Molecular Characterization of ERα-positive and Triple Negative Breast Cancer

Abstract

Breast cancer, one of the most common of all cancers, is diagnosed in over 1.5 million people world-wide each year. Overall, treatments for breast cancer are considered relatively successful, however recurrence is a clinical problem of paramount importance. Molecular subtypes of breast cancer, defined as Luminal A, Luminal B, HER2-type and basal-like, are closely associated with the clinical markers ERα, PR and HER2 and have clinical implications. The basal-like subtype overlaps substantially with the so-called ‘triple negative’ (TN) histological subtype, which lacks ERα/PR expression and HER2 over-expression. ERα-positive breast cancers in both male and female breast cancers make up 70 to 80% of diagnoses, respectively. More rare subtypes, although smaller in overall proportion, still affect a substantial amount of people. For example, invasive lobular breast cancer, which makes up 15% of all breast cancer diagnoses, translates to around 225,000 total patients in a given year worldwide. Moreover, subgroups within the subtypes (and molecular differences therein) may be clinically important. Despite treatments for breast cancer available in the clinic today targeted to specific subtypes, initial poor response and recurrence remain a clinical problem. The fact that some patients do not respond to initial treatment suggests that treatment is simply not aimed at the correct node in the tumor’s signaling pathway. A prime example is the extremely poor prognosis for breast cancer patients whose tumors over-express HER2 prior to the introduction of HER2 targeted therapies. These patients now derive significant benefit from multiple lines of anti-HER2 therapy. This demonstrates subtype information for the primary tumor is imperative to guide the clinician in treatment decisions, as this is critical to the understanding of the likely prognosis of the patient. Notably, although the prognosis of ERα-positive breast cancer patients is relatively good compared to triple negative breast cancer and long-term survival remains around 75 to 80%, around 20-50% of these patients still recur after initial endocrine therapy. In addition, it has also been shown in BRCA1-deficient triple negative breast cancer that recurrence can follow initial successful PARP inhibitor treatment via different mechanisms. These examples illustrate the importance of prediction of response to specific treatments is also critical for successful durable patient response. Importantly, treatment-induced changes are largely unexplored in patient material although they are likely to grant researchers the most understanding of response and recurrence. With matched pre- and post-treatment tumor samples, we can learn of induced changes from treatment and the efficacy of the therapy for a particular group. The vast majority of deaths from breast cancer occur at the stage of metastasis, pointing to the importance of gaining knowledge about the molecular mechanisms both for poor outcome and initial response and acquired resistance to reduce chances of recurrence.