Prognostication in early breast

cancer

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Breast cancer: one size does not fit all
Different subtypes of breast cancer have different risk of recurrence
Subtype Absolute distant Relative risk Absolute % of Fatal, life-
recurrence risk reduction with pts who threatening,
chemotherapy will benefit permanent
from chemotherapy
chemotherapy toxicity rate
TNBC 50-60% 30% 15-20% 2-3%
HR+ HER2- 10-15% 30% 2-3% 2-3%
early-stage

Clear evidence for personalization & de-escalation of

chemotherapy in HR+ HER2- early stage breast cancer
References: 1) Lancet, 2005, vol. 365 9472 (pg. 1687 -1717) 2) Annals of Oncology 23, no. suppl_10 (2012): x211-x218, 3) Harris et al.,
2
JCO 2016
 Paradigm shift in Breast Cancer treatment: Era of
De-Escalation beyond surgery

Maximum dose tolerated (1970s)

Minimum Effective Dose (Today)

Avoid physiological and financial toxicity and improve quality of life

More is not always better, Less is always not inferior

 Clinical Dilemma

• Which patients have good prognosis with endocrine therapy alone?

(low-risk for recurrence)

• Which patients need/benefit from chemotherapy? (high-risk for recurrence)

Prognostic tests/tools aid clinicians to identify those

patients
 Just going by tumour size may be misleading

Excessive reliance on size of

tumour to guide treatment can
cause some “high-risk” cases to be
undertreated

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Online calculators and equations for risk prediction

•PREDICT NHS
Online
calculators
•Adjuvant! Online

•Nottingham Prognostic Index (NPI)

Equations
IHC4

6
Sub-optimal performance of online tools in Asian cohorts

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Role of biomarker based tests in disease prognosis

Multi-gene prognostic tests

2 generation
nd

1 generation
st
(with clinical
parameters)

Mammaprint by
Agendia (van’t Veer Endopredict by
et al. 2002, Nature) Sividon (Filipits et al.
2011, CCR)

Oncotype DX by Prosigna by Nanostring

Genomic Health (Paik (Dowsett et al. 2013,
et al. 2004, NEJM) JCO)
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 Mammaprint

• 70 gene signature developed from a training set of 98 lymph node-negative patients References:
• Validated on 295 patients initially van’t Veer et al. 2002, Nature
• Further validation on TRANSBIG and RASTER trials in node-negative patients Vijver et al. 2002, NEJM
• FDA 510(k) approved Buyse et al. 2006, JNCI
• Prospectively validated in trial MINDACT Drukker et al. 2013, IJC
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 MINDACT Trial

Conducted on N0 and N1 patients

Included HER2+ and TNBC patients References:
10 Cardoso et al. 2016, NEJM
 MINDACT Trial

Clinically high risk but

genomically low risk who were
randomized not to receive
chemotherapy had 5-year
distant metastasis–free survival
of 94.7%

MINDACT was underpowered

to determine whether
chemotherapy is beneficial in
patients who had discordant
test results.

11
 Updated analysis ASCO 2020

• subgroup analyses was performed regarding the effect of chemotherapy per age group.
• omitting chemotherapy in Clinical-High/Genomic-Low postmenopausal women continues to be safe,
(DMFS gain 0.2% ± 2.3%)
• in premenopausal women the difference seen might be clinically relevant (DMFS gain 5% ± 2.8%)
• This effect may possibly be related to chemotherapy-induced ovarian function suppression.

