Education
Clinical Care
Research
Breast Cancer in Older Adults:
Asian perspectives
(with a local flavour)
Tan Sing Huang
Senior Consultant
Dept of Haematology-Oncology
National University Cancer Institute, Singapore
Overview
�Disease characteristics
• Western vs Asian
• Interethnic differences
�Treatment
• Chemotherapy, Endocrine therapy, TCMs
�Local physicians perspectives on the
treatment of elderly cancers
Estimated age-standardised rates (World)
per 100,000
BREAST CANCER
GLOBOCAN 2012
Incidence rates : 27 /100,000 in
Middle Africa and Eastern Asia
to 96/100 000 in Western Europe.
Mortality rates: 6 /100,000 in
Eastern Asia to 20 /100,000
in Western Africa
Breast cancer, just like Asian people, can be strikingly
variable among Asia countries and among regions and
ethnic groups within individual countries
Breast Cancer is heterogeneous in Asia
Age Standardized Incidence
and Mortality rates of breast cancer for SEA
countries
Country Incidence Rate* Mortality Rate*
Entire SE Asia 34.8 14.1
Brunei 48.6 11.3
Burma 22.1 11.3
Cambodia 19.3 9.3
East Timor 32.6 16.4
Indonesia 40.3 16.6
Malaysia 38.7 18.9
Philippines 47.0 17.8
Singapore 65.7 15.5
Thailand 29.3 11.0
Vietnam 23.0 9.9
* per 100,000 person years for year 2012
Source: GLOBOCAN 2012website (globocan.iarc.fr)5
Top 3 Cancers in Singapore: Interethnic
Differences
Breast
Colorectal
Lung
Breast
Colorectal
Lymphoid
Breast
Uterus
Colorectal
CHINESE
MALAY
INDIAN
Age-Standardised Incidence Rates for Breast
Cancer in Singapore, 1974-2013
Singapore Cancer Registry Interim Annual Registry Report.
Trends in Cancer Incidence in Singapore 2009-2013
Age-Specific Incidence Rates for Breast
Cancer, 2009-2013
Singapore Cancer Registry Interim Annual Registry Report.
Trends in Cancer Incidence in Singapore 2009-2013
The Singapore population is aging
Median age: 39
Median age: late 50s
Studies typically define older women as age ≥65yo
though this varies
Age distribution of breast cancer patients, 2004-2013
5-year Age-Standardised Observed Survival of Breast Cancer by
Ethnicity and Age Group 2004-2013
Singapore Cancer Registry Interim Annual Registry Report.
Trends in Cancer Incidence in Singapore 2009-2013
Why treat the elderly differently?
• Breast cancer is “less aggressive” in the
elderly
• They are more likely to die of other causes
• They tolerate treatment less well
Myth or reality in Asia?
• Aim: Comparison of clinico-pathological characteristics of elderly breast cancer in
Asian/Han-Chinese (n=432) compared to Caucasian/Austrian (n=198) women
• Histo-pathological findings: consecutive primary, unilateral, non-metastatic breast
cancer analyzed during 2005-2010 at Medical University of Vienna and Fudan
University, Shanghai
