A discussion session at the virtual San Antonio Breast Cancer Symposium explored biological features in HER2-positive disease that are linked to clinical outcomes, such as pathological complete response and survival.
In this video, courtesy of the Video Journal of Hematological Oncology (VJHemOnc), Aleix Prat, MD, PhD, of the Hospital Clinic Barcelona in Spain, provides an overview of his talk on biological heterogeneity in HER2-positive breast cancer and predicting outcomes.
Following is a transcript of his remarks:
So there’s no doubt in 2021 that HER2-positive disease is biologically heterogenous. It’s been now a decade of studies. In my talk, I summarize what are the main features that not only characterize HER2-positive disease into different biologically relevant groups, but also biological features that are linked to clinical outcomes. And in particular, one particular biological aspect that is important in HER2-positive disease is intrinsic subtype, defined by RNA expression.
It’s been now 10 years of studying that, not all HER2-positive disease is not always HER2 enriched. It can be luminal A, it can be luminal B, it can even be basal, like a triple-negative kind. And what the data shows is that these tumors, HER2-positive, and if they are HER2 enriched, they respond more to anti-HER2-based therapies, whether it’s trastuzumab with chemo or just anti-HER2 therapy without chemo, as has been shown by trials looking at lapatinib and trastuzumab, for example, without chemo.
And the question is why? And I think when we look at intrinsic subtype, what we’re looking at really is the phenotype of these tumor cells, how is the pathway activated? Whereas when we only look at HER2 by itself, we are looking at the target, we’re looking at the receptor, we’re just looking at one particular feature. And actually, it’s when we integrate both the target, the expression of the receptor together with the signaling pathway activation, is then when we identify these patients that respond the most to anti-HER2-based therapy. So definitely intrinsic subtype is there and potentially could be used in the clinic in the near future.
The other aspect I think it’s important also to highlight is the immune microenvironment. HER2-positive disease in general tends to be inflamed. You see TILs [tumor-infiltrating lymphocytes] in a large proportion of patients. We now know that this feature is linked to more response to neoadjuvant anti-HER2-based therapy, but not only that, this is linked also to long-term outcomes.
So now we’re starting to have studies that look at different features, integrating all of that, because usually we tend to evaluate one biomarker by one biomarker. Now we are starting to integrate immune features, tumor-cell features, and clinical outcomes. And one particular example is the CLGB40601 trial that performed gene expression analysis and linked these features with probability of achieving pathological complete response, and also relapse-free survival. And what’s interesting is that it’s easier to predict pathological complete response than long-term outcome. That there are features that predict response to neoadjuvant therapy, but do not predict long-term outcome. And the opposite — there are biological features that are linked to clinical outcomes, survival, but not pathological complete response.
I think now we’re starting to tease out how these biological features play a role and potentially in the future. And that’s my last message of the presentation, is that we will have to integrate many of these features altogether into multi-feature-based predictors to define who will respond, who will benefit, and potentially design trials to escalate or de-escalate therapy in this particular context.