Introduction
Breast cancer is a major health issue and the most common cause of death among women worldwide. [Ed: I don’t think it is – see here.] In 2018 reported, estimated 2.1 million new cases of breast cancer were diagnosis and overall 6270000 women death from breast cancer disease. This number expected to increase to 24 million by 2035.The primary prognosis is good due to early detection of breast cancer and advances therapies. This devastating number warrants further research order to discover and establish new and improved therapies. One method for improving the outcome is through targeted combination therapy. It may be combination target with chemotherapy and radiotherapy. As breast cancer is among the most prevalent cancers worldwide and the disease itself is heterogeneous, a plenty of possible targets for targeted combination therapy has arisen in recent years.
Background
Breast cancer is an uncontrolled development of breast cells and it may be begin and malignant. It is most common among 60 to 70-year-old women. Breast cancer target therapies included drugs that prevent cancer growth by interfering with specifically particles that alter survival and proliferation of tumor cells. Breast cancer cells may overexpress receptors which, when activated can start downstream signal leading to the progression of genes for cancer cell proliferation, migration, angiogenesis and growth, survival and other fundamental cell cycle pathways.
The etiology of breast cancer is higher level of exposure to endogenous and exogenous hormone replaced hormone therapy. Factors association with estrogen and progesterone exposure such as Age at menarche and menopause, Breast feeding. And parity. Other factors are, family history of breast cancer, Ionizing radiation, Alcohol consumption and tobacco smoking, obesity, diet. Physical activity. 90% specific mutation of breast cancer occurs by hereditary gens like BRCA 1 and BRCR2. BRCA1 and BRCA2 tumor suppressor gene. BRCA2- is more aggressive in high-grade invasive ductal carcinomas.
Approximately 75% of Breast cancer is classification based on common heterogenous features such as hormone receptor positive, human epidermal growth factor receptor 2over expressing (HER2+) and triple negative. Breast cancer therapies are based on the classification decision. The purpose of studies is to assess the current target therapy and current combination therapy for HR positive, HER2 positive and triple negative breast cancer patients. therapies improved new development of drugs, the death rate, overall survival and recurrence rate.
Breast cancer Therapies;
Local therapies; Surgery
Surgery is the primary treatment of early invasive breast cancer. Over the last two decades, breast-conserving therapy was established as a viable alternative to modified radical mastectomy. Breast cancer surgery is removing the breast cancer with operation followed by Sentinel node biopsy, axillary lymph node dissection, BCS, Mastectomy and lumpectomy. Surgery is depending on the diagnosis, age and patients. Breast cancer surgery should be done alone or combine with chemotherapy and radiation therapy and hormone therapy.
The sentinel lymph-node biopsy (SLNB) has shown promise as a conservative approach to staging the axillary dissection of levels I and II lymph nodes and recommends 1cm margins. SLNB is significantly reduce the lymphedema the risk than completed axillary node dissection.
Axillary lymph-node status is most prognostic factor for breast cancer. Adjuvant systemic and regional therapy decisions are based on tumor size, clinical and pathological nodal status. The SENTINA and ACOSOG trails both represent the sentinel node and axillary node for women with node-positive breast cancer following neoadjuvant chemotherapy. The overall rate of false Negative result of lymph node biopsy was 24%,18%, and<5%, if only remove 1,2,3 sentinel lymph node respectively. Furthermore, the False negative rate was 10.8% if radiotracer and blue dye were used. Approximately 10%-30% begin of metastatic patients are treated with Breast conserving surgery after neoadjuvant therapy. Breast conserving surgery studies investigating the treatment of early breast cancer were survival with lumpectomy and mastectomy followed by irradiation. The output improved local surgical treatment, screening and diagnosis of nonpalpable cancer. Breast conserving surgery (BCS) surgery is not the optional choice for all women because it depends on the tumor size and inoperative breast cancer but it best for operable breast cancer patients. The combined therapies of chemo and radiotherapy was the best choice for tumor shrinkage in inoperable breast cancer patients, while operable patients were treated by adjuvant chemotherapy. The overall treatment was 4 to 24 weeks and 3 to 38 weeks for neoadjuvant and adjuvant respectively. Mastectomy is best decision for woman who had radiation to the affected side, distance from the tumor to the nipple of> 2.5 cm, Tumor size <5cm, her2 positive, negative ER and PR. The electing mastectomy was reconstruction during the surgical procedure. Mastectomy followed by immediate reconstruction of Skin sparing mastectomy along with suitable for small tumor, however, nipple sparing mastectomy was safe for in stage I and II invasive cancer.