• IHC status (ER, PR and HER2) defined identically at both institutions. Chinese
samples re-evaluated by repeating immunostains in Vienna by an independent
pathologist
Tea et al. Maturitas 2012; 73: 251-254
Breast-conserving surgery rate 10.4% (45/432)
in Shanghai and 73.7% (146/198) in Vienna (lower
income, advice from others, knowledge, skepticism)
G3 cancers: 13.1%
(Chinese) vs 27.2% (Austrian) (p<0.001)
Receptor Status: Geriatric Asian (≥70yo) compared to
Caucasian breast cancer cases
Receptor
status
Shanghai,
n(%)
Vienna,
n(%)
P-value
ER positive 261 (73.7) 144 (84.2) <0.001
ER negative 93 (26.3) 27 (15.8)
PR positive 236 (66.5) 103 (60.2) 0.162
PR negative 119 (33.5) 68 (39.8)
HER2 positive 21 (5.9) 16 (9.7) 0.129
HER2 negative 333 (94.1) 149 (90.3)
Triple negative 74 (20.9) 19 (11.5) 0.027
Tea et al. Maturitas 2012; 73: 251-254
Limitations:
(1) lack of info on hormonal, reproductive and lifestyle factors
(2) Lack of data on adjuvant therapy
Increased HER2-positivity in Asians compared to Caucasians:
California Cancer Registry (n=89,009)
Telli et al. Breast Ca Res and Treat 2011; 127: 471
N=58,555N=58,555 N=18, 524N=18, 524 N=11, 930
Singapore-Malaysia Breast Cancer Registry Data (n=5769)
Merger between National University Hospital and University
Malaya Medical Centre Bhoo-Pathy et al. PlosOne 2012; 7: e30995
Cumulative OS by ethnicity in SEA women (n=5264)
5Y OS: Chinese (75.8%), Indians
(68%), Malays (58.5%)
Malays: higher all-cause
mortality HR 1.34; 95% CI: 1.19-
1.51), independent of age,
stage, tumour characteristics
and treatment
Bhoo-Pathy et al. PlosOne 2012; 7: e30995
Limitations:
lacking HER2 info
Inadequate info on
causes of deathSocioeconomic and
cultural factors
-income, religious
and cultural beliefs ,
use of alternative
meds
Tumour biology
Treatment response
and tolerability
Lifestyle
-alcohol, soy, obesity
2195 women, ≥40 years, diagnosed with primary invasive or in-situ breast cancer
between 1990–2007 at the National University Hospital in Singapore
Data from the Breast Cancer Registry of NUH established in 1995 (1990-1995
data collected retrospectively)
What are the differences in tumor characteristics, treatment and survival among older (>65 years) and younger (40 to 65 years) female breast cancer patients in Singapore?
Variable ≥ 65 yrs
n=326 (14.9%)
< 65 yrs
n=1869 (85.1%)
Adjusted OR (95%CI)
Ethnicity
Chinese 277 (85%) 1473(78.8%) 1
Malay 20 (6.1%) 197(10.5%) 0.5(0.3-0.9)
Indian 13 (4%) 105(5.6%) 0.7(0.4-2.5)
Others 16 (4.9%) 94(5%) 0.7(0.3-1.2)
Stage^
0 15(4.6%) 194(10.4%) 0.2(0.1-0.6)
1 58 (17.8%) 454(24.3%) 0.7(0.5-1.0)
2 117 (35.9%) 760(40.7%) 1
3 38 (11.7%) 240(12.8%) 1.0(0.6-1.5)
4 53 (16.3%) 123(6.6%) 1.6(1.0-2.6)
