Meeting Report: [Новость добавлена - 03.02.2010]

The 2009 San Antonio Breast Cancer Symposium Understanding the role of antiangiogenesis therapies in metastatic disease and optimizing treatment of patients with HER2-positive disease were common themes.

The San Antonio Breast Cancer Symposium (SABCS; December 9-13, 2009) has
been a forum for the latest basic science and clinical research in breast
cancer for 31 years. The Editor-in-Chief of Journal Watch Oncology and
Hematology, William J. Gradishar, MD, discusses several important studies
of therapy in the metastatic and early-stage disease settings. Readers are
encouraged to visit the SABCS website for additional information on these
and other topics in breast cancer.

Bevacizumab plus Chemotherapy in Metastatic Breast Cancer
The RIBBON-1 study (JW Oncol Hematol Jun 16 2009) showed that the
antiangiogenesis agent bevacizumab -- a monoclonal antibody directed
against vascular endothelial growth factor (VEGF) -- plus chemotherapy
extended progression-free survival (PFS) when compared with chemotherapy
alone in first-line treatment of women with metastatic breast cancer.
Investigators leading the phase III RIBBON-2 trial (Abstract 42) evaluated
chemotherapy plus bevacizumab or chemotherapy plus placebo for second-line
treatment of women with human epidermal growth factor receptor 2
(HER2)-negative metastatic breast cancer. Chemotherapy could include a
taxane, capecitabine, vinorelbine, or gemcitabine. Prior use of bevacizumab
or other VEGF pathway-targeting therapies was prohibited.

For the primary efficacy analysis (in pooled chemotherapy cohorts), PFS was
7.2 months for those who received bevacizumab versus 5.1 months for those
who received placebo (hazard ratio, 0.78; P=0.0072). A similar PFS
advantage for the bevacizumab-containing treatment arm was observed in each
of the chemotherapy cohorts. Objective response rate was 39.5% in the
bevacizumab arm versus 29.6% in the placebo arm (P=0.0193), but overall
survival was similar in the two groups. No unexpected adverse effects were
observed in any of the chemotherapy-plus-bevacizumab cohorts. Patients who
received bevacizumab were more likely to experience neutropenia,
hypertension, sensory neuropathy, and proteinuria.

RIBBON-2 is the first phase III trial to demonstrate positive outcomes with
bevacizumab combination therapy when used as second-line treatment for
patients with metastatic breast cancer. Many questions remain, however,
including how bevacizumab might be used, if at all, following disease
progression on bevacizumab-containing regimens. The ideal chemotherapy
partner for bevacizumab is also under investigation in clinical trials such
as that conducted by a large cooperative group to study first-line
treatment of metastatic breast cancer.

Combination Therapy with Sorafenib
Sorafenib is an oral inhibitor of multiple kinases involved in cell growth
and angiogenesis (sorafenib targets include c-kit, RAF, receptors for VEGF
and for platelet-derived growth factor). Although sorafenib is approved for
treatment only in patients with advanced renal cell carcinoma and
hepatocellular carcinoma, investigators studied its efficacy and safety in
two recent phase IIb trials of patients with metastatic breast cancer. One
group of investigators examined sorafenib in combination with weekly
paclitaxel versus paclitaxel plus placebo (Abstract 44), while other
investigators randomized patients to sorafenib plus capecitabine or
capecitabine plus placebo (Abstract 45). Patients in the first study were
from the U.S., Brazil, and India and were previously untreated for
HER2-negative, metastatic breast cancer. The second study included patients
from Spain, France, and Brazil who also had HER2-negative metastatic or
locally recurrent disease and who underwent <2 prior chemotherapy regimens
for advanced or metastatic disease (prior therapy must have included a
taxane and anthracycline unless the anthracycline was contraindicated).

In both studies, patients who received sorafenib plus chemotherapy
experienced longer PFS than did patients who received chemotherapy plus
placebo (see the table); however, differences in PFS for sorafenib versus
placebo were significant only in the second study (sorafenib plus
capecitabine vs. capecitabine plus placebo; P=0.0006).

