Novel Therapies and Emerging Actives for Treatment of Luminal Breast Cancer

Preeti Tanaji Mane¹*,Balaji Sopanrao Wakure², Pravin Shridhar Wakte¹

¹University Department of Chemical Technology, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad - 431004, Maharashtra, India.

²Vilasrao Deshmukh Foundation, Group of Institutions, VDF School of Pharmacy,

Latur - 413 531, Maharashtra, India.

*Corresponding Author E-mail: preetimane23@gmail.com

ABSTRACT:

Breast cancer, being the most common cancer worldwide, has threatened women health tragically. Conventionally, it is classified into three types as hormone receptor positive, HER2 positive, and triple-negative disease. Standard treatments for this neoplasm lack desired therapeutic efficacy and is associated with troublesome side effects. This irrational response is attributed to the molecular heterogenicity and biological diverse nature of tumors. So, neoteric therapies are being developed continuously in the quest to obtain an improved safety profile and therapeutic efficacy. The novel approaches primarily target key components involved in cancer cell regulating pathways like cell cycle progression, cell proliferation, angiogenesis, apoptosis, DNA repair mechanisms, immunomodulation, metastasis, etc. Targeted therapies are also designed to evade resistance mechanisms involved in chemotherapy resistance. The clinical trials are too being devised to hand-pick the appropriate combination of chemical actives to achieve the projected synergism while maintaining safety criterion. For the treatment of all types of breast cancer, this review highlights standard medicines and focuses on novel targets, their involvement in cancer pathogenesis, experimental molecules being explored, their stage of development, and a description of relevant clinical trial data. All these innovative therapies have given rise to a new hope of finding a revolutionary treatment for the management of breast cancer.

KEYWORDS: Breast cancer, Hormone receptor positive, Novel therapy, Clinical trials, New drugs.

INTRODUCTION:

The reports of Globocan 2021 highlight that breast cancer have surpassed lung cancer and has emerged as the most common cancer worldwide. It is also the second leading cause of death amongst women¹. Therefore, thunderous research is being carried out to treat this condition safely and effectively. Established treatment for breast cancer lacks desired therapeutic efficacy and is associated with numerous side effects. Also, selection of an accurate therapeutic option during treatment is necessary as it ultimately decides the fate of patient².

This selection process is based on careful examination of patient, molecular nature of tumor and critical evaluation of biomarkers like hormones, genes, subsequent proteins and receptors. All this information, taken altogether, helps the oncologist choose the best therapeutic agent or their combination to effectively treat or control the malignancy³. The underlying causes of malignancy can now be speculated due to recent advances in gene expression analysis, and novel agents as well as therapies are emerging to treat the condition more specifically and effectively^4,5. All of these innovative therapies, as well as their foundations, are highlighted in this review which will help oncologists and concerned personnel to understand the current standing of novel anti-neoplastic agents in treatment of breast cancer.

Classification of Breast Cancer:

Breast cancer (BC) is classified into different types based on the cell origin, molecular basis, invasiveness, and staging. Yet, the molecular classification of breast cancer portrays a major role in deciding suitable therapy for malignancy. Based on the receptor involvement, BC is majorly classified into five types, these classes along with their major traits are depicted in the Table 1.

Therapeutic Regimen For Luminal Breast Cancer:

The highly prevalent molecular subtype of BC affecting women is luminal cancer. The preferred therapeutic regimen for this type of cancer includes the use of hormonal therapy, which acts by reducing hormonal levels or by interfering with their production mechanism or by blocking their interaction with the receptor or by degrading the receptor itself. All these anti-estrogenic drugs that are currently available on the market for therapeutic use are (i) selective estrogen receptor modulator (Tamoxifen), (ii) selective estrogen receptor degrader (Fulvestrant), (iii) aromatase inhibitors (Exemestane, Anastrazole), (iv) GRH analogues (Goserelin, Buserelin, Triptorelin, Leuprolide). All these drugs are used in combination in order to obtain better antitumor efficacy⁸. Still, some cases do not respond effectively to this endocrine therapy and develop drug resistance¹¹. This phenomenon of resistance can be attributed to the genetic alterations in estrogen receptors (ER) or the altered operation of signaling pathways involved. Hence, novel therapies are emerging that target the crucial mediators (enzymes/proteins) involved in the concerned pathway^9,10. Such classes of therapeutic agents are discussed below.

