Randal West MD Ovarian cancer standard of care Surgery or neoadjuvant chemotherapy then surgery Chemotherapy Carboplatin Taxane 70 will recur and be retreated Nearly all of those will die of disease ID: 719301
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Slide1
Precision Medicine in the management of gynecologic cancers
Randal West, MDSlide2
Ovarian cancer standard of care
Surgery or neoadjuvant chemotherapy then surgery
Chemotherapy
Carboplatin
Taxane
70% will recur and be re-treated
Nearly all of those will die of diseaseSlide3
Standard of care for endometrial cancer
Minimally invasive total hysterectomy-
salpingo
-oophorectomy
Sentinel node resection
Lymphadenectomy if high grade
Radiation for local control
Chemotherapy and/or hormonal therapy for metastatic disease
98% with low grade disease will be cured
85% with local disease will be cured
Most with recurrent or advanced disease will die of diseaseSlide4
Standard of care for cervical cancer
Minimally invasive radical hysterectomy for stage I-
IIa
disease
Chemo/radiation for locally advanced disease
Chemotherapy for metastatic disease
85% with early stage disease will be cured
50% of those with locally advanced disease will be cured
None of those with recurrent metastatic disease will be curedSlide5
Precision medicine
The right therapy
The right time
The right patient
Elucidation and strategic intervention of the molecular framework of cancer will illuminate and introduce novel approaches to cancer careSlide6
Histopathologic classification of tumors
Ovarian cancer
Type I – low grade serous,
endometrioid
, mucinous and clear cell
Genomic level – higher mutations in oncogenic driver genes as KRAS and BRAF
Type II – high grade serous
Endometrial cancer
Type I – hormone driven
endometrioid
cancers
Type II – higher grade, non-hormone dependent, serous, clear cell
Higher level oncogenic driver genesSlide7
Standard of care
Despite the usefulness of these classifications, the standard of care for treatment of these diseases is based on morphological/histological subtype, tumor stage, and tumor grade with few effective standard options for refractory or recurrent disease
We need to look at cancer from a different standpoint Slide8
New paradigm
Investigate putative “actionable” molecular alterations
Determine feasibility and impact of point-of-care at those molecular alterations
Base on tumor genomic profile
The Cancer Genomic Atlas ProjectSlide9
Ovarian, tubal and peritoneal cancers
Hereditary breast and ovarian cancer genetic abnormalities
BRCA 1&2
RAD51C
RAD51D
BRIP1
PALB2
BARD1
MMR genesSlide10
BRCA 1 &2
BRCA1 - chromosome 17q21
BRCA2 – chromosome 13q12.3
High frequency in Ashkenazi Jewish
Testing $1000- 3000
Refer to genetic counselorSlide11
Risk reducing options
Surveillance
Every 6 month CA125 and pelvic ultrasound
Risk of ovarian cancer algorithm (ROCA)
Chemoprevention
Combined oral contraception
No increase in breast cancer risk
Risk reducing
salpingo
-oophorectomy -age 35
Lowers worry of cancer
Decreases sexual health
Early cancer found in 3-8%
Serous tubal intraepithelial carcinomas – just remove tubes?Slide12
Endometrial cancers
Lynch syndrome
Mutations in DNA mismatch repair genes
MLH1 - 20-54% risk of endometrial ca by cancer age 70
MSH2 - 21-49% risk
MSH6 - 16-71% risk
PSM2 - 15 % risk
Also at risk for ovarian cancer in the 4-20% range
Cowden syndrome
Germline mutation in the phosphatase and
tensin
gene (PTEN)
19-28% chance of endometrial cancer by age 70Slide13
Lynch associated cancer risks
Endometrial - 15 -71%
Colon cancer - 15-68%
Ovarian cancer - 2-24%
Upper urologic – 0.4-9%
Gastric – 2-6%
Small bowel – 6%
Biliary/pancreatic – 4%
Brain tumors - 1.7-2.5%Slide14
Bethesda criteria for genetics referral
Endometrial or colorectal cancer before age 50
Endometrial or ovarian cancer with synchronous or
metachronous
colon or other Lynch/HNPCC tumor at any age
Colorectal cancer with tumor-infiltrating lymphocytes,
