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HIGHLIGHTS ON
BREAST CANCER
Eyad Alsaeed MD, FRCPC.
Consultant Radiation Oncologist
Acting Chairman of Radiation Oncology
Prince Sultan Hematology @ Oncology center
KFMC
Breast Cancer In KSA
Saudis





676 new cases among women (3317) in 2003
16 new cases among men (3327) in same year
1st ca among women (20.8%)
1st of all ca 10.6% all 6516 ca cases among both genders
ASR 13.9/100000
–
–
–
–
–

Eastern
Makkah
Riyadh
Northern
Jouf
27.6/100000
19.1/100000
16.2/100000
15.5/100000
14.6/100000
Mean age at diagnosis was 48y (19-98)
SAUDI NCR REPORT 20033
Cancer Incidence for Most Common Sites (2004)
Cancer
Male
Female All
%
Breast
15
783
798
11.5
CRC
366
281
647
9.3
NHL
332
224
556
8.0
Leukemia
241
194
435
6.2
Thyroid
87
328
415
6.0
Liver
231
93
324
4.6
Lung
233
63
296
4.2
HD
166
98
264
3.8
Skin
136
125
261
3.7
Brain, CNS
147
100
247
3.5
Prostate
214
-
214
3.1
Stomach
141
70
211
3.0
Bladder
160
41
201
2.9
Uterus
-
117
117
1.7
Ovaries
-
108
108
1.5
All Others
1009
866
1875
26.9
Total
3478
3491
6960
100
Gulf Cancer Registry 2001 Data
Country
Breast ca
All F ca
%
KSA
534
2677
20.3%
Kuwait
97
327
29.7%
Bahrain
88
204
43.4%
Qatar
17
90
18.9%
UAE
47
186
26%
Oman
74
419
17.7%
Age of BC Females Cases in Selected
Arab Countries
Breast Cancer Global View
Total No.
1301867
1st Women Ca
No. Ca Deaths
464854
2nd cause of ca deaths
Developed Countries
679682
1st Women Ca
Developed Countries
203528
2nd cause of ca deaths
Developing Countries 593233
1st Women Ca
Developing Countries 255576
2nd cause of ca deaths
Global Cancer Facts & Figures Report (2007)American Cancer Society
Breast Cancer Global View


