Jakarta 11th Nov 2009

Breast Unit – University Malaya Medical Centre

CH Yip Professor Department of Surgery University Malaya Medical Centre

Female Breast Cancer – NCR report 2003-2005
• • • • • • 11 952 new cases over 3 years Commonest cancer in Malaysia overall Commonest cancer in Malaysian women Crude rate 41.3 per 100,000 Age standardised rate (ASR) 46.4 per 100,000 Cumulative risk 5.0 ie a woman in Malaysia have a 1 in 20 chance of developing breast cancer in her lifetime

Female Breast Cancer– NCR report 2003-5 Race Incidence
Ethnic Group Malay Chinese Indian Malay women Chinese women Indian women No % CR 27.7 66 47 ASR CumR 34.9 59.8 54.1 3.6 6.3 6

4969 33.6 5051 30.3 1265 31.2

1 in 28 lifetime risk 1 in 16 lifetime risk 1 in 17 lifetime risk

Introduction
• The Breast Unit in UMMC was started in 1993 • The main activities of the Breast Unit are: - Clinical services - Education and training - Research activities

Breast Unit in UMMC
Multidisciplinary clinical services
• • • • • • • • Surgery – breast surgery (mastectomy and lumpectomy, axillary dissection) , immediate and delayed breast reconstruction Radiology – screening and diagnostic mammogram, ultrasound, MRI, guided biopsies Pathology – cytopathology and histopathology Oncology – chemotherapy, radiotherapy, targeted therapy (Oncology Unit started in 1999) Psycho-oncology (In 2007) Breast care nurse (In 2003) Palliative care (In 2007) Rehabilitative Medicine (2005)

Clinical Services
• Breast clinics – new cases clinic, follow-up clinic, results clinic, screening clinic, familial breast cancer clinic (risk assessment and risk management clinic) • Multidisciplinary meeting ( radiology, patholgoy, surgery oncology) – once a week • Main operating theatre – once a week • Daycare surgery – once a week • Breast cancer combined clinic (0ncology and surgery) - once a week

Education and Training
• Undergraduate teaching - MBBS • Postgraduate training – Master of Surgery programme, Mastectomy and axillary clearance is an index operation • Breast Surgery Fellowship

Research
Collaboration
• • • • • • • • • Cancer Research Initiatives Foundation (CARIF) Monash University University of Ohio Clinical Trials Centre Medical University of Vienna University of West of England Irish Cancer Registry Dharmais Cancer Centre, Jakarta UICC-ARO Within UM - Social and Preventive Medicine, Biostatistics, Molecular Biology, Institute of Mathematics, Faculty of Science

UMMC Breast Cancer Database
• Since the breast unit began in 1993, all new cases of breast cancer presenting to the UMMC was recorded • The current database has nearly 4 000 patients registered • This valuable database is the source of most of the clinical research eg stage, age, race, pathological features • With the IC number, survival data is available

Breast Cancer in UMMC Stage at presentation 1993-2008 (3689 cases)
Early Stage –Stage 1 and 2 Late Stage – Stage 3 and 4
100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0%
95 97 99 19 93 20 01 20 03 20 05 19 19 19 20 07

Stage 4 Stage 3 Stage 2 Stage 1

Breast Cancer in UMMC Stage at presentation and race 2008 (442 cases)
Malays 72

Chinese 313

Early Stage –Stage 1 and 2 Late Stage – Stage 3 and 4
100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Malays Chinese Indians

Indians

57

Stage 4 Stage 3 Stage 2 Stage 1 Stage 0

Hormone receptor status at presentation
White ER+PR+ ER+PRER-PR+ ER-PRHispanic Blacks UMMC 44% 14% 8% 35% 42.9% 11.1% 7% 8.8% 37.2% 58% 58% 15% 12% 6% 20% 22%

13239 cases. Gapstur etal Cancer 1996

15 year review of ER status in UMMC
Year 1994-1998 1999-2003 2004-2008 Total ER positive 150 (54.3%) 588 (56.6%) 1019 (58.3%) 1757 (57.4%) ER negative 126 451 728 1305 Total 276 1039 1747 3062

