Abstract
Background
HER2DX is a clinically available genomic assay that provides prognostic (relapse risk score), predictive [pathological complete response (pCR) likelihood score], and ERBB2 expression data in stage I-III human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC). This real-world study evaluated its clinical impact.
Patients and methods
This prospective study enrolled newly diagnosed patients with stage I-III HER2-positive BC across 12 hospitals in Spain (November 2021-September 2024). Thirty-four oncologists ordered HER2DX and completed questionnaires before and after receiving results to assess treatment changes (primary objective). Secondary objectives included evaluating the HER2DX pCR likelihood score association with pCR, test turnaround time, changes in physician confidence regarding treatment decisions, and cost-effectiveness.
Results
Among 297 recruited patients, 48.1% (95% confidence interval 42.5% to 53.7%) experienced treatment adjustments after HER2DX. Within these cases, 73.5% involved reduced treatment intensity, 24.5% involved increased treatment intensity, and the remaining cases (2.0%) involved mixed adjustments. Of the cases with reduced treatment intensity, 56.2% had a reduction in chemotherapy intensity, 26.7% had a reduction in anti-HER2 therapy, and 17.1% in both. Among the 182 patients with available pathological data at surgery, the pCR likelihood score was a significant predictor of pCR (P < 0.001). In 69 patients with pCR-high disease, less intensive treatment achieved similar pCR rates compared with multi-agent chemotherapy (81.5% versus 69.0%; odds ratio = 1.97, P = 0.256). Physician confidence improved (P < 0.001) and the estimated total cost savings, including direct drug costs, vein access devices, and HER2DX costs, amounted to €98 031.
Conclusions
HER2DX impacts clinical management in stage I-III HER2-positive BC by supporting treatment adjustments, enhancing physician confidence, maintaining pCR rates, and reducing health care costs.
Key words: early breast cancer, HER2 positive, genomic test, health economics, HER2DX
Highlights
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HER2DX assay led to treatment adjustments in nearly half of early-stage HER2-positive cases, mainly through de-escalation.
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The HER2DX pCR likelihood score was a significant predictor of pCR outcomes.
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HER2DX pCR-high patients had similar pCR rates with paclitaxel and dual anti-HER2 blockade as with multi-agent chemotherapy.
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HER2DX results enhanced physician confidence in treatment decisions.
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HER2DX reduced health care costs by minimizing expensive therapies and associated medical resources.
Introduction
Human epidermal growth factor receptor 2 (HER2)-positive breast cancer accounts for ∼15%-20% of all breast cancer cases and is characterized by aggressive tumor growth and poor prognosis if left untreated.1 The advent of targeted therapies, particularly anti-HER2 agents, has substantially improved outcomes for patients with early-stage disease.1 However, identifying the most effective and tailored treatment strategy from the numerous guideline-recommended regimens remains a clinical challenge.2,3
Current treatment approaches often involve multi-agent chemotherapy combined with anti-HER2 therapy,4,5 which can lead to substantial toxicity and impact patients’ quality of life. Recent advances in genomic profiling have opened new avenues for more personalized therapeutic strategies, supporting the reduction of treatment intensity in selected patients without compromising efficacy.6, 7, 8 To achieve this, reliable tools that can accurately predict prognosis and response to therapy are urgently needed.9
HER2DX is an analytically and clinically validated laboratory-developed test that integrates clinical data including tumor stage and nodal status with the evaluation of 27 genes involved in four key biological processes: immune infiltration, luminal differentiation, tumor cell proliferation, and HER2 amplicon expression. HER2DX provides both prognostic (relapse risk score) and predictive information [pathological complete response (pCR) likelihood score].6,10, 11, 12, 13, 14, 15, 16, 17 Additionally, the test measures ERBB2 expression levels (ERBB2 mRNA score), providing an opportunity to confirm HER2 status using a continuous score.12,18 This assay has the potential to inform therapeutic decisions in early-stage HER2-positive breast cancer by identifying patients who might benefit from less intensive treatment regimens, reducing toxicity and health care costs, while maintaining high treatment efficacy.
