molecular biology and high ri

1. MOLECULAR BIOLOGY OF BREAST
CANCER AND
IDENTIFICATION AND
MANAGEMENT OF HIGH RISK
PATIENT
DR.BARUN KUMAR

2. MOLECULAR BIOLOGY
The markers and pathways of interest in breast ca are :
• Steroid hormone receptor pathway (ER & PR)
• Human epidermal growth factor receptor pathway ( HER
family)
• Cell cycle ( CDKs)
• COX-2
• PPAR-y
• IGF family
• TGF-y
• PDGF
• p53

3. .
STEROID HORMONE RECEPTOR PATHWAY (ER &PR)
• Belongs to the family of G-protein coupled receptors
• 2 different forms- alpha (breast cancer cells) and beta
• Over- expression is seen in more than half of breast tissue
biopsies
• 2 mechanisms have proposed for tumor genesis
First, binding of oestrogen to the ER stimulates proliferation
of mammary cells, with the resulting increase in cell
division and DNA replication, leading to mutations.
Second, oestrogen metabolism produces genotoxic waste.

5. .
• Tumours are classified as oestrogen dependent
and independent according to their need for
oestrogen for growth
• Assessment of receptor expression helps in
prognostication and decision making about
endocrine therapy as chemoprevention

6. HER2/neu
• Human epidermal growth factor receptor 2
• Member of ErbB protein family
• Cell membrane bound tyrosine kinase
mediated pathway
• Approx 30% of breast cancer show over
expression of her2/neu which is associated
with bad prognosis

7. • Co-localized with GRB7 (proto-oncogene)
• Targeted by monoclonal antibody
TRANSTUZUMAB
• Pertuzumab (inhibits dimerization of HER2 &
HER3 receptors) used in combination of
transtuzumab

8. Molecular pathways in pathogenesis of breast cancer

9. .
A classification system based on expression of
ER/PR and HER2/neu has been made
However, tumours in same group don't follow
similar behaviour, which warrants further sub
classification system
A special category is TRIPLE NEGATIVE tumours
• Express proteins common with myoepithelial
cells at the base of mammary ducts, so called
BASAL LIKE CANCERS

10. • High association with BRCA1 has been shown
• As no chemoprevention is effective, hard to
treat
• Surgery is the treatment of choice with
adjuvant chemo (very chemo sensitive) and
radiotherapy
• Addition of a taxane improve outcome

11. HIGH RISK PATIENT
RISK FACTORS THAT CANNOT
BE MODIFIED
• Increasing age
• Female gender
• Menstrual factors
• Early age at menarche
• Older age at menopause
• Nulliparity
• Family history of breast cancer
• Genetic predisposition
• Personal history of breast ca
• Race, ethnicity
• H/O of radiation exposure
RISK FACTORS THAT COULD
BE MODIFIED
•Reproductive factors
•Age at first live birth
•Parity
•Lack of breast feeding
•Obesity
•Alcohol consumption
•Tobacco smoking
•Use of hormone replacement
•Decreased physical activity
•Night shifts
HISTOLOGICAL FACTORS
•ADH ALH
•Proliferative breast disease
•LCIS

12. .
1. GENDER : female:male incidence is 100:1
2. AGE: rare in <20 years.
after that, incidence progressively increases with
age
3. PERSONAL H/O OF BREAST CA (RR=6.8)
4. HISTOLOGICAL RISK FACTORS:
LCIS (RR=16.4)
DCIS ( RR= 17.3)
NON PROLIFERATIVE DISEASE (RR= 1)
PROLIFERATIVE DS WITHOUT ATYPIA (RR=1.3-1.9)
PROLIFERATIVE DISEASE WITH ATYPIA ( RR= 3.7-4.2)

13. .
5. FAMILY HISTORY
• first degree relative (parent, sibling, or child) with
premenopausal breast ca (RR=3.3)
postmenopausal breast ca (RR=1.8)
• Risk is more with relative having bilateral breast ca
• 2 OR MORE second-degree (grandmother,
granddaughter, aunt, niece, half-sibling) relatives
with breast or ovarian cancer.