P=0.406

15 year review of ER status in UMMC
Race Malay Chinese Indian Total ER positive 318 (52%) 1218 (59.4%) 221(55.1%) 1757 ER negative 293 832 180 1305 Total 611 2050 401 3062

P=0.003

15 year review of ER status in UMMC
Age Less than 40 40 and above Total ER positive 192 (51.1%) 1565 (58.3%) 1757 ER negative 185 1120 1305 Total 377 2685 3062

P=0.007

Ongoing analysis of breast cancer database
Master of Surgery projects – funding from the Clinical Masters research grant
• • A Review of Pathological Subtypes of Breast Cancer in UMMC. The association between estrogen, progesterone and HER2 receptors with patient characteristics and prognosis in breast cancer. Early Breast Cancer Survival and the Nottingham Prognostic Index

Data management
• Improving breast cancer management delivery through the development of a comprehensive data management system and survival analysis (Funded by MOSTI)

Breast Cancer Survival in Malaysia
• Mortality statistics inaccurate • Only 40% of deaths are medically certified • Hospital data – UMMC database on breast cancer 1993-2002. Exclude DCIS and patients who absconded. Total of over 800 patients • Patient’s IC checked with the Registry Dept (JPN) to see if they are alive or dead • Study of survival in 2 cohorts – 1993-1997 and 1998-2002

Yip etal APJCP 2006

Overall Survival Breast Cancer Patients in UMMC- 1993-1997 (n=423)
Overall survival plot 1.0 Estimated survival probabilities 0.8

0.584
0.6 0.0 0 0.2 0.4

20

40

60 Survival times

80

100

Median follow-up : 55 months(1 month to 107 months)

Survival by Stage in UMMC
Survival Plot by Stage
1.0

1993-1997 (n=423)
Stage 1
Stage 1 Stage 2 Stage 3 Stage 4

Estimated survival probabilities

0.8

Stage 2
0.6

0.2

0.4

Stage 3

Stage 4 p < 0.05

0.0 0

20

40

60

80

100

Survival times

Mohd Taib NA, Yip CH, Mohamed I. Survival analysis of Malaysian women with breast cancer: results from the University Malaya Medical Centre. Asian Pac J Cancer Prev 2008 Apr-Jun;9(2):197-202

Survival by Race in UMMC1993-1997 (n=423)
Survival Plot by Race
1.0
Chinese Indian Malay

Estimated survival probabilities

0.8

p = 0.0025
0.6 0.0
0

0.2

0.4

20

40

60 Survival times

80

100

Survival analysis
• The Cox regression model by stepwise selection showed stage, nodal status and grade of tumour to be independent prognostic factors, whereas ethnicity, age and ER status were not. • Survival analysis ongoing – comparing survival in 5-year cohorts

5-year Overall Survival
1.0 0.8

76.2%

Survival Probability

0.4

0.6

59.1%
patients 93 - 97 patients 98 - 02

0.0 0

0.2

20

40 Months

60

80

100

93-97 Median follow-up : 56 months 98-02 Median follow-up : 53 months

Ethnic Group
1993-97
1.0
Chinese Indian Malay

0.8

Survival Probability

Survival

0.6

0.4

0.4

0.6

0.8

1.0

1998-2002

0.2

Others Malay Indian Chinese p= 2.85e-010

0.0

p-value0.00631

0.0
0

0.2

20

40 Months

60

80

100

0

20

40 Months

60

80

100

5-year survival probability

1993-1997 63.5% 57.4% 47.5% NA

1998-2002 81.6% 80.4% 58.9% 92.9%

p=0

Chinese Indian Malay Other

Survival Probability

1.0

1993-97

I II III IV

0.4

0.6

0.8

Stage
0.8 Survival 0.6

1.0

1998-2002

0.0

stg IV stg III stg II stg I stg 0 p= 0

0.2
0

0.4

20

40

60

80

100

Months

0.2

0.0

p-value=0 0 20 40 Months 60 80 100

1993-1997 1998-2002 Stage 0 Stage 1 NA 82.6% 72.8% 39.8% 13.2% 100% 95% 87.1% 56.3% 20.7%

p=0.