To explore the clinical utility of HER2DX, we conducted an observational, prospective, multicenter study involving several hospitals in the Catalonia and Valencia regions of Spain. The primary objective of this study was to evaluate the impact of HER2DX on treatment decision making in early-stage HER2-positive breast cancer.
Patients and methods
Study protocol
This is an observational, prospective, multicenter study, conducted from November 2021 to September 2024, to evaluate the impact of HER2DX on clinical decision making for patients with early-stage HER2-positive breast cancer. The study involved 12 hospitals across Spain, including 10 publicly funded and 2 privately funded institutions. Eligible participants included all patients with newly diagnosed stage I-III HER2-positive breast cancer, either at the time of diagnosis or following primary surgery. The HER2DX test was ordered by 34 medical oncologists for all patients who met the eligibility criteria. At the beginning of the study no oncologist had prior experience with the test. Before receiving the HER2DX results, treating physicians completed a questionnaire to document their initial treatment plan and their level of confidence in the proposed approach. An identical follow-up questionnaire was conducted after the HER2DX results became available to document any changes in the treatment strategy and reassess physician confidence. HER2DX was used by clinicians based on their professional judgment, without a formal protocol or specific instructions.
Due to the long duration of treatments (often over a year) and limited follow-up, we based our study on clinicians’ reported treatment intentions from questionnaires. This allowed us to capture planned treatments soon after receiving HER2DX results. However, the final treatment administered may have differed due to availability or clinical considerations.
Physician confidence in therapeutic decision making was measured using a five-point Likert scale,19 a commonly used psychometric scale designed to assess attitudes or perceptions. In this case, 1 indicated the lowest level of confidence in the therapeutic decision made, and 5 represented the highest level.19 The translated version of the questionnaire in English is available in the Supplementary Material, available at https://doi.org/10.1016/j.esmorw.2025.100123.
Study objectives
The primary objective of the study was to evaluate the impact of the HER2DX genomic assay on therapeutic decision-making. Secondary objectives include assessing the test turnaround time, evaluating the association between the pCR likelihood score and actual pCR rates, measuring changes in physician confidence before and after receiving the HER2DX report, and carrying out a cost analysis that included the cost of the test, direct drug expenses, and vein access devices.
HER2DX evaluation
HER2DX standardized testing was carried out on formalin-fixed, paraffin-embedded tumor tissue samples at the central laboratory in the Hospital Clinic of Barcelona, Spain.16 The assay generates three outputs: relapse risk score, a pCR likelihood score, and an ERBB2 mRNA score (the different categories of scores are explained in Supplementary Material, available at https://doi.org/10.1016/j.esmorw.2025.100123).12,16,17
Cost-saving analysis
Questionnaire responses collected before and after HER2DX testing were analyzed to identify changes in drug usage resulting from therapy modifications. Official drug prices were sourced from the national public health system in Spain (https://www.sanidad.gob.es/profesionales/nomenclator.do). Additionally, the analysis included the costs of premedication drugs and vein access devices, such as port-a-caths and peripherally inserted central catheters. Total drug cost savings were calculated based on the number of treatment cycles administered following HER2DX-guided decisions. The net cost savings were determined by subtracting the cost of the HER2DX test from the total drug savings. A detailed report of this analysis is available in the Supplementary Material, available at https://doi.org/10.1016/j.esmorw.2025.100123.
Statistical analysis
All statistical analyses were conducted using R statistical software version 4.3.2, with a two-sided alpha level of 0.05 for significance. Descriptive statistics summarized patient demographics, tumor characteristics, and treatment changes. Logistic regression models, adjusted for hormone receptor status and treatment type, evaluated the association between HER2DX scores and pCR rates. Variables for the multivariate logistic regression model were selected based on clinical relevance and statistical significance in univariate analysis. Paired Student’s t-tests assessed changes in physician confidence before and after the HER2DX report. The cost-saving analysis focused on the drug cost reductions resulting from treatment modifications guided by HER2DX.
