breast cancer and its risk factors

1. Risk factors for Breast
cancer
Pushpa Lal Bhadel
FCPS Resident
KMH
Department of General Surgery
Schwartz’s club

2. Hormonal and non-hormonal risk factors
Hormonal
 Increased estrogen exposure: increased risk and vice versa
 Risk factors: Early menarche, nulliparity, late menopause, older age at
first live birth
 Protective factors: Moderate levels of exercise, longer lactation period,
terminal differentiation of breast epithelium
 Obesity: conversion of androstenedione to estrone by adipose tissue

3. Hormonal and non-hormonal risk factors
Non-Hormonal
Radiation exposure: during period of breast development
Alcohol: increase serum levels of estradiol
Consumption of high fat content: increased serum estrogen

4. Risk assessment models
Average lifetime risk of breast ca: 12% in US
Woman aged 50: lifetime risk 11%
Aged 70: 7% lifetime risk
Several risk assessment models:
oCancer Detection Demonstration Project
oGail model
oClaus model
oBRCAPRO model
oTyrer-Cuzick model

5. Risk assessment models
Gail model(1970)
Incorporates: age, age at menarche, age at first live birth, the no.
of breast biopsy specimens, any history of atypical hyperplasia
and no. of first degree relatives with breast cancer
Predicts the cumulative risk of breast ca according to decade of
life
Risk score compared to adjusted population risk of breast ca to
determine absolute risk(5 year and lifetime)
Revised model including body weight and mammographic
density
Excludes age at menarche

6. Risk assessment models
Claus model:
Incorporates more familial history
Provides individual estimates of breast ca risk according to
decade of life
Risk factors: diet, use of OCP, lactation radiation exposure,
mutations in breast ca are not included

7. Risk assessment models
BRCAPRO model:
Mendelian model
Calculates probability that individual is a carrier of mutation
Based on family h/o breast or ovarian ca
Tyrer-Cuzick model:
Utilizes both family history and individual risk information

8. Risk management
 Medical decisions :
oUse of postmenopausal HRT, mammography screening age, role of MRI, use
of tamoxifen as chemoprevention
 Post menopausal HRT:
ovasomotor symptoms: hot flashes, night sweats, sleep deprivation,
osteoporosis, cognitive changes
oReduce CAD
 Increased risk of uterine ca
 National Institute of Health: increased risk of breast ca by 3-4
folds(>4yr use), no significant reduction in coronary artery and
cardiovascular risks

9. Risk management
Collaborative Group on Hormonal Factors in Breast
Cancer:
o52,705 breast ca, 108,411 healthy women
oConcluded increased risk among current users with
increased duration of HRT
Supported by studies from
Cheblowski et al, Million Women study

10. Breast cancer screening
Screening mammography in women ≥50Yr reduce breast ca by
25%
UK regarding the benefits and harm of breast screening
o20% reduction in breast ca mortality
o11% over-diagnosis
Screening mammography < 50y is controversial
oBreast density is greater and is less likely to detect (reduced sensitivity)
oMore false-positive test findings (reduced specificity)
oYounger women has lower incidence, so few will benefit

11. Breast cancer screening
Targeting mammography to women at higher risk
Women aged 40-49 with abnormal mammography had 3 times
more likelihood of ca
Incorporating breast in risk assessment models appears
promising strategy provided the accuracy of these tools
Use of breast USG(dense breast), no available data

12. Breast cancer screening
United States Preventive Services task Force:
oWomen to undergo biennial mammographic screening 50-74years
American Cancer Society(ACS):
oAnnual mammography beginning at age 40 yrs
oClinical breast examinations by health professional annually
oUse of MRI in women with 20-25% lifetime risk based on family
history, BRCA mutation carriers, positive carrier history in family,
prior radiation exposure, h/o Li-Fraumeni syndrome, Cowden
syndrome, Bannayan-Riley-Ruvalcaba syndrome

