Y3

Is Breast Cancer in Asia any different?

B C
R Dent MD FRCP (Canada)
Senior Consultant, National Cancer Center Singapore
Associate Prof Duke-NUS
 Y3
BC
 Ethnic Groups in the City of Toronto

3
South Asian 12.0 %
Chinese 11.4%
59.1 %

Y
Filipino 4.1 %
Other or
Multi
Ethnic 4.1%

C
Othe
r

B Multi-
Ethnic
Philippine General Hospital 1998

Y3
B C
National Cancer Center Singapore, Duke-NUS
Jan 2011 - present

Y3
B C
 Outline

Y3
• Is the incidence any different?

• Is the presentation any different?

B C
• Biological heterogeneity?

• Should Asian patients be treated differently?

“Breast cancer incidence rates in Asia look set
to converge with the much higher ones in the

3
West, as younger cohorts of Asian women age”

C Y
B 2016
GLOBOCAN 2012

Y3
B C
Female Breast Cancer Incidence Among Asian and
Western Populations: More Similar Than Expected

Y3 Approaching
Western
Incidence

B C Sung JNCI 2015

 Y3
B C
rest of Asia still a lot lower than West

…but Singapore and other more developed countries

1 in 15 up to age 75, 1 in 11 up to age 99
 Y3
B
https://www.nrdo.gov.sg/
C
 #1 Most Frequent Cancer
in Females

3
NCCS New Cases Breast Cancer
600-800/ year

Y
#1 Most Frequent Cancer
Death in Females

B 12
C
 Y3
B
https://www.nrdo.gov.sg/
C
 Why the increase?
Breast Cancer Risk is Multifactorial…

3
• Very obvious changes from 3rd worlds to first – Survival of childhood

Y
illness, and a decrease in maternal complications during pregnancy,
decrease in infections and deaths from traumas

• Rapid lifestyle changes –drop in fertility can explain partly higher

C
incidence in younger Asian cohorts

• Lifestyle changes with economic development …“Westernization”

B
– greater calorie consumption with high levels of obesity and alcohol

• Likely only partial explanation in Singapore and other countries

– in some countries obesity has not increased
– more visible is drop in fertility, later age of giving first birth and great
reduction in breast feeeding
 Y3
BC
 Outline

Y3
• Is the incidence any different?

• Is the presentation any different?

B C
• Biological heterogeneity?

• Should Asian patients be treated differently?

 Genetic Etiology

Earlier Onset
Chinese Asians

Y3
C
Later Onset
Caucasians
MDM2 SNP309

B
G allele inc risk
T allele earlier age

0 20 40 60 80 Age
M enopause

Lum Carcinogenesis 2008

Age specific Incidence of Breast Cancer
in Asia differs from Western countries

Y3 Mean age in Asia 50 yo

C
compared to 60 yo
in the West

B Globoscan
 Comparing Presentation between
US and Singapore

Y3
C
18.6%
10.0%

B
Twice as common with advanced disease; Younger age of onset
Courtesy Dr. Mikael Hartman
 Spectrum of breast cancer

3
• Retrospective study in cancer centres:
– India 1998-2004 n=544
– Malaysia 1995-2004 n=2009

Y
– Hong Kong 2003-2005 n=901
60%
India

C
50%
Malaysia
40% Hong Kong

B
30%

20%

10%

0%
0 I II III IV
Agarwal et al World J Surgery 2007
 Age at presentation
Data from the California Registry
25%

20%
Age< 40y

Y3 15%

C
15%
13%
12%
10%
10%

B
7%

5% 4%

0%

NH White Chinese Filipino Korean Vietnamese S Asian

Telli M et al Breast Can Res Treat 2011

Summary from Economist Analysis

3
• The recent rise in Asian breast cancer has seemed

Y
weighted toward the young only because they
now have incidence rates similar to Western
peers, while older generations still have a far

C
lower propensity to develop the disease.

B
• As the current generation of younger Asian
women age, international differences will
disappear.
 Y3
B C
• De novo MBC 1996-2010 SE Asia (Malayasia & Singapore)

• Time periods: 1996-2000, 2001-2005, 2006-2010

• N = 856

• Chinese 60%, Malay 27%, Indians 11%

 Y3 Possible factors for improved OS
 Tumour burden migration
 Decreased % of ‘no treatment’
 Increased chemotherapy use

B
Relative 3yr-survival:
C
1996-2000
20.6%
2001-2005
28.8%
2006-2010
33.6%

Bhoo-Pathy et al Sci Report 2015

 Y3
BC Improved OS:

Younger
Women and

Asian Women
 Ethnic Differences in Survival in
Singapore
1

0,9

0,8

Y3 Chinese

C
Cumulative
overall 0,7
survival Indian

B
0,6 Malay

0,5

0,4
0 6 12 18 24 30 36 42 48 54 60

Months after diagnosis

Courtesy Dr. Mikael Hartman

 Outline

Y3
• Is the incidence any different?

• Is the presentation any different?

B C
• Biological heterogeneity?

• Should Asian patients be treated differently?

