University of Calcutta

Hormonal Therapies:
A Safer Approach for Cancer Treatment

A systematic review submitted for partial fulfilment of the degree of M.sc in Human
Physiology, 2021
(DSEC- Endocrinology & Reproductive Physiology, P20)

Submitted By,
Soumik Kumar Sarkar
Roll No. - 113/HPY/191021
Registration No. – 115-1224-4199-16

Under the supervision of,

Dr. Sonali Ghosh

Department of Physiology
Rammohan College (Affiliated to University of Calcutta)
102, 1, Raja Ram Mohan Sarani, Baithakkhana, Kolkata, West Bengal 700009

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 CERTIFICATE

It is hereby certified that the review entitled “Hormonal Therapies: A Safer

Approach for Cancer Treatment” has been carried out by Soumik Kumar
Sarkar of department of Human Physiology (Endocrinology and Reproductive
Physiology Special Paper), Rammohan College, affiliated to University of
Calcutta under my supervision and guidance.

8/08/2021
DR. SONALI GHOSH
HOD & Assistant Professor
Department of Physiology
Rammohan College

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 ACKNOWLEDGEMENT

Foremost, I would like to express my sincere gratitude to my advisor Dr. Sonali Ghosh for the
continuous support in my review work, for her patience, motivation, enthusiasm and immense
knowledge. I could not be more thankful to give me the opportunity to work on “Hormonal
Therapies: A Safer Approach for Cancer Treatment”. Her guidance helped me to complete my
research and writing of this review paper.

My sincere thanks also go to Dr. Gouri Prasad Dutta, Head of the Department, Course Co-
ordinator and Dr. Neela De for offering me the opportunity to work on this review, for their
help and supervision to complete my review work and opening up me to more diverse
knowledge.

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 CONTENT TABLE
SL No. CONTENT PAGE
1. ABSTRACT 5

2. INTRODUCTION 5-7

3. TYPE OF HORMONE THERAPY IN CANCER 7-8

4. BREAST CANCER 8-22

• Pathophysiology 8-9
• Classification 9-11
• Staging 11
• Early-Stage Treatments 12-18
• Advanced-Stage Treatments 19-22

5. PROSTATE CANCER 22-30

• Grading System 23
24
• Staging
25-26
• Pathophysiology
26
• Early-Stage Treatments
• Advanced-Stage Treatments 26-30

6. ENDOMETRIAL CANCER 30-35

• Risk Factors 31
• Pathophysiology 32
33-34
• Staging
34
• Early-Stage Treatments
34-35
• Advanced-Stage Treatments

7. 35-40
OVARIAN CANCER
36-37
• Classification
• Pathophysiology 37-39
• Early-Stage Treatments 39
• Advanced-Stage Treatments 39
• Hormone Treatment 40

8. METHODOLOGY 41-42

9. RESULSTS 43

10. DISCUSSION 43-44

11. CONCLUSION 44

12. REFERENCES 44-52

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ABSTRACT:

H
ormone therapy is the use of synthetic hormonal agents to treat or cure various types
of medical conditions. Hormones are chemical messengers in biological system,
overexpression or disbalance or hormone level in the body can lead to neoplastic
formation of cells (benign or malignant). Hormone therapy in oncology used to manipulate the
level hormone or expression of hormone receptors associated with cancer cell formation to
limit or stop the growth, proliferation, survival of cells to cure the cancer. This includes breast
cancer, prostate cancer, endometrial cancer and ovarian cancer. With growing rates of these
cancers worldwide, treatment is essential. As many options available in the market like
chemotherapy, radiation therapy and surgery, it is essential to know what makes hormone
therapy stand out in them. This review highlights different types of hormones therapy options
according to the cancer type, their stages, their mechanism of action and ongoing studies on
the future of hormone therapy as well as briefly outlining how those hormones are related to
those cancers.

INTRODUCTION:
Hormones are chemical messengers that transfer information from one point to another in our
body, typically through soluble mediums like extracellular fluid or blood. Hormones can be of
different classes (e.g., peptides, proteins, monoamines, steroids and eicosanoids) and signal
through a various general and mechanisms in target cells. In them steroid hormones are
powerful regulators of gene expression and cell proliferation, also high level of certain
hormones can lead to the neoplasm, like high level of estrogen causes endometrial cancer.
Malignant tumors caused by hormonal imbalance or overexpression referred as hormone
dependent malignancy or hormone sensitive cancer, which includes breast, endometrial,
prostate and ovarian cancers. Different types of cancers have different mechanism of getting
influenced by hormones where hormone receptors play a big role.

Management of cancer includes chemotherapy, targeted therapy, radiation therapy, hormonal

therapy, immunotherapy and also surgical removal. As chemotherapy agents works via killing
dividing cells, damaging the gene in those cells, in that process chemotherapy damages healthy
cells causing various types of serious adverse effects like pulmonary fibrosis, cardiomyopathy,

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nephrotoxicity, neurotoxicity, drop in platelet number, chemo-induced nausea and vomiting
with serious late side effects like second cancer formation, cognitive dysfunction. While
radiation therapy also damages healthy tissues and immunotherapy lacks inability to predict
therapy efficacy and patient response, lack of effective biomarkers, high cost and also lack of
clinical study [Ventola C. L. 2017]. And surgery was never been an easy option to take for its
high cost and after surgery complications. This is where hormone therapy serves as one of the
best options for treatment over others with comparatively fewer side effects, high efficacy in
certain cancers and cost effect. In hormonal therapy, hormones are administrated exogenously
on the malignant cells or to alter endocrine system involved in that specific cancer by binding
to the hormone receptors (HR) expressed or involved in that specific cancer. Hormone therapy
agents or drugs binds to the cancer cell HR or receptors involved in the endocrine pathways
that specific type of cancer, supressing or blocking the action of that HR and in turn preventing
hormones to act on cancer cells. Hormone therapy is also considered as systematic therapy
because of the drugs used in it, those drugs travel through the body to find the target receptor
which makes it different from local therapies which acts on a certain part of the body like
radiation therapy.

Hormone therapy was first though to treat and prevent breast cancers but, after its initial
discovery it made its way into other hormone sensitive cancer treatments. Thomas Beastson in
1896 tested on rabbits’ breast and ovaries, found out “one organ holding control over the
secretion of another and separate organ.” Later he decided to do oophorectomy and resulted in
improvement for breast cancer and also suspected that “the ovaries maybe the exciting cause
of carcinoma” of the breast, discovered simulating effect of the female ovarian factor/hormone
(estrogen) on breast cancer, even before estrogen was discovered [ACS]. His classic paper “On
the Treatment of Inoperable Cases of Carcinoma of the Mamma: Suggestions for a New
Method of Treatment, with Illustrative Cases” was published in 1896 [Stockwell 1983]. After
half a century later 1941 Charles Huggins measured hormone has effect on prostate function,
castration or estrogen administration resulted in glandular atrophy. In 1958 he got Nobel prize
for being the first person to show that cancers can be controlled by chemicals. This
establishments provided the roots for the modern hormone therapies, such as like tamoxifen
and aromatase inhibitors. Recently aromatase inhibitors, LHRH analogues and inhibitors like
new classes drugs have improved breast and prostate cancer treatments. There various types of
hormones therapy but, all work on the same principle as to alter or down-regulate the hormones,
hormone receptor (HR) and pathways involved in the cancer system.

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But, like other therapies this need routine imaging care for patients to view the progress of
treatment and detecting side effects, which ranges from mild to moderate includes tiredness,
menopausal symptoms, hair thinning, obesity, headaches, thrombosis, digestive problems, to
severe like avascular necrosis, embolism, bone loss. As for the limitations, not all types of
cancers can be cured with hormone therapy because of its dependence over HR. In this review
we will discuss in detail about how hormone therapies are implicated in cancer treatment, what
are its advantages over other therapies, what are the limitations or hormone therapy, how to
overcome them and what is the future of hormone therapies in cancers treatment.

TYPE OF HORMONE THERAPIES IN CANCER:

Hormone therapy used in cancer patients can be broadly classified according to their mode of
action. Here are some types of therapies with their examples that are used like –

1. Aromatase Inhibitors (AI): AI acts via inhibiting aromatase enzyme, which is

essential for estrogen synthesis. Letrozole, Anastrozole, Exemestane and Testolactone
are approved AI drugs by FDA.
2. Selective estrogen receptor modulators (SERM): SERMs act by diffusing
into cells and binding to estrogen receptor (ER) α or/and β subunits, results in
dimerization and structural changes of the receptors and modulating their action.
Tamoxifen, Raloxifene, Toremifene and Clomiphene all are approved by FDA.
Although, clomiphene is used in ovulation dysfunction, not in cancer treatment.
3. Selective Estrogen Receptor Degrader (SERD): SERD acts via
competitively binds to ER and degrades or downregulates it. Fulvestrant is most
commonly used SERD.
4. Luteinizing hormone-releasing hormone (LHRH) agonists: also called
gonadotropin-releasing hormone (GnRH) agonist which acts via stimulating LHRH
hormone and eventually decresing the LHRH level in serum. Goserelin, Leuprolide,
Triptorelin, Histrelin and Nafarelin all are approved by FDA.
5. Luteinizing hormone-releasing hormone (LHRH) Antagonist: also
called gonadotropin-releasing hormone (GnRH) antagonist acts via competitively
blocking LHRH receptors. Degarelix and Elagolix are two of the most commonly used
LHRH antagonist. Also, recently FDA approved relugolix to be used as an LHRH
antagonist.

