Role Of P53 Signaling In Breast Cancer Development And

Diagnostics

BY

KUMARI PRIYA (12326607)

SUBMITTED TO: DR. ANURADHA SHARMA

SUBJECT: ADVANCED CELL BIOLOGY

DEPARTMENT OF ZOOLOGY
UNIVERSITIY OF BIOSCIENCE AND BIOENGINEERING
PHAGWARA, PUNJAB

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Introduction

Breast cancer develops when normal breast cells transform into malignant cells that grow and create
tumors. Breast cancer is most common in women and individuals assigned female at birth (AFAB)
over the age of 50, although it can also afflict males and people assigned male at birth (AMAB), as
well as younger women. Breast cancer can be treated with surgery to remove tumors or with
chemotherapy to eliminate malignant cells.(1)

An estimated 30% of breast cancer incidences are linked to modifiable risk factors such as obesity,
physical inactivity, alcohol consumption, they may be avoidable. Secondary prevention by
mammography screening, together with break thoughts in therapy, has been linked to significant
reduction in breast cancer mortality rate.

Prevalence

Breast cancer is the commonest malignancy among women globally. It has now surpassed lung
cancer as the leading cause of global cancer incidence in 2020, with an estimated 2.3million new
cases, representing11.7% of all cancer cases.(2) ).

According to the most recent study results, Kerala has India’s highest cancer rate. Mizoram, Haryana,
Delhi, and Karnataka are among the other Indian states having high cancer rates. Mizoram has the
highest rate of cancer deaths in the country, followed by Kerala and Haryana. Breast cancer incidence
rates have risen by 0.5% per year over the last four decades, with 287,850 and 297,790 new cases of
invasive breast cancer expected to be diagnosed in the United States in 2022 and 2023, respectively.
(3)

As the most frequent cancer type in Indian women, women in their early thirties to fifties are at high
risk of developing breast cancer, and the risk grows until it reaches a peak by the time they are 50-64
years old. One in every twenty-eight Indian women will acquire breast cancer in her lifetime. It is
higher for urban women (1 in 22) than for rural women (1 in 60)

Impact of Breast Cancer on Individual and Society

To assess the impact of these expert opinion guidelines, as well as the overall impact of the
pandemic, the ASBrS leadership formed a working group in march 2020 to develop a COVID-19
supplemental module to the existing Mastery of Breast Cancers Surgery registry. The ASBr Mastery of
Breast Surgery Database was created in 2006 as a web- based platform for the physicians to
document their breast procedures and surgeries, as well as patient care outcomes, with the purpose
of allowing internal performance review and same peer comparisons. The database contains de-
identified, Health Insurance and Accountability Act (HIPPA)- compliant information about patients,
procedures, risk stratification, and demographic data about providers) .(4)

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Types and staging of Breast Cancer And How Staging Is Used To
Determine The Extent Of Disease

Breast cancer is defined by tumor size, nodal involvement, metastasis, and particular biomarkers
such as estrogen receptors, progesterone, receptors, and the ERBB2 receptor (previously HER2).(5)
After a histologic diagnosis of breast cancer, all pathology samples should be examined for estrogen
receptors, progesterone receptors, ERBB2 status.(6)(7) Breast show none of these markers as
referred as triple-negative.

Ductal carcinoma is a non invasive stage 0 Breast cancer. Early invasive cancer refers to stages
1,2a,3b, while locally progressed cancer refers to stages 3a, 3b, 3c. All of these phases of Breast
cancer are nonmetastatic. Metastatic breast cancer is defined as stage 4.(8)

0 Stage Non Invasive Breast Cancer

DCIS is a type of pure, non invasive cancer detected by mammography, which shows
microcalcifications restricted to the breast ducts.(9) If left untreated, upto 40% of DCIS cases will
proceed to aggressive breast cancer.(10)

DCIS is treated with lumpectomy and radiotherapy, or with mastectomy.(11) Sentinel lymph node
(SLN) biopsy is performed during mastectomy to detect the involvement of lymph nodes. An SLN
biopsy after a mastectomy may be technically impossible.

Patients undergoing a lumpectomy are offered a radiation therapy; the combination of lumpectomy
and radiation is referred to as breast- conserving therapy. Patients with small, low grade lesions with
a low risk of recurrence may be spread from radiations. Radiation therapy is not recommended for
patients who have had a mastectomy.(12)

Patients with estrogen receptor- positive DCIS and residual breast tissue should be treated with
endocrine therapy for a minimum of five years. If the patient is premenopausal, aromatase inhibitor
is used, and if the patient is postmenopausal, tamoxifen or aromatase inhibitor is used.(12)

Previously, lobular carcinoma in insitu was thought to be cancer. However, contrary to its name, it is a
proliferative disease that increase the risk of future breast cancer. It is no longer recommended for
breast cancer staging.(13)

