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?