Incidence Rates varies By 25-30 folds
from as low as 3.9/100000 in
Mozambique to 10.1/100000 in USA
(2002)
This variation can be attributed to
under reporting as well as many
factors are of importance
Global Cancer Facts & Figures Report (2007)American Cancer Society
Breast cancer mortality
(1980-2007)
Histopathologic Subtypes
Morphology
Total
%
Infiltrating duct carcinoma (IDC)
518
76.6%
Lobular carcinoma
33
4.9%
Carcinoma,
20
3.0%
IDC mixed with other types of carcinoma
17
2.5%
Infiltrating duct & Lobular carcinoma
14
2.1%
Adenocarcinoma
13
1.9%
Medullary carcinoma
12
1.8%
Paget disease & Infiltrating duct carcinoma
10
1.5%
Infiltrating duct carcinoma (IDC)
7
1.0%
All Others
32
4.7%
SAUDI NCR REPORT 20033
Stage Distribution 2003
Unknown
11.7%
Regional
50.0%
Distant
15.5%
Localized
22.8%
SAUDI NCR REPORT 20033
Breast Cancer Facts
 BC is most common lethal cancer in women.
 2nd leading cause of death
 All women are at risk
 Incidence increases with age
One out of eight women will be diagnosed with
breast cancer
BREAST CANCER RISK FACTORS
70% of cases have no risk factors
FACTORS THAT CAN NOT BE CHANGED:
Age
Race
Menstrual History (<12 & >50)
Reproductive History (1st child after 30 y/40%)
Family/Personal History
Genetic Factors
Radiation
Treatment with DES (35%)
BREAST CANCER RISK FACTORS
FACTORS THAT CAN BE Controlled:
Obesity (postmenopausal obesity)
Exercise (60%)
Alcohol (2-5 drinks/1.5 )
Breast Feeding (1.5-2 years / 50%)
Hormone Replacement Therapy
Birth Control Pills (slight/?)
Not having children
(slight)
Risk Factors by Category
High Risk
> 4 times
▪ Female
Moderate Risk
2- 4 times
slight Risk
1-2 times
▪ Any first degree relative with
history of BC
▪ Moderate alcohol
intake
▪ High socioeconomic class
▪ Menarche <12 years
old
▪ Age (>50)
▪ Country of birth in North
America, North Europe
▪ Personal history of prior
Beast Cancer
▪ Prolonged uninterrupted
menses (late first pregnancy,
nulliparous)
▪ Postmenopausal obesity
▪ Family history, bilateral,
premenpausal, or familial
cancer syndrome
▪ Atypical proliferative
benign breast disease/
family history
▪ Personal history of prior CA
of ovary/ endometrium
▪ Proliferative benign breast
disease, if no atypia
▪ ? HRT
▪ ? Oral
contraceptives
▪ Diet
Histopathologic Subtypes
• Carcinoma Insitu (Cis)
– Ductal carcinoma insitu (DCIS)
– Lobular carcinoma insitu (LCIS)
– Paegt`s Diease
• Invasive Cancer
–
–
–
–
–
–
Ductal
Lobular
Modularly
Papillary
Mucinous
Tubular
Inflammatory Carcinoma
IDC
Tubular
ILC
Mucinous
DCIS
Medullary
This photomicrograph demonstrates strong positive
nuclear staining for estrogen receptor in an
infiltrating ductal carcinoma
Immunoperoxidase stains assess protein overexpression by
the presence of strong membrane reactivity. This
photomicrograph illustrates strong (3+) membrane
positivity in an IDC.
Pathological and prognostic factors
 Histological subtypes ( IDC = 85% = NOS),( ILC= 5-10%),.
Mucinous, Medullary, Tubular, Papillary
 Nuclear and histological Grade
 Estrogen and progesterone receptor status
 HER-2 overexpression
 Proliferation marker (s-phase fraction, Ki-67)
 Aneuploidy / P53
 LN +ve vs –ve numbers
 LVI
Warning
Signs

A Hard, Painless, Lump or Thickening.

Change In Breast Size, or Shape.

Nipple Pain or Retraction.

Breast Skin Irritation or Dimpling.

Nipple Discharge
(spontaneous, unilateral, or bloody)
Grave Signs ?
BIOPSY
 Core biopsy / fine-needle aspiration.
 Experienced breast-imaging radiologist for tissue sampling
( ultrasound or mammogram guidance).
 Manual Expression of spontaneous nipple discharge (Cytopathology
examination).
 Ductal lavage with saline solution to obtain nipple aspirate fluid.
FNAC cannot differentiate between invasive and noninvasive cancer , and even
sometimes difficult to differentiate between Benign /Malignant lesion alone.
 Request special studies for ER/PR (IHC) and, possibly, for HER2 over expression
(FISH or IHC) if histopathology confirms invasive breast cancer.
Management of palpable breast mass

Clinical breast examination by primary provider.
If pt is under 30 and mass feels benign ultrasound
may be sufficient to verify cyst.

If mass is cystic, it can be aspirated with follow up
in 3-4 months.

