The main obstacle for designing effective treatment approaches in breast cancer is the extensive and the characteristic heterogeneity of this tumor. The vast majority of critical genomic changes occurs during breast cancer progression, creating a significant variability within primary tumors as well as between the primary breast cancer and their metastases, a hypothesis have already demonstrated in retrospective studies (1). A clear example of this is the HER2-positive breast cancer. In these tumors, we can find all of the transcriptional subtypes of breast cancer, even the basal like or luminal A subtypes. Although the HER2-enriched is the most representative transcriptional subtype in the HER2-positive breast cancer, we can find it too in breast cancers with HER2-negative status. This intrinsic subtype shows a high expression of the HER2 and is associated with proliferation-related genes clusters, among other features. Therefore, two hypotheses can be suggested. First, the HER2 amplification can be a well-defined driver event present in all of the intrinsic subtypes, and not a subtype marker isolated. Secondly, HER2-enriched subtype can have a distinctive transcriptional landscape independent of HER2 amplification. In this review, we present an extensive revision about the last highlights and advances in clinical and genomic settings of the HER2-positive breast cancer and the HER2-enriched subtype, in an attempt to improving the knowledge of the underlying biology of both entities and to explaining the intrinsic heterogeneity of HER2-positive breast cancers.

Finally, although our study does have certain limitations, we believe that it can provide useful information and encouraging evidence that the routine use of bevacizumab as part of first-line treatment of patients with advanced cervical cancer may be associated with outcomes comparable with those obtained in GOG240 study.

Neoadjuvant Chemotherapy (NAC) in Breast Cancer (BC) has proved useful for the reduction in tumor burden prior to surgery, allowing for a more extensive breast preservation and the eradication of subjacent micrometastases. However, the impact on prognosis is highly dependent on the establishment of Pathological Complete Response (pCR), in particular for Triple Negative (TN) and Hormonal Receptor negative/Human Epidermal growth factor Receptor 2 positive (HR−/HER2+) subtypes. Several pCR predictors, such as PAM50, Integrative Cluster (IntClust), mutations in PI3KCA, or the Trastuzumab Risk model (TRAR), are useful molecular tools for estimating response to treatment and are prognostic. Major evolution events during BC NAC that feature the Residual Disease (RD) are the loss of HR and HER2, which are prognostic of bad outcome, and stemness and immune depletion-related gene expression aberrations. This dynamic nature of the determinants of response to BC NAC, together with the extensive heterogeneity of BC, raises the need to discern the individual and subtype-specific determinants of resistance. Moreover, refining the current approaches for a comprehensive monitoring of tumor evolution during treatment, RD, and eventual recurrences is essential for identifying new actionable alterations and the integral best management of the disease.

Invasive breast cancer (BC) is the most common cancer in women with a slightly increasing yearly incidence. BC immunohistochemical characterisation is a crucial tool to define the intrinsic nature of each tumour and personalise BC patients’ clinical management. In this regard, the characterisation of human epidermal growth factor receptor 2 (HER2) status guides physicians to treat with therapies tailored to this membrane receptor. Standardly, a tumour solid biopsy is therefore required, which is an invasive procedure and has difficulties to provide the complete molecular picture of the tumour. To complement these standard-of-care approaches, liquid biopsy is a validated methodology to obtain circulating tumour components such as circulating tumour DNA (ctDNA) and circulating tumour cells (CTCs) from body fluids in an easy-to-perform minimal-invasive manner. However, its clinical validity in cancer is still to be demonstrated. This review focusses on the utilisation of both ctDNA and CTCs in early and metastatic HER2-positive BC tumours. We discuss recently published studies deciphering the capacity of liquid biopsy to determine the response to neoadjuvant and adjuvant therapies as well as to predict patients’ outcomes.