Stage II Stage III Stage IV

History of Breast Services
1993-1996
Breast Clinic database - non-dedicated serviceGeneral Surgeons performing surgery and chemotherapy

1998
In-house radiotherapy services

1996
Dedicated Breast Unit with surgical chemotherapy service

1999
Daycare Oncology chemotherapy service

History of Breast Services
1993 to present 1993 Radiologist services 2000 Reconstruction 2003 Combined pathology meeting

Support Services
1993- Survivor Support-BCWA 2003- Breast Care Nurse sanctioned 2005-Breast Cancer Resource Centre

2007- Free basic prosthesis kit 2007-Psychooncology services 2007- Palliative care consultancy

Psycho-social research
• • • Qualitative study on why women with breast cancer come late. (MD research project ongoing) Husband Support during adjuvant chemotherapy after different modalities of breast cancer treatment (PhD completed 2008) The self-management intervention of Malaysian women with breast cancer – enabling participation and quality of life (PhD completed 2009) Measuring Disability using ICF core sets in Breast Cancer Survivors. WHO Collaboration (Rehab Medicine Dept) Information Needs of Breast Cancer Patients on Chemotherapy from the patients and nurses perspective. (M Med Sc completed 2008)

• •

Why do women present late?
• Small pilot study in UMMC on 25 women presenting with late disease • 60% had tried alternative therapy as the first choice of treatment; the rest ignored the symptoms or prayed, hoping that it would go away • One had spent over USD10 000 of alternative therapy • Main reasons was fear of surgery and belief in traditional treatment, others were financial, family problems, did not know that cancer could spread…. • Most had been diagnosed early but did not agree to conventional treatment
Taib NA, Yip CH etal APJCP 2007

32 year old woman, diagnosed with early breast cancer, refused treatment, went for traditional medicine, returned after a year with locally advanced breast cancer

Traditional medicine
• Scars on the breast from traditional medicine

Traditional Medicine
• 33 yr old diagnosed with breast cancer when 36 weeks pregnant • After delivery defaulted surgery • Presented 5 months later with a large right breast mass • Alternative therapy with joss sticks

Clinical trials
• Phase 3 Randomized Study of Luteal Phase vs Follicular Phase Surgical Oophorectomy and Tamoxifen in premenopausal women with metastatic hormone-receptor positive breast cancer – Multicentric international study in collaboration with the Professor Richard Love, University of Ohio Clinical Trials Centre. A multi-national, multicentre randomized, double-blind, parallel group, placebocontrolled clinical trial to investigate safety and efficacy of tibolone (Org OD14) in women with climacteric symptoms and a history of breast cancer Organon Randomised Phase 2 trial of Gemcitabine combined with a Taxane for metastatic breast cancer Eli Lilly Phase II, open label study of SB-715992 in subjects with advanced or metastatic breast cancer. GSK A Phase III trial of novel Epothilone BMS-247550 plus capecitabine versus capecitabine alone in patients with advanced breast cancer previously treated with or resistant to an anthracycline and who are taxane resistant. BMS

• • •

Clinical trials
• A Phase II, Open-label, Randomised, Multicenter Trial of GW786034 (Pazopanib) in combination with Lapatinib (GW 572016) compared to Lapatinib alone as first line therapy in subjects with advanced or metastatic breast cancer with erb-B2 FISH positive tumours. GSK A phase 3 multicentre, randomised, placebo-controlled trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy regimens in subjects with previously treated metastatic breast cancer. Roche BEATRICE studyPhase 3 adjuvant standard chemotherapy vs standard chemotherapy plus bevacizumab for triple negative breast cancer. Roche Real-Life Extended Adjuvant Surveillance Study Upon registration (REASSURE) Trial: Observational study on the use of LETROZOLE In the Extended Adjuvant Treatment of patients with hormone-receptor-positive early breast cancer. Novartis

