Breast Cancer: A Molecularly Heterogenous Disease Needing Subtype-Specific Treatments

Abstract

Breast cancer is the most commonly occurring cancer in women. There were over two-million new cases in world in 2018. It is the second leading cause of death from cancer in western countries. At the molecular level, breast cancer is a heterogeneous disease, which is characterized by high genomic instability evidenced by somatic gene mutations, copy number alterations, and chromosome structural rearrangements. The genomic instability is caused by defects in DNA damage repair, transcription, DNA replication, telomere maintenance and mitotic chromosome segregation. According to molecular features, breast cancers are subdivided in subtypes, according to activation of hormone receptors (estrogen receptor and progesterone receptor), of human epidermal growth factors receptor 2 (HER2), and or BRCA mutations. In-depth analyses of the molecular features of primary and metastatic breast cancer have shown the great heterogeneity of genetic alterations and their clonal evolution during disease development. These studies have contributed to identify a repertoire of numerous disease-causing genes that are altered through different mutational processes. While early-stage breast cancer is a curable disease in about 70% of patients, advanced breast cancer is largely incurable. However, molecular studies have contributed to develop new therapeutic approaches targeting HER2, CDK4/6, PI3K, or involving poly(ADP-ribose) polymerase inhibitors for BRCA mutation carriers and immunotherapy.

Keywords: biomarkers; breast cancer; cancer; cancer genomics; target therapy.

Figure 1

Genomic landscape of recurrent genetic alterations of breast cancer. Top Panel: recurrent genetic alterations in primary breast cancers subdivided according to intrinsic subtype. The data shown in the Figure are reported bt TCGA [46]. Bottom Panel: Most recurrent somatic mutations observed in primary and metastatic ER⁺/HER2^- breast cancers. The data shown in the Figure are reported by Angus et al. [47].

Figure 2

Hormone receptor status (top panel, left) and intrinsic subtype overall (top panel, right) or by hormone receptor status (middle panels) in a population of HER2-positive breast cancer patients undergoing neoadjuvant treatment with trastuzumab plus paclitaxel with or without lapatinib. The bottom panels report the rate of pathological complete response (pCR) observed in all HER2-positive patients (right panel) or in HER2 patients with a HER2-enriched expression subtype, subdivided according to hormonal receptor status (left panel). The data shown in this Figure are reported by Coarey et al. [85].

Figure 3

Genetic alterations observed in triple-negative breast cancers (TNBC). Top and middle panels: most recurrent somatic mutations (top panel) and copy number alterations (middle panel) observed in TNBC. The data shown are reported in Jiang et al. 2019 [119]. Bottom panel: most recurrent somatic mutations, subdivided according to functional gene groups, observed in estrogen receptor (ER)-negative breast cancers. The data shown are reported in Pereira et al. 2016 [49].

Figure 4

Landscape of somatic genetic alterations observed in mucinous breast cancer. Top panel: comparison of the frequency of most recurrent genetic alterations observed in pure mucinous breast cancers and ER⁺/HER2^- invasive ductal breast cancers. Bottom panel: comparison of the most frequent genetic alterations observed in pure mucinous and mixed breast cancers. The data shown in this Figure are reported by Pareja et al. 2019 [214].

Figure 5

Comparison of the most recurrent somatic mutations reported in male ER⁺/HER2^- breast cancers, compared to female ER⁺/HER2^- breast cancers. The data shown in this figure are reported by Piscuoglio et al. 2016 [257].