13. Chemoprevention
Tamoxifen: selective estrogen receptor modulator
Breast Cancer Prevention Trial (NSABP p-01):
o>13,000 women with 5yr Gail relative risk of breast ca of 1.66% or
higher or LCIS
oCases of ER-positive
oMean f/u of 4yrs
oIncidence of breast ca reduced by 49%
oNo significant change in ER negative tumors

14. Chemoprevention
 The Royal Marsden Hospital Tamoxifen Chemoprevention Trial, the Italian
Tamoxifen Prevention Trial showed reduction in ER + breast ca with use of
Tamoxifen
 No effect in mortality
Increased risk:
o Endometrial ca, thromboembolic events, cataract formation and vasomotor
disturbances
Recommended: women with Gail relative risk of 1.66% or higher, aged 45-
59, age 60 or over with diagnosis of LCIS or atypical ductal/lobular
hyperplasia
 American Society of Clinical Oncology/U.S. preventive Services Task Force

15. Chemoprevention
Tamoxifen Vs Raloxifene
 STAR trial (19,747 post menopausal women at high risk for breast ca)
 Initial report showed neat identical ability to reduce risk
 Updated analysis 75% efficacy of Tamoxifen in prevention of invasive
breast ca
 More favorable side effect profile
 Higher incidence of endometrial ca with Tamoxifen
 No effect of Raloxifene on LCIS and DCIS

16. Chemoprevention
Aromatase inhibitors (AI)
 More effective in reducing incidence of c/l breast ca
 MAP.3 trial (4,560 women on exemestane 24mg daily for 5 years)
 Median f/u of 35mths
 Reduced invasive breast ca by 65%
 Side effect: grade 2 or higher arthritis and hot flashes
 IBIS II trial (6,000 pt)

17. Risk-Reducing Surgery
Prophylactic mastectomy reduced risk by >90%
oWomen with lifetime risk of 40%, surgery added almost 4yrs of life
oWith lifetime risk of 85%, added >5yrs of life
Domchek et al evaluated cohort of BRCA ½ mutation carrier
Highly effective at preventing breast ca in both BRCA 1 and 2
mutation carrier
Risk reducing Salpingo-oophorectomy
oReduction in incidence of ovarian and breast ca
oReduction in breast & ovarian ca-specific mortality

18. BRCA mutations
 To be contd.

19. BRCA mutations
 Both are tumor suppressor
genes
 Role in DNA damage
response pathways
 Loss of both alleles is req.
for initiation of ca

20. BRCA mutations
BRCA1:
 Located on chromosome arm 17q, spans a genomic region of approx.
100kb of DNA
 Contains 22 coding axons for 1863 AA
 Role in transcription, cell-cycle control and DNA damage repair pathways
 Autosomal dominant
 Female mutation carriers have
o 85% lifetime risk for breast ca
o 40% lifetime risk for ovarian ca
 Families with high penetrance: Average lifetime risk 60-70%

21. BRCA mutations
BRCA1:
BRCA 1 associated breast ca:
oInvasive ductal ca, poorly differentiated, majority hormone receptor
negative and TNBC or basal phenotype
Distinguishing c/f:
oEarly age of onset compared to cases, higher prevalence of b/l ca,
presence of associate ca (ovarian, colon and prostate ca)
Two most common mutations:
o1185delAG and 5382insC (10% of all mutations)

22. BRCA mutations
BRCA2:
 Located on chromosome arm 13q, spans a genomic region of approx.
170kb of DNA
 Contains 26 coding axons for 3418 AA
 BRCA 2 messenger RNA expressed at high levels in late G1 and S
phases of cell cycle
 >250 mutations have been found
 BRCA 2 mutation
o85% lifetime risk for breast ca
o20% lifetime risk for ovarian ca

23. BRCA mutations
BRCA2:
In males risk of ca in 6%
BRCA 2 associated ca:
oInvasive ductal ca, well-differentiated, express hormone receptors
Distinguishing c/f:
oEarly age of onset, higher prevalence of b/l breast ca, presence of
associated ca(ovarian, colon, prostate, pancreatic, GB, bile duct,
stomach ca and melanoma)

