Optimizing Breast Cancer Care With Predictive and Prognostic Assays

Genetic assays have transformed how clinicians approach treatment decisions in breast cancer, offering both predictive and prognostic insight that helps tailor therapy to individual patients. From established tools like Oncotype DX and MammaPrint to emerging evidence shaping the role of chemotherapy across different patient populations, the landscape of genomic testing continues to evolve. During a Community Case Forum, Victoria Rizk, MD, Tampa General Hospital Cancer Institute, explored the current state of these assays, how menopausal status and nodal involvement influence their use, and what long-term data from landmark trials like TAILORx (NCT00310180) and RxPONDER (NCT01272037) reveal about optimizing adjuvant treatment strategies in hormone receptor-positive, HER2-negative breast cancer.

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Targeted Oncology: What is the state of predictive and prognostic genetic assays in breast cancer?

Victoria Rizk, MD: As of now, there are 2 options that are both predictive and prognostic. That would be the Oncotype DX for node-negative or up to 3 nodes, and the Breast Cancer Index. Both are predictive of the benefit of extended adjuvant endocrine therapy as well as prognostic. Interestingly enough, Oncotype DX has the NCCN category 1 preferred level of evidence, whereas the MammaPrint also has category 1 for 1 to 3 positive nodes. The Prosigna and the EndoPredict assays are category 2, which is probably part of why they're not really widely used. There is also a difference between pre and postmenopausal patients and the role of Oncotype DX in those patients. For node-positive premenopausal patients, it's a category 2a listing.

What else can influence the choice of assay?

For HER2-positive breast cancer, there's no evidence for us to be using these biomarker tests for this patient population. We don't use these tools to make decisions. It's all about stage, node involvement, and tumor size. For the HER2-negative and [estrogen receptor (ER)-positive cohorts, that's really where these tests shine. For premenopausal or postmenopausal patients with less than 4 lymph nodes involved, Oncotype DX is the preferred option because it does have a high quality of evidence and a strong sense of the strength of recommendation. There are some listed options for postmenopausal greater than 50 years old with no negative disease.

For premenopausal patients who have node involvement, there’s not a lot of evidence for us to recommend a specific biomarker test. That's an area that certainly can be controversial when you're talking with patients.

Can you discuss how these assays have been validated?

Oncotype DX has 21 genes that are listed with 5 reference genes. Between the TAILORx and RxPONDER trials, we're very clear on knowing that 26 and above, there is a chemotherapy benefit. But for TAILORx, they were looking at those patients with 11 to 25 and 0 to 10. RxPONDER lumped everybody between 0 and 25 together. TAILORx specifically was designed to determine whether chemotherapy was beneficial for that middle range.

A total of 10,273 patients were enrolled in TAILORx.¹ Looking at the mid-range population of 11 to 25, there were 6711 patients. These patients were split between arm B, which was endocrine therapy alone, and arm C, which was endocrine therapy plus chemotherapy.

There were some stratification factors throughout the trial: tumor size being less than or greater than 2 centimeters, menopausal status, planned chemotherapy with a taxane-containing regimen vs no planned chemotherapy, radiation therapy, and the recurrence score.

There were key eligibility criteria. Patients had to be either node negative, ER-positive/HER2-negative, or high-risk T1b or T1c to T2. The primary end point was invasive disease-free survival for the score of 11 to 25.

Endocrine therapy was not inferior to endocrine therapy plus chemotherapy. In the mid-range cohort, the overall survival at 9 years was 93.9% with endocrine therapy and 93.8% for endocrine therapy and chemotherapy, so 0.1% worse with chemotherapy.

When you break it down based on age, there was a big difference in recurrence score. For those between 11 to 25, age was broken down between those younger than 50 and older than 50. Those younger than 50 had a chemotherapy benefit. For those older than 50 years old, when they adjusted for the tumor size and grade, there was no benefit for those patients.

What has long-term data from TAILORx showed?

TAILORx estimated freedom from distant recurrence in patients less than or equal to 50 years old. The 9-year rate for those who received just endocrine therapy with a score of 11 to 15 was 97.2% vs 98% with endocrine therapy and chemotherapy. For 16 to 20, there was a little bit of a difference as well [93.6% vs 95.2%, respectively]. You see a bigger difference at 21 to 25, with 86.9% for endocrine therapy vs 93.4% with added chemotherapy. That’s consistent when you look at the 12-year rates [85.5% vs 93.3%, respectively]. Any patient who had a score greater than 26 received chemotherapy, so there's no control arm for that.

What is the role of anthracyclines for high genomic risk patients?

There was a study published at the 2024 San Antonio Breast Cancer Symposium trying to compare if there was a benefit based on if someone got a taxane plus cyclophosphamide [TC] vs taxane and anthracycline-based therapy [TAC] depending on their recurrence score.² It was clear that there was more of a benefit with dose-dense TAC for those who had a recurrence score greater than 31, whereas there were similar outcomes between TC and dose-dense TAC for those with a recurrence score less than 31. These were adjusted based on age, ER status, tumor size, and treatment received.

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REFERENCES

1. Sparano JA, Gray RJ, Makower DF, et al. Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer. N Engl J Med. 2018 Jul 12;379(2):111-121. doi: 10.1056/NEJMoa1804710. Epub 2018 Jun 3. PMID: 29860917; PMCID: PMC6172658.

2. Chen N, Freeman JQ, Yarlagadda S, et al. Impact of anthracyclines in genomic high-risk, node-negative, HR-positive/HER2-negative breast cancer. Ann Oncol. 2025 Nov;36(11):1356-1365. doi: 10.1016/j.annonc.2025.08.002. Epub 2025 Sep 17. PMID: 40972946; PMCID: PMC12753151.