The most common adverse event among patients receiving sorafenib plus
paclitaxel was hand-foot syndrome (HFS; grade 3 in 30% of patients vs. 3%
of patients who received placebo). There were several unusual causes of
death (e.g., malaria, tuberculosis) among patients enrolled in India, which
might have skewed the PFS results. The combination of sorafenib plus
capecitabine also was associated with high rates of grade 3 HFS (45% vs.
13% in those who received capecitabine alone). These trials clearly
demonstrate the activity of sorafenib in metastatic breast cancer; however,
to ensure the viability of combination sorafenib plus chemotherapy as a
treatment option, high rates of severe HFS must be lowered by changing
dosing frequencies or amounts.

When Trastuzumab Therapy Fails in Metastatic Breast Cancer
Patients with HER2-positive breast cancer usually receive therapy with
trastuzumab, a monoclonal antibody that binds to the extracellular portion
of HER2. Lapatinib targets the intracellular portion of HER2 and is used in
patients whose disease progresses on trastuzumab. However, preclinical data
suggest that simultaneously targeting the intracellular and extracellular
segments of HER2 with lapatinib plus trastuzumab might produce additional
benefits in patients whose disease advances on monotherapy. To test this
combination in a clinical setting, investigators randomized 296 women who
were heavily pretreated with trastuzumab for HER2-positive metastatic
breast cancer (median of 3 prior trastuzumab-containing regimens) to
lapatinib monotherapy or a combination of lapatinib plus trastuzumab
(Abstract 61). Patients who experienced disease progression after [&ge;]4
weeks of lapatinib monotherapy could switch to combination therapy.

About half of the women who initially received lapatinib monotherapy later
added trastuzumab. Median PFS was 12 weeks for those in the combination arm
and 8.1 weeks for those receiving lapatinib monotherapy (HR, 0.73;
P=0.008). Median survival was 14 months for patients receiving combination
therapy and 9.5 months for those in the lapatinib-only treatment arm (HR,
0.74; P=0.026). Although the frequencies of adverse events were somewhat
greater in patients receiving combination therapy, most adverse events were
grade 1 or 2. The extent of the benefits are difficult to assess
definitively given the high crossover rate; nonetheless, these findings
indicate that dual targeting of the HER2 pathway in the absence of
chemotherapy is effective in patients with metastatic breast cancer, even
in those previously treated with trastuzumab.

Evaluating Anthracycline- and Nonanthracycline-Based Regimens in
HER2-Positive Disease
Long-awaited data from this third planned efficacy analysis of the BCIRG
006 trial provide important information about the efficacy and safety of
trastuzumab combined with either anthracycline-based or
nonanthracycline-based regimens for adjuvant treatment of patients with
early-stage, HER2-amplified breast cancer (Abstract 62). In this
randomized, phase III trial involving 3222 women, investigators compared
three combination regimens:

Doxorubicin plus cyclophosphamide followed by docetaxel (AC-T)
Doxorubicin plus cyclophosphamide followed by docetaxel and trastuzumab
(AC-TH)
Docetaxel, carboplatin, and trastuzumab (TCH)


After a median follow-up of 65 months, rates of disease-free survival were
84% for those in the AC-TH arm, 81% in the TCH arm, and 75% in the AC-T
arm. Overall survival rates were better in patients who received AC-TH
(92%; HR, 0.63; P<0.001) and TCH (91%; HR, 0.77; P=0.038) than in those who
received AC-T (87%). Even among high-risk patients (defined as having
[&ge;]4 positive axillary lymph nodes), outcomes among those treated with
AC-TH were similar to those among patients who received TCH.

Risk for congestive heart failure was substantially higher in patients who
received AC-TH (1.95%) than in those who received TCH (0.37%; P<0.001).
Since the second report of these data, seven cases of leukemia have
developed in patients who received AC-containing regimens. Although not yet
peer reviewed and published, these efficacy and safety data continue to
make a compelling argument for using nonanthracycline therapies plus
trastuzumab in patients with early-stage, HER2-positive disease; the
findings also might accelerate the trend toward avoiding anthracyclines in
the adjuvant setting.

-- William J. Gradishar, MD

Dr. Gradishar is the lead author of Abstract 44.

Published in Journal Watch Oncology and Hematology February 2, 2010

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