Radiotherapy
Radiotherapy (RT) is primary treatment for early breast cancer and followed by Neoadjuvant and adjuvant therapy. RT before surgery to shrink the breast cancer cells. Adjuvant Radiotherapy is used after breast-conserving surgery and mastectomy. RT reduce local recurrence, improve survival rate and decrease death rate. External Radiation therapy is based on locoregional and regional node after mastectomy and breast conserving surgery.
The trail studies confirmed the combination of radiation with BCS or BCS single for clinical positive and Pathologic features. The combination therapy reduces recurrence rate compare with alone. Local recurrence after without BCS and only BCS radiotherapy is depends on the small tumor of size, age, negative lymph node, Margins and low grade for early stage of breast cancer women.
Regional node radiation therapy is reducing the risk of regional nodal disease for high risk of stage 1 and stage 3 breast cancer. The national prospective trail combination study with 1-3 include lymph node treatment with BCS to whole breast irradiation or regional nodal irradiation with whole breast irradiation. They showed regional nodal irradiation reduce the local regional recurrence rate was 5.2 %-3.2% as well as improved overall survival and disease-free survival rate that was 90%-92% and 84% -90% respectively.
Postmastectomy radiation is adjuvant treatment for women in high risk of local recurrence. The prospective postmastectomy radiation study was increased the survival rate and decreased in local regional recurrence. The meta-analysis study decreases death rate and recurrence who 10 years received chemotherapy with three positive lymph nodes after mastectomy and axillary dissection. Hypofractionated whole breast radiation is standard therapy for postlumpectomy. Accelerated partial breast irradiation therapy used for near the primary tumor and early stage breast cancer
Chemotherapy
Chemotherapy is first setting of anticancer treatment for breast cancer and chemotherapy regimens followed by neoadjuvant and adjuvant and advance disease of breast cancer along with it may be used Sigle or combination of drugs. The combination of dugs significantly improves over-survival rate, DFS and pathologic complete response (pCR) as well as trastuzumab comparing to single agent. The growth inhibitors effects of chemotherapeutics Cisplatin ,5-Fu (5-Flurouracil) and docetaxel against the breast cancer cells. (TNF-alpha sensitizes)
Adjuvant chemotherapy treatment is increased overall survival with combination of endocrine therapy and anthracycline chemotherapy for early stage and inoperable breast cancer. Adjuvant clinical trial study was used combination with capecitabine to epirubicin and docetaxel for early stage of breast cancer. Combination therapy significantly improved PCR rate. Neoadjuvant is first line treatment for invasive breast cancer. The combination clinical trial represented capecitabine to epirubicin and docetaxel and outcome developed the pCR. The phase 3 studies reported showed HER2 overexpress tumor activity with combination of nab-paclitaxel plus trastuzumab for HER2 positive metastatic of breast cancer.
CURRENT TREATMENT REGIMENS AND NOVEL THERAPIES ACCORDING TO SUBTYPE OF BREAST CANCER
Hormone receptor Positive breast cancer
Endocrine therapy is a major treatment for hormone receptor positive breast cancer in developing countries and HR positive breast cancer disease is developed in premenopausal women. Endocrine therapy is which blocking the effects of hormone and to prevent the risk of recurrences.
Current Treatment Regimens
Currently used drugs include (I) tamoxifen (block estrogen receptors) is gold standard treatment for preoperative (neoadjuvant) and postoperative (adjuvant) in advance metastatic.(ii) aromatase inhibitors (letrozole(1st line Rx), anastrozole, and exemestane), which suppress the conversion of androgens to estrogens, thus leading to reducing estrogen level (iii) fulvestrant ; (2nd line Rx) a selective Estrogen receptor degrader, which is suitable for metastatic breast cancer patients refractory to previous hormonal therapy.
Cyclin-Dependent Kinases 4 and 6 (CDK4/6) Inhibitors
ER inhibition therapy is best choice treatment for ER positive breast cancer patients. CDK4/6 regulate cell cycle promote via cross interaction with cyclin D1. ER activation G1 to S cell cycle, which ultimately leads to cell division. Activation of Rb phosphorylation development of endocrine resistance. Palbociclib, Ribociclib, and Abemaciclib CDK inhibitors used in advance breast cancer patients
The second phase studies show the Palbociclib and letrozole was FDA approved in combination with a non-steroidal aromatase inhibitor as first-line New treatment of post-menopausal women with ER+ and HER2 negative advanced BC. The results significantly improved the median PFS by 7.5 months to 26.1 months respectively, compared to letrozole alone.
