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A Personalized Approach to Ovarian Cancer: One Size No Longer Fits All
Amanda Nickles Fader, MD Associate Professor and Director, The Kelly Gynecologic Oncology Service Johns Hopkins Medicine
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Disclosures/Interests
I have no financial relationships to disclose I have a strong clinical and research interest in rare gynecologic cancers and in developing screening tests for ovarian cancer Direct the Center for Rare Gynecologic Cancers at Johns Hopkins and Co-Direct the Ovarian Cancer Center of Excellence A member of the Rare Tumor Committee, NRG/Gynecologic Oncology Group
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Disclosures “It is only about things that do not interest one that one can give really unbiased opinions, which is no doubt the reason why an unbiased opinion is always valueless.” -Oscar Wilde
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One of my First Patients: Erin
Optimal Debulking Surgery Stage III, low-grade serous carcinoma A chemo regimen that included carbo/doxil/avastin No evidence of disease x 9 years
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Johns Hopkins Center for Rare Gynecologic Cancers
Emphasizes personalized, patient-cented care for women with low-grade serous ovarian carcinoma, clear cell and mucinous tumors of the ovary, germ cell (ie, dysgerminoma, immature teratoma etc) and sex cord stromal tumors of the ovary (ie, granulosa cell tumors)
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Objectives To review the environmental, molecular and genetic differences in the epithelial ovarian cancer subtypes To define personalized medicine and how it relates to ovarian cancer care To understand the evidence supporting best treatment strategies for women with rare epithelial ovarian tumors
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Ovarian Cancer Ovarian cancer diagnosed in approximately 23,000 women annually in the United States Nearly 90% of ovarian malignancies are epithelial ovarian tumors
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Epithelial Subtypes Serous carcinomas Clear Cell: 11%
75% of all epithelial ovarian cancer High-grade (65%) and low-grade serous (10%) Clear Cell: 11% Endometrioid: 11% Mucinous: 3% Malpica et al, Am J Pathol 2007; Vang et al, Am J Surg Path, 2008 Although several studies have shown that histologic grade is an important prognostic factor in serous carcinoma of the ovary, no universal grading system has been accepted
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Is Ovarian Cancer A Single Entity?
Historically, women w/ epithelial ovarian cancer treated similarly and “lumped” in the same surgery and chemo treatment trials, irrespective of their tumor subtype Differences in genetic profiles, tumor biology and treatment responses among women with different tumor types were discovered, with a distinction emerging between tumor types To Lump or Split?
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Tumor Grade The description of a tumor based on how abnormal the tumor cells and the tumor tissue look under a microscope An indicator of how quickly a tumor is likely to grow and spread Low grade or high grade Low grade High grade
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What Are Genetic Mutations?
DNA-our genetic makeup Made up of chromosomes which include many genes Gene mutation: a permanent change in DNA sequence that makes up a gene, such that the sequence differs from what is found in most people Mutations range in size; can affect anywhere from a single DNA building block to a large segment of a chromosome with multiple genes
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Different Types of Genetic Mutations
Hereditary mutations: inherited from a parent; are present throughout a person’s life in every cell in the body Are germline mutations: are present in the parent’s egg or sperm cells, also called germ cells Acquired (somatic) mutations occur at some time during a person’s life; are present only in certain cells Caused by environmental factors or can occur if a mistake is made as DNA copies itself during cell division Acquired mutations in somatic cells (cells other than sperm and egg cells) cannot be passed on to the next generation
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Epithelial Ovarian Cancer
Epithelial ovarian cancer (EOC) is not one, but several, distinct entities More than one disease Advances in the understanding of ovarian malignancies Refining pathologic diagnostic criteria Molecular biology and genetics Over the past decade, it has become increasingly clear that ovarian cancer is not one but several distinct entities. Even today, the vast majority of ovarian cancer clinical trials include women with all histologic subtypes. Such is true in trials for both front-line and recurrent treatment. However, advances in our understanding of the heterogeneity of ovarian cancer have emerged on the basis of refinement of pathologic diagnostic criteria, molecular biology and genetic investigations, Jemal, Cancer Stats. 2014
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Epithelial Ovarian Cancer Differences
Type I Type II Lower grade, slower tumor growth Genetic mutations—PTEN, KRAS, BRAF, Src etc Younger women, sometimes earlier stage Higher grade, faster tumor growth Genetic mutations in P53 Middle age or older women, more advanced stage T
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One Size Doesn’t Fit All
Most medical treatments are designed for the “average patient ” as a “one-size-fits-all-approach,” that is successful for some patients but not for others Precision medicine: an innovative approach to disease prevention and treatment that takes into account differences in people’s genes, environments and lifestyles President Obama’s Precision Medicine Initiative
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Precision Medicine Tailoring of medical treatment to the individual characteristics of each patient The ability to classify individuals into subpopulations that differ in their susceptibility to a particular disease, in the biology and/or prognosis of those diseases they may develop, or in response to a specific treatment Preventive interventions or therapies can then be concentrated on those who will benefit, sparing expense and side effects for those who will not
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Precision Medicine An emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment, and lifestyle for each person While some advances in precision medicine have been made, the practice is not currently in use for most diseases We must gain better insights into the biological, environmental, and behavioral influences on these diseases to make a difference for the millions of Americans who ar e diagnosed with chronic illness Far too many diseases do not have a proven means of prevention or effective treatments.