CDK inhibitors:

Cyclin dependent kinase 4 and Cyclin dependent kinase 6 (CDKs), by interacting with cyclin D, regulates the progression of the cell cycle and therefore cell proliferation. These enzymes are mainly required for the transition of the cell to S phase from G1 phase. Therefore, using CDK inhibitors arrests the cell cycle at this point. The drugs acting via this mechanism include Palbociclib, Ribociclib, and Abemaciclib. The efficacy of treatment is more pronounced in HR+ breast cancers when it is taken in combination with endocrine therapy. These drugs got approval in 2015 by USFDA for HR+ advanced and metastatic BC in Palbociclib combination with aromatase inhibitors. In 2017, Ribociclib as well as Abemaciclib were approved by the USFDA and EMA for the same purpose. Clinical studies have proven the efficiency of CDK inhibitors as the beneficial antitumor agents as they have increased progression free survival (PFS) of breast cancer cases¹¹.

PI3K inhibitors:

The deviant instigation the of PI3K-Akt-mTOR pathway occurs in about 70% of BC patients, and it has a critical role in developing drug resistance in HR+ BC patients. Mutation or amplification of PTEN or PI3KCA genes is mainly responsible for hyperactivation of this pathway, promoting cancer cell growth and angiogenesis. The use of PI3K inhibitors, restricts this amplification phenomenon and helps to control the progress of the disease, though modestly¹². A number of chemical entities are developed that act by inhibiting PI3K like Alpilicib, Bupralisib, Copanlisib, Idelalisib, Pilaralisib, Picitlisib, Taselisib and many more. However, due to off-target side effects and other toxicities, they are either withdrawn from further studies or are under further clinical investigation¹³. Only one drug belonging to this class, Alpelicib, has been approved by the USFDA in May 2019, for treating hormone receptor positive (HR+) advanced or metastatic breast cancer in post-menopausal women in combination with Fulvestrant. This permission was granted depending on the findings of the SOLAR-I trial, which showcased that the drug inhibited p110 isoform in a powerful and specific manner¹⁴.

Bupralisib was withdrawn from further studies after the results of several trials in combination with suitable standard drugs due to the unmanageable toxicity as evident from the BELLE-II, III, and BELLE-IV trials^15,16. Taselisib has shown promising preclinical results. So, a phase-II clinical trial, LORELEI, was conducted using Taselisib with letrozole and placebo-letrozole. The findings of the study revealed moderate clinical benefits and toxicities associated with the Taselisib-letrozole combination¹⁷.

Pictilisib, another favorably specific class I pan-PI3K inhibitor, was found to show promising anticancer action in cell lines of BC. Phase-II trials “PEGGY” of Pictilisib were conducted to check its efficiency with Paclitaxel, considering the duo will exhibit a powerful effect. However, no significant outcome of treatment was seen in mBC as well as PIK3CA-mutated tumor carrying patients¹⁸.

Copanlicib has also shown potent cell growth inhibition in ER+ cell lines, and the effect was further pronounced when it was combined with Letrozole. The study confirmed that along-with inhibition of the PI3CK pathway, Copanlicib also inhibit the RAS-MAPK pathway¹⁹. Currently, Copanlicib is undergoing a phase-I/II trial (NCT03128619) to check its efficacy in combination with Palbociclib and Letrozole²⁰. It is also under phase-I/II investigation (NCT03803761) in combination with Fulvestrant to study its efficacy in ER+, HER- advanced breast cancer²¹.

Another, GDC-0077, is a persuasive and specific PI3Kα inhibitor that has shown tremendous anticancer action in PIK3CA-mutant models of BC. The studies carried out in a PIK3CA-mutant human BC xenograft model demonstrated enhanced anticancer activity with combination of GDC-0077 and Fulvestrant or Palbociclib, a CDK4/6 inhibitor²². Currently, INAVO120, a phase III clinical trial, is being performed to assess the potency and toxicity of this active with Palbociclib and Fulvestrant in PIK3CA mutant, HR+, HER2-ve metastatic BC patients²².

