2.

Incidence of Breast Cancers

A profound and accurate knowledge of cancer epidemiology provides essential information on possible
causes and the population trends of these conditions, thus making it possible to establish timely and
accurate healthcare interventions aimed at developing efficient and effective policies for prevention ,
screening and diagnosis [1] . Evidence shows that dominant cause of cancer death from the most
commonly invasive forms of cancer ,including Breast cancer involves metastasis which is defined as
the rapid creation of abnormal cells growing beyond their usual boundaries invading adjoining parts of
the body and thus spreading to other organs [2]. Metastasis is regarded as an important hallmark of
cancer and has proven to be a potential challenge in the field of Cancer management [3]. It has been
observed that developed nations have higher rates of breast cancer than developing ones which may be
attributed to certain notable factors such as unhealthy lifestyle , ethnicity and reproductive factors that
are associated more commonly to developed countries in comparison to that of the developing ones [4].
In recent years ,incident rates of breast cancer have increased to 0.5% per year. In 2012 , 1.67 million
new cases of Breast Cancer were identified worldwide accounting for 25% of all cancers [5].According
to the recent statistics released by IARC (International Agency For Research on Cancer) , Breast cancer
has overtaken Lung cancer as the world’s most commonly diagnosed cancer with an estimate of 2.3
million cases and 6,85,000 deaths accounting for approximately 15% of all cancer related deaths in the
world in 2020 [6]. According to WHO (World Health Organization),at the end of 2020, there were
about 7.8 million alive women who were diagnosed with Breast cancer , thus making it world’s most
prevalent cancer . The cases of breast cancer are expected to reach around 3.2 million in 2050 and 4.4
million in 2070 [7].The epidemiological data and studies of populations of developing countries
especially in the Asian and African regions are not sufficient enough to attribute to various factors
which could increase the rise of development of Cancer including Breast cancer. Thus , there is a
significant increase in the morbidity and mortality in the Indian sub-continent as per the latest Indian
and global studies. India is facing a challenging situation due to approximately 50% increase in Breast
cancer incidence between 1965-1985 [8]. Over the last 26 years , the age - standardized incidence rates
of Breast Cancer in females has increased by 39.1% from 1990 to 2016.This increase is observed in
every state of India [9]. As per the Globocan data , 2020, in India, Breast Cancer accounted for 13.5%
of all Cancers and 10.6% of all Cancer deaths with a cumulative risk of 2.81 [10]. In 2020 , more than
two lakh women in India were estimated to have been diagnosed with breast cancer and more than
76,000 deaths were reported as per estimates . As per the 2020 National Cancer Registry Programme
Report , the number is expected to rise to more than 2.3 lakh cases in 2025. Increasing urbanization and
westernization associated with changing lifestyle and food habits has led breast cancer to attain the top
position in all major urban registries of India whereas cervical cancer is still at the topmost position in
rural registries and breast cancer holds the second position[11]. Nearly about 24% of all breast cancer
cases of the world occur in the Asia-Pacific region with the highest rates observed in China
(46%)followed by Japan (14%) and Indonesia (12%) [12]. As per the American Cancer Society’s
estimates , Breast cancer is the most common cancer in women in the US , except for skin cancer ,thus
accounting for about 30% (1 in 3)of all new female cancers each year .For the year 2022, it has been
estimated that about 2,87,850 new cases of invasive Breast cancer will be diagnosed in women and
about 43,250 of them will die from breast cancer. Overall , the average risk of a woman developing
Breast cancer in the US in her lifetime is about 13%. The incidence (age-standardized rate per
1,00,000) of Breast cancer in different regions of the world as per Globocan data 2020 is as follows -
Western Europe 90.7% , Northern America (89.4%), Northern Europe (86.4%) , Australia-New
Zealand (95.5%) ,South-Central Asia (26.2%) and East Asia (46.3)%
Although , the prevalence of Breast cancer is higher in developed countries , higher mortality rates are
being observed in less developed countries due to improved surveillance , rapid diagnosis and better
therapeutic methods in the advanced countries as compared to developing or less developed ones [13].
Most of the Asian and African countries are low to middle income countries and therefore, breast
cancer is one of the main causes of morbidity and mortality [14] . In 2020 , China had the largest
number of Breast cancer deaths followed by the US which accounted for 6.2% of Breast cancer deaths
in the world [15 , Table -1] . The mortality (age - standardized rate per 1,00,000) of Breast cancer in
different regions of the world is as follows - Western Europe (15.6%) , Northern America (12.5%),
Northern Europe (13.7%) , Australia - New Zealand (12.1%), South-Central Asia (13.1%) and East
Asia (9.8%).
According to WHO (World Health Organization) , certain habits and interventions like prolonged
breast-feeding , regular physical activity , weight control , avoiding excessive consumption of alcohol
and exposure to tobacco smoke could potentially lower the risk of Breast cancer .
3 . Types Of Breast Cancers