peri-tumoral
lymphocytes or medullary growth pattern before age 60
Endometrial or colorectal cancer and a first-degree relative with a Lynch/HNPCC tumor before age 50
Endometrial or colorectal cancer at any age with two first or second-degree relatives with Lynch/HNPCC tumor at any ageSlide15
Additional referral criteria for endometrial cancer
Endometrial cancer showing mismatch repair deficiency on tumor screening
Endometrial cancer and 2 additional cases of Lynch Syndrome-associated cancer in same person or close relatives
Endometrial cancer and two additional Cowden syndrome criteria in the same patientSlide16
Exploration and implementation of
new treatment
optionsSlide17
Molecular characterization of tumors
Tumor microenvironment
Leading area of research in cancer medicine
Leveraging these molecular data to therapeutic targets
Early success in biomarker-driven therapies
Imatinib
–
bcr-abl
chronic myelogenous leukemia
Erlotinib
– EGFR mutant lung cancerSlide18
Role in gyn cancers
Complexity of advanced and recurrent cancer makes tumor succumbing to single agent therapy unlikely
Therefore, understanding the robustness and intricate signaling networks driving tumorigenesis and resistance is paramount
The Cancer Genome Atlas
Ovarian
Endometrial
Cervical Slide19
Poly-adp-ribose polymerase (
parp
) inhibition
PARP needed for single-strand DNA repair
When not repaired, cell is more dependent on double-strand repair mechanisms – Homologous Recombination
Leads to the potential for increased toxicity to PARP inhibitors in cells deficient in HR Slide20
Homologous recombination deficient tumors
Cells deficient in BRCA2
BRCA deficient tumors
Ovarian cancer
Olaparib
33% response
Maintenance therapy significantly prolonged disease free survival Slide21
Parp inhibitors
BRCA tumors
Reponses in non- BRCA ovarian cancers -
niraparib
PTEN deficient cells
Endometrial cancers commonly have PTEN deletions
Ongoing trialsSlide22
Anti-angiogenic agents
Oxygen supplied by vasculature is crucial for normal cell function
Cells typically reside within 100 micrometers of a capillary
T
umors recruit vasculature by releasing various growth factors
Vascular endothelial growth factor (VEGF)
Fibroblast growth factor (FGF)
Placental growth factor(PGF) Slide23
Bevacizumab (avastin)
Inhibition of human tumor xenograft growth by a monoclonal antibody specific to VEGF
Efficacy in
colo
-rectal, lung, breast and renal cancers
In ovarian cancers has increased disease free survival, but not overall survival
Used in maintenance therapy
Improved responses in advanced endometrial cancers
Improved responses in advanced cervical cancersSlide24
Resistance and escape mechanisms
Alternatives to angiogenesis for neovascularization
Acute hypoxia
Implicated in the promotion of tumor progression and resistance to therapy
Recruitment of marrow-derived cell
Monocytes and macrophages- fuel tumors by eliciting new vessels
Endothelial progenitors – differentiate into endothelial cells that line vessels
Pericyte
coverage
Tumor vessels lacing coverage are more susceptible to VEGF inhibitorsSlide25
Signaling pathway abnormalities
Key in tumorigenesis
Impacts cell survival
Growth
Avoidance of apoptosisSlide26
Targeted nodes
mTORC1
AKT
PI3K
There have been few objective responses when these single site nodes have been targeted Slide27
Phosphoinositide 3-kinase (PI3K)pathway
Importance in ovarian cancer
Mechanism of resistance to paclitaxel and carboplatin
PI3K amplification
PTEN loss
XL147
PI3K inhibitor
Preliminary results show well tolerated and tumor regression
Higher levels of PI3K and PTEN loss in less common cancers – low grade serous, clear cell and
endometrioid
Slide28
Retrovirus-associated dna
sequences (RAS)/v-
raf
1 murine leukemia viral oncogene homolog 1 (
raf
) pathway
Roles
Cellular survival
Proliferation
Motility
Avoidance of apoptosis