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 Oncotype DX

• 21 gene assay developed using a training set of 447 NSABP-20

patients Low-risk High-risk
• Initially validated on NSABP-14 and NSABP-20
cohorts on node-negative patients
• Further validation on SWOG and TransATAC cohorts
• Prospectively validated in TAILORx trial
References:
Paik et al. 2004, NEJM, Pail et al. 2006, NEJM, Albain et al. 2010,
Dowsett et al. 2010 13
 TAILORx Trial

• RS cut-offs revised for

trial
• Original RS cutoffs 0-
17, 18-30 and >30
revised to 0-10, 11-25
and > 25
• 67% patients stratified as
“intermediate group with
RS 11-25” and
New “low-
randomized
risk” with RS
<11 had 99% References:
DMFS 14
Sparano et al. 2015, NEJM
Sparano et al. 2018, NEJM
TAILORx trial
Results were indicated that for women aged >50, RS 0-25 is
“low risk” BUT for women aged <50 there is still some
chemotherapy benefit in the RS 16-25 group. In the younger
age group, clinical risk factors are important!

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 Prosigna

• 50 gene signature initially developed for molecular sub-typing

• Includes clinical parameters, has intermediate risk category
• Validated on ABCSG-8 cohort (post-menopausal women) References
• FDA 510(k) approved for post-menopausal women only Dowsett et al. 2013
Gnant et al 2014.
• Prospective validation in OPTIMA trial initiated 16 Martin et al. 2016
Endopredict

• 12 gene signature developed on

ER+ HER- patients
• Includes clinical parameters
(EPclin score)
• Validation on ABCSG-6 &
ABCSG-8 cohorts (post-
menopausal women)
• Prospective validation in
UNIRAD trial initiated

References
Filipits et al. 2011
Martin et al. 2016
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Re-defining staging definition: Improved prognostication
8th Edition of AJCC Staging System

Anatomic Stage Group -Purely TNM based

Prognostic stage Group - TNM stage + (tumor grade, HER2, ER, PR status; and multigene panels)

Study results on re-staging based on prognostic staging

N=58,053 breast cancer patients with 5-7 year follow up

~30 % of patients were upstaged; >20% of patients were downstaged

Source: https://www.oncnet.com/news/new-ajcc-breast-cancer-prognostic-stage-more-accurate-anatomic-stage

Prognostic staging customizes patient’s prognosis aiding in effective

treatment
Confidential 19
Majority of early-stage breast cancer patients may not
need chemotherapy: TAILORx trial
Early-stage cancer patients may skip
chemotherapy, based on test results
• Several western tests to determine need for chemotherapy are
routinely used in Europe and US
• These tests are recommended by NCCN, ESMO, NICE guidelines
Patients are factoring ‘quality of life’ into
treatment choice
• Patients are increasingly aware of the short & long-term side
effects of chemotherapy
• Treatments such as hormone therapy have fewer side effects
than chemotherapy

Patient centric care

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 Consequences of overtreatment: Indian scenario

Indians largely pay out-of-pocket

for medical expenses

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What are the gaps & barriers?
Generalizability outside Western
world
High cost and long TAT
• Validated largely in post-
menopausal patients
• Younger age groups less
represented
• Asians poorly represented
in validation
• Lack of affordability in
developing countries
• Long TAT
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Performance of prognostic tests in non-Caucasian cohorts/other
ethnicities?

Should we
extrapolate results
from Western
populations to other
ethnicities and
populations?

23
 Performance of prognostic tests in non-Caucasian
cohorts/other ethnicities?
Prognostic tests perform differently in Asian vs European patients
Japanese cohort (Ishitobi et al.
2010):
• Lower proportion of low-risk in
Japanese vs European patients
• Recalibration of cutoff may be
required in Asian populations?

South Korean cohort (Na Kuk Young et

al. 2011):
• Lower proportion of low-risk in
Korean patients vs European
patients
• Gene disparities in Asians vs
Europeans?