Usually , the cancer is named after the body part in which it has originated and thus breast cancer refers
to the erratic growth and proliferation of cells that originate in the breast tissue [16] . There are various
types of breast cancers as it can be present in the distinct areas of the breast such as ducts , lobules or
tissues in between . The breast is composed of two important types of tissues - glandular tissue that
houses the lobules (milk producing glands) , the ducts (the milk passages) and the stromal tissues
which are composed of fatty acids , fibrous connective tissues and blood vessel cells of the breast . The
breast is also made up of lymphatic tissues (immune system tissue that removes cellular fluids and
waste) [17] .Breast cancer can be benign or malignant. The benign tumors are not life-threatening , can
be removed , do not invade to adjacent tissues or spread to other parts of the body. It includes fibrocytic
tissues , fibro adenomas and benign breast disease. Malignant breast tumors are cancerous and can
invade surrounding tissue or metastasize to other parts of the body via the blood vessels or the
lymphatic system ( composed of lymph vessels and lymph nodes ) such as liver or bone . The type of
breast cancer is determined by the specific types cells that are affected. Based on the origin of cell
involved , breast cancers can be divided into two broad classifications - Carcinomas and Sarcomas.
Carcinomas are breast tumors arising from epithelial component of the breast which consist of the
cells that line the lobules and the terminal ducts responsible for making milk .Sarcomas are much rarer
form of breast cancers ( <1% of primary breast cancer) arising from the stromal components of the
breast. These groups are not sufficient enough as a single breast tumor can be a combination of
different cell types.
Most of the breast cancers are Carcinomas . Within the group of carcinomas there are many different
types of breast cancers identified based on their invasiveness related to the primary tumor site . Based
on the citeria of invasiveness and pathological features , common breast cancers can be divided into
three major groups :- non-invasive (in situ), invasive and metastatic breast cancer.

3.1 Non-invasive or in situ breast cancer

3.1.1. Ductal Carcinoma in situ (DCIS) :- DCIS is also called as intraductal carcinoma. It is the most
common form of non-invasive cancer(90%) . DCIS is non-invasive or pre-invasive breast cancer which
develops inside of pre-existing normal ducts . Usually DCIS is itself not invasive but it has a higher
potential to become an invasive cancer[18] . Sometimes DCIS grows so slowly that even without
treatment, it wont affect a woman’s health. Long term studies predict that DCIS is a non - obligate
precursor of invasive breast cancer and up to 40% of these lesions progress to invasive disease if
untreated [19]. DCIS patients who are pre - menopausal at diagnosis or who had their DCIS detected
by palpation are at a greater rise of being diagnosed with a future invasive breast cancer [20] .
Therefore , early and adequate treatment is important in preventing the DCIS from developing an
invasive cancer .

3.1.2. Lobular Carcinoma In Situ (LCIS): - Lobular Carcinoma In Situ (LCIS ) is both a risk factor
and a non - obligate precursor of breast carcinoma . LCIS is an uncommon condition in which
abnormal cells form in the lobules (milk glands) of the breast . The analysis of SEER (Surveillance ,
Epidemiology and End Results )data revealed that the cumulative risk of developing invasive breast
cancer after LCIS to be 7.1% at 10 years with equal predisposition in both breasts . The risk of
developing invasive carcinoma after the diagnosis of LCIS is 8-10 times greater than in general
population.

