Precision Medicine and Evolving Indications for Hereditary Cancer Genetics
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Precision Medicine and Evolving Indications for Hereditary Cancer Genetics

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Precision Medicine and Evolving Indications for Hereditary Cancer Genetics




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Presentation on theme: "Precision Medicine and Evolving Indications for Hereditary Cancer Genetics"— Presentation transcript:

Slide1

Precision Medicine and Evolving Indications for Hereditary Cancer Genetics

Robert A. Somer, MDHead, Medical Oncology and HematologyDirector, Office of Clinical ResearchMD Anderson Cancer Center- Cooper

Slide2

What is Cancer?

Official Definition: A malignant proliferation of cells that is a result of a

mutation

in the regulation of normal cell growth

control

Slide3

Precision Medicine

What is it?

“Precision medicine is an emerging approach for disease treatment and prevention

that takes into account individual variability in genes, environment, and lifestyle for each person

.”

https://www.nih.gov/precision-medicine-initiative-cohort-program

Slide4

Graphic generated with data obtained from

https://www.genome.gov/

& https://www.nih.gov/precision-medicine-initiative-cohort-program

Human DNA = approximately 3 billion DNA base pairs located on 23 pairs of chromosomes

Human genome contains 20,000 to 25,000 genes

Each encode average of 3 proteins

The Human Genome Project took blood samples from over 100 people and used some of these anonymous samples as the raw material from which to sequence the first complete human genome to provide a basis for ongoing biomedical research

Completed in 2003

Slide5

Cell

 

2011

144, 646-674DOI: (10.1016/j.cell.2011.02.013)

Hallmarks of

Cancer:

Therapeutic Precision

Slide6

Cancer Care

15

Years Ago

Cancer treated primarily based on

histology

,

location

and

size;

few biomarkers

Roughly

200 fewer treatment options than today

Three

basic treatment modalities

Limited supportive care options

Slide7

Common Cancers Now Collections

of Rare

Cancers

Catherine B. Meador et al.

Clin

Cancer Res 2014;20:2264-2275

Slide8

Timeline of Selected Major Discoveries in Lung Cancer Treatment

Katerina

Politi

, and Roy S.

Herbst

Clin

Cancer Res 2015;21:2213-2220

Slide9

Slide10

But precision medicine has brought new complexity – and challenges

Photographs were taken:

Before initiation of

vemurafenib

After 15 weeks of therapy

with

vemurafenib

At relapse, after 23 weeks of therapy.

Wagle

, N et al. Dissecting Therapeutic Resistance to RAF Inhibition in Melanoma by Tumor Genomic Profiling. JCO August 1, 2011 vol. 29 no. 22 3085-3096

Precision

Medicine: The BRAF Story

Slide11

Baseline:

GIST resistant

to

Imatinib

After 1 week

of

Sunitinib

Therapy

After 2 months

of

Sunitinib

Therapy

Rapid

Response Assessment

Normal

Heart

Resistant

GIST

Slide12

Tumor Evolution and Mutation Burden

Puente, Nat. Genet.,

2013; B

. Vogelstein, Science. 2013

Slide13

Rise of Immunotherapy

2014

2011

Long-term disease control against recalcitrant cancers

Game-changing discoveries – more coming

Ipilimumab

introduced for melanoma

Pembrolizumab

,

nivolumab

approved for melanoma

2015-2016

PD-1/L-1 drugs benefit even more of cancers

Slide14

CART-cell therapy

Customized vaccines

Rise of Immunotherapy

Slide15

New Clinical Trial Designs

Herbst

et al.

Clin

Cancer Res

2015;21:1514-1524; JAMA Oncology Dec 2016

Slide16

Molecular profiling in triple negative breast cancer – Parsons et al.

Clinical Cancer Research 2016

Slide17

Breast Cancer:

Not all ER Positive Cancers are the Same!245 DCIS in

population-based study:

Livasy, Human Pathol 2007

Subtype

N (%)

Basal-like

19 (8%)

Luminal A

149 (61%)

Luminal B

23 (9%)

HER2+/ER-

38 (16%)

Unclass

.