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Unplanned age-based analysis shows prognostic
differences in <50 subgroup of MINDACT study

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Asian Breast Cancer Cooperative Group 2019 Consensus

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ICMR guidelines don’t include western tests due to
inadequate validation on Indian patients
ICMR consensus document on breast cancer management
 Indian patients are likely to be younger and have more
aggressive tumor biology
Indian breast cancer patients
48+ • Younger at onset
• Higher tumor burden, primarily
node-positive
• Symptomatic detection –
primarily Stage 2 cases
Western breast cancer patients
60+ • Older at onset, mostly post
menopausal
• Smaller tumors, primarily node-
negative
• Screen based detection – primarily
Stage 1 cases

Unmet need is to have a test developed on Indian patients

 Role of biomarker based tests in disease prognosis

CanAssist Breast, developed on Indian patients, is an cost-effective

alternative to western tests

CanAssist Breast is developed using a training set of 298 patient samples Biomarker Insights 13: 1-9; 2018
29 Cancer Medicine 8: 1755-1764; 2019
Role of biomarker based tests in disease prognosis

Role of CanAssist-Breast Biomarkers

CD44 ABCC4 /
ABCC11 CD44
Events in cancer progression
Cancer in duct

Epithelial-mesenchymal transition (EMT) 1. CD44

ABCC4
RhoA / ROC /
RAS
Loss of cell-cell adhesion,

Beyond proliferation and

dissociation Signaling domain / lipid raft

Invasion
Hormonal Indices RAF

Cadherins
PI3K
ABCC11

Extravasation /Mesenchymal epithelial 2. N-Cadherin

transition (MET) 3. Pan Cadherin FAK
MEK
AKT
MAPK
Chemotherapy resistance 4. ABCC 4 N-Cadherin
5. ABCC 11

Distant metastasis Self renewal, loss of cell adhesion,

migration, invasion, drug resistance,
EMT/MET lead to METASTASIS
Pan-Cadherin
Cancer Medicine 8: 1755-1764; 2019
Role of biomarker based tests in disease prognosis

CanAssist Breast has undergone development and

rigorous validation over a period of 9 years

Analytical Validity Clinical Validity Clinical Utility

• Analytical validation on • Clinical validation on ~1400 • CanAssist Breast used on

~100 patient samples patient samples ~600 patients to prognose
risk of recurrence
• CAB is reproducible and • CanAssist Breast is
repeatable prognostic and predictive

High concordance on: • Further validation is

• Inter/Intra-operator ongoing
• Inter/Intra-run • Biomarker Insights 13: 1-9; 2018
• Cancer Medicine 8: 1755-1764; 2019
• Inter/Intra-observer • BMC Cancer 19:249; 2019

• Inter-lot
Scientific publications

32
Scientific publications

33
Role of biomarker based tests in disease prognosis

Clinical Validation

Cancer Medicine 8: 1755-1764; 2019

34
Role of biomarker based tests in disease prognosis

Doing away with indeterminate intermediate risk category

~1400 patients, predominantly Indian (63%) All patients with 80 months f/up

100 100
95%
90 90 93%
84% 80
80

% DMFS
% DMFS

70 70
CAB Low-risk 63%
60 CAB High-risk 60
CAB Low-risk
n=1385, P<0.0001 50 CAB High-risk
50
n=458, P<0.0001

0 20 40 60 0 20 40 60 80 100 120
# at risk
Time in months
# at risk Time in months
985 969 956 914 282 278 274 266 261 69 10
400 382 359 332 176 158 136 115 111 39 9

• All patient results are actionable

• CanAssist Breast prognosis is valid even 7yrs after diagnosis
35
• Unpublished data
Role of biomarker based tests in disease prognosis

CanAssist Breast risk stratification unaffected by chemotherapy

Cohort who received only endocrine therapy

100
96% 100
98%
90
87% 90
80 83%
80
% DMFS

70 (Total cohort)

% DMFS
(T1N0)
CAB Low-risk (80%) 70
60 CAB Low-risk (89%)
CAB High-risk (20%)
60 CAB High-risk (11%)
n=423, P=0.0017
50 n=219, P=0.0002
50

0 20 40 60 80
0 20 40 60 80
# at risk Time in months
339 335 313 99
# at risk Time in months
333 184 40
84 82 19 195 195 194
81 72 20 5
24 24 24