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 6. Androgen receptor (AR) antagonist: AR antagonist or blockers acts via
competitively binding to AR and prevents binding of andorgens (male sex hormone)
from binding. Enzalutamide, Bicalutamide, Flutamide, Nilutamide and Apalutamide all
are approved by FDA.
7. Progestin: Progestins are synthetic progesterone supplements.
Medroxyprogesterone, Megestrol, Gestonorone caproate and Hydroxyprogesterone
caproate all are FDA approved for cancer uses. Progestins are also used in birth control
pills.

BREAST CANCER
Breast cancer is the most frequently diagnosed cancer in women and ranks second among
causes for cancer related death in women (1.7 million cases worldwide) [Winters S. et al
2017]. Breast cancer is a heterogenous
disease, build on complex genetics and
shows phenotypic features, seen
through X- Rays and felt as a limp.
Breast cancer can be caused by genetic
mutation and, can be inherited, but also
can be caused by life-style issues like
eating and drinking habits. Breast
cancers almost entirely in women but,
men can also get breast cancer. It’s important to know most limps are benign and not
cancerous but, some type of benign growths can increase the risk of getting breast cancer,
which is generally caused by genetic mutations.

• Pathophysiology: About 10% of breast cancer is inherited. BRCA1 and BRCA2 are
two tumor suppressor gene, their mutation is most frequent in the inherited breast cancers
but, also in other type of cancers like ovarian, pancreatic and prostate they are prominent.
Tumor suppressor genes are important for normal cell growth, proliferation and
regulation. Mutations in them, specifically BRCA1 and BRCA2 are linked in the
development of breast and/or ovarian malignancy, mutation can be inherited or
spontaneous. In US, 1 out of 500 carry these mutations [Winters S. et al 2017]. Still, the
exact mechanism of initiation of breast cancer is still unknown. Most commonly TP53
(41%), PIK3CA (30%), MYC (20%), CCND1 (16%), ERBB2 (13%), FGFR1 (11%) and
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 GATA (10%) are the genes that mutate or get amplified in breast cancers but, most breast
cancers are have multiple low-grade mutations working simultaneously [Harbeck N. et al
2019]. Also, hormones also play big role in breast cancer development. During menstrual
cycle the imbalance between estrogen and progesterone helps in the breast cell
proliferation but, also may cause DNA damage and continuous damage may lead to
malignancy. After malignancy estrogen supports and proliferates cancer cell development
by interacting with
ER, even in the
absence of estrogen
extracellular signals
stimulate the ER.
Progesterone
upregulates genes that
are involved in BR
ERBB2 is also
overexpressed in 13-
15% of cancers
causing activation of Fig: Heterodimer formation of members of the HER family and
downstream signalling. HER2 has no identified ligand and always
human epidermal
in an open conformation, allowing dimerization.
growth factor receptor
2 (HER2) [Harbeck N. et al 2019]. Activates through heterodimerization of HER
receptors, although there is no specific ligand for HER2 and signalling activates different
pathways like RAS and PI3K, that enhances cancer cell proliferation, survival, apoptosis-
resistance and metastasis [Arteaga CL et al 2011]. Recent researches shows that some
oncogenic viruses are capable of inducing breast cancers. This includes mouse mammary
tumor virus (MMTV) which can increase the risk of getting breast cancer by 15 folds,
Human papilloma virus (HPV) increases up to six folds and Epstein bar virus (EBV) five-
fold increase [Lawson JS et al 2021].
• Classification: There are different types of breast cancers ranging from common to
rare and they occur in two types; invasive and non-invasive or in-situ. Common type of
invasive cancers includes invasive ductal carcinoma (IDC) and invasive lobular
carcinoma (ILC) and common in-situ cancers include Ductal carcinoma in-situ (DCIS)

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and Lobular carcinoma in-situ (LICS) to the rare ones like inflammatory breast cancer,
metastatic breast cancer, Paget’s disease of the breast and male breast cancer.

Breast cancers can also be classified based on the factors involved in tumor growth, type,
morphology, behavioural pattern of the cells, and expression of estrogen receptor (ER),
progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2), called
molecular subtyping. To make it accurate, immunochemistry analysis is also been
utilized. In addition, standard biomarkers are also been assessed with
immunohistochemistry [Al-Thoubaity F. K. 2019]. Furthermore, the St. Gallen
International Breast Cancer Conference, 2013 included Ki67 (a biomarker of cell
proliferation) as a factor associated with subtyping. There are primarily four subtypes
largely depending upon the hormone receptor (HR) and proteins involved in each cancer;
Luminal A or HR+/HER2-, Luminal B or HR+/HER2±, Triple-negative or HR-/HER2-
and HER2-positive. Subtyping can be done by two methods; gene-based assays and IHC-
based markers. In 2013, St. Gallen defined Luminal A as ER+, PR ≥20%, HER2 negative,
Ki67 <14%, if available, “low” recurrence risk based on gene‐based assays, which is the
most common subtype (about 73% of the cases in US, according to ACS) and grows
slower than other types. Luminal B tumors are considered to be more aggressive and less
common than Luminal A (about 11%), this have two subgroups; HRE- tumors are ER+,
HER2-, and at least Ki67 ≥20% and/or PR negative or <20%, and, if available, “high”
recurrence risk based on multi‐gene expression assay and, HRE+/HER enriched tumors are
ER+, HER2+, any Ki67 level, and any PR level (4% in all BC cases, ACS). Triple negative
breast cancer (TNBC) or HR-/HER- are invasive cancers and defined as HR, PR, HER
negative [Harbeck, N et al 2013]. TNBC are highly heterogenous at gene level and
according to gene expression TNBC can be sub-grouped into six types;
1. Basal-like 1 (BL1) - high TP53 mutation rate (92%), high RhoA signalling and low
PTEN-low/miRNA lesion clusters
2. Basal-like 2 (BL2) - overexpression of growth factor and myoepithelial markers,
3. Mesenchymal like (M) - cell motility can MET gene mutation and mesenchymal
differentiation,
4. Mesenchymal/stem-like (MSL) – mutation of genes involved in angiogenesis
(VEGFR2) and enriched in epithelial-mesenchymal markers
5. Immunomodulatory (IM) – mutation of genes involved in immune response and
elevation of programmed cell death 1 (PD1)
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 6. Luminal androgen receptor (LAR) – increased PI3KCA (55%), AKT1 (13%) and
CDH1 (13%) mutation [Wang, DY. et al 2019] [Yin, L 2020].

Each type has a different therapeutic target and different prognosis. TNBC’s are the biggest
hurdle in cancer treatment development because cannot be treated with hormonal therapy
because they do not contain any HR, although with modern researches TNBC can be treated
with chemotherapy or targeted therapy. 10-15% of the breast cancer cases are triple negative
and are usually higher in younger patients. All including symptoms like breast, lump, shape
change in breast, swelling, pain and abnormal discharge.

• Staging:

There are 5 stages of breast cancer according to tumor-nodules-metastasis (TNM) system,

starting from O to IV. O stage being the earliest stage and cancer is confined to breast, usually
non-invasive; stage I is the start of invasive cancer and spread into breast fatty tissues but, not
in lymph nodes; in stage II tumor size has grown larger (2-5 cm) and spread to auxiliary lymph
nodes; in stage III cancer has spread to bones and surrounding tissues and tumor size is larger
than 5 cm. In advanced form of breast cancer which is locally inoperable and metastatic called
stage IV; commonly spreads to bone, livers, lungs and brain. 20-30% of breast cancer patients
may develop metastatic even after primary treatment. Without metastasis, 80% breast cancer
patients may live up to 5 years, however with metastasis the rate decreases approximately 25%.
Tumor metastasis is cumulative and sequential process of several factors, such as escaping
from origin tissue cluster, invasion into blood and lymphatic system, survival of circulation
tumor cells, invading tissues from the fluid system (extravasation) and epithelium-to-
mesenchymal transition (EMT). Although further research needed to understand molecular
alterations during metastasis [Liang, Y. et al 2020].

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 Fig: Common metastatic sites in breast cancer.

• EARLY STAGE TREATMENTS:

With the increasing number of breast cancer patients and majority of them diagnosed in early
stages neoadjuvant therapy is now standard procedure to stop metastatic growth of tumor
because 5-15% patients are presented with possible metastatic growth [Liang, Y. at al 2020]
[Martí, C. et al 2021]. Neoadjuvant therapy is basically early treatment of the tumor with
chemotherapy and/or endocrine therapy. Neoadjuvant chemotherapy (NCT) is more suited for
ER- tumors whereas neoadjuvant endocrine therapy (NET) is still remains’ one of the best
solutions of ER+ breast cancers in early stages. Patients must be selected cautiously before
taking either NCT or NET; evaluation of the tumor type, gene expression, size and extent of
the tumor, nodal evaluation, health condition and the age of the patients must come into
consideration as elderly or frail patients are not very suited for chemotherapy [Hyder, T. et al
2021].

