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PROGNOSTIC AND PREDICTIVE FACTORS FOR METASTATIC CARCINOMA BREAST
PREDICTIVE FACTOR IN
Dr ANKITA SINGH PATEL
Apex Hospital Cancer Institute
TRAINING AND FELLOWSHIP
Fortis Research Institute ,New Delhi
Tata Memorial Hospital,MUMBAI
Tumor size (all 3 dimensions)
Tumor grade (Modified Richardson Bloom Score)
Presence of extensive intraductal carcinoma(EIC)
Cut margin status
Num of positive/total axillary lymph node dissected
Receptor status : ER/PR (IHC or EIA)
Extensive involvment of a cut margin or more than 3 foci of invasive or in situ
carcinoma in any inked margin (requires revision excision or mastectomy)
Is 3 or less foci of invasive or in situ carcinoma in any inked margin (revision surgery
only if EIC positive)
EIC Presence of DCIS in>25% of any low power field within or outside the tumor and is a
strong predictor of local recurrence after BCT.
Prognostic factor defined as measurement taken at time
of diagnosis or treatment that is associated with outcome.
Predictive factor is a measurement that predict response
or lack of response to a specific treatment.
Prognostic factors for systemic relapses and for local
relapse differ significantly
CATEGORY I : They were proven to be of prognostic importance and
useful in clinical patient management.
CATEGORY II: Factors had been extensively studied biologically and
clinically, but their importance remains to be validated
CATEGORY III: Included all other factors not sufficiently studied to
demonstrate their prognostic value.
1. Tumor size
2. Lymph node status
4. Histological grade
5. Mitotic count
6. Hormonal receptor status
1. HER-2/neu expression
2. p53 mutation
3. Lymphovascular invasion
4. DNA ploidy
1. Tumor angiogenesis
3. Transforming growth factor
Strongest predictors of distant metastasis, disease-free,
and overall survival.
Strongly correlates with the presence and number of
involved axillary lymph nodes.
Rosen et al. (632)--:
88% <1 cm
72% 1.1 to 3 cm
59% 3.1 to 5 cm
2) Axillary Nodal Status
Primary factor that governs breast cancer staging .
Strongest predictor of disease-free and overall survival.
Direct relationship between the number of axillary nodes
involved and the risk of distant metastasis.
There are four prognostic category.
Category I Node negative 82.8%
Category II 1 to 3 LN+ve 73%
Category III 4 to 12 LN +ve 45.7%
Category IV >13 LN+ve 28.4%
By using a combination of blue dye and radiolabeled colloid
techniques the sentinel node can be identified in >95% of
Prognosis of sentinel node-negative patients is similar to
node-negative patients who have undergone a complete
The tubular, mucinous, and medullary subtypes have been
shown to have a more favorable prognosis, compared to
Invasive lobular tumors appear to have a prognosis similar
to invasive ductal tumors.
Poor prognostic categories include metaplastic,
Rosen et al. reported more favorable relapse rates in
medullary, mucinous, tubular, and papillary subtypes,
compared to invasive ductal and invasive lobular tumors.
The Scarff-Bloom-Richardson classification system utilizes
each with scores of 1 to 3.
This is commonly employed and has been shown to be of
independent prognostic significance.
SCORE DEGREE OF
3 to 5 well differentiated
6 to 7 moderately
8 to 9 poorly differentiated
Patients with hormonal receptors have a significantly
higher survival rate .
LIGAND BINDING ASSAY
Estrogen – I-125 estradiol
Progesteron – H3-R5020
considered to be positive if ER>3fmol/mg of
IHC – Antibodies against receptor are used
Receptor +ve if score >2
NO OF +VE CELLS INTENSITY OF STAINING
None o O no staining
< 1/100 1 1 weak
1/100 – 1/10 2 2 Intermediate
1/10 - 1/3 3 3 strong
1/3 - 2/3 4
> 2/3 5
Receptor status Pre menopausal Post menopausal
ER/PR + 45% 63%
ER/PR - 28% 17%
ER+ only 12% 15%
witteff jl.steroid harmone receptors in breast cancer. cancer 53:630,1984
Receptor status in Indian population
Tata Memorial Hospital Breast. 2000 Oct;9(5):267-70
Also a independent prognostic factor.
Rosen et al. (632)
LVI-positive (stage I) 38%
Proliferative rate of a tumor is correlate with distant
metastasis and survival.
The most common marker are the fraction of cells in S-
phase (SPF), TLI, mitotic index, or antibodies directed
against proliferative markers such as Ki-67 and PCNA
(proliferating cell nuclear antigen).
Thymidine labeling represents the fraction of cells in the
S-phase of the cell cycle .
TLI is able to identify patients at different levels of risk for
locoregional or distant metastases .
Measured by flow cytometry
Toikkanen et al. (746), in 351 patients monitored for a
minimum of 22 years, observed a 25-year survival rate of
28% for patients with nondiploid tumors, in contrast to 48%
for those with a diploid DNA pattern.