Akt is also one of the most important mediators of the PI3K-Akt-mTOR pathway. Therefore, an Akt inhibitor can hamper the pathway progression, thereby, inhibiting neoplasm progression. One of the potent AKT inhibitors developed is Capivasertib (AZD5363) which can selectively inhibit all the three isoforms of AKT. The drug has shown promising anticancer action along-with Fulvestrant in both hormone-sensitive and hormone-resistant ER+ breast cancer models. The study was further advanced with human trials, FAKTION (phase II clinical trial), to assess this combination in postmenopausal females with AI-resistant, ER+, HER2-, advanced or mBC. Results of this trial have given new horizon for further studies (phase-III studies) as significantly longer PFS was observed in subjects who have received Capivasertib and Fulvestrant combination than placebo-Fulvestrant combination²³.

mTOR inhibitors:

One of the crucial intermediates involved in the PI3K-Akt-mTOR pathway, mTOR (mammalian target of Rapamycin), is primarily engaged in protein synthesis via S6K and EIb6. The expression of mTOR is increased in several cancers, including BC. Therefore, it is one of the favorite goals of medicinal chemists and several mTOR inhibitors have been developed²⁴. Everolimus is the first one belonging to this category that has been approved by USFDA in 2016 along with Exemestane to treat HR+ advanced breast cancer. Another mTOR inhibitor, Sirolimus, was also found to be another effective choice for HR+ advanced BC patients, especially when combined with endocrine therapy²⁵.

Ridaforolimus, another agent belonging to this category, was evaluated for its anti-malignant activity when combined with Paclitaxel and carboplatin. Its phase I trial (NCT01256268) on patients with solid tumor malignancies showed excellent results, prompting it to begin a phase II trial. Also, tolerable toxicity was observed²⁶.

Histone deacetylase inhibitors (HDAC inhibitors):

The impairment in the acetylation profile of both histone and non-histone proteins results in dysregulation of gene expression that results in abnormal cell apoptosis and cell-cycle arrest. The use of HDAC inhibitors can avoid these unusual modifications and, in turn, can prevent the disease progression²⁷. Also, the use of these chemical actives can reverse the histone deacetylase mediated gene silencing of estrogen receptor-α, thereby upregulating expression of ER-α will respond better to hormone therapy. This hypothesis has proven correct indeed when superior tumor suppression was observed with both Entinostat and Vorinostat when they were given with Exemestane and Tamoxifen, respectively, in ER+ BC patients²⁸.

Steroid sulphatase inhibitors (STS inhibitors):

Biologically active steroid hormones are stored as sulphated steroids. The activity as well as the level of steroid sulphatase is enhanced significantly in ER+ breast cancer. Therefore, this enzyme represents an ideal therapeutic target for preventing the formation of active steroid, estrogen and in turn control breast tumor growth. The STS inhibitors when given as monotherapy did not show any promising results. However, when were combined with aromatase inhibitors, they showed beneficial effects in Phase-II trials in post-menopausal women. Irosustat, a first-generation drug belonging to this category, has been used for this study purpose. Irosustat, when added to aromatase inhibition therapy has presented clinical benefits and a safety profile²⁹. The dual aromatase and STS inhibitors are also being developed and studied for their activity in breast malignancy³⁰.

IGF-1R monoclonal antibodies:

A number of monoclonal antibodies acting on Insulin like growth factor receptor, IGF-1R, were developed in an attempt to inhibit the pathway mediated by it in breast cancer. But the chemical actives developed so far have shown significant drug induced hyperglycemia, rendering their further development impossible. However, Figitumab has bypassed this side effect and has shown promising results with Exemestane during phase – II trial in ER+ BC cases with no prior intake of endocrine treatment³¹. Ganitumab, was also studied in a phase II clinical trial in postmenopausal women who had previously had endocrine therapy³². Another IGF-neutralizing antibody, Xentuzumab, was tested in association with Exemestane and Everolimus in a phase Ib/II (NCT03659136) trial in HR+, HER2-negative locally advanced/mBC cases. The combination showcased improved PFS in cases without visceral metastases, which encouraged startup of the phase II XENERA™-1 trial (NCT03659136)³³.