 If
pt is over 30, ultrasound and diagnostic
mammogram are indicated.
 If
 If
mass is solid, FNA or core needle biopsy.
initial biopsy is negative, excisional biopsy mass
be warranted.
WHAT TO DO NOW AFTER DIAGNOSIS
?
Triple assessment
Physical Examination •
Mammogram +/- US •
Core biopsy (Tue Cut) •
Diagnosis
Pretreatment workup
Bloods (CBC, LFTs, Bone profile,
Markers, U & Es)
Echo &/or Muga Scan
CT CAP
Bone Scan
Staging & Fitness
•
•
•
•
What further imaging tests are required?
DCIS or pathological Stage I •
routine bone scan, liver ultrasound and CXR –
are not indicated as part of baseline staging.’
% of pts with  test result
CXR
0.1 %
Liver U/S
0%
Bone scan
0.5 %
Cancer Care Ontario Practice Guidelines, CMAJ 164, 1439-1444, 2001.
What further imaging tests are required?
Pathological Stage II •
Bone scan –
‘…routine liver ultrasound and CXR are not –
indicated …but could be considered for patients
with  4 positive nodes.’ OR Close margine < 2m
% of pts with  test result
CXR
~ 0.2 %
Liver U/S
~ 0.4 %
Bone scan
~ 2.4 %
Cancer Care Ontario Practice Guidelines, CMAJ 164, 1439-1444, 2001.
STAGING
STAGING
STAGING
Stage
0
cancer breast
DCIS
(± LCIS)
LCIS
Paget’s
Breast Cancer Continuum:
intervention possibilities
Prevention of Recurrence
PreWomen at
Malignant
Increased
Conditions
Risk
LCIS
NonInvasive
Cancer
DCIS
Prevention of Clinically
Detectable Breast Cancer
Tumors
< 1cm
Early
Stage
node -ve
Early
Stage
node +ve
Prevention of Contralateral
Breast Cancer 3.2%
Prevention of
Progression
Late
Stage
Cancer
Recurrence
of Breast
Cancer
SURVIVAL
STAGE
SURVIVAL RATE %
I
96%
II
82%
III
53%
IV
18%
Treatment of early Breast Cancer
LOCO-REGIONAL
CONTROL
Surgery +Radiotherapy
SYSTEMIC CONTROL
Chemotherapy + Hormonal
New Modalities
What treatment would you
recommend?
“For patients with stage I or II breast cancer,
BCS followed by radiotherapy is generally
recommended. In the absence of special
reasons for selecting mastectomy, the choice
between BCS and mastectomy can be made
according to the patient’s circumstances and
…preferences.”
Canadian consensus document. CMAJ 158(Suppl 3), 1998
What treatment would you recommend?
Advantages of BCT
Disadvantages of BCT
• Cosmetic
• Psychological
• Time
• Convenience
• Late toxicity
*Major criteria for BCT,negative margin , mammography is
also important
Stage I – II breast cancer
Outcome after BCS + RT  Mastectomy
• Survival
DFS
Distant metastases
Loco-Regional Control (except EORTC)
No Disadvantage in the use of BCS in Axillary N+ pt.
No different in the rate of ….breast or control ……
See next
Mastectomy vs BCT
•
•
•
•
•
•
•
NCI (Milan)
trial
NSABP B-06 trial
NCI(France) trial
NCI (USA)
trial
Danish Group trial
Metaanalysis Morris et al
Metaanalysis EBCTCG
All shows no difference in OS , DFS , Distance mets.,
Except EORTC is the only trial whaich showed significant
difference in loco-regional recurrence at 10 years 20%
vs 12 in favor of mastectomy
Reasons for Choosing Mastectomy
(Contraindications to Radiotherapy)
• patient preference
• physical / psychological inability to
tolerate radiotherapy
Reasons for Choosing Mastectomy
(Contraindications to Radiotherapy) – 2
High risk of recurrence
• Multicentric disease
–  2 primary tumors in separate quadrants
• Diffuse malignant calcifications
• Persistant positive margins
• Locally advanced disease (most T3, T4)
Reasons for Choosing Mastectomy
(Contraindications to Radiotherapy) – 3
Contraindications to radiotherapy
• Pregnancy
