Date post: | 15-Jan-2016 |
Category: |
Documents |
Upload: | doris-gardner |
View: | 221 times |
Download: | 6 times |
Personalized Breast Cancer Care
Sunil Patel, MDMedical Oncology and Hematology
Collom and Carney Clinic.
No financial disclosure
Personalized Breast Cancer CareTopics
• Role of genetic/familial high risk assessment• Role of specific markers on breast tissue in
decision making of treatment.• For some patients, more(=chemo) is not
better. - Role of genetic profiling of the tumor in decision making.
Breast Cancer Progress Report
• Breast Cancer mortality rates have decreased by 2.3% annually since 1990
Source: Breast Cancer Facts and Figures 2005-2006 National Center for Health Statistics data as analyzed by NCI
• The decline in mortality is primarily due to early detection and new treatment methods
The Stages of Breast Cancer
Breast Cancer is diagnosed according to stages (stages 0 through IV) under the TNM classification. Factors used in staging of Breast Cancer:
• Tumor SizeSize of primary tumor
• Nodal statusIndicates presence or absence of cancer cells in lymph nodes
• MetastasisIndicates if cancer cells have spread from the affected breast to other areas of the body (i.e. skin, liver, lungs, bone)
Source: National Cancer Institute
Genetics Help us Identify Patients at High Risk of Developing Breast CancerGenetics – Genetics is the study of heredity• While genetics influence genomics, genetics is responsible for
only 5-10% of breast cancer
• Genetics focuses primarily on the likelihood of developing cancer
• Genetic tests find mutations, not disease
Source: Understanding Cancer Series: Gene Testing,National Cancer Institute
Genomics Help us Look at the Patients Individual Tumor Biology
Genomics Genomics is the study of how genes interact and are
expressed as a whole• Genomics and gene expression profiling tools focus on the
cancer itself and can help determineHow aggressive is the cancer (prognosis)What is the likely benefit from treatment (prediction)
Examples of Genetic and Genomic Tests
Genetic Test
• BRCA1 and BRCA2 • The genetic make up of patients is tested for BRCA1 and BRCA2 mutations. Patients with those mutations have higher chances of developing breast cancer.
Genomic Test• Oncotype DX® Breast Cancer Assay
• The expression level of 21 genes is measured in tumor tissue from patients that have already been diagnosed with breast cancer. This assay evaluates if a patient is going to recur (prognostic) and predicts benefit from chemotherapy and hormonal therapy (predictive)•Mammaprint assay
Genetic Risk Factor Assessment
• NX 42 year old white female with no family history of breast cancer, now has 4 cm right breast cancer.
• Biopsy confirmed IDC,ER+, HER2/neu +• What’s next? – Surgery- ipsilateral or bilateral
mastectomy, chemo, hormonal therapy? Or more?
Breast & Ovarian Cancer Risk Assessment – for patients
- Age 50 y or younger- Triple negative breast cancer ( ER-PR-Her2/Neu-)- Two breast cancer primaries- Breast cancer at any age - 1 or more close relative with breast or ovarian cancer at age 50 or
younger -2 or more close relatives with breast and/or pancreatic cancer -women of Ashkenazi Jewish descent at any age breast/ovarian
cancer.- Other cancer history – Thyroid, sarcoma, adrenal , endometrial,
pancreatic, brain cancer- Ovarian cancer- Male breast cancer.
Patient NX
• NX 42 year old white female with no family history of breast cancer, now has 4 cm right breast cancer.
• Biopsy confirmed IDC,ER+, HER2/neu +• What’s next? – Surgery- ipsilateral or bilateral
mastectomy, chemo, hormonal therapy? Or more?
Patient NX
• Should go I go for surgery first? Then chemo?• Blood for BRCA 1 and 2 mutation.
Patient MB
• MB is a 53 year old white male with right sided breast cancer, stage I.
BReastCAncer Genes
BReast CAncer
• Women have about a 1 in 7 chance of getting breast cancer in their lifetime.
• Most cancer is sporadic, about 5-10% of cases are genetically linked
• Women inheriting mutation of BRCA gene have increased chance of disease
• Also can lead to ovarian cancer
The Numbers
Frequency of BRCA Mutations in the U.S.
U.S. citizens 1 in 500
Ashkenazi Jews 1 in 40
Women with breast cancer under age 50 Approx. 1 in 13
Women with breast cancer under age 40 1 in 10
Ashkenazi Jews with breast cancer under age 50 Approx. 1 in 8
BRCA Genes
• BRCA 1 and BRCA 2
• Roles they play
Life is all about the right balance.
What are they?