All the novel categories of these agents had given a templet for development of new moieties surrounding the target and has changed the prospective in HR+ BC outcome. All the clinical outcomes of these investigational drugs are summarized in Table 2. Also, the novel categories of drugs with examples are summarized in Figure 1.

Table 2: Novel drugs for treatment of luminal breast cancer

Name of Drug	Type of therapy	Study population	Stage of clinical development
CDK inhibitors
Palbociclib	Combination with AI	HR+ advanced and MBC	Approved in 2015 by USFDA
Ribociclib	Combination with AI	HR+ advanced and MBC	Approved in 2017 by USFDA and EMA
Abemaciclib	Combination with AI	HR+ advanced and MBC	Approved in 2015 by USFDA and EMA
PI3K inhibitors
Alpelicib	Combination with Fulvestrant	HR+ advanced or MBC in post-menopausal women	Approved in 2019 by USFDA based on SOLAR-I trial
Alpelicib	Combination with Letrozole	HR+ early BC patients	Disappointing response (will not be further pursued) in NEO-ORB trial
Bupralisib	Combination with placebo or Paclitaxel	HER2-, locally advanced MBC	BELLE-II, III, and IV trials- Stopped in phase-II as no significant improvement in PFS
Taselisib	Combination with placebo or Fulvestrant	ER+/PIK3CA-mutant MBC cases	phase III clinical trial SANDPIPER - Discontinued due to higher toxicity and marginal benefits of symptoms
Taselisib	Combination with letrozole and placebo-letrozole	ER+/PIK3CA-mutant MBC cases	Phase-II clinical trial, LORELEI, completed and objective response was obtained
Pictilisib	Combination with Paclitaxel	HR+, HER2- locally recurrent or MBC and PIK3CA-mutated tumor	Phase-II trial, PEGGY- No significant improvement in PFS
Copanlicib	Combination with Palbociclib and Letrozole	ER+, HER- advanced BC	Phase-I/II trial (NCT03128619) - Ongoing
Copanlicib	Combination with Fulvestrant	ER+, HER- advanced BC	Phase-I/II trial (NCT03803761) - Ongoing
GDC-0077	Combination with Palbociclib and Fulvestrant	PIK3CA mutant, HR+, HER2-ve MBC	Phase-I trial, INAVO120 - Ongoing
Capivasertib (AZD5363)	Combination with Fulvestrant	Postmenopausal women with AI-resistant, ER+, HER2, advanced or MBC	Phase-II trial, FAKTION - Significantly longer PFS
Capivasertib (AZD5363)	Combination with Paclitaxel	ER+ advanced BC	Phase-II trial, BEECH – Stopped s no significant improvement in PFS
mTOR inhibitors
Everolimus	Combination with Exemestane	HR+ advanced BC	Approved in 2016 by USFDA
Sirolimus	Combination with endocrine therapy	HR+ advanced BC	Potentially effective treatment option
Ridaforolimus	Combination with Paclitaxel and carboplatin	Solid tumor cancers	Phase-I trial (NCT01256268) - showed antineoplastic activity with no acute toxicity – Phase II trial recommendation
Histone deacetylase inhibitors
Entinostat	Combination with Exemestane	ER+ BC patients	Superior tumor suppression
Vorinostat	Combination with Tamoxifen	ER+ BC patients	Superior tumor suppression
Tucidinostat	Combination with Exemestane	Endocrine treatment resistant, HR+, postmenopausal women	Phase-III trial, ACE - Significant clinical benefits – Further research
Steroid sulphatase inhibitors
Irosustat	Combination with AI	ER+ BC patients	Phase-II trial, IRIS – Major clinical benefits with an acceptable safety profile
IGF-1R monoclonal antibodies
Figitumab	Combination with Exemestane	ER+ BC patients	Phase-II trial – Clinical benefits
Ganitumab	Combination with Exemestane or Fulvestrant	Postmenopausal women with previous endocrine therapy	Phase-II trial - No major clinical outcome
Xentuzumab	Combination with Exemestane and Everolimus	HR+, HER2-, locally advanced/MBC cases	Phase Ib/II trial (NCT03659136) – No improvement in PFS
Xentuzumab	Combination with Exemestane and Everolimus	HR+, HER2-, advanced BC, without visceral metastases	Phase II trial (NCT03659136), XENERA™-1 - Improvement in PFS