Ethical approval
The study was approved by the relevant ethics committees and institutional review boards (expedient number HCB.2022.0843) and was conducted in accordance with the principles of the Declaration of Helsinki. Written informed consent was obtained from all patients. Material transfer agreements and ethical approvals covered the use of patient samples and data for the analyses presented in this study.
This study was conducted in accordance with the ESMO-GROW reporting guidelines,20 and the corresponding checklist is provided in the Supplementary Material, available at https://doi.org/10.1016/j.esmorw.2025.100123.
Results
Patient characteristics
As of the data cut-off on 30 September 2024, 304 patients with stage I-III HER2-positive breast cancer were recruited (Table 1). In seven cases (2.3%), an HER2DX ERBB2-low score classification led to tumor reclassification as HER2-negative by immunohistochemistry and those patients were excluded from the analysis. The remaining 297 patients with early-stage HER2-positive breast cancer had a median age of 54 years (range 28-90 years), with most presenting with stage II disease (54.2%). Forty percent had nodal involvement, and most tumors were hormone receptor-positive (61.3%).
Table 1.
Characteristics of patients with early-stage HER2-positive breast cancer participating in the study
| All patients with HER2+ breast cancer (N = 297) | |
|---|---|
| Age, median (range) | 54 (28-90) |
| Histology, n (%) | |
| Ductal | 270 (91.2%) |
| Lobular | 11 (3.7%) |
| Apocrine | 5 (1.7%) |
| Micropapillary | 5 (1.7%) |
| Mucinous | 5 (1.7%) |
| NA | 1 |
| Menopausal status, n (%) | |
| Premenopausal | 114 (39.3%) |
| Postmenopausal | 176 (60.7%) |
| NA | 7 |
| cT/pT, n (%) | |
| T1 | 125 (42.1%) |
| T2 | 128 (43.1%) |
| T3 | 31 (10.4%) |
| T4 | 13 (4.4%) |
| cN/pN, n (%) | |
| N0 | 178 (60.0%) |
| N1 | 96 (32.3%) |
| N2 | 20 (6.7%) |
| N3 | 3 (1.0%) |
| Stage, n (%) | |
| I | 83 (28.0%) |
| II | 167 (56.2%) |
| III | 47 (15.8%) |
| IHC HER2, n (%) | |
| 2+ | 58 (19.8%) |
| 3+ | 235 (80.2%) |
| NA | 4 |
| Grade, n (%) | |
| G1 | 22 (7.8%) |
| G2 | 161 (56.9%) |
| G3 | 100 (35.3%) |
| NA | 14 |
| Hormone receptor, n (%) | |
| Positive | 179 (61.3%) |
| Negative | 113 (38.7%) |
| NA | 5 |
| Ki67, median (range) | 35 (2-95) |
| TILs, median (range) | 8 (<1-90) |
| Treatment, n (%) | |
| Adjuvant | 65 (22.2%) |
| Neoadjuvant | 228 (77.8%) |
| NA | 4 |
HER2, human epidermal growth factor receptor 2; ICH, immunohistochemistry; NA, not available; TILs, tumor-infiltrating lymphocytes.
HER2DX results
The distribution of the relapse risk score, pCR likelihood score, and ERBB2 mRNA score within the cohort is summarized in Figure 1A-C and Supplementary Tables S1-S3, available at https://doi.org/10.1016/j.esmorw.2025.100123. These distributions are highly consistent with those reported in prior HER2DX validation studies.10, 11, 12, 13,15,17
Figure 1.
Distribution of HER2DX scores across all patients. (A) Relapse risk score. (B) pCR likelihood score. (C) ERBB2 mRNA score. pCR, pathological complete response.
Overall, as determined by the HER2DX relapse risk score, 52.5% of cases were classified as low-risk, while 47.5% were high-risk. Among hormone receptor-positive cases, 56.4% were low-risk and 43.6% were high-risk, whereas for hormone receptor-negative cases, 46.9% were low-risk and 53.1% were high-risk (Supplementary Figure S1, available at https://doi.org/10.1016/j.esmorw.2025.100123).