• Scleroderma or active SLE
• Previous breast radiotherapy (e.g. mantle RT)
Cosmetic
• Large tumor in small breast
Absolute Contraindications
1. Multicentric disease
 2 primary tumors in separate quadrants
2.
3.
4.
5.
Diffuse malignant calcifications
Persistant positive margins
Locally advanced disease (most T3, T4)
Pregnancy
Relative Contraindications
• Hist. Of collage / vascular Disase
– Scleroderma or active SLE
• Multiple gross tumors in the same quarant +
intermediate calcification
• Large tumor in small breast (significant cosmetic alteration )
Factors which are NOT contraindications
to BCS + RT
•
•
•
•
•
•
•
•
•
•
Age
Histology
Central tumor
Paget’s disease of nipple
LCIS, DCIS, EIC (if clear margins)
Breast implants
N+ disease
High risk of distant metastases
Strong family history
BRCA 1 / 2 +(hearedatery breast
ca)
Factors affecting Radiotherapy
Treatment Decisions
•
•
•
•
•
•
Patient fit for treatment?
Multicentric disease?
Diffuse malignant calcifications?
Tumor size, stage
Nodal status
Margins
Margins
• Margins status remain one of the most important independent
factor involved with long term local recurrence .
Risk of local recurrence (5y) with xrt is approximately :
5% in negative
10% in focally+
20% in diffusely+.
Indications for Re-excision
1. Positive margin
a) Invasive tumor cells at margin
b) DCIS at margin
c) EIC with positive margin
2. Unknown margin
3. Inadequate excision by specimen
mammography
4. Focally positive*
*But…focally positive margin ( 3 LPF) or close margin can be treated with many Rx.
Option :
1.
Re-exceision
2.
Radiotherapy boost
3.
Chemotherapy
Is radiotherapy necessary ?
(given small tumor size and clear margins )
• “Women who undergo BCS should be
advised to have postoperative breast
irradiation”
Canadian consensus document. CMAJ 158(Suppl 3), 1998
Randomized Trials of BCS vs. BCS +
RT
n
Local Recurrence Rate
(%)
BCS
BCS+RT
NSABP
1265
15 yr
36
12
OCOG
837
10 yr
40
18
See Table 2
Is radiotherapy necessary ?
(given small tumor size and clear margins )
Low Risk for IBTR after Breast Conserving
Surgery alone
•
•
•
•
•
Age > 50
Tumor  1 cm
Clear margins (  2 mm )
N0
Mucinous or tubular histology
…but
Is radiotherapy necessary ?
(given small tumor size and clear margins )
In randomized trials of BCS + RT,
all subgroups appeared to benefit from
RT
INDICATIONS FOR ADJUVANT
RADIOTHERAPY TO THE BREAST
• Indications for Breast
Adjuvant Radiotherapy post
Lumpectomy?
All cases.
No subset has been found for
which radiotherapy does not
reduce local recurrence
significantly.
• Indications for Chest
Wall Adjuvant
Radiotherapy?
T3 especially if other risk
factors present (2-3
lymph nodes, high grade,
very large, etc.)
T4
4 or more axillary lymph
nodes +
Systemic Therapy
 Chemotherapy
 Hormonal
Therapy
 Targeted Therapy
Chemotherapy
 Neoadjuvant
 Adjuvant
 Palliative
Why Chemotherapy ?
EBCTCG summarized results of 47 trials comparing chemotherapy
and no chemotherapy .
A significant reduction in mortality was seen in pts receiving
chemotherapy regardless of nodal status, and use of Tamoxifen.
Benefit of chemotherapy does vary with pt age and menopausal status.
 Women under age of 50 derive a greater survival benefit.
 Tumor with higher “recurrence scores” may derive much greater
benefit whereas “low recurrence rate” tumors may derive little or no
benefit.
Bonadonna et al.1995: : the results of 20 years of follow-up
meta-analysis by the (EBCTCG)
Chemotherapeutic agents In Metastatic Disease











