HR+ Breast Cancer: Oncotype DX RS and TAILORx

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Priyanka Sharma, MD: Oncotype DX is one of the multigene assays that is utilized for this decision-making. Earlier data for the Oncotype DX recurrence score came from prospective retrospective trials. The clinical utility was really established by the TAILORx study, which demonstrated that for patients with lymph node-negative, hormone receptor-positive, HER2-negative breast cancer, those who had a recurrence score between 11 and 25 and were taking chemotherapy as well as endocrine therapy, versus endocrine therapy alone, did not show improvement in all comers. In subgroup analysis, it was shown that in patients younger than 50, there might be some benefits of chemotherapy, especially for those who had a recurrence score greater than 16 up to 25. That’s the landscape regarding the utility of Oncotype and why it’s widely used in decision-making for patients with hormone receptor-positive, HER2-negative breast cancer, especially those with lymph node-negative breast cancer.

Lajos Pusztai, MD, PhD: The TAILORx trial was conducted between 2006 and 2010, and asked an important clinical question at that time: do patients with ER-positive breast cancer, early stage disease, lymph node-negative, who had a recurrence score between 11 and 25, benefit from the addition of chemotherapy to their adjuvant endocrine treatment? By this time, there was a fairly good consensus that a recurrence score of less than 11 predicts a very good prognosis. Those patients could be safely spared from chemotherapy. At the other end of the spectrum, patients with a recurrence score greater than 25 had a high risk of recurrence. Multiple, smaller, more randomized studies and retrospective analysis of randomized trials showed that they do benefit significantly from adjuvant chemotherapy. However, a very large proportion of ER-positive patients fall into the middle, in the recurrence score category of between 11 and 25, and their benefit from chemotherapy was not clear, or unknown at that time.

TAILORx randomized 6000 patients to chemotherapy plus endocrine therapy or endocrine therapy alone, and the results were announced in 2018. It showed resoundingly that overall, there is no benefit from adjuvant chemotherapy in this recurrence score group. However, there was a very strong and significant interaction with age. Patients who were 50 or younger had a significant benefit from adjuvant chemotherapy. This benefit was seen across all recurrence score categories above 16. Below 16, between 11 and 15, the prognosis of the patients was outstanding. The benefits from chemotherapy were minuscule, nonsignificant, and clinically irrelevant. This study changed practice; it established the value of adjuvant chemotherapy for younger women with lymph node-negative disease, but the recurrence score had to be between 16 and 25. It also showed that as the recurrence score increases, the prognosis gets worse, and therefore, the absolute benefit from the chemotherapy increases. In other words, a woman with a recurrence score of 16 gained a little bit of benefit from chemotherapy. Women with a recurrence score of 25 gained much more benefit, absolute benefit, from adjuvant chemotherapy.

Based on this result, recurrence score gained quite a broad acceptance. I think today, and for the past several years, the recurrence score, or a similar molecular assay, is broadly used in most patients who have lymph node-negative disease. It also started to be used, although with less data, in patients with 1 to 3 positive lymph nodes.

This is standard of care today, to run a recurrence score or a similar molecular assay for most women who have lymph node-negative disease, and have a tumor size of between 1 and 5 cm.

It’s a very important question, how risk is defined and how the clinical risk factors complement the molecular risk factors, such as the recurrence score. It’s important to understand that prognostic risk is determined by multiple individual variables that are oftentimes unrelated to each other. A set of them relates to the anatomical and pathological features of the tumor, such as the tumor size, the number of lymph nodes involved, the histological grade, age, and to some extent, the lymphovascular invasion. These are called clinical risk variables, and the best way to determine the clinical risk is when we integrate these.

There are multivariate models that perform better than just physicians’ judgment because they are more objective and integrate these various variables in a mathematically correct way. One that has been broadly used is the PREDICT assay, a free web tool from the United Kingdom. There are other methods as well that combine tumor size and lymph node status to make a prediction about anatomical risk. Molecular assays complement this. The most accurate risk prediction is relying on a combination of both the recurrence score or a similar genomic essay, and the anatomical variables, such as tumor size and nodal status. Some of the assays, such as the Prosigna assay, incorporate tumor size to make a prediction from the beginning. The recurrence score does not take into account any anatomical variables, which are the molecular features of the tumor. However, the recurrence score can be integrated with tumor size to arrive at a more precise risk estimate for recurrence and estimation of the absolute benefit that a woman would get from chemotherapy. That’s called RSClin. This is a free tool that’s available at the website of Exact Sciences Corporation, the company that produces the recurrence score assay.

Transcript Edited for Clarity