This document discusses personalized medicine and targeted therapies for gynecologic cancers. It describes how molecular profiling identifies specific mutations that can be targeted with FDA-approved drugs like bevacizumab and olaparib. Ongoing clinical trials are exploring new targeted therapies and combinations of targeted drugs with immunotherapy. Challenges to personalized medicine include availability of genetic testing and targeted therapies as well as tumor heterogeneity. The document encourages patients to consider molecular profiling and enrollment in clinical trials to access targeted treatment options.
3. What is personalized
medicine?
treatment tailored to
unique characteristics of
an individual person
every patient has a
unique set a factors that
cause their cancer to
grow
“molecular profiling” is
used to identify specific
treatment targets
6. Vulnerabilities of cancer
identified mutations
unique to cancer
(oncogenes, suppressor
genes)
cancer cells resist normal
death signals
cancer cells recruit blood
vessels for growth
(changes in
“microenvironment)
8. FDA approved for
gynecologic cancer
Bevacizumab ( Avastin) : an antibody that disrupts
abnormal blood vessel formation by tumors. Affects
“tumor microenvironment”. Approved for ovarian,
fallopian tube, peritoneal and cervical cancer.
Olaparib ( Lynparza): prevents repair of damaged
DNA that is prevalent in tumor cells. Most effective in
patients who have BRCA mutation.
9. Bevacizumab
angiogenesis inhibitor
first approved for colon
cancer 2004
FDA approval for breast
cancer withdrawn
effective in drug resistant
cancers
unique side effect profile
10.
11. FDA approved for other
cancers (some)
Bortezomib (Velcade) multiple myeloma
Cabozantanib renal and thyroid cancer
Cetuximab (Erbitux)head and neck, colon
Erlotinib ( Tarceva) lung, pancreatic
Gefitinib ( Iressa) lung
Imatinib ( Gleevec) CML, GIST
Lapatinib( Tykerb) breast cancer/HER2+
Nivolumab ( Opdivo)Hodgkins, melanoma, lung
Pazopanib(Votrient) renal, sarcoma
Trastuzamab(Herceptin) breast cancer, gastric
12. genetic profiling
no more carpet bombing
treatment based on
specific mutations rather
than cancer site
14. clinical trials
NCI-MATCH trial
5000 patients with a
variety of cancers
DNA sequencing
“actionable” mutations=
targeted drug exists
24 treatment arms
15. Immunotherapy
our immune system uses
“checkpoints” (PD1, PD-L1)
to identify cells as foreign
cancer cells use
checkpoints to evade
attack by the immune
system
antibodies against
checkpoint inhibitors
boost immune response to
cancer
16. In reach right now
treatment with FDA targeted approved therapies
Phase III study of Carboplatin/Paclitaxel +/- Veliparib
( PARP) for newly diagnosed ovarian cancer
Phase II study of Niraparib ( PARP) for recurrent
ovarian cancer
Phase I study of BBI608(targets cancer stem cells) for
advanced malignancies
Phase III study of Avelumab (checkpoint inhibitor)+/-
Doxil ( Javelin 200) for recurrent drug resistant ovarian
cancer
17. on going clinical trials
activity of new targeted therapies for gynecologic
cancer
combining targeted therapy with standard treatment
PARP, immunotherapy, (checkpoint inhibitors)
Timing of targeted therapy. Is maintenance therapy
helpful? What about for recurrent cancer?
18. new clinical trial design
established molecular heterogeneity of cancer
requires use of new clinical trial designs
treating large, unstratified patient populations with
regimens that have toxicity and no benefit is no longer
necessary and not economically sustainable
important to test tissue for mutations and markers
that will predict response to treatment
new endpoints to determine activity of treatment
19. challenges to personalized
medicine
availability of reliable genetic diagnostic
tests/companion diagnostics
tumor heterogeneity
availability of targeted therapies
insurance coverage of genetic testing
education and dissemination in the community
20. what does this mean for
me?
ask questions, lot’s of them!
consider molecular profiling
consider clinical trials
21. where do I find more information?