AI: Aromatase Inhibitor, MBC: Metastatic Breast Cancer, PFS: Progress Free Survival

Figure 1. Novel categories of therapeutic agents with examples that are under clinical investigation for use in HR+ BC

CONCLUSION:

With the emergence of modern technologies, the identification of molecular or genetic drivers involved in the pathogenesis of breast cancer has become possible. Better prognosis and improved PFS or OS were seen when these crucial targets were targeted by fabricating a suitable molecule³⁴. Synergistic effects of newly developed molecules and established standards were also seen in several clinical trials. Luminal cancer responded better to therapy with mTOR, CDK, PI3K, Akt, STS, HDAC inhibitors, and IGF-1R antibodies. Altogether, it can be stated that innovative therapies are totally altering the mindset of breast cancer globally.

CONFLICT OF INTEREST:

The authors have no conflicts of interest regarding this investigation.

ABBREVIATIONS:

AI: Aromatase Inhibitor, BC: Breast cancer, CDKs: Cyclin dependent kinase, ECD: Extracellular domain, EGFR: Epidermal growth factor receptor, ER: Estrogen receptor, HDAC: Histone deacetylase, HER2: Human epidermal growth factor receptor 2, MBC: Metastatic breast cancer, mTOR: mammalian target of Rapamycin, ORR: Overall response rate, OS: Overall survival, PD-1: Programmed cell death protein , PFS: Progress free survival, PI3K: Phosphoinositide 3-kinase, PR: Progesterone receptor, STS: Steroid sulphatase, TKI: Tyrosine kinase inhibitors, TNBC: Triple negative breast cancer

REFERENCES:

1. Sung H, Ferlay J, Siege RL, Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. Cancer Journal for Clinicians. 2021; 71(3): 209-249. doi: 10.3322/caac.21660

2. Jayashree V, Velraj M. Breast Cancer and various Prognostic biomarkers for the diagnosis of the disease: A Review. Research Journal of Pharmacy and Technology. 2017; 10(9): 3211-3216. doi: 10.5958/0974-360X.2017.00570.4

3. Dange VN, Shid SJ, Magdum CS, Mohite SK. A review on breast cancer: an overview. Asian Journal of Pharmaceutical Research. 2017; 7(1): 49-51. doi: 10.5958/2231-5691.2017.00008.9

4. Mane PT, Patil SP, Wakure BS, Wakte PS. Breast cancer: understanding etiology, addressing molecular signaling pathways, identifying therapeutic targets and strategizing the treatment. International Journal of Research in Pharmaceutical Sciences. 2021;12(3):1757-1769. doi: 10.26452/ijrps.v12i3.4779

5. Shaikh GA. Major roles of technology and analytics together towards advancement in clinical trials. Asian Journal of Research in Pharmaceutical Sciences. 2021; 11(2): 155-9. doi: 10.52711/2231-5659.2021-11-2-11

6. Asaad RA, Abdullah SS. Breast Cancer Subtypes (BCSs) Classification according to hormone receptor status: Identification of patients at high risk in Jableh- Syria. Research Journal of Pharmacy and Technology. 2018; 11(8): 3703-3710. doi: 10.5958/0974-360X.2018.00680.7

7. Sudhakar GK, Pai V, Pai A. An overview on current Strategies in breast cancer therapy. Research Journal of Pharmacology and Pharmacodynamics. 2013; 5(6): 353-355.

