about breast cancer ,stages ,etiopathogesis with pharmacological treatment.

1.  DEFINATION:
Breast cancer is defined as a malignant
neoplasm of the breast arising from the
epithelial lining of the lobule, ducts and the
nipple. The cancer originating from the
ducts is called ductal carcinomas and which
are originating from lobes is called as lobular
carcinomas.
Breast cancer is a disease that
occurs when cells in breast tissue change (or mutate) and keep reproducing. These abnormal
cells usuallyclustertogether to form atumor. A tumor is cancerous (or malignant) when these
abnormal cells invade other parts of the breast or when they spread (or metastasize) to other
areas of the body through the bloodstream or lymphatic system, a network of vessels and
nodes in the body that plays a role in fighting infection. Breast cancer usually starts in the
milk-producing glands of the breast (called lobules) or the tube-shaped ducts that carry milk
from the lobules to the nipple. Less often, cancer begins in the fatty and fibrous connective
tissue of the breast.
 ETIOLOGY:
Breast cancer is caused by some following
factors. they are:
1.age and gender (woman and older persons
are at risk).
2.family history (close blood relatives with
breast cancer are at risk).
3.a breast cancer gene mutation (many of these
cases are due to defects in one or more genes,
especially the BRCA1 or BRCA2 genes).
4.breast changes and mutation.
5.race and ethinity (white women are at greater
risk than Asian women)
6.hormones.
7.weight.
8.alcohol consumption.
9.Radiation exposure.
10.late first pregnancy after age 30.
11.DES exposure(diethylstilboestrol).

2.  SIGNS AND SYMPTOMS:
Following are the signs and symptoms:
 New lump in the breast or armpit, with or without pain. Lumps are often hard but can
be soft as well. (Not all lumps are breast cancer. Some lumps may be noncancerous
changes or benign, fluid-filled cysts.)
 Change in breast size or shape. Swelling, thickening, or shrinkage, especially in one
breast.
 Dimpling, pitting, or redness. Breast skin may take on the appearance of an orange
peel.
 Peeling, flaking, or scaling breast skin.
 Red, thick, or scaly nipple.
 Breast, nipple, or armpit pain.
 Inverted nipple. Nipple that turns inward or flattens.
 Nipple discharge. It may be clear or bloody.
 Redness or unusual warmth. This can be a sign of inflammatory breast cancer, a rare
and aggressive form of the disease.
 Swollen lymph nodes under the arm or around the collarbone, which could be a sign
that breast cancer has spread.
 TYPES OF BREAST CANCER:
Ductal carcinoma in situ (DCIS)
This highly treatable pre-cancer (sometimes called
“stage 0” breast cancer) starts in a milk duct. It’s the
most common type of non-invasive breast cancer,
meaning the cells are abnormal but haven’t spread to
the surrounding tissue. Over time, DCIS may progress to
invasive breast cancer.
 Invasive ductal carcinoma (IDC)
This is the most common breast cancer, accounting for
80% of all invasive breast cancer diagnoses. Also called
“infiltrating ductal carcinoma,” IDC starts in a milk duct,
breaks through the duct wall, and invades the
surrounding breast tissue. It can spread to other parts of
the body as well. There are also several subtypes of IDC,
which are categorized based on features of the tumors
that form.

3. Invasive lobular carcinoma (ILC)
This type of breast cancer begins in the milk-producing
glands, called lobules. Also known as “infiltrating lobular
carcinoma,” ILC can spread beyond the lobules into
surrounding breast tissue and metastasize to other parts of
the body. It accounts for about 10% of invasive breast
cancers.
Lobular carcinoma in situ (LCIS)
LCIS, also called lobular neoplasia, starts in the milk-producing
lobules. Technically, it’s not breast cancer (even though it has
carcinoma in its name), but rather a collection of abnormal
cells. People with LCIS are more likely to develop breast cancer
in the future.
Inflammatory breast cancer (IBC)
This rare, aggressive type of breast cancer causes redness and swelling of the breast. The
affected breast can feel warm, heavy, and tender. The skin may become hard or ridged like
an orange rind. See a doctor right away if you have these symptoms. Inflammatory breast
cancer tends to strike five years earlier, on average, then other types of breast cancer, and it
might not show up on a mammogram. African American women are at greater risk for IBC
than white women.
Paget disease of the breast (or the nipple)
This rare cancer affects the skin of the nipple and the darker circle of skin, called the areola,
surrounding it. People with Paget disease may notice the nipple and areola becoming scaly,
red, or itchy. They may also notice yellow or bloody discharge coming from the nipple. Most
people who have this condition also have one or more tumors (either DCIS or invasive cancer)
in the same breast.
Metaplastic breast cancer
This rare, invasive breast cancer begins in a milk duct and forms large tumors. It may contain
a mix of cells that look different than typical breast cancers and can be more difficult to
diagnose.
Angiosarcoma of the breast
This quickly growing cancer is rare. It is usually a complication of a prior radiation treatment
of the breast.