Patients that receive NCT have a pathological complete response (pCR) and low recurrence
rate but, only achieved in 20-30% patients and it’s a predictive value depends on tumor biology.
Although, ER+ cancers are less responsive to NCT than other subtypes, in which case they
presented with NET. Patients with HRE2+ and TNBC are more suited for NCT as they have
higher pCR probability [Selli, C. et al 2019].

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NET is proven to be one of the safest and most cost-effective option amongst the patients
because of its availability, applicability and frequently less time involved in health care facility
in compared to NCT. In recent years, clinical trials of new drugs new drugs increased. But,
with 50 – 70% predicted value of NET for ER+ patients, which indicates heterogenous response
from patients leads to the recent interest of identifying reliable biomarkers because pCR is not
an optimal option for HR+ tumors. This led to the development of preoperative endocrine
prognostic index (PEPI) predicting the survival rate after NET using ER status, HER2 status,
ki67 level, tumor size and nodal status. Although, at first PR was not considered as a prognostic
factor in the original PEPI but, later studies show PR expression is an essential prognostic
factor for NET with the cut-off of 50% and later modified the PEPI [Lerebours, F. et al 2021]
[Thomssen, C. et al 2021].

Fig: Integrated mechanism for the target site specific action of SERMs in breast or uterine
cancer
o SERM: Selective estrogen-receptor modulators (SERM) present great therapeutic value
in treatment of breast cancer, osteoporosis and postmenopausal syndromes in recent years.
SERM acts selectively on various estrogen targets as estrogenic or antiestrogenic action
based on the target tissue. With ongoing researches on SERM new classes of drugs are
being discovered and many old drugs tissue specificity also being recognized.
Antiestrogenic effect is strong in mammary epithelium.

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Tamoxifen (brand name – Nolvadex) was the first generation of SERM, developed in
1970s, and being used widely as a treatment for ER+ breast cancer, also can be used as an
osteoporotic drug but, as tamoxifen can also act as an agonist for uterus endometrial
hyperplasia and polyp production, therefore increasing the risk for endometrial cancer
tamoxifen is not prescribed. Also, there’s a second generation of SERM, raloxifene, which
is antagonist to ER on uterus and approved by FDA to treat osteoporosis in postmenopausal
women, also can be used on high-risk breast cancer patients. The advantage over tamoxifen
is reduced effect on uterus. There’s also the third generation SERM, arzoxifene,
lasofoxifene and bazedoxifene, which is under development [Jordan V. C. 2002]. In which
only bazedoxifene is clinically used but, all of them are still under investigation and
recently lasofoxifene has shown potent effect on clinical trials. [Lainé, M. et al, 2021] With
every generation, the specificity of SERM increases as their core structure being refined.

SERM primarily binds competitively with ERα or ERβ and inhibits the estrogen receptor,
recruits co-repressor proteins (i.e., NCoR AND SMRT in case of tamoxifen) and
downregulating pathways involved in HER2, PKC, PI3K to inhibit estrogenic effect on ER
[Feng, Q. et al, 2014]. In tamoxifen it recruits PAX2 protein; high PAX2 supresses the pro-
proliferative ERBB2 protein. In recent studies, TGF- β has also seen to contribute to
antiestrogenic effect; specifically stromal region of breast, which acts as a negative
autocrine molecule. Other studies show tamoxifen can lower the levels of IGF-1 in
circulation in BC patients, which is a potent mitogen and increase sex hormone binding
globulin which limits the binding of free estradiol and reduces the level of TGF stimulation
[Shang, Y. et al 2000]. Also, apoptotic features also been seen in tamoxifen on ER+ cells
which thought to be the result of inhibition protein kinase C, this action also thought to be
the underline cause of tamoxifen’s effectiveness on bipolar disorders [Chang M. 2012]
[Shagufta, & Ahmad, I. 2018]. When tamoxifen was been tested as a drug, it was feared
that tamoxifen will act as an ER antagonist on all tissue including bone which will cause
osteoporosis. But fortunately, the opposite effect was observed clinically because of
tamoxifen’s tissue specific action, and from this the concept of SERMs came.

Pharmacological studies show tamoxifen’s conversion to three active metabolites 1) 4-

hydroxytamoxifen 2) N-des-methyltamoxifen and 3) 4-hydroxy-N-desmethyltamoxifen.
Studies suggest that tamoxifen itself has a lower affinity towards ER (about 7% for ERα
and 6% for ERβ) so it acts as a prodrug via its active metabolites, where 4-
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hydroxytamoxifen (also known as Afimoxifene) and 4-hydroxy-N-desmethyltamoxifen
(also known as Endoxifen) has an affinity of 178% and 338% for ERα and ERβ,
respectively.

All these metabolites are synthesized by hepatic CYP450 2D6 and CYP450 3A4/3A5 and
studies show different forms of CYP2D6 gene have no therapeutic benefit from tamoxifen,
also suffer from relapses from slow tamoxifen metabolism. In recent years,
pharmacogenomics’ impact on drug development and heath care has grown significantly,
tamoxifen derivatives i.e., droloxifene, idoxifene, lasofoxifene, toremifene and ospemifene
are being studied extensively to provide the best possible tamoxifen derivative, modifying
chemical structure, substituting amino alkyl and ether chains with several groups, also
adding additional methylene or heteroaromatic group has shown great results [Shagufta, &
Ahmad,2018].

Fig: Metabolic pathways of tamoxifen in humans, following activation by cytochrome

P450.

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With many benefits, tamoxifen has some common adverse effects also like, hot flashes,
irregular periods, vaginal discharges, hypertension, mood swings, depression, rashes, nausea
and vomiting, with some less common like insomnia, back pain, thrombocytopenia and
cataracts are also seen. And warnings for those who has uterine malignancies, pulmonary
embolism and stroke, and for females, tamoxifen is associated with uterine and endometrial
cancer, also many drug-drug interactions are present with tamoxifen. Although these are
serious but, not fatal however in breast cancer patients, benefits exceed the risks. Also, many
patients develop resistance to tamoxifen which involves HER2, IGFR1, FGFR1, MAPK and

PI3K with altered expression of ERα. Also, some studies shown slicing of NOTCH4 pathway
makes regain of hormone therapy responsiveness [Hayes, E. L. et al 2015].

Also, there is also the second generation of SERM, raloxifene (brand name – Evista), approved
by FDA is 1997 mainly used for the treatment of post-menopausal osteoporosis and also
reduces invasive breast cancer risk. In clinical trials, raloxifene (60mg/day) is 78% as effective
as tamoxifen (20mg/day) in non-invasive breast cancer prevention [Vogel, V. G. et al 2006].
Mechanism of action same as tamoxifen but with opposite effect on breast, uterus
(antiestrogenic) and bone, liver (estrogenic). On receptor level, raloxifene have partial agonist
effect on ERα and pure antagonist on ERβ. Although, it is highly advised that there are cases
of deep vein thrombosis, renal vein thrombosis and pulmonary embolism associated with
raloxifene. Also, common side effects like hot flashes, muscle spasm, infection, insomnia,
nausea and vomiting are documented [Quintanilla Rodriguez, B. S. et al 2021]. There are

16
ongoing studies and trials whether it can be used in malignant BC and extensive used in
hormone therapy for BC in general.

o Aromatase Inhibitors: As estrogen promotes the growth and survival of cancerous

epithelial cell and aromatase being the key
enzyme for synthesis of estrogen, hence
aromatase inhibitors (AI) being one of the
best options for postmenopausal BC
patients as estrogen mainly produced in
peripheral tissues in them. And with the
breakthrough of third generation of AIs
i.e., letrozole, anastrozole and exemestane
is on the verge of replacing tamoxifen as Fig: Metabolic pathways in ER+ cells
affected by AIs. Left side represents cellular
preferred hormone therapy treatment as pathway of ER blocked by AI. Right side
multiple studies shown AIs reduce represents pathways involving ER blocked
SERM and SERM
recurrence rates by 30% approximately in
compared to tamoxifen and also reduced 10-year breast cancer mortality rate by 15% in 5-
year AI treatments, as for that AIs is being the first choice in NET [EBCTCG 2015].

The primary action of aromatase inhibitors being supressing the aromatase enzyme activity, as
aromatase converts androgen to estrogen. Before menopause, ovarian aromatase is responsible
for majority of circulating estrogen and highly sensitive to changes in LH. In postmenopausal
women, the conversion of androgen to estrogen is due to the aromatase activity in adrenal
gland, muscles and adipose tissues. With increasing age, circulating cytokines increase, also
aromatase gene promoter in breast tissues is much more sensitive to inflammatory cytokines
than ovarian LH fluctuations, so it’s no surprise at in breast cancers aromatase activity is greatly
increased in postmenopausal women. AIs supress the activity of aromatase, therefore
decreasing the circulating estrogen which influences proliferation and survival cancer tissues
in breast [Fabian C. J. 2007] [Peters, A 2021].

