Breast Cancer: Genetic Tests

Genetic Tests Are Changing How Doctors Treat Breast Cancer — And Whether Women Need Chemotherapy at All

The Genomic Crystal Ball: Predicting Breast Cancer Recurrence and Treatment Response

 

In today’s age of personalized medicine, the most important decision a woman with early-stage breast cancer may face is not whether she’ll have surgery or radiation — but whether she truly needs chemotherapy at all.

A growing number of patients are now skipping chemotherapy altogether, not because they’re refusing it, but because of what their genes — or rather, their tumor’s genes — are telling their doctors.

Using powerful genomic tests, oncologists can now analyze the activity of dozens of genes in a tumor to predict how likely the cancer is to return — and whether chemo will make a difference. These tests, including Oncotype DX, MammaPrint, Prosigna, and EndoPredict, are reshaping how treatment is delivered in breast cancer clinics across the U.S. and beyond.

“This is one of the most profound shifts in cancer treatment we’ve seen in decades,” said Dr. Lisa Carey, a breast oncologist at the University of North Carolina. “For many women, we’re moving from one-size-fits-all chemotherapy to far more personalized, biology-driven decisions.”

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What Do These Tests Actually Do?

The tests aren’t designed to detect inherited risk — like BRCA1 or BRCA2 mutations — but rather to look inside the tumor and assess which genes are active or dormant. These gene activity patterns can reveal whether a cancer is aggressive, slow-growing, or likely to spread.

The Oncotype DX test, for example, examines 21 genes and generates a Recurrence Score from 0 to 100. A low score suggests a low risk of the cancer returning — meaning the patient may be able to skip chemotherapy and rely on hormonal therapy alone. A high score, by contrast, suggests a higher risk, making chemotherapy more beneficial.

In a landmark study known as TAILORx, published in the New England Journal of Medicine, researchers found that up to 70% of women with early-stage, hormone receptor–positive breast cancer could safely avoid chemo based on their Oncotype DX score.

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Other Tests Offer Similar Insights

• MammaPrint, which uses a 70-gene panel, categorizes patients into “high risk” or “low risk” groups and is FDA-approved for a wide range of early-stage breast cancers.

• Prosigna, also known as PAM50, goes further by assigning tumors to molecular subtypes like Luminal A (slow-growing) or Basal-like (often more aggressive), along with a long-term risk of recurrence.

• EndoPredict is used to predict late recurrence — the chance of cancer returning after 5 years of hormone therapy — which can help patients decide whether to extend endocrine treatment beyond the typical window.

These tests rely on gene expression technology — typically RT-PCR or microarray — performed on tumor tissue collected during surgery or biopsy. Results are combined with clinical data such as tumor size and lymph node involvement to generate a tailored treatment recommendation.

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Changing the Chemotherapy Conversation

Until recently, many early-stage breast cancer patients were routinely offered chemotherapy “just in case.” But for women with hormone receptor–positive, HER2-negative cancers — the most common subtype — the evidence now suggests that many don’t need it.

That matters, because chemotherapy comes with real risks: fatigue, hair loss, nerve damage, immune suppression, and in rare cases, life-threatening complications.

“I was terrified of chemo,” said Nicole Thompson, a 54-year-old breast cancer survivor from Baltimore. “But my doctor ran the test, and when the results came back low-risk, I cried — tears of relief. I did radiation and hormone therapy instead. Two years later, I’m still cancer-free.”

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Limitations and Future Promise

Genomic testing isn’t appropriate for all breast cancer cases. It’s primarily used for early-stage, HR+, HER2–, and node-negative or limited node-positive cancers. Women with triple-negative or HER2-positive tumors still require more aggressive treatment, including chemotherapy.

Still, the shift toward biologically guided care is helping women avoid unnecessary treatments — and giving others the confidence to proceed with therapy that truly benefits them.

“Every cancer has a fingerprint,” says Dr. Carey. “Now we can read it.”

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What Patients Should Ask

If you or someone you love is facing a breast cancer diagnosis, ask your oncologist:

• Am I eligible for genomic testing like Oncotype DX or MammaPrint?

• How will the results affect my treatment plan?

• Can this test help avoid chemotherapy or guide hormonal therapy?

These questions are not just scientific — they’re deeply personal. And thanks to genomic testing, breast cancer care is becoming more personal than ever.

Breast Cancer Recurrence or Guide Treatment

These aren’t traditional BRCA gene tests (which assess inherited risk), but rather tumor profiling tests used after diagnosis to evaluate:

• How aggressive the cancer is

• Whether chemotherapy is likely to help

• The chance of the cancer coming back

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 1. Oncotype DX®

Purpose: Predicts risk of recurrence in early-stage, hormone receptor-positive (HR+), HER2-negative breast cancer.

• How It Works: Measures the activity of 21 genes in a tumor sample (16 cancer-related, 5 reference).

• Method: RT-PCR on RNA extracted from preserved tumor tissue.

