December 18, 2009 (San Antonio, Texas) — Postmenopausal women with hormone-receptor-positive and node-positive breast cancer who are at especially high risk for recurrence might be the main beneficiaries of the addition of chemotherapy to tamoxifen to prevent recurrence. This suggestion comes from 10-year results of a landmark clinical trial published online December 10 in the Lancet.
Furthermore, a multigene assay might help rule out women who do not benefit from the added chemotherapy, according to a related study.
This second study, which uses a group of patients from the same landmark trial, was presented as a poster here at the 32nd Annual San Antonio Breast Cancer Symposium (SABCS).
The landmark trial, known as Southwest Oncology Group (SWOG)-8814, randomized 1477 patients. The new results from a 10-year follow-up show that chemotherapy added to tamoxifen (in both a concurrent and sequential fashion) provides statistically significantly better disease-free survival than tamoxifen alone (57% vs 48%; P = .002).
For the secondary end point of overall survival, chemotherapy added to tamoxifen is superior to tamoxifen alone, but not statistically significantly so (65% vs 60%; P = .043).
The chemotherapy regimen used was anthracycline-based CAF (cyclophosphamide, doxorubicin [Adriamycin], and fluorouracil), which was one of the "most commonly used regimens when this trial was designed," write SWOG investigators. Tamoxifen was taken daily for 5 years.
Despite the 5% improvement in overall survival from adjuvant chemotherapy, the majority of the patients (95%) who received the chemotherapy did not derive any additional benefit, notes an editorial that accompanies the study.
"There is a price to pay" for the incremental improvement that is seen, write editorialists Michael Gnant, MD, and Guenther Steger, MD, both from the Medical University of Vienna in Austria. The price includes toxic effects in many of those who do not have a survival benefit, including early deaths, congestive heart failure, and secondary neoplasms, they write.
Because of all the toxicity of chemotherapy, identifying "subgroups of patients who have an above-average outcome" and predicting response are important, say the editorialists.
"Avoidance of ineffective treatment should be one of the main goals in adjuvant breast oncology today," declare Dr. Gnant and Dr. Steger.
High-Risk Women Seem to Benefit
To see if there was "variation in the efficacy of chemotherapy," the SWOG investigators performed an unplanned subgroup analysis.
"Patients with 4 or more positive nodes derived more benefit than did those with 1 to 3 positive nodes" observe the investigators, led by Kathy Albain, MD, from Loyola University Stritch School of Medicine in Maywood, Illinois. Also, "patients less than 65 years might have had a greater degree of benefit than older patients," they note.
In short, in this postmenopausal, hormone-receptor-positive, node-positive breast cancer population, the patients at "high risk of relapse" (large tumors, age younger than 65 years, and more than 4 affected nodes) mainly show a benefit of adjuvant chemotherapy, summarize the editorialists.
Although this unplanned analysis from SWOG-8814 lacks statistical power, the editorialists note that this finding is in keeping with findings from other adjuvant trials. Namely, "overall benefit is mainly accounted for by the high-risk subgroup of patients," they write
This is where the second study, which was presented as a poster here at SABCS by Dr. Albain and published online December 10 in the Lancet Oncology, comes in.
"It might be possible to identify some subgroups that do not benefit from anthracycline-based chemotherapy despite positive nodes," write the SWOG investigators.
Among the patients in SWOG-8814, there were 367 specimens with sufficient RNA for analysis with a 21-gene recurrence-score assay (Oncotype DX, Genomic Health).
The 21-gene recurrence-score assay was developed to predict which patients with estrogen-positive breast cancer can avoid adjuvant chemotherapy, explain Fabrice Andre, MD, and Suzette Delaloge, MD, from Institut Gustave Roussy in Villejuif, France, in an editorial in Lancet Oncology.
Sixteen of the genes in the test are cancer-related, including those related to estrogen receptor and HER2.
"The test is all about the biology of the tumor," Julie Gralow, MD, told Medscape Oncology. Dr. Gralow is a member of the Fred Hutchison Cancer Research Center in Seattle, Washington, and a coinvestigator of the recurrence-score study.
The 21-gene recurrence-score assay is prognostic for women with node-negative, estrogen-receptor-positive breast cancer treated with tamoxifen, note Dr. Albain, Dr. Gralow, and their colleagues. A low recurrence score predicts little benefit from chemotherapy.
The SWOG team therefore investigated whether the assay would be prognostic in node-positive women.
Assay is Prognostic in This Setting Too
Specifically, Dr. Albain and colleagues looked at node-positive SWOG-8814 patients treated with both tamoxifen alone and with chemotherapy plus tamoxifen.
Although reported as a continuous variable, the recurrence score is usually split into 3 categories — low risk (score <18),>
The study authors conclude that the recurrence score predicts "significant benefit of CAF" in patients with tumors with a high recurrence score.
A low recurrence score identifies women who "might not benefit from anthracycline-based chemotherapy, despite positive nodes," they also conclude.
Editorialists Dr. Andre and Dr. Delaloge say that the 21-gene recurrence-score assay is clearly a prognostic tool, but that more studies are needed to better define its indications.
Dr. Albain agreed. "Prospective studies with larger sample sizes are needed to determine who will optimally benefit from chemotherapy," she said in a press statement.
Dr. Gralow currently uses the assay in her clinic. "I send it in when I need to decide about chemotherapy," she said. "But it is not 100% of the decision," she added.
Avoiding chemotherapy in patients who will not benefit is a very worthwhile thing, explained Dr. Gralow. "Chemotherapy is awful," she said, referring to adverse effects and quality of life for patients.
Dr. Albain and coauthors report being speakers bureau members, lecturers, or advisory board members for Genomic Health, the maker of the Oncotype DX assay. Dr. Andre reports receiving honorarium from Genomic Health. Dr. Gralow reports receiving honoraria from Genentech, Novartis, and Roche, and research funding from Amgen, Bayer, Bristol-Myers Squibb, Genentech, Novartis, Roche, and Sanofi-Aventis.
32nd Annual San Antonio Breast Cancer Symposium (SABCS): Abstract 112. Presented December 10, 2009.