Docetaxel
Paclitaxol
Vinorelbine
Capecitabine
Gemcitabine
Liposomal doxorubicin
Abraxane
Epirubicin
Irinotecan
Cyclophosphamide
5FU
- Debate exists over whether maximum tumor reduction through
combination chemotherapy leads to prolonged survival.
- Usage of sequential single agent s to minimize side effects and
preserve quality of life.
Best regimen still (unknown)
Node negative
Node positive
AC x 4 or 6
AC x 4 →Taxol x4
FAC or CAF x 6
TAC
FEC or CEF x 6
AC x 4 → Taxol/Herceptin
C MF
FAC or FEC x 6
A/E →CMF
A→T→C

Retrospective
evidence
suggests
that
doxorubicin-based
chemotherapy regimens may be superior to non-doxorubicin-based
regimens in patients with tumors over-expressing HER-2 by IHC.
Am J Clin Oncol 1989; 12; 123-128
 For node-positive patients, anthracycline-containing chemotherapy
regimens are preferred.
J Clin Oncol 20:2812-2823, 2002

Nausea and vomiting

Hair loss
Weight control

Diarrhea

Constipation

Low blood counts

Taste changes

Mouth sores

Premature menopause

How should radiotherapy
and chemotherapy be
combined?
How should radiotherapy and chemotherapy be
combined?
Sequential RT CT
 Sequential CT  RT
 “Sandwich” CT  RT  CT
 Concurrent

How should radiotherapy and chemotherapy be
combined?
“Sandwich” CT  RT  CT
 Concurrent CT + RT



Increased acute and late
toxicity,especially with concurrent
treatment
Cosmetic result probably inferior
How should radiotherapy and chemotherapy be
combined?
Sequential RT CT
 Sequential CT  RT

? Delay in RT   local recurrence
 ? Delay in CT   distant mets

How should radiotherapy and chemotherapy be
combined?
Dana Farber Study of Sequencing





244 Stage I,II
CT  RT vs RT  CT
Early results showed
– CT first arm   local recurrence
– RT first arm   distant failure
ASTRO 2001 update:
at 11 yrs median F/U;
no difference in TTF, time to DM, OS, local
recurrence
Additional studies required
Hormonal Therapy
Neoadjuvant
Adjuvant
Palliative
Endocrine Therapy: Approaches
• Estrogen receptor modulators
– Tamoxifen (selective estrogen-receptor
modulator, or SERM)
– Toremifene
– Raloxifene
• Sex steroids
• Aromatase inhibitors
– Nonselective AIs
– Selective AIs
• pure anti-estrogens
• ovarian ablation or suppression
– Medical
– Surgical
– Radiotherapy
Mechanism of Hormonal Therapy
(FSH + LH)
Oestrogens
Progesterone
Ovary
Premenopausal
LHRH analogue
Down- Regulation of HRH R
TAMOXIFEN
LHRH
(hypothalamus)
Pituitary gland
Pre/postmenopausal
Adrenal
glands
Androgens
(ACTH)
Oestrogens
Progesterone
Peripheral conversion
AROMATASE
Inhibitor
Definition/Criteria of Menopause
Profound and permanent decrease in ovarian estrogen
synthesis.
Criteria for menopause include:
- Prior bilateral oophorectomy
- Age 60 y
- Amenorrheic for ≥12 months (In the absence of chemotherapy,
tamoxifen, Toremifene, or ovarian suppression and FSH and
Estradiol in the postmenopausal range).
- If taking Tamoxifen or Toremifene, and age < 60 y, then
FSH and plasma Estradiol level in postmenopausal ranges.
In women premenopausal at the time of adjuvant chemotherapy,
amenorrhea is not a reliable indicator of menopausal status.
Mechanism of action of Tamoxifen
as an antitumour agent
Antioestrogen effects
- blockage of oestrogen
receptor
Local effects - independent
of oestrogen receptor
DECREASE
TGF-α
+
INCREASE TGF-β
-
STROMAL
CELL
The inhibition of oestrogen-stimulated growth in BC by
TAMOXIFEN
Autocrine
Growth Factors
TGF-a
IGF-1
INHIBITS
Plasminogen -Activator
INHIBITS
ER→ER-TAM
TAMOXIFEN
GROWTH
ARREST
STIMULATES
TGF-b
Sites of peripheral aromatisation
Breast
Tumour
Muscle
Fat
Liver
Mechanism of action of LHRH analogue
Figure A
Hypersecretion of LH following
acute administration of LHRH
analogue
Pituitary
Cell
LH
Figure B
Hyposecretion of LH following
chronic administration of LHRH
analogue
Pituitary
Cell
LH
Targeted Therapy
Therapeutic intervention at key stages
in tumour development

