High rates of inherent primary resistance to the humanized
monoclonal antibody trastuzumab (
Herceptin) are frequent among HER2 gene-amplified
breast carcinomas in both metastatic and adjuvant settings. The clinical efficacy of
trastuzumab is highly correlated with its ability to specifically and efficiently target HER2-driven populations of
breast cancer stem cells (CSCs). Intriguingly, many of the possible mechanisms by which
cancer cells escape
trastuzumab involve many of the same
biomarkers that have been implicated in the biology of CS-like tumor-initiating cells. In the traditional, one-way hierarchy of CSCs in which all
cancer cells descend from special self-renewing CSCs, HER2-positive CSCs can occur solely by self-renewal. Therefore, by targeting CSC self-renewal and resistance,
trastuzumab is expected to induce
tumor shrinkage and further reduce
breast cancer recurrence rates when used alongside traditional
therapies. In a new, alternate model, more differentiated non-stem
cancer cells can revert to
trastuzumab-refractory, CS-like cells via the activation of intrinsic or microenvironmental paths-to-stemness, such as the epithelial-to-mesenchymal transition (EMT). Alternatively, stochastic transitions of
trastuzumab-responsive CSCs might also give rise to non-CSC cellular states that lack major attributes of CSCs and, therefore, can remain "hidden" from
trastuzumab activity. Here, we hypothesize that a better understanding of the CSC/non-CSC social structure within HER2-overexpressing
breast carcinomas is critical for
trastuzumab-based treatment decisions in the clinic. First, we decipher the
biological significance of CSC features and the EMT on the molecular effects and efficacy of
trastuzumab in HER2-positive
breast cancer cells. Second, we reinterpret the genetic heterogeneity that differentiates
trastuzumab-responders from non-responders in terms of CSC cellular states. Finally, we propose that novel predictive approaches aimed at better forecasting early
tumor responses to
trastuzumab should identify
biological determinants that causally underlie the intrinsic flexibility of HER2-positive CSCs to "enter" into or "exit" from
trastuzumab-sensitive states. An accurate integration of CSC cellular states and EMT-related
biomarkers with the currently available
breast cancer molecular taxonomy may significantly improve our ability to make a priori decisions about whether patients belonging to HER2 subtypes differentially enriched with a "mesenchymal transition signature" (e.g.,
luminal/HER2 vs. basal/HER2) would distinctly benefit from
trastuzumab-based
therapy ab initio.