Download - Personalized Breast Cancer Care
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Personalized Breast Cancer Care
Sunil Patel, MDMedical Oncology and Hematology
Collom and Carney Clinic.
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No financial disclosure
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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.
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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
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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
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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
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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)
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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
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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?
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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.
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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?
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Patient NX
• Should go I go for surgery first? Then chemo?• Blood for BRCA 1 and 2 mutation.
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Patient MB
• MB is a 53 year old white male with right sided breast cancer, stage I.
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BReastCAncer Genes
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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
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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
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BRCA Genes
• BRCA 1 and BRCA 2
• Roles they play
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Life is all about the right balance.
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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
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BRCA 1
• Cloned in 1994 (Miki et al)–Mapped to chromosome 17q21–5,592kb long–24 exons
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BRCA 2
• Cloned in 1995 (Wooster et al.)• Mapped to chromosome 13q12-13• 10,254 kb (3,418 aa)• 27 exons
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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%
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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.
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Patient MB
• BRCA 2 mutation positive• Chemotherapy• Contra-lateral mastectomy• PSA screening test.
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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.
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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
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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 +
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Triple-Positive Breast Cancer
Triple-Negative Breast CancerH&E ER-Neg PR-Neg
HER2/neu-Neg
ER-Pos PR-Pos HER2/neu-PosH&E
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Treatment options Chemotherapy Endocrine therapy – Tamoxifen or Aromatase
inhibitor - Anastrozole (Arimidex) , Letrozole (Femara) , Exemestane (Aromasin)
Trastuzumab (Herceptin)
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HerceptinTM(trastuzumab)
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Triple negative breast cancerHormone Receptor - /HER2 -
• Chemotherapy for tumor more than 0.5 cm.• Nodal involvement.
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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.
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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.
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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.
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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.
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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?
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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.
![Page 38: Personalized Breast Cancer Care](https://reader036.vdocuments.us/reader036/viewer/2022070420/56815e25550346895dcc7f3e/html5/thumbnails/38.jpg)
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
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Adjuvant Treatment for Early Stage Breast Cancer Today
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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
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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
11Benefited fromChemotherapy
Relapsed despiteChemotherapy
Disease freeregardless ofChemotherapy
Fisher et al. J Natl Cancer Inst 1997;89:1673-82
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Copyright © American Society of Clinical Oncology
Outcomes of Adjuvant Chemotherapy in Breast Cancer
Walgren et al. JCO 2005;23:7342-7349
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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
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Patient A
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Patient B
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Patient C
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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
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Oncotype DX®: A Genomic Assay
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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
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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
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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+
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Patient A
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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
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Patient B
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• 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
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Patient C
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• 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
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Copyright © American Society of Clinical Oncology
Outcomes of Adjuvant Chemotherapy in Breast Cancer
Walgren et al. JCO 2005;23:7342-7349
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TamoxifenTamoxifen
ChemotherapyChemotherapyAnth, Taxane, Anth, Taxane,
PlatimunPlatimun
Women with Women with HR+ breast HR+ breast
CancerCancerAromatase Aromatase
InhibitorInhibitor
Biologic agentsBiologic agentsHer2, EGFR, VEGF, ParpHer2, EGFR, VEGF, Parp
The Promise of Personalized Medicine in Breast Cancer
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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
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Thank you.
Questions?