 Y3
BC
Ethnic differences in prevalence of
TNBC

Y3
B C
 Patient & tumour characteristics

• California registry

Y
• N=89,009 known receptors3
• Population-based study Jan 2002 – Dec 2007

C
– Asians (Japanese, Chinese, Filipina, Korean, Vietnamese, South
Asian)

B
– 13% of total population
– 8140 (71% of Asian pts) known receptors
• 78% foreign-born

Telli M et al Breast Can Res Treat 2011

 Tumour characteristics

3
*
HR+/HER2- HER2+ TN

Y
100%

90%

80%

C
70% * * *
60%

50%

B
40%

30%

20%

10%

0%
Japanese Chinese Filipino Korean Vietnamese S Asian Other Asian NH White

HER2-positive breast cancer is overrepresented

Telli M et al Breast Can Res Treat 2011
among Korean, Filipina, Vietnamese, and Chinese
 Genetic Etiology

3
Differences in mutational spectrum between our local
population and the Caucasian population

Y
• No CHEK2*1100delC mutations in Asian Patients (J Clin Oncol
2008)

C
• Higher frequency of mutations in BRCA2 compared to the
BRCA1 (Cancer Epidemiology, Biomarkers and Prevention
2007)

B
• Founder mutation identified in Malays (Human Mutation 2003)

32
 Genetic Etiology

– rs7696175/TLR1,TLR6
– rs13281615/8q24

Y3
• Eight SNPs increased breast cancer risks in Chinese:
– rs2046210/6q25.1
– Four SNPs at 10q26.13/FGFR2

C
– rs16886165/MAP3K1

• Five SNPs were associated with breast cancer risk predominantly

B
among ER-positive tumors

• The risk of developing breast cancer increased by 90% for those

with a combination of 6 or more risk alleles, compared to patients
with ≤3 risk alleles.

Chan Br Ca Res Treat 2012

 Outline

Y3
• Is the incidence any different?

• Is the presentation any different?

B C
• Biological heterogeneity?

• Should Asian patients be treated differently?

 Y3
BC
 Pharmacogenomics:
CYP2D6 and Metabolism of Tamoxifen

Y3
Tamoxifen is widely used as endocrine therapy for hormone-
receptor positive breast cancer
• its clinical effects rely on efficient conversion to 4-

C
hydroxytamoxifen (4-OH-tam) and endoxifen by the
cytochrome P450 2D6 (CYP2D6) enzyme

B
Tamoxifen can likely take credit for saving more patient’s lives
than any other cancer drug currently available
• a great deal is unknown about who benefits and why
 Y3
C
Tan et al. Clin Cancer Res 2008 , 14(24): 8027-41

North Central Cancer Treatment Group

B
Paraffin-embedded samples (n=223)

DFS

Goetz et al. JCO 2005; 23:9312

 Doxorubicin: Asians vs Caucasians

Retrospective study

3
HK Chinese treated with doxorubicin/CTX
vs Caucasians treated on NSABP protocol
Gd 3/4 neutropenia:
77% (Asians) vs 3.7% (Caucasians)

Y
Doxorubicin-induced myelosuppression

C
B
Ma et al. Radiother Oncol 2002; 62: 185

Degree of neutrophil suppression:

Chinese>Malays>Indians

Hor et al. Pharmacogenomics J 2008; 8: 139

 Docetaxel: Asians have higher neutropenia and
febrile neutropenia rates

Y3
• Asians have higher reported febrile neutropenia rates compared to
Caucasians
– Differing starting doses: Caucasians docetaxel 100mg/m2,
China/Korea/Singapore 70-75mg/m2, Japan docetaxel 60mg/m2

• Possibly due to differences in drug clearance

C
• PK and PD of docetaxel 75mg/m2 (n=24) or 100mg/m2 (n=8) studied in 32
patients from NUH (majority NSCLC, 3 breast patients)

B
– Clearance was about 30% lower while drug exposure (AUC) was about
25% higher in Asians compared to reported data in Caucasians
– Febrile neutropenia rates 29%
– No definite genetic etiology identified

Goh et al. JCO 2002; 20: 3683

 Capecitabine tolerability:
Asians vs Caucasians

Y3
• American and European Caucasians have 2-3 fold higher risk of developing
grade 3 or 4 gastrointestinal toxicities compared to Asians

• One implicated gene: thymidylate synthase (TYMS) gene. Variants in

enhancer region of TYMS affects thymidylate expression level and hence

C
5-FU outcome

• Most Caucasians carry the 2R/2R variant, one-third has the 3R/3R variant.