4.  STAGES OF BREAST CANCER:
STAGE 4 BREAST CANCER
AT STAGE 4, BREAST CANCER HAS TRAVELLED TO DISTANT
SITES INTHE BODY, OFTENTHE BONES, LIVER,BRAIN, OR
LUNGS. THIS IS CALLED METASTATIC BREAST CANCER.
ALTHOUGH THIS STAGE IS CONSIDERED INCURABLE,NEW
TREATMENTS ALLOW PATIENTS TO LIVE LONGER WITHTHEIR
DISEASE.
STAGE 3 BREAST CANCERS
STAGE 3 BREAST CANCER IS AN ADVANCED CANCER. IT’S IN
THE LYMPH NODES BUT HAS NOT SPREAD TO OTHER
ORGANS. THIS STAGEIS DIVIDED INTO THREECATEGORIES,
3A, 3B AND 3C, BASED ONTHE SIZEOF THE TUMOR AND
HOW MANY AND WHICHLYMPHNODES ARE INVOLVED.
STAGE 2 BREAST CANCER
AT STAGE 2, BREAST CANCER IS GROWINGBUTIS ONLY INTHE BREAST OR NEARBY LYMPH NODES.THIS STAGE
HAS TWO CATEGORIES,2A AND 2B, BASED ON HOW LARGE THE TUMORIS AND WHETHER ORNOTIT HAS SPREAD
TO NEARBY LYMPH NODES.
STAGE 1 BREAST CANCER
STAGE 1 IS AN INVASIVECANCER, MEANING ITIS INVADINGHEALTHY BREAST TISSUE,BUT IT HAS NOT SPREAD
OUTSIDETHE BREAST. THIS STAGE ALSO HAS TWO CATEGORIES,1A AND 1B, BASED ONWHETHER THERE IS ANY
EVIDENCE OF SMALL CLUSTERS OF BREAST CANCER CELLS INNEARBY LYMPH NODES.
STAGE 0 BREAST CANCER
ALSO CALLED PRE-CANCER, THIS IS THE EARLIEST STAGE OF BREAST CANCER. IT INVOLVES ABNORMAL CELLS THAT
HAVE NOT SPREAD INTO BREASTTISSUE FROMTHE DUCTS ORLOBULES WHERE THEY BEGAN. STAGE 0 BREAST
CANCER ALSO HAS NOTSPREAD TO LYMPH NODES OROTHER PARTS OF THE BODY. STAGE 0 BREAST CANCER IS
NON-INVASIVE,LIKEDUCTAL CARCINOMAINSITU(DCIS)
PATHOPHYSIOLOGY:
Breast cancer etiopathogenesis is that invasive cancers arise through a series of
molecular alterations at the cell level. These alterations result in breast epithelial cells with
immortal features and uncontrolled growth.
These generally align with the presence or absence of estrogen receptor (ER),
progesterone receptor (PR), and human
epidermal growth factor receptor 2 (HER2).
 Cancer pathogenesis driven by activation
of estrogen and progesterone receptors
and also driven by activation of HER
(human epidermal receptors) family.
 HER 2 mutation is the major cause of
breast cancer.

5.  HER family receptors form homodimerization.
Such as ligand – HER4 dimer; HER3 dimer; EGFR
dimer; HER2 dimer.
 HER family receptor forms heterodimerization.
Such as EGFR-HER2 dimer; HER2-HER4dimer;
HER2-HER3dimer are most potent oncogenic
(dimer) pain of HER family.
 HER2-HER3dimer formation plays major role in the
breast cancer by activation of P13Kpathway; PIP3
pathway; activation of AKTpathway which results
in cell survival and cell proliferation by inhibiting of
programmed cell death of defect cell.
 HER2-HER4 dimerization results in activation of
Shc-GRB2-SOS complex and RAS activation;
activation of RAF and activation of MEK; activation
of MAPK.this activated MAPK enters the nucleus
and help the defected cell for survival and proliferation.
 These cellsignaling if mutated gene results in the abnormal cell growth and inhibition
of apoptosis.
 These causes breast cancer.
 DIAGNOSIS:
Most breast-cancer-related tests fall into one or more of the following
categories:
Screening tests: Screening tests (such as yearly mammograms) are given routinely to
people who appear to be healthy and are not suspected of having breast cancer. Their

