Editor’s Note: Precision testing is only as valuable as its timing. During the “Deep Dive” session at the 8th North–South Breast Cancer Forum, Professor Hao Wang from Sichuan Cancer Hospital delivered a focused presentation on the optimal timing of endocrine-related molecular testing in patients with HR+/HER2– metastatic breast cancer. She emphasized that the clinical value of precision testing lies in whether actionable therapeutic interventions are available. For mutations such as ESR1 and PIK3CA, where targeted therapies exist, early and comprehensive testing should be encouraged. In contrast, for alterations such as TP53, where effective interventions are lacking, testing should be approached more cautiously.
In the context of increasingly diverse treatment options, integrating prior therapies, expected PFS/OS benefits, and quality of life considerations into a dynamic and individualized strategy remains the cornerstone of clinical decision-making.
The Shift Toward Precision Oncology
Professor Hao Wang: Cancer treatment is steadily evolving toward precision medicine. Tumor heterogeneity remains one of the major challenges in clinical management, and integrating multi-dimensional biological data to guide molecularly targeted therapies represents a key pathway toward improved outcomes and, ultimately, cure.
In HR-positive metastatic breast cancer, treatment has evolved from traditional endocrine therapies targeting estrogen and progesterone receptors to more sophisticated approaches, including PARP inhibitors targeting BRCA mutations and novel endocrine-targeted therapies directed at alterations in the PAM pathway and ESR1 mutations.
However, despite the availability of actionable targets, progress in clinical implementation has been relatively slow. Compared with other malignancies, molecular testing in breast cancer remains largely centered on cost-effective immunohistochemistry for ER and PR. The adoption of next-generation sequencing (NGS) has not yet become widespread, likely due to concerns regarding cost-effectiveness.
Clinical Value of Testing: Actionability Is Key
In clinical practice, the value of molecular testing depends primarily on whether the results can guide treatment decisions. Specifically, we consider whether testing can:
- Predict treatment response or resistance
- Identify actionable targets for intervention
- Inform individualized treatment strategies
For example, alterations in the PAM signaling pathway are associated with poor prognosis and endocrine resistance. Similarly, ESR1 mutations are strong predictors of resistance to aromatase inhibitors and have important prognostic implications in HR+/HER2– disease.
For patients at risk of harboring such mutations, early and comprehensive testing should be encouraged. In contrast, for alterations such as high tumor mutational burden (TMB-H) or RET fusions—where predictive value remains uncertain—routine testing is not currently recommended.
A particularly illustrative example is TP53 mutation testing. Although TP53 mutations are associated with poor prognosis and occur at higher frequencies in Chinese patients, the lack of effective targeted interventions limits the immediate clinical utility of testing in routine practice.
When to Test: The Importance of Timing
The ultimate goal of molecular testing is to identify actionable therapeutic opportunities. When effective targeted therapies are available, timing becomes critical.
In situations where no competing treatment options exist, testing should be performed at the earliest actionable timepoint. Strong evidence supporting early testing comes from studies such as SERENA-6. This trial enrolled patients receiving first-line AI plus CDK4/6 inhibitors who developed ESR1 mutations detected via circulating tumor DNA (ctDNA) without clinical progression. Patients were randomized to receive camizestrant or continue AI therapy. The results demonstrated significant improvements in PFS (16.0 vs 9.2 months) and quality of life in the camizestrant group, highlighting the value of early molecular detection.
Similarly, the INAVO120 study demonstrated the importance of early testing for PIK3CA mutations. In patients with PIK3CA-mutated HR+/HER2– advanced breast cancer, the combination of inavolisib, palbociclib, and fulvestrant significantly improved both PFS and OS compared with standard therapy. These findings support proactive testing in patients without alternative treatment options.
Complex Scenarios: When Multiple Options Exist
The clinical situation becomes more complex when multiple therapeutic options are available. For patients who already have established treatment strategies, molecular testing may reveal additional options—but whether to act on these findings requires careful consideration.
For example, in HR+/HER2– metastatic breast cancer, PIK3CA mutation testing is recommended in the first-line setting. However, as patients progress to later lines of therapy, treatment selection becomes increasingly nuanced.
With the evolving classification of HER2 expression, patients can now be stratified into HER2-zero and HER2-low/ultra-low subgroups, each associated with different therapeutic options. Studies such as CAPItello-291 have demonstrated that capivasertib plus fulvestrant improves PFS in patients with PIK3CA/AKT1/PTEN alterations, particularly in the second-line setting.
In addition, antibody–drug conjugates (ADCs) have emerged as important treatment options in later lines. Sacituzumab govitecan (SG), evaluated in the TROPiCS-02 study, significantly improved both PFS and OS compared with chemotherapy in endocrine-resistant HR+/HER2– metastatic breast cancer. Similarly, DESTINY-Breast06 demonstrated that trastuzumab deruxtecan (T-DXd) significantly prolongs PFS in patients with HER2-low or ultra-low expression, regardless of the presence of endocrine resistance–related mutations.
These findings underscore that treatment decisions must be individualized, taking into account prior therapies, expected survival benefits, and toxicity profiles.
A Dynamic, Patient-Centered Strategy
Patients with HR+/HER2– metastatic breast cancer often undergo multiple lines of therapy—sometimes seven or more—before reaching overall survival endpoints. Therefore, treatment strategies must be dynamic and continuously reassessed.
In early treatment lines, oral, convenient, and home-based therapies may be prioritized to maintain quality of life. Upon disease progression, treatment should be adjusted based on evolving clinical data and patient characteristics.
Importantly, current international and domestic guidelines—including the NCCN Guidelines (2026.V2) and Chinese clinical guidelines—recommend molecular testing at the onset of endocrine resistance. In particular, PAM pathway–related testing has been explicitly emphasized in recent Chinese guidelines.
Conclusion
Precision molecular testing holds significant clinical value—but its utility depends on actionability and timing. When test results can inform treatment selection and lead to meaningful improvements in survival and quality of life, testing is clearly warranted.
Ultimately, each additional test represents an additional opportunity for patients. Providing more options—and more precise options—remains at the heart of modern oncology practice.
Expert Profile
Hao Wang, MD, PhD Associate Chief Physician, Master’s Supervisor
Deputy Director, Department of Breast Oncology Sichuan Cancer Hospital
Professor Wang specializes in the precision management of breast cancer, with a focus on integrating molecular diagnostics into individualized treatment strategies.
