Agendia’s VP of clinical development notes that new FLEX study data show genomic signatures predict chemotherapy benefit, improving personalized treatment for early breast cancer. 

Agendia’s genomic testing guides breast cancer care: SABCS25

The foundation of Agendia’s presentations is the FLEX study (NCT03053193), a large-scale, prospective, observational registry, which aims to enroll 30,000 patients with stage I-III breast cancer.

Agendia, a precision oncology company focused on early-stage breast cancer, presented a robust series of studies from its ongoing FLEX registry this week.

The data was presented at the annual San Antonio Breast Cancer Symposium (SABCS), taking place from December 9-12. Agendia’s presentations collectively argued for a more nuanced, biology-driven approach to treatment decisions, moving beyond standard clinicopathologic features. Data highlighted the predictive power of the company’s 70-gene signature, MammaPrint, and the 80-gene molecular subtyper, BluePrint, in identifying which patients benefit from specific chemotherapies, even within underrepresented populations like the elderly or diverse racial groups.

To understand the data and its implications, Drug and Device World caught up with Dr. Andrea Menicucci, PhD, Vice President of Clinical Development at Agendia. Dr. Menicucci notes how the FLEX study’s real-world framework complements RCTs to fill critical knowledge gaps. “Real-world evidence and randomized control trials create a very complete, comprehensive evidence database for physicians to draw information from,” she explained.

FLEX: Building a Real-World Evidence Engine

The foundation of Agendia’s presentations is the FLEX study (NCT03053193), a large-scale, prospective, observational registry. The study aims to enroll 30,000 patients with stage I-III breast cancer, linking standard-of-care MammaPrint and BluePrint results with full transcriptome data and long-term clinical outcomes. With over 21,000 patients already enrolled from more than 100 sites internationally, FLEX has deliberately enriched participation from racially and ethnically diverse groups and those with rare tumor histologies.

Dr. Menicucci emphasizes that this design addresses inherent limitations in RCTs. “Extended follow-up in prospective early breast cancer (EBC) treatment trials is essential for generating high-quality evidence, but can leave clinicians with unanswered questions during critical decision-making periods,” she noted. Furthermore, RCTs often suffer from “poor representation of less common tumors” and “limited enrollment of patients of diverse racial/ethnic backgrounds.” FLEX, as a real-world database, captures a heterogeneous patient population receiving care in everyday clinical settings.

The analytical rigor applied to this vast dataset is paramount. “We try to achieve the same effect [as randomization] so that we can really look at treatment effect and how biomarkers… can predict treatment benefit,” Dr. Menicucci states, referring to the use of advanced statistical methods like propensity score matching (PSM) to minimize confounding variables. This approach allows researchers to extract robust, clinically actionable signals from observational data.

Refining Chemotherapy Selection

One of the most practice-oriented findings presented at SABCS 2025 was the ability of MammaPrint to identify which patients with high-risk, HR+/HER2- disease derive a specific benefit from anthracycline-based chemotherapy. Anthracyclines, while effective, carry risks of long-term cardiotoxicity, creating a clinical need for biomarkers to guide their use.

The poster titled ‘Improved 3-year IDFS with anthracycline-based therapy for patients with 70-gene signature High 2, Luminal B, HR+HER2- early-stage breast cancer’ provided compelling data. The study focused on patients classified as MammaPrint High Risk, which is further subdivided into High Risk 1 (H1) and the more aggressive High Risk 2 (H2). Using PSM to balance groups, researchers compared outcomes between patients treated with taxane-cyclophosphamide (TC) versus anthracycline-taxane (AC-T) regimens.

The results were striking in their dichotomy. For patients with H1 tumors, there was no significant difference in 3-year invasive disease-free survival (IDFS) between AC-T (95.6%) and TC (94.6%) regimens. The poster concluded that the absolute difference remained below 1% through 5 years.

In stark contrast, for patients with H2 tumors, the 3-year IDFS was 100% for those receiving AC-T versus 89.3% for those receiving TC, an absolute benefit of 10.7%. This benefit persisted at four and five-year marks. Multivariate analysis showed a strong trend favoring AC-T in H2 patients, though it did not reach significance, likely due to the smaller sample size after matching.

Dr. Menicucci highlights this as a key finding for oncologists. “The field today really needs a biomarker that can determine who really benefits from adding anthracyclines… versus those who can avoid it,” she says. This data suggests that “if a patient has a MammaPrint High Risk 2 result, they have improved survival benefit when anthracyclines are included.” Conversely, H1 patients “can potentially avoid having the associated toxicities of anthracycline without compromising their outcomes.”

Genomics vs. Histologic Grade

Another presentation challenged the reliance on traditional histologic grade for defining high-risk disease, especially in the context of escalating therapies like CDK4/6 inhibitors and immunotherapy. The poster titled ‘70-Gene Signature High Risk Classification Provides Stronger Prognostic Value Than Histologic Grade in HR+HER2– Early Breast Cancer’ made a direct comparison.

The study analyzed 1,407 HR+/HER2- patients from FLEX with MammaPrint High Risk disease who received chemotherapy. It confirmed that H2 patients had significantly worse 5-year distant relapse-free survival (DRFS) than H1 patients (86.4% vs. 93.1%). More importantly, when looking only at patients with grade 3 (G3) tumors, which are clinically considered high-risk, MammaPrint provided further stratification. Among G3 patients, those with H2 status had an 8.4% lower 5-year DRFS than G3 patients with H1 status.