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Precision Medicine Initiative
On January 20, 2015, President Obama announced the Precision Medicine Initiative® The President called for $215 million in 2016 to support the Initiative, which includes several components with efforts from across the federal government
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Precision Medicine in Cancer
How molecular or genetic information about a person’s disease is being used to diagnose or treat their disease Cancer is a disease of the genome (ie, results from genetic mutations) As more is learned about cancerous tumors, the more we are finding that each tumor has its own set of molecular and genetic changes Understanding these changes in cancer cells is leading to more effective treatment strategies that are tailored to the genetic profile of each patient’s cancer
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Cancer Genomics Aims to advance personalized medicine through the DNA sequencing and analysis of patient tumors to find new genetic alterations associated with specific cancers Providing researchers with comprehensive catalogs of the key genomic changes in many major types and subtypes of cancer will support advances in developing more effective ways to diagnose, treat and prevent cancer
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Molecular/Genomic Profiling of Tumors
A wide variety of testing platforms performed in CLIA-certified labs PCR, next generation sequencing, massive parallel sequencing, FISH etc.
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A Developing Industry
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Profiling Report
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Examples of Precision Medicine
Breast cancer drug trastuzumab (Herceptin), a monoclonal antibody which works only for women whose tumors have a particular genetic profile called HER-2 positive Breast cancer drugs tamoxifen and aromatase inhibitors—work well to prevent cancer recurrence in women w/ Estrogen (hormone) positive breast cancers Ovarian cancer drugs olaparib, niraparib etc, PARP inhibitors, FDA approved for women w/ BRCA1/2 mutations and recurrent ovarian cancer Genomic information has already helped to shape the development and use of some of the newest cancer treatments
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The Dilemma We have knowledge of far more genetic mutations than we have treatments for “Actionable” gene mutations or protein expression—those mutations or proteins that we have potential targeted treatments for
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Examples of Precision Medicine in Ovarian Cancer Screening
An important development is the recognition that all human cancers result from mutations in a limited set of genes and an even more limited set of pathways through which these genes act
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The Pap Smear Story Has revolutionized cancer screening
Prior to the introduction of the Pap smear in the 1940s, cervical cancer was one of the leading causes of cancer death in women Reduced cancer incidence and death rates by 80% in U.S.
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Pap Smear and DNA Testing
Permits the detection of early, surgically curable tumors and or precancers Traditional Pap smear replaced by a liquid-based method, which allows not only cytologic evaluation but also collection of DNA for detection of human papillomavirus (HPV), the causative agent of cervical cancer
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Pap Smear..the Old Becomes New?
