How have genomic assays transformed decision-making for early-stage breast cancer, particularly in determining whether patients benefit from adjuvant chemotherapy?
Genomic assays have redefined adjuvant decision-making in early-stage breast cancer by shifting the focus from traditional clinicopathologic factors, to the intrinsic biology of the tumor. For example, a patient might now be offered an 80-gene molecular subtyping test, alongside a 70-gene signature risk-of-recurrence test. These tests not only help identify which patients are likely to benefit from adjuvant chemotherapy, but also inform the selection of specific treatment regimens based on underlying tumor biology.
For example, the randomized phase III MINDACT trial demonstrated that hormone-receptor-positive/HER2-negative (HR+/HER2-) patients with genomically low-risk disease, including those with clinically high-risk features, do not derive significant benefit from adjuvant chemotherapy and have excellent long-term outcomes with endocrine therapy alone.
Because MINDACT was designed to establish the non-inferiority of withholding chemotherapy in genomic low-risk disease, subsequent analyses have focused on identifying patients who do benefit from chemotherapy. Real-world evidence (RWE) from the FLEX Study (NCT03053193), published summer 2025, showed a significant chemotherapy benefit in patients with HR+/HER2- early breast cancer for whom genomic testing indicated a high risk of recurrence.
More recently, data presented at SABCS 2025 demonstrated that combined tumor and recurrence risk profiling can predict benefit from anthracycline-based adjuvant chemotherapy, leading to the tests’ inclusion in NCCN clinical practice guidelines for the personalization of anthracycline use. In parallel, we are also actively evaluating the ability of genomic profiling to predict response to emerging therapies, including immunotherapy and CDK inhibitors.
In what ways do you see genomic testing complementing traditional histopathologic assessment to refine prognosis and treatment selection?
Histopathologic assessment remains essential for diagnosis and initial classification, but it provides limited insight into tumor biology. Genomic testing complements histology by capturing tumor-intrinsic biology that is not apparent from morphology or receptor status alone, which is especially valuable for heterogeneous populations such as estrogen-receptor-positive/HER2- breast cancers.
For example, almost 30 percent of HR+/HER2- tumors classified as high risk of recurrence are further classified as basal-type via genomic profiling. Such tumors, being biologically similar to triple negative breast cancer and characterized by aggressive intrinsic biology, may otherwise be missed.
Furthermore, these tumors warrant alternative therapeutic strategies, including neoadjuvant chemotherapy or immunotherapy. Together, histopathologic and genomic data provide a more precise and detailed assessment of prognosis and enable more personalized treatment decision-making.
How are genomic and molecular profiles being used to tailor neoadjuvant therapy regimens for patients with HR+/HER2- breast cancers?
In HR+/HER2- breast cancer, genomic and molecular profiling is being increasingly used to analyze pre-operative core needle biopsy tumor samples and inform both surgical and neoadjuvant treatment decisions.
Within six days of receipt of the core biopsy in the laboratory, genomic test results can help identify which women are likely to respond to neoadjuvant therapy, predicting the expected magnitude of response and likelihood of achieving nodal downstaging.
This is a particularly important question for women with HR+ early-stage breast cancer, because there are no clear guidelines for the use of neoadjuvant therapy in this group. The most recent NCCN guidelines do, however, now recognize the value of genomic testing for neoadjuvant decision-making in both pre- and post-menopausal women with HR+/HER2- breast cancer. By predicting treatment response, genomic profiling informs surgical timing/planning, and better co-ordination with medical oncologists.
Can tumor biology derived from genomic testing meaningfully influence surgical planning — such as the decision between breast-conserving surgery and mastectomy?
Tumor biology derived from genomic testing is crucial in surgical planning, moving beyond traditional imaging and histopathological features to determine the most appropriate surgical path. Genomic tools provide a deeper understanding of a tumor’s underlying behavior.
Specifically, identifying a high-risk signature can signal a more aggressive disease course that may require more extensive surgery or prioritize neoadjuvant chemotherapy to downstage the tumor before surgery.