• A sub cohort of patients treated with endocrine therapy alone CanAssist Breast had an
accuracy of 98% in low-risk
• In T1N0s the accuracy was still higher, 98%
36
• Unpublished data
Role of biomarker based tests in disease prognosis

CanAssist Breast is useful irrespective of age

Age <50 Age >50
100
94% 100
90 96%
90
80 81% 87%
% DMFS

80

% DMFS
70
CAB Low-risk 70
60 CAB Low-risk
CAB High-risk 60 CAB High-risk
n=460, P<0.0001 n=916, P<0.0001
50
50

0 20 40 60 80 0 20 40 60 80
# at risk Time in months # at risk Time in months
341 337 330 318 98 642 633 626 536 168
119 114 104 94 30 274 265 253 216 82

Risk stratification was similar in patients aged

below and above 50 with similar NPV
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Role of biomarker based tests in disease prognosis

CanAssist Breast risk stratification in independent of

node status
Node negative cohort Node negative cohort N1 cohort
(chemotherapy treated and naïve) (chemotherapy naïve only) (chemotherapy treated and naïve)

100 100 100

96% 97%
90 90% 90 89% 90 92%
85%
% DMFS

80 80 80

% DMFS

% DMFS
70 70
CAB Low-risk 70
CAB Low-risk CAB Low-risk
60 CAB High-risk 60 CAB High-risk 60 CAB High-risk
n=824, P=0.001 n=355, P=0.009
50 50 n=449, P=0.03
50

0 20 40 60 80
0 20 40 60 80 0 20 40 60 80
# at risk Time in months # at risk
# at risk Time in months Time in months
675 670 664 572 186 266 257 240
250 72
149 146 142 134 41 302 302 300 282 82
183 176 166 155 56
53 53 53 47 10

CanAssist Breast was useful for node negative

and node positive patients
38
Role of biomarker based tests in disease prognosis

CanAssist Breast demonstrates chemotherapy benefit

for ‘high-risk’ patients only

BCanAssist
Oncotype Breast
DX ‘low-risk’
‘low-risk’ Oncotype Breast
CanAssist DX ‘high-risk’
‘high-risk’
100 100
95%
92%
90 90 ~91% 88%

% DMFS
80 80 80%
% DMFS

70 ~62% 60%
70
Chemoendocrine Chemoendocrine
60 Endocrine
60 Endocrine
n=601, P=0.9356 n=149, P=0.05
50
50

0 20 40 60 80 100
0 20 40 60 80 100 # at risk Time in months
# at risk Time in months 119 117 114 107 29 12
440 431 424 411 98 26 30 30 25 9 3
161 161 159 151 44 9 30

• Paik et al., JCO 2006

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Role of biomarker based tests in disease prognosis

CanAssist Breast is an independent predictor of prognosis- Cox

proportional hazards regression
Covariate Hazard Ratio P-value 95% CI
Age: <50, >50 1.45 0.074 0.96-2.17
Tumor size: <T1, >T1 1.30 0.249 0.83-2.05
Node status: <N1, >N1 1.36 0.578 0.44-3.97
Grade: G1, G2+G3 0.99 0.994 0.52-1.93
TN: T1N0+T2N0, T3N0+T1-T3N1-N3 1.56 0.437 0.51-4.81
Therapy: chemo endocrine, endocrine 1.19 0.510 0.71-1.98
CAB risk score: high, low 2.59 <0.0001 1.72-3.91

CanAssist Breast had higher and significant hazard

ratio of 2.59
40
• Unpublished data
Role of biomarker based tests in disease prognosis

Performance of CanAssist Breast in Indian patient

cohort

41
Role of biomarker based tests in disease prognosis

Patients with endocrine and chemoendocrine Patients who received only endocrine therapy
therapy
100 100
95% 97%
90 90
87%
80 82%
80
% DMFS

% DMFS
70 70
CAB Low-risk CAB Low-risk
60 CAB High-risk 60 CAB High-risk
n=872, P<0.0001 n=182, =0.019
50 50