• •

Molecular Medicine and Pathology
• • • A Study of Hormonal Receptors and Topoisomerase II Alpha as Prognostic Markers in Asian Breast Cancer Patients. Collaboration with Monash University and UM Dept of Pathology Analysis of genetic factors that contribute to increased risk o breast cancer in Malaysia’s multi-ethnic population- Role of TP 53. Collaboration with CARIF The clinical predictors, spectrum and frequency of BRCA1 and BRCA2 mutations in an ethnically diverse high risk clinic population and to evaluate the performance of various risk prediction models (BRCAPRO, BOADICEA, MYriad statistical models) and the Manchester scoring system in predicting the likelihood of a mutation. Collaboration with CARIF. Association between Low Penetrance Gene(s) and Risk to Breast Cancer in Malaysian High-Risk Breast Cancer Patients. Collaboration with CARIF. Gene Analysis of Selected Oncogenes in Breast Cancers and Correlation with Patient Survival. Collaboration with Monash University. Gene Analysis of Selected Oncogenes in Breast Cancers and Correlation with Patient Survival. Collaboration with Monash University. Role of immunohistochemistry in the diagnosis of proliferative breast lesions. Collaboration with Dept of Pathology

• • • •

CARIF-UM Familial Breast Cancer Study
• Objectives of the CARIF-UM breast cancer study : – To determine the prevalence of BRCA1 & 2 mutations To determine risk assessment model in an Asian population – To determine impact of genetic testing in this multi-ethnic population • 282 breast cancer patients were screened

(Thirthagiri et al, Breast Cancer Research August 2008)

Research Methodology
Recruitment into CARIF-UMMC research study n = 901 Cohort selection for BRCA1 / 2 screening n = 282 Patients with deleterious mutations n = 41 Patients approached for genetic counseling

Patients with unclassified variants n = 63

Patients with no mutations n = 183

Patients approached genetic counseling & family studies

Other genetic studies

Uptake of BRCA status results
Patients with deleterious mutations n = 41

Patients who want genetic counseling n = 33

Patients who are deceased / cannot be contacted n=3

Patients who do not want genetic counseling n=5
• 3 - do not want the burden of carrier status • 1 - do not want to relive treatment trauma • 1 - spouse did not want patient to have further information about her genes.

• 28 (85%)decided after 1st intake • 2 (6%) decided after 2 intakes • 3 (9%) decided after 3 intakes

Informing relatives
Index patients with deleterious mutations counseled n = 33

Yes, I want to inform my relatives n = 25

I am considering informing my relatives n=1

No, I don’t want to inform my relatives n=7 • Have poor relationships with family members • Do not want to burden family with carrier information

Families who want counseling n = 15

Families considering counseling n=4

Families who declined counseling n=6

• Worried about insurance • Doesn’t think that Information will be useful • Doesn’t think they can cope with the knowledge

Lessons learnt from pilot study

• Risk assessment challenges • Organisational challenges • Counseling challenges / Issues raised

Translation of research project into clinical practice
• Genetic counseling under auspice of research serve as a basis for planning of a familial cancer service • Pilot study revealed counseling issues which can expected in future clinics

Translating research into clinical practice – Other examples
• Self management research – translate into setting up a clinical service for patients • Results from the qualitative study on why women present late will translate into overcoming barriers to early detection

Future research plans
• Genetics – applying for ERI grant for collaborative studies with Hong Kong and Singapore • Collaborative research with University of West of England to compare breast cancer in Asians and Caucasians • Clinical Epidemiology - research project with Indonesia to compare presentation of breast cancer in two neighbouring countries

The success of a breast unit depends on collaboration between all the members of the unit – surgeon,radiologist, pathologist, breast care nurse, oncologist, basic scientist, biostatisticians etc AND most important of all, THE PATIENTS……

Thank you

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