Genomic tests in breast cancer: when chemo helps

A 47-year-old female accountant, still menstruating, underwent surgery for a 1.8-centimeter invasive carcinoma in the right breast. The report shows strongly positive estrogen receptor, positive progesterone receptor, HER2 negative, grade 2, and a sentinel lymph node biopsy with no metastasis. The breast specialist ordered a genomic test, which came back with a recurrence score of 19. She arrives at the oncology consultation with a direct question: "Does this number mean I need chemotherapy or not?". The scene is fictional and was written for teaching.

This text uses the case as a clinical reasoning scenario for students and health professionals. The question comes from Dr. Alexei's list for the oncology series: how to use genomic tests in hormone receptor-positive, HER2-negative breast cancer to avoid unnecessary chemotherapy without undertreating those who need it? The reference studies are TAILORx, RxPONDER and MINDACT. The text does not replace your country's guideline or your service's protocol. If you play the case of the day in NEXO, you will recognize the challenge: a number only makes sense when age, menopause status and lymph nodes are put together.

Key points

• Genomic tests measure the expression of tumor genes and estimate the risk of recurrence and the benefit from chemotherapy.
• TAILORx showed that, with no involved lymph node and over 50 years of age, a score up to 25 does not indicate benefit from chemotherapy.
• In women aged 50 or younger, there was a modest benefit with a score of 16 to 25, especially 21 to 25.
• RxPONDER extended the logic to 1 to 3 lymph nodes and showed benefit in premenopausal women, regardless of the score.
• MINDACT showed that, with high clinical risk and low genomic risk, chemotherapy adds little to metastasis-free survival.
• Part of the benefit in younger women may come from ovarian suppression caused by chemotherapy, which opens the discussion about alternatives.

Why this is a reasoning scenario

Most breast cancers diagnosed today are hormone receptor-positive and HER2-negative. For these patients, endocrine treatment is the basis of adjuvant therapy, and chemotherapy adds benefit only to a portion of them. The problem is knowing which portion. For decades, size, grade and lymph nodes were the only guides, and many women received chemotherapy as a precaution.

Genomic tests emerged to better separate these groups. They do not replace the pathology report. They add a layer of biological information that helps answer two different questions: what is the risk of the disease coming back and how much does chemotherapy reduce that risk. Confusing these questions is one of the most common errors in interpretation.

The accountant's scenario brings together the elements that make the decision difficult. She is under 50, is premenopausal, has no involved lymph node and fell into the intermediate score range. This is exactly the group in which the studies showed less simple results. The post about who decides the treatment sequence in breast cancer explains how the multidisciplinary meeting organizes these choices.

The error the scenario wants to avoid

The most frequent error is reading the score as if it were the decision. A score of 19 means different things for a 62-year-old woman and for a 47-year-old one. Another error is ordering the test without knowing what will be done with the result, or ordering it in situations where it does not change management.

What a genomic test measures

The 21-gene test, the most studied, measures the expression of genes linked to proliferation, estrogen receptor, HER2 and invasion, as well as reference genes. These groups are combined into a recurrence score from 0 to 100 (Zhang and colleagues, 2022). The test was validated retrospectively in several studies before being tested prospectively in TAILORx and RxPONDER (Zhang and colleagues, 2022).

The 70-gene test, used in MINDACT, classifies the tumor as high or low genomic risk, with no intermediate range. Gene expression analysis is done on a large scale, and MINDACT itself had to control technical variation across thousands of microarrays to ensure reliable results (Jacob et al., 2020).

What each result is for

• Estimate the risk of distant recurrence with endocrine therapy alone.
• Estimate how much chemotherapy adds to that treatment.
• Avoid chemotherapy in those at low risk, even with concerning clinical factors.
• Identify those at high risk, even with a small tumor.
• Support the conversation with the patient with a number she can understand.

What the test does not do

The test does not replace pathology assessment of receptors and HER2. In a MINDACT substudy, there was disagreement between central immunohistochemistry and the gene expression measurement of receptors and HER2, especially in the low expression ranges (Viale et al., 2016). The test was also not designed for triple-negative or HER2-positive disease, which have their own decisions.

