evidencing their malignant potential in the first place.”