1. Precision Medicine and Evolving Indications for Hereditary Cancer Genetics
Robert A. Somer, MD
Head, Medical Oncology and Hematology
Director, Office of Clinical Research
MD Anderson Cancer Center- Cooper

2. 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

3. 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.”

4. Human genome contains 20,000 to 25,000 genes
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
Graphic generated with data obtained from
&

5. Hallmarks of Cancer: Therapeutic Precision
Therapeutic Targeting of the Hallmarks of Cancer
Drugs that interfere with each of the acquired capabilities necessary for tumor growth and progression have been developed and are in clinical trials or in some cases approved for clinical use in treating certain forms of
human cancer. Additionally, the investigational drugs are being developed to target each of the enabling characteristics and emerging hallmarks depicted in Figure 3, which also hold promise as cancer therapeutics. The drugs
listed are but illustrative examples; there is a deep pipeline of candidate drugs with different molecular targets and modes of action in development for most of these hallmarks.
Cell  , DOI: ( /j.cell )

6. 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

7. Common Cancers Now Collections of Rare Cancers
Catherine B. Meador et al. Clin Cancer Res 2014;20:

8. Timeline of Selected Major Discoveries in Lung Cancer Treatment
Timeline of selected major discoveries in lung cancer in recent years (above the arrow) and related clinical trials (below the arrow).
Katerina Politi, and Roy S. Herbst Clin Cancer Res 2015;21:

10. Precision Medicine: The BRAF Story
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.
Precision medicine is bringing better care, but bigger challenges than we ever anticipated -- as we see here with rapid success and then rapid resistance with melanoma immunotherapies
Need to deepen understanding of tumor heterogeneity, treatment resistance, and better pinpoint the most important cancer-driving mutations
Need to refine our treatment approaches - identify combinations of targeted therapies that more comprehensively fight cancer and prevent development of treatment resistance
We also have a long way to go still with many other common cancers – brain, pancreatic and bladder – where success has been slower
Health IT technologies – including rapid-learning tools like ASCO’s CancerLinQ – can help us tackle some of these challenges, and help clinicians keep up with the rapidly evolving science.
Wagle, N et al. Dissecting Therapeutic Resistance to RAF Inhibition in Melanoma by Tumor Genomic Profiling. JCO August 1, 2011 vol. 29 no

11. Rapid Response Assessment
Normal
Heart
Resistant
GIST
Baseline:
GIST resistant
to Imatinib
After 1 week
of Sunitinib
Therapy
After 2 months of Sunitinib Therapy

12. Tumor Evolution and Mutation Burden
Puente, Nat. Genet., 2013; B. Vogelstein, Science. 2013

13. Rise of Immunotherapy
Long-term disease control against recalcitrant cancers
Game-changing discoveries – more coming
2011
2014
Ipilimumab introduced for melanoma
Pembrolizumab, nivolumab approved for melanoma
PD-1/L-1 drugs benefit even more of cancers
Until 2011, immunotherapy was seen as unreliable, often with extreme toxicity for patients. But we’ve seen a paradigm shift in recent years.
Now, immunotherapy is quickly becoming a core component of care for a growing number of cancers
2011: Ipilimumab becomes the first treatment to improve melanoma survival – and the first glimpse of immunotherapy’s promise
2014: First PD-1 inhibitors approved for melanoma; lung cancer approvals soon after 
: We are seeing continued breakthroughs in historically resistant cancers with PD-1 and PD-L1 drugs – alone and in combination
Lung cancer – survival gains of a year or more, often with less toxicity than existing treatments
Early signs of success in other cancer trials – kidney, bladder, head/neck cancers and Hodgkin lymphoma