TAILORx: node-negative

TAILORx included 9,719 patients with estrogen receptor positive, HER2 negative breast cancer and no node involvement (Beltran-Bless and Ng, 2022). Patients with a score up to 10 received endocrine therapy alone, patients with a score of 26 or more received chemotherapy plus endocrine therapy, and patients with a score of 11 to 25 were randomized between the two approaches (Beltran-Bless and Ng, 2022).

The main result

In the randomized group, endocrine therapy alone was not inferior to combined treatment for patients with a score of 11 to 25, except for women aged 50 or younger with a score of 16 to 25 (Park et al., 2025). In other words, most women over 50 with a score up to 25 can skip chemotherapy without loss of invasive disease-free survival (Freeman et al., 2025).

Women aged 50 or younger

Among women aged 50 or younger, there was a modest benefit with a score of 21 to 25, or of 16 to 20 with higher clinical risk (Freeman et al., 2025). A later analysis showed that this benefit was concentrated in premenopausal women aged 46 to 50, precisely the group most likely to enter menopause with chemotherapy (Zhang et al., 2022). In TAILORx, only 13 in every 100 premenopausal women with an intermediate score received ovarian suppression (Zhang et al., 2022).

The high score

With a score of 26 or more, chemotherapy added to endocrine therapy remains indicated, and the 12-year follow-up of TAILORx confirmed the benefit in this group (Ünal et al., 2023). For the accountant's scenario, with a score of 19 and age 47, the decision involves assessing clinical risk and discussing ovarian suppression as an alternative or addition.

Study	Population	Test	Main finding	Source
TAILORx	Node-negative, 9,719 patients	21 genes	Score of 11 to 25 with no gain from chemotherapy over age 50	Beltran-Bless and Ng, 2022
RxPONDER	1 to 3 nodes, score up to 25	21 genes	No gain after menopause, gain of up to 5 points before menopause	Freeman et al., 2025
MINDACT	High clinical and low genomic risk	70 genes	5-year metastasis-free survival of 95.9 with and 94.4 without chemotherapy, in every 100	Steyerberg et al., 2021

How to explain the result to the patient

The patient often hears "intermediate score" as "average risk of dying". The score needs to be translated into the question she asked: will chemotherapy help or not? For a woman over 50 with no node involvement and a score up to 25, the answer based on TAILORx is that the expected gain is nil or very small (Freeman et al., 2025). For the 47-year-old accountant with a score of 19, the honest answer is that there is a modest gain in women her age, and that part of this gain can be obtained with ovarian suppression (Zhang et al., 2022).

This conversation takes time. Many patients prefer to receive chemotherapy out of fear, even when the benefit is small, and others refuse it even when the benefit is clear. The physician's role is to present the numbers in an understandable way and to respect the informed choice.

RxPONDER: with one to three lymph nodes

RxPONDER asked the same question for patients with 1 to 3 involved lymph nodes and a score up to 25. In postmenopausal patients, chemotherapy brought no gain for those with low or intermediate genomic risk (Freeman and colleagues, 2025). In premenopausal patients, there was an absolute benefit of up to 5 points with chemotherapy, regardless of the score (Freeman and colleagues, 2025).

Why menopause weighs so heavily

The authors and reviewers hypothesized that part of this gain comes from ovarian failure induced by chemotherapy, and not from the cytotoxic effect (Freeman and colleagues, 2025). In RxPONDER, ovarian suppression was added for 19 in every 100 premenopausal patients who received endocrine treatment alone (Zhang and colleagues, 2022). An exploratory analysis of the study showed no significant difference with ovarian suppression, but the number of patients was small and the analysis was not designed for this (Zhang and colleagues, 2022).