• Results:

  • Gives a Recurrence Score (RS) from 0 to 100

  • Low score (0–25): low risk — may avoid chemo

  • High score (26+): higher recurrence risk — chemo likely beneficial

• Used In: Postmenopausal and some premenopausal women with early-stage HR+ cancers.

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2. MammaPrint®

Purpose: Estimates the 10-year risk of distant metastasis in early-stage breast cancer (any hormone status).

• How It Works: Analyzes expression of 70 genes involved in tumor proliferation and metastasis.

• Method: Microarray on fresh or frozen tumor tissue.

• Results: Classifies patients as either:

  • Low Risk

  • High Risk
    (Regardless of age, node status, or hormone receptor status)

• FDA-approved and validated in the MINDACT trial.

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3. Prosigna® (PAM50 test)

Purpose: Estimates risk of distant recurrence in HR+/HER2− breast cancer, especially useful after 5 years of hormonal therapy.

• How It Works: Measures expression of 50 genes to categorize tumor into one of 4 intrinsic subtypes:

  • Luminal A (best prognosis)

  • Luminal B

  • HER2-enriched

  • Basal-like (triple-negative)

• Method: Nanostring technology using FFPE tissue.

• Results: Provides a Risk of Recurrence (ROR) score and molecular subtype.

• Useful For: Long-term treatment planning.

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4. EndoPredict®

Purpose: Predicts late recurrence (5–10 years) in ER+/HER2− cancers.

• How It Works: Measures 12 genes involved in cell proliferation and hormone response.

• Method: RT-qPCR.

• Results: Combined with tumor size and nodal status to give an EPclin Score (low vs. high risk).

 How Are These Tests Carried Out?

1. Sample Collection

• Typically performed on formalin-fixed, paraffin-embedded (FFPE) tumor tissue from the original biopsy or surgery.

 2. RNA Extraction & Gene Expression Analysis

• RNA is extracted from the tissue.

• Reverse transcription creates complementary DNA (cDNA).

• Gene expression is measured using:

  • RT-PCR (Oncotype DX, EndoPredict)

  • Microarray (MammaPrint)

  • Nanostring nCounter (Prosigna)

 3. Data Analysis

• Expression values are normalized against control genes.

• Algorithms calculate risk scores (Recurrence Score, ROR, EPclin, etc.).

• These are combined with clinical features (tumor size, grade, lymph nodes) for a personalized risk profile.

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 What the Results Mean Clinically

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 Additional (Less Common) Tools

• Breast Cancer Index™ (BCI): Predicts benefit of extended endocrine therapy (after 5 years)

• Genomic Grade Index (GGI): Quantifies tumor aggressiveness

• Tumor Mutation Burden (TMB) / NGS panels: Being explored in advanced/metastatic settings

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 Summary: Clinical Genomic Tools in Breast Cancer

References

1. Sparano, J. A., et al. (2018). Adjuvant Chemotherapy Guided by a 21-Gene Expression Assay in Breast Cancer.New England Journal of Medicine, 379(2), 111–121. https://doi.org/10.1056/NEJMoa1804710

   • Landmark TAILORx trial validating Oncotype DX for treatment guidance.

2. Cardoso, F., et al. (2016). 70-Gene Signature as an Aid to Treatment Decisions in Early-Stage Breast Cancer. New England Journal of Medicine, 375(8), 717–729. https://doi.org/10.1056/NEJMoa1602253

   • The MINDACT study validating MammaPrint’s clinical utility.

3. Dowsett, M., et al. (2013). Comparison of PAM50 Risk of Recurrence Score With Oncotype DX and IHC4 for Predicting Risk of Distant Recurrence After Endocrine Therapy. Journal of Clinical Oncology, 31(22), 2783–2790. https://doi.org/10.1200/JCO.2012.46.1558

   • Validates Prosigna (PAM50) in postmenopausal HR+/HER2− breast cancer.

4. Filipits, M., et al. (2011). Clinical validation of the EndoPredict test in node-positive, chemotherapy-treated ER+/HER2− breast cancer patients: results from the GEICAM 9906 trial. Clinical Cancer Research, 17(18), 6012–6020. https://doi.org/10.1158/1078-0432.CCR-11-1120

   • Establishes EndoPredict as a predictor of late recurrence.

5. Paik, S., et al. (2004). A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer.New England Journal of Medicine, 351(27), 2817–2826. https://doi.org/10.1056/NEJMoa041588

   • Original study that laid the groundwork for Oncotype DX.

6. National Comprehensive Cancer Network (NCCN). (2024). Breast Cancer (Version 1.2024), NCCN Clinical Practice Guidelines in Oncology. Available at: https://www.nccn.org

7. American Society of Clinical Oncology (ASCO). (2023). Use of Biomarkers to Guide Adjuvant Systemic Therapy for Early-Stage Breast Cancer. Available at: https://www.asco.org