In the full cohort, as per the pCR likelihood score, 36.7% of cases were classified as pCR-low, 28.6% as pCR-medium, and 34.7% as pCR-high. When stratified by hormone receptor status, 57.5% of hormone receptor-positive cases were pCR-low, 30.7% were pCR-medium, and 11.7% were pCR-high. Among hormone receptor-negative cases, 3.5% were pCR-low, 23.9% were pCR-medium, and 72.6% were pCR-high (Supplementary Figure S1, available at https://doi.org/10.1016/j.esmorw.2025.100123).
Based on the ERBB2 mRNA score, in the full cohort, 10.4% of cases were ERBB2-low, 18.9% were ERBB2-medium, and 70.7% were ERBB2-high. For hormone receptor-positive cases, 12.8% were ERBB2-low, 22.9% were ERBB2-medium, and 64.2% were ERBB2-high. Among hormone receptor-negative cases, 7.1% were ERBB2-low, 12.4% were ERBB2-medium, and 80.5% were ERBB2-high (Supplementary Figure S1, available at https://doi.org/10.1016/j.esmorw.2025.100123).
Impact on treatment planning
The primary objective was to assess changes in therapeutic modifications following HER2DX testing. Treatments were modified in 143 of 297 cases [48.1%; 95% confidence interval (CI) 42.5% to 53.7%] based on HER2DX results (Figure 2A). Among these cases, 73.5% involved reduced treatment intensity (Figure 2B). Of those, 56.2% had a reduction in chemotherapy intensity, 26.7% experienced a reduction in anti-HER2 therapy, and 17.1% had reductions in both. Specific changes included avoiding anthracycline-based regimens (40.8%), removing one anti-HER2 drug (29.5%), and/or shortening the duration of trastuzumab treatment (15.2%). Conversely, in 24.5% of cases with therapeutic modifications (Figure 2B), HER2DX results prompted an increase in therapy intensity. Within these cases, 57.1% involved the addition of another anti-HER2 agent, such as pertuzumab and/or neratinib, 20.0% involved more intensive chemotherapy, and 22.9% involved both.
Figure 2.
Treatment modifications based on HER2DX results. (A) Percentage of treatment changes in the overall cohort. (B) Types and percentages of treatment changes among the 143 patients with treatment modifications. chemo, chemotherapy; HER2, human epidermal growth factor receptor 2.
To evaluate whether treatment modifications changed over time as more HER2DX evidence became available, we analyzed their relationship with time since patient inclusion. Logistic regression showed no significant association [odds ratio (OR) 1.006, 95% CI 0.981-1.033, P = 0.626]. To further explore this, we divided the study timeline into three phases: initial (November 2021-December 2022), intermediate (January 2023-December 2023), and late (January 2024-September 2024). Logistic regression found no significant differences in treatment modification rates across these periods (P = 0.351).
Associations of HER2DX with pCR
Of the 228 patients who received neoadjuvant therapy, 182 (79.8%) had undergone surgery and had pCR data available at the data cut-off. Among these, 63 (34.6%) were classified as pCR-low, 50 (27.5%) as pCR-medium, and 69 (37.9%) as pCR-high. The pCR rate in the 182-patient analysis dataset was 56.6% (95% CI 49.1-64.0). Notably, the HER2DX pCR likelihood score was significantly associated with pCR (adjusted OR per 10-unit increase = 1.31, 95% CI 1.12-1.53, P = 0.001), independent of hormone receptor status, type of systemic treatment, and clinical stage (Supplementary Table S4, available at https://doi.org/10.1016/j.esmorw.2025.100123).
