ORLANDO - Oncotype DX was prognostic and predicted estrogen-receptor (ER)-positive, node-negative breast cancer patients' response to adjuvant tamoxifen(Drug information on tamoxifen) in a study presented by Soonmyung Paik, MD, at the American Society of Clinical Oncology 41st Annual Meeting (abstract 510). "The advantage of Oncotype DX is that it is quantitative in nature," Dr. Paik said.
Prior studies have shown the commercially available 21-gene Recurrence Score (RS) assay, also known as Oncotype DX (see Figure), was independently prognostic of distant metastasis in tamoxifen-treated patients. It also showed a linear relationship between increased recurrence score and increased benefit of chemotherapy, thus allowing women with low-risk scores to avoid chemotherapy.
"The academic question remained as to whether the Oncotype DX assay is a purely prognostic factor or predictive of tamoxifen response," said Dr. Paik, director of the Division of Pathology at the National Surgical Adjuvant Breast and Bowel Project (NSABP), Pittsburgh.
Dr. Paik and his colleagues sought to discover if RS could predict prognosis, response to hormonal therapy, or both in patients participating in the NSABP B-14 trial, a 1980s' study designed to determine whether tamoxifen was more effective than placebo in prolonging disease-free and overall survival.
For about 20% of the B-14 patients, 645 women, the investigators could evaluate tumor tissues extracted from paraffin(Drug information on paraffin) blocks: 355 in the placebo arm and 290 in the tamoxifen cohort. The original B-14 trial measured ER status using ligand binding.
The assay proved prognostic in the placebo arm of B-14, with low-risk patients (RS < 18) having a 10-year distant-recurrence-free survival of 86%, intermediate risk (RS between 18 and 30) 62%, and high risk (RS ≥ 31) 69% (P = .0001).
The assay also was shown to be a predictive factor for women receiving tamoxifen. For low-risk patients, there was a 51% relative benefit with tamoxifen use and a 7.2% absolute benefit at 10 years (P = .04). For intermediate-risk patients, researchers found a 46% relative benefit and a 17.3% absolute benefit (P = .02). And in high-risk women, they found a 5% relative benefit and a 1.6% absolute benefit (P = .82).
The researchers also looked at whether individual components of the RS predicted benefit of tamoxifen. ER level measured by ligand binding correlated with tamoxifen benefit: the higher the ER, the higher the benefit, Dr. Paik said. Quantitative measurement of ER gene expression level using the Oncotype DX assay proved highly predictive of benefit from tamoxifen, with a hazard ratio of 0.43 at the highest ER level, compared with 4.86 for the lowest ER level (ER negative). "This ER-tamoxifen interaction was highly significant with a P value of .0006," Dr. Paik said. He noted that HER2 or progesterone(Drug information on progesterone)-receptor status did not significantly predict tamoxifen response.
Dr. Paik pointed out that there was no absolute correlation between ER gene expression and the RS score itself. "Those patients with a high ER score can also have a low or high RS," he said, "so you cannot use ER level to predict RS."
He concluded that "the Oncotype DX assay captured both prognosis and response to tamoxifen treatment, and could predict the likelihood of recurrence in node-negative, ER-positive breast cancer patients. With further validation, Oncotype DX may eventually help us determine which patients will benefit from hormonal treatment. However, we do not recommend the use of Oncotype DX to exclude patients from receiving endocrine therapy at this point."
During the discussion, Joseph A. Sparano, MD, professor of medicine, Albert Einstein Comprehensive Cancer Center, Bronx, New York, called Dr. Paik's conclusions conservative and supported by the data presented. He said the findings raise a question of whether the assay can identify ER-positive disease that doesn't benefit from hormone therapy. "This could spare some patients up to 10 years of unnecessary treatment," Dr. Sparano said. "Although this is an exciting potential application of this technology, it is premature to withhold therapy from those with a high recurrence score." Dr. Paik agreed with this comment.
Dr. Sparano indicated that two prospective, randomized clinical trials, now under development or under way, will attempt to evaluate breast cancer markers and tests to determine their clinical use. The studies are the Program for the Assessment of Clinical Cancer Tests (PACCT) and Microarray in Node Negative Disease May Avoid Chemotherapy (MINDACT). "Completion of these two important studies will hopefully let us know precisely what type of molecular profiling may be applied in every day clinical trials," Dr. Sparano said.