6. purpose is to find breast cancer early, before any symptoms can develop and the cancer
usually is easier to treat.
Diagnostic tests: Diagnostic tests (such as biopsy) are given to people who are
suspected of having breast cancer, either because of symptoms they may be experiencing or
a screening test result. These tests are used to determine whether or not breast cancers
present and, if so, whether or not it has travelled outside the breast. Diagnostic tests also are
used to gather more information about the cancer to guide decisions about treatment.
Monitoring tests: Once breast cancer is diagnosed, many tests are used during and after
treatment to monitor how well therapies are working. Monitoring tests also may be used to
check for any signs of recurrence.
 TREATMENT:
Goals of treatment:
 Currently, MBC is largely considered to be incurable, and the goals of treatment are
generally palliative. Nevertheless, with the development of newer agents, prolongation
of survival has become a goal in the metastatic setting. Other primary goals of
treatment, such as improvements in time to progression and duration of response, have
also been achieved [3, 11–13] with newer combinations of agents so that, while long-
term survival rates are modest, many patients with MBC are now living longer with
minimal disease-related symptoms.
 Recent options for treatment of patients with MBC are expanding and include the
potential use of single-agent or combination chemotherapy, hormonal therapy, and
immunotherapy.
 To ovoid relapse of breast cancer.
 SURGERY:
Breast-conserving surgery (BSC): also known as lumpectomy or wide local excision, BSC
involves resection of the tumour along with a margin of tissue while conserving the cosmetic
appearance of the breast. Most breast surgeries are of this type because (i) most tumours are
locally invasive and (ii) large primary tumours can be reduced in size by neoadjuvant
chemotherapy prior to conservative surgery.
Mastectomy: surgical removal of entire breast, including the fascia over the pectoralis
muscles. Surgeons may preserve some skin and the nipple/areola for reconstruction. The
indication for mastectomy is multicentric invasive carcinoma, inflammatory carcinoma, or
extensive intraductal carcinomas.
Axillary lymph node dissection: removal of the lymph nodes draining the breast tissue for
lymph node micrometastasis. This is done at the same time as BSC or mastectomy. However,
recent evidence suggests that axillary lymph node biopsy is unnecessary regardless of
whether the sentinel lymph node biopsy is negative or positive because there is no mortality
benefit.
Adjuvant therapy: cytotoxic chemotherapy, endocrine therapy, or radiation therapy may be
used postsurgery to prevent relapse.

7.  RADIATION THERAPY:
Either whole or partial breast irradiation may be used. Adjuvant radiation therapy is applied
post-BCS or post-mastectomy to prevent recurrence. Since most recurrence of early-stage
breast cancer occurs locally, partial irradiation at the tumour site has similar mortality
benefits as whole breast irradiation. However, new evidence suggests an increased risk of
local and axillary recurrence with partial irradiation.
Radiation of metastatic disease (e.g. bone or brain metastases) is also used.
 ENDOCRINETHERAPY:
Breast cancer is a hormone-sensitive cancer. Most breast cancer cells are ER-positive, and
thus will respond to reduction of circulating estrogens. HR-negative breast cancers will not
respond to endocrine therapy.
Mainly used as (i)adjuvant therapyforearly-stagehormone-sensitivebreast cancer oras (ii)
first line therapy for metastatic hormone-sensitive breast cancer.
Cancer Care Ontario recommends 5 years of adjuvant endocrine therapy for early-stage
breast cancer in postmenopausal women.
Antiestrogens (e.g. tamoxifen): Competitively binds ER and inhibits estrogen binding.
Aromataseinhibitors:Aromatase,also known as estrogen synthase, is an enzyme responsible
for estrogen synthesis. There are two types: steroidal (type I) and non-steroidal (type II).
The steroidal type (e.g. exemestane) is an androgen analogue that binds permanently with
the aromatase enzyme, leading to long-term and specific inhibition of the enzyme. The non-
steroidal type (e.g. anastrozole and letrozole) originates from an anti-epileptic drug that
reversibly binds and inhibits the cytochrome P450 unit in aromatase. Because the non-
steroidal type has a good molecular fit with the substrate-binding site, it is more potent than
the steroidal type. Both types have good efficacy and high specificity for the aromatase
enzyme.
Ovarian ablation: induction of artificial menopause by ovariectomy significantly reduces
breast cancer risk. Adrenalectomy eliminates a source of androgens in females, which is the
precursor to aromatase-derived estrogens. However, these surgical approaches are
irreversible and cause major side effects, so they are less often used.
Ovarian suppression: LHRH (GnRH) agonist (e.g. goserelin and leuprorelin) can be used to
reversibly suppress LH/FSH release and thus estrogen release.
Chemotherapy is used asinitial therapy for women with hormone receptor–negative tumors; with
rapidly progressive or symptomatic lung, liver, or bone marrow involvement; and after failure of
endocrine therapy.
•The choice of treatment depends on patient characteristics, expected toxicities, and previous
exposure to chemotherapy. Single agents are associated with lower response rates than combination
therapy, but time to progression and OS are similar. Single agents are better tolerated, an important
consideration inthe palliative metastatic setting.
TYPES:
There are three major types of chemotherapy.
 Neoadjuvant chemotherapy
 given before surgery to shrink the size of a tumor
 Adjuvant chemotherapy
 given after surgery to reduce the risk of recurrence