The pCR rate was comparable between cases without HER2DX-driven treatment changes (n = 89) and those with treatment changes (n = 93): 56.2% (95% CI 45.3-66.7) versus 57.0% (95% CI 46.3-67.2) (OR 1.03, 95% CI 0.57-1.86, P = 0.912). Among the 69 cases classified as HER2DX pCR-high, 27 (39.1%) were treated with a 3-month regimen of paclitaxel, trastuzumab, and pertuzumab, achieving a pCR rate comparable to the 42 patients (60.9%) treated with multi-agent chemotherapy (anthracycline- or carboplatin/taxane-based), trastuzumab, and pertuzumab [81.5% (95% CI 61.9% to 93.7%) versus 69.0% (95% CI 52.9% to 82.4%); OR 1.97, 95% CI 0.61-6.36, P = 0.256] (Table 2 and Figure 3A). For 41 of the 42 (97.6%) patients treated with multi-agent chemotherapy, and 19 of the 27 (70.4%) treated with paclitaxel and dual blockade, the oncologist had initially selected multi-agent chemotherapy before receiving the HER2DX results.
Table 2.
Clinical characteristics and pCR rates among patients with HER2DX pCR-high disease treated with multi-agent or single-agent chemotherapy combined with dual HER2 blockade
| Multi-agent chemotherapy + TP (n = 42) | Single taxane + TP (n = 27) | P value | |
|---|---|---|---|
| Multi-agent chemo + TP indicated pre-HER2DX, n (%) | 41 (97.6%) | 19 (70.4%) | 0.377 |
| Age, median (range) | 49 (29-73) | 56 (42-81) | 0.001 |
| Stage I-II, n (%) | 31 (73.8%) | 24 (88.9%) | 0.219 |
| cN positive, n (%) | 26 (61.9%) | 8 (29.6%) | 0.013 |
| HR+, n (%) | 12 (28.6%) | 4 (14.8%) | 0.248 |
| pCR rate, % | 69.0% | 81.5% | 0.256 |
cN, clinical nodal status; HR, hormone receptor; pCR, pathological complete response; TP, trastuzumab and pertuzumab.
Figure 3.
Pathological complete response (pCR) rates according to HER2DX pCR likelihood score group and treatment regimen. (A) HER2DX-high pCR likelihood score group. (B) HER2DX-medium pCR likelihood score group. (C) HER2DX-low pCR likelihood score group. chemo, chemotherapy; pCR, pathological complete response; TP, trastuzumab and pertuzumab.
In contrast, in 50 patients with HER2DX pCR-medium disease, those treated with multi-agent chemotherapy and dual HER2 blockade achieved a pCR rate of 70.4% (95% CI 49.8% to 86.2%), compared with 47.6% (95% CI 25.7% to 70.2%) in those treated with single-agent taxane and dual HER2 blockade (OR 2.61, 95% CI 0.79-8.59, P = 0.114) (Figure 3B).
Turnaround time and physician confidence
The median turnaround time for the HER2DX test, measured from sample receipt at the central laboratory to report release, was 7 working days (range 3-19 days). Physicians reported a significant increase in confidence regarding their treatment decisions after reviewing the HER2DX results. On a scale of 1-5 (maximum score),19 the median confidence score increased significantly from 4 [interquartile range (IQR) 3-5] to 5 (IQR 4-5) (P < 0.001, Wilcoxon signed-rank test). This increase was consistent across settings: in the neoadjuvant setting, from 4 (IQR 3-5) to 5 (IQR 4-5) (P < 0.001), and in the adjuvant setting, from 4 (IQR 3-4) to 5 (IQR 4-5) (P < 0.001). Similarly, in cases where treatment plans were modified based on HER2DX results, the median confidence score rose from 4 (IQR 3-5) to 5 (IQR 4-5) (P < 0.001). Even when no changes were made, the median score still increased from 4 (IQR 4-5) to 5 (IQR 4-5) (P < 0.001).
HER2DX ERBB2 mRNA-low score category
The HER2DX assay identified tumors as ERBB2-low in 38 of 304 (12.5%) cases. Among them, 14 (36.8%) cases could be retested for HER2 status, resulting in reclassification of the tumor in 7 (50%) as HER2-negative. Of the remaining cases, four were HER2-positive (immunohistochemistry 2+ with positive in situ hybridization; median HER2/cr17 ratio: 2.1, range 2-3.9), and three exhibited heterogeneous positivity (with HER2-positive cell populations of 60%, 25%, and 10%, respectively). All the seven negative cases had hormone receptor-positive disease. Except for one case, these patients did not receive chemotherapy and were treated with adjuvant endocrine therapy.