8. Nahla EE, et al. New Shining Stars in The Sky of Breast Cancer Diagnosis and Prognosis: A Review. Research Journal of Pharmacy and Technology. 2022; 15(8): 3808-3. doi: 10.52711/0974-360X.2022.00639

9. Andrahennadi S, Sami A, Manna M, Pauls M, Ahmed S. Current landscape of targeted therapy in hormone receptor-positive and HER2-negative breast cancer. Current Oncology. 2021; 28(3): 1803-1822. doi: 10.3390/curroncol28030168

10. Fayyad RJ, Ali ANM, Hamdan NT. The specific anti-cancerous mechanisms suggesting Spirulina Alga as a promising breast cancer fighter. Research Journal of Pharmacy and Technology 2021; 14(10): 5599-2. doi: 10.52711/0974-360X.2021.00974

11. Luque-Bolivar A, Pérez-Mora E, Villegas VE, Rondón-Lagos M. Resistance and overcoming resistance in breast cancer. Breast Cancer. 2020; 12: 211–229. doi: 10.2147/BCTT.S270799

12. Karale PA, Karale MA, Utikar MC. Advanced molecular targeted therapy in breast cancer. Research Journal of Pharmacology and Pharmacodynamics. 2018; 10(1): 29-37. doi: 10.5958/2321-5836.2018.00006.X

13. Zhang M, Jang H, Nussinov R. PI3K inhibitors: review and new strategies. Chemical Science. 2020; 11: 5855-5865. doi: 10.1039/d0sc01676d

14. Rusquec PD, Blonz C, Frenel JS, Campon M. Targeting the PI3K/Akt/mTOR pathway in estrogen-receptor positive HER2 negative advanced breast cancer. Therapeutic Advances in Medical Oncology. 2020; 12: 1-12. doi: 10.1177/1758835920940939

15. Ellis H, Ma CX. PI3K Inhibitors in breast cancer therapy. Current Oncology Reports. 2019; 21: 110. doi: 10.1007/s11912-019-0846-7

16. Leo AD, Johnston S, et al. Buparlisib plus fulvestrant in postmenopausal women with hormone-receptor-positive, HER2-negative, advanced breast cancer progressing on or after mTOR inhibition (BELLE-3): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncology. 2018; 19(1): 87-100. doi: 10.1016/S1470-2045

17. Verret B, Cortes J, Bachelot T, Andre F, Arnedos M. Efficacy of PI3K inhibitors in advanced breast cancer. Annals of Oncology. 2019;30:x12–x20. doi: 10.1093/annonc/mdz381-

18. Vuylsteke P, Huizing M, et al. Pictilisib PI3Kinase inhibitor (a phosphatidylinositol 3-kinase [PI3K] inhibitor) plus paclitaxel for the treatment of hormone receptor-positive, HER2-negative, locally recurrent, or metastatic breast cancer: interim analysis of the multicentre, placebo-controlled, phase II randomised PEGGY study. Annals of Oncology. 2016; 27: 2059–2066. doi: 10.1093/annonc/mdw320

19. Spathas N, Economopoulou P, et al. Exceptional response to copanlisib in a heavily pretreated patient with pik3ca-mutated metastatic breast cancer. ASCO Precision Oncology. 2020; 4: 335-340. doi: 10.1200/PO.19.00049

20. Copanlisib, letrozole, and palbociclib in treating patients with hormone receptor positive her2 negative stage I-IV breast cancer. NCT03128619. https://clinicaltrials.gov/ct2/show/NCT03128619. Accessed 26 August 2022.

21. A study of a new drug combination, copanlisib and fulvestrant, in advanced breast cancer. NCT03803761. https://clinicaltrials.gov/ct2/show/NCT03803761. Accessed 26 August 2022.

22. Turner N, Jhaveri K, et al. Phase III study of GDC-0077 or placebo (pbo) with palbociclib (P) + fulvestrant (F) in patients with PIK3CA-mutant/hormone receptor-positive/HER2-negative locally advanced or metastatic breast cancer (HR+/HER2- LA/MBC). Annals of Oncology. 2020; 31: S391-S392. doi: 10.1016/j.annonc.2020.08.457

23. Jones RH, Casbard A, et al. Fulvestrant plus capivasertib versus placebo after relapse or progression on an aromatase inhibitor in metastatic, oestrogen receptor-positive breast cancer (FAKTION): a multicentre, randomised, controlled, phase 2 trial. Lancet Oncology. 2020; 21: 345-357. doi: 10.1016/S1470-2045(19)30817-4