• BRCA 1 and BRCA 2– Known as breast and ovarian cancer susceptibility
genes– Tumor suppressor genes
• regulate the cycle of cell division by keeping cells from growing and dividing too rapidly or in an uncontrolled way
• inhibit the growth of cells that line the milk ducts in the breast
– Involved in many other functions including control of DNA replication and damage repair
BRCA 1
• Cloned in 1994 (Miki et al)–Mapped to chromosome 17q21–5,592kb long–24 exons
BRCA 2
• Cloned in 1995 (Wooster et al.)• Mapped to chromosome 13q12-13• 10,254 kb (3,418 aa)• 27 exons
More Numbers
Type of Cancer
General Population That Will Develop Disease
People With BRCA1 Mutation Who Will Develop Disease
People With BRCA2 Mutation Who Will Develop Disease
Breast 12.5% 55 – 85% 33 – 86%
Ovarian 1.43% 28 – 44% 10 – 30%
Prostate 4 – 6% 12 – 18% 12 – 18%
Male breast cancer Less than 1% 6% 4 – 14%
Pancreatic 0.6% not applicable 6 – 7%
Patient NX
• BRCA 1 mutation positive• Neo-adjuvant chemotherapy then bilateral
skin sparing mastectomy.• Hormonal therapy• Prophylactic bilateral salpingo-oopherectomy• Genetic counseling for family members.
Patient MB
• BRCA 2 mutation positive• Chemotherapy• Contra-lateral mastectomy• PSA screening test.
Topics
• Role of genetic/familial high risk assessment• Role of specific markers on breast tissue in
decision making of treatment.• For some patients, more is not better. - Role of genetic profiling of the tumor in decision making.
How Do We Assess Risk in Breast Cancer Patients?
Classic Pathological Criteria
Age
Tumor Size
Lymph Node Status
ER/PRHER2
Tumor Grade
AdjuvantOnline!Computer-based model
ER/PR/Her2-Neu
• Estrogen receptor• Progesterone receptor• Her2/Neu – Human epidermal growth factor
Receptor 2• ER/PR+ Her2/Neu –• ER/PR – Her2/Neu – (Triple negative)• ER/PR – Her2/Neu +• ER/PR+ Her2/Neu +
Triple-Positive Breast Cancer
Triple-Negative Breast Cancer
H&E ER-Neg PR-NegHER2/neu-Neg
ER-Pos PR-Pos HER2/neu-PosH&E
Treatment options
Chemotherapy Endocrine therapy – Tamoxifen or Aromatase
inhibitor - Anastrozole (Arimidex) , Letrozole (Femara) , Exemestane (Aromasin)
Trastuzumab (Herceptin)
HerceptinTM(trastuzumab)
Triple negative breast cancerHormone Receptor - /HER2 -
• Chemotherapy for tumor more than 0.5 cm.• Nodal involvement.
Hormone Receptor Positive,HER2 Positive Breast Cancer
• 0.5 cm or less tumor size – Adjuvant endocrine therapy
• 0.6 to 1 cm – Adjuvant endocrine +/- chemo with trastuzumab.
• > 1 cm tumor size and/or lymph node involvement – adjuvant endocrine therapy, chemotherapy with trastuzumab.
Hormone Receptor Negative,HER2 Positive Breast Cancer
• 0.5 cm or less tumor size – No chemo.• 0.6 to 1 cm – Consider chemo with trastuzumab.• > 1 cm tumor size and/or lymph node involvement –
chemotherapy with trastuzumab.• HORMONAL THERAPY NOT USEFUL.
Hormone Receptor Positive,HER2 Positive Breast Cancer
• 0.5 cm or less tumor size – Adjuvant endocrine therapy
• 0.6 to 1 cm – Adjuvant endocrine +/- chemo with trastuzumab.
• > 1 cm tumor size and/or lymph node involvement – adjuvant endocrine therapy, chemotherapy with trastuzumab.
Hormone Receptor Positive HER2 Negative Breast Cancer -
Tumor size
• Tumor size < 0.5 Cm and No LN involvement – Adjuvant endocrine therapy. No chemotherapy
• T > 0.5 Cm and No LN involvement - adjuvant endocrine therapy +/- ?? Chemo.
Hormone Receptor Positive HER2 Negative Breast Cancer
• Nodal involvement > 2mm focus – adjuvant endocrine therapy + chemotherapy
• 1 to 3 Lymph nodes or >3 nodes involved – does every one need chemo?
Topics
• Role of genetic/familial high risk assessment• Role of specific markers on breast tissue in
decision making of treatment.• For some patients, more(=chemotherapy) is
not better. - Role of genetic profiling of the tumor in decision making.
How Do We Assess Risk in Breast Cancer Patients?