Unknown 45 (13.8%) 98(5.2%) 1.7(1.0-3.0)
Lymphovascular invasion
Yes 179(54.9%) 1035(68.9%) 1
No 78(23.9%) 221(11.8%) 2.4(1.4-4.2)
Unknown 69(21.2%) 343(18.4%) 1.1(0.7-1.8)
Patient and Tumor Characteristics
(1/3)
Saxena et al. Journal of Geriatric Oncology 2 (2011): 50-57
Variable ≥ 65 yrs
n=326
< 65 yrs
n=1869
Adjusted OR
(95%CI)
Histology
Ductal 248(76.1%) 1562(83.6%) 1
Lobular 12(3.7%) 88(4.7%) 0.5(0.2-1.1)
Mucinous 9(2.8%) 33(1.8%) 1.5(0.7-3.5)
Other 25(7.7%) 121(6.5%) 1.4(0.9-2.3)
Unknown 32(9.8%) 65(3.5%) 1.3(0.7-2.4)
Number of positive
lymph nodes#+
0 nodes 116(63%) 777(59.5%) 1
1-3 nodes 34(18.4%) 279(22.2%) 0.7(0.5-1.2)
4-9 nodes 22(12.0%) 155(11.7%) 0.9(0.5-1.6)
>=10 nodes 12(6.6%) 87(6.6%) 1.0(0.5-2.1)
Unknown 142 553 0.5(0.1-1.5)
Tumor Size+
<2 cm 73(22.4%) 562(30.1%) 0.6(0.4-0.9)
2-5 cm 86(26.4%) 450(24.1%) 1
>5 cm 16(4.9%) 114(6.1%) 0.7(0.3-1.4)
Unknown 151(46.3%) 743(39.7%) 0.6(0.4-1.0)
Patient and Tumor Characteristics
(2/3)
Saxena et al. Journal of Geriatric Oncology 2 (2011): 50-57
Variable ≥ 65 yrs
n=326
< 65 yrs
n=1869
Adjusted OR
(95%CI)
ER Status#
Negative 67 (28.8%) 628(44.0%) 1Positive 165 (71.2%) 797(56.0%) 2.6(1.7-3.8)
Unknown 94 444 2.8(0.4-19.3)
PR StatusNegative 97 (29.8%) 639(34.2%) 1Positive 133 (40.8%) 775(41.5%) 0.6(0.4-0.9)
Unknown 96(29.4%) 455(24.3%) 0.4(0.1-2.9)
Grade+
Good 43 (13.2%) 200(10.7%) 1Moderate 99 (30.4%) 640(34.2%) 0.8(0.5-1.2)
Poor 91 (27.9%) 587(31.4%) 0.9(0.6-1.5)
Unknown 93 (28.5%) 442(23.6%) 0.7(0.4-1.2)# Valid percentage has been calculated (i.e., not considering “unknown”).^ Unadjusted and Adjusted OR included stage 4 patients.
All other Odds Ratios (ORs) and confidence intervals (CIs) have been calculated
after excluding stage 4 patients.+ Logistic regression model adjusted for ethnicity, year of diagnosis,
lymphovascular invasion, histology, ER and PR status.
All other ORs are adjusted for ethnicity, year of diagnosis, lymphovascular
invasion, histology, ER and PR status, stage.
Patient and Tumor Characteristics
(3/3)
Saxena et al. Journal of Geriatric Oncology 2 (2011): 50-57
Variable ≥ 65 yrs
n =326
< 65 yrs
n=1869
Adjusted OR (95%CI)
Surgery type*
Mastectomy 216 (66.3%) 1191(63.7%) 1
BCS 59 (18.1%) 579(31.0%) 0.4(0.3-0.7)
No surgery/Unknown 51 (15.6%) 99(5.3%) 1.0(0.4-2.0)
Radiotherapy*
No
Yes
247(75.8%)
79(24.2%)
983(52.6%)
886(47.4%)
1
0.3(0.2-0.5)
Chemotherapy*
No
Yes
275(84.4%)
51(15.6%)
906(48.5%)
963(51.5%)
1
0.08(0.05-0.12)
Hormone therapy*
No
Yes
114(35%)
212(65%)
851(45.5%)
1018(54.5%)
1
2.8(1.9-4.0)
* variable is significant.
All ORs and CIs have been calculated after excluding stage 4 patients.
All ORs are adjusted for ethnicity, year of diagnosis, lympho-vascular invasion, histology, ER and PR status,
stage.