Conversely, patients with lower-risk tumors may be candidates for less extensive surgery, as their tumors are less likely to exhibit spread or high recurrence rates. Insights from genomic testing can help surgeons align their technical approach with the tumor’s underlying molecular profile, ensuring that surgical plans are personalized for each patient.
What are the challenges of balancing recurrence risk reduction with quality-of-life considerations, and how can genomic data guide these nuanced conversations with patients?
Balancing recurrence risk with quality-of-life considerations is a huge challenge in breast cancer care. Despite their effectiveness, intensive therapies such as endocrine therapies and anthracycline-based chemotherapy can cause significant toxicities and unpleasant side effects. Genomic insights help guide treatment plans by providing objective evidence to personalize treatment intensity.
For example, the NCCN Clinical Practice Guidelines now officially recognize the ability of genomic tests to identify which HR+/HER2- patients actually benefit from anthracycline-based chemotherapy and who can safely avoid it.
A three-year analysis of outcomes from a cohort of 1,261 HR+/HER2- early-stage breast cancer patients from the FLEX Study found that High Risk 2 patients treated without anthracyclines had a significantly worse three-year invasive disease-free survival of 89 percent compared to 100 percent for those who received them. Conversely, the study demonstrated that High Risk 1 patients do not derive a meaningful benefit from this drug class and can be spared its associated toxicities including secondary leukemia and irreversible cardiotoxicity that can lead to heart failure.
Beyond chemotherapy, genomic insights can also guide clinical decisions regarding extended endocrine therapy. While these treatments have unpleasant side effects that impact long-term quality of life, genomic testing can determine if a patient truly benefits from continuing therapy for five years or beyond.
How do genomic risk stratification tools help clinicians avoid overtreatment, especially in patients with low-risk disease profiles?
Genomic risk stratification tools help identify patients whose biological risk of recurrence is lower than their traditional clinical risk based on histopathological features alone.
The MINDACT study, published in the New England Journal of Medicine, enrolled 6,693 patients to evaluate de-escalation by comparing clinical and genomic risk. The study specifically examined whether patients with high clinical risk, but low genomic risk, could safely forgo chemotherapy.
Findings revealed that 46 percent of patients who would traditionally receive chemotherapy (clinically high risk, genomic low risk) could be spared from the treatment with no significant impact on their survival. By prioritizing tumor biology, these tools provide clinicians with the evidence needed to reduce treatment intensity without compromising the quality of care.
How critical is the timing of genomic test results in guiding multidisciplinary treatment planning, and what impact can delays have on clinical outcomes or patient anxiety?
Timing is vital in guiding multidisciplinary breast cancer planning, since results can immediately help determine whether a patient requires neoadjuvant chemotherapy before surgery or should proceed to other treatments. Delays within this window can not only compromise clinical outcomes, but also take a significant mental toll on both patients and their families.
Genomic tests aim to address these challenges with results available in six days. Beyond immediate decision-making, these genomic insights map the entire treatment journey, including the identification of late recurrence risks to determine if a patient needs extended endocrine therapy a decade down the line.
How can genomic research and testing be made more inclusive — ensuring that underrepresented patient populations are adequately represented in datasets and benefit from personalized approaches?
Traditional clinical trials often fail to properly reflect diverse populations, creating a genomic gap where findings do not apply to all patients – resulting in significantly underrepresented patient populations. This lack of diversity helps explain the disparity in outcomes across different ethnic groups.
Inclusivity in genomic research can be achieved by leveraging RWE. This is the goal of the FLEX Study, a large-scale prospective registry that has enrolled more than 23,000 patients so far. Unlike restrictive clinical trials, FLEX aims to capture a true representation of the patient population by enrolling diverse ethnicities, ages, and patients with comorbidities across 100 global sites.
Leveraging RWE, it’s possible to gain insights into racial and ethnic disparities that clinical trials might miss – such as the overrepresentation of aggressive basal-type tumors in Black patients. In doing so, care plans can be personalized based on a patient’s unique tumor biology as opposed to generalized and limited datasets.
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