Crucially, in a multivariate Cox regression, MammaPrint risk group (H2 vs. H1) remained an independent prognostic factor for worse DRFS, while histologic grade (G3 vs. non-G3) lost its significant association after adjusting for genomic risk and other factors like tumor size and nodal status.

“This shows that capturing tumor biology by genomic classifiers is going to be more accurate than classifying them based on the morphology of their tumor,” Dr. Menicucci explains. This data reinforces the prognostic utility of MammaPrint and suggests that genomic risk should be weighed heavily when considering intensified treatment strategies.

Personalizing Care

Patients aged 70 and older are frequently underrepresented in clinical trials due to comorbidities and quality-of-life concerns, leaving clinicians with limited evidence to guide therapy. Agendia’s poster, titled ‘HR+ HER2- Early Breast Cancer (EBC) Patients ≥70 with High Risk 70-gene Signature Benefit from (Neo)adjuvant Chemotherapy (CT): Real World FLEX Study’, addressed this gap.

The analysis found that while older patients were less likely to have high-risk disease, a substantial portion did: 37.4% were H1 and 6.0% were H2. Notably, these high-risk older patients were significantly less likely to receive chemotherapy than their younger counterparts (H1: 49.4% vs. 77.1%; H2: 72.1% vs. 90.9%). They also had a higher comorbidity burden.

Despite these factors, the data revealed a benefit for chemotherapy. For patients ≥70 with high-risk tumors, the 4-year DRFS trended higher for those who received chemotherapy plus endocrine therapy versus endocrine therapy alone (H1: 88.5% vs. 84.8%; H2: 88.1% vs. 78.3%). In a multivariate model adjusting for comorbidities and other variables, chemotherapy was associated with a significantly reduced risk of distant recurrence for both H1 and H2 patients.

Dr. Menicucci points to this as critical, practice-informing evidence. “We are seeing in FLEX that the patients who are over 70 and have a MammaPrint high risk… actually benefit from having chemotherapy. They have improved survival independent of existing comorbidities.” This suggests that genomic testing can provide valuable risk information to support individualized treatment decisions in this complex population, potentially overcoming therapeutic nihilism based on age alone.

Uncovering Biological Drivers of Disparities

A translational strength of the FLEX study is its ability to explore biological differences across racial and ethnic groups. The poster titled ‘Distinct Immune and Metabolic profiles in Latin American Breast Cancer Patients With Obesity Enrolled in FLEX’ presented a whole transcriptome analysis comparing Latin American, Black, and Non-Hispanic White (NHW) patients.

The study confirmed significant epidemiological disparities: Latin American and Black patients were younger, more frequently obese, and had more aggressive tumor features, including higher rates of MammaPrint H2, BluePrint Basal subtype, and ImPrint+ (immune-positive) tumors. In a matched analysis of obese patients, Latin American women had a higher prevalence of Type 2 diabetes.

The genomic analysis revealed distinct biology. In obese Latin American patients, metabolic pathways related to adipogenesis and oxidative phosphorylation were suppressed compared to other groups. Conversely, in Latin American patients with Basal-type tumors, immune activation pathways were enriched. “These findings highlight potential therapeutic targets and underscore the need for racially and ethnically diverse representation in clinical trials,” the poster concluded.

Dr. Menicucci elaborates on the clinical implications of such findings. “We see a higher proportion of patients with High 2 or basal type tumors in Black patients and Latin American patients. So, they have this more aggressive tumor within HR positive… and possibly should be treated accordingly.” This biological insight, gleaned from real-world data, argues against a one-size-fits-all approach and emphasizes the need for precision medicine that accounts for ancestral and socioeconomic context. “Our mission is really to ensure that precision medicine works for every patient, not just those who fit the typical clinical trial profile,” she adds.

The Future of Adaptive Precision Oncology

The collective data from FLEX points toward a future of more dynamic, biology-informed cancer care. Dr. Menicucci envisions FLEX as a platform for “adaptive precision oncology,” moving beyond initial treatment decisions to monitoring and adaptation throughout a patient’s journey. “Can we monitor how tumors evolve and how they respond to therapy? Can we flag early resistance?… Can we help clinicians adapt treatment based on the changing evolution of the biology?” she posits.

This is enabled by the study’s core design: the pairing of longitudinal clinical outcomes with full transcriptome data. It creates an infrastructure to discover novel gene signatures predictive of response or resistance to a wide array of therapies, from CDK4/6 inhibitors to immunotherapy.

Integrating these genomic platforms into global standard care faces challenges, primarily the historical reliance on RCT evidence. Dr. Menicucci acknowledges this but sees a shifting landscape. “Real-world databases… are becoming more recognized as a clinical resource that can provide evidence that informs practice,” she says, citing the inability of RCTs to reflect everyday clinical diversity or answer certain ethical questions. The rigorous methodology applied within FLEX is Agendia’s answer to building the necessary confidence among clinicians.

Path Ahead

Agendia’s suite of presentations at SABCS 2025 demonstrates a multi-faceted evolution in the application of genomic testing in early breast cancer. The data moves MammaPrint and BluePrint beyond prognostication into the realm of predictive biomarkers, capable of guiding specific chemotherapy choices and identifying benefit in underserved populations like the elderly.

Through the FLEX study, Agendia is leveraging real-world evidence on an unprecedented scale to address the nuances and gaps left by traditional clinical trials. As Andrea Menicucci summarizes, this effort is about generating “evidence that’s more equitable… more clinically relevant, more actionable.”

The findings underscore a central theme in modern oncology: effective personalization requires a deep understanding of individual tumor biology, which in turn demands inclusive and comprehensive genomic research.

See article by Dr. Phalguni Deswal via Drug and Device World