Breast cancer is the most common cancer in women, accounting for 26% of cancers. Genetic factors play a role, with around 10% of cases having inherited mutations like BRCA1/BRCA2. Risk is increased by factors like family history, benign breast disease, older age at first birth, hormone therapy, obesity, alcohol. Screening includes annual mammograms from age 40 and clinical exams. High risk women may benefit from more intense screening or preventative surgery/drugs due to genetic mutations or family history. Molecular markers help classify subtypes with different prognoses.

1. BREAST CANCER

2. • Breast cancer is the m/c neoplasm in women,
~ for 26% of all cancers diagnosed annually
• 2nd leading cause of cancer death following
lung cancer
• More in higher socio-economic status group
• Incidence of breast cancer is higher in whites,
but mortality is more in black women ( higher
frequency of triple negative )

6. 15 % in outer quadrant lesion
25 % in inner quadrant lesion

7. • Genetic predisposition :
• Most breast cancer are sporadic
• 10% have inherited germline mutation
1. GERMLINE GENETIC DEFECTS :-
BRCA-1 BRCA-2
Chr .17 (long arm) chr . 13 (long arm)
Asso. Breast cancer - Asso. Breast cancer -
Invasive ductal carcinomas ; B/L Invasive ductal carcinomas ; B/L
PD WD
HR –ve HR +ve
Early age of onset Older age then BRCA-1
OVARIAN, COLON, PROSTATE Ca. OVARIAN, COLON, PROSTATE ,
MALE BREAST , GB, STOMACH &
MELANOMA

8. • Genetic testing is commercially available
• Indicative factors for having BRCA germline mutation:-
- Non-Ashkenazi Jewish women -
a. Two first degree relatives with breast cancer, one diagnosed
<_ 50 yrs.
b. 3 or more first or second degree relatives with breast cancer,
any age
c. Breast and ovarian ca. among first and second degree relatives
d. First degree relative with B/L breast ca.
e. Breast ca. in male relatives
f. 2 or more first or second degree relatives with ovarian cancer
- Ashkenazi Jewish women –
a. First degree relative with breast and ovarian ca.
b. 2 second degree relatives with breast and ovarian ca.

9. • ASCO guidelines for genetic testing – should be
offered when
a. personal/family h/s/o genetic cancer
susceptibility
b. Test can be adequately interpreted
c. The test result will influence medical
management

10. • Li-Fraumani syndrome - life time risk = 50%
• Cowden syndrome - life time risk = 50%

11. Breast cancer susceptibility genes and
loci
a. HIGH PENETRANCE/ LOW FREQUENCY
• BRCA1/BRCA2
• TP53- li fraumeni syndrome
• PTEN- cowden syndrome
• CDH1- familial diffuse gastric cancer
• STK11/LKB1- peutz jegher syndrome

12. b. MODERATE PENETRANCE
• CHEK2- Li- fraumeni syndrome
• ATM- ataxia telangiectasia
c. LOW PENETRANCE
• FGFR2, TOX3, LSP1, TGFB1 etc.

13. • Etiologic factors :
1. Endogenous estrogen exposure :
a. Nulliparity
b. Late 1st full term pregnancy (risk with 2-5 times)
c. Early menarche ( < 12 yrs)
d. late menopause ( > 55 yrs)
2. HRT :
The Women Health Initiatives (WHI) study – 2003- showed
that the group received CEE + MPA -
• 24 % risk of breast ca. with an intact uterus
• Larger mean tumor size and abnormal mammograms
• More likely to have LN metastasis
• Breast ca. mortality was more

14. • So these data led to a revised view of postmenopausal
HRT :
- HRT with CEE + MPA should be used at lowest possible
dose and shortest duration sufficient to control
vasomotor or vaginal symptoms.
- women with prior hysterectomy treated with CEE for
a short term have no significant increase in breast
cancer risk, although the risk of stroke increased.
3. AGE : - es steadily with age ;
- 75 % diagnosed females are post-menopausal
age group

15. 4. Dietary and Lifestyle Factors
• positive association between alcohol and breast
cancer risk.
• Obesity is associated with both an increased
risk of breast cancer development in
postmenopausal women and increased breast
cancer mortality.
• In the placebo arm of the WHI study, women
with a body mass index (BMI) of 31.1 or higher
had a 2.5-fold greater risk of developing breast
cancer than those with a BMI of 22.6 or lower.

16. 5. BENIGN BREAST DISEASE : Dupet & Page Classification:
Nonproliferative
changes
RR = 1.0 Fibr ocystic diseases
Duct ectasia
proliferative changes
without atypia
RR = 1.5-2.0 Florid hyperplasia
Pappiloma
Sclerosing adenosis
proliferative changes
with atypia
RR = 4-8
( if family history +ve
then 20 times risk
increases )
Atypical ductal
hyperplasia
Atypical lobular
hyperplasia

17. 6. BREAST DENSITY :
• In a case control study of 1,112 case control
pairs undergoing screening mammography,
women with more than 75% breast density
had a 4.7-fold increase in the odds of breast
cancer development compared to those with
less than 10% breast density (95%
confidence interval [CI].

