Despite major advances for targeted treatment, 30-50% of advanced HER2-positive patients develop CNS metastases [52]. mTOR inhibitor Afinitor (everolimus) was approved in 2012 for metastatic HR-positive/HER-negative breast cancer in combination with an AI exemestane in patients whose malignancy experienced progressed despite treatment with letrozole or anastrozole [44]. In 2015, CDK 4/6 inhibitors that block phosphorylation of retinoblastoma protein Rb was approved. Inhibition of Rb phosphorylation prospects to cell cycle arrest and reverses endocrine resistance. The approved CDKs inhibitors, Sch-42495 racemate Ibrance (palbociclib), Kisqali (ribociclib), and Verzenio (abemaciclib) are to be used in combination with AI as initial hormone-based therapy in post-menopausal women or with fulvestrant in patients whose disease progressed even with hormonal therapy [45]. The timeline of approved CDK 4/6 inhibitors is usually summarized in Physique 2. In 2019, FDA approved Piqray (alpelisib) in combination with fulvestrant to treat postmenopausal women and men with advanced HR-positive/HER2-unfavorable breast cancer with a gene mutation that experienced occurred during or after treatment with AIs. Randomized SOLAR-I trial estimated improved progression-free survival (PFS) by 11 months with remarkable regularity [46]. Open in a separate window Physique 2 Timeline for the discovery of CDK4/6 inhibitors for HR-positive/HER2-unfavorable breast malignancy. aBC: Advanced breast malignancy; mBC: Metastatic breast malignancy; PM: Postmenopausal. Two novel therapies for endocrine resistance metastatic breast cancer include Capivasertib (AZD5363) in combination with fulvestrant and Histone deacetylase (HDAC) inhibitor in combination with exemestane. Capivasertib inhibits PI3K/AKT (E17K), one of the most frequently activated pathways in malignancy. Phase II FAKTION trial with capivasertib and fulvestrant showed significantly longer PFS (10.3 months) and improved overall survival (OS) by six months in patients with hormonal therapy-resistant breast cancer [47]. The second novel treatment option is usually HDAC inhibitor, Epidaza (tucidinostat), in combination with exemestane. HDAC inhibitor is an epigenetic therapy and can reverse the resistance to hormone therapy by increasing histone acetylation. The combination of steroid and AI exemestane is used to target the disease systemically. Sch-42495 racemate This combination has Isl1 shown encouraging Sch-42495 racemate anti-tumor activity in patients with metastatic HR-positive/HER-negative breast malignancy with PFS of 7.8 months compared to 3.8 months in placebo group that was given exemestane alone. Patients in this study experienced previously received hormonal therapy [48]. 2.2. Human Epidermal Growth Factor Receptor 2/neu Positive (HER2-Positive) Breast Malignancy One in five women with breast cancer have an amplified transcript of ERBB2/neu oncogene and/or overexpression of growth-promoting protein HER2 [49]. Elevated level of HER2 receptor has been correlated with aggressive disease concomitant with high occurrence rate and mortality [49]. The HER2 humanized antagonist mAb Herceptin (trastuzumab) binds to the extracellular domain name of HER2 and blocks its signaling. Multiple approval granted for trastuzumab is usually depicted in Physique 3. Although a successful treatment for breast cancer, intrinsic and acquired resistance post trastuzumab therapy has limited its use. Another HER2 antibody, pertuzumab, was developed as a neoadjuvant along with trastuzumab to reduce malignancy reoccurrence [50]. Interestingly, adding pertuzumab did not increase the rate of heart problems, which was the greatest concern with HER2-targeted therapy. In 2020, FDA Sch-42495 racemate approved a new fixed-dose combination of pertuzumab, trastuzumab, and hyaluronidaseCzzxf (phesgo) with chemotherapy as neoadjuvant therapy. The combination is now used as part of the total treatment regimen for locally advanced or early-stage HER2-positive malignancy and as adjuvant treatment for early-stage HER2-positive breast cancer with high risk of reoccurrence. This therapy is also approved in combination with docetaxel for HER-positive patients who had not received prior anti-HER2 therapy or chemotherapy [51]. Despite major improvements for targeted treatment, 30-50% of advanced HER2-positive patients develop CNS metastases [52]. The onset of symptomatic brain disease can be delayed by the administration of HER2 antibodies but their efficacy is hindered possibly due to the inability of the antibody to cross the blood-brain barrier (BBB) [53]. Open in a separate window Physique 3 Approval timeline of tastuzumab in combination with different drugs for different stages of breast malignancy. aBC: Advanced breast malignancy; mBC: Metastatic breast malignancy; Ebc: Early breast malignancy; PM: Postmenopausal. A significant breakthrough in the treatment of HER-positive breast cancer came from the discovery of kinase inhibitors. Kinase inhibitors can penetrate BBB with much higher efficacy compared to antibodies, hence they can be useful against brain metastasis [54]. The first approved tyrosine kinase inhibitor to treat HER2-positive metastatic breast malignancy was Tykerb (lapatinib), which was used in combination with capecitabine [52]. The addition of the chemotherapy agent capecitabine strongly enhanced the efficacy of Lapatinib. Nerlynx (neratinib), an irreversible pan-HER tyrosine kinase inhibitor was the first extended adjuvant therapy approved.