Treatment
Saxena et al. Journal of Geriatric Oncology 2 (2011): 50-57
Age-stratified differences in standard treatment (excluding
stage 4 patients)
0
20
40
60
80
100
120
Stage 1 patients
receiving BCS
Patients
undergoing BCS
receiving
radiotherapy
ER negative, LN
positive patients
receiving
chemotherapy
ER positive
patients
receiving
hormonetherapy
ER positive, LN
positive patients
receiving
chemotherapy
Pe
rce
nt
<65 years
≥65 years
Saxena et al. Journal of Geriatric Oncology 2 (2011): 50-57
Relative Survival
0
0.2
0.4
0.6
0.8
1
0 2 4 6 8 10 12
Cumulative
relative survival
Follow up years
<65 yrs
≥65 yrs
Logrank test p value
<0.001
5 Year Relative Survival
<65 Years ≥ 65 Years
Overall 76.5% (73.4% - 79.3%) 65.8% (56.0% - 74.8%)
Stage 1 100% (97.0% - 101.3%) 98.2% (68.0% - 111.7%)
Stage 2 82.9% (78.6% - 86.6%) 77.7% (61.7% - 90.3%)
Stage 3 46.0% (36.0% - 55.6%) 40.6% (19.6% - 63.3%)
Stage 4 12.7% (6.1% - 21.8%) 23.0% (8.1% - 44.6%)
observed survivors in the patient pool
expected survivors in general population
(Estimates excess mortality
attributable to the disease)
Saxena et al. Journal of Geriatric Oncology 2 (2011): 50-57
ConclusionElderly patients
1) Presented with late stage disease
-Patient delay, higher prevalence of fatalistic views, lower awareness of breast cancer, fear and anxiety of treatment
2) More likely to present with ER+ tumors
3) Less likely to receive chemotherapy and radiotherapy and standard treatment
-comorbid conditions, limited life expectancy, assumptions that breast cancer is less aggressive in older women, decision based on toxicity profiles of drugs and comorbidities, patients/families wishes, financial, cultural reasons
4) Had a poorer overall relative survival but differences were reduced on stage stratification
25
Teo et al Am J Health Behav 2013; 37: 667-682
MMG Screening:Ethnic Differences
• Only 37% overall underwent a regular mammography
– Lack of time (56.7%) and cost (54.3%) most commonly cited barriers.
• Older Malays (≥50yo) were less likely than older Chinese and Indians to
undergo regular mammograms (13% vs 43% vs 25%; p=.003)
– Older Malays had more children, lower per capita income, and knew
less about mammograms than other 2 ethnic groups
• Cited pain, that one does not need mammograms as one is healthy, and having
other health problems taking precedence as barriers
• Strategies
– targeted assistance to older groups, and lower income groups;
increasing awareness in Malay and Indian communities; increasing no.
and awareness of mobile MMG services near the workplace, increase
awareness of Medisave payments ( low knowledge at present 33%)
Why treat the elderly differently?
• Breast cancer is “less aggressive” in the elderly
• They are more likely to die of other causes
• They tolerate treatment less well (local
perspective)
Myth or reality in Asians ?
Tamoxifen
Approved since 1970s
Used widely in breast
cancers
-metastatic, adjuvant,
prevention
Complex metabolic pathway
Tan et al. Clin Cancer Res 2008 , 14(24): 8027-41
Bradford et al. Pharmacogenomics 2002, 3: 229-43
Distribution of CYP2D6 functional alleles
in different populations
Poor metabolizer
Intermediate
metabolizer
Fast metabolizer
CYP2D6 *3
CYP2D6 *4
CYP2D6 *5
CYP2D6 *6
CYP2D6 *10
CYP2D6 *17
CYP2D6*2xn
Tan et al. Clin Cancer Res 2008 , 14(24): 8027-41
Goetz et al. JCO 2005; 23:9312
DFS
North Central Cancer Treatment Group
Paraffin-embedded samples (n=223)
Doxorubicin: Asians vs
Caucasians
Doxorubicin-induced myelosuppression
Hor et al. Pharmacogenomics J 2008; 8: 139
Retrospective study
HK Chinese treated with doxorubicin/CTX
vs Caucasians treated on NSABP protocol
Gd 3/4 neutropenia:
77% (Asians) vs 3.7% (Caucasians)
Degree of neutrophil suppression:
Chinese>Malays>Indians
Ma et al. Radiother Oncol 2002; 62: 185
Fan et al. Pharmacogenet Genomics 2008; 18: 623
CBR3 correlates with doxorubicin clearance and toxicity
CBR3 11G>A a/wlower conversion of doxorubicin to doxorubicinol, inc tumour reduction, inc hematologic toxicities
CBR3 11G>A variant more common in Chinese cfCaucasians(57% vs 36%)
CB
R e
xp
res
sio
n%
de
cre
as
e W
BC
AU
C
ABCB1 polymorphisms influence doxorubicin exposureABCB1 polymorphisms influence doxorubicin exposure
Lal et al. Cancer Sci 2008; 99: 816
Increased doxorubicin exposure in patients with at least one ABCB1 c. 1236T allele
Those homozygous for CC-GG-CCgenotype had sig lower doxorubicin exposure cf to those with CT-GT-CT and TT-TT-TT genotypes
Docetaxel: Asians have higher neutropenia and
febrile neutropenia rates
• 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
• 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)
– 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
• 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
5-FU outcome
• Most Caucasians carry the 2R/2R variant, one-third has the 3R/3R variant.