8.  Palliative chemotherapy
 used to control (but not cure) the cancer in settings in which the cancer has spread
beyond the breast and localized lymph nodes. See metastatic breast cancer.
 Combined therapies
 combining, for example, non-drug treatments with localized chemotherapy to limit
toxicity and achieve better results
REGIMENS:
Multiple chemotherapeutic agents may be used in combination to treat patients with breast
cancer. Determining the appropriate regimen to use depends on many factors; such as, the
character of the tumor, lymph node status, and the age and health of the patient. In general,
chemotherapy has increasing side effects as the patient's age passes 65.
The following is a list of commonly used adjuvant chemotherapy for breast cancer:
 CMF: cyclophosphamide, methotrexate, and 5-fluorouracil given 4-weekly for 6 cycles
 FAC (or CAF): 5-fluorouracil, doxorubicin, cyclophosphamide given 3-weekly for 6 cycles
 AC (or CA): Adriamycin (doxorubicin) and cyclophosphamide given 3-weekly for 4 cycles
 AC-Taxol: AC given 3-weekly for 4 cycles followed by paclitaxel given either 3-weekly for
4 cycles or weekly (at a smaller dose) for 12 weeks
 TAC: Taxotere (docetaxel), Adriamycin (doxorubicin), and cyclophosphamide given 3-
weekly for 4-6 cycles
 FEC: 5-fluorouracil, epirubicin and cyclophosphamide given 3-weekly for 6 cycles
 FECD: FEC given 3-weekly for 3 cycles followed by docetaxel given 3-weekly for 3 cycles
 TC: Taxotere (docetaxel) and cyclophosphamide given 3-weekly for 4 or 6 cycles
 Dose dense regimen: Some of the regimens above (e.g. AC followed by paclitaxel) may be
given in a shorter period (i.e. every 2 weeks instead of every 3 weeks).
 In addition to chemotherapy, trastuzumab may also be added to the regimen depending
on the tumour characteristics (i.e. HER2/neu status) and risk of relapse. It is usually given
either 3 weekly or weekly for a total duration of 1 year.
Since chemotherapy affects the production of white blood cells, granulocyte colony-
stimulating factor (G-CSF) is sometimes administered along with chemotherapy. This has
been shown to reduce, though not completely prevent, the rate of infection and low white
cell count. Most adjuvant breast cancer chemotherapy regimens do not routinely require
growth factor support except for those associated with a high incidence of bone marrow
suppression and infection. These may include chemotherapy given in the dose dense fashion
i.e. 2-weekly instead of 3-weekly or TAC chemotherapy
NEWER DISCOVERY CHEMOTHERAPY FOR BREAST CANCER:
ANTHRACYCLINES:
New discovery: By conducting a meta-analysis of four large breast cancer trials including
nearly 3,000 patients, the researchers have discovered that an abnormality on chromosome
17, called CEP17, is associated with a worse outcome for patients, but also that its presence
is a highly significant indicator that the tumour will respond to anthracyclines.
CEP17 is detected by a common and straightforward test (fluorescent in situ hybridisation or
FISH), which is carried out routinely in breast cancer patients; it is used to test for the HER2

