HER2DX Demonstrates Clinical Promise Among Patients With HER2-Positive Early Breast Cancer

Paolo Tarantino, MD, Dana-Farber Cancer Institute, Boston, Massachusetts, and Guillermo Villacampa, MS, Vall d'Hebron Institute of Oncology, Barcelona, Spain, discuss results from an individual patient-level meta-analysis which analyzed HER2DX, a genomic test to stratify risk, among patients with HER2-positive early breast cancer. 

Results demonstrated that HER2DX demonstrates clinical promise as a prognostic stratification tool in this patient population. 

Key Clinical Takeways

HER2-Positive Breast Cancer Advances

• HER2-positive disease (~20% of breast cancers) has shifted from highly aggressive to highly curable with anti-HER2 therapies.
• Expanded treatment toolkit includes trastuzumab, pertuzumab, neratinib, trastuzumab emtansine, and other antibody-drug conjugates (ADCs).
• Increasing focus on tailoring therapy intensity (de-escalation vs intensification) to balance efficacy and toxicity.

HER2DX Assay: Multigene Classifier

•  Integrates 27 genes across four domains: HER2 expression/addiction, tumor immunogenicity, proliferation, luminal differentiation.
• Combined with clinical factors (tumor size, T stage, nodal status) for enhanced prognostic and predictive accuracy.
• Provides both continuous score and dichotomized low- vs high-risk classification.

Meta-Analysis (Lancet Oncology)

• Patient-level pooled analysis of 11 trials, >2500 patients, median follow-up >6 years.
• Event-Free Survival (EFS):

Low-risk HER2DX → 6-year EFS ~93%.

High-risk HER2DX → 6-year EFS ~82% (Δ >10%).

• Prognostic capacity consistent across subgroups:

·       Stage I without adjuvant therapy.

·       Stage II/III with residual disease.

·       Patients achieving pathological complete response (pCR).

Exploratory Findings

• In high-risk HER2DX patients achieving pCR, pertuzumab + trastuzumab showed improved outcomes vs trastuzumab alone.
• Suggests role for HER2DX in guiding escalation with dual HER2 blockade in select subgroups.

Clinical Implications

• HER2DX complements clinical staging by identifying patients who may:
  • Require intensification despite low clinical risk.
  • Be spared overtreatment despite high clinical risk.
• Potential role in treatment sequencing decisions (e.g., neoadjuvant vs adjuvant).
• Supports precision medicine by stratifying recurrence risk more effectively than traditional clinical features alone.

Future Directions

• Ongoing prospective validation trials (quality of life and treatment tailoring).
• Expanding analyses in metastatic HER2-positive disease.
• Anticipated integration with results from upcoming studies (e.g., DESTINY-Breast11).

Transcript: 

Paolo Tarantino, MD: I am Paolo Tarantino, I'm a medical oncologist originally from Italy, now a clinical fellow at Dana-Farber Cancer Institute in Harvard. I'm super happy to be joined by Guillermo.

Guillermo Villacampa, MS: Thank you, Paolo, I'm Guillermo Villacampa, I'm a statistician working in Barcelona, Vall d'Hebron Institute of Oncology. Today we're going to explain our manuscript, the paper that we published recently in Lancet Oncology. 

Paolo Tarantino, MD: I was super glad to be part of this effort because I think it's extremely timely. We've seen over the last 10 years several changes in the way we treat HER2-positive breast cancer. HER2-positive breast cancer has been one of the greatest success stories in oncology, in breast oncology, but in overall oncology because anti-HER2 drugs have turned one of the most aggressive diseases in oncology, with the poorest prognosis, into one of the most curable diseases. And this happened over the course of 25 years, but really over the last 10 years we started learning that besides chemotherapy and trastuzumab we could utilize a second antibody, pertuzumab, to further boost response. And then we learned we could use a TKI [tyrosine kinase inhibitor], neratinib, we could use T-DM1 [trastuzumab emtansine] antibody drug conjugates, basically the toolkit for HER2-positive breast cancer, has expanded constantly. We're talking of about 20% of all breast cancer diagnoses that are found to be HER2-positive. This also has allowed to deescalate, reduce the amount of chemotherapy required to cure some patients which allow to spare some side effects but to keep the percentages of cure very high. 

In truth, with more tools available, one major question has become how to tailor all of these drugs, how to understand which patients require doublet chemo or single-agent chemo, which patients require dual anti-HER2 treatment, which patients require T-DM1, neratinib, etc. and this is why there's been a lot of attempts to try to develop biomarkers in this sense and I think one understanding over the past decade has been that a single biomarker may not be enough. We would need an integration of the knowledge that has been developed into several aspects of tumor biology, which has led them to what now we call HER2DX, which includes 27 genes, and Guillermo, correct me if I'm wrong, 27 genes related to 4 different aspects of breast cancer biology including HER2 expression and addiction, immunogenicity of the tumor proliferation and luminal differentiation. Putting all of this together with clinical features, such as the size of the tumor, the T and the nodal status, has proven to really be able to dissect the biology and the prognosis of HER2-positive breast cancer in a way we never were able to do before. And this really allows us to understand which patients require more, which patients require less. 

