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MINISTRY OF HEALTH OF UKRAINE
VINNITSA NATIONAL PIROGOV MEMORIAL MEDICAL
UNIVERSITY
"CONFIRM"
at the methodical meeting
Department of Ray diagnostics,
Ray therapy and Oncology
Head of the department
As. of Prof., M.S.D. Kostyuk A.G.
________________________
"______" ________ 2013 year
METHODICAL GUIDELINES
For self-study for students in preparing for the practical (seminary) lessons
Subject of Study
Oncology
Module No
1
Theme No
11
Topic of Lesson
Brest cancer.
Risk factors. Classification by TNM. Methods of
diagnostics. Clinics. Treatment: surgery, radiotherapy,
chemotherapy, combined.
Course
5
Faculty
General Medicine
2
1. Topicality. Female breast cancer is a major medical problem with
significant public health and societal ramifications. Despite major advances that have
been made in the past 25 years in understanding the biologic and clinical nature of
the disease, and notwithstanding dramatic changes in its treatment, the problem
continues to persist and has become more complex. For 2003, 211,300 new cases and
39,800 deaths are projected. The National Cancer Institute estimates that there are
currently more than 2 million breast cancer survivors in the United States. The
lifetime risk for women of being diagnosed with breast cancer is currently between 1
in 7 and 1 in 8. However, these statistics portray only one aspect of the problem. As
new information accumulates, new paradigms of management compete for
acceptance with existing ones. It is axiomatic that good scientific data provides the
bedrock for good clinical management. Information obtained from molecular,
biologic, and pathologic investigations and from clinical trials provides the major
focus of this chapter.
2. Learning Objectives:
1. Benign Breast diseases. Treatment of benign breast disease and profilactic of
Breast cancer.
2. Risk factors.
3. Differential diagnosis between benign breast diseases and Breast cancer.
3. Diffuse and nodular macroscopic form of breast cancer. Treatment tactics.
4. The ways of spreading cancer: infiltrative growth, and lymphogenous
hematogenous metastasis.
5. Classification TNM. Stages of breast cancer.
6. Methods for obtaining of material for cytological and histological examination
7. Surgical treatment of breast cancer.
8. Adjuvant and neoadjuvant chemotherapy. Regimen of chemotherapy.
9. Choice the method of radical operation (mastectomy, hemiresection,
quadrantectomy, lumpectomy).
10. Indications and contraindications for hormonotherapy
11. Indications and contraindications for radiotherapy.
12. Complication and adverse event of chemo- and radiotherapy
13. Survival and prognosis.
3
Breast cancer
Breast cancer is a cancer that starts in the cells of the breast in women and men.
Worldwide, breast cancer is the second most common type of cancer after lung
cancer (10.4% of all cancer incidence, both sexes counted) and the fifth most
common cause of cancer death. In 2005, breast cancer caused 502,000 deaths
worldwide (7% of cancer deaths; almost 1% of all deaths).
Breast cancer is about 100 times as frequent among woman as among men, but
survival rates are equal in both sexes
Classification
Breast cancers are described along four different classification schemes, or
groups, each based on different criteria and serving a different purpose:
Pathology - Each tumor is classified by its histological (microscopic anatomy)
appearance and other criteria.
Grade of tumor - The histological grade of a tumor is determined by a
pathologist under a microscope. A well-differentiated (low grade) tumor resembles
normal tissue. A poorly differentiated (high grade) tumor is composed of
disorganized cells and, therefore, does not look like normal tissue. Moderately
differentiated (intermediate grade) tumors are somewhere in between.
Protein & gene expression status - Currently, all breast cancers should be tested
for expression, or detectable effect, of the estrogen receptor (ER), progesterone
receptor (PR) and HER2/neu proteins. These tests are usually done by
immunohistochemistry and are presented in a pathologist's report. The profile of
expression of a given tumor helps predict its prognosis, or outlook, and helps an
oncologist choose the most appropriate treatment. More genes and/or proteins may
be tested in the future.