The investigation studies show the combination with Palbociclib and fulvestrant in HR+/HER2− advanced BC. they show significantly longer median PFS by 9.2months and 3.8 months, respectively, compared to fulvestrant alone as well as the studies determine the better quality of life rather than fulvestrant single.
The phase 3 studies show the combination between the Ribociclib and leterozole was first line treatment with ER positive and HER2 negative advanced BC in postmenopausal women. The results showed that Ribociclib and leterozole significantly improved PFS compared with letrozole alone.
The phase 3 combination therapy was conducted on abemaciclib with fulvestrant or without for HR positive and HER2negative advanced breast cancer who had improvement with endocrine therapy. The median PFS was 16.4 months and 9.3 months respectively, compared with fulvestrant alone. The study represented combination of first setting treatment with abemaciclib plus letrozole in advanced HR positive breast cancer in postmenopausal women. The Result was the significant improved in PFS.
Inhibitors Targeting Phosphatidylinositol 3-Kinase (PI3K)/Protein Kinase B (Akt)/Mammalian Target of Rapamycin (mTOR) Pathway
Activation of the P13K/AKT/mTOR signaling pathway produces endocrine resistance and combination target therapies restore the sensitivity. Over 70% of breast cancer pathway activated sub unit of P13K mutation. PI3k inhibitors and letrozole, anastozole, exemestane (Aromatase inhibitors) combination used for second line treatment with HR positive and HER negative advance breast cancer. Buparlisb, pictilisib, pilaralisib, alpeisib and taselisib pan-1 inhibitors are significantly improved PFS and efficacy due to low toxicity. While, voxtalisib (mTOR) not benefit in clinical used because it produces high toxicity.
Buparlisib is pan1 -PI3K inhibitors that inhibitors PI3K isoforms. The belle 2 study investigation was on combination of buparlisib plus fulvestrant or without fulvestrant for HR positive and HER2 negative advance breast cancer in post-menopausal women. The combination treatment improved the median PFS and similar toxicity compare as fulvestrant alone. The second study combination of buparlisib with letrozole for HR positive metastatic breast cancer in postmenopausal women.
Pictilisib is small oral inhibitors. The phase 2 study was combined with pictilisib and fulvestrant for ER positive and HER2 negative advanced in post-menopausal female with and without P13K mutation. The results showed PFS non-significant different between with or alone PIK3 mutation. The combination of neoadjuvant therapy with Pictilisib and taselisib with letrozole or anastrozole for HR positive in early breast cancer. The outcome was improved the antitumor effects.
mTOR recently clinical approved study was evaluated on the combination of everolimus with exemestane or exemestance alone after failure of aromatase inhibitors (letrozole or anastrozole) for HR positive advance in postmenopausal women. They significantly improved PFS and objective response rate. The combination median PFS was 7.8 months compare with exemestane alone had 3.2 months.
Entinostat and vorinostat are Histone Deacetylase (HDAC) Inhibitors. HDAC inhibitors activated signal pathways and overexpression Estrogen receptor alpha (ERα) and aromatase. Ongoing phase 2 study on entinostat and vorinostat plus exemestane or tamoxifen for HR positive advance breast cancer. The results comparison with or without exemestane or tamoxifen and upgrade the antitumor activities.
HER2 positive breast cancer
Current Treatment Regimens
Target agent was approved by FDA and it may be used to alone or in combination with standard chemotherapy treatment for HER2-positive breast cancer. HER2 gene assessed the protein overexpression and benefit from anti-HER2 therapy for breast cancer patients.
Target agents Action
Trastuzumab anti-her2 monoclonal antibody that binds with specific protein
Ado-trastuzumab emtansine, An antibody-cytotoxic agent conjugate consisting of trastuzmab linked to a small-molecule microtubule inhibitor (emtansine)
Lapatinib, A dual tyrosine kinase inhibitor (TKI) that interrupts both her2 and EGFR pathways
Pertuzumab anti-her2 monoclonal antibody with a different binding site on her2 than trastuzumab
Neratinib It is a tyrosine kinase inhibitor and used for treat the early stage of breast cancer in which HER2 is overexpressed, who had 1 year received treatment with trastuzumab.