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)]
• Different populations or ethnic groups are likely to be more
similar to each other than they are different in terms of drug
metabolism
• Differences in disposition to some drugs between races do
exist due to genetic of other influences
• Despite exciting pharmacogenetic data, there has been a lack
of validation studies
• Clinical application of pharmacogenetic testing to determine
response and toxicities are still limited
Interethnic Differences in Drug Response
Alternative and Complementary
Medicines
Use of Complementary and Alternative
Medicine (CAM) in Breast Cancer Survivors
Singapore
• Tan Tock Seng
Hospital, n=300
interviewed
• 35% reported using
TCM
• 75% perceived a
benefit
• Younger patients,
Chinese
• Most did not inform
clinicians
Taiwan
• 9 hospitals, n=230
survivors
• Prayer,
antioxidants
(39%), eating
various grains,
vegetarian diet,
Malaysia
Wong et al.Ann Acad of Med 2014; 43: 74
• 8 hospitals, 4 support
groups ; 7 Malaysian
states, n=394
• 51% used CAM
• Vitamins, spiritual
activities, dietary
supplements
• Increase ability for
ADL, enhance
immunity, improve
emotional well-being
Saibul et al. Asia Pacific J of Canceer P
revention 2012; 13: 4081
Wang et al. Asia Pacific J of Canceer
Prevention 2012; 13: 4789
2. Divider
•Introducing new topic
Prognostic Factors:
Local Perspective
Retrospective analysis of CGA data; 249
cancer patients ≥70yo who attended the
outpatient geriatric oncology clinic
at NCC Singapore
Univariate and multivariate analysis
identified prognostic factors within the CGA
Simple nomogram to predict OS developed
Median age: 77yo
Independent survival predictors
Age
Serum albumin
Poor ECOG
Abnormal geriatric depression scale
High malnutrition risk
Advanced disease stage
CGA questionnaire: Seven domains
Functional status, comorbidity, cognitive
status, affective status, pharmacy,
nutritional status, geriatric syndromes
What are our local physicians’
outlook towards elderly cancers?
57 physicians practising in Singapore; questionnaire survey (11 MCQs; 2 clinical scenarios)Two hypothetical scenarios (Rx regime for younger/older patients): (1) Stage IV DLBCL; (2) Stage IIB node-positive HR+ breast cancer
Pang et al. BMC Geriatrics 2013; 13:35
Most participants (61%) had
never engaged a geriatricians
help in treatment
90% welcomed the introduction
of a geriatric oncology program
DISCLOSURE OF DIAGNOSIS
Older patients
Family members first: 54% of
physicians
-family’s wishes, concern about
patient’s inability to accept or
understand diagnosis
Patient directly: 9%
Younger patientsPatient: 61%
Both younger/older patientsFamily and patient together:
About one-third of physicians
DISCLOSURE OF DIAGNOSIS
Older patients
Family members first: 54% of
physicians
-family’s wishes, concern about
patient’s inability to accept or
understand diagnosis
Patient directly: 9%
Younger patientsPatient: 61%
Both younger/older patientsFamily and patient together:
About one-third of physicians
Conclusion
• Breast cancer in elderly women is an increasing health issue locally due to
demographic changes and increasing screening
• Breast cancer in the elderly may not always be less aggressive a disease
compared to the younger population
• Interethnic differences in socioeconomic, cultural, disease biology and
pharmacogenetic factors may influence treatment choices and disease
management
• Under-treatment will lead to poorer survival and they should be offered
standard options with certain exceptions
• There is an increasing need for increased education and training in
geriatric oncology and for the formation of formal geriatric oncology
services
2014/8/6
Thank you for your attention
“Age is an issue of mind over matter.
If you don’t mind, it doesn’t matter”
MarkTwain