Stage of a tumor - The currently accepted staging scheme for breast cancer is
the TNM classification. This considers the Tumor itself, whether it has spread to
lymph Nodes, and whether there are any Metastases to locations other than the breast
and lymph nodes.
Breast cancer is usually, but not always, primarily classified by its histological
appearance. Rare variants are defined on the basis of physical exam findings. For
example, Inflammatory breast cancer (IBC), a form of ductal carcinoma or malignant
cancer in the ducts, is distinguished from other carcinomas by the inflamed
4
appearance of the affected breast. In the future, some pathologic classifications may
be changed. For example, a subset of ductal carcinomas may be re-named basal-like
carcinoma (part of the "triple-negative" tumors).
Signs and symptoms
The first symptom, or subjective sign, of breast cancer is typically a lump that
feels different from the surrounding breast tissue. According to the Merck Manual,
more than 80% of breast cancer cases are discovered when the woman feels a lump.
According to the American Cancer Society (ACS), the first medical sign, or objective
indication of breast cancer as detected by a physician, is discovered by mammogram.
Lumps found in lymph nodes located in the armpits and/or collarbone can also
indicate breast cancer.
Indications of breast cancer other than a lump may include changes in breast
size or shape, skin dimpling, nipple inversion, or spontaneous single-nipple
discharge. Pain is an unreliable tool in determining the presence or absence of breast
cancer, but may be indicative of other breast-related health issues such as
mastodynia.
When breast cancer cells invade the dermal lymphatics, small lymph vessels in
the skin of the breast, its presentation can resemble skin inflammation and thus is
known as inflammatory breast cancer (IBC). Symptoms of inflammatory breast
cancer include pain, swelling, warmth and redness throughout the breast, as well as
an orange peel texture to the skin referred to as peau d'orange.
Another reported symptom complex of breast cancer is Paget's disease of the
breast. This syndrome presents as eczematoid skin changes such as redness and mild
flaking of the nipple skin. As Paget's advances, symptoms may include tingling,
itching, increased sensitivity, burning, and pain. There may also be discharge from
the nipple. Approximately half of women diagnosed with Paget's also have a lump in
the breast.
Occasionally, breast cancer presents as metastatic disease, that is, cancer that
has spread beyond the original organ. Metastatic breast cancer will cause symptoms
that depend on the location of metastasis. More common sites of metastasis include
bone, liver, lung and brain. Unexplained weight loss can occasionally herald an
occult breast cancer, as can symptoms of fevers or chills. Bone or joint pains can
sometimes be manifestations of metastatic breast cancer, as can jaundice or
5
neurological symptoms. These symptoms are "non-specific," meaning they can also
be manifestations of many other illnesses.
Most symptoms of breast disorder do not turn out to represent underlying breast
cancer. Benign breast diseases such as mastitis and fibroadenoma of the breast are
more common causes of breast disorder symptoms. The appearance of a new
symptom should be taken seriously by both patients and their doctors, because of the
possibility of an underlying breast cancer at almost any age.
Epidemiology and etiology
Although many epidemiological risk factors have been identified, the cause of
any individual breast cancer is often unknowable. In other words, epidemiological
research informs the patterns of breast cancer incidence across certain populations,
but not in a given individual. Due to breast cancer is vary in different racial and
ethnic group. The primary risk factors that have been identified are sex, age,
childbearing, hormones, a high-fat diet, alcohol intake, obesity, and environmental
factors such as tobacco use, radiation and shiftwork.
No etiology is known for 95% of breast cancer cases, while approximately 5%
of new breast cancers are attributable to hereditary syndromes. In particular, carriers
of the breast cancer susceptibility genes, BRCA1 and BRCA2, are at a 30-40%
increased risk for breast and ovarian cancer, depending on in which portion of the
protein the mutation occurs.
Worldwide, breast cancer is by far the most common cancer amongst women,
with an incidence rate more than twice that of colorectal cancer and cervical cancer
and about three times that of lung cancer. However breast cancer mortality
worldwide is just 25% greater than that of lung cancer in women. In 2005, breast
cancer caused 502,000 deaths worldwide (7% of cancer deaths; almost 1% of all
deaths). The number of cases worldwide has significantly increased since the 1970s,
a phenomenon partly blamed on modern lifestyles in the Western world.