Cost savings
The analysis included 232 patients who were initially planned for neoadjuvant systemic therapy and 65 patients planned for primary surgery. Two patients were excluded because their treating physicians recommended clinical trial enrollment based on HER2DX results. We also included seven cases confirmed as HER2-negative when retested. Thus, 302 cases were included in the analysis (Supplementary Tables S5-S9, available at https://doi.org/10.1016/j.esmorw.2025.100123). For all the cases, we evaluated the systemic regimens selected pre-test and post-test (Supplementary Figure S2, available at https://doi.org/10.1016/j.esmorw.2025.100123). The analysis also assessed the impact of HER2DX on decisions regarding adjuvant therapy following neoadjuvant treatment and the use of adjuvant neratinib.
Using these data, the cost of each regimen was calculated pre-test and post-test, factoring in the retail price of the HER2DX assay (€2950 per test). Despite this limitation, significant savings in drug regimens were achieved, resulting in total net savings of €98 031.4 (details provided in the Supplementary Material, available at https://doi.org/10.1016/j.esmorw.2025.100123).
Discussion
HER2-positive breast cancer impacts patient mortality, morbidity, quality of life, financial burden, and health care resource allocation. While the use of adjuvant chemotherapy and trastuzumab has markedly improved survival rates,1 variability persists in patients’ prognoses and treatment responses due to differences in their clinical and tumor biological characteristics. The increasing use of neoadjuvant therapy has also added complexity to disease management.4 Given that clinicians’ attitudes toward treatment strategies vary substantially2,17 and clinical guidelines often provide only general recommendations,4 there is uncertainty regarding the optimal treatment plan for each patient.
The HER2DX genomic assay provides precise information to guide critical treatment decisions through three key scores offering a more comprehensive understanding of each patient’s prognosis and response potential, helping clinicians navigate the complexities of personalized treatment strategies.12,17
This study is the first to assess the decision impact of HER2DX in clinical practice, incorporating data from all three HER2DX scores across both the neoadjuvant and adjuvant settings. A key finding is the ability of HER2DX to reduce therapy intensity in selected patients, which occurred in 73.5% of modified treatment plans (35.4% of the 297-patient cohort). These reductions included shortening the duration of trastuzumab, omitting a second anti-HER2 agent, or de-escalating chemotherapy regimens. By minimizing exposure to aggressive treatments, HER2DX contributes to reducing treatment-related toxicity and health care costs, ultimately benefiting patients’ quality of life. This approach aligns with precision medicine principles, aiming to balance efficacy with tolerability.
Conversely, HER2DX results also led to an increase in therapy intensity in 24.5% of cases with modified treatment plans (11.8% of the cohort)—for example, the addition of another anti-HER2 agent, such as pertuzumab or neratinib, or intensification of chemotherapy regimens. Such increases in intensity are critical for patients identified as being at higher risk of recurrence, as preventing disease relapse can have profound benefits for both patients and the health care system. Overall, this dual capability to adjust treatment intensity highlights the value of HER2DX in providing an unbiased, evidence-based assessment of patient risk profiles. By tailoring treatment strategies to individual risk and across different settings, HER2DX supports more personalized and effective clinical decision making, potentially improving long-term survival outcomes and reducing the overall burden of managing recurrent disease.
It is important to mention that during the patient inclusion period (2021-2024) there have been ongoing developments in clinical evidence supporting the use of HER2DX. Research studies and publications during this time may have refined the understanding of HER2DX’s utility in decision making, potentially influencing its clinical application; however, the percentage of treatment change observed in our study remained consistent during this period.
