Robert A Somer MD Head Medical Oncology and Hematology Director Office of Clinical Research MD Anderson Cancer Center Cooper What is Cancer Official Definition A malignant proliferation of cells that is a result of a ID: 731546
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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- CooperSlide2
What is Cancer?
Official Definition: A malignant proliferation of cells that is a result of a
mutation
in the regulation of normal cell growth
controlSlide3
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-programSlide4
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 2003Slide5
Cell
2011
144, 646-674DOI: (10.1016/j.cell.2011.02.013)
Hallmarks of
Cancer:
Therapeutic PrecisionSlide6
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 optionsSlide7
Common Cancers Now Collections
of Rare
Cancers
Catherine B. Meador et al.
Clin
Cancer Res 2014;20:2264-2275Slide8
Timeline of Selected Major Discoveries in Lung Cancer Treatment
Katerina
Politi
, and Roy S.
Herbst
Clin
Cancer Res 2015;21:2213-2220Slide9Slide10
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 StorySlide11
Baseline:
GIST resistant
to
Imatinib
After 1 week
of
Sunitinib
Therapy
After 2 months
of
Sunitinib
Therapy
Rapid
Response Assessment
Normal
Heart
Resistant
GISTSlide12
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 cancersSlide14
CART-cell therapy
Customized vaccines
Rise of ImmunotherapySlide15
New Clinical Trial Designs
Herbst
et al.
Clin
Cancer Res
2015;21:1514-1524; JAMA Oncology Dec 2016Slide16
Molecular profiling in triple negative breast cancer – Parsons et al.
Clinical Cancer Research 2016Slide17
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 2001Slide19
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
≥ 31Slide20
Oncotype: Prognostic and Predictive!Slide21
Foundation One - reportingSlide22
Limitations of enrollmentSlide23
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 REMAINSSlide24
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
nonheritableSlide25
-
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 CancerSlide26
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 drawSlide30
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:
negativeSlide31
Current 23andMe Kits:
$199 dollars
Tests for:
>35 carrier traits
>19 appearance traits
3 ancestry reports
4 wellness reports
www.23andme.comSlide32
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 diseasesSlide33
Thank You!