Clinical Topics & News
![](https://cdn-uat.mdedge.com/files/s3fs-public/styles/max_width_small/public/Image/September-2017/Dr_Laronna_Colbert_01.jpg)
Extending Therapy for Breast Cancer
Watch as Laronna Colbert, MD, discusses how recent breast cancer studies could potentially change current practice standards for the disease.
Dr. Silva-Lopez is a professor of surgery, Division of Surgical Oncology, Department of Surgery at the University of Nebraska Medical Center, Omaha, Nebraska. He is a practicing surgical oncologist and a member of the Fred and Pamela Buffett Cancer Center, Omaha, Nebraska. Dr. Silva-Lopez is also a staff surgeon at the VA Nebraska-Western Iowa Health Care System, Omaha, Nebraska.
Oncotype DX
The Oncotype DX assay is the first commercially available GES assay to illustrate the variability in survival of patients with node-negative, ER+ breast tumors. Sixteen selected cancer proliferative genes are paired with 5 control nonproliferative genes whose relative activity can be measured in paraffin-embedded breast cancer tissue. The ability to retrieve reliable ribonucleic acid (RNA) expression from cancer cells embedded in paraffin was a stroke of genius; it enabled the investigators to correlate the gene expression profile of patient subgroups treated decades earlier with their long-term clinical outcomes and survival.
The normalized summation of the proliferative activity of the 16 cancerproliferation genes in the Oncotype DX assay is expressed as the RS. The RS increases linearly and so does the average rate of distant recurrence in 10 years as a function of the RS. Three risk recurrence groups are defined by the RS: low risk (RS < 18); intermediate risk (RS > 18 to 30); and high risk (RS > 31).10,11
Clinical Trials
In the National Surgical Adjuvant Breast and Bowel Project (NSABP) clinical trial B-14, ER+ node-negative patients were randomized to observation or tamoxifen. In the untreated control patients, a low RS (< 18) was accompanied by a 6.8% risk of metastasis at 10 years, and a high RS (> 31) was accompanied by a 30.5% rate of distant recurrence.11 In another study, the low RS tamoxifen-treated arm showed a 2.8% risk of breast cancer death at 10 years vs a 15.5% risk in the high RS cohort.12
The remarkable significance of the RS is demonstrated when the RS is plotted against patient age, grade, or tumor size.10 This illustrates the huge variability in these traditional histopathologic and clinical features within a given RS group. For any patient with a low RS, there is marked variability in patient age, tumor grade, or tumor size. A very small or low-grade tumor can have a very high 10-year recurrence rate, as measured by the gene prognostic signature or RS. Similarly, a very large tumor in a young patient can have a very low 10-year recurrence rate or RS. This is due to the heterogeneity of the biology of these cancers, regardless of their favorable or unfavorable histologic features.
In most cases, decisions about chemotherapy in patient who are postmenopausal, node-negative, and ER+ are made by risk estimates based on patient age, tumor grade, and tumor size, without knowledge of their RS. However, the large variability in 10-year rates of metastases and death among patients clearly demonstrates that, for some, chemotherapy affords no benefit. Their RS suggest that their risk of metastases at 10 years is only 2.8% when treated with EA (ie, tamoxifen) and no chemotherapy. In fact, 51% of the patients who are postmenopausal, node-negative, and ER+ in NSABP B-14 fell within the low risk RS category for 10-year distant recurrence, whereas about 27% fell within the high risk (RS > 31) category.13
Confidence in the Oncotype DX assay RS stems from the ability of investigators to plot the recurrence rates of distant metastases in patientstreated with tamoxifen vs placebo in the NSABP B-14 trial. Their clinicaloutcomes could be correlated with their GES samples retrieved from paraffin-embedded archival tissue many years after treatment. Corresponding plotting was done for similar patient cohorts treated with chemotherapy with or without tamoxifen in NSABP Trial B-20.
Among patients with low RS, the distant recurrence rate at 10 years was 2.2%, whether treated with systemic chemotherapy plus tamoxifenor with tamoxifen alone. Thus, in study participants with low RS, regardless of tumor size, grade, or patient age, 10-year recurrence rates were not affected by the addition of chemotherapy.13
Note that, in the absence of the new information provided by the Oncotype gene prognostic signature, nearly all these patients would be treated with systemic chemotherapy. Studies have shown that the additional risk assessment estimate provided by the Oncotype assay causes a change in systemic therapy recommendations from chemotherapy to no chemotherapy in 30% of patients.14,15 Among patients with high RS, 10-year distant recurrence rates decreased by an absolute 27% with the addition of chemotherapy to tamoxifen. These patients clearly benefited from chemotherapy.13
The relative benefits of chemotherapy vs tamoxifen in a third RS group with an intermediate RS of 18-21 awaits publication of the now-closed Trial Assigning Individualized Options for Treatment (TAILORx) trial. This group accounts for 22% of patients who are postmenopausal, node-negative, and ER+ identified by the Oncotype DX assay. Initial reports show no significant benefit from the addition of chemotherapy to tamoxifen in this group.10
Watch as Laronna Colbert, MD, discusses how recent breast cancer studies could potentially change current practice standards for the disease.
A new breast cancer research group aims to help doctors in the federal health system to identify etiology, biology, and improve treatment of both...