High pCR rates observed in patients classified as pCR-high who received single-agent taxane-based regimens underscore the assay’s ability to guide effective de-escalation in selected cases. Importantly, the high pCR rate observed in HER2DX pCR-high disease treated with paclitaxel-trastuzumab-pertuzumab is consistent with the rates reported in the retrospective analysis of HER2DX in tumor samples from the DAPHNe clinical trial.10,21 On the other hand, high pCR rates were observed in patients with pCR-medium scores treated with multi-agent chemotherapy, compared with those treated with single-agent taxane and dual HER2 blockade. While no statistically significant difference was detected, our findings are in line with the results from Villacampa et al.’s patient-level meta-analysis, which suggested a potential benefit of multi-agent chemotherapy in patients with HER2DX pCR-medium disease.10 These findings reinforce the role of the HER2DX pCR score in stratifying patients for treatment intensity. Importantly, the results validate the cut-off between medium and high pCR scores as appropriate for guiding decisions between less intensive and more intensive treatment regimens, which can have a profound impact on therapy choices in the adjuvant setting.
The HER2DX relapse risk score also plays a critical role in adjuvant therapy decision making, providing a continuous estimate of recurrence-free survival likelihood.17,22 This approach allows clinicians to assess patients within low- and high-risk profiles, potentially guiding the choice between single-agent therapies and more intensive chemotherapy. Notably, the risk score has been validated in over 2000 patients across seven studies,22 reinforcing its prognostic robustness in both adjuvant and neoadjuvant settings, even for patients with residual disease after neoadjuvant therapy.10,13
Additionally, the HER2DX ERBB2 mRNA score offers a refined assessment of HER2 expression, distinguishing between low-, medium-, and high-expression categories. This can help identify cases where HER2-directed therapies might be less effective and prompt re-evaluation of HER2 status.17 The identification of HER2DX ERBB2-low cases that were subsequently reclassified as HER2-negative underscores the test’s ability to refine treatment decisions in complex scenarios.
Beyond its clinical implications, HER2DX has demonstrated a substantial impact on utilization of health care resources. By guiding treatment modifications, the study highlights the potential for more efficient resource use. While the current analysis focused mainly on drug use and vein access devices, HER2DX also affects indirect societal resources. Reducing intensive chemotherapy and dual anti-HER2 therapies can lower side-effects, which reduces the need for supportive medications, emergency room visits, and hospitalizations. Additionally, less intense and shorter treatments can reduce patients’ work absenteeism, improving their quality of life and productivity. On the other hand, treatment intensification based on HER2DX has resource implications, particularly in preventing disease recurrence. Although adding extra anti-HER2 agents or intensifying chemotherapy may increase upfront resource use, these strategies have been shown to reduce relapse rates. Recurrence often requires more aggressive treatments, longer hospital stays, and palliative care, all contributing to higher health care costs. Moreover, recurrent disease has significant emotional, physical, and financial impacts on patients and families, emphasizing the value of early and effective intervention.
This study has limitations. Firstly, its observational design and the absence of a randomized control group limit our ability to establish causal relationships between HER2DX-guided decisions and clinical outcomes. Additionally, we relied on clinician-reported questionnaires to capture treatment intentions, which introduces bias, as the actual treatment may differ from the reported intentions due to factors beyond the HER2DX report, such as treatment availability or clinical considerations. However, in most cases, clinicians’ reported treatment intentions were followed, as demonstrated in the neoadjuvant setting where clinical reports were reviewed, validating the reported decisions. Moreover, patient-reported outcomes are not included in this analysis. Additionally, the study was conducted in a specific population in Catalonia and Valencia regions, which may limit the generalizability of the results. Another limitation is the short follow-up period; thus, no survival outcomes are available, restricting our understanding of the long-term impact of HER2DX risk score-guided treatment strategies. Long-term outcomes will be measured in future analyses to provide deeper insights into the clinical and economic benefits of HER2DX-guided care. Finally, while the cost-savings analysis suggests an economic benefit, it does not account for potential long-term health care costs related to patient outcomes, including side-effects or recurrences. A comprehensive cost-effectiveness analysis is under way in the prospective DEFINITIVE (NCT06446882) clinical trial, incorporating management of side-effects, patient quality of life, and broader societal costs.