0 20 40 60 80 100 0 20 40 60 80 100
# at risk
Time in months # at risk
Time in months
627 615 604 583 167 39 11
144 144 142 136 56
245 234 211 197 55 19 5
38 38 38 33 12

Risk stratification is accurate with NPV >95% in

Indian cohort
42
• Unpublished data
Role of biomarker based tests in disease prognosis

CAB risk stratification in clinically low-risk sub-cohort

T1N0 (endocrine therapy alone) T1-T2N0 (endocrine therapy alone)
100 100% 100
98%
90 90
80 80
79%
% DMFS

% DMFS
70 70
CAB Low-risk 66% CAB Low-risk
60 CAB High-risk 60 CAB High-risk
n=63, P<0.0001 n=141, P=0.0004
50 50

0 20 40 60 80 100 0 20 40 60 80 100
# at risk Time in months # at risk Time in months
57 57 57 57 21 3 122 122 117 44
122 9
6 6 6 5 3 1 19 19 16 6
19 4

• NPV of 100% in low-risk • NPV of 98% in low-risk

• 10% stratified as high-risk with • 13% stratified as high-risk with
34% recurrence rates 21% recurrence rates
43
• Unpublished data
Role of biomarker based tests in disease prognosis

CanAssist Breast demonstrates chemotherapy benefit

for ‘high-risk’ patients only

CanAssist Breast ‘low-risk’ CanAssist Breast ‘high-risk’

100
100 97% 96%
95% 90
90
80 79%
80

% DMFS
70
% DMFS

70 Chemoendocrine
Chemoendocrine 60 Endocrine
60 Endocrine n=63, P=0.04
n=379, P=0.2 50
50

0 20 40 60 80 100
0 20 40 60 80 100 # at risk Time in months
# at risk Time in months 44 43 43 42 10 3
257 253 238 54 12 19 19 18 16 6 4
248
122 122 122 117 44 9

44
• Unpublished data
Role of biomarker based tests in disease prognosis

CanAssist Breast is an independent predictor of prognosis- Cox

proportional hazards regression
Co-variate Hazard Ratio P-value 95% CI
Age: <50, >50 1.32 0.27 0.80 to 2.19
Tumor size: <T1, >T1 1 0.99 0.54 to 1.86
Node status: <N1, >N1 1.73 0.049 1 to 2.97
Grade: G1, G2+G3 0.59 0.05 0.35 to 1
ER: <20%, >20% 1.62 0.11 0.9 to 2.92
PR: <20%, >20% 1.94 0.01 1.17 to 3.22
Chemotherapy treatment: no, yes 1.01 0.98 0.46 to 2.24

CanAssist Breast risk score: high, low 3.19 <0.0001 1.91 to 5.31

CanAssist Breast had higher and significant hazard

ratio of 3.19
45
• Unpublished data
Role of biomarker based tests in disease prognosis

Comparison of CanAssist Breast with Oncotype DX

46 • Cancer Medicine 8: 1755-1764; 2019

Role of biomarker based tests in disease prognosis

Comparison of CanAssist Breast with Oncotype DX

Good concordance on low-risk

classification

47 • J. Clinical Oncology 2020

Role of biomarker based tests in disease prognosis

How CanAssist Breast is impacting treatment

Chemotherapy Chemotherapy Percentage

Total no. of given not given Adherence
patients Risk proportions by CAB

795 Low risk 528 (66%)

*288 Low risk 198 (69 %) 14 184 93%

48 *Sankaran et al., IJSO 5 (2019)

CanAssist Breast timeline

2011-2015
2016-2017
• OncoStem • Multi-centric global 2018-2020
Diagnostics • Papers published in
validation endpoint
founded international peer-
met
• Clinical partners • Regulatory reviewed journals
signed in India and • CAP accreditation
approvals achieved:
USA achieved
NABL and ISO
• Biomarkers 13485 certification,
• New study partners
identified added
CE mark
• Machine-learning • Commercially
• Validation numbers
based algorithm increased
launched in India
developed

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