Micrometastasis in the lymph node

A frequent situation is lymph node micrometastasis. In a registry of 72,068 women under 50, chemotherapy was associated with better overall survival when there were 1 to 3 lymph nodes with metastasis and a score below 26, but not when there was only micrometastasis (Bilani and colleagues, 2023). This finding is observational and must be read with caution.

MINDACT: clinical risk against genomic risk

MINDACT used another logic. It assessed clinical risk and risk by the 70-gene test and randomized the patients in whom the two disagreed. The most important group was the one with high clinical risk and low genomic risk.

The main result

In patients with high clinical and low genomic risk who did not receive chemotherapy, 5-year distant metastasis-free survival was 94.7 in every 100, and the non-inferiority criterion was met (Steyerberg and colleagues, 2021). In the intention-to-treat analysis, this number was 95.9 in every 100 with chemotherapy and 94.4 in every 100 without it, a difference of 1.5 points (Steyerberg and colleagues, 2021). The adjusted hazard ratio was 0.78, without statistical significance (Steyerberg and colleagues, 2021).

Small tumors

In an analysis of MINDACT with tumors up to 1 centimeter, with no involved lymph node, the long-term prognosis of patients with high genomic risk was similar to that of those with low risk, and chemotherapy did not appear to improve survival in the high-risk group (Hilbers and colleagues, 2024). The number of randomized patients was small, and the authors call for caution (Hilbers and colleagues, 2024).

The test changes the specialists' opinion

In a survey with 41 specialists from MINDACT itself, the information of low genomic risk changed 19 in every 100 recommendations of chemotherapy to no chemotherapy (Lopes Cardozo and colleagues, 2023). The same study showed variation between specialists in the assessment of risk, which reinforces the value of objective information (Lopes Cardozo and colleagues, 2023).

What MINDACT adds to the reasoning

MINDACT teaches that a tumor that looks clinically high risk can have low-risk biology. A patient with a 3-centimeter tumor, grade 3 and up to 3 lymph nodes can be classified as high clinical risk, and the 70-gene test can show low genomic risk. In this situation, the 1.5-point difference at 5 years must be weighed against the effects of chemotherapy (Steyerberg and colleagues, 2021). A decision model built from the 6,693 women in MINDACT showed that who benefits from the test depends heavily on the minimum gain the patient considers acceptable (Steyerberg and colleagues, 2021). Preference studies cited by the authors showed that this minimum gain varies widely among women, from less than 1 to 7 points (Steyerberg and colleagues, 2021). The authors concluded that the indication for the test may be narrower than the study suggested at first glance (Steyerberg and colleagues, 2021). In practice, this means asking the patient how much benefit she requires before accepting chemotherapy, and only then deciding whether the test will change anything.

The premenopausal woman

Premenopause is the point where genomic tests least simplify the decision. In older women, the score separates well those who need chemotherapy. In younger women, the benefit appears even with an intermediate score, and the most likely explanation involves the hormonal effect of chemotherapy.

The score remains prognostic

In a cohort of women aged 40 or younger, the score kept its prognostic value. Six-year distant recurrence-free survival was 96.9 per 100 without node involvement and 85.2 per 100 with node involvement, in the 11 to 25 range (Poorvu and colleagues, 2020). With a score of 26 or more, these numbers fell to 85.1 and 71.3 per 100 (Poorvu and colleagues, 2020).

Questions for the conversation with the patient

• Is the patient really premenopausal, with regular cycles?
• What is the clinical risk, considering size, grade and age?
• Would she accept ovarian suppression for several years as an alternative?
• Does she have pregnancy plans that change the choice?
• Which chemotherapy effects worry her most?
• Can the service offer follow-up for ovarian suppression?

An intermediate score in a young woman is not a tie. It is an invitation to discuss the options in more detail. The post about diagnostic uncertainty shows how to handle decisions where the evidence does not point to a single path.

What changed in practice and what still fails

Genomic tests have already changed conduct. In a German study with 366 patients, the score changed the treatment recommendation in 33 per 100 patients, and physicians' confidence increased in 45 per 100 (Eiermann and colleagues, 2013). In that same study, 33 per 100 fewer patients received chemotherapy compared with the initial recommendation (Eiermann and colleagues, 2013).