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With each generation, AIs developed higher specificity for aromatase, greater suppression of
aromatase activity and less side effects.
There are two variants of AIs, steroidal
and non-steroidal. Steroidal AIs (i.e.,
exemestane and formestane) are
androstenedione scaffolds with a
sterane nucleus core, showing
irreversible aromatase inhibition. But,
in non-steroidal AIs (i.e., anastrozole,
letrozole, fadrozole, vorozole and
aminoglutethimide) have no steroidal moiety, azole ring attached a planar aromatic structure
with heterocyclic nitrogen atom and reversable interaction with aromatase. Both are associated
with very rare (1 out of 10,000 patients) adverse effects like ulcers, blisters, allergic reactions,
hot flashes, fatigue and bone density loss on long term use [Geisler, J et al 2008]. As in
premenopausal women’s decreasing estrogen activates HPA axis to produce more
gonadotropins, as ovarian aromatase promoter is highly sensitive to gonadotropins, it will
increase the production of ovarian estrogen. Thus, AIs are generally not prescribed to
premenopausal breast cancer patients. but like tamoxifen, AIs also suffer from the same therapy
resistance problem. This includes MAPK, Akt and PI3K, in this case cancer cells produce
active ligand-independent mutant ERα. Not only that, studies show disturbance in the pro-
apoptotic anti-apoptotic genes which block and resist from AIs apoptotic effect [Hayes, E. L.
et al 2015].

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• ADVANCED STAGE TREATMENTS: Advanced breast cancer depicts
inoperable locally advanced breast cancer, which is not speared and metastatic (stage IV)
breast cancer, commonly speared to lungs, brain, bone and liver. As breast cancer being the
most frequently diagnosed malignancy among women’s and reported 20-30% of the
patients develop metastasis. With current advances it is treatable but, incurable as 2-3 years
being the overall survival rate of metastatic patients. Treatments of metastatic breast cancer
is to cure the symptoms and increase their life expectancy and quality [Hayes, E. L. et al
2015].

With many therapeutic options available, they are divided into two types; first one being
local treatments like surgery and radiation therapy and second one is systematic treatments
like hormone therapy, chemotherapy, targeted therapy and combination therapy. As
metastatic breast cancer considered as incurable, and majorly focusing on life quality and
curing the symptoms surgeries and radiation is not considered. Only for the liver metastasis
surgeries are considered as removal of tumor in metastatic breast cancer patients is a are of
great debate. As for radiation, it is more effective on peripheral malignancy, especially on
CNS metastasis.

As for hormones therapies, it is highly depended on subtypes of breast cancer. As hormone

therapies does not cause any harm compared to other options like chemotherapy, which
have many negative after effect, for metastatic breast cancer patient’s hormone therapy is
likely the first choice. Treatment options for both pre- and post-menopausal women are
different. Here combination therapy plays a big role as combining targeted therapies with
hormone therapy increasing the effectiveness of the therapy [Alkabban, F. M. et al 2020].
o Premenopausal Women: In premenopausal, the source of aromatase is ovaries in
ER+ breast cancer. Premenopausal women’s have less number of options for endocrine
therapies unless they undergo surgical ovarian ablation like oophorectomy, following with
AI, or SERM to limit estrogen production. Or can undergo chemical ovarian ablation with
LHRH agonist like goserelin, which has shown same effect as surgical ablation in many
studies. LHRH agonists interfere with pituitary signals and inhibit ovarian function.

Whether it is surgical or chemical, it is advised to combine with antiestrogenic therapy like

AI or SERM, in a trial comparing LHRH alone and combination therapy, 506 combination

19
 therapy patients shown improvement in response, progression free survival and overall
survival rate [Salkeni, M. A. et al 2017].
o Postmenopausal Women: as in postmenopausal women the source of estrogen
production peripheral tissue. As studies show endocrine therapies are much more effect on
postmenopausal women than premenopausal women. According to the diagnosis,
postmenopausal patients are categorized in two subgroups- de novo metastatic breast
cancer patients and recurrence metastatic breast cancer patients.

As de novo metastatic breast cancer patients which haven’t had any therapy before, are
prescribed with AIs like letrozole with a selective CDK4/6 inhibitor like Palbociclib or
ribociclib. As in cell cycle CDK4/6 binds with cyclin D and progresses through cell division
by phosphorylating retinoblastoma (Rb) protein; here CDK 4/6 inhibitors restrict the cells
to progresses through cell cycle. As in a
trial with 666 post-menopausal de novo
metastatic patients receiving Palbociclib
and letrozole combination therapy
shown greater progression free survival
rate than letrozole alone by
approximately 10 months, as it
irreversibly seizes cell cycle
progression. Although has shown some Fig: Mode of action of CDK4/6 inhibitors

myelotoxic effects like febrile neutropenia (1.8%) is likely due to CDK4/6 inhibitory effect
on bone marrow, leading to nonapoptotic cell-cycle arrest [Corona SP, Generali D et al
2018]. Also, ribociclib is also as good as Palbociclib but, it requires continuous monitoring
due to association with hepatotoxicity. Also, it is not recommended to use CDK4/6 beyond
progression. Although, in PALMO-2 trials, more than 30% of patients shown recurrence
of cancer within 2 years after the therapy, as cancer cells shown resistance to CDK4/6
inhibitors.

20
 In recent years, mTOR inhibitor uses have grown because it could reverse resistance.
Recurrence metastatic patients who had neoadjuvant AI therapy for 12 months, they should
not go for AIs and CDK4/6 combination, they are presented with combination of
exemestane, as steroidal AI with
mTOR inhibitor, like everolimus.
Mechanistic target of rapamycin
(mTOR) which regulates different
cellular, metabolic and physiological
functions including signalling
pathways, growth and proliferation.
mTOR signalling plays a important
role in cancer formation and cancer Fig: Effects of rapamycin and rapalogs in cancer
cell survival as mutations in cells

mTORC1 and mTORC2 alters the signalling cascade in which leads to the hyper activation
of mTOR and cause mutation in tumor suppressor gene as in breast cancer RICTOR, a
component of mTORC2, was found to be amplified. What mTOR inhibitor does is it makes
mTOR binds with rapamycin and rapamycin derivatives, called rapaloges (i.e., sirolimus,
temsirolimus, everolimus) which binds with tacrolimus (FK506BP-12), this complex then
interferes with mTOR activity and downstream the S6K1 and 4E-BP1 as it decreases the
cell mortality, size and cell cycle arrest, also studies shown that it also leads cancer cells to
apoptosis.

Based on studies the combination therapy of AI and mTOR shown improved PFS rate of
approximately 6 months and with some minor adverse effects like stomatitis, pneumonitis
and anaemia in about 3-8% of patients.

Also, there is a second option of using combination of selective estrogen receptor down-
regulator like fulvestrant and Palbociclib as in trial the combination of these two in patients
shown improved PFS by about 6 months with some common side effects like neutropenia,
anaemia, fatigue, headache, nausea and vomiting [Salkeni, M. A. et al 2017].

And as for TNBC patient’s, chemotherapy with taxens, anthracyclines, cyclophosphamide,

flurouracil and platinum agents are the only options available as it has no expression of ER,

21
PR, HER2 and also highly metastatic and poorly prognostic. Also, there is ongoing trails of
targeted therapies like mTOR inhibitor [Wahba, H. A. et al 2015].

In recent years with the improvement of biotechnology, combination therapies with

monoclonal antibody agents like Trastuzumab and Bevacizumab and hormonal agents shown
great result in patients with HER2+/ER+ metastatic breast cancers. Although these are
associated with serious adverse effects so it is still under trails whether it can be used in mass
scale.

Although 50-70% patients shown resistances to single type of hormone therapies so, sometimes
patients can benefit from two or three types of hormones therapies as to counter their drug
tolerances of the body. In general, using combination therapies delivered promising advances
in metastatic breast cancer patients to improve their symptoms and improving the quality of
life to greater extent than previously thought [Lei, J. T. et al 2019].

PROSTATE CANCER
Being the most common malignancy prostate cancer is the second leading cause of cancer
related death in men. Most prostate cancers are slow growing hence there is no initial symptoms
making it hard to diagnose at early stages and also related to age, family history and race. As
6 out of 10 cases diagnosed with prostate cancer are 65 or above with new cases increasing per
year. If cancer is limited to prostate, is considered to be curable. Death mainly occurs when
cancer becomes metastatic and spreads to bladder, bone, spinal cord or brain, this is when
symptoms start to show like fatigue, anaemia, bone pain, renal failure and paralysis due to
spinal metastasis. And prostate cancers are generally considered metastatic. Prostate glands are
primarily made up of
glandular cells producing
fluids that constitutes 30-
35% of semen, require male
hormone androgens to grow
and function properly.
Cancer begins when
glandular cells mutate,
usually starts with the
peripheral basal cells.

