A Review on Current and Novel Treatment Regimen on Luminal

A Breast Cancer

 

Jayhind L Bharti*, Anjali M Wankhade, J V Vyas, Vivek V Paithankar, Pratiksha R Morey

Department of Pharmacology, Vidyabharati College of Pharmacy, Amravati, Maharashtra, India – 444602.

 

ABSTRACT:

The second-leading cause of cancer-related death in women is breast cancer, which is the most prevalent disease among females. The majority of breast cancers (about 70%) fall under the luminal A subtype, which is indicated by the presence of the estrogen receptor (ER +) but not by the amplified human epidermal growth factor receptor (HER2). The understanding of breast cancer has advanced with the identification of various intrinsic subtypes. This review focuses on the landscape of the luminal A subtype, its standard treatment regimen, under process clinical trial and the novel treatment regimens of luminal A breast cancer.  OTUD7B oestrogen receptor stabiliser, BTG2 as a tumour target, CCAT2 in Regulating Luminal Subtype of Breast Cancer, and miRNA Expression Profiles in Luminal A Breast Cancer are some of the newer therapies for luminal A breast cancer that are discussed in this review. The ideal course of treatment for people with luminal A-subtype cancers is still unknown in the age of precision medicine. Our ability to actualize the promise of precision medicine—the correct treatment, for the right patient, at the right time—will be made possible by the development of tumour panels to examine these validated biomarkers. These unique tumour traits will become more significant in deciding the best course of treatment for each individual patient in the current era of precision medicine, where the aim is to neither overtreat nor undertreat patients. However, more thorough investigation is required in this area.

 

 

INTRODUCTION:

Breast cancer is the most common type of cancer in women worldwide. It rose from fourth to first on the list of the most common cancers in India in the 1990s. According to epidemiological studies, the global burden of BC is expected to exceed 2 million by 2030¹. Gender, age, familial history, inherited genetic mutations, alcohol intake, smoking, obesity, and hormone exposure, which is elevated between early menarche and late menopause, are all risk factors for the development of breast cancer². 

 

In 2023, the United States is expected to have 1,918,030 new cancer cases and 609,360 cancer deaths. Female breast cancer incidence increased slowly (by 0.5% per year) from 2014 to 2018³.

 

Stages of breast cancer:

According to a breast cancer.org report the stage of breast cancer is determined by the size and type of tumour, as well as how deeply the tumour cells have invaded the breast tissues. Whereas stage 0 refers to non-invasive tumours, stage 4 refers to invasive tumours⁴.

•     Stage 0:

This is a non-invasive stage of tumour that indicates that both cancerous and non-cancerous cells are within the boundaries of the part of the breast where the tumour begins to grow and there is no evidence of their invasion in the surrounding tissues of that part; ductal cell carcinoma in situ is an example of this tumour stage (DCIS)⁵

•     Stage 1:

This stage is known as invasive breast cancer, and microscopic invasion is conceivable. It is divided into two stages: 1A and 1B. Stage 1A refers to a tumour that is up to 2 cm in size and does not involve any lymph nodes, whereas stage 1B refers to a small group of cancer cells larger than 0.2 mm that are identified in lymph nodes⁶

•     Stage 2:

There are two categories in Stage 2: 2A and 2B. Stage 2A indicates that the tumour is identified in the axillary or sentinel lymph nodes but not in the breast. The tumour can be less or larger than 2 cm, but not more than 5 cm. However, stage 2B depicts a tumour that is larger than 5 cm but does not reach the axillary lymph nodes⁷

•     Stage 3:

It has been separated into three sections: 3A, 3B, and 3C. Stage 3A describes no tumour in the breast but it can be found in 4-9 axillary lymph nodes or in sentinel lymph nodes, whereas stage 3B describes a tumour of any size that has caused swelling or ulceration on the skin of the breast and has spread to up to 9 axillary lymph nodes or to sentinel lymph nodes. Inflammatory breast cancer, stage 3B, is characterised by red, heated, and swollen breast skin. However, stage 3C describes tumour progression to 10 or more axillary lymph nodes, as well as involvement of the lymph nodes⁸

•     Stage 4:

This is the advanced and metastatic stage of cancer, and it explains the spread of cancer to other organs of the body such as the lungs, bones, liver, brain, and so on⁹