https://clinicaltrials.gov/ct2/help/how-find/basic
http://www.cancer.org/research/acsresearchupdates/
more/personalized-medicine-redefining-cancer-and-
its-treatment
http://www.cancer.gov/research/key-
initiatives/moonshot-cancer-initiative
Trialfinder.usoncology.com (download the App)
Editor's Notes
On February 16, 2013, at age 37, Jolie underwent a preventive double mastectomy after learning she had an 87% risk of developing breast cancer due to a defective BRCA1 gene.[201] Her maternal family history warranted genetic testing for BRCA mutations: her mother, actress Marcheline Bertrand, had breast cancer and died from ovarian cancer, while her grandmother died from ovarian cancer.[202][203] Her aunt, who had the same BRCA1 defect, died from breast cancer three months after Jolie's operation.[204] Following the mastectomy, which lowered her chances of developing breast cancer to under 5 percent, Jolie had reconstructive surgery involving implants and allografts.[202] Two years later, in March 2015, after annual test results indicated possible signs of early ovarian cancer, she underwent a preventive oophorectomy, as she had a 50% risk of developing ovarian cancer due to the same genetic anomaly. Despite hormone replacement therapy, the surgery brought on premature menopause.[203]
"I choose not to keep my story private because there are many women who do not know that they might be living under the shadow of cancer. It is my hope that they, too, will be able to get gene tested, and that if they have a high risk they, too, will know that they have strong options."
—Jolie on her reasons for speaking out about her mastectomy[201]
After completing each operation, Jolie discussed her mastectomy and oophorectomy in op-eds published by The New York Times, with the aim of helping other women make informed health choices. She detailed her diagnosis, surgeries, and personal experiences, and described her decision to undergo preventive surgery as a proactive measure for the sake of her six children.[201][203][205] Jolie further wrote, "On a personal note, I do not feel any less of a woman. I feel empowered that I made a strong choice that in no way diminishes my femininity."[201]
Jolie's announcement of her mastectomy attracted widespread publicity and discussion on BRCA mutations and genetic testing.[206] Her decision was met with praise from various public figures,[207] while health campaigners welcomed her raising awareness of the options available to at-risk women.[208] Dubbed "The Angelina Effect" by a Time cover story,[209] Jolie's influence led to a "global and long-lasting" increase in BRCA gene testing:[210] the number of referrals tripled in Australia and doubled in the UK, parts of Canada, and India,[210][211][212] as well as significantly increased in other European countries and the U.S.[213][214][215] Researchers in Canada and the UK found that despite the large increase, the percentage of mutation carriers remained the same, meaning Jolie's message had reached those most at risk.[210] In her first op-ed, Jolie had advocated wider accessibility of BRCA gene testing and acknowledged the high costs,[216] which were greatly reduced after the U.S. Supreme Court, in a June 2013 ruling, invalidated BRCA gene patents held by Myriad Genetics.[217][218]
typically, doctors use surgery, chemotherapy and radiation to treat cancer cells and this affects normal cells in a sweeping blanket approach of cell killing. The hope for personalized medicine is that treatment can better target the unique abnormalities found in cancer cells and have less effects on normal cells
targeted therapy, also called biologic therapy attacks specific molecular targets, genes or enzymes, hopefully with less affects on normal cells. Also called precision medicine
standard chemotherapy is cytotoxic/cell killing while targeted therapy is often cytostatic/keeps cells from growing
If you recall from greek mythology, The legend that achilles was dipped into the river Styx held by the tendon of his heel and everyother part of his boby that touched the water was made impervious to harm. It was a single arrow during the battle of Troy that killed him
The goal of personalized medicine is to exploit the vulnerabilities of cancer cells, to find whats different in cancer cells compared to normal cells
MAB is a monoclonal antibody
ib is small molecule with inhibitory properties
examples Ketruda, Opdivo
unique mechanism is showing promise in many types of cancer
A number of studies under development including Nivolumab for advanced malinancies ( will include cervix, vaginal, endometrial and rare women’s cancers)
chemotherapy plus atezolizumab for newly dx ovarian cancer ( checkpoint inhibitor)
there are thousands of drugs that have been developed for targeted medicine
