After surgery to remove early-stage breast cancer, many women are treated with a combination of chemotherapy medicines. If a woman is post-menopausal and the cancer is hormone-receptor-positive, she'll also take hormonal therapy (tamoxifen or an aromatase inhibitor) for 5 years. Treatments given after surgery are called adjuvant therapies and are given to lower the risk of the cancer coming back (recurrence).
One research study reviewed here showed that post-menopausal women diagnosed with early-stage, hormone-receptor-positive breast cancer that had spread to the lymph nodes who got adjuvant chemotherapy AND adjuvant hormonal therapy had a lower risk of recurrence and were more likely to be alive than women who got only hormonal therapy.
The study also showed that starting hormonal therapy after chemotherapy was done was better than giving hormonal therapy and chemotherapy at the same time.
The second related study reviewed here showed that a type of genetic test, called a genomic assay, can help figure out if women diagnosed with early-stage, hormone-receptor-positive breast cancer that has spread to the lymph nodes will benefit from adjuvant chemotherapy. Other research has shown that genomic assays can help figure out if women diagnosed with early-stage, hormone-receptor-positive breast cancer that hasn't spread to the lymph nodes will benefit from adjuvant chemotherapy.
These results were presented at the 2009 San Antonio Breast Cancer Symposium.
In the first study, 1,477 post-menopausal women diagnosed with hormone-receptor-positive, early-stage breast cancer that had spread to the lymph nodes got one of three adjuvant treatment plans after surgery:The chemotherapy combination was Cytoxan (chemical name: cyclophosphamide), Adriamycin (chemical name: doxorubicin), and methotrexate -- called CAF for short. Most of the women were followed for about 9 years and some were followed for as long as 13 years.
The researchers found that women who got both adjuvant chemotherapy and adjuvant tamoxifen were 24% less likely to have a recurrence than women who got only adjuvant tamoxifen:
Overall survival (with or without a recurrence), was 16% better in the women who got both adjuvant chemotherapy and adjuvant tamoxifen compared to women who got only adjuvant tamoxifen:
Still, this difference in survival rates wasn't statistically significant, which means it could have been due to chance and not because of the difference in treatment.
Women who got tamoxifen after chemotherapy was done were 16% less likely to have a recurrence compared to women who got tamoxifen at the same time as chemotherapy. This difference also wasn't statistically significant, which means it could have been due to chance and not because of the difference in treatment.
To see if a genomic assay could help figure out if women diagnosed with early-stage, hormone-receptor-positive breast cancer that had spread to the lymph nodes would benefit from chemotherapy after surgery, the researchers tested these types of cancer from 367 women involved in the first study with a genomic assay.
The researchers found:
So it seems that a genomic assay can help decide if women diagnosed with early-stage, hormone-receptor-positive breast cancer that had spread to the lymph nodes would benefit from chemotherapy after surgery. This is important because it allows women with a low risk of recurrence to avoid chemotherapy and its possible side effects.
If you've been diagnosed with early-stage, hormone-receptor-positive breast cancer, your doctor will probably recommend hormonal therapy (either tamoxifen or an aromatase inhibitor) for at least 5 years after any other treatments are done. You and your doctor also will have to decide if chemotherapy makes sense for your unique situation. If the breast cancer spread to the lymph nodes, this study suggests that you may benefit from chemotherapy before hormonal therapy to lower your risk of recurrence.
Still, if your risk of recurrence is low -- even though the cancer has spread to the lymph nodes -- you and your doctor may want to avoid chemotherapy. As you work through your decision, ask your doctor about the reasons for and against chemotherapy and if a genomic assay could help you make that decision. Armed with the most accurate and up-to-date information about the breast cancer and treatment, you and your doctor can decide on a treatment plan that makes the most sense for you and your unique situation.
SAN ANTONIO (MedPage Today) -- After more than two decades of follow-up, anthracycline-based chemotherapy added to tamoxifen continues to offer a survival advantage for postmenopausal breast cancer, according to a study reported here at the San Antonio Breast Cancer Symposium and online.
Women treated with chemotherapy and then tamoxifen had a 24% improvement in disease-free survival compared with women treated with tamoxifen alone (P=0.002). Chemotherapy also led to a trend toward improved overall survival.
The trial also showed a trend toward better survival when the chemotherapy and tamoxifen were given sequentially rather than concurrently.
"We believe that for postmenopausal women with few comorbidities who have a substantial risk of recurrence or death based on the prognostic profile of their tumor, the risk-benefit balance favors anthracycline-based chemotherapy followed by tamoxifen," Kathy Albain, MD, of Loyola University in Maywood, Ill., and colleagues concluded online in The Lancet.
"However, characteristics of the tumor should also be factored into the risk-benefit ratio. This study shows the necessity of long-term follow-up of adjuvant therapies to determine the outcome of treatment," they wrote.
A companion study, also reported here as well as online in The Lancet Oncology, suggested that genetic profiling can identify a subset of women who may not benefit from chemotherapy -- in particular those whose tumors had low scores on an assay of gene expression.
Researchers said the risks and toxicity of chemotherapy make it critical to identify patients who are highly unlikely to respond to it.
Upon its approval for clinical use, tamoxifen became the gold standard of adjuvant therapy for estrogen receptor-positive, postmenopausal breast cancer.
Adding chemotherapy to tamoxifen offered attractive theoretical benefits, but no consensus existed about chemotherapy for tamoxifen-responsive postmenopausal breast cancer patients.
Most trials of chemotherapy in postmenopausal breast cancer involved regimens containing cyclophosphamide, methotrexate, and fluorouracil (CMF), but some studies had suggested the superiority of anthracycline-containing regimens, the authors wrote.