The change in cutoffs also had an effect. In a Swiss center with 326 patients, the new TAILORx ranges reduced the proportion of low scores from about 60 to 20 per 100 and doubled the intermediate range (Chiru and colleagues, 2023). Even so, the overall chemotherapy recommendation did not change significantly, 19 versus 22 per 100 (Chiru and colleagues, 2023). This shows that reclassification does not automatically lead to more chemotherapy, as long as the team knows that the 11 to 25 range still offers no gain for most women over 50.

Trends after the major studies

In a United States database with 504,937 women, chemotherapy use in premenopausal women without node involvement and with an intermediate score fell from 29.6 per 100 in 2010 to 11.1 per 100 in 2022 (Freeman and colleagues, 2025). In premenopausal women with node involvement and a low or intermediate score, use nearly doubled between 2019 and 2022, coinciding with the publication of RxPONDER (Freeman and colleagues, 2025).

Common interpretation errors

• Using the score of 26 as a single cutoff for all ages.
• Forgetting that the result guides chemotherapy, not endocrine treatment.
• Applying the TAILORx result to patients with node involvement.
• Ignoring menopausal status or defining it by age alone.
• Ordering the test when chemotherapy is already decided for other reasons.

These errors come up often in case discussions and in exams. Each one leads to a course of action that looks defensible at first glance, but differs from what the studies support. Training yourself to read the score together with age and the axilla avoids most of them.

Barriers that persist

The cost of the test limits access in low- and middle-income countries, and many decisions are still made with clinical and pathological data alone (Ünal et al., 2023). Differences by race and ethnicity were also described in TAILORx, with worse invasive disease-free survival in Black women even with a similar score (Beltran-Bless and Ng, 2022). These differences probably involve biological and social factors (Beltran-Bless and Ng, 2022).

How NEXO helps train this reasoning

In NEXO, the case of the day is fictional, with a real clinical presentation and up to six progressive clues, and you propose the diagnosis by looking up the ICD-10 code. Genomic testing is a good exercise because the same number changes meaning according to age, menopause and lymph nodes. The post on differential diagnosis with clues shows how to train with progressive clues.

Three exercises with cases

Change the age. Say what changes if the patient in the scene is 63 years old and postmenopausal.

Change the axilla. Say how to act if the sentinel node shows metastasis in 2 lymph nodes, with the same score.

Change the score. Say what to discuss if the score is 28 and the patient refuses chemotherapy.

The post on clinical decision-making deals with when a test changes the course of action. The limits on using the game are on the NEXO Economy page. If you research teaching of clinical reasoning, the page for Researchers explains how to get in touch.

Frequently asked questions

Does a low recurrence score rule out endocrine therapy?

No. The test guides the decision about chemotherapy. In MINDACT, endocrine therapy was associated with better outcomes even in small tumors with low genomic risk (Hilbers et al., 2024).

Is it worth ordering the test with 4 or more involved lymph nodes?

The large studies with the 21-gene test included up to 3 lymph nodes (Freeman et al., 2025). With more lymph nodes, chemotherapy is usually indicated by clinical risk.

Why is the result different for young women?

Because the benefit from chemotherapy appeared even with an intermediate score, and part of it may come from the ovarian suppression caused by chemotherapy (Zhang et al., 2022).

Are the two tests equivalent?

They were not compared directly in the large studies. The 21-gene test gives a continuous score, and the 70-gene test classifies risk as high or low (Steyerberg et al., 2021).

Does the test apply to HER2-positive tumors?

No. The studies included HER2-negative tumors, and HER2-positive disease has its own treatment, discussed in the post on adjuvant pertuzumab.

Final checklist

• I confirmed hormone receptor positive and HER2 negative on the report.
• I defined the number of involved lymph nodes and whether there is only micrometastasis.
• I recorded age and menopausal status with an objective criterion.
• I ordered the test only when the result can change the course of action.
• I interpreted the score together with clinical risk.
• I discussed ovarian suppression with premenopausal women.
• I explained to the patient what the number means and what it does not mean.
• I planned endocrine therapy independently of chemotherapy.