18. 7. Environmental Factors :
• Exposure to ionizing radiation
• survivors of the atomic bombings, those
undergoing multiple diagnostic x-ray
examinations, and in women receiving
therapeutic irradiation
• Breast cancer due to radiation typically have
long latency, often a decade or more following
the exposure.

19. Magnitude of Risk of Known Breast
Cancer Risk Factors
Relative Risk <2 Relative Risk 2-4 Relative Risk >4
Early menarche One first-degree relative with Mutation BRCA1 or BRCA2
Late menopause breast cancer LCIS
Nulliparity CHEK2 mutation Atypical hyperplasia
Estrogen plus progesterone Age >35 first birth Radiation exposure before 40
HRT Proliferative breast disease
Alcohol use, Postmenopausal
obesity
Mammographic breast
density

20. • Pathology and molecular classification :
A. CLASSIC HISTOLOGICAL CLASSIFICATION :
1. Ductal adenocarcinoma : 70 – 80 % ;
- m/c invasive histology
- indolent to rapidly progressive
- prognosis may be estimated by cellular
morphology or by molecular markers ER, PR ,
HER2, Ki67 (marker of cell proliferation)
2. Lobular carcinoma: 10 -15 %
- staged prognosis is similar to IDC
- difficult to diagnose because of their unique
single cell radial pattern of tissue invasion
(Indian filing on light microscopy)
- so they become nonpalpable and
mammographically silent

21. 3. Special subtypes : < 10 % , favorable prognosis
- papillary
- tubular
- mucinous
- medullary – BRCA -1 asso. ; Triple negetive
4. Inflammatory breast cancer : < 1 %
- aggressive subtype , recognised microscopically
by presence of DERMOLYMPHATIC INVASION
- so clinically asso. Cuteneous erythema and peau-
d-orange
5. Paget’s dis. of breast : u/l eczematous change in nipple
with underlying DCIS.
5. Rare tumors : SCC , Lymphoma , Sarcoma

23. B. MOLECULAR CLASSIFICATION :
• Based on single gene assay like ER , PR , HER2 , Ki67 copy
numbers, proliferation index
• Or multigene expression assay –
- RT –PCR tech. : Oncotype DX assay
- gene chip expression microarray :
mammaprint :- used to analyze early stage
tumor like stage I, II
On basis of gene expression breast ca. has devided into five
subgroups :
1. Luminal A :- luminal tumors express cytokertains 8 , 18
- max ER + , low grade , good prognosis

24. 2. Luminal B: luminal origin but diff. gene expression
prognosis somewhat worse than A
3. Normal – like breast tumors : gene expression profile
reminiscent of nonmalignant “normal ”
breast epithelium
prognosis similar to B
4. HER 2 amplified : HER 2  ER , PR & VEGF
5. Basal : ER - , PR - , HER2 – ve
char. by markers of basal or myoepithelial cells
high grade
cytokeratines 5/6 & 17 , vimentin, p63, CD 10, actin,
EGFR
Poor prognosis , likely benefit from CT

25. • SCREENING AND EARLY DETECTION :
A. MAMMOGRAPHY :
- low voltage (40 kv), high amp (300mA) , 0.1 cGy rad. dose
- 90 % Sp & 90 % Sn
- detects ~ 85 % of breast cancers
- 45 % seen before they are palpable
- screening mammogram- no s/s of breast ca.
- diagnostic mammogram- to check when breast ca. found
- American college of radiology has given – BIRADS system

26. . Cat - 1 – negetive ----> routine mammo after 1 yr
. Cat - 2 – benign findings ----> routine mammo after
1 yr
. Cat – 3 – probably benign ----> short interval f/u
needed
. Cat – 4 – suspicious abnormality ----> Bx considered
. Cat – 5 – highly suggestive of malignancy ---->
appropiate action
. Cat – 6 – known Bx proven malignancy

27. • Features of malignancy on mammography –
Opacity – ill defined margins, irregular stellate,
spiculated margins, comet tail
- high density , wide halo
Microcalcification - ( <0.5 mm in diameter )
Thickened skin and cooper’s ligament
Distorted architectural of breast parenchyma
Obliterated subcuteneous retromammary space

28. • The ACS recommends an annual mammogram for
women at average risk beginning at age of 40 yrs. &
should continue annually regardless of age as long as
the women remains in good health, has a life
expectancy of at least 12 to 24 months.
• Meta-analysis of eight randomized screening trials has
shown a 24 % reduction in mortality.

