Navigating Genomic Assays and Clinical Evidence in Early Breast Cancer

In the evolving landscape of breast cancer management, genomic assays have become indispensable tools for tailoring adjuvant therapy. However, the integration of multiple tests and the interpretation of borderline results present ongoing clinical challenges. During a Community Case Forum, Victoria Rizk, MD, a medical oncologist at Tampa General Hospital, discusses the practicalities of utilizing assays like MammaPrint and Oncotype DX. Rizk also highlights the importance of the FLEX registry (NCT03053193) in capturing real-world data and expanding the understanding of tumor biology across diverse patient populations.

This is part 2 of a 2-part series.

Targeted Oncology: Do you ever order more than one genomic assay for a single patient?

Victoria Rizk, MD: This typically only occurs when a patient is enrolled in the FLEX trial. In some instances, an Oncotype DX may be ordered automatically upon receipt of pathology results before it is recognized that a MammaPrint assay is already being processed through the trial.

We generally try to avoid ordering both tests, as interpreting discordant results can be complex. For example, it is challenging when a patient receives a high-risk score on MammaPrint, but the reported chemotherapy benefit is less than 6%. Determining if a 6% benefit is sufficient requires a conversation that varies significantly based on patient age; the decision-making process for a 75- or 80-year-old is entirely different than for a 40- or 50-year-old. In these "low-level" high-risk cases, I also consider nodal involvement and other clinical features to determine the overall clinical risk.

Can you discuss the objectives and current status of the FLEX registry?

The FLEX registry analysis is an ongoing initiative. It collects real-world data in conjunction with MammaPrint to better understand and predict chemotherapy benefit for patients.¹ While MammaPrint has been evaluated as a continuous variable for predicting adjuvant chemotherapy benefit in patients diagnosed between 2017 and 2020, the FLEX registry remains open for enrollment at Tampa General Hospital.

Our goal is to advance the understanding of the role of these genomic signatures by looking at diverse real-world data. We are specifically focused on increasing the representation of African American, Latin American, and Asian patients to better understand tumor biology across all demographics. The registry enrolls both lymph node-negative and lymph node-positive patients.

This information is helpful in determining where patients fall on the spectrum of recurrence risk. Recent data has emerged regarding the 5-year disease recurrence-free interval for patients receiving endocrine therapy vs endocrine therapy plus chemotherapy across the MammaPrint index. This data is now being reported directly on the test results to help clinicians identify the relative benefit of treatment. The results provide a clear understanding of where chemotherapy benefit lies across the full spectrum of disease, including Ultra Low, Low, High Risk 1, and High Risk 2. For instance, the data currently favors chemotherapy benefit in premenopausal patients. However, clinicians can still utilize variables such as tumor size and lymph node involvement to further refine the treatment approach.

Can you discuss the RxPONDER trial (NCT01272037)?

RxPONDER was designed to refine our understanding of chemotherapy benefit in patients with HR-positive, HER2-negative, node-positive early-stage breast cancer.² There was a great deal of excitement surrounding this trial because it addressed the specific needs of node-positive patients. Stratification factors included menopausal status and the type of nodal surgery—specifically, whether patients underwent axillary node dissection or a sentinel lymph node biopsy.

The eligibility criteria required patients to be women aged 18 years or older with involvement of 1 to 3 lymph nodes; patients with 4 or more positive nodes were ineligible. The study design was largely consistent with the TAILORx trial [NCT00310180], with the exception of the nodal involvement. Utilizing the 21-gene Oncotype DX assay, patients with a recurrence score [RS] between 0 and 25 were randomized 1:1 to receive either endocrine therapy alone or chemotherapy followed by endocrine therapy. Approximately 5000 patients were enrolled in the study. Patients who received an RS of 26 or higher were taken off the study to receive standard-of-care chemotherapy.

What were the findings of the trial?

The results for invasive disease-free survival [IDFS] in postmenopausal women showed no statistically significant difference between those who received chemotherapy plus endocrine therapy and those who received endocrine therapy alone. This was specific to patients with an RS of 0 to 25. Clinicians can therefore feel confident that for postmenopausal patients with up to 3 involved lymph nodes, the Oncotype DX assay is an accurate tool to predict recurrence risk and guide the omission of chemotherapy.

For the purposes of this trial, postmenopausal status was defined as a last menstrual period more than 12 months prior or a history of bilateral salpingo-oophorectomy [BSO].

Were there any findings specific to the postmenopausal cohort?

When breaking the data down by age within the postmenopausal subgroup—looking at cohorts aged 50 to 55, 55 to 65, and older than 65—it was interesting to note that tumor grade did not have a significant impact on who improved with chemotherapy. Historically, before the advent of genomic assays, grade was a primary factor in determining chemotherapy benefit, but the RxPONDER data suggests it is less helpful in this specific context.

Regarding tumor size, the majority of patients had T1 tumors, though the study also included those with T2 or T3 disease. There was a balanced distribution between patients with 1 positive lymph node and those with 2 to 3 positive nodes, regardless of whether a sentinel node was sampled or an axillary dissection was performed.

What were the findings for the premenopausal cohort?

Looking at the premenopausal data, we find ourselves in a more complex area. In the RxPONDER trial, the definition of premenopausal required a patient to have had a menstrual period within the last 6 months. Even a 49-year-old patient who still had a period was considered premenopausal.

The analysis revealed a clear benefit for those who received chemotherapy in addition to endocrine therapy compared to those who received endocrine therapy alone. The absolute difference in 5-year IDFS was 5.2%. Subgroup analysis further showed that for patients older than 50, endocrine therapy alone was considered more appropriate, whereas the benefit of chemotherapy was pronounced in those younger than 50. This 50-year-old benchmark was established because it represented the statistical "line" observed in the analysis.

Interestingly, when looking at the RS, the benefit of chemotherapy persisted across the cohorts. Even premenopausal patients with a score of 0 to 13 or 14 to 25 showed benefit. For instance, a premenopausal patient with node involvement and an RS of 8 would still technically benefit from chemotherapy based on these data.

How do you define the transition between pre- and postmenopausal status in these borderline cases?

This is a controversial question. Historically, the standard definition of postmenopausal has been the absence of a period for 2 years. However, for patients aged 48 or 49 who may have a period only occasionally, the definition becomes difficult to apply.

Previously, we relied heavily on follicle-stimulating hormone [FSH], luteinizing hormone [LH], and estradiol levels to assess menopausal status. Today, we are seeing a much wider adoption of anti-Müllerian hormone [AMH] as a tool to help clinicians understand how close a woman is to the menopausal transition.

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REFERENCES

1. MammaPrint, BluePrint, and Full-genome Data Linked With Clinical Data to Evaluate New Gene Expression Profiles (FLEX). ClinicalTrials.gov identifier: NCT03053193. Updated December 19, 2023. Accessed April 1, 2026. https://clinicaltrials.gov/study/NCT03053193

2. Kalinsky K, Barlow WE, Gralow JR, et al. 21-Gene Assay to Inform Chemotherapy Benefit in Node-Positive Breast Cancer. N Engl J Med. 2021;385(25):2336-2347. doi:10.1056/NEJMoa1804710