Breast Cancer Therapeutics and Biomarkers: Past, Present, and Future Approaches

Abstract

Breast cancer (BC) is the leading cause of cancer death in women and the second-most common cancer. An estimated 281 550 new cases of invasive BC will be diagnosed in women in the United States, and about 43 600 will die during 2021. Continual research has shed light on all disease areas, including tumor classification and biomarkers for diagnosis/prognosis. As research investigations evolve, new classes of drugs are emerging with potential benefits in BC treatment that are covered in this manuscript. The initial sections present updated classification and terminology used for diagnosis and prognosis, which leads to the following topics, discussing the past and present treatments available for BC. Our review will generate interest in exploring the complexity of the cell cycle and its association with cancer biology as part of the plethora of target factors toward developing newer drugs and effective therapeutic management of BC.

Keywords: Breast cancer; FDA; anti-cancer drug resistance; anti-cancer therapy; clinical trial; hormone receptor.

Figure 1.

Timeline of drug approvals by the FDA (1974-2020) and the respective main clinical indications to treat breast cancers. ABC indicates advanced breast cancer; AI, aromatase inhibitor; BC, breast cancer; BRCA, breast cancer gene; DCIS, ductal carcinoma in situ; EBC, early breast cancer; ER, estrogen receptor; FDA, Food and Drug Administration; HER2, human epidermal growth factor receptor 2; HR, hormone receptor; MBC, metastatic breast cancer; PD-L1, programed cell death ligand 1; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha; TNBC, triple-negative breast cancer.

Figure 2.

Timeline (2007-2020) of drugs under clinical trial toward the treatment of breast cancers and those that had their trials not completed. BC, breast cancer; BRCA, breast cancer gene; EBC, early breast cancer; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; HER2BAT, a study of HER2+ breast cancer patients with active brain metastases treated with afatinib & T-DM1 vs. T-DM1 alone; HR, hormone receptor; IL-2, interleukin-2; LORELEI, study of neoadjuvant letrozole + taselisib versus letrozole + placebo in post-menopausal women with breast cancer; BRAVO, trial of niraparib versus physician’s choice in HER2 negative, germline BRCA mutation-positive breast cancer patients; MBC, metastatic breast cancer; PHOEBE, pyrotinib plus capecitabine versus lapatinib plus capecitabine in patients with HER2+ metastatic breast cancer; POSEIDON, safety, efficacy and circulating tumor DNA response of the beta isoform-sparing PI3K inhibitor taselisib (GDC-0032) combined with tamoxifen in hormone receptor-positive metastatic breast cancer patients; SANDPIPER, a study of taselisib + fulvestrant versus placebo + fulvestrant in participants with advanced or metastatic breast cancer who have disease recurrence or progression during or after aromatase inhibitor therapy; TNBC, triple-negative breast cancer.

Figure 3.

Schematic diagram depicting sites of action of prominent drugs affecting principal pathways associated with breast cancer: (A) aromatase is the enzyme that catalyzes the conversion of androgens to estrogens. AIs inhibit the enzyme, therefore reducing the levels of estrogen which is needed for ER+ cancer cells growth. SERMs (ER antagonism) act as estrogen receptor antagonists in breast tissue. SERD (fulvestrant) is an ER antagonist leading to degradation and downregulation of ER. Zoledronate is a direct γδ T cell stimulator and also leads to accumulation of IPP in cancer cells leading to stimulation and activation of γδ T cell via γδ TCR recognition of phosphoantigens presented by butyrophilin 3A1 (BTN3A1) on the BC target cells and/or interaction of MICA with NKG2D. The immune response of γδ T cells can be via stimulatory and regulatory effects on other components of the immune system (secretion of cytokines or direct antigen presentation) and via direct cytotoxicity (through perforin-granzymes). Monoclonal antibodies: (B) PARP inhibitors lead to PARP inhibition and PARP trapping at sites of DNA damage. PARP acts as damage recognition repair protein for initiation of base excision repair of DNA SSB. PARP inhibition causes inability to repair and accumulation of SSB, leading to DSBs, which in cells with BRCA1/2 mutation cannot be fixed and accumulate ultimately triggering cell death. CDK4/6 inhibitors prevent DNA replication by arresting progression from the G1 to the S phase of the cell cycle. mAbs inhibit activation of the signaling pathway of HER involved in promoting cell growth and opposing apoptosis. Pertuzumab inhibits HER2 dimerization; trastuzumab prevents cleavage of the extracellular domain of the HER2 receptor, which leads to the formation of a truncated form of HER2 (p95HER2). p95HER2, which contains tyrosine kinase activity, can form constitutively active stable homodimers. PI3K inhibitor (alpelisib) selectively inhibits the p110α catalytic subunit of PI3K interrupting both AKT-dependent and AKT-independent PI3K signaling pathways. HDAC inhibitors block the enzyme, resulting in hyperacetylation of histones, relaxation of the chromatin, and allowing for higher transcription of the DNA. Tyrosine kinase inhibitors: tucatinib, lapatinib, neratinib are homologous of the adenosine triphosphate (ATP) that act by competing for the ATP-binding domain of protein kinases preventing phosphorylation and subsequent activation of the signal transduction pathways, leading to apoptosis and decreasing cellular proliferation. Moreover, TKIs target other kinase receptors due to the homology that they share with the EGFR family in the catalytic domain. (C) Anthracyclines: doxorubicin and epirubicin inhibit cancer through multiple pathways: to intercalate within DNA base pairs, causing breakage of DNA strands and inhibition of both DNA and RNA synthesis. Doxorubicin inhibits the enzyme topoisomerase II (TopII), causing DNA damage and induction of apoptosis—also cause ROS-mediated oxidative damage to DNA, further limiting DNA synthesis. Alkylating agents: cyclophosphamide (a nitrogen mustard compound), carboplatin and cisplatin (platinum-containing compounds) develop cytotoxic effects mainly due to substitution of alkyl groups for hydrogen atoms on DNA, resulting in the formation of cross-links within the DNA chain and thereby resulting in misreading of the DNA code and the inhibition of DNA, RNA, and protein synthesis and the triggering apoptosis in rapidly proliferating tumor cells. Taxanes: paclitaxel and docetaxel stabilize microtubules act mainly by binding to beta-tubulin, enhancing its proliferation and stabilizing its conformation. Doing so inhibits the proper assembly of microtubules into the mitotic spindle, arresting the cell cycling during G2/M. conferring enhanced survival. AI indicates aromatase inhibitor; AKT, serine/threonine-protein kinase 1 (also known as PKB); ATP, adenosine triphosphate; BC, breast cancer; BRCA, breast cancer gene; CDK, cyclin-dependent kinase; DSB, double-strand breaks; EGFR, epidermal growth factor receptor; ER, estrogen receptor; ERE, estrogen-responsive element; ERK, extracellular signal-regulated kinase; HAT, histone acetyl transferase; HDAC, histone deacetylase; HER2, human epidermal growth factor receptor 2; IPP, isopentenyl pyrophosphate; MHC, major histocompatibility complex; MICA, MHC Class I polypeptide-related sequence type A; mTOR, mechanistic target Of rapamycin; PARP, poly ADP-ribose polymerase; PI3K, phosphatidylinositol-4,5-bisphosphate 3-kinase; RE, responsive element; ROS, reactive oxygen species; SERD, selective estrogen receptor degrader; SERM, selective estrogen receptor modulator; SSB, single-strand break; TF, transcription factor; TIL, tumor-infiltrating lymphocytes; TKI, tyrosine kinase inhibitor; γδ TCR, gamma delta T cell receptor.