VIENNA, AustriaBreast 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 10th
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 FDAs 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, youll 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 cells 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 were really going to make ad-vances in cancer
therapeutics, were going to have to stop concentrating on just
killing cells, ie, decreasing mitosis or increasing apoptosis, and
were 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 cells 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.