Breast ca riskk & prognostic factors the lect

RISK AND PROGNOSTIC
FACTORS IN BREAST CANCER
Professor of surgery Banha University - Egypt
HAMED RASHAD

Incidence of Br. Ca.:
 Breast cancer is the commonest cancer in women .
 Account for 32% of new cancer cases in American
women
 The life time probability risk of developing breast
cancer in USA is 1 in 7 (cancer statistics, 2004)
----- 1 in 12 in England.
Saturday, August 28, 2021 2

Breast Cancer Epidemiology
Breast Cancer epidemiology
• Variation among countries
• Variation among populations
• Variation among ethnic groups

By Region
• The incidence of breast cancer varies
greatly around the world: it is lowest in
less-developed countries and greatest in
the more-developed countries.

BREAST CANCER
RISK FACTORS
About 90 – 95 % of all br. Ca. Are sporadic
with about 5 – 10 % inherited

Definition
• A risk factor is anything that affects the chance of
getting a disease, such as cancer.
• About 70% of women diagnosed with BC did
not have known risk factors.
• It is hard to define the contribution of different
risk factors in the development of BC.
• Multiplicity of risk factors increase the likelihood
for disease development.

Risk factors of Breast Cancer:
• 1- Female gender
• Simply being a woman is the main risk
factor for developing breast cancer (BC).
• BC is about 100 times more common
among women than men.

Risk factors of Breast Cancer:
2- Age
- br. Ca. Is rare before age 20
- incidence increase with age
- there is a slight downward trend
during menopausal years ( menopausal hook )
• Only 5% of all breast cancers occurring in women under 40
• Women aged 50 – 69 are most at risk

3- Geographic variations
higher in developed countries
- higher incidence in populations migrating from
nations with low incidence.

4- Productive risk factors
a- Age at menarche
→ earlier age at menarche increases risk
→ shorter menstrual cycles → increases risk
→ long & irregular cycles → increases risk
b- Late menopause
55 years or more higher risk
c - Nulliparity → increases risk
d- Higher numbers of births → decreases risk
e- Bilateral oophrectomy before age 45 → decreases risk

Menstrual periods
• Early menarche (before age 12) and/or late
menopause (after age 55) have a slightly
higher risk of breast cancer.
• The increase in risk may be due to a longer
lifetime exposure to the hormones
estrogen and progesterone.

Menopause
• Early menopause reduces risk
• Women who have undergone bilateral
oophorectomy at a young age before age 45 years
have approximately half the risk (50%) of breast
cancer compared to those with a natural menopause
at age 55 years or older.
• On average, the risk of breast cancer increases by
some 3% per year of delay in age at menopause.

d- Age at first full pregnancy
- after age 30 → increases risk twice than those before 20
- after age 35 → higher risk even more than nulliparas
- earlier age at the second child reduces risk
• The susceptibility of mammary tissue to
carcinogens decreases after the first pregnancy,
reflecting the differentiation of the mammary
gland.

e- Spontaneous and induced abortion
• It is hypothesized to increase a woman’s
risk of developing breast cancer.
• By far the strongest study to date on the association
between breast cancer and abortion was a population
based cohort study made up of 1.5 million Danish
women born April 1, 1935, through March 31, 1978.

f-Number and spacing of births
• A higher number of births is consistently related
to lower risk of breast cancer; each additional
birth beyond the first reduces long-term risk of
breast cancer.
• In addition to a protective effect of higher parity,
more closely spaced births are associated with a
lower lifetime risk of breast cancer.

5- Lactation
Lactation may give reduced risk ( for at least 30 months)
• It is estimated that, if women in developed countries had
the number of births and lifetime duration of
breastfeeding of women in developing countries, the
cumulative incidence of breast cancer by age 70 years
would be reduced by as much as 60%

Breast-feeding
• Breast-feeding may slightly lower breast
cancer risk, especially if breast-feeding is
continued for 1½ to 2 years.
• The explanation for this possible effect may
be that breast-feeding reduces a woman's
total number of lifetime menstrual cycles.