Table 1: Table show the current target agents
Neoadjuvant treatment combines with anti-HER2 targeted therapy and chemotherapy is currently standard regimen for early-stage HER2-positive breast cancer. Neoadjuvant therapies followed by surgery, radiotherapy and HER2-targeted therapy. Endocrine adjuvant therapy depends on the cancer biology. HER2-targeted therapies increased the overall survival (OS) with HER2 positive advanced BC patients.
Novel Therapies
Trastuzumab is first line clinical used therapy for HER2 positive breast cancer and trastuzumab adapted immunity system. Treatment outcome was improved by targeted agent and immunotherapies.
The phase 3 investigation studies show the combination with trastuzumab and standard chemotherapy ((paclitaxel or anthracycline/cyclophosphamide) as the first line treatment for HER2-positive metastatic breast cancer who received standard chemotherapy with or without trastuzumab. The combination results were improved median overall survival response rates and extended time to progression
The report show combination of trastuzumab and docetaxel with pertuzumab alone or combined with pertuzumab and approved with FDA in the first line treatment with HER2 positive MBC patients. They show the 3-combination therapy significantly increased overall survival and PFS contrast with docetaxel and trastuzumab.
The pivotal phase III trial showed combination used of anthracycline, taxane and trastuzumab who receive capecitabine plus lapatinib or capecitabine alone who treated with her positive metastatic. The lapatinib to capecitabine was significantly improved increased extended time to progression (TTP 8.4 vs. 4.4 months) Compared as capecitabine alone.
The EGF30001 phase III evaluation the combination with lapatinib plus paclitaxel with paclitaxel alone in the first line treatment with HER+ BREAST CANCER metastasis. The combined resulted was significant increase response rate, event-free survival, and extended time rather than without paclitaxel therapy.
PI3K/Akt/mTOR Inhibitors
PI3K/Akt/mTOR inhibitors combination with trastuzumab and used for pretreated her2 positive breast cancer patients. Trastuzmab work through binding with her2 receptors and downregulate growths cells.
Pan-class I PI3K inhibitors therapy (buparlisib and pilaralisib) used for her2 positive untreated in advance breast cancer patients. The inhibitors were combined with paclitaxel, lapatinib, and trastuzumab. They improved effectiveness in pretreated HER2 positive BC patients
AKT inhibitor combined with trastuzumab and paclitaxel therapy. They improved antitumor activities. Everolimus, ridaforolimus and sirolimus are oral small-molecule inhibitor of mTOR. Ridaforolimus and sirolimus are new mTOR inhibitor with trastuzumab. Combination therapy with mTOR inhibitor and trastuzumab was more effective than single agent therapy. The clinical results were no significant improved with used of everolimus with trastuzumab and vinorelbine in pretreated HER positive breast cancer patients. The combination of phase Ib study was conducted on everolimus with vinorelbine and trastuzumab and second studies was study combine with everolimus plus paclitaxel and trastuzumab in patients with trastuzumab-resistant breast cancer. The overall response rate was 19% and 44% respectively.
Inhibitors Targeting HER-Family Receptors
The HER family of receptors (ERBB) are available on the cell surface as monomers, without activation of ligand. Growth ligands of her2 family receptors depends on HER1 (EGFR), HER2, HER3 and HER4 and inhibitors are influence anticancer effects than trastuzumab alone. They are formed of heterodimers and homodimers. Heterodimerization are more active and overexpression through HER2/ her3 as compared to homodimerization, have been reported to cause trastuzumab resistance.
Multi-Targeting TKIs
Neratinib, an irreversible orally administered or active small molecule tyrosine kinase inhibitor (TKI) of HER1/HER2/HER4. The phase 3 clinical study was drastically progressed after 2-year invasive disease-free survival rate had 94% after chemotherapy and trastuzumab adjuvant therapy with HER2 positive metastatic breast cancer in women.
Lapatinib
TKI is first line treatment with metastatic positive breast cancer that target with HER2 and EGFR.Lapatinib progressed the dual inhibitors such as HER1 and HER 2. The combination of reserved used of lapatinib and trastuzumab for the HER2 positive metastatic of breast cancer who cannot tolerate with cytotoxic chemotherapy. Thus, clinical activity shows inactive and excessive toxicity compare with trastuzumab. Lapatinib and letrozole was effective therapy for ER + and HER+ breast tumor.