BRAF mutations render tumors highly sensitive to MEK (mitogen-activated kinase enzyme) inhibition – colon ca and melanoma
Low grade serous cancers and mucinous ovarian cancers have highest
Ras
/
Raf
pathway aberrations – BRAF and KRAS
Mucinous not yet tested (rare)
Low grade serous with 65% showing stable disease with MEK inhibitor
Endometrial cancer with high KRAS mutationsSlide29
Promising Futures
P53 most prevalent molecular aberration
Thought “
undruggable
”
Wee 1 inhibitor acts on key G2 cell cycle checkpoint which is essential for DNA damage repair among tumors with dysfunctional p53
Li-
Fraumeni
syndrome – endometrial, sarcoma, breast, adrenal, lung
Combination targeted therapy
PI3K/MEK
PARP/anti-angiogenic
PARP/PI3K
PARP/Immunotherapy
Immunotherapy Slide30
Immunotherapy
Epithelial ovarian cancer has not been traditionally considered amenable to immunotherapy
Presence of tumor-infiltrating lymphocytes (TILs) has emerged as an important biomarker in ovarian cancer
Increased TILs predict longer survival
Tumor reactive antibodies
T cellsSlide31
Immunotherapeutic strategies
Direct targeting with tumor specific antibodies
Modalities to enhance antigen presentation (vaccines)
Activation of tumor specific T cellsSlide32
Targeting with tumor specific antibodies
CA 125
Oregovomab
targets
Early studies show anti-CA-125 T cell responses
EpCAM
- epithelial cell adhesion molecule
Associated with worse prognosis in ovarian cancer
Catumaxomab
is antibody recognizing
EpCAM
and T cell antigen CD3
FRa
– folate receptor alpha
Farletuzumab
– anti-
FRa
Mixed resultsSlide33
vaccines
Majority of studies demonstrated evidence of cellular and antibody response to the antigens
Clinical benefit has unfortunately been marginal at best
Not sufficient to overcome T cell tolerance Slide34
Vaccines and immune checkpoint blockades – on the horizon
Toll like receptor agonists
Proteins playing a role in innate immune response to tumor antigens
Motolimod
and
Doxil
trial ongoing
Type 1 IFN
Innate immune response cytokine
Oncolytic viruses
Responses rare
Stable, durable diseaseSlide35
Activation of tumor-specific T cells
Cytokines
IL2 – T cell growth factor
Potent activator of T cell lymphocytes and NK cells
Response rate of 25% in phase 1-2 study
Immune checkpoint blockade
Targets T cell receptors
Nivolumab
showed 15% response and 45% stable disease in ovarian cancer
Adoptive T cell therapies
Aim to overcome the immunosuppressive effect of tumor micro-environment
Studies underway to target ovarian cancer antigens Slide36
Other immunotherapies on the horizon
Antibodies targeting co-stimulatory receptors
Studies are underway looking at antibodies that target T cell co-stimulatory and co-regulatory receptors
Targeting mechanisms of immunotherapy resistanceSlide37
Immunotherapy in endometrial cancer
20-30% of endometrial cancers have high microsatellite instability (MIS-H)
Due to defects in components of DNA mismatch repair pathway
Pembrolizumab
(an anti-PD-1 antibody) demonstrated 40-70% response rates in MIS-H colorectal and non-colorectal cohorts Slide38
Therapeutic vaccines for cervical cancer
Prophylactic vaccines need only to block viral entry into the cell
Therapeutic vaccines must target integrated HPV virus that has become intracellular and has a non lytic cycle
Targets HPV E6 and E7 proteins
Vaccinia vaccines
Injected directly into the dysplastic areas of cervix, vulva, urethra, anus
89.3% complete elimination of the lesion
83% had undetectable HPVSlide39
conclusions
Past standard of care options based on morphological/histological criteria have been inadequate for refractory or recurrent disease
Hereditary cancers are at the heart of the precision medicine movement
Identified those eligible for life-saving prevention
Aided in understanding tumor biology, biomarkers and therapy targets
Rapid advances in molecular discovery will allow greater discovery bio-marker targeted therapies
BRCA1/2 mutation as response to PARP inhibitors is a marked advance