22
• Grading System: Gleason system grades prostate cancers according to their tissue
condition under microscope. Commonly scoring from a scale of 3 to 5 from two different
locations. Healthy looking tissues get low score and aggressive ones get higher score,
detecting the growth pattern and searching for a different location and finally adding up the
score with overall score between 6 to 10. This helps to predict the prognosis and deciding
the therapeutic options according to the grade. In 2016 WHO presented a new classification
system based on clinical experiences in past few years as the old Gleason system wasn’t
very good at distinguishing patterns at very low level. The newly modified Gleason system
suggests –
1) Grade group I (Gleason score <6): well-formed health glands.
2) Grade group II (Gleason score 3+4 = 7): predominance of healthy glands alongside
a smaller number of poorly formed, fused or cribriform glands.
3) Grade group III (Gleason score 4+3 = 7): predominance of poorly formed, fused or
cribriform glands and a smaller number of healthy glands.
4) Grade group IV (Gleason score 8): only poorly formed, fused or cribriform glands or
glomerulation.
5) Grade group V (Gleason score >8): lacks gland formation, necrosis with/without
poorly formed, fused or cribriform glands.

23
• Staging: Combining grading system, Prostate Specific Antigen (PSA) system and TNM
system doctors assign the stage of cancer in four different groups –
1) Stage 1: tumor is half or less of one side and hasn’t spread beyond prostate.
2) Stage 2: Still restricted to prostate and further divided into three subgroups according to
the grade –
a) Stage 2A: Gleason score ≤ 7, tumor is not in both lobes and cannot be felt.
b) Stage 2B: Gleason score 7, tumor can be in both lobes and may or may not be felt.
c) Stage 2C: Gleason score 7 or 8, tumor is in both lobes and can be felt.
3) Stage 3: tumor is locally advancing and likely to spread and further sub divided into three
subgroups-
a) Stage 3A: Gleason
score ≤ 8 and hasn’t
spread outside the
prostate.
b) Stage 3B: Gleason
score 8 and starting to
spread into seminal
vesicle but, hasn’t gone
to lymph nodes.
c) Stage 3C: Gleason
score >8 and spread to
lymph nodes.
4) Stage 4: the advanced
stage of cancer where
cancer has spread into
distant parts of our body
and divided into two
subgroups-
a) Stage 4A: cancer has
spread to regional lymph nodes
b) Stage 4B: cancer has spread to distant part of body like bones and brain.

There is also the recurrent stage where cancer comes back after treatment.

24
• Pathophysiology: As mentioned earlier, BRCA1 and BRCA2 are also associated with
prostate cancer as well as over 100 single nucleotide polymorphisms (SNPs) increase the
risk for prostate cancer. Metastatic transformation of prostate cancer includes several steps,
initially starting with prostatic intraepithelial neoplasia (PIN), a condition “defined by
neoplastic growth of epithelial cells within pre-existing benign prostatic acini or ducts”.
PIN is the most established precursor of prostatic adenocarcinoma and classified as low-
grade PIN which shows no abnormal pattern under the microscope and high-grade PIN
(HGPIN) which shows abnormal patterns. HGPIN shares many similarities with prostate
cancer with same number of genetic and molecular markers. HGPIN have four main
patterns according to the presence of prominent nuclei in duct structure – tufting,
micropapillary, cribriform and flat. If the biopsy turns out to have HGPIN it doesn’t always
mean you have a cancer as earlier thought but still there is a very high risk (about 24%)
[Wang, G et al 2018] [Leslie S. W. et al 2021].

HGPIN is followed by localized prostate cancer then progresses towards advanced prostate
adenocarcinoma and then metastatic breast cancer. On the molecular level, insufficient
level PTEN, NKX3.1 leads to the depletion of p27, which normally contributes to
proliferation and survival of prostate cells. Prostate cancers are usually lack zinc, which is
a core component of prostate gland as it produces citrate, an important component of semen
and it requires zinc. Absence of zinc is related to suppression of zinc transporter 1 (ZIP1)

Fig: Molecular Events in Prostate Cancer formation.

25
 encoded by SLC39A1 gene [Nelson, W. G. 2002]. Androgen receptors (AR) plays a pivotal
role in prostate cancer cell survival. Point mutation (15-30%) and amplification (30-50%)
of AR are two of the major important contributing factors in prostate cancer development.
Also, loss of AR co-repressor NCOR1/2, which contributes to the castration resistance
where cancer cells start to produce their own androgen [Fujita, K 2019].

Apart from genetic factors prostate cancer is also linked with food habits. As studies show there
is a relation of milk consumption and prostate cancer development. High calcium intake, lower
vitamin D levels, red meat consumption all are pose risk to develop prostate cancer. Also, fish
consumptions and vegetable diet shown to lower the risk of getting prostate cancer.

• EARLY STAGE TREATMENTS: As being a slow growing disease, the first thing
to do is to decide whether the treatment is needed or not, especially in low-grade tumors,
as it may cause complications in later life is patient is young. Active surveillance is first
thing doctors suggest with periodic PSA, DRE testing and at least one biopsy in 12 to 18
months. If PSA score gets higher (25%), doctors will recommend for further treatment
options. Surgeries are also the option if patient wants to avoid any future complication as
in early stage, tumor hasn’t spread so surgically removing prostate (prostatectomy)
sometimes cure the disease. There is a new treatment emerging, called cryosurgery where
cold gas is used to freeze and kill cancer cells but for its dangerous side-effects it is not
recommended. Studies show hormone treatment in early-stage prostate cancer won’t make
any difference in the men’s lifespan so, hormone therapies aren’t recommended to early-
stage prostate cancer patients.
• ADVANCED STAGE TREATMENTS: As being a slow growing cancer, often
prostate cancer doesn’t progress to advance stages with routine surveillance and early-stage
treatments. Advance stage cancers are stage 3 and 4 cancers where the tumor is locally
advanced and may or may not be metastatic. Metastatic prostate cancer speared to the
lymph nodes and surrounding organs like bones, spine and brain. The most commonly used
treatment is androgen deprivation therapy (ADT); as prostate cancer cells are androgen
dependent; androgen deprivation leads to the reduction of tumor by 30-40%. There are
various types of ADTs available, one of most common is LHRH analogues [Gamat, M. et
al 2017].
o LHRH Analogues: Luteinizing hormone- releasing hormone (LHRH) or gonadotropin-
releasing hormone (GnRH) analogues are synthetic drugs that affects gonadotropin and sex

26
 hormone release. First discovered in 1970s. There are two types of analogues, agonist and
antagonist. Both comes with sets of advantages and disadvantages and both work
differently.
➢ LHRH Agonists: Two FDA approved LHRH agonist include leuprolide (brand name-
Lupron) and goserelin (Brand name – Zoladex). As when LHRH agonist is given initially,
the testosterone levels rise in a couple of weeks which can briefly stimulate the growth of
prostate cancer cell, known as “flare response” which can be blocked by using 5α-reductase
inhibitors (finasteride), flutamide, bicalutamide, nilutamide, diethylstilbestrol,
ketoconazole, and cyproterone acetate. This is usually short lived (7-10 days). This happens
due to the agonism of LHRH receptor initially increasing LH and FSH level. Constant
exposure to LHRH causes downregulation of LHRH via negative feedback loop and
desensitizes the receptors. This causes androgen levels in the body fall by 5-10%, as low
as orchiectomy level known as “castrate level”. Because of this the growth of prostate
cancer cells slows down to as low as 95% [Turner, B. et al 2012].
As like all therapies it also has some side effects. Common side effects of LHRH agonist
burning, redness, pain, hot flashes, weight gain, headaches, depression, gynecomastia,
impotency and osteoporosis. Studies show patients after LHRH agonist treatment, heart
problem increased by 30%. Whereas LHRH antagonists have different sets of problems
like injection site reactions, chills, anaemia, diarrhoea, testicular atrophy, erectile
dysfunction with some common ones like hot flashes, weight gain, gynecomastia.
➢ LHRH Antagonist: For past 25 years, patients with advanced prostate cancer provided
with LHRH agonist. However, with the introduction of LHRH antagonists and the benefits
it shows over agonist’s limited advantages, LHRH antagonists are recently accepted as
safer alternative of ADT. As LHRH agonist’s flare reaction if one of down sides of it, as it
associated with pain, urethral obstruction and spinal cord compression which are life
threatening. In degarelix trials, it is as responsive as leuprolide. Rapid suppression in the
testosterone (95.5-96.1%), median LH levels also with FSH values going down which
leuprolide cannot do effectively. Also, degarelix provide rapid reduction of PSA levels
(65% from baseline in 14 days) than leuprolide (14%). As for its limitations, patient
acquiescence with treatment and cost-effectiveness are important issues as ADT is
administered for long periods of time. Degarelix in its current form, is administered
monthly, as opposed to the longer and more convenient depot formulation of LHRH
agonists. This is certainly one of the major limitations of the newer agent, since most

27
 patients treated with LHRH agonists are treated on an every-3-month basis, which reduces
the treatment cost by taking less number of injections in four-year treatment [Crawford, E.
D et al 2009] [Engel, J. B et al 2007].