In addition to genetic susceptibility, the following clinical factors are used to identify high risk women:

i.    first degree relative with a breast cancer diagnosis before the age of 50;

ii.   history of atypical hyperplasia;

iii.  history of lobular carcinoma in situ (LCIS);

iv.  chest radiation between the ages of 10 and 30;

v.   5-year risk of 1.7% according to the Gail model; and

vi.  lifetime risk of 20% according to the International Breast Cancer Intervention Study (IBIS) model.¹⁰

 

Breast cancer is classified into several categories based on where it begins to form in the breast, how much it has grown or spread, and specific characteristics that determine how the disease behaves. whereas the molecular subtype of invasive breast cancer is determined by the genes expressed by the cancer cells, which regulate how the cells behave. Five major molecular subtypes of invasive breast cancer have been identified by researchers.¹¹

 

 

A.  LUMINAL A BREAST CANCER:

Luminal Breast cancer is oestrogen and progesterone receptor-positive, HER2-negative, and has low levels of the protein Ki-67, which regulates how quickly cancer cells develop.

 

B.  LUMINAL B BREAST CANCER:

Luminal B breast cancer is oestrogen receptor-positive and HER2-negative, with either high Ki-67 levels (indicating quicker cancer cell proliferation) or progesterone receptor negativity.

 

C.  LUMINAL B-LIKE BREAST CANCER:

Luminal B-like breast cancer is estrogen-receptor-positive, HER2-positive, and can have any degree of Ki-67, as well as being progesterone receptor-positive or progesterone receptor-negative. Luminal B malignancies grow faster and have a slightly worse prognosis than luminal A tumours.

 

D.  HER2-ENRICHED BREAST CANCER:

Breast cancer with HER2 is oestrogen receptor-negative, progesterone receptor-negative, and HER2-positive. HER2-enriched tumours grow more quickly than luminal malignancies and have a worse prognosis.¹²

 

E.  TRIPLE-NEGATIVE OR BASAL-LIKE BREAST CANCER:

Triple-negative or basal-like breast cancer is estrogen receptor-negative, progesterone receptor-negative, and HER2-negative¹³.

 

Fig   Intrinsic Subtypes of Breast Cancer ¹⁴

 

LUMINAL A BREAST CANCER

ER-positive (or luminal) breast tumours account for almost two-thirds of all cases. Luminal breast cancer is a very heterogeneous illness with numerous histologies, gene-expression profiles, and mutational patterns, as well as widely disparate clinical outcomes and responses to systemic therapy.¹⁵ The bulk of breast cancers in Western countries are luminal-like tumours, which account for over 70% of all instances.¹⁶

 

Although most women with luminal-like disease respond effectively to endocrine therapy alone, others experience deadly recurrences, necessitating extra cytotoxic therapy. Due to the severe side effects of chemotherapy, the need to separate women for whom it will be useful from those for whom it may not be necessary remains a difficulty in translational breast cancer research¹⁷.

Unless endocrine resistance emerges, endocrine therapy (ET) is the primary treatment for almost all luminal A-subtype breast tumours¹⁸. To diminish tumour resistance to hormone therapy, recognised ETs and innovative targeted medicines have been combined in recent years¹⁹.

 

These targeted drugs are divided into two main categories:

i.    Specific rapamycin (mTOR)/phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α inhibitors and

ii.   cyclin-dependent kinase 4/6 (CDK4/6) inhibitors.

 

However, significant obstacles stand in the way of developing an effective treatment for metastatic luminal A breast cancer. Drug resistance can emerge, for example, when CDK4/6 inhibitors are used with ETs²⁰.

 

STANDARD TREATMENT REGIMEN OF LUMINAL A BREAST CANCER:

Treatment options should be reviewed with your healthcare professional and may vary depending on personal preferences, risks, cancer stage, and tumour size, among other things.

Breast cancer treatment often includes:

•     Hormone therapy

•     Chemotherapy

•     Surgery

•     Radiation therapy

•     Targeted medication therapy

•     Immunotherapy²¹

 

Hormone therapy appears to be the most effective treatment for luminal A breast cancer, according to research²². Luminal Breast cancer does not respond as effectively to chemotherapy or radiation therapy as it does to hormone therapy²³.