3.2 Invasive or Infiltrating breast cancer :- Invasive breast cancers have cancer cells that invade and
spread outside of the normal breast lobules and ducts growing into the surrounding region of breast
stromal tissue . About two-thirds of women with an invasive form breast cancer are 55 or older when
they are diagnosed . Invasive breast cancer can spread to other parts of the body such as lymph nodes
leading to metastasis thus ultimately entering into the classification of metastatic breast cancer.
Invasive breast cancer is further divided into two types based on the type of cells and tissues involved.

3.2.1 Invasive Ductal Carcinoma ( IDC ) :- This is the most common type of invasive breast
carcinoma that accounts for 80 % of all breast cancers constituted by invasive breast carcinoma . With
IDC, cancer cells start in a milk duct , break through the walls and invade the breast tissue . It can
remain localized (stay near the site where the tumor started ) or can spread anywhere in the
body .Based on the morphology and arrangement of cancerous cell under the microscope. The invasive
ductal carcinoma classification includes different subtypes such as IDC-NST (Invasive Ductal
Carcinoma - Non Specific Type) ,Tubular carcinoma of the breast , mucinous carcinoma of the breast ,
medullary carcinoma of the breast ,metaplastic carcinoma of the breast , apocrine carcinoma of the
breast , papillary carcinoma of the breast , neuroendocrine carcinoma of the breast and cribriform
carcinoma of the breast

3.2.1.1. Invasive Ductal Carcinoma - Non Specific Type (IDC-NST ) : - This histological subtype
is most common constituting about 40% to 75% of all invasive ductal carcinomas . Normally it has a
wide scope of morphological variation and clinical behaviour [22].Tumor cells are pleomorphic with
protruding nuclei and numerous mitoses.In majority of cases regions of necrosis and calcifications may
be detected [23]

3.2.1.2. Tubular Carcinoma Of The Breast : This is a type of invasive ductal carcinoma that
accounts for < 2% of all breast cancers . A well - differentiated sub type that usually occurs in women
between 50-60 years of age . Like other types of invasive ductal carcinoma , tubular ductal carcinoma
begins in the milk duct of the breast before spreading to tissues around the duct . Most tubular
carcinomas are associated to a wide range of potential pre-malignant tumors [24]. This sub type is
characterized by proliferation of prominent tubules (>90%) , which can be angled , oval or elongated
with a disorganized disposition and open lumen covered by a single layer of epithelium usually without
presentation of necrosis and mitosis [25 , 26] .

3.2.1.3 Mucinous Carcinoma Of The Breast (MBC) : - Mucinous breast cancer , also called
colloid , gelatinous , mucous and mucoid carcinoma is also responsible for 4% of all newly diagnosed
breast cancer cases [27] . This subtype has been associated with a favourable prognosis and is usually
observed in women above 60 years of age . Morphologically , these tumors have abundant amounts of
extracellular mucin , surrounding small clusters of cancer cells with different growth patterns and mild
nuclear atypia [28] . According to the WHO (World Health Organization) classification of the tumors
of the breast (2019) , MBC is classified as a special type of breast cancer and based on its cellularity
can be divided into two sub types -Pure type( PMBC ) and mixed type (MMBC) [29]

The pure type (PMBC) is composed entirely of tumor cells with extracellular and intracellular mucin in
over 90% of tumor mass and occurs more frequently. They are again classified into two subgroups -
hypocellular (PMBC -A) tumors which are characterized by microcapillary , papillary , tubular ,
cribriform or cord like growth pattern and hypercellular (PMBC-B) tumors forming solid nests of cells
floating in mucin [30]

On the other hand , the mixed type (MMBC) which is composed of infiltrating components such as
ductal or lobular breast cancer-like and contains less than 90% mucin [31]. Like PMBC , this is also
divided into two groups based on amount of mucinous component .

3.2.1.4 . Medullary Carcinoma Of The Breast : - It accounts for 5 % of all cases and is associated
with better clinical results and lower rates of axillary lymph node involvement [32] . When viewed
under the microscope , they appear to be bulky , soft and well - circumscibed with pushing borders that
donot infiltrate into the surrounding breast tissue or fat . They show diffused growth pattern with high
grade nuclei , frequent mitoses and abundant eosinophilic cytoplasm with a syncytial appearance .

