As an oncologist, I’ve seen firsthand how rapidly evolving diagnostic tools — beyond the standard pathology and imaging — are reshaping how we approach care. These tests don’t just guide treatment decisions during active therapy; they also help survivors reduce the risk of recurrence and live with greater confidence after treatment.

Foundational Markers: ER, PR, and HER2

The first step in breast cancer testing is determining whether tumor cells carry three key proteins: estrogen receptors (ER), progesterone receptors (PR), and HER2. These markers, measured by a lab technique called immunohistochemistry (IHC), shape the entire treatment plan.

• ER- or PR-positive cancers rely on hormones to grow, so endocrine therapy — medications that block hormones (SERMs, AIs, SERDs) — can be highly effective.
• HER2-positive cancers tend to grow faster but often respond dramatically to targeted HER2 therapies.
• Tumors lacking all three markers are called triple-negative, and they require different approaches, often involving chemotherapy and immunotherapy.

These markers are the foundation for personalized treatment and are measured from the initial biopsy in nearly all breast cancer cases [1].

Genomic Testing: Oncotype DX and Alternatives

For people with early-stage, hormone receptor-positive, HER2-negative breast cancer, genomic testing provides a deeper look at tumor biology. Oncotype DX, a 21-gene test performed on the breast tumor tissue, calculates a Recurrence Score (0–100) predicting the likelihood of distant recurrence and whether chemotherapy adds benefit.

• 0–25: Usually low risk; endocrine therapy alone is typically sufficient.
• ≥26: High risk; chemotherapy adds clear benefit.
• Intermediate scores in premenopausal women: Chemotherapy or hormone blockers with ovarian suppression may be advised, as ovarian hormones can fuel recurrence risk.
• A high score supports chemotherapy even in small tumors because it reflects aggressive tumor biology [2].

Other genomic tests include MammaPrint, PAM50/Prosigna, and EndoPredict. However, Oncotype DX remains the most validated and widely used [2].

Extending Hormone Therapy: The Breast Cancer Index (BCI)

Five years of endocrine therapy is standard, but deciding whether to extend it to 10 years can be difficult. The choice involves weighing ongoing benefits against side effects like bone loss or hot flashes. The Breast Cancer Index (BCI) — the only genomic test endorsed by the NCCN — helps predict whether extended therapy is likely to be beneficial.

• Low BCI score: Little benefit; safe to stop at five years.
• High BCI score: Significant benefit from continuing therapy [3].

This test is especially useful for survivors struggling with side effects, providing objective guidance on whether to continue or stop therapy.

Liquid Biopsy and ctDNA: Detecting Cancer in the Blood

Liquid biopsy technology analyzes circulating tumor DNA (ctDNA) fragments in blood. In early-stage cancer, ctDNA can detect minimal residual disease (MRD) — microscopic cancer cells that persist after surgery and radiation.

• Signatera (tumor-informed): Personalized to a patient’s tumor mutations; detects MRD with ~85–90% sensitivity, often up to 10 months before recurrence is visible [4].
• Guardant Reveal (tumor-agnostic): Uses common DNA patterns; ~71% sensitivity, detecting recurrence ~5 months earlier [4].

A positive MRD test indicates a much higher recurrence risk, but acting on these results is still under study. Trials are ongoing to determine whether early treatment based on ctDNA improves outcomes [5].

Next-Generation Sequencing (NGS)

NGS panels analyze hundreds of tumor genes to identify actionable mutations — genetic changes that can be targeted by specific drugs. NGS is recommended for metastatic or unresectable breast cancer, either at diagnosis or progression. These panels may be done on a tissue biopsy (e.g., FoundationOne CDx, Caris) or blood (e.g., Guardant360).

• AKT1 mutations → capivasertib therapy
• ESR1 mutations → elacestrant therapy
• NTRK fusions → larotrectinib therapy
• PIK3CA mutations → alpelisib therapy
• PTEN/RET mutations may guide trial enrollment [6]

NGS provides a molecular “map” of the cancer and is an important tool for matching patients to targeted therapies or clinical trials (note: not all mutations have approved therapies).

Germline Genetic Testing: Inherited Risk

About 5–10% of breast cancers are caused by inherited mutations. Testing for BRCA1/2, PALB2, CHEK2, ATM, TP53, and other high-penetrance genes can guide surgical decisions, screening, targeted therapy options, and family counseling.