B
The 3R/3R variant 2X more common in Asians

• Phase I genotype-guided dosing study: Asians with the 3R/3R genotype

could tolerate 20% higher capecitabine doses (1500mg/m2) with minimal
toxicities [Soo et al. J Clin Oncol 30, 2012 (suppl abstr 2551)]
 CLEOPATRA: Exposure to docetaxel in

3
patients from Asia
Other regions Asia

Y
Docetaxel dose reductions below 75 mg/m2
HT occurred
PHT in 47% of patients
HT PHT
n = 269 n = 282
from Asia compared with13% of patients from other regions. n = 128 n = 125
Median number of all study treatment cycles (range) 15.0 (1−50) 18.0 (1−56) 15.0 (1−46) 20.0 (1−50)
Median number of docetaxel cycles (range) 8.0 (1−27) 7.0 (1−35)
But did not adversely affect efficacy in patients from Asia, with9.0PFS
(1−41)
and 9.0 (1−30)

C
Median docetaxel dose intensity, mg/m2/week 25.0 24.7 23.6 23.9
overall survival being comparable with that of patients from other
Docetaxel dose escalation to 100 mg/m2, n (%) 56 (20.8) 47 (16.7) 5 (3.9) 1 (0.8)
regions.
Docetaxel dose reduction to <75 mg/m2, n
(%) A reduction in the docetaxel starting32dose
(11.9)
should42therefore
(14.9) be57 (44.5) 62 (49.6)

B
One dose reduction to <75 mg/m 2 31 (11.5) 39 (13.8) 56 (43.8) 61 (48.8)
considered in patients from Asia…
Two dose reductions to <75 mg/m2* 1 (0.4) 3 (1.1) 1 (0.8) 1 (0.8)
Docetaxel permanently discontinued
No, n (%) 97 (36.1) 78 (27.7) 45 (35.2) 31 (24.8)
Yes, n (%) 172 (63.9) 204 (72.3) 83 (64.8) 94 (75.2)
166/172 (96.5) 194/204 (95.1) 79/83 (95.2) 91/94 (96.8)

Data cut-off: May 2011

* Includes patients with initial dose escalation to 100 mg/m2 followed by two subsequent dose reductions Swain SM, et al. The Oncologist 2014; 19:1–9
H, trastuzumab; P, pertuzumab; T, docetaxel
 First Analysis of Efficacy in Asian
Patients; Oral Targeted Therapy

3
Asian
100
Palbociclib + Placebo +
Fulvestrant Fulvestrant
n=74 n=31

Y
80 HR (95% 0.485
CI) (0.270–0.869)
1-sided P
0.0065
60 value
PFS, %

C
40
Non-Asian
Palbociclib + Placebo +
Fulvestrant Fulvestrant
20
n=273 n=143

B
HR 0.451
(95% CI) (0.343‒0.593)
0
1-sided
<0.0001
P value

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Time, mo

Similar Benefit in PFS of Palbociclib between Asian and

Non-Asian Patients HR 0.48 vs. 0.45
 Secondary Endpoints:
Response Assessment

100

90
Asian 3
Control of arm of Fulvestrant:
Higher Response in Asian 52% vs. 37% non-Asians

Y
(may just be due to small sample size or possibly due
to median lower weight in Asian patients?)
Median weight 57 kg vs. 72kg
Non-Asian

C
80
70
70 66
60
52
CBR, %

CR

B
50
PR
40 37
SD ≥24 wk
30
Objective
20 16% 19% 17% 36%
progression

10

0
Palbociclib + Placebo + Fulvestrant Palbociclib + Placebo + Fulvestrant
Fulvestrant (n=74) (n=31) Fulvestrant (n=273) (n=143)
CBR = clinical benefit response rate; CR = complete response; PR = partial response; SD = stable disease
Date of data cut-off: March 16, 2015 43
 Asian vs. Non-Asian patients

3
Asian Non-Asian
(n=105) (n=416)

Y
Demographics:
• Premenopausal/perimenopausal 44 (42%) 64 (15%)

• Median (range) weight, kg 56kg (35-83) 72kg (43- 142)

C
AE – All grades (Palbo + Fulvestrant) Real or Body
• Neutropenia 67 (92%) 212 (78%) Surface
• Stomatitis 19 (26%) 24 (9%) Area

B
• Rash 18 (25%) 17 (6%) Differences?
• Nasopharyngitis 15 (21%) 26 (10%)
• Fatigue 14 (19%) 121 (45%)

3% Not reported
Febrile Neutropenia (Palbo + Fulvestrant) (0.6% from all patients,
(2/73 patients) NEJM Turner et al. 2015)
 Summary
• Is the incidence any different?

Y3
– Yes, increasing across Asia, incidence approaching the West
– Not clear if higher rates of breast cancer young women will persist

• Is the presentation any different?

C
– Higher rates of LABC and de novo

• Biological heterogeneity?

B
– SNPs different but more work needed
– Higher rate of her2 + in subset Asian patients
– Higher rate of TNBC in Indian patients

• Should Asian patients be treated differently?

– YES significant differences require local adaptation & trials
 Y3
BC
 Y3
B
Highlights for 2017
C
Pre –meeting Genetics Workshop lead by Prof Jeffrey Weitzel

Dr. Laura Esserman (iSPY) Prof Tony Mok

Prof Charles Swanton
 Acknowledgements
•
•
•
Dr. Benita Tan

Y
Dr. Veronique Tan
Dr. Lee Guek Eng 3
C
• Dr. Arlene Chan
• Dr. Mikael Hartman
•
•
B
Dr. Cheng Har Yip
Dr. Nirmala Bhoo-Pathy