Classic Pathological Criteria
Genetic Profiling of Tumor
New tools in the Genomic Era…
Age
Tumor Size
Lymph Node Status
ER/PRHER2
Tumor Grade
AdjuvantOnline!Computer-based model
Adjuvant Treatment for Early Stage Breast Cancer Today
Hormonal Therapy
If 100 women with ER+, N- disease are treated with hormonal therapy how many will recur within 10 years?
Based on the Landmark NSABP B-14 Study using Tamoxifen
85
15 Recurrence
Disease free
Fisher et al. N Engl J Med 1989;320(8):479-84
Chemotherapy and Hormonal Therapy
If all 100 women with ER+, N- disease are treated with chemotherapy and hormonal therapy, how many will benefit from the addition of chemotherapy?
Based on the Landmark NSABP B-20 Study using Tamoxifen + Chemotherapy
4
85
11
Benefited fromChemotherapy
Relapsed despiteChemotherapy
Disease freeregardless ofChemotherapy
Fisher et al. J Natl Cancer Inst 1997;89:1673-82
Copyright © American Society of Clinical Oncology
Outcomes of Adjuvant Chemotherapy in Breast Cancer
Walgren et al. JCO 2005;23:7342-7349
How Do We Assess Risk in Breast Cancer Patients?
Classic Pathological Criteria
Genetic Profiling of Tumor
New tools in the Genomic Era…
Age
Tumor Size
Lymph Node Status
ER/PRHER2
Tumor Grade
AdjuvantOnline!Computer-based model
Patient A
Patient B
Patient C
With Genomic Tools We Can Now Analyze Cancer at the Molecular Level
1. Patient’s tumor
4. Oncotype DX® Report
3. Analyze expression of tumor’s genes
2. Oncotype DX® Assay
5. Shared Decision Making
Oncotype DX®: A Genomic Assay
Oncotype DX® 21-Gene Recurrence Score® (RS) Assay
PROLIFERATIONKi-67STK15SurvivinCyclin B1MYBL2
ESTROGENERPRBcl2SCUBE2
INVASIONStromelysin 3Cathepsin L2
HER2GRB7HER2
BAG1GSTM1
REFERENCEBeta-actinGAPDHRPLPOGUSTFRC
CD68
16 Cancer and 5 Reference Genes From 3 Studies
Paik et al. N Engl J Med. 2004;351: 2817-2826
Oncotype DX® 21-Gene Recurrence Score® (RS) Assay
Calculation of the Recurrence Score Result
Category RS (0-100)Low risk RS <18
Int risk RS ≥18 and <31
High risk RS ≥31
Paik et al. N Engl J Med. 2004;351: 2817-2826
RS =Coefficient x Expression Level+ 0.47 x HER2 Group Score - 0.34 x ER Group Score + 1.04 x Proliferation Group Score+ 0.10 x Invasion Group Score + 0.05 x CD68- 0.08 x GSTM1- 0.07 x BAG1
The Oncotype DX® Assay mostly used for N-, ER+ Breast Cancer Patients
Invasive Breast Cancer
Stage I Stage II Stage III Stage IV
ER- ER+ N- N+
ER- ER+
Patient A
Patient A
• Patient was identified as low risk by Oncotype DX® with a Recurrence Score ® result of 4
• Patient received hormonal therapy since she was in a group in which chemotherapy does not provide benefit
Patient B
• Patient was identified as high risk by Oncotype DX® with a Recurrence Score® result of 34
• The Recurrence Score helped convince the patient on the likely benefits of taking chemotherapy given the biology of her disease
• Patient received chemotherapy and hormonal therapy
Patient B
Patient C
• Patient was identified as intermediate risk by Oncotype DX® with a Recurrence Score® result of 25
• Is there benefit from chemotherapy for this patient? The TAILORx trial evaluates the utility of chemotherapy in the mid-range risk group
Patient C
Copyright © American Society of Clinical Oncology
Outcomes of Adjuvant Chemotherapy in Breast Cancer
Walgren et al. JCO 2005;23:7342-7349
TamoxifenTamoxifen
ChemotherapyChemotherapy
Anth, Taxane, Anth, Taxane, PlatimunPlatimun
Women with Women with HR+ breast HR+ breast
CancerCancer
Aromatase Aromatase InhibitorInhibitor
Biologic agentsBiologic agents
Her2, EGFR, VEGF, ParpHer2, EGFR, VEGF, Parp
The Promise of Personalized Medicine in Breast Cancer
The Molecular Portrait Hypothesis
You can recognize theMona Lisa by her smile
and her nose and her eyes and even her hands – if you are really good,but not the sky or the trees
Thank you.
Questions?