Fig: Mechanism of action of LHRH/GnRH agonist and antagonist

o Anti-Androgen Therapy: Despite subsequently lower the testosterone level,

androgen production still can persist and it is a known fact that prostate cancer cell can
produce androgens, called castration-resistance. Hence other therapies are combined for
better outcome. Here, anti-androgen therapies (AAT) are being used as these drugs simply
blocking/inhibiting androgen receptor, preventing androgens like testosterone or
dihydrotestosterone (DHT) to work. Mechanism of action may differ in different drugs like;
androgen receptor antagonists which is most common type of anti-androgen drug used,
which includes flutamide (brand name – Eulexin), bicalutamide (brand name – Casodex),
nilutamide (brand name – Anandron), enzalutamide (brand name – Xtandi), and
apalutamide (brand name – Erleada). AR antagonist works simply by binding competitively
to ARs inhibiting binding of androgen. AR antagonist are of two types based on chemical
structure – steroidal and non-steroidal.

Steroidal AR antagonist have similarities with other steroid hormone, for that it tends to
have off-target hormonal action like progestogenic, glucocorticoid and anti-
mineralocorticoid and also partially agonistic hence activates AR receptors in absence of
stronger AR agonist causing the acceleration of prostate cancer growth. Till date there is
only one steroidal AR agonist, cyproterone acetate (brand name – Androcur).

28
 In contrast, non-steroidal AR antagonist have relatively low AR affinity in compared to
steroidal ones but, they do not show any off -target hormonal reaction because they are
silent AR antagonist, means they have non-intrinsic activity for activating the receptor, also
called pure antiandrogen, blocking receptors in the central nervous system and negative
feedback mechanism of testosterone on hypothalamus and hypophysis.

Even though steroidal AR antagonist have higher effectiveness on lowering testosterone

(70-80%) but, due to its limitations and adverse effects non-steroidal antagonists are mostly
used in prostate cancer treatment. There are some common side effects anti androgens like
loss of muscularity, feminization in males, bone density loss, infertility, hot flashes,
depression, fatigue, nausea and vomiting [Helsen, C. et al 2014].

Fig: Mechanism of action of enzalutamide (AR antagonist) in the AR signalling pathway

There is also a new type of anti-androgen drug where its binds to N-terminal domain of AR
rather than the ligand-binding domain, preventing protein-protein interactions and stopping
transcription in cancer cells. These includes bisphenol A diglycidyl ether (BADGE), ralaniten
and its prodrug, ralaniten acetate. These are all under trials and thought to be have more
effectiveness than traditional AR antagonist. Also, selective androgen receptor degraders
(SARD) are currently under development and example of it is dimethylcurcumin.

• mCRPC: However, majority of patients can be castrate resistance, forming metastatic

castration-resistance prostate cancer (mCRPC). In mCRPC cancer cells stop responding to

29
 lower levels of testosterone and starts to produce its own androgens; this can be happened
in many was like production of intratumoral androgens, increased expression of ARs and
mutation of ARs. For mCRPC all the above-mentioned treatments are approved by FDA
but, for curing symptom as expected life benefit is still controversial. Although many AR
targeted agents under development for mCRPC such a s galeterone, a triple mechanism
steroidal antiandrogen which acts as AR antagonist, down-regulator, keto inhibitor, kinase
inhibitors, HSP inhibitors and CYP17A1 inhibitor. Although trials are ongoing on going.
Studies indicate that CYP17A1 inhibitors like abiraterone, orteronel and gelaterone despite
the castrate level still can act on AR as overexpression of AR upregulates CYP17 for
androgen synthesis [Gomez, L et al 2015]. Also, N-terminal domain antagonists shown
progression on resisting CRPC and trails are in elevated phase. but, as of now systematic
therapies are the best for mCRPC which shown survival benefits. This includes docetaxel
(brand name – Taxotere) a microtubule inhibitor. Selective androgen receptor degraders
(SARD) are also under investigation for potential treatment option for prostate cancer. In
SWOG trials docetaxel shown a medial OC gain of 1.9 to 2.4 months. In addition, since
docetaxel developed, FDA approved 5 newly developed drugs for treatment of mCRPC;
Sipuleucel-T, Cabazitaxel, Abiraterone acetate, Enzalutamide and Radium-223. In them,
Enzalutamide is a non- steroidal AR antagonist [Teo, M. Y et al 2019].

ENDOMETRIAL CANCER
Uterine endometrial cancer is the most common gynaecological malignancy in women, over
66,750 new cases in American women are expected and 12,940 deaths will happen due to
endometrial cancer this year with increasing
cases each year, endometria cancer being sixth
most common cancer occurs in women. With 5
years of overall survival depending upon the
stage ranges from 74% to 94% in patients without
metastasis and as low as 20% in stage 4
metastatic. Trials are ongoing to find the best
balance the survival and quality of life. as low as
20% in stage 4 metastatic EC

Endometrial cancers (EC) are defined as tumor

originating in the uterine body, and can arise from the inner lining of the uterus, called

30
endometrium. There two major classes of uterine cancer; adenocarcinoma, arising from
endometrium (75-80%) and sarcomas, arising from myometrium. Both are treated differently.
ECs primarily affect postmenopausal women of about 60 or above years of age. But also, young
premenopausal women are also diagnosed with EC, they tend to have increased BMI or genetic
factors as well.

• Risk Factors:
o Estrogen: The main contributing factor of EC is estrogen. In postmenopausal women
estrogen production happens in peripheral tissues like adrenal gland, along with loss of
negative feedback, inhibin B mediated inhibition on FSH increases gonadotropin level in
serum. This in turn, increased androgen or estrogen production in peripheral tissues.
Prolonged exposure to estrogen in compared to progesterone causes uterine lining
thickening and tumor formation. Progesterone inhibits estrogen-induced endometrial
growth during the luteal phase while also transitioning the endometrium to a receptive state
of implantation. This balance between estrogen and progestogens is often dominated by
estrogen during cancer formation [Rodriguez, A. C. 2019].
o Obesity: One of the major contributing factors into this is obesity (3-fold increase). High
adipose tissue content causes excessive peripheral conversion of androgen to estrone,
causing increased proliferation of endometrium therefore evolving into hyperplasia.
Finally, leading to carcinogenesis.
o PCOS: Polycystic ovary syndrome (PCOS) also can contribute to ECs as it causes irregular
ovulations causing obesity. Obesity is a risk factor for PCOS, although many nonobese
women develop PCOS and many obese women do not exhibit PCOS. In PCOS
progesterone levels are not always reduced and the levels of other hormones can be
affected.

Hormone replacement therapies (HRT) during menopause via estrogen to control menopausal
syndrome causes high exposure to estrogen, developing risk of getting EC if not balanced with
progestin. Also, early onset of menarche, nulliparity, infertility and late menarche are also
associated with ECs. Although, majority of EC are sporadic but, 5% of cases are hereditary.

31
• Pathophysiology: Genetically, phosphate and tensin homolog (PTEN) encoding gene
is altered in most ECs about 37-83%. PTEN exerts effects on lipid phosphate which causes
arrest of cell in G1/s phase, upregulates apoptosis, downregulation of BCL2 and stimulate
MAPK signalling. So, alteration in PTEN causes uncontrolled cell growth and escape from
apoptosis. Also, in 10-26% shown KRAS proto-oncogene mutations. KRAS gene is
necessary for initiation of Raf and PI3K signalling cascade. β-catenin and microsatellite
instability (MSI) are also involved in the causes of genetic alteration in endometrial cancer
for about 20 – 45% [ Ohgami, T et al 2014].

Fig: Models for type I and type II endometrial carcinogenesis.

(A) Type I and (B) type II. The red and blue boxes indicate oncogenes and tumor suppressor
genes, respectively.
Genetic disorders also contribute to ECs. In Lynch syndrome, which happens due to
mutation in one of four DNA mismatch repair gene; MLH1, MSH2, MSH6 and PMS2,
there is a is risk of getting EC (40-60%), which comes from MLH1 promoter
hypermethylation. Also in Cowden syndrome patients, associated with PTEN mutation,
have a higher risk of getting EC (19-28%), usually in age of 70 [Passarello, K. 2019].

About 90% of women with EC have abnormal vaginal bleeding occurs as the first sign with
bleeding, pelvic pain, painful intercourse as common symptom and development of
oligomenorrhea or amenorrhea and signs of defeminization after regular menstruation. Doctors
usually seek for medical history of the patients and physically examine to proceed further
biopsy to confirm the disease [Casey, M. et al 2021].

32
• Staging: According to FIGO (International Federation of Gynaecology and Obstetrics)
system and the American Joint Committee on Cancer TNM staging system endometrial
cancers are divided into 4 major stages on the basis of TNM method by tissue examining –
1) Stage 1: cancer is confined to the uterus and hasn’t speared to lymph nodes. Further
divided into two subgroups –
a) Stage 1A: tumor is confined into endometrium of the uterus
b) Stage 1B: tumor has grown from endometrium to myometrium
2) Stage 2: cancer has spread into cervix stroma but, hasn’t spread to lymph nodes.
3) Stage 3: cancer has spread to vagina, ovaries, bladder and outside of the uterus and
further divided into three subgroups –
a) Stage 3A: tumor has spread to serosa and ovaries and/or fallopian tubules
b) Stage 3B: tumor has spread to vaginal tissues
c) Stage 3C1 and 3C2: tumor may or may not have spread to distant tissues but,
has spread to pelvic lymph nodes or around aorta in 3C2.
4) Stage 4: cancer has spread in not only bladder, vagina but, also distant parts like lungs
and bones through lymph node and blood circulation.

