LOS ANGELES--Tamoxifen (Nol-vadex) may not prevent breast cancer
recurrence in women whose tumors over-express the HER2 oncogene (also
known as c-erbB-2), and such overexpression may be a predictor of
responsiveness to chemotherapy, researchers said at the ASCO
integrated symposium on HER2 in breast cancer.
The tamoxifen/HER2 interaction was reported in a 20-year update of
the GUN (Group of the University of Naples) trial of adjuvant
tamoxifen. Angelo R. Bianco, MD, reporting for the Naples
investigators, noted that in vitro studies have shown that
overexpression of HER2 induces resistance to tamoxifen.
This long-term clinical trial found that "tamoxifen improved
disease-free survival and overall survival in c-erbB-2-negative
patients only." The proportion of breast cancers that
overexpress HER2 appeared to be about 26% in Dr. Biancos sample.
The GUN trial randomized 308 patients to receive either tamoxifen, 30
mg/d for 2 years, or no hormonal therapy. HER2 expression was
evaluated on 245 paraffin-embedded specimens by immunohistochemistry.
A sample was considered positive if at least 10% of the cells stained
with antibody for HER2.
At 20 years, when the median follow-up was 13.1 years, both
disease-free survival and overall survival were significantly longer
for patients treated with tamoxifen than for controls, Dr. Bianco
reported. This improvement occurred regardless of menopausal status
or lymph node status.
"More interestingly," he said, "when we evaluated the
interaction between c-erbB-2 and tamoxifen, we found that tamoxifen
improved disease-free and overall survival only in c-erbB2-negative
patients, while showing a paradoxical detrimental effect in
c-erbB-2-positive patients (Table 1)."
A multivariate test for interaction adjusting for lymph node status,
menopausal status, estrogen receptor (ER) status, and ER/tamoxifen
interaction confirmed the predictive value of HER2 expression
(overall survival, P = .006; disease-free survival, P = .03).
A significant association was observed between HER2 expression and ER
expression, with ER-positive tumors more likely than ER-negative
tumors to be HER2 negative (Table 2).
A multivariate analysis showed no significant interaction between the
effects of treatment with tamoxifen and ER status, but the analysis
did demonstrate a first-order interaction between expression of HER2
and treatment with tamoxifen. This interaction, Dr. Bianco said, is a
significant prognostic factor for disease-free survival and overall
survival, "suggesting that total expression of c-erbB-2 affects
the outcome of adjuvant therapy with tamoxifen."
He noted that the results of this study need to be confirmed
"before the routine evaluation of c-erbB-2 expression can be
recommended for the selection of patients who are likely to benefit
A related role for HER2 expression was reported by Peter M. Ravdin,
MD, and his colleagues from the Southwest Oncology Group (SWOG).
He said that an Intergroup trial of 1,470 ER-positive, node-positive,
postmenopausal breast cancer patients found a modest but
statistically significant disease-free survival advantage for
patients who received adjuvant cyclophosphamide-doxorubicin-fluorouracil-tam-oxifen
(CAFT), compared with tamoxifen alone. "This raised the
question of whether c-erbB-2 overexpression could identify a subset
of patients who would benefit from the addition of CAF to
tamoxifen," he said.
He noted that a study by the Cancer and Leukemia Group B (CALGB-8541)
had earlier suggested that patients with overexpression of HER2 are
more likely to benefit from high doses of CAF, compared with low or
In the Biological Correlative study reported by Dr. Ravdin, HER2 was
retrospectively measured in 595 samples from the Intergroup trial.
The results showed that CAFT appeared to be superior to tamoxifen
alone in patients whose tumors overexpressed HER2. However, a formal
statistical analysis found only a trend toward an interaction between
HER2 overexpression and additional benefit of CAF, in part, he said,
"because of the low number of c-erbB-2-positive patients
randomized to receive tamoxifen alone (21 patients)."
Thus, Dr. Ravdin said, "we are unable to state with statistical
confidence whether the addition of CAF was more effective in c-erbB-2
positive patients. This study has low statistical power to answer
predictive questions, given the short follow-up, the 10:3
randomization of CAFT vs T, and the 16% rate of overexpression of
c-erbB-2." He added that the researchers are currently
collecting and analyzing additional cases for HER2 overexpression.
Dr. Ravdin concluded that "this study, like several others,
provides tantalizing but as yet inconclusive evidence that c-erbB-2
expression may be a predictor of particular chemoresponsiveness to
anthracycline-containing combination chemotherapy."
In his discussion of the papers, Edison Liu, MD, director of the
NCIs Division of Clinical Sciences, said that the two studies
considered together "raise a very important concept: That tumors
that overexpress HER2 do poorly with tamoxifen as the sole adjuvant
therapy, and that this bad outcome may be overcome by use of adequate
doses of adjuvant chemotherapy and especially by the use of agents
such as doxorubicin."