Moreover, preclinical studies suggested possible interference with cytotoxicity when tamoxifen and CMF were given concurrently. Nonetheless, concurrent therapy had been the standard in many clinical trials, the authors continued.
To address the unresolved issues, Southwest Oncology Group investigators in 1988 launched a randomized clinical trial involving postmenopausal patients with receptor-positive, node-positive breast cancer.
Patients were randomized 2:3:3 to tamoxifen alone or to tamoxifen plus chemotherapy, administered sequentially or concurrently. The chemotherapy regimen consisted of cyclophosphamide, doxorubicin, and methotrexate (CAF).
The primary outcome was disease-free survival, and investigators performed two comparisons: tamoxifen alone versus tamoxifen plus chemotherapy; and sequential versus concurrent therapy with CAF and tamoxifen.
Albain and colleagues reported findings from an analysis of 1,477 patients. After a median follow-up of 8.94 years (maximum of 13), chemotherapy plus tamoxifen (sequential or concurrent) was associated with a 10-year disease-free survival of 57%, compared with 48% for tamoxifen alone.
The difference translated into a hazard ratio of 0.76 in favor of chemotherapy (95% CI 0.64 to 0.91, P=0.002).
Women who received chemotherapy had a 10-year overall survival of 65% compared with 60% for tamoxifen alone. The 5% absolute difference represented a 17% improvement compared with tamoxifen alone, but the difference did not reach statistical significance (HR 0.83, 95% CI 0.68 to 1.01, P=0.057).
The comparison of sequential versus concurrent therapy favored the former for both disease-free survival (HR 0.84, 95% CI 0.70 to 1.01, P=0.061) and overall survival (HR 0.90, 95% CI 0.73 to 1.10, P=0.30), but the differences did not achieve statistical significance.
The second study reported by Albain and colleagues involved use of a multigene tumor assay to identify women who were likely or unlikely to respond to the CAF chemotherapy regimen.
They used a 21-gene recurrence score assay that previously demonstrated prognostic value for women with node-negative, estrogen-receptor positive breast cancer treated with tamoxifen.
Albain and colleagues extended the evaluation to the SWOG study, examining the assay's ability to determine which women with node-positive, receptor-positive breast cancer are unlikely to benefit from chemotherapy.
The study included tumor specimens from 367 patients. The investigators assessed correlation between the recurrence score and disease-free survival by treatment group (tamoxifen versus CAF-tamoxifen). Derived from RT-PCR analysis of gene-expression, the recurrence score ranged from 0 to 100.
The results confirmed the recurrence score's prognostic value for treatment with tamoxifen alone (HR 2.64, P=0.006, for a 50-point difference in the score).
Additionally, the results showed that a recurrence score of less than 18 predicted no benefit from chemotherapy with respect to the trial's primary endpoint of disease-free survival (HR 1.02, P=0.97).
In contrast, women whose tumors had a score of 31 or greater had a significantly greater likelihood of improved disease-free survival with chemotherapy (HR 0.59, P=0.033).
Recurrence score by treatment group remained significant throughout the first five years of follow-up (P=0.029) but not beyond that time period (P=0.58).
Analyses of overall survival and cancer-specific survival yielded similar findings.
In a commentary that accompanied the Lancet article, Michael Gnant, MD, and Guenther G. Steger, MD, of the Medical University of Vienna in Austria, said the 5% overall survival benefit is a worthwhile improvement but comes at a price of increased toxicity.
"For that reason, identification of subgroups of patients who have an above-average outcome is important," Gnant and Steger wrote.
"Since risk is something we cannot change, response prediction is nowadays judged more important for clinical decision-making than risk itself, but calculation of individual benefit is still poor," they added. "Avoidance of unnecessary or ineffective treatment should be one of the main goals in adjuvant breast oncology today."
Acknowledging the 21-gene assay score's correlation with recurrence, Gnant and Steger noted that the benefit of therapy was limited to the highest risk patient subgroup (score ≥31), which constituted less than a third of the trial cohort.
Moreover, the finding that low-risk patients derived little or no benefit from chemotherapy could mean that overtreatment is an even greater problem for patients with node-negative breast cancer.
Albain and co-authors of The Lancet article had no relevant disclosures.
Albain and co-authors Wiliam E. Barlow, Robert B. Livingston, Peter Ravdin, George W. Sledge, Clifford Hudis, Daniel F. Hayes, and D. Craig Allred disclosed relationships with Genomic Health. Ravdin also disclosed a relationship with Adjuvant Online. Co-authors Steven Shak, Roberto Bugarini, Frederick L. Baehner, and Carl Yoshizawa are employees of Genomic Health.
Gnant and Steger had no relevant disclosures.
Primary source: The Lancet Source reference: Albain KS, et al "Adjuvant chemotherapy and timing of tamoxifen in postmenopasal patients with endocrine-responsive, node-positive breast cancer: a phase 3, open-label, randomized controlled trial" Lancet 2009; DOI:10.1016/S0140-6736(09)61523-3.Additional source: The LancetSource reference: Gnant M, Steger GN "Fighting overtreatment in adjuvant breast cancer therapy" Lancet 2009; DOI:10.1016/S0140-6736(09)62097-3.Additional source: Albain KS, et al "Prognostic and predictive value of the 21-gene recurrence score assay in postmenopausal women with node-positive, estrogen-receptor-positive breast cancer on chemotherapy: a retrospective analysis of a randomized trial" Lancet Oncol 2009; DOI:10.1016/S1470-2045(09)70314-6. Source reference: Albain KS, et al "Prognostic and predictive value of the 21-gene recurrence score assay in postmenopausal women with node-positive, estrogen-receptor-positive breast cancer on chemotherapy: a retrospective analysis of a randomized trial" Lancet Oncol 2009; DOI:10.1016/S1470-2045(09)70314-6.
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