9. gene to see whether the women might benefit from the drug Herceptin. Prof Bartlett said
that assessment for CEP17 could be easily carried out in the same FISH analysis as for HER2.
 TARGETED THERAPY BREAST CANCER:
Patients with significant visceral involvement of the lung, liver, or brain and
those with rapidly progressive disease rarely benefit from hormonal maneuvers, and
initial systemic chemotherapy is indicated in such cases. For the 25–30% of breast cancer
patients whose tumors express the HER2/neu cell surface receptor, a humanized
monoclonal anti-HER-2/neu antibody, trastuzumab, is available for therapeutic use alone
or in combination chemotherapy.
HER2 POSITIVE:
For about 1 in 5 women with breast cancer, the cancer cells have too much of a
growth-promoting protein known as HER2/neu (or just HER2)on their surface. These cancers,
known as HER2-positive breast cancers, tend to grow and spread more aggressively. A
number of drugs have been developed that target this protein:
Trastuzumab(Herceptin): This is a monoclonal antibody, which is a man-made version
of a very specific immune systemprotein. It is often given along with chemo, but it might also
be used alone (especially if chemo alone has already been tried). Trastuzumab can be used to
treat both early- and late-stage breast cancer. When started before or after surgery to treat
early breast cancer, this drug is usually given for a total of a year. For advanced breast cancer,
treatment is often given for as long as the drug is helpful. This drug is given into a vein (IV).
Pertuzumab (Perjeta): This monoclonal antibody can be given with trastuzumab and
chemo, either before surgery to treat early-stage breast cancer, or to treat advanced breast
cancer. This drug is given into a vein (IV).
Ado-trastuzumab emtansine (Kadcyla, also known as TDM-1): This is a monoclonal
antibody attached to a chemotherapy drug. It is used by itselfto treat advanced breast cancer
in women who have already been treated with trastuzumab and chemo. This drug is alsogiven
in a vein (IV).
Lapatinib (Tykerb): This is a kinase inhibitor. It is a pill taken daily. Lapatinib is used
to treat advanced breast cancer, and might be used along with certain chemotherapy drugs,
trastuzumab, or hormone therapy drugs.
Neratinib (Nerlynx): This is another kinase inhibitor. It is a pill that is taken daily.
Neratinib is used to treat early-stage breast cancer after a woman has completed one year of
trastuzumab and is usually given for one year. Some clinical trials show that it may also be
effective in advanced breast cancer, as well.
Side effects of targeted therapy for HER2-positive breast cancer
The side effects of these drugs are often mild, but some can be serious.
 congestive heart failure
 shortness of breath, leg swelling, and severe fatigue.
 Pertuzumab can also cause diarrhea.

10. Targeted treatment for women with BRCA gene mutation:
Olaparib (Lynparza) is a type of drug known as a PARP inhibitor. PARP proteins
normally help repair damaged DNA insidecells.The BRCA genes (BRCA1 and BRCA2) alsohelp
repair DNA (in a slightlydifferent way), but mutations in one of those genes can stop this from
happening. PARP inhibitors work by blocking the PARP proteins. Because tumor cells with a
mutated BRCA gene already have trouble repairing damaged DNA, blocking the PARP proteins
often leads to the death of these cells.
Targeted therapy for hormone receptor-positive breast cancer
 CDK4/6 inhibitors
Palbociclib (Ibrance), ribociclib (Kisqali), and abemaciclib (Verzenio) are drugs that
block proteins in the cell called cyclin-dependent kinases (CDKs), particularly CDK4 and CDK6.
Blocking these proteins in hormone receptor-positive breast cancer cells helps stop the cells
from dividing. This can slow cancer growth.
Everolimus (Afinitor): Everolimus is used for women who have gone through
menopause and have advanced hormone receptor-positive, HER2-negative breast cancer. It
is used along with the aromatase inhibitor exemestane (Aromasin) for women whose cancers
have grown while being treated with either letrozole or anastrozole (or if the cancer started
growing shortly after treatment with these drugs was stopped).
This targeted therapy drug blocks mTOR, a protein in cells that normally helps them
grow and divide. Everolimus may also stop tumors from developing new blood vessels, which
can help limit their growth. In treating breast cancer, this drug seems to help hormone
therapy drugs work better. Everolimus is a pill that is taken once a day.