The NCCN recommends genetic testing for people with breast cancer if results could change treatment, or if they:

• Were diagnosed at age 50 or younger
• Have triple-negative breast cancer at age 60 or younger
• Have two separate breast cancers, male breast cancer, or Ashkenazi Jewish ancestry
• Have close relatives with early breast, ovarian, pancreatic, or prostate cancers [7]

BRCA carriers may consider bilateral mastectomy, ovary removal, and enhanced screening. Importantly, PARP inhibitors such as olaparib are approved for HER2-negative BRCA-related cancers, improving outcomes [8].

Endoxifen Monitoring for Tamoxifen

Tamoxifen is converted into an active metabolite, endoxifen, which is 30–100 times more potent. Studies show that blood levels below ~14–16 nM may reduce protection against recurrence [9]. The TOTAM study showed that adjusting tamoxifen doses based on blood levels raised nearly 90% of patients to therapeutic levels without added toxicity [9]. Though not routine everywhere, endoxifen monitoring is a promising way to personalize tamoxifen dosing, improve symptoms, and outcomes.

DiviTum: Monitoring CDK4/6 Inhibitor Response

CDK4/6 inhibitors are vital for metastatic ER+ breast cancer. The DiviTum test measures thymidine kinase 1 (TK1) activity in blood, reflecting tumor growth. High TK1 levels at baseline or during treatment predict shorter benefit from CDK4/6 inhibitors. While still investigational, TK1 monitoring may eventually help physicians gauge whether reduced doses of CDK4/6i remain effective or if the drug is failing, prompting drug changes in real time [10].

Imaging: The Continuing Cornerstone

Imaging is a vital part of follow-up care, offering insights that blood tests alone can’t provide. Mammograms remain essential for spotting new cancers or early recurrences and detecting subtle changes like microcalcifications. Ultrasound adds extra detail when needed, and MRI — which uses no radiation at all — is especially useful for dense breast tissue or higher-risk patients. While CT, PET, and bone scans do involve small amounts of radiation, they are key to checking for spread and monitoring treatment, giving your care team a clear picture to guide next steps [11].

Emerging Frontiers

Some of the most exciting innovations are still on the horizon:

• Multi-cancer early detection (MCED) blood tests can scan for dozens of cancers at once by detecting tumor-derived DNA fragments in the blood [12].
• Immune profiling and dormancy assays are being developed to reveal whether microscopic residual cancer cells are likely to remain dormant or reactivate — a key factor in understanding recurrence risk [13].
• MRD-guided clinical trials are exploring whether acting on ctDNA positivity before visible disease emerges can improve outcomes [5].
• Artificial intelligence (AI) is being trained to integrate imaging, pathology, and genomics, offering increasingly accurate recurrence predictions and more personalized follow-up strategies [14].

These are not yet standard of care, but they represent the next wave of precision oncology.

Putting It All Together

Modern breast cancer care blends foundational pathology with genomic assays, liquid biopsies, inherited testing, drug-level monitoring, and imaging. Answering survivors’ concerns, supporting them through testing, and preparing for future advances are all part of truly personalized oncological care. The ultimate goal is clear: to deliver the right treatment, at the right time, for the right person — always guided by precision and compassion.

References

1. National Breast Cancer Foundation – Lab Tests
2. Oncotype DX criteria and recurrence score interpretation – oncolink.org
3. BCI predictive value for extended endocrine therapy – cancernetwork.com
4. ctDNA sensitivity and lead times – pmc.ncbi.nlm.nih.gov
5. Ongoing MRD-guided clinical trials – ASCO, Nature Reviews Clinical Oncology
6. NGS panels and actionable mutations – lbbc.org
7. Genetic testing criteria – breastcancer.org
8. PARP inhibitors for BRCA-related breast cancer – komen.org
9. Endoxifen thresholds and the TOTAM study – pmc.ncbi.nlm.nih.gov
10. Thymidine kinase activity and DiviTum – nature.com
11. American Cancer Society – Imaging Tests if Cancer Has Spread
12. Multi-cancer early detection blood tests (MCED) – National Cancer Institute, ASCO 2024 updates
13. Immune profiling and dormancy assays – Nature Reviews Cancer
14. AI in breast cancer diagnostics – Cancer Discovery, 2024