14. .
• Family history of both breast and ovarian
cancer.
• One or more relatives with 2 cancers (breast
and ovarian cancer or 2 independent breast
cancers).
• Male relatives with breast cancer.
6. PRIOR RADIATION EXPOSURE
more with high dosage given at early age <30
years as in Hodgkin's disease (RR=5.2)

15. .
7.GENETIC PREDISPOSITION
SYNDROME DEFECT ASSSOCIATED CONDITIONS
BRCA1 Chr 17q Ca breast, ovary , prostate and colon
BRCA2 Chr 13q Breast ca (including male), ovary, prostate,
larynx and pancreas
LI-FRAUMENI Mutation of
p53
Ca breast, brain, adrenal, soft tissue sarcoma
MUIR-TORRE DNA mismatch
gene
(Hmlh1&2)
Malignancy of breast and GI tract
Sebaceous tumour , keratocanthoma
COWDEN
disease
PTEN gene
Chr 10q
Ca Breast, colon uterus, thyroid, lung
Hamartomous polyp in GI tract
PEUTZ –
JEGHERS
STK11 gene Ca breast and pancreas
Mucocutaneous melanin deposition
Hamartoma of GI tract

16. .
8. ENDOCRINE FACTORS
• EARLY MENARCHE (before 12 yrs) RR=1.3
• LATE MENOPAUSE (>55yrs) RR=1.2-1.5
• Women who menstruate for >30 yrs
• AGE AT FIRST CHILDBIRTH (>30 yrs ) RR=1.7-
1.9
9. EXOGENOUS HORMONE USE
5 yr use has a RR of 1.3

17. BREAST CANCER RISK ASSESSMENT TOOLS
A. GAIL MODEL
• It takes into account of
1. Age
2. Age at first period
3. Age at first childbirth
4. Family H/O breast cancer
5. No of past breast biopsies
6. No of breast biopsies showing atypical
hyperplasia
7. Race/ ethnicity

18. .
• Women with 5 yr risk of 1.67% or higher are
classified as HIGH RISK.
LIMITATIONS:
• Women with personal H/O DCIS or LCIS
• Women with strong family H/O breast cancer
who might have an inherited gene mutation
With all its limitations, it is still used as an initial
scoring system

19. B.NSABP (national surgical adjuvant breast and bowel project)
www.cancer.gov/bcrisktool

20. .
C. CLAUSE MODEL
• Based on assumptions about the high
penetrance breast cancer susceptibility genes
• Provides individual estimate of breast cancer
according to decade of life.

21. MANAGEMENT OF HIGH RISK PATIENTS
A close surveillance for women with high risk is
recommended as:
• Monthly self breast examination starting at 18-20 years
of age
• Semi-annual clinical breast examination at age of 25
years
• Annual mammography beginning at age 25 years or 10
years before the onset of breast cancer in a family
member
• Addition of annual MRI to mammography is optional

22. .CHEMOPREVENTION
TAMOXIFEN and RALOXIFEN are the currently
approved for reducing breast cancer risk
TAMOXIFEN : oestrogen antagonist
• Proven benefit against ER pos breast ca
EBCTCG trial: 47% reduction
NSABP P-1 trial: 49% reduction
META-ANALYSIS: 38%
• Side effects include increased risk for endometrial
ca (RR=2.5), deep vein thrombosis (RR=1.7),
pulmonary embolism (RR=3)

23. .
RALOXIFEN : selective ER modulator (SERM)
• Has comparable efficacy in prevention of a
second primary breast carcinoma and a
favourable toxicity profile
STAR trial (reported in NSABP P-2 trial)
Includes finding from more than 10000 women
Showed that raloxifen usage reduced no of
uterine cancer by 36% and episodes of
embolism by 29%

24. .
PROPHYLACTIC MASTECTOMY
Reduce the risk of breast cancer in high risk
patients by 90%
RISK REDUCING MASTECTOMY (RRM)
RISK REDUCING SALPINGO-OOPHORECTOMY (SSRO)
Has been advocated in patients with BRCA1 & BRCA2
mutation
CONTRALATERAL PROPHYLACTIC MASTECTOMY :
Reduced mortality risk by 4.8% in 5 years

25. Flowchart for
management of
high risk
patients

26. THANK YOU
• .