16 (6%)

Molecular subtype persists before and after therapy and in metastases:

*

*

*

Weigelt et al., Cancer Res, 2005

4 studies find basal-like present but uncommon in DCIS (5-10%)

Slide18

Subtypes and Prognosis

Sorlie T et al, PNAS 2001

Slide19

Oncotype

DX 21 Gene

Recurrence Score (RS) Assay

PROLIFERATION

Ki-67

STK15SurvivinCyclin B1MYBL2

ESTROGENERPR

Bcl2

SCUBE2

INVASIONStromolysin 3Cathepsin L2HER2GRB7HER2BAG1GSTM1REFERENCEBeta-actinGAPDHRPLPOGUSTFRC

CD6816 Cancer and 5 Reference Genes From 3 Studies

Category

RS (0 – 100)

Low risk

RS < 18

Int risk

RS

≥ 18 and < 31

High risk

RS

≥ 31

Slide20

Oncotype: Prognostic and Predictive!

Slide21

Foundation One - reporting

Slide22

Limitations of enrollment

Slide23

Personalized Approach

Multi-gene testing

RATIONALE

Identify driver mutations that promote survival or proliferation

Individualize treatment with targeted drugs that block those key pathways

Improve efficiency of screening for clinical trials with targeted drugs.

CURRENT REALITY:

Limited number of “

druggable

” genomic alterations (~20)Targetable mutations found in ~50% tumorsEnrollment on trials based on results small BUT – MUCH EXCITEMENT REMAINS

Slide24

Cancer Arises From Gene Mutations

Somatic mutations

Somatic mutation (

eg

, breast

)

Results

may help direct

treatment

of the cancer

Potentially

also detects hereditary changes

Occur in

nongermline

tissues

Are

nonheritable

Slide25

-

Sporadic cancer: Occurs by chance

-Familial cancer: Multiple shared genes and environmental factors increase a family’s risk to develop cancer

-Hereditary cancer: Caused by a change in a single gene that is being passed from generation to generation

The Etiology of Cancer

Slide26

When to Suspect Hereditary Risk

Young age at cancer diagnosis (less than 50y)

People diagnosed with multiple cancers

Cluster of cancers in individual or family

Breast / Ovary

Colon/uterine

Two or more close relatives affected across two generations

Individuals with rare types of cancer (male breast cancer)

A history of breast or ovarian cancer in an Ashkenazi Jewish family

Precursor lesions (Colon polyps, breast biopsies)

Slide27

The more common cancer genetics syndromes you may come across

Hereditary breast and ovarian cancer

56-87% lifetime risk for breast cancer

27-44% lifetime risk for ovarian cancer

Caused by mutations in BRCA1 and BRCA2 genes

Hereditary nonpolyposis colon cancer (HNPCC)-Colon/uterine/GI cancers

82% lifetime risk for colon cancer

Up to 60% lifetime risk for uterine cancer

Caused by mutations in MLH1, MSH2, MSH6 genesFamilial adenomatous polyposis (FAP)

50% of patients will develop polyps by the age of 15, 95% will develop polyps by 35Almost 100% risk of cancer if left untreated Caused by mutations in the APC geneKeep in mind: There are over 400 described cancer genetics syndromes, each with their own risks and each with their own medical management guidelines.

Slide28

Who can benefit from cancer genetic counseling?

Families with same or related cancers (breast/ovary) in 2 or more close relatives in the same lineage

Early age at cancer diagnosis (under 50 years)

Multiple primary tumors in one person

Bilateral or multiple rare cancers

Single cases of cancer with high-risk of genetic predisposition (medullary thyroid cancer, adrenocortical carcinoma, pheochromocytoma, paraganglioma, Wilm’s tumor, retinoblastoma)

Slide29

How do we test for mutations?

Testing is done by a BLOOD TEST (or

mucosal swab

)

DNA is taken from the white blood cells and analyzed for mutations

Results available in 4 weeks from time of blood draw

Slide30

Breast

@60

Maternal Ancestry: European, non-Jewish

Genetic testing 2015

32 gene panel :

PALB2

+

PALB2

:

breast, pancreas, ?ovarian, ?male breast cancers

70

adopted

Breast @36 (triple negative)

s/p BL mastectomy

Genetic testing 2006

67

43

3

BL Breast

@42 & 55

45

Single site testing:

PALB2

+

64

died @69

65

72

2

2

BRCA1/BRCA2:

negative

Slide31

Current 23andMe Kits:

$199 dollars

Tests for:

>35 carrier traits

>19 appearance traits

3 ancestry reports

4 wellness reports

www.23andme.com

Slide32

Role of the health care provider in cancer genetics

Understand genetic complexity of cancer and implications in terms of treatmentIdentify patterns in families or individualsIncreased awareness of genetic predispositions of malignancyEncourage screening of high-risk populationsMaintain finger on pulse of advances, not just for cancer, but for all diseases

Slide33

Thank You!