LOW GRADE DIPLOID BETTER
HIGH GRADE ANEUPLOID POOR
Member of EGFR family
Also k/a CD340 & p185
Her2 is a cell membrane surface bound receptor tyrosine
Her2 gene is a proto-oncogene located at long arm of ch.17.
Neu terminology is used, as it was derived from a rodent
glioblastoma cell line, a type of neural tumor .
15-20% of breast cancers have an amplification of Her2neu
Over-expression of this receptor in breast cancer is associated
with increased disease recurrence and worse prognosis.
FISH – Probe tagged with fluorescent label if >2 fluorescent light
come out cell considered to be overexpressing HER - 2
0 Absence of staining or < 10% cells are +ve
1 Weak & incomplete staining in > 10% cells
2 Weak & moderate staining in > 10 % cells
3 Strong & complete staining in >10 % cells
Bilous M, et al. Mod Pathol 2003;16:173–82
Patient Tumour Sample
- Monoclonal antibody.
- Acts on cell membrane bound her 2 receptor.
- Duration- 1 yr.
- Initial trastuzumab dose of 4 mg/kg i.v. over 90 minutes,
followed by a weekly maintenance dose of 2 mg/kg i.v.
administered over 30 minutes if the initial dose is well
- Toxicity- cardiac dysfunctioning.
The p53 is a tumor suppressor gene .
Encodes a nuclear phosphoprotein that is thought to be
important to cell cycle regulation and DNA repair and that
also may regulate induction of apoptosis by ionizing
Most frequently mutated in sporadic breast cancer.
Node-negative patients with low UpA/PAI-1 have an
excellent prognosis .
Based on DNA-microarray technologies .
Mamma Print is a 70 gene signature developed in Nethetland,
approved by FDA in 2007.
It analyses 70 genes from an early stage breast cancer tissue
sample to figure out if the cancer has LOW RISK or HIGH RISK of
coming back in 10 years.
Stage I and II
LOW RISK: <10% risk of coming back within 10 years w/o
any additional treatment after surgery .
With hormonal therapy risk reduces to 5%
HIGH RISK : cancer has 29% risk of coming back within
10years w/o additional treatment after surgery.
Analyzes 80 different genes to classify your tumor into its own
unique molecular subtype.
Different molecular subtypes respond differently to different
categories of drugs.
High Risk patients can benefit by being further divided into
subtypes that will help fine tune their treatment plans.
BluePrint also identifies a specific subtype of patient who will
not benefit from chemotherapy.
TargetPrint is a test that will determine if you are a candidate for
It quantifies your ER, PR, and HER2 levels, often referred to as
“markers”, by measuring the messenger RNA (mRNA) gene-
In certain circumstances it is critical to measure mRNA gene-
expression levels for these markers in order to more precisely
select what the best options are to treat your cancer.
The Oncotype DX assay is based on reverse
transcriptase polymerase chain reaction assays.
To quantify expression of selected genes in paraffin-
A panel of 16 cancer-related genes and five reference genes
were employed to compute a recurrence score (0 to 100).
Low risk <18
Intermediate risk 18-30
High risk 31-100
A. Estimate the risk of recurrence of early stage ,hormonal
receptor +ve ca breast .
B. Estimate how much she will be benefited from CT after
C. Estimate recurrance risk of DCIS or new invasive Ca in
D. Estimate benefit from RT after surgery.
Young age(35 year) is a predictor of local relapse following
It has prognostic significance for distant metastasis and
overall survival .
Vanlemmens et al. (773) demonstrated that younger
women had a higher proportion of patients with ER-
negative and high-grade tumors, and lower disease-free
and breast cancer specific survival.
In multivariate analysis, young age at diagnosis was an
independent poor prognostic factor.
African American women are commonly diagnosed with more
advanced stages of breast cancer than white women
On multivariate analysis, obesity remained a statistically
significant prognostic factor after controlling for tumor size,
number of positive axillary lymph nodes, age at diagnosis, and
NON OBESE 19%
The RRs for smokers and exsmokers, compared with those
who had never smoked, is 1.44 and 1.13, respectively.
Women with primary childbirth between 20 - 29 years,
significantly reduced risk of death compared with women
with primary childbirth<20 years (20 to 24 years, RR = 0.88;
25 to 29 years, RR = 0.80).
Women with a history of breast cancer should be reassured
that there is no strong evidence to suggest that subsequent
pregnancy will increase the risk of recurrence.
Medially located tumors have a poorer prognosis than laterally
Gaffney et al. demonstrated that the hazard ratio for inner
quadrant location compared to outer quadrant is 1.27 .
They postulate that this may be due to occult spread to internal
CA 15-3 is a used tumor marker in carcinoma of the breast.
Its role in the management of patients with early disease
stage II and III breast cancer, CA 27-29 had a high
probability of predicting posttreatment recurrence.