The incidence of breast cancer varies greatly around the world, being lower in
less-developed countries and greatest in the more-developed countries. In the twelve
world regions, the annual age-standardized incidence rates per 100,000 women are as
follows: in Eastern Asia, 18; South Central Asia, 22; sub-Saharan Africa, 22; SouthEastern Asia, 26; North Africa and Western Asia, 28; South and Central America,
42; Eastern Europe, 49; Southern Europe, 56; Northern Europe, 73; Oceania, 74;
Western Europe, 78; and in North America, 90.
6
United States
Women in the United States have the highest incidence rates of breast cancer in
the world; 141 among white women and 122 among African American women.
Among women in the US, breast cancer is the most common cancer and the secondmost common cause of cancer death (after lung cancer). Women in the US have a 1
in 8 (12.5%) lifetime chance of developing invasive breast cancer and a 1 in 35 (3%)
chance of breast cancer causing their death. In 2007, breast cancer was expected to
cause 40,910 deaths in the US (7% of cancer deaths; almost 2% of all deaths).
In the US, both incidence and death rates for breast cancer have been declining
in the last few years in Native Americans and Alaskan Natives. Nevertheless, a US
study conducted in 2005 by the Society for Women's Health Research indicated that
breast cancer remains the most feared disease, even though heart disease is a much
more common cause of death among women. Many doctors say that women
exaggerate their risk of breast cancer.
Racial disparities in diagnosis and treatment
Several studies have found that black women in the U.S. are more likely to die
from breast cancer even though white women are more likely to be diagnosed with
the disease. Even after diagnosis, black women are less likely to get treatment
compared to white women. Scholars have advanced several theories for the
disparities, including inadequate access to screening, reduced availability of the most
advanced surgical and medical techniques, or some biological characteristic of the
disease in the African American population. Some studies suggest that the racial
disparity in breast cancer outcomes may reflect cultural biases more than biological
disease differences. Research is currently ongoing to define the contribution of both
biological and cultural factors.
UK
45,000 cases diagnosed and 12,500 deaths per annum. 60% of cases are treated
with Tamoxifen, of these the drug becomes ineffective in 35%.
Prevention
Further information: Epidemiology and etiology of breast cancer
Several factors can influence breast cancer incidence either positively or
negatively. Those factors are discussed in a specific Wikipedia article.
Screening
7
Breast cancer screening is an attempt to find unsuspected cancers. The most
common screening methods are self and clinical breast exams, x-ray mammography,
and breast Magnetic Resonance Imaging (MRI). Genetic testing may also be used.
Breast self-examination involves examining one's own breasts using a specific
palpation technique to detect any lumps in the breast tissue, which may be cancerous.
Clinical exams are similar, except they are performed by a clinician or doctor.
X-ray mammography uses x-rays to examine the breast for any uncharacteristic
masses or lumps. Regular mammograms -- the process of getting breast
mammography -- is often recommended as a preventative measure, particularly for
older women and at-risk individuals. A recent study involving 160,921 women
recruited at age 39-41 showed that annual screening mammograms up to age 48 did
decrease breast cancer mortality over an average of 10.7 years. This reduction,
however, was not statistically significant. The results may be due to chance.
According to these findings, about 2,500 women would need to be screened to
prevent one breast cancer death during this time period.
Breast MRIs are another imaging technique that can be used to spot potentially
cancerous masses.
The most recent technology for breast cancer screening is ultrasound computed
tomography, which uses sound waves to create a three-dimensional image and detect
breast cancer without the use of dangerous radiation used in x-ray mammography.
This method was discovered at Los Alamos National Laboratory.
Genetic testing for breast cancer typically involves testing for mutations in the
BRCA genes. This is not generally a recommended technique except for those at
elevated risk for breast cancer.