24. Zagouri F, Sergentanis TN, et al. mTOR inhibitors in breast cancer: A systematic review. Gynecologic Oncology. 2012; 127: 662–672. doi: 10.1016/j.ygyno.2012.08.040

25. Yi z, Lieu B. Safety and efficacy of sirolimus combined with endocrine therapy in patients with advanced hormone receptor-positive breast cancer and the exploration of biomarkers. The Breast. 2020; 52: 17-22. doi: 10.1016/j.breast.2020.04.004

26. Chon HS, Kang S. Phase I study of oral ridaforolimus in combination with paclitaxel and carboplatin in patients with solid tumor cancers. BMC Cancer. 2017; 17: 407. doi: 10.1186/s12885-017-3394-2

27. Eckschlager T, Plch J, Stiborova M, Hrabeta J. Histone deacetylase inhibitors as anticancer drugs. International Journal of Molecular Sciences. 2017; 18: 1414. doi: 10.3390/ijms18071414

28. Jiang Z, et al. Tucidinostat plus exemestane for postmenopausal patients with advanced, hormone receptor-positive breast cancer (ACE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncology. 2019; 20(6): 806-815. doi:10.1016/S1470-2045(19)30164-0

29. Foster PA. Steroid sulphatase and its inhibitors: past, present, and future. Molecules. 2021; 26(10): 2852. doi: 10.3390/molecules26102852

30. Sonawane RK, Nere KR, Mohite SK. Heterocyclic system containing bridgehead nitrogen atom: Substituted 1,2,3-Triazolo [3,4-b]-1,3,4-Thiadiazole derivative useful for the treatment of breast cancer and other diseases. Asian Journal of Research in Chemistry. 2022; 15(4): 295-8. doi: 10.52711/0974-4150.2022.00052

31. Ryan PD, Neven P, Blackwell KL, Dirix L. P1-17-01: Figitumumab plus exemestane versus exemestane as first-line treatment of postmenopausal hormone receptor-positive advanced breast cancer: a randomized, open-label phase II trial. Cancer Research. 2012; 71: P1-17-01-P1-17-01. doi: 10.1158/0008-5472.SABCS11-P1-17-01

32. Robertson FR, Ferrero JM, et al. Ganitumab with either exemestane or fulvestrant for postmenopausal women with advanced, hormone-receptor-positive breast cancer: a randomised, controlled, double-blind, phase 2 trial. Lancet Oncology. 2013; 14(3): 228-35. doi: 10.1016/S1470-2045(13)70026-3

33. Schmid P, Sablin MP, et al. A phase Ib/II study of xentuzumab, an IGF-neutralising antibody, combined with exemestane and everolimus in hormone receptor-positive, HER2-negative locally advanced/metastatic breast cancer. Breast Cancer Research. 2021; 15: 23(1):8. doi: 10.1186/s13058-020-01382-8

34. Wahyuni, Ajeng Diantini, Mohammad Ghozali, I Sahidin. A Review of Current treatment for Triple-Negative Breast Cancer (TNBC). Research Journal of Pharmacy and Technology. 2022; 15(1): 409-8. doi: 10.52711/0974-360X.2022.00068

Received on 07.12.2022 Modified on 17.06.2023

Research J. Pharm. and Tech 2023; 16(11):5522-5527.

DOI: 10.52711/0974-360X.2023.00893

Type of breast cancer	Expression of receptor	% Occurrence	Characteristic traits	Potential treatment
Luminal A	ER +, PR +, HER -, Low ki-67	40-60	Slow growing tumor Best prognosis	Hormonal therapy
Luminal B	ER +, PR +, HER +/- ki-67: High	12-20	Slightly faster growing tumor Worse prognosis	Hormonal therapy
HER2 Enriched	ER -, PR -, HER +, ki-67: High	5-15	Faster growing tumor Worse prognosis	Anti HER therapy
Triple negative	ER -, PR -, HER -	10-20	Faster growing tumor NWorse prognosis	PARP Inhibitors
Normal like BC	ER +, PR +, HER -,ki-67: Low	< 2	Slow growing tumor Worse prognosis	Hormonal therapy