6- Family history
• Up to 10% is due to genetic predisposition
- inherited as autosomal dominance
- BRCA1 o long arm of chromosome 17
- BRCA2 on long arm of chromosome 13 n (males with
Br.Ca.)
• Women most likely to carry inherited gene are those
who develop a combination of breast cancer & another
epithelial cancer

Family history of breast cancer
• Having one first or second-degree relative
(mother, sister, or daughter) with breast cancer
approximately doubles a woman's risk.
• Having 2 first-degree relatives increases her risk
about 3-fold.
• Women with a family history of breast cancer in a
father or brother have an increased risk of BC.
• The younger the first degree relative to have br.ca.
the higher risk

Hereditary Breast Cancer
• Approximately 40% of hereditary breast cancer is
caused by mutations in the BRCA1 or BRCA2 genes
• Women who inherit a BRCA mutation have a 50% to
85% chance of developing breast cancer in their lifetime
• These Women may consider preventive surgery to
remove breast tissue and/or chemoprevention
• Genetic counseling and testing is available for most syndromes

Genes
• BRCA1: A gene on chromosome 17 or BRCA2: A
gene on chromosome 13 that normally helps to
suppress cell growth. A person who inherits certain
mutations (changes) in a BRCA1or 2 genes has a
higher risk of getting breast, ovarian, prostate, and
other types of cancer.

BRCA1 and BRCA2 mutations
• The most common cause of hereditary breast cancer.
• In normal cells, these genes help prevent cancer by making
proteins that keep the cells from growing abnormally.
• Inheritance of a mutated genes increase the risk for BC.
• The risk may be as high as 80% for members of some
families with BRCA mutations. Cancers tend to occur in
younger women and more often affect both breasts, with
increased risk for developing other cancers (ovarian).
• BRCA mutations are found most often in Jewish women of
Ashkenazi (Eastern Europe) origin, but they can occur in
any racial or ethnic group.

Personal history of breast cancer
• A woman with cancer in one breast has a 3-
to 4-fold increased risk of developing a new
cancer in the other breast or in another part
of the same breast.

7 .Multiple primary neoplasm:
– Hx of primary breast CA ---> 4x fold
increase of secondary CA
– Hx of primary CA of uterus and
ovary ----> 1-1.5 risk

8 .Irradiation
Multiple exposure
Radiotherapy for breast CA of contralateral breast
• Depends on dose and age at irradiation, being highest for
women exposed before age ten years.

9- Obesity
- before menopause → no
- after menopause → higher risk
Fat is an important source of oestrogen
production postmenopausal.

10- Benign breast disease
risk Disease type
No risk - Mild hyperplasia
- Duct ectasia
- Simple fibro adenoma
- Microcysts
- Periductal mastitis
-Adenosis
Slightly increased risk 1.5 – 2
times
- Gross or complicated cysts
- Moderate & florid hyperplasia
- Papilloma
- Sclerosing adenosis
- complex fibroadenoma
Moderately increased risk 4-5
times
- Atypical hyperplasia
34

Lobular carcinoma in situ
• In lobular carcinoma in situ (LCIS) (also called
lobular neoplasia) is sometimes grouped with ductal
carcinoma in situ (DCIS) as a non-invasive breast
cancer, but it differs from DCIS in that it doesn’t
seem to become an invasive cancer if it isn’t
treated.
• Women with this condition have a 7- to 11-
fold increased risk of developing invasive
cancer in either breast.

11- Diet
- fat and red meat ???
- dietary fibre , vit.C , vit.E , selenium - vit.A →
modest protection
- phytooestrogen in soy → decreases risk
- caffeine → no increased risk
- alcohol → increases risk esp. Two drinks / day

Tobacco smoke
• For a long time, studies found no link
between cigarette smoking and breast
cancer.
• In recent years though, some studies have
found that smoking may increase the risk of
breast cancer. The increased risk seems to
affect certain groups, such as women who
started smoking when they were young.

12-Physical activity
• Evidence is growing that physical activity in
the form of exercise reduces breast cancer risk.
• In one study from the Women's Health
Initiative (WHI) as little as 1.25 to 2.5 hours
per week of brisk walking reduced a woman’s
risk by 18%.
• Walking 10 hours a week reduced the risk a
little more.