Want to practice reasoning with progressive clues? Play the case of the day.

References

1. Beltran-Bless AA, Ng TL. Race, ethnicity, and clinical outcomes in hormone receptor-positive, human epidermal growth factor 2 negative (HER2-), node negative breast cancer in the randomized TAILORx trial: gaps in biologic and social determinants of health. Ann Transl Med. 2022. PMID 36660702.
2. Bilani N, Patel R, Crowley F, et al. Outcomes in Premenopausal Patients with HR+/HER2- Breast Cancer and Lymph Node Micrometastasis Based on the 21-Gene Recurrence Score. Oncologist. 2023. PMID 37682780.
3. Chiru ED, Oseledchyk A, Schoetzau A, et al. Application of a 21-Gene Recurrence Score in a Swiss Single-Center Breast Cancer Population: A Comparative Analysis of Treatment Administration before and after TAILORx. Diagnostics (Basel). 2023. PMID 38201405.
4. Eiermann W, Rezai M, Kümmel S, et al. The 21-gene recurrence score assay impacts adjuvant therapy recommendations for ER-positive, node-negative and node-positive early breast cancer resulting in a risk-adapted change in chemotherapy use. Ann Oncol. 2013. PMID 23136233.
5. Freeman JQ, Saha P, Peiffer DS, et al. Adjuvant Chemotherapy Use for Hormone Receptor-Positive, ERBB2-Negative Breast Cancer After RxPONDER Trial. JAMA Netw Open. 2025. PMID 41632146.
6. Hilbers FS, Poncet C, Tryfonidis K, et al. Benefit of systemic therapy in MINDACT patients with small, ER-positive, HER2-negative breast cancers. NPJ Breast Cancer. 2024. PMID 39488549.
7. Jacob L, Witteveen A, Beumer I, et al. Controlling technical variation amongst 6693 patient microarrays of the randomized MINDACT trial. Commun Biol. 2020. PMID 32719399.
8. Lopes Cardozo JMN, Veira SE, Ait Hassou L, et al. Agreement on risk assessment and chemotherapy recommendations among breast cancer specialists: A survey within the MINDACT cohort. Breast. 2023. PMID 37225592.
9. Park JM, Lee SJ, Ahn JH, et al. Characteristics of premenopausal breast cancer patients with a midrange 21-gene recurrence score. Ann Surg Treat Res. 2025. PMID 40226167.
10. Poorvu PD, Gelber SI, Rosenberg SM, et al. Prognostic Impact of the 21-Gene Recurrence Score Assay Among Young Women With Node-Negative and Node-Positive ER-Positive/HER2-Negative Breast Cancer. J Clin Oncol. 2020. PMID 31809240.
11. Steyerberg EW, de Wreede LC, van Klaveren D, et al. Personalized Decision Making on Genomic Testing in Early Breast Cancer: Expanding the MINDACT Trial with Decision-Analytic Modeling. Med Decis Making. 2021. PMID 33655778.
12. Viale G, Slaets L, de Snoo FA, et al. Discordant assessment of tumor biomarkers by histopathological and molecular assays in the EORTC randomized controlled 10041/BIG 03-04 MINDACT trial breast cancer : Intratumoral heterogeneity and DCIS or normal tissue components are unlikely to be the cause of discordance. Breast Cancer Res Treat. 2016. PMID 26820652.
13. Zhang S, Fitzsimmons KC, Hurvitz SA. Oncotype DX Recurrence Score in premenopausal women. Ther Adv Med Oncol. 2022. PMID 35295864.
14. Ünal Ç, Özmen T, İlgün AS, et al. MCM-2 Levels as a Potential Biomarker for Predicting High-Risk Breast Cancer Patients According to TAILORx Classification. Breast Cancer (Dove Med Press). 2023. PMID 37674872.