This has been mostly validated retrospective study to date, although prospective validations are ongoing and probably the most comprehensive retrospective study to date, which included a pooled analysis of 11 different studies and additional pieces of data available was conducted in this study, published a few weeks back on Lancet Oncology and led by Guillermo. I would like to leave it to Guillermo to basically review what has been done in the study and what were the findings of this pool analysis over HER2DX, Guillermo. 

Guillermo Villacampa, MS: Thank you Paolo. As explained, in analysis we conducted an individual patient level meta-analysis using data of studies with stage 1 to 3 HER2 breast cancer that incorporates HER2DX risk score, clinical information, and survival outcomes and we pull all of them all together. HER2DX, that was our main question to be answered, it was evaluated as a continuous score and as a risk group using the defined cutoffs and classifying tumors in high and low risk. 

In the study, the primary end point was event-free survival using standard statistical methods such as Kaplan-Meier and Cox model. After all the scaling phase and on the systematic review, we identified 11 studies that met inclusion criteria with over 2500 patients included in this study, with a median follow up time of more than 6 years. The first analysis that we conducted in this meta-analysis, in the specified meta-analysis, was to evaluate in univariable analysis the association between HER2DX and event-free survival and it was statistically significant in the univariable analysis but also in the multivariable analysis after adjusting by tumor stage, nodal stage, hormone receptor status and PCS status. Then, to be more precise we classified patients in low- and high-risk. Those with low risk have a 6-year event-free survival of 93% compared with 82% for patients with HER2DX risk score, high-risk score so we're representing a delta of more than 10%. 

We also conducted several sub analyses within clinically relevant subgroups. For example, in patients with stage 1 [disease] who did not receive adjuvant treatment, in patients with stage 2/3 with residual disease, those with pathological complete response at surgery, etcetera to observe that the prognostic capacity of the test, of HER2DX, consistent across all those groups. 

Finally, we also evaluated the role of pertuzumab as an adjuvant treatment in patients with pathological complete response at surgery according to HER2DX risk groups and amongst patients classified as HER2 high-risk, those receiving pertuzumab and trastuzumab have medically better outcomes compared with those receiving only trastuzumab. That was exploratory analyses, but also something meaningful that we found in the meta-analysis. 

With all of this, Paolo, what are your main conclusions about the impact of the results? 

Paolo Tarantino, MD: I think the results were awesome and quite expected somehow based on what we had seen in the past. We had the chance to contribute to this analysis with the APT dataset, with ATEMPT, with DAPHNe, with with several studies, some of which have shaped the way we treat HER2-positive breast cancer, but what the finding of this pooled analysis and each separate analysis I like is that clinical features alone may not be enough. 

Even stage 1 tumors, there are tumors smaller than 2 cm without nodal involvement, which are considered to be low-risk clinically, we still know that patients, if they have a high-risk HER2DX score, they may have a relevant risk of recurrence so there is an opportunity there with all the tools we have to try to optimize that and to change the way we treat these patients. Maybe we decide to utilize neoadjuvant treatment instead of adjuvant and see if the tumor responds and if to use adjuvant treatment. 

I think this analysis solidified what we know about HER2DX, meaning that it helps, besides clinical variables, to understand which patients are more likely to undergo pCR [pathological complete response], which patients have a high-risk of recurrence, despite having a low-risk, low clinical risk or the opposite. You have some tumors that are high clinical risk, large tumors with high level burden, but they're indolent tumors and not expected to undergo pCR and to recur, so there's a lot to learn here and I think also with the studies ongoing, especially the definitive trial, that is a prospective trial looking at finding an improvement in quality of life with HER2DX, I think there is a chance to implement this more regularly in clinical practice. 

There is already some clinical use of the assay because once again there is great interest, and I think this interest will grow even more with upcoming data. We know that at ESMO this year, DESTINY-Breast11 will report. We know that it's positive and will show that neoadjuvant and T-DXd followed by THP [paclitazel, trastuzumab, pertuzumab] is better than AC [doxorubicin-cyclophosphamide]-THP and there's many questions. It's a lot of treatment using an ADC and THP, are there patients needing this treatment– and I think in all of this scenario, HER2DX can really help much more than any biomarker that has been tested for HER2-positive disease. 

I would say I'm very optimistic for the future of both HER2-positive disease and patients with this disease and this biomarker, HER2DX is already helping, I think will help more and more to treat these patients. I think this is not going to be the last pooled analysis just because all the groups developing the biomarker, but also all Guillermo's efforts in this space are expanding in time. And so, I think we're having more and more analyses conducted not only in early, but also in metastatic HER2-positive breast cancer, so more to come stay tuned. Personally, it's a pleasure to contribute to this story and congratulations to Guillermo for leading this awesome analysis.

Source: 

Villacampa G, Pascual T, Tarantino P, et al. HER2DX and survival outcomes in early-stage HER2-positive breast cancer: an individual patient-level meta-analysis. Lancet Oncol. Published online: July 14, 2025. doi: 10.1016/S1470-2045(25)00276-1