Stage1- 3, Early Invasive and Locally Advanced Non Metastatic Breast Cancer

Non Metastatic breast cancer is treated with preoperative and postoperative systemic therapies such
as chemotherapy, endocrine therapies, immunotherapy with monoclonal antibodies directed at
tumor receptors, surgery, radiations. Molecular testing can help determine whether chemotherapy
should be added to treatment plan. A 21-gene expression assay 9OncotypeDX) is the preferred assay
for disease prognosis and chemotherapy decisions in patients with hormone receptor- positive,

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node- negative breast cancer, including males. (12) When chemotherapy and endocrine therapy are
administered postoperatively, chemotherapy always comes first.(12)

Preoperative Systemic Therapy

Preoperative systemic therapy is used to shrink or reduce the resectable breast tumors (allowing for
better cosmetic and treatment outcomes), make unresectable tumors operable, and allow for SLN
biopsy instead of axillary lymph node dissection (ALND) if axillary node are not longer detectable.
Preoperative therapy is not generally recommended or early invasive breast cancer (1,2A,3B)
because tumors are frequently small enough to be resected with lumpectomy. Preoperative
chemotherapy is used for patients who have large primary tumors in relation to their breast size and
want to have breast conserving surgery. It is used to treat patients who have incurable diseases. For
patients with triple negative breast cancer, the only systemic therapy available is chemotherapy.(12)

Patients with low risk estrogen receptor- positive disease or adults may be eligible for
preoperative systemic therapy alone, without undergoing surgery. A complete response to
preoperative systemic therapies is associated with improved disease free survival and overall
survival.(12) The degree of tumor response to preoperative systemic therapies influences the need
for and response to any postoperative systemic therapies.

Surgical Interventions

If negative margins can be achieved with acceptable cosmesis, a lumpectomy with radiations should
be considered. When the excised tissue is sent to pathology, the outer surface of the specimen is
marked with ink. A negative margin is a specimen that is free of cancer cells adjacent to the ink
surface.(14)
Surgical interventions, in addition to removing the tumor, can be address the potential spread of
breast cancer through the lymphatic system. To perform an SLN biopsy, a tracer is injected into the
breast and the first several axillary nodes into which the tracer drains are removed. For patients with
no clinical evidences of nodal disease or low nodal burden based on imaging studies, an SLN biopsy is
preferred over ALND(15) ALND is reserved for patients who have positive lymph nodes and adipose
tissue of the axilla on SLN biopsy and will have a mastectomy, patients with inflammatory breast
cancer and patients with positive nodes with preoperative chemotherapy.(16)

Post operative therapy

RADIATION: Radiation therapy is used to eliminate any remaining subclinical disease after surgical
excision of breast cancer. It is advised for who have had lumpectomy, as well as for patients eith high-
risk, node- positive disease who have had mastectomy.(17) Radiations lowers the breast cancer
recurrence rate after lumpectomy by 20 years.(18)

ENDOCRINE: Women who are premenopausal at the time of their hormone receptor- positive breast
cancer diagnosis should receive 5 years of ovarian suppression therapy plus tamoxifen or an

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aromatase inhibitor.(19) Ovarian suppression prevents the ovaries from releasing estrogen, which
can lead to accelerated growth in hormone receptor- positive breast cancer. Patients with hormone
receptor-positive, ERBB2-negative breast cancer who are at high risk of recurrence may benefit more
from GnRH plus aromatase inhibitor.(12) Patients who are premenopausal and have past received
tamoxifen are given an additional five years of tamoxifen, and patients who had received tamoxifen
and now postmenopausal may be given tamoxifen or an aromatase inhibitor for an additional five
years.

Stage 4, Non Metastatic Breast Cancer

With advancements in breast cancer therapies, the median survival rate for patients with metastatic
breast cancer has improved over the last several decades. Although metastatic breast cancer is rarely
cured, the average survival time is now between 24 and 40 months.(20)

The treatment goals are to reduce symptoms, extend life, and maintain quality of life.(17) Endocrine
therapy, chemotherapy, and immunotherapy may all be used to target specific breast cancer
subtypes. For patients whose tumor burden is affecting their quality of life, surgery or radiation
following systemic therapy may be appropriate.(21)

Recurrent Breast Cancer

Recurrent breast cancer treatment needs a multidisciplinary approach that considers all potential
options for best results. Additional radiation is not recommended for locally recurrent breast cancer
that has been treated with breast conserving therapy; total mastectomy is the standard of care. (12)
The status of estrogen, progesterone, ERBB2 receptor influence the treatment of recurrent disease
with distant metastases ie (stage4). Endocrine therapy, chemotherapy, ERBB2-targeted therapies are
the part of treatment plan.