 

Estrogen, a hormone generated by the ovaries as well as other organs, encourages the formation of HR+ breast tumours. Approximately 83% of breast cancers are HR+ and can be treated with hormone therapy to prevent the effects of oestrogen on breast cancer cell development. These medications are not the same as menopausal hormone therapy, which raise hormone levels²⁴

 

Tamoxifen for up to 10 years is typical treatment for premenopausal women; however, for those women at high risk of recurrence, a combination of ovarian suppression plus either tamoxifen or an aromatase inhibitor is advised²⁵

 

Aromatase inhibitors (letrozole, anastrozole, and exemestane) are the preferred hormonal treatment for postmenopausal women. The choice to continue treatment with an aromatase inhibitor after 5 years is dependent on patient considerations and the projected benefit from reduced risk of recurrent breast cancers²⁶.

According to studies, adherence to hormone therapy remains unsatisfactory, particularly among black women, which may be owing in part to out-of-pocket expenditures²⁷.

 

1.   Selective ER Modulators (SERMs):

SERMs are anti-estrogen chemicals that operate as ER antagonists, reducing estrogen-ER interaction by competing with oestrogen and modulating ER transcriptional activity²⁸.

 

Tamoxifen:

Tamoxifen, the most well-known SERM, is the preferred ER+ BC therapy, administered orally to women before and/or after menopause; its active metabolite endoxifen may be used as an alternative. Triphenylethylenes, which include tamoxifen and tamoxifen-like drugs; benzothiophenes, which include raloxifene and arzoxifene; phenylindoles, which include basedoxifene and pipindoxifene; and tetrahydronaphthalenes, which include lasofoxifene, are currently utilised SERMs²⁹.

 

Large randomised clinical trials have been done to assess the role of extended ET in avoiding or postponing distant relapses. The rationale for these trials was based on the known natural history of breast cancer, which has a 5% yearly mortality rate for at least 15 years, even after 5 years of tamoxifen medication³⁰.

 

The National Surgical Adjuvant Breast and Bowel Project B-14 (NSABP-B14), aTTom trial, the three biggest prospective trials investigating the role of extended tamoxifen treatment were the Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) trial11, which included the most participants. They used a similar design: after 5 years of tamoxifen medication, patients were randomly assigned to extra tamoxifen. In the ER-positive subgroup of patients, ET plus tamoxifen dramatically lowered recurrence rates and mortality^31-33

 

2.   Aromatase Inhibitors (AIs):

AIs now represent the standard treatment in postmenopausal patients and are effective as initial therapy for metastatic or locally advanced ER+ BC that has progressed after treatment with tamoxifen.

 

CYP19, an aromatase (oestrogen synthase) enzyme, catalyses the final and rate-limiting step in oestrogen production. As a result, inhibitors of this enzyme are effective as targeted therapy for ER+ BC³⁴.

 

Letrozole, anastrozole, and exemestane are FDA-approved reversible AIs, with exemestane also serving as an irreversible aromatase inhibitor. Unlike tamoxifen, AIs had no influence on the overall survival of ER+ breast cancer patients³⁵.

Letrozole:

After a median follow-up of 2.5 years, the first interim analyses of the trial results confirmed that letrozole significantly reduced the risk of recurrent breast cancer (42%), regardless of the patient's nodal status or prior chemotherapy, and significantly reduced the risk of distant metastasis (40%). Letrozole as extended adjuvant therapy significantly improved overall survival (OS) in women with node-positive illness. Mortality was reduced by 39% among the approximately 2500 women with node-positive disease randomized in the study³⁶.

Other two smaller trials, the NSABP-B33 and the Austrian Breast and Colorectal Study Group (ABCSG) trial 6a^37-38, also confirmed the efficacy of extending aromatase inhibitor (AI) treatment beyond the standard 5 years of tamoxifen therapy.

 

 

Currently, new therapeutic targets are being researched in order to either kill aroused dormant cells or keep them dormant indefinitely³⁹.

 

3.   Selective ER Downregulators (SERDs):

SERDs (for example, fulvestrant) have antagonistic effects on the ER and ER. Fulvestrant has been licenced by the United States Food and Drug Administration (FDA) for the treatment of metastatic ER+ BC in postmenopausal women after tumour progression and after using anti-estrogen therapies such as tamoxifen for more than ten years. Fulvestrant usage causes ER downregulation by causing its breakdown⁴⁰.

 

The activation of co-activators, dimerization, and nuclear localization of the ERs are all disrupted when SERDs bind to ERs⁴¹.