Promising agents in research
– EGFR
– Anti angiogenesis
– Vascular targeting
– Gene therapy
Epidermal Growth Factor Receptor
(EGFR)
Tumour
EGFR Expression Rate
Breast
14 % - 91 %
Colon
25 % - 77 %
NSCLC
40 % - 80 %
Head & Neck
80 % - 95 %
Ovarian
35 % - 70 %
Pancreatic
30 % - 50 %
Targeted Therapy




Trastuzumab
(Herceptin)
Bevacizumab (Avastin)
Lapatinib (taykreb)
Erlotinib (Tarceva)
Herceptin Combination Pivotal Trial:
Overall Survival
FISH+
Probability of survival
1.0
FISH–
1.0
Trast. + CT (n = 176)
Trast. + CT (n = 50)
CT (n = 169)
CT (n = 56)
RR = 0.71
p = 0.007
0.8
0.6
0.8
RR = 1.11
p = NS
0.6
26.2 mo
24.0 mo
19.8 mo
20.0 mo
0.4
0.4
0.2
0.2
0
0
0
10
20
30
Months
EM, RMH 30.11.2006
40
50
0
10
20
30
40
50
Months
Update of Mass. Proc Am Soc Clin Oncol. 2001;20:22a. Abstract 85.
Docetaxel ± Herceptin trial (M77001)
Probability 1.0
of survival 0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Herceptin + docetaxel
Docetaxel
+37%
22.7
0
5
10
15
31.2
20
25
30
Time (months)
Documented crossover 57%
8.5 months
EM, RMH 30.11.2006
35
40
45
50
Extra et al.
ASCO 2005; abs 555
HERA DFS
Patients
1-year Herceptin
100
(%)
80
Observation
60
40
Events
2-year
DFS
20
127
220
85.8
77.4
HR
95% CI
p value
0.54
0.43, 0.67
<0.001
0
No.
at risk
0
6
1694
1693
1172
1108
12
18
Months from randomisation
Median follow-up: 1 year
HR, hazard ratio; CI, confidence interval
EM, RMH 30.11.2006
885
767
532
445
24
268
224
B31 / N9831 combined analysis
Overall survival
Patients 100
(%)
94%
91%
90
92%
87%
80
70
n Deaths
1672 62
1679 92
ACPH
ACP
HR=0.67; p=0.015
60
50
0
EM, RMH 30.11.2006
1
2
3
Years from randomisation
4
5
Romond et al 2005
Nutritional Guidelines
 Eat a variety of healthful foods, with an emphasis
on plant sources.
 Adopt a physically active lifestyle.
 Maintain a healthful weight throughout life.
 No alcoholic beverages.
Case 1
34 yr. old, premenopausal female with
upper outer quadrant mass in left
breast. Mammogram shows a 2 cm.
spiculated nodule and core biopsy is
positive for carcinoma. She is referred
prior to surgery for a discussion of
treatment options for the breast.
Case 2

65 yr. old, postmenopausal female with upper
outer quadrant mass in left breast, undergoes
wide local excision and axillary node dissection.
She is otherwise in good health.
Pathology:
– invasive lobular carcinoma, 2.5 x 2.1 x 1.8 cm;
– Bloom- Richardson grade 2 (SBR 6/9)
– ER+ PR+
– lymphovascular invasion present
– Margins clear by 1 mm. or more
– 2 lymph nodes contain metastases (of 10
resected nodes) with microscopic extranodal
extension
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