13- Oral contraceptive pills
Slightly increased the risk – not clinically
significant as :
- women on pills are more likely to be
examined at regular intervals → br.ca. Is more
likely to be detected earlier

14- postmenopausal oestrogen
replacement
- HRT → increases the risk of br.ca.
- oestrogen combined with progesterone
→ reduce risk of endometrial carcinoma
but not br.ca.
- other non hormonal preparations are
available for ttt of menopausal symptoms

15-endogenous sex hormones
• Estrogens risk of breast cancer increased
• Androgens increase breast cancer risk either directly, by
increasing the growth and proliferation of breast cancer cells, or
indirectly, by their conversion to estrogen.
• Prolactin Prolactin receptors have been found on more than
50% of breast tumors, and prolactin increases the growth of both
normal and malignant breast cells in vitro, although these
findings have not been entirely consistent.
• Insulin-like Growth Factor• There is increasing evidence
that the growth hormone- IGF-I axis stimulates proliferation of both breast
cancer and normal breast epithelial cells.

16-Silicone Breast Implants
• Most studies examining the relation of silicone
breast implants with breast cancer risk have actually
reported lower rates of breast cancer among women
with implants.
• There is strong epidemiologic evidence that breast
implants do not lead to increased risk of breast
cancer

17-Synthetic Chemicals
(Organochlorines, synthetic chemicals, DDT,
Dioxins)
• Many of these chemicals are weak estrogens
and may act as estrogenic agents in breast
tissue, thereby hypothesized to increase breast
cancer risk by mimicking endogenous estradiol.

Chemicals in the environment
• Of special interest are compounds in the environment
that found to have estrogen-like properties.
• These could in theory affect breast cancer risk. For
example, substances found in some plastics, certain
cosmetics and personal care products, pesticides
(such as DDE), and PCBs (polychlorinated
biphenyls) seem to have such properties.
• Research does not show a clear link between breast
cancer risk and exposure to these substances.

18-Electromagnetic Fields
• Electromagnetic fields (EMF) have been proposed
to alter breast cancer risk, perhaps by altering
melatonin secretion by the pineal gland.
In case-control studies designed specifically to study
occupational exposure to EMF and breast cancer in
women, small increases in risk have been
inconsistently observed.

19-Dense breast tissue on mamo
• Women with denser breast tissue
(mammogram) have more glandular tissue
and less fatty tissue, and have a higher risk
of breast cancer.
• Unfortunately, dense breast tissue can also
make it harder to spot problems on
mammograms.

20-Antiperspirants
• Rumors have suggested that chemicals in underarm
antiperspirants are absorbed through the skin, interfere
with lymph circulation, cause toxins to build up in the
breast, and eventually lead to breast cancer.
• There is very little evidence to support this rumor.
• One small study has found trace levels of parabens (used
as preservatives in antiperspirants and other products),
which have weak estrogen-like properties, in a small
sample of breast cancer tumors.
• But this study did not look at whether parabens caused the
tumors.

21-Bras
• Internet e-mail rumors and at least one
book have suggested that bras cause breast
cancer by obstructing lymph flow.
• There is no good scientific or clinical basis
for this claim.

22-Night work
• Several studies have suggested that women
who work at night — for example, nurses
on a night shift — may have an increased
risk of developing breast cancer.
• Some researchers think the effect may be
due to changes in levels of melatonin, a
hormone whose production is affected by
the body’s exposure to light, but other
hormones are also being studied.