29. B. BREAST PHYSICAL EXAMINATION :
- Either by self (BSE) or by clinical examination (CBE)
- CBE - . recommended for women at average risk
beginning in their 20s , as a part of periodic
health examination done at least every 3 yrs.
. For age >_ 40 yrs -- > annually and ideally
before or in conjunction with annual screening
mammogram.
- BSE – should be started in their 20s with proper
instructions
. Once a month just after menstruation or in
post menopausal female once in month at
regular interval
. Nursing mother should after feeding

30. MANAGEMENT OF HIGH RISK PATIENT
• High risk patient : - BRCA 1 or 2 mutation +ve
- +ve family history
- recevied radiations (like
mantle irradiation)
- atypical hyperplasia or LCIS

31. • Risk assessment models
Gail model Claus model
m/c used model, includes Includes both 1st and 2nd degree
relatives
1. Age at menarche Does not include other risk factors
2. no. of breast Bx Based on assumption about the
prevalence of high penetrance breast
cancer susceptibilty genes
3. Age at first live birth
4. no. of 1st degree relatives with breast
cancer
It predicts the cumulative risk of breast
cancer according to decade of life

32. • Management strategies available for high-risk women
include intensive surveillance, chemoprevention with
endocrine agents and prophylactic surgery
1. Intensive Surveillance :
- monthly breast self-examination, annual screening
mammography, and clinical breast examinations once
or twice yearly
- but it did not clearly result in early detection in high-
risk women in the placebo arm of the NSABP P1
prevention trial where 29% of the women who
developed breast cancer had axillary node metastases
at diagnosis.

33. • Women at risk as a result of known or suspected
BRCA1 or BRCA2 mutations warrant screening with
magnetic resonance imaging (MRI), which results in
- earlier detection of breast cancer
- higher specificity and sensitivity among high-risk
women
- Because the cancers detected by MRI are smaller
and less likely to be associated with nodal positivity, it
is likely that a survival benefit is present
- However, there is no benefit for MRI screening in
women with atypical hyperplasia or LCIS.

34. • ACS guidelines for MRI screening :
a. Annual MRI recommended based on evidence-
- BRCA mutation
- untested 1st degree relative of BRCA carrier
- life time cancer risk 20-25 %
b. Annual MRI recommended based on expert opinion-
- radiation to chest b/w age 10 to 30 yrs
- Li-Fraumani syn. & first degree relatives
- cowden syn & first degree relatives
c. Insufficient evidence to recommend for or against MRI-
- LCIS , atypical hyperplasia (ductal/lobular)
- extremely heterogenous dense breast on mammogram
- personal h/o breast cancer, including DCIS

35. 2. Chemoprevention :
• Two SERMs, tamoxifen and raloxifene, have been
shown to reduce the incidence of ER+ breast cancer
• Four prospective, randomized trials showed that
tamoxifen --- > 38% in breast cancer incidence
48% in the incidence of ER+ breast ca.
• In the largest of these studies, the NSABP P1 trial, seen
that with tamoxifen in all age groups
- 49% risk in both invasive and noninvasive ca.
- 84% risk in seen with pt. of atypical hyperplasia

36. • women most likely to have a favorable risk-benefit ratio
for tamoxifen prevention include -
- premenopausal women
- younger postmenopausal women without a uterus
- those at risk on the basis of atypical hyperplasia or LCIS.
• Raloxifene - SERM used for the treatment and
prevention of osteoporosis that was noted to reduce the
incidence of ER+ breast
• Study of Tamoxifen and Raloxifene (STAR) trial – showed
- No difference in the incidence of invasive cancer was
seen between women taking tamoxifen and those
taking raloxifene

37. • More cases of noninvasive cancer were noted in the
raloxifene group then tamoxifen group at 6 years
• Significantly fewer thromboembolic events and
cataracts occurred with raloxifene.
• Raloxifene is thus a viable alternative to tamoxifen for
the chemoprevention of breast cancer in
postmenopausal women at increased risk for the
disease.
• Trials of aromatase inhibitors (AI) for breast cancer
prevention suggest qualitatively similar results as seen
with SERMs.
• After a median follow-up of 3 years, a 65% reduction
in invasive breast cancer was seen with exemestane.

38. 3. Prophylactic surgery
- in the form of bilateral mastectomy or bilateral
salpingo-ophorectomy, is another option for
breast
cancer risk reduction.
- B/L mastectomy risk of ca. Breast in BRCA
mutation
carriers by > 90 %.
- BSO risk of ca. ovary > 90 % & risk of ca. breast
by >
65 % in premenopausal women.

39. • More recently, recognition that BRCA-
associated cancers arise in the fallopian tube
rather than the ovary has led some to propose
bilateral salpingectomy, with ovarian
preservation, as a risk-reducing strategy, but
the efficacy of this approach is uncertain.

40. •Thank you……