Monoclonal Antibodies
Pertuzumab/ Patritumab (anti-HER2/anti-HER3 monoclonal antibody) monoclonal antibody directed against the extracellular domain of HER2 binding to various site of trastuzumab. Preclinical studies improved the antitumor activity and able to inhibit the formation HER2/ HER3 heterodimers. Margetuximab is new antibody that target her2 positive express tumor cells
Maggetuximab and trastuzmab mechanism are used to treat HER2 positive tumor through dependent fab process antibody-dependent cell-mediated cytotoxicity. The phase II trial investigation with conjunction of pertuzumab and trastuzumab for her2 positive metastatic breast cancer. Trastuzmab combination was remarkable improvement that was 24.2% of Response rate and 50% of clinical benefit.
Antibody-Drug Conjugate (ADC)
Ado-Trastuzumab emtansine(T-DM1) is antibody-drug are combination with trastuzumab. T-DM1 new cytotoxic agent reduce toxicity and enhance their efficacy. The phase 3 study was conducted on combination with T-DM1 and trastuzumab who had auxiliary lymph node following adjuvant therapy with HER2 positive breast cancer for women. The outcome enhanced clinical efficacy of T-DM1.
MARIANNE study showed the T-DMI was first line treatment with pertuzumab alone or combined with trastuzumab-taxane for HER+ breast cancer. Ado-Trastuzumab emtansine is non-inferior to trastuzumab and taxane and they showed was best tolerability.
Farnesyl Transferase Inhibitors (FTI)
Lonafarnib and tipifarnib both are a Farnesyltransferase inhibitors (FTIs), inhibit the farnesylation of proteins (RAS). Ras mutations incidence was less than 2% in breast carcinomas. Ras protein is activated the downstream effectors lead to overexpression of upstream signaling molecules. The phase I trial represented combination of lonafarnib to trastuzumab with paclitaxel in HER2+ advanced BC. Combination therapy was improved antitumor activities and efficacy. The study was conducted on used of tipifarnib with capecitabine, 5-fluorouracil and Herceptin in metastatic breast cancer patients.
Immunotherapy
The cancer immunotherapy is preventing cancer cells and maintain the ability of the immune system by various methods of immune response. These are immunotherapeutic approaches in breast cancer such as therapeutic cancer vaccines (developed antitumor response), immune checkpoint blockade therapies (monoclonal antibodies are restoring the activity of cell-mediated immunity and promote antitumor response) and adoptive T cell transfer immunotherapy (regulated the proliferation cells and activation of T cells).
Therapeutic cancer vaccines and CTLs
HER2/nue is a therapeutic target for peptide-based cancer vaccines. Nelipepimut-S is a nine amino acid peptide from the extracellular domain of HER2/neu. It is binds with human leukocyte antigens A2 and A3 molecules on antigen-presenting cells which then stimulate cytotoxic T lymphocytes (CTLs) to recognize and lyse HER2-expressing tumor cells. The Immune therapy prevent recurrence of breast cancer patients.
The phase 2 studies investigation combination with HER2 peptide-based intracellular domain protein (nelipepimut-S vaccine) plus trastuzumab with metastatic HER2-overexpressing patients. The combination study was conducted on Ipilimumab with cryoablation or without cryoablation in early-stage breast cancer patients. The outcome was improved with activated effector T cells who received ipilimumab treatment alone or in combination with cryoablation.
The adjuvant was combination therapy with recombinant HER2 protein plus trastuzmab and lapatinib for HER positive breast cancer in advance. The combination therapy significantly improved extended survival rate and succeeded in trastuzumab refractory for HER2-overexpressing breast tumor.
successful for HER2-overexpressing breast tumor refractory to trastuzumab.
The study is evaluating the combination of HER2-pulsed DC1 vaccine with trastuzumab and pertuzumab with HER2-positive breast cancer patients with ductal carcinoma in situ DCIS patients. The phase 3 study was combination trastuzumab and vinorelbine who received autologous DC vaccine therapy with her2 positive breast cancer metastasis and locally recurrences.
Combinations of immunotherapy and targeted therapy
Phase II PANACEA combination study was evaluated with pembrolizumab and trastuzumab in HER2-positive metastatic breast cancer patients who previous received trastuzumab. Second combination study was conducted on atorolimumab with paclitaxel, trastuzumab, and pertuzumab in HER2 positive and metastatic patients. The assessed the overall survival and antitumor activity.
Triple Negative Breast Cancer; Current Treatment Regimens
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