In type I endometrial cancer, the PTEN pathway is the most frequently mutated (more than
90% of lesions) along with PIK3CA pathway, MSI, KRAS, β-catenin, 12FGFR2 mutation.

33
 Type II endometrial cancers (serous adenocarcinoma) include a range of histological
subtypes, each showing distinct molecular and genomic features but 90% of the have p53
mutations but, PI3K, p16, Wnt/β mutations and FGFR amplification are also seen.

• EARLY STAGE TREATMENTS: At the early stages, after diagnosed with EC

that are confined to uterus and has a very low
risk is go through hysterectomy where
cancer is not speared to lymph nodes but, for
additional safety, lymphadenectomy is also
done to surgically remove lymph node;
although there is a growing controversy
surrounding lymphadenectomy in low grade
endometrial carcinoma because of
additional risk factors it comes with like
patients who have both surgeries take simply Fig: Types of hysterectomy
longer operation time, hospital stay and
additional medical care with no survival benefits getting from it which shown in many
randomized studies. Lymphadenectomy provides benefit to patients with ECs clinically
confined to the uterine corpus hence rejecting lymphadenectomy in low grade can preserve
positive pelvic sentinel nodes. While hysterectomy alone can provide 95% relapse-free
survival in patients with low grade endometrial cancer.
• ADVANCED STAGE TREATMENTS: ECs that has spread to uterine body and
cervix radical hysterectomy is the go-to recommendation for treatment with addition
adjuvant therapy to further improve overall survival by 40- 80%; which include
chemotherapy. Patients treated with adjuvant chemoradiation followed by chemotherapy
tolerated and completed treatment without major toxicities apart from haematological side-
effects [Emons, G. et al 2019].

Hormone therapies are more suited in metastatic stage, especially in low grade recurrent
ECs as it slows the growth of tumor and often used alongside with chemotherapy.

o Progestin: The main one being the use of synthetic progestins, progesterone like drugs
as endometrial cancer cells respond to progesterone; it basically helps to reverse
endometrial hyperplasia by activating PRs and resulting in stromal decidualization and
subsequent thinning of the endometrial lining. In case of recurrent cancer there is down

34
 regulation of PR so high doses of progestin still may cause lower response.
Medroxyprogesterone acetate (brand name – Provera) and Megestrol acetate (brand
name – Megace) are two of the most commonly used progestin supplements used in
endometrial cancer, others include gestonorone caproate (brand name – Depostat) and
hydroxyprogesterone caproate (brand name – Delalutin) were also approved by FDA.
Progestins also comes with come common set of adverse effects like hot flashes,
palpitation, weight gain, depression, nausea and vomiting.

Also, there are some commonly used hormonal drugs for cancer treatment like aromatase
inhibitors i.e., letrozole, anastrozole and exemestane is used to treat postsurgical estrogen
levels as peripheral tissues make estrogen; LHRH agonists i.e., goserelin and leuprolide is
used to lower estrogen levels of ovaries in premenopausal patients and also tamoxifen has
anti-estrogenic effect to.

OVARIAN CANCER
As being the fifth most common cause of cancer related deaths in women, ovarian cancer
occurs in 2.5% of cancers in women. The American cancer society estimates about 21,410
women will be diagnosed with ovarian cancer in 2021 and 13,770 women will die. Even
though the mortality rate has been decreased since the advancement of medical science. 1
out of 78 women can develop ovarian cancer and chance of death is 1 out of 108. Most
ovarian cancers are diagnosed at age of 63 with approximately 5 years of survival rate also
there are high rates of recurrences observed.

35
Ovarian cancer is malignancy initiated in the ovarian tissues, most commonly in epithelial
cells. Remember, many ovarian cancers can initiate in fallopian tube as molecular profile
of cancerous cells in fallopian tube, ovaries
and peritoneum look all the same. Due to the
indistinct nature of initial signs and symptoms,
most of the time cancer goes unnoticed and
symptoms gets serios once the disease
progresses. Initially there are symptoms like
bloating, irritable bowel syndrome (IBS),
abdominal and pelvic pain, loss of appetite and Fig: Origin cites of ovarian tumors
frequent urination. Once the disease
progresses symptoms get serious like development of ovarian torsion which itself can cause
severe pain including swelling, vaginal bleeding and teratoma syndrome development.

o Classification: There are three main types according to the origin of the tumor –
epithelial (95% of cases), germ cell and sex-cord-stromal, both combined 5% in all
ovarian cancer. Epithelial tumors are originated from ovarian cell surface. Germ cell
and stromal tumors originate from reproductive cells and connective tissue cells,
respectively. There is also a fourth type of unknown origin called small-cell
carcinomas, which are extremely rare. Histologically epithelial ovarian cancers are
further subdivided into four category –
1) Serous carcinoma: being the most common (75%), it has a low-grade (10% of all
serous carcinomas) and high grade (90% of all serous carcinomas) subcategory.
Low-grade serous carcinomas (LGSC) show minimal nuclear atypia. mitosis is rare
and less molecular abnormalities. In the contrary, high-grade serous carcinomas has
notable nuclear atypia and mitosis under microscope (>12/10 high-power field) and
serious amount of abnormalities in the cell. P53 mutations are common in these.
2) Endometrioid carcinomas: these are diagnosed at early stages and usually
originate form endometriosis. Prognostically it is better than all other types because
it is chemo-sensitive and respond to treatments better. Biopsy reveal cystic areas
showing soft masses and bloody fluid, with less common solid areas showing large-
scale haemorrhage and necrosis. β-catenin and PTEN gene mutation is the most
common molecular abnormality.

36
 3) Clear-cell carcinomas: account for 10% of all epithelial cancer and mostly seen in
Asian origin women. with relatively good prognosis clear cell carcinomas are
diagnosed majorly in early stages. They show cellular clearing, cystic growth
pattern, and a characteristic hobnail growth pattern. BAX and BCL-2 over-
expressions are two major molecular abnormalities including PIK3CA mutations.
4) Mucinous carcinoma: being the least common of all, mucinous carcinomas are
often heterogenous, diagnosed at early stages and also related to metastasis from
gastrointestinal tract. KRAS and ERBB2 mutations are common in these
carcinomas.

Fig: Histological subtypes of ovarian cancer

a) High-grade serous carcinoma (HGSC)

b) Serous tubal intraepithelial carcinoma (STIC), they are thought to be precursor for HGSC
and has same morphological features as HGSC.
c) Low-grade serous carcinomas (LGSC)
d) Clear-cell carcinoma
e) Endometrioid Carcinoma
f) Mucinous Carcinoma

Also, epithelial ovarian malignancies have two types of tumors, type I and type II, formed due
do continuous ovarian cycles causing inflammation and endometriosis. Type I tumors are seen
in low-grade, serous, endometroid, clear-cell and mucinous carcinomas. In the contrary, type
II tumors are seen exclusively in high-grade and advanced carcinomas [Stewart, C et al 2019].

• Pathophysiology: For decades it was though that ovarian surface is the origin site of
cancer. But, in 1970s a hypothesis stated that ovarian surface epithelial cells underwent

37
repeated stress through multiple rounds of ovulation, leading to inflammation, DNA
damage, and the initiation of tumor formation. This supports that fact of decreasing ovarian
cancer due to high usage of contraceptive pills as it inhibits ovulation. A second theory of
ovarian cancer precursor development in fimbria from serous tubal intraepithelial
carcinoma (STIC), which states HGSC are instead metastatic lesions from fallopian tubule
epithelial cells. To support this, women carried BRCA mutation have salpingo-
oophorectomy done and shown to prevent from higher risk. Biopsies showing TP53
alterations just like HGSC [Hirst, J et al 2018].
Ovulation have direct action on formation of ovarian cancers, women’s having incomplete
ovulation have high risk of getting cancers. During ovulation, overlying ovarian cells
incorporate into the ovary and proliferate, called spurring cell proliferation. This can
damage DNAs due to inflammatory oxidative stress during release of egg from follicles.
Continuous or incomplete ovulation can cause retrograde menstruation, causing more
oxidative stress development and release of pro-inflammatory cytokinin (IL-6, IL-1, IL-8),
leading to the mutations in the DNAs. Akt is one of the most frequently altered pathways

Fig: Role of ovulation and inflammation in ovarian carcinogenesis

in this process including BRCA1/2, BRAF, NF1 and CDK12 mutations. Also, type I
ovarian carcinomas have MSI including BRAF, PTEN and KRAF mutations. In type II,

38
 with p53 mutations there are BRCA1/2 mutation, notch and FOXM1 pathways
dysfunctions. This contributes to homologous DNA repair deficiencies [Karnezis, A. N., et
al 2017] [Macciò, A. et al 2012].

As genetics being one of the major contributing factors, having family history is very beneficial
for treatments. As mutations of BRCA1/2 and MMR genes are majorly associated with genetic
risk of ovarian cancer (about 10-40%). While genetic factors have high risk of developing
ovarian cancer, lifestyle factors also shown significant influence on ovarian cancer. Some
studies shown dietary fibres intake have some relation with ovarian cancer. Also, low level of
vitamin D is associated with increased risk of getting ovarian cancer. Smoking seems to have
relation with developing ovarian cancer but alcohol consumption does not [Stewart, C et al
2019].