 

COMPLETED AND ONGOING CLINICAL TRIALS FOR LUMINAL A BREAST CANCER

Table 1: completed and ongoing clinical trial protocol⁴²

NOVEL TREAT REGIMEN:

1.   CCAT2 in Regulating Luminal Subtype of Breast Cancer⁴³:

Despite the fact that CCAT2 has been linked to the development of tumours in a number of cancer types⁴⁴, Breast cancer tumours of the oestrogen receptor (ER) positive luminal subtype showed low expression of CCAT2⁴⁵. 

 

The current study also identified a dual role for CCAT2 in the regulation of tumorigenesis and cancer cell stemness in luminal breast cancer, wherein cytoplasmic CCAT2 interacted with miRNA 221/222 to inhibit p27-dependent cell proliferation and nuclear CCAT2 accumulation interacted with an OCT4 pseudogene (OCT4-PG1) to induce cancer stem cells. As a hormone-activated transcription factor, ER boosts the expression of numerous genes that control breast cancer tumour development and cell proliferation⁴⁶.

 

ER state may be correlated with the subcellular localization and expression level of lncRNAs in breast cancer cells. For instance, in ER+ luminal breast cancer cell MCF-7 but not in ER- breast cancer cells, suppression of lncRNA152 and lncRNA67 decreased cell proliferation⁴⁷. In individuals with breast cancer who are resistant to endocrine therapy, upregulation of lncRNA H19 has been linked to higher ER expression. It was discovered that H19 knockdown offered an additional therapeutic approach for ER+ drug-resistant breast cancer⁴⁸.

 

The current study also discovered that the carrier and/or transfection method may be connected to the subcellular distribution of foreign RNAs. A donor gene may end up in the host cell's cytoplasm, nucleus, mitochondria, or other organelles after transfection to perform various functions. For lncRNAs, this has received widespread recognition and favourable reviews⁴⁹.

 

Collectively, these results from the current study about the subcellular distribution-related function of lncRNAs will help us understand how non-coding RNAs are involved in the regulation of cancer and will help us apply novel therapeutic targets for the treatment of breast cancer with greater medical precision.

 

2.   BTG2 as a tumour target⁵⁰:

The BTG2 gene is highly expressed in a variety of organs and tissues, including the lung, intestines, pancreas, and prostate, and functions as a tumour suppressor in a variety of biological processes in cancer cells⁵¹.

 

According to reports, BTG2 plays a crucial part in cell proliferation, DNA damage repair, and apoptosis. Pancreatic and lung cancer cells exhibit reduced cell proliferation when BTG2 is overexpressed⁵². However, overexpression of BTG2 also encourages bladder cancer cells to migrate and lowers patients' chances of survival, suggesting that the biological effects of BTG2 as a tumour suppressor may vary depending on the kind of cancer⁵³.

 

To the best of our knowledge, there aren't many studies that have been reported on BTG2 and luminal A breast cancer. Consequently, the discovery of BTG2's biological role in luminal the discovery of efficient treatment targets for luminal A breast cancer may be accelerated.

 

In the current study, critical target genes linked to breast cancer were identified using bioinformatics analysis. It was found that low expression of BTG2 was substantially correlated with the poor prognosis of breast cancer patients, suggesting that BTG2 could be employed as a biomarker for the disease⁵⁴.

 

It is important to comprehend how BTG2 works in various breast cancer subtypes, such as luminal A breast cancer, given the potential cancer-type dependent involvement of BTG2. Because MCF-7 cells had positive ER and PR expression and negative HER expression, which is similar to the molecular expression profile of luminal A breast cancer, they were chosen for the current investigation.

 

The present study's findings, in summary, showed that BTG2 was a crucial targeted gene related to breast cancer, and that overexpression of BTG2 may inhibit cell proliferation, invasion, and migration in luminal A breast cancer. BTG2 may therefore be a new target for the therapy of luminal A breast cancer, although further research is needed to fully understand the mechanisms underlying its unique role.

 

3.   OTUD7B stabilizes estrogen receptor α and promotes breast cancer cell proliferation⁵⁵:

Through post-translational modification, OTUD7B, which was strongly expressed in human breast cancer samples, was a new ER co-regulator. ER polyubiquitination and degradation are inhibited by OTUD7B, which has been linked to ER. In particular, OTUD7B is crucial for the development of breast cancer⁵⁶.

 

OTUD7B is known to have a significant role in carcinogenesis, although its exact molecular mechanism of action in the development of breast cancer is yet unknown⁵⁷. When matched nearby normal tissue is compared to breast cancer tissue, OTUD7B is overexpressed, and high expression of OTUD7B is linked to a bad prognosis for breast cancer patients⁵⁸.

