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Findings may point toward new beginnings for treatment of luminal A breast cancer
As the adjuvant treatment of early-stage breast cancer has become more effective, many of us are now turning our efforts toward making this effective therapy less toxic.
Over the past 10 years — with assays such as the 21-gene assay (Oncotype DX, Genomic Health), 70-gene assay (MammaPrint, Agendia), breast cancer prognostic gene signature assay (Prosigna, NanoString Technologies) and others — investigators are defining women with early-stage breast cancer who likely have an excellent prognosis with anti-hormonal therapy alone, allowing us to forgo cytotoxic chemotherapy.
For example, recent data from the TAILORx trial suggest that women with node-negative, ER-positive cancers with a 21-gene recurrence score of 11 or less have an excellent 5-year DFS (in excess of 97%) with anti-hormonal therapy alone.
It is on this background that data presented by the Danish Breast Cancer Cooperative Group are extremely intriguing.
Nielson and colleagues examined formalin-fixed paraffin-embedded primary breast cancer tissue blocks collected during the DBCG77B trial. This trial, conducted in the 1980s, included 1,146 premenopausal women with primary breast cancers with tumor size larger than 5 cm or with positive lymph nodes. Researchers randomly assigned women to chemotherapy (single-agent cyclophosphamide or CMF, which consists of cyclophosphamide, methotrexate and 5-FU) or no chemotherapy.
In the total population, chemotherapy appeared associated with a significant improvement in 10-year DFS and 25-year OS.
The investigators then obtained tissue microarrays from this trial containing tissue from 709 of the 1,146 patients enrolled. These samples were stained by immunohistochemistry for ER, PR, Ki67, CK 5/6 and EGFR.
Luminal A tumors were defined as ER positive, PR greater than 10% positive, HER-2 negative, and Ki67 less than or equal to 13%. Of the samples retrieved, 633 were informative for subtype, of which 165 were luminal A by this definition.
The patients with luminal A tumors had a better 10-year DFS and 25-year OS compared with non-luminal A subtypes. In contrast to patients with non-luminal A cancers, patients with luminal A cancers derived no benefit from adjuvant chemotherapy, with similar 10-year DFS and 25-year OS in this analysis.
Although this was not a prospective trial, and endocrine therapy as well as modern chemotherapy with taxanes or anthracyclines was not given, these data strongly suggest that there are biologic subtypes of early-stage breast cancer for which cytotoxic chemotherapy is of no benefit, regardless of anatomic stage.
We already know that some node-negative breast cancers do not need chemotherapy, and these data appear to expand this set to higher stage disease. Whether the oncology community adopts the practices these data suggest is an open question.
If chemotherapy does not provide benefit to women with these luminal A cancers, what therapies other than endocrine therapy can?
In another presentation, DFS data from the ABSCG 18 trial of denosumab (Prolia, Amgen) vs. placebo for women receiving adjuvant aromatase inhibitors for early-stage breast cancer were presented.
In this trial of 3,425 women, those receiving the bone-modifying agent denosumab 60 mg subcutaneously every 6 months had a 50% reduction in the incidence of fracture compared with those assigned placebo.
Given these data, patients were offered unblinding, and therefore an early EFS analysis was undertaken. A relative reduction in the rate of recurrence of about 20% (HR = 0.81; P = .051) was found for women receiving denosumab, which just missed statistical significance. The difference was more profound (HR = 0.66 for denosumab) and statistically significant (P = .017) in women with tumors greater than 2 cm.
It was noted in the presentation that the benefits in these EFS data are very similar to those seen in meta-analyses of trials of other bone-modifying agents, such as bisphosphonates. The drug also was safe, with no differences in adverse events vs. placebo. Additionally, the vast majority of women entered into this trial appeared to have luminal A breast cancer.
These presentations from San Antonio Breast Cancer Symposium may be giving us a glimpse of the future management for luminal A early-stage breast cancer regardless of anatomical stage. Endocrine therapy — perhaps with a bone-modifying agent — will be paramount, cytotoxic chemotherapy will be far less important, and clinical trials of targeted therapies such as everolimus (Afinitor, Novartis) or CDK 4/6 inhibitors will attempt to further improve these excellent outcomes.
References:
Gnant M, et al. Abstract S2-02.
Nielsen TO, et al. Abstract S1-08.
Sparano JA, et al. N Engl J Med. 2015;doi:10.1056/NEJMoa1510764.
For more information:
Adam M. Brufsky, MD, PhD, is professor of medicine, associate chief of the division of hematology/oncology, co-director of Comprehensive Breast Cancer Center and associate director of clinical investigation at University of Pittsburgh. He also is a HemOnc Today Editorial Board member.
Disclosure: Brufsky reports personal fees from Novartis and Thar Pharmaceuticals, as well as stock ownership in Thar Pharmaceuticals.