24. BRCA mutations
Identification of BRCA Mutation carrier:
 4 steps process
I. Obtaining complete, multigenerational family history
II. Assessing the appropriateness of genetic testing for particular patient
III. Counseling the patient
IV. Interpreting the results of testing
 Genetic testing to be offered in conjunction with pt education and
counseling

25. BRCA mutations
Identification of BRCA Mutation carrier:
Manchester scoring system and BODICEA to be used to refer to
specialist
Hereditary breast ca is considered:
oIf family includes Ashkenazi Jewish heritage, first-degree relative with
breast cancer before age 50, h/o ovarian ca at any age in pt or first- or
second-degree relative with ovarian ca, breast and ovarian ca in same
individual, two or more first- or second-degree relative with breast ca at
any age, pt or relative with b/l breast ca and male breast ca in relative
at any age

26. BRCA mutations
BRCA Mutation testing:
Appropriate counseling with documentation of informed
consent
Gene sequence analysis
Family with history suggestive of hereditary breast cancer &
no previously tested member:
oFirst test an affected member
oComplete sequence analysis of both BRCA genes
oIf mutation identified relatives then only tested for specific
mutation

27. BRCA mutations
BRCA Mutation testing:
 Positive test result: one that discloses the presence of BRCA mutation
that interferes with the translation or function of the BRCA protein
 If mutation is not present the risk for the breast or ovarian cancer is
same as that of the general population
 In absence of previously identified mutation, -ve test refers that BRCA
mutation is not responsible for the familial cancer
 Possibility of unusual abnormality in one of genes that cannot be
identified thru’ clinical testing remains

28. BRCA mutations
BRCA Mutation testing:
 Phenocopy identifiable BRCA mutation but tested as sporadic cancer.
 Possible if pt develops ca close to the age of onset of general
population (age 60 yr or older)
 False-negative rate for BRCA mutation <5%
 Missense mutation can be difficult to be identified

29. BRCA mutations
Cancer prevention for BRCA Mutation carriers:
 Risk management strategy for carriers:
I. Risk-reducing mastectomy and reconstruction
II. Risk-reducing salpingo-oophorectomy
III. Intensive surveillance for breast and ovarian cancer
IV. Chemoprevention
 Removal of breast tissue reduces the likelihood of BRCA 1 and 2
mutation carriers
 As some breast tissue remains, women continue to be at risk

30. BRCA mutations
Cancer prevention for BRCA Mutation carriers:
 Post-menopausal BRCA 1 & 2 carriers without mastectomy: advisable
to avoid HRT
 Screening mammogram likely to be effective in BRCA mutation
carriers
 Present screening recommendations for breast mutation carriers not
undergoing mastectomy:
oClinical breast examination every 6mths
oMammography every 12 mths beginning at age 25yrs
oUse of MRI for detection of benign breast lesion

31. BRCA mutations
Cancer prevention for BRCA Mutation carriers:
 American Cancer Society:
oAnnual MRI for women with 20-25% or greater lifetime risk of developing
breast ca
oFamily h/o breast or ovarian ca
oWomen treated for Hodgkin’s disease in their teens or early twenties
 Despite 49% reduction in overall incidence of breast ca and 69%
reduction in incidence of ER+ tumors in high risk women on
tamoxifen
 Insufficient evidence to recommend tamoxifen in women with BRCA 1
mutation

32. BRCA mutations
Cancer prevention for BRCA Mutation carriers:
 In women with documented BRCA 1 and 2mutation, consideration for
b/l risk reducing salpingo-oophorectomy to be done between 35 & 40
years after completion of child bearing
 Removing ovaries reduces risk of ovarian and breast ca when
performed premenopausal BRCA mutation carrier
 HRT is discussed with pt during surgery

33. THANK YOU