3.2.1.5 . Metaplastic Carcinoma Of The Breast :- Metaplastic carcinoma refers to heterogenous

group of invasive breast carcinomas characterized by differentiation of neoplastic epithelium towards
squamous cell or mesenchymal looking elements that include but is not restricted to spindle , chondroid
and osseous cells . This histological subtype is characterized by dominant component of metaplastic
differentiation representing 1 % of all cases and affecting women in post - menopause [33]. This group
of tumors show aggressive biological behaviour and often lymph node involvement [34] .

3.2.1.6. Apocrine Carcinoma Of The Breast :- Apocrine carcinoma is a rare type of invasive ductal
breast cancer.It begins in the milk duct of the breast before spreading to the tissues around the duct.
When viewed under the microscope , they appear like cells found in the sweat glands and in the
underarm and groin region.The cells are large,with an abundant glandular eosinophilic
cytoplasm,positive for PAS (Periodic Acid-Reactive Shiff) staining and prominent nucleoli. In addition
to this,bizzare tumor cells with multilobulated nucleoli can also be observed [35].This constitutes about
1-4% of all cases with prominent apocrine differentiation comprising of atleast 90% of tumor cells
[36].
3.2.1.7.Papillary Carcinoma of the breast:- A rare sub type of invasive ductal carcinoma with
infiltrating papillary growth that comprises about <3% of all invasive breast cancers . The name comes
from finger-like projections or papules which are seen when the cancer cells are visualized under the
microscope . Tumor cells show a circumscibed solid growth pattern with interspersed delicate fibro-
vascular cores characterized by low or intermediate grade nuclear atypia . However , invasive papillary
carcinomas usually have a better prognosis than other invasive breast cancers . Papillary carcinomas
may also be detected at the non-invasive stage and in this case , they are considered as a variety of
Ductal Carcinoma In Situ ( DCIS ) .

3.2.1.8. Neuroendocrine Carcinoma Of The Breast :- It constitutes about 0.5 to 5 % of all cases of
breast cancers and mainly occurs in older ages [37] . Morphologically , an infiltrative growth pattern
with an arrangement of solid aggregates of tumor cells is observed in alveolar, trabecular or rosette
patterns . Sometimes , peripheral palisades can also be observed . Cancer cells are usually of different
sizes and have a fine eosinophilic glandular cytoplasm [38].

3.2.1.9 . Cribriform Carcinoma Of The Breast :- This is a rare type of breast cancer that is usually
slow growing and low grade . This is an indication of good prognosis after treatment . Cribriform
cancers can be of pure type or mixed type (mixed with other types of breast cancer cells ) . Women
who are approximately 50 years of age are affected and this sub type of IDC constitutes about 1 % -
3.5% of all breast cancer cases [39] . When the cells are viewed under the microscope , islands of
uniform tumor cells are observed with low grade atypia , cribriform appearance in 90% of tumor and
often associated with ductal carcinoma in situ without well defined stromal invasion .Cribriform
carcinoma has almost no evidence of regional or distant metastasis [40].

3.2.2 Invasive Lobular Carcinoma (ILC) : - Invasive Lobular Carcinoma (ILC) is a type of breast
cancer that begins in the lobules (milk producing glands) of the breast . It is the second largest
biologically distinct carcinoma that accounts for 10-15% of all breast cancers . Invasive lobular
carcinoma can be difficult to diagnose as unlike other cancer cells who grow and form clumps , ILC
cells can grow into lines that can be difficult to detect on physical examination or see on a
mammogram . Age increases the risk of invasive lobular carcinoma. About two-thirds of women
diagnosed with ILC are 55 years or older . ILC is again divided into two subtypes - classical and
pleomorphic.

Together , 90-95% of all breast cancers fall into the invasive sub-categories . IDC and ILC cancers
exhibit different pathological , histological and clinical features. Lobular carcinomas grow as single
lines or sheets that have distinct molecular and genetic aberrations , difficult to detect and late
recurrences that distinguish them from ductal carcinomas . Ductal and lobular carcinomas have
different lines of prognosis and treatment .