BREAST CANCER
PROGNOSTIC FACTORS

Prognostic factors in Breast Cancer
Survival depends on two groups of
factors:
A- Tumour stage (TNM)
B- Biological factors
(biology or aggressiveness of tumour)

A- Tumour stage
1- Nodal status
• The single gold standard against which all
other factors should be compared is Nodal
Status
• Node negative 70% 10 year survival
• Node positive 20-30% 10 year survival

Survival Rates for patients w/ Breast Cancer Relative to
Histologic Stage
Histologic Staging
(NSABP)
Crude survival
(%)
5yr 10yr
5-yr Disease-
free survival
(%)
All patients 63.5 45.9 60.3
Negative axillary lymph nodes 78.1 64.9 82.3
Positive axillary lymph nodes 46.5 24.9 34.9
1 - 3 positive axillary lymph nodes 62.2 37.5 50.0
> 4 positive axillary lymph nodes 32.0 13.4 21.1

2- Histology
• Tumours of special type ( classical, lobular, tubular,
cribriform .........) have a much better prognosis than
tumours of no special type (NST)
• This association appears independent of grade.
- 5 year survival 91% in tumours of special type
- 40% alive after 20 years
- 5 year survival 47% for ca NST
- 15% alive after20 years

3- Tumour size:
- Larger tumours have higher incidence of
metastasis to regional LNs
- tumours < 1 cm still have 17% nodal
involvement

4- Tumour grade
- 5 years survival → 86% in grade I
→ 57% in grade III

B- Biological factors:
OLD DECTUM
- Many are still experimental = further work is needed
- Treatment decisions are still made on the basis of
conventional factors

B- Biological factors
1- Oestrogen receptors (ER)
- 60% of tumours are ER +ve
- only 5-10% difference in survival between ER +ve and ER –ve
cases
- survival and response to therapy is better after first recurrence
in ER +ve cases
2- Progesteron receptors (PR)
Their presence corrilate with the ER status

3- Cell kinetics and ploidy
- S-phase (% of active cell division) is better
predictor of relapse and survival than ploidy
- Diploid tumours have a low risk of relapse
than aneuploid ones
- Low S-phase tumours have a more
favourable prognosis regardless of ploidy

4- erbB2
- this protein is a cell membrane receptor
- A product of “neu” oncogene
- erbB2 positive tumours have a worse prognosis
Saturday, August 28,
2021
61

What is HER 2/neu
• Other names
– Receptor tyrosine-protein kinase erbB-2
– CD340
– proto-oncogene Neu
– ERBB2 (human)
Located in chromosome 17 (17q12)
Rodent glioblastoma cell line a neural tumour

Cont….
Plasma membrane bound receptor tyrosine kinase
Positive in 15-30% cases of breast carcinoma
Associated with increase disease recurrence and
poor prognosis
• Tested by-
– Immunohistochemistry
– FISH
– Serum HER2 by ELISA- Trastuzumab response

Her-2 overexpression in breast cancer-
1985-1998
• About 20-30% of breast cancers overexpress HER-2
protein (usually because of gene amplification)
• Monotherapy with anti-HER-2 monoclonal antibody
(trastuzumab or Herceptin) has a 30% response rate in
HER-2-positive metastatic breast cancer
• Combination of trastuzumab plus chemotherapy improves
time to progression and overall survival in advanced HER-2
positive breast cancer
• Trastuzumab plus anthracycline results in a 20% incidence
of cardiotoxicity

5- Epidermal growth factor receptor
(EGFr)
- Another cell membrane protein
- Promote growth of cancer cells
- Elderly patients treated with tamoxafen alone are 5
times to respond if their tumours were EGFr negative

6- Cathepsin D
- A protease whose activity is stimulated by
oestrogen
- May contribute to metastasis by dissolving
basement membrane and extracellular matrix that
allowing cancer spread

7- p53
- this is the product of a nuclear oncogene
- coded on the short arm of chromosome 17
- responsible for preventing cellular division in an un
controlled fashion

8- Pathological complete
response is a prognostic factor
• patients who achieve pathological complete
response after neoadjuvant anti-HER2 therapy
have longer event-free and overall survival
than do patients without pathological
complete response.
De Azambuja et al. Lancet Oncol 2014; 15:1137-46.