Often times due to presence of vouge symptoms ovarian cancers are hard to identify although
regular health check-ups, pelvic examination is recommended for early detection. About 20%
of ovarian cancers are diagnose in early stages and 94% of patients living longer than the
overall 5-year survival rate if diagnosed early.

• EARLY STAGE TREATMENTS: At early stages of the cancer, it is recommended

to take neoadjuvant therapy usually targeted or chemotherapies to decrease the size of the
tumors, drugs like carboplatin and liposomal doxorubin/carboplatin regimens are approved
by FDA. New treatments like poly ADP-ribose polymerase (PARP) inhibitors, PARP
protein help in self-regeneration of cells when DNA damages. New drugs like Olaparib,
rucaparib have been introduced and combined with chemotherapy has shown great results.
Also, combination treatment of vitamin D3 and chemotherapy is also under development
[Arora, T. 2021].
• ADVANCED STAGES TREATMENTS: About 75% of ovarian cancers are
presented in advanced stages. They are recommended to perform debulking cytoreductive
surgery. Especially when tumor is metastatic and spread into nodules so, nodules of 1 cm
in diameter are all considered into the surgery. Also, chemotherapy is applied to reduce the
tumor size to meet optimal surgical status. Various randomized trials shown combination
of neoadjuvant therapy with surgery has better survival outcomes in invasive metastatic
tumors.

39
 But, large tumors or residual tumors after initial operation have been shown to have
negative side-effects on efficacy of treatment. They can block perfusion to the area, which
can lead to cellular and tissue damage, as well as possible growth of multidrug-resistant
clones [Arora, T. 2021].

HORMONE TREATMENT: Regardless of having estrogen receptors in 60% of tumors,

ovarian cancer cells rarely respond to hormonal therapies. A Cochrane studies show lack of
evidence assessing the effectiveness of tamoxifen on recurrent ovarian cancer and large
randomized controlled trial needed to find best supportive evidence. Most trials of hormonal
treatment in ovarian cancer have been retrospective, involved only limited numbers of patients,
and lacked important patient-related data and information pertaining to tumor characteristics.
In addition, there is no synergy between different degrees of potency and in different dosages
of hormone in these studies. A literature review shows that response to hormonal therapy even
in a preterminal setting, is modest, with about 8% objective response but almost no side effects.
In a similar patient setting, more toxic therapeutic agents do not yield a better response [Makar
A. P., 2000]. Meta-analyses of large datasets including the Million Women study have shown
that the risk of ovarian cancer is increased 1.28-fold in women using HRT compared to never
users. Estrogen-only formulations appeared to carry a higher risk than estrogen / progesterone
combinations and both dose and duration are associated with enhanced risk.
Despite of all, hormones therapies are one of the leading research subjects in ovarian cancer.
As letrozole trails shown ERα expression decrease and disease stabilization, anastrozole and
exemestane shown disease stabilization in 42% and 38% of patients in trials, respectively.
Summarizing, approximately 30% disease stabilization and 10-155 of response rate is received
with AIs. Several clinical trials investigating anti-estrogen agent use in ovarian cancer are
underway at present. Trials comparing tamoxifen and thalidomide in “biochemically recurrent”
disease, tamoxifen shown superior results in PFS and OS. Fulvestrant trials also shown disease
stabilization in 50% of patient but, response rates were low. A study on 10 ovarian cancer
patients using combination of anastrozole and the mTOR inhibitor everolimus has shown
disease stabilization.
As the data suggests there is significant effect of hormone treatment in ovarian cancer, although
the trials are not large scale and optimal effect on population is still not defined [Langdon, S.
P. 2017].

40
METHODOLOGY:

1. Search strategy- A systematic review was conducted with reporting topics

according to PRISMA guideline the electronic database “PUBMED” was used foe
searching the required papers. The was conducted by the keywords- Hormone therapy,
hormone therapy oncology, breast cancer, prostate cancer, ovarian cancer,
endometrial cancer. The search was limited to full text availability and English
language.

2. Inclusion and exclusion criteria- Research papers were chosen on the basis of
each topic discussing in the review. I have taken such papers which supports each of
the topic covering in this review individually. All those paper that supports to establish
possible link among the subtopics for fulfilment of the review were included and rest
was excluded.

3. Selection process- The electronic database showed around 540 records after
searching specific topic. Paper from additional source was 50. After the removal of
duplicate paper 356 records were there. 184 abstract was screened. Among them 57 full
texts were downloaded. 17 studies are focused for writing of this review.

4. Data extraction- 26 papers were studied well and important part was noted. Various
related papers were studied because of extraction of relevant date for proper
summarization of the conclusion. The review was tried to keep as far as self-
explanatory. And every diagram flowchart and writing were modified uniquely from
references and Google.

41
 Records identified Additional records
Identification

through database identified through other

searching (n =540) sources (n =50)

Records after duplicates removed (n =356)

Screening

Records screened (n Records excluded

=184) (n =172)

Full-text articles Full-text articles

Eligibility

assessed for eligibility excluded, with reasons

(n =26) (n =10)
Included

Studies included in
qualitative synthesis (n
= 94)

42
RESULTS:

As from the above review on hormone therapies in various hormone sensitive cancers, the
results show not only that hormone therapies are much safer in patients with minimum adverse
effects but, also much more cost-effective and readily available for patients than its
counterparts like chemotherapy and radiation therapy as there is high chance of toxicity and
not suited for aged or frail patients. Hormone therapies shown great numbers in overall survival
rate in cancer patients and also improving their quality of life. Although we can see that not
every cancer is sensitive of hormone therapies and sometimes cancer cells can produce
resistance to a specific therapy, in that case therapies need to be change which can result in the
increase in the predicted cost of therapy but, still it is less than the other therapies in the market.

DISCUSSION:

In this review, we came to know that hormone therapies are widely used as one of the primary
modes of treatment in hormone sensitive cancer patients, more in the frail or aged patients. but,
not only aged patients, young patients who are suffering from early stages of hormone sensitive
cancer specifically breast cand prostate cancer, they are presented with hormone therapy
treatment options hormone treatment can supress the growth or to some extent cure the tumor
and stop the tumor to become metastatic, avoiding the patients to go under surgery or highly
toxic therapies that have various of life-threatening adverse effects. As well as in many of the
cases hormone therapy can be used with other therapies like surgery, chemotherapy, radiation
therapy or targeted therapy as a combination therapy when cancer progresses to advanced
stages like in breast cancer and in endometrial cancer. Combination therapy has shown great
results over single use of hormone therapy or any therapy instead, it increases the efficacy of
the treatment and sometimes decreasing the amount of side effects. But, using combination
therapy can cause adverse reactions sometimes so proper long-term clinical trials must be done
before general use.

We also came to know that there are some major limitations of hormone therapy. One of them
being cancer cells resistance to hormone therapy. As we found out cancer cells produce
resistance to hormone therapy if they are used in long term, not only that they colonize the
resistance cell and spreads it. Although there are studies showing how to counteract the
resistance but, this is in early stages of trials and going with another therapy increases the

43
predicted cost of the treatment. Another one is, not all cancers respond to hormone therapy like
TNBC as it does not show any hormone receptors on the cancer cells. Also, in case ovarian
cancer even if it expresses receptor, it shows little or non-efficacy upon using hormone
treatment, although clinical trials are ongoing to develop suitable hormonal treatments for
ovarian cancer. Also, hormone therapy treatments are usually long term, so it can be tedious to
patients especially young patients, somewhat costly, although not as much as other treatment
options.

CONCLUSION:

In summary, hormone therapy has major impact in cancer related treatments for it’s effective,
easy and innoxious implication over other options. Hormone treatment showing not only it can
be used as a single treatment method but, also combining with other therapies like
chemotherapy, targeted therapy or surgery made the treatment efficacy increase with good
overall survival rate and quality of life. Most importantly in the sea of expensive cancer
treatments, hormone therapy is comparatively less, easy accessibility as hormone treatment
come in a form of drug, readily available in the market for easy use, can be administered via
injection or can be taken orally, making it much more accessible for general patients who
cannot afford high treatment cost unlike in chemotherapy or surgery. However, due to HR
dependency, cancers that doesn’t express HR cannot be treated with hormone therapy, also
some cancer even though express HR, they are poorly responsive. Also, hormone therapies are
kind of long treatment process so it may become tedious to some patients.

As the studies and clinical trials progresses more and more new types of hormone therapies
being discovered for more cancer types and not only that, new drugs of existing therapies are
also being under trial to provide more efficacy and faster treatment process. Clinical studies
showing female sex hormones have possible effect on glioma and meningioma. With ongoing
trials of new N-terminal AR antagonist, new generations of SERM and AIs showing great
results over older generation drugs in clinical trials. Also making combination therapy more
effective as new drugs being discovered including co-relationship with other hormones are the
leading research topics in recent days. But, all of them need more large-scale trials and clinical
data before reaching general use. With these ongoing researches to slowdown the progression
of cancers, that thought will never be cured, can eventually be cured and not only their
symptoms but also the overall disease.

44
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