Diagnosis
While screening techniques discussed above are useful in determining the
presence of cancer, they are not in and of themselves diagnostic of cancer. Pathology
is the study and diagnosis of disease; only microscopic evaluation of a biopsy
specimen can yield a cancer diagnosis. A number of procedures can obtain tissue or
cells for histological or cytological examination. Such procedures include fine-needle
aspiration, nipple aspirates, ductal lavage, core needle biopsy, and local surgical
excision. Occasionally, pre-surgical procedures such as fine needle aspirate may not
yield enough tissue to make a diagnosis, or may miss the cancer entirely.
Staging
8
Breast cancer is staged according to the TNM system, updated in the AJCC
Staging Manual, now on its sixth edition. Prognosis is closely linked to results of
staging, and staging is also used to allocate patients to treatments both in clinical
trials and clinical practice. The information for staging is as follows:
TX: Primary tumor cannot be assessed. T0: No evidence of tumor. Tis:
Carcinoma in situ, no invasion T1: Tumor is 2 cm or less T2: Tumor is more than 2
cm but not more than 5 cm T3: Tumor is more than 5 cm T4: Tumor of any size
growing into the chest wall or skin, or inflammatory breast cancer
NX: Nearby lymph nodes cannot be assessed N0: Cancer has not spread to
regional lymph nodes. N1: Cancer has spread to 1 to 3 axillary or one internal
mammary lymph node N2: Cancer has spread to 4 to 9 axillary lymph nodes or
multiple internal mammary lymph nodes N3: One of the following applies:
Cancer has spread to 10 or more axillary lymph nodes, or Cancer has spread to
the lymph nodes under the clavicle (collar bone), or Cancer has spread to the lymph
nodes above the clavicle, or Cancer involves axillary lymph nodes and has enlarged
the internal mammary lymph nodes, or Cancer involves 4 or more axillary lymph
nodes, and tiny amounts of cancer are found in internal mammary lymph nodes on
sentinel lymph node biopsy.
MX: Presence of distant spread (metastasis) cannot be assessed. M0: No distant
spread. M1: Spread to distant organs, not including the supraclavicular lymph node,
has occurred
Summary of stages:
Stage 0 - Carcinoma in situ (DCIS)
Stage I - Tumor (T) does not involve axillary lymph nodes (N).
Stage IIA – T 2-5 cm, N negative, or T <2 cm and N positive.
Stage IIB – T > 5 cm, N negative, or T 2-5 cm and N positive (< 4 axillary
nodes).
Stage IIIA – T > 5 cm, N positive, or T 2-5 cm with 4 or more axillary nodes
Stage IIIB – T has penetrated chest wall or skin, and may have spread to < 10
axillary N
Stage IIIC – T has > 10 axillary N, 1 or more supraclavicular or infraclavicular
N, or internal mammary N.
Stage IV – Distant metastasis (M)
9
Approximately 90% of new breast cancer cases in the US will be classified as
"early-stage" cases (DCIS, Stage I,IIA, IIB or IIIA), due to early detection and
prevention techniques. Early-stage treatment options are different from late-stage
options.
Hormone receptors
Breast lesions are examined for certain markers, notably sex steroid hormone
receptors. About two thirds of postmenopausal breast cancers are estrogen receptor
positive (ER+) and progesterone receptor positive (PR+). Receptor status modifies
the treatment as, for instance, only ER-positive tumors, not ER-negative tumors, are
sensitive to hormonal therapy.
The breast cancer is also usually tested for the presence of human epidermal
growth factor receptor 2, a protein also known as HER2, neu or erbB2. HER2 is a
cell-surface protein involved in cell development. In normal cells, HER2 controls
aspects of cell growth and division. When activated in cancer cells, HER2 accelerates
tumor formation. About 20-30% of breast cancers overexpress HER2. Those patients
may be candidates for the drug trastuzumab, both in the postsurgical setting (socalled "adjuvant" therapy), and in the metastatic setting.