3.2.3 Metastatic Breast Cancers: - Metastatic breast cancer, which is also called stage 4 breast cancer
or advanced breast cancer , is the last stage of breast cancer. Metastatic breast cancer break away from
the primary tumor and enter into the bloodstream , lymphatic system ,in the armpits or into the distant
sites such as lung , liver , bone and brain. Metastatic breast cancer is responsible for more than 90% of
deaths[39]. A SEER based study showed that for metastatic breast cancer patients , 30-60% have
metastasis in the bone , 21-32% in the lungs, 15-32% in the liver and 4-10% in the brain [40]. In
clinical terms , the patients may be diagnosed with metastatic disease ( or de novo metastatic breast
cancers ) or they develop metastasis months or years after receiving initial treatment. The risk of breast
cancer returning and metastasizing is not clearly understood or predictable as it varies from person to
person, mostly depending on the molecular biology of the tumor and its prevailing stage at the time of
diagnosis .

3.3 Less Common Types Of Breast Cancers

3.3.1 . Inflammatory Breast Cancer :- Inflammatory breast cancer is an appearance of inflamed

breast ( red and warm). It is caused by cancer cells blocking the lymph vessels or channels in the skin
over the breast. Inflammatory breast cancer often doesn’t present with a breast lump and may not be
identifiable with mammograms . Though IBC is rare , accounting for only 1% of breast cancers , it is
extremely fast growing as compared to the common types of breast cancers. IBC is more common in
young women and women who are obese.
3.3.2 Male , Children and Adolescents Breast Cancer - Like female breast carcinomas , male breast
carcinomas can either be in situ or invasive that account for <1% of all breast cancer cases.The most
common types of breast cancer in men are same as that of women which includes DCIS , invasive
ductal carcinomas , invasive ductal carcinomas with ER expression and invasive lobular carcinoma.
The most common types of breast lesion in males is gynecomastia ( breast enlargement ) which may
involve unilateral or bilateral breasts. Breast lesions , though uncommon in adolescents and children
include both benign lesions such as juvenile fibroadenoma and malignant lesions such as secretory
carcinoma or alveolar rhabdomyosarcoma.

3.3.3 Paget’s Disease Of The Breast - A rare form of breast cancer that begins in the milk ducts and
spreads to the skin of the nipple and then expands to the aerola (dark circle around the nipple ) .
Paget”s disease makes up <3% of breast cancer cases . The tumor cells often have a large , round
appearance when viewed under the microscope . They may be found as single cells or as group of cells
within the epidermis . They look significantly different from normal cells and divide rapidly. The
cancer is typically diagnosed with tissue biopsy , sometimes followed by a mammogram , sonogram or
biopsy to confirm the diagnosis

3.3.4 Phyllodes Tumor - These are rare breast tumors that develop in the connective ( stromal tissue of
the breast) and not in the ducts or glands where most breast cancer start . Most phyllodes tumor are
benign and are very unlikely to grow and spread . About one-quarter are malignant and grow the fastest
. Borderline phyllodes tumors have features between benign and malignant. This is most commonly
found in women in their 40s and women with Li-Fraumeni’s syndrome . Sometimes , these tumors can
be visualized first on an imaging test (ultrasound , mammogram)and if the entire tumor needs to be
removed then excisional biopsy is required .

3.3.5 Angiosarcoma Of The Breast - Angiosarcoma is a very rare form of sarcoma that represents <
1% of all breast cancers . This cancer occours in the breast, in the stroma of the arms and it begins to
develop in the blood or lymphatic vessels of the breast. It is again sub - categorized into Primary
Angiosarcoma ( occurs in people who have never been treated for breast cancer ) and secondary
angiosarcoma ( most commonly associated with therapy ,but sometimes it can also be associated with
lymphedema in the breast and arm). Although rare , angiosarcomas tend to grow and spread quickly
and need to be treated accordingly.

4 . Molecular ( Intrinsic) Sub Types Of Breast Cancer

Breast cancer research over these years has uncovered more information about different types of
Breast cancer cells , based on the factors involved in tumor growth . This has led to defining
Breast cancer at the molecular or smallest - cell level . Breast cancer encompasses a group of
heterogenous and phenotypically diverse group of diseases . Molecular classification of Breast
cancer refers to the type of cancer cells present and to the pattern and behaviour these cells
display .