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Targeted Therapies and Personalized Medicine for Gynecologic Cancers
- 1. Noelle Gillette Cloven MD Gynecologic Oncologist Texas Oncology
- 2. A Tale of Two Women
- 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
- 5. “Achilles heel” to HEAL
- 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)
- 7. The long journey of targeted drug development
- 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 Bevacizumab angiogenesis inhibitor first approved for colon cancer 2004 FDA approval for breast cancer withdrawn effective in drug resistant cancers unique side effect profile
- 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