9 - Age as prognostic factor
 Patients ≤44 years exhibited more often
triple negative and less frequently luminal
A tumors compared to patients >45 years.
Agrup M, Stäl O, Olsen K, Winren S (2000). C-erbB-2 Over expression and survival in
early onset breast cancer. Breast Cancer Res Treat, 63, 23-9

Molecular Classification
Breast cancers are classified into 5 molecular subtypes
1. Luminal A
2. Luminal B
3. Normal breast like
4. Her2neu enriched
5.Basal Like including Triple negative BC[TNBC]

• Express ER & PR (+ve)
• Do not express HER2/neu (- ve)
• Ki-67 proliferation index- low
• Most common.
• Luminal A tumours are associated with a
better prognosis
Luminal A

• Express ER & PR
• Variable HER2/neu expression
• Increased frequency of TP53 mutations
• Ki-67 proliferation index- high
• Luminal B tumours are associated with
worse prognosis compared to Luminal A
Luminal B

• Associated with a high histological grade, low
expression of ER and PR
• Poor clinical outcome.
HER2/neu enriched subtype

• Hormone receptor (ER and PR) and HER2/neu
receptor negative
• Aggressive with a poorer disease-free and overall
survival than the other breast cancer subtypes
• Termed triple negative breast cancer (TNBC)
because they typically lack ER, PR, and HER2
Basal-like subtype

Normal breast-like
• 5%-10% of all breast carcinomas they express gene
characteristics of adipose tissue
• usually do not respond to neoadjuvant chemotherapy.
• As they lack the expression of ER, PR and HER2,
these tumors can also be classified as triple-negative but
they are not considered to be basal-like cancers as they
are negative for CK5 and EGFR.
• an intermediate prognosis between luminal and basal-
like cancers

Algorithm for breast cancer subtypes
All cases
ER - PR -
ER+ or PR +
HER2 - HER2 + HER2 +
HER2 -
EGFR - CK5/6 – EGFR + or CK5/6 +
Unclassified
(normal breast like)
Basal
Like
Luminal B Luminal A
HER2+/E
R-

Survival Rates for patients w/ Breast Cancer Relative to
Clinical Stage
Clinical staging
(American Joint Committee)
Crude 5-yr
survival (%)
Range
Survival
(%)
STAGE I Tumor < 2cm in diameter
Nodes, if present, not felt to contain metastases
w/o distant metastases
85 82 - 94
STAGE II Tumors < 5 cm in diameter
Nodes, if palpable, not fixed
w/o distant metastasis
66 47 – 74
STAGE III Tumor > 5cm in diameter
Tumor any size w/ invasion of skin attached to
chest wall
Nodes in supraclavicular area
Without distant metastases
41 7 – 80
STAGE IV With distant metastases 10 -

Breast Cancer Myths
•Everyone dies from breast cancer
–No!
•Stage 0 99%
•Stage I 97%
•Stage II 83%
•Stage III 54%
•Stage IV 16%
•All breast lumps are cancer
–No!
•Breast cancer is always painless
–No!
•You can always feel breast cancers
–No!

Breast Cancer Myths
•Breast cancer is mostly genetic
–No!
•5-10% genetic
•20% lifestyle
•70% unknown
•Women with breast cancer cannot nurse
–No!
•Breast cancer will spread when exposed to air
–No!

Breast Cancer Myths
•All breast cancer patients need chemotherapy
and/or radiation therapy
–No!
•All of the armpit lymph nodes will be removed if
there is cancer in one or two
–No!

Breast Cancer Myths
The breasts should be removed if there is a
genetic mutation associated with higher
future risk of breast cancer
–No!
•The nipple needs to be removed during a
mastectomy
–No!

Everything causes breast cancer
•Coffee, NO!
•Antiperspirants, NO!
•Underwire bras, NO!
•Cell phones, NO!
•Breast implants, NO!
•Oral C Pills , NO!
–Older vs newer data

What is the magic pill?
•Nighttime sleep
•Exercise
–30 min walk several times per week
•Establish a reasonable BMI
•Eat fruits and vegetables
•Limit red meat & fat
•Limit alcohol
•Limit smoking
•Limit stress

Take home messages
Breast Cancer is a major Public Health problem.
In several parts of the world, it remains the most
common cancer among women.
Most breast cancer deaths occur in less developed
countries
The number of cases worldwide has significantly
increased since the 1970s, a phenomenon partly
attributed to the modern lifestyles

Breast ca riskk & prognostic factors the lect

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