Treatment
The mainstay of breast cancer treatment is surgery when the tumor is localized,
with possible adjuvant hormonal therapy (with tamoxifen or an aromatase inhibitor),
chemotherapy, and/or radiotherapy. At present, the treatment recommendations after
surgery (adjuvant therapy) follow a pattern. This pattern is subject to change, as
every two years, a worldwide conference takes place in St. Gallen, Switzerland, to
discuss the actual results of worldwide multi-center studies. Depending on clinical
criteria (age, type of cancer, size, metastasis) patients are roughly divided to high risk
and low risk cases, with each risk category following different rules for therapy.
Treatment possibilities include radiation therapy, chemotherapy, hormone therapy,
and immune therapy.
In planning treatment, doctors can also use PCR tests like Oncotype DX or
microarray tests like MammaPrint that predict breast cancer recurrence risk based on
gene expression. In February 2007, the MammaPrint test became the first breast
cancer predictor to win formal approval from the Food and Drug Administration.
This is a new gene test to help predict whether women with early-stage breast cancer
10
will relapse in 5 or 10 years, this could help influence how aggressively the initial
tumor is treated.
Interstitial laser thermotherapy (ILT) is an innovative method of treating breast
cancer in a minimally invasive manner and without the need for surgical removal,
and with the absence of any adverse effect on the health and survival of the patient
during intermediate followup .
Radiation treatment is also used to help destroy cancer cells that may linger
after surgery. Radiation can reduce the risk of recurrence by 50-66% (1/2 - 2/3rds
reduction of risk) when delivered in the correct dose.
Prognosis
A prognosis is the medical team's "best guess" in how cancer will affect a
patient. There are many prognostic factors associated with breast cancer: staging,
tumour size and location, grade, whether disease is systemic (has metastasized, or
traveled to other parts of the body), recurrence of the disease, and age of patient.
Stage is the most important, as it takes into consideration size, local
involvement, lymph node status and whether metastatic disease is present. The
higher the stage at diagnosis, the worse the prognosis. The stage is raised by the
invasiveness of disease to lymph nodes, chest wall, skin or beyond, and the
aggressiveness of the cancer cells. The stage is lowered by the presence of cancerfree zones and close-to-normal cell behaviour (grading). Size is not a factor in
staging unless the cancer invasive. Ductal Carcinoma in situ throughout the entire
breast is stage zero.
Grading is based on how biopsied, cultured cells behave. The closer to normal
cancer cells are, the slower their growth and the better the prognosis. If cells are not
well differentiated, they will appear immature, will divide more rapidly, and will
tend to spread. Well differentiated is given a grade of 1, moderate is grade 2, while
poor or undifferentiated is given a higher grade of 3 or 4 (depending upon the scale
used).
Younger women tend to have a poorer prognosis than post-menopausal women
due to several factors. Their breasts are active with their cycles, they may be nursing
infants, and may be unaware of changes in their breasts. Therefore, younger women
are usually at a more advanced stage when diagnosed.
11
The presence of estrogen and progesterone receptors in the cancer cell, while
not prognostic, is important in guiding treatment. Those who do not test positive for
these specific receptors will not respond to hormone therapy.
Likewise, HER2/neu status directs the course of treatment. Patients whose
cancer cells are positive for HER2/neu have more aggressive disease and may be
treated with trastuzumab, a monoclonal antibody that targets this protein.
Elevated CA15-3, in conjunction with alkaline phosphatase, was shown to
increase chances of early recurrence in breast cancer.
Psychological aspects of diagnosis and treatment
The emotional impact of cancer diagnosis, symptoms, treatment, and related
issues can be severe. Most larger hospitals are associated with cancer support groups
which provide a supportive environment to help patients cope and gain perspective
from cancer survivors. Online cancer support groups are also very beneficial to
cancer patients, especially in dealing with uncertainty and body-image problems
inherent in cancer treatment.
Suggested Reading:
1. Manual Of Clinical Oncology, - Dennis A. Casciato, Barry B. Lowitz, 2000
2. Oxford Handbook of Oncology, - Oxford University Press, 2002
3. Basics of Oncology, - Frederick O. Stephens · Karl R. Aigner, 2009
4. HARRISON’S Manual of Oncology, - Bruce A. Chabner, Thomas J. Lynch,
Jr., Dan L. Longo, 2008