Adjuvant chemotherapy for postmenopausal women with endocrine-responsive breast cancer is still debated, and no biomarkers have been proven to predict benefit. But an analysis of biomarkers in a large North American breast cancer trial suggests that estrogen receptor (ER) score, nuclear grade, and HER-2/neu status do predict survival outcomes and treatment benefit after chemo-hormonal therapy in postmenopausal, node-positive ER+ and/or progesterone receptor (PR)+ women.
The Breast Cancer Intergroup of North America Phase III Study 0100 (SWOG-8814) has already shown that a combination of CAF (cyclophosphamide, doxorubicin, fluorouracil) plus tamoxifen is superior in terms of survival for patients compared with patients receiving tamoxifen alone.
The latest analysis, presented at the San Antonio Breast Cancer Symposium, continues to show higher disease-free survival rates with sequential chemo-hormonal therapy than with tamoxifen alone or with chemotherapy given concurrently with tamoxifen.
Lead author Kathy S. Albain, MD, Professor of Medicine in the Division of Hematology/Oncology at Loyola University Medical Center, said the initial report in 2002 included biomarker data on HER-2 alone but that now there are significantly more blocks and unstained slides to analyze.
In her presentation she reported data on 782 specimens tested for ER positivity (IHC Allred score), nuclear and mitotic grades, HER-2 status by immunohistochemistry (IHC) and by fluorescence in situ hybridization (FISH), and p53 protein expression.
“High mitotic rate was a significant adverse prognostic variable, as were HER-2 by IHC and positive p53 protein expression,” Dr. Albain said, but a particularly favorable subgroup of women were those with HER-2-negative and PR-positive disease.
Factors that did not appear significantly prognostic were levels of ER (IHC) positivity, HER-2 status (IHC), and nuclear grade.
One informative factor predicting benefit from CAF-tamoxifen was a low or intermediate ER score, associated with a 44% improvement in disease-free survival over tamoxifen alone.
“The strongest interaction was observed for a high ER IHC score, with no CAF benefit,” she said
HER-2 positivity was associated with a 54% improvement in disease-free survival with CAF-tamoxifen versus tamoxifen alone. For patients with HER-2 negative disease the advantage was only 22%.
If p53 protein expression was positive, there was a 56% benefit to CAF-tamoxifen, but only 20% if p53 was negative.
And patients with nuclear Grade 3 tumors derived a 48% improvement from CAF added to tamoxifen, but only 7% if Grade 1 or Grade 2.
The prediction of benefit from timing of tamoxifen administration in the two CAF arms was also studied, Dr. Albain said, but ER score was the only informative analysis.
“Only patients with tumors that had a high ER score had additional disease-free survival improvement by sequencing the tamoxifen after CAF,” she said.
The researchers concluded that:
* Strong, independent adverse predictors of disease-free survival were four or more positive nodes, p53 positivity, and PR negativity.
* CAF added significant long-term disease-free survival and overall survival benefit to tamoxifen in postmenopausal women with node-positive receptor-positive breast cancer.
* This survival advantage was greatest when tamoxifen followed CAF rather than when given concurrently.
* There was no added benefit from CAF vs tamoxifen alone in a favorable group with one to three positive nodes and HER-2 negative tumors.
Dr. Albain added that ER levels were not prognostic but were strongly predictive of response to therapy in the receptor-positive cohort.
She noted that therapy with CAF was particularly effective if a low or intermediate ER level was found in the tumor, whereas the advantage to sequencing tamoxifen after CAF was observed especially in the subset with high ER levels.
In the trial, 1,477 postmenopausal women with node-positive, ER/PR-positive breast cancer were randomly allocated to receive tamoxifen alone (controls), sequenced CAF followed by tamoxifen, or concurrent tamoxifen and CAF.
CAF consisted of oral cyclophosphamide for 14 days, with doxorubicin and fluorouracil given on Days 1 and 8, for six 28-day cycles.
When CAF was added to tamoxifen there was a 31% improvement in disease-free and a 21% improvement in overall survival.
The benefit was greatest when tamoxifen followed CAF, Dr. Albain said, with an additional 20% improvement in disease-free survival and 12% better overall survival time compared with the use of concurrent CAF-tamoxifen.
Ten-year disease-free survival estimates are 60%, 53%, and 48%, respectively, for the sequential, concurrent, and tamoxifen-alone study arms.
For overall survival, the 10-year estimates are 68%, 62%, and 60%, respectively.
“These differences for disease-free and overall survival are larger than those presented two years ago,” Dr. Albain said.
Are Tamoxifen Data Relevant?
After Dr. Albain's presentation, an oncologist in the audience asked about the relevance of the study. “Since tamoxifen has been replaced with aromatase inhibitors, can you still defend the use of chemotherapy [in these patients]?,” asked Jan G. M. Klijn, MD, PhD, Chief of the Department of Medical Oncology at Rotterdam Cancer Institute.
Dr. Klijn elaborated in an e-mail message after the meeting, noting that replacement of tamoxifen by an aromatase-inhibitor results in an improvement of 3% to 6% in disease-free survival benefit, and perhaps more by 10 years of follow-up.
Therefore it can be expected that fewer patients will potentially benefit from chemotherapy when an aromatase-inhibitor is used, especially in the HER-2/neu-positive and/or PR-negative subgroups and patients with relatively low ER-levels, he said.
“Personally, I am more restrictive with adjuvant chemotherapy in postmenopausal patients with clearly ER-positive tumors.”
During the meeting, session moderator C. Kent Osborne, MD, Director of Baylor Cancer Center, also asked, “As the benefit from endocrine therapy goes up with the use of aromatase inhibitors, would this make the relative benefits from chemotherapy even less?”
Expanding on the topic by e-mail after the meeting, Dr. Osborne said that even though tamoxifen given simultaneously with chemotherapy seemed to inhibit the effectiveness of chemotherapy in the SWOG trial, that does not necessarily mean an aromatase inhibitor (AI) given simultaneously with chemotherapy would do the same.
“The data [Dr. Albain] has shown, that it is best to give tamoxifen after chemotherapy is finished rather than giving it at the same time, may not apply to AIs which are now being used more in the adjuvant setting,” Dr. Osborne said. “This needs to be studied.”
He added that it is a separate issue whether certain groups of patients such as those with tumors negative for HER-2 and with very high ER levels would benefit at all from chemotherapy.
“Data are accumulating that the benefit may be small,” he said, “but more data like this are needed, looking at the more modern chemotherapy regimens to see whether they benefit these patients, before we can say chemotherapy should not be given.”
Dr. Osborne said he still treats high-risk patients with chemotherapy plus hormone therapy, using either tamoxifen or an aromatase inhibitor.