This study provides valuable real-world evidence supporting the clinical impact of the algorithm-powered HER2DX test in guiding treatment decisions for early-stage HER2-positive breast cancer. By offering precise prognostic and predictive information, HER2DX supports personalized treatment approaches, enhancing physician confidence and potentially improving patients’ quality of life and reducing cancer care costs. The ongoing prospective validation, including the DEFINITIVE (NCT06446882) and CompassHER2 pCR (EA1181, NCT04266249) trials, will further define the role of HER2DX in optimizing treatment strategies.17 Future studies should aim to validate HER2DX’s utility in diverse clinical settings, emphasizing its role in initial risk stratification at diagnosis. Additionally, research should explore combining HER2DX with emerging biomarkers designed to monitor therapy responsiveness and refine personalized cancer care. Given the multifaceted nature of HER2-positive breast cancer, it is essential to transition from a one-size-fits-all approach to a more tailored, precision medicine framework.
In conclusion, the HER2DX genomic assay has the potential to become an important tool in the personalized management of early-stage HER2-positive breast cancer guiding treatment intensity adjustments, enhancing physician confidence, and potentially reducing health care costs. Notably, this study is the first to prospectively demonstrate the feasibility of incorporating the HER2DX pCR likelihood score in selecting patients for a 3-month therapy regimen with single-agent taxane-based chemotherapy, showing that those identified for less intensive treatment achieve comparable pCR rates to patients receiving more intensive regimens. Further research, including long-term follow-up and comprehensive cost-effectiveness analyses, will be essential to solidify HER2DX’s role in the evolving treatment paradigm for HER2-positive breast cancer.
Acknowledgements
We thank the patients who participated in these trials, their families, and caregivers.
Funding
FS is supported by a Rio Hortega clinical scientist contract from the Instituto de Salud Carlos III (ISCIII) [grant number CM22/00073]. FBM received funding from Fundación científica AECC Ayudas Investigador AECC 2021 [grant number INVES21943BRAS].
Disclosure
OMS reports advisory/consulting fees from Reveal Genomics, Roche, and AstraZeneca; lecture fees from Daiichi Sankyo, Novartis, Pfizer, and Eisai; and travel expenses from Gilead and Novartis. LP is an employee of Reveal Genomics and has patents filed: PCT/EP2021/070788, EP23382703 and EP23383369. GV has received a speaker’s fee from MSD, Pfizer, GSK, and Pierre Fabre; has held an advisory role with AstraZeneca; and received consultant fees from Reveal Genomics. MMA is an employee of Reveal Genomics. PG reports part-time employment from Reveal Genomics. AP reports advisory and consulting fees from AstraZeneca, Roche, Pfizer, Novartis, Daiichi Sankyo, and Peptomyc; lecture fees from AstraZeneca, Roche, Novartis, and Daiichi Sankyo; institutional financial interests from AstraZeneca, Novartis, Roche, and Daiichi Sankyo; stockholder and employee of Reveal Genomics; patents filed PCT/EP2016/080056, PCT/EP2022/086493, PCT/EP2023/060810, EP23382703, and EP23383369. FBM reports part-time employment from Reveal Genomics, and has patents filed: PCT/EP2022/086493, PCT/EP2023/060810, EP23382703, and EP23383369. BC reports speaker fees from Veracyte and payment for educational events from Medsite and Novartis. PVG is a stockholder of Reveal Genomics. FS declares personal fees for educational events and/or materials from Gilead, Daiichi Sankyo, and Novartis; travel expenses from Gilead, Daiichi Sankyo, and Novartis; and advisory fees from Pfizer. E. Segui declares personal fees for educational events and/or material from Novartis, Pfizer, Eisai, and Daiichi Sankyo; advisory fees from Pfizer and Seagen; and travel/accommodation expenses from Gilead, Daiichi Sankyo, Novartis, and Lilly. WB is an employee of Reveal Genomics. All other authors have declared no conflicts of interest.
Supplementary Data
References
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