14. Rise of Immunotherapy CART-cell therapy Customized vaccines
Just this past year, we’ve seen exciting promise in other immunotherapy strategies
CART-cell therapy - Last year, one study showed 27/30 heavily pre-treated adults and pediatric ALL patients achieved complete remissions (Maude SL et al. N Engl J Med 2014; 371: )
Cancer vaccines:
Phase II study of rindopepimut extended survival by several months in glioblastoma with EGFRvIII, which occurs in 25% of these cancers but not in healthy cells; a phase III trial is underway (Reardon DA, et al: ReACT: Overall survival from a randomized phase II study of rindopepimut (CDX-110) plus bevacizumab in relapsed glioblastoma. J Clin Oncol 33, 2015 (suppl; abstr 2009))
Cancer vaccines are also being explored as treatments for a range of other cancers including breast, lung, bladder, cervical, kidney, pancreatic, prostate, and blood cancers.
Key challenge: Determining who benefits from these new, costly treatments and treatment combinations

15. New Clinical Trial Designs
Herbst et al. Clin Cancer Res 2015;21: ; JAMA Oncology Dec 2016

16. Molecular profiling in triple negative breast cancer – Parsons et al
Molecular profiling in triple negative breast cancer – Parsons et al. Clinical Cancer Research 2016

17. Breast Cancer: Not all ER Positive Cancers are the Same!
245 DCIS in population-based study:
Molecular subtype persists before and after therapy and in metastases:
Subtype
N (%)
Basal-like
19 (8%)
Luminal A
149 (61%)
Luminal B
23 (9%)
HER2+/ER-
38 (16%)
Unclass.
16 (6%) * *
Vincent-Salomon CCR 2008;
Livasy, Human Pathol 2007
4 studies find basal-like present but uncommon in DCIS (5-10%) *
Weigelt et al., Cancer Res, 2005

18. Subtypes and Prognosis
Prognosis of the types varied. Useful to use proxies- with IHC stains.
In the next slide I will show you natural history of breast cancer. Point out that it is highly likely that only a subtype of breast cancer is shown– slower growing versus rapidly fatal-
May have missed them in our thinking- but useful to illustrate the point.
Sorlie T et al, PNAS 2001

19. Oncotype DX 21 Gene Recurrence Score (RS) Assay
16 Cancer and 5 Reference Genes From 3 Studies
PROLIFERATION
Ki-67
STK15
Survivin
Cyclin B1
MYBL2
ESTROGEN ER PR
Bcl2
SCUBE2
Category
RS (0 – 100)
Low risk
RS < 18
Int risk
RS ≥ 18 and < 31
High risk
RS ≥ 31
GSTM1
BAG1
INVASION
Stromolysin 3
Cathepsin L2
CD68
REFERENCE
Beta-actin
GAPDH
RPLPO
GUS
TFRC
HER2
GRB7

20. Oncotype: Prognostic and Predictive!

21. Foundation One - reporting

22. Limitations of enrollment

23. 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% tumors
Enrollment on trials based on results small
BUT – MUCH EXCITEMENT REMAINS

24. 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

25. The Etiology of Cancer -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

26. 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)

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

28. 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)

29. 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

30. PALB2: breast, pancreas, ?ovarian, ?male breast cancers
Genetic testing 2015
32 gene panel : PALB2+
PALB2: breast, pancreas, ?ovarian, ?male breast cancers
BL Breast
@42 & 55 67 70 64 72 65
Single site testing:
PALB2+
Breast
@60
adopted 45 43
(triple negative)
s/p BL mastectomy
Genetic testing 2006 2 2
BRCA1/BRCA2: negative
Maternal Ancestry: European, non-Jewish 3

31. Current 23andMe Kits: $199 dollars Tests for: >35 carrier traits
>19 appearance traits
3 ancestry reports
4 wellness reports

32. Role of the health care provider in cancer genetics
Understand genetic complexity of cancer and implications in terms of treatment
Identify patterns in families or individuals
Increased awareness of genetic predispositions of malignancy
Encourage screening of high-risk populations
Maintain finger on pulse of advances, not just for cancer, but for all diseases

33. Thank You!