Traditional Treatments In Breast Cancer

1. Chemotherapy: Chemotherapy is the most widely used systemic treatment strategy for
breast cancer. Most conventional cytotoxic chemotherapeutic drugs' main anticancer
mechanism is to suppress cancer cell rapid division and growth (22), which typically results in
cancer cell death by targeting cancer cells at various cell cycle stages. Anthracyclines
(doxorubicin, epirubicin), taxanes (PTX, docetaxel), platinum agents (cisplatin, carboplatin),
cyclophosphamide, and other agents are currently used in the chemotherapy of BC (23).
These chemotherapeutic agents can be administered orally, intravenously, or intrathecally to
treat cancer. Furthermore, it was discovered that multidrug combination therapy can
generally improve anti-tumor effect, which cannot be achieved by administering a single
chemotherapy drug.

Adjuvant chemotherapy is chemotherapy given after surgery to breast cancer patients who have
lymphatic metastases or are at high risk of recurrence (24). While chemotherapy administered to

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patients prior to surgery is known as neoadjuvant chemotherapy, it determines tumor response to
chemotherapy, lowers tumor stage, and increases patient eligibility for breast conservation surgery,
and it has important clinical value for patients with locally advanced breast cancer.

 After examined some of the papers , one of the report told about the chinease medicines
which is traditionally made used most effective and gives positive results to the breast
cancer patients. There is emerging evidence that Traditional Chinease Medicine is effective
in the reducing side effects of chemotherapy. A growing number of patients use traditional
Chinese medicine (TCM) as an adjunct to conventional treatment, including acupuncture,
Chinese herbal medicine, moxibustion, cupping, Tui Na, Qi Gong, Tai Chi, and diet
modification.(25-27). TCM employs a holistic approach to comprehending normal body
function and disease processes. TCM also emphasizes both prevention and treatment. In
comparison to chemotherapy alone, TCM combined with chemotherapy significantly
improved tumor response, performance status, and alleviated chemotherapy-induced
toxicity in BC patients.(28) Lee et al. discovered that TCM reduced the risk of death in
patients with advanced cancer who were also receiving chemotherapy.(29-31) After they
came out with the results that about 60-70% of the patients got improved.

3. Radiotherapy: Radiation therapy is a treatment that uses high energy radiation to destroy
cancer cells and has been used for over a century to treat various cancers. The effect of
radiation on tumor cells was discovered by treating a woman with locally advanced BC, and
radiation is now a key component in the treatment of BC (32). Radiation therapy is divided
into two types of treatments: external beam radiotherapy (EBRT) and internal radioisotope
therapy. Radiation therapy can be used to destroy cancerous cells in the breast after breast-
conserving surgery, the chest wall after mastectomy, and regional lymph nodes (33).

4. Immunotherapy: Immunotherapy is another systemic treatment regimen for BC that can

prevent, regulate, and eliminate BC cells by stimulating the patients' natural defense system
(34). Immunotherapy's internal mechanism is to strengthen the immune system in order for
it to specifically identify and destroy malignant cells (35). Furthermore, immunotherapeutic
agents can not only treat the primary tumor but also prevent distant metastasis and lower
the recurrence rates (36). Because of the presence of mutations, tumor-infiltrating
lymphocytes (TILs), and increased levels of programmed death ligand 1 (PD-L1) expression,
patients with TNBC are more likely to benefit from immunotherapy than those with other
types of BC. In addition, atezolizumab, a PD-L1 inhibitor, has been approved for use in
combination with nab-paclitaxel in the treatment of patients with locally advanced or
metastatic TNBC whose tumors express PD-L1 (37).

5. Surgical Therapy: Mastectomy and lumpectomy (also known as breast-conserving surgery)

are the two most common surgical procedures used to treat various stages of breast cancer
(38). In addition, studies have shown that mastectomy and lumpectomy followed by
radiotherapy are equally effective in terms of recurrence and overall survival (39). In most
patients with early BC, SLNB, a definitive method for excluding axillary metastases, has
replaced ALND as the primary method for evaluating the axilla (40).

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Modern Methods Used In The Treatment Of Breast Cancer

Use Of Nanomedicines

In recent years, nanomedicine has demonstrated a number of advantages in assisting with the
challenges of traditional BC treatments. Nanotechnology allows for operation in materials with at
least one dimension ranging from 1 to 100 nm (41). NPs not only improve drug biological distribution
by targeting active molecules to diseased tissues, but they also protect healthy tissues by avoiding
drug distribution in normal tissues (42). Small size, high surface-to-volume ratio, adjustable physical
and chemical properties, ability to load large amounts of drugs, longer circulation time, high uptake
and retention, tumor-targeting efficacy, sustained release of the chemotherapeutic
payload, ,bioavailability, increased circulation time, and overcoming multidrug resistance are some of
the unique properties of NPs (41). The compact size of nanoparticles allows them to pass through
biological barriers such as the BBB (43), opening up the possibility of treating BC patients with brain
metastases.

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