 

In the current investigation, we discovered that OTUD7B was a new modulator in regulating ER stability and ubiquitination, which is dependent on its DUB activity. The quantity of ER protein was markedly reduced and er signalling activity was blocked by the depletion of OTUD7B.

 

We subsequently investigated the molecular mechanism by which OTUD7B controls ER, and discovered that ER protein level was markedly reduced upon OTUD7B removal⁵⁹. Further evidence that OTUD7B-promoted ER stability was a result of the enzymatically active location of OTUD7B-catalyzed ER deubiquitination was provided by the fact that the catalytically inactive mutant of OTUD7B (C194S) did not modulate the degree of ubiquitination on ER⁶⁰.

 

Our data also showed that ER-positive breast cancer cell proliferation and migration were significantly reduced when OTUD7B was depleted. By overexpressing ER, the suppressive effects brought on by OTUD7B depletion could be undone. These findings showed that OTUD7B increased ER stability, which facilitated breast cancer migration and proliferation.

 

By expressing ER, OTUD7B might promote breast tumour growth. OTUD7B may be a potential target for breast cancer treatment because ER signalling is crucial for the proliferation of ER-positive breast cancer cells.

 

4.   miRNA Expression Profiles in Luminal A Breast Cancer⁶¹:

Additionally, complex miRNA expression profiles are a viable area of focus for a cutting-edge luminal A BC treatment. Because malignant diseases are varied, it is necessary to manage each patient more precisely in order to provide tailored care under the notion of precision medicine. Identification of useful BC biomarkers is made possible by the assessment of the precise levels of expression of various miRNAs or panels of numerous miRNAs. Rich evidence has recently been published on the precise amounts of individual miRNA expression at BC settings, which significantly increases the significance of the prospective application of epigenetic analysis in the therapy of BC⁶².

 

The expression of miRNA in liquid biopsies primarily highlights its use as a non-invasive biomarker⁶³. Moi et al. concentrated on the variations in molecular subtypes and miRNA expression in the cohort of Norwegian women. They examined FFPE from 36 benign and 102 cancerous samples. The results revealed that the group of LumA patients had considerably lower levels of miR-17-5p and miR-20a-5p, which have been shown to be crucial in the invasion and migration of cancer cells through inhibition of Wnt/-catenin⁶⁴.

MiR-338-3p, miR-223, and miR-148a levels in the blood were found to be lower in post-operative samples compared to pre-operative samples from post-menopausal women with a molecular characteristic corresponding to LumA, including ER+ HER2 EBC, and to be higher in post-operative samples compared to pre-operative samples for miR-107. But in order to assess these miRNAs' potential as clinical biomarkers, it is important to evaluate the change in their expression in more extensive prospective investigations⁶⁵.

 

Studying LumA in vitro found that MCF-7 BC cells expressed more miR-1273g-3p than the typical Hs 578Bst breast cells did. Comparable findings were found between breast ductal carcinoma patients and healthy donors. The findings demonstrated the potential of miR-1273g-3p as a biomarker for the early detection of breast ductal carcinoma, as its enhanced expression is linked to BC progression by modulating PTEN⁶⁶.

 

For a better understanding of the role of miRNA within the heterogeneous nature of BC, however, as well as for the determination of the strategy of BC treatment, it is necessary to overcome the limitations observed so far in the investigation of the applicability of miRNA expression or panels of multiple miRNAs in the diagnosis or determination of the treatment strategy. In conclusion, a customised strategy utilising miRNA diagnostics and targeted therapy could result in a significant shift in the BC paradigm, accurate prognostication of patients, and improved survival rates.

 

CONCLUSION:

Over the last few decades, there has been a substantial advancement in our understanding of the molecular biology and heterogeneity of breast cancer. Breast cancer no longer exists as a single entity but rather as a number of subtypes, each with unique genetic and immunohistochemical characteristics, responses to therapy, and consequences for survival. Studies have shown that patients with the luminal A subtype may have a better prognosis in particular, which raises the question of whether de-escalating treatment and skipping chemotherapy are appropriate in some situations. These unique tumour traits will become more significant in deciding the best course of treatment for each individual patient in the current era of precision medicine, where the aim is to neither overtreat nor undertreat patients. However, more thorough investigation is required in this area.

 

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Received on 27.01.2023         Modified on 21.02.2023

Accepted on 16.03.2023 ©Asian Pharma Press All Right Reserved