Georgios Papanicolaou published his seminal work, entitled Diagnosis of Uterine Cancer by the Vaginal Smear, in 1943 Suggested that cervical sampling could in theory be used to detect not only cervical cancers but also other cancers arising in the female reproductive tract, including uterine and ovarian cancers
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Advances in Ovarian Cancer Screening
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Circulating Tumor DNA
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Study Methods DNA from Pap smears was purified and areas from the following 18 genes were investigated: AKT1, APC, BRAF, CDKN2A, CTNNB1, EGFFBXW7, FGFR2, KRAS, MAPK1, NRAS, PIK3CA, PIK3R1, POLE, PPP2R1A, PTEN, RNF43, and TP53 DNA from plasma (blood) was purified and the following 16 genes were queried: AKT1, APC, BRAF, CDKN2A, CTNNB1, EGFR, FBXW7, FGFR2, GNAS, HRAS, KRAS, NRAS, PIK3CA, PPP2R1A, PTEN, and TP53 A Pap smear or plasma specimen was considered "positive" if it harbored at least one driver mutation found in the primary tumor of the same patient
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Results >200 patients with ovarian cancer enrolled Stage I = 40%
Stage II-IV = 60% Pap smears were positive in 47% for a tumor driver mutation Ovarian N=108 47% Stage I and II 31 68% Stage III and IV 48 38% Unknown 4 0%
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Ovarian Pap Gene & Circulating Tumor DNA Results
When the plasma (blood) DNA results were added, this increased the ovarian cancer detection rate to 65% Papadopoulos N, Fader et al, Sci Transl Med, 2018
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Precision Medicine in Ovarian Cancer?
Pioneering studies in GYN Oncology with an emphasis on rare tumors NRG/Gynecologic Oncology Group Rare Tumor Group MD Anderson & Johns Hopkins Research Groups
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Evolution of Clinical Trials in Rare Ovarian Cancers
Development of the binary grading system for serous carcinoma and establishment of the GOG Rare Tumor Committee in 2005 Led to recognition of this histologic subtype Dawn of separate clinical trials for women diagnosed with this rare malignancy Principle of separate clinical trials for major rare histologic subtypes of ovarian cancer subsequently validated in two consensus confereneces Clear cell carcinoma, mucinous carcinoma, and LGSC Stuart GCE, In J Gynecol Oncol, 2011
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Standard treatment for epithelail ovarian cancer: NCCN
Debulking surgery Carbo/taxol or cisplatin/taxol therapy, either IV or IV/IP
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Clear Cell and Mucinous Tumors
Protein/Gene expression +Vascular endothelial growth factor MET & AKT gene amplification +KRAS overexpression; + HER2 Mutations ARID1A, loss of heterozygosity chromosome 3p Treatments Carbo/taxol; carbo/gemcitabine Avastin, Pelvic, radiation CAPOX or Folfox 5-FU, Capcetabine, Avastin
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Rare Epithelial Ovarian Cancer Subtypes
Low-grade serous carcinoma Clear cell carcinoma Mucinous carcinoma Endometrioid carcinoma
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Two-tiered Histologic Criteria
Variable Low grade (Grade 1) High grade (Grade 2/3) Nuclear atypia Uniform round to oval with little variation +++ Marked variation Mitotic Index <12 mitosis per 10 hpf >12 mitoses per 10 hpf Chromatin and variation in size of nucleus Little Marked (nuclear size ratio ≥3) Mutation KRAS ++ BRAF + ER/PR +++ PAX2 + P53 +++ Precursor Serous borderline tumor Tubal intraepithelial neoplasia Low grade Recent studies suggest a two-tiered classification of serous ovarian carcinoma --Low grade (LGSC) versus high grade serous carcinoma (HGSC) More molecularly and clinically relevant staging system Primarily based on nuclear atypia; mitotic rate secondary High grade Malpica et al, Am J Path, 2007
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Map Kinase Pathway The mitogen-activated protein kinase (MAPK) pathway appears to play a prominent role in the pathogenesis of this ovarian subtype. MAP kinases are serine/threonine/tyrosine-specific protein kinases involved in regulate proliferation, gene expression, differentiation, mitosis, cell survival, and apoptosis - among many others the high frequency of mutational alterations in the MAPK pathway found in low-grade serous ovarian cancers, .
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Hormonal Receptors Low-grade serous 2x more likely to express estrogen and progesterone (hormone) receptors than high-grade tumors There is also growing evidence that the distinction between LGSC and HGSC is validated based on molecular and genetic differences observed in the subtypes. Immunohistochemical comparisons between these entities reveal differential tumoral protein expression. Markers such as estrogen and progesterone receptors are more likely expressed in LGSC, whereas Ki67 and p53-mutations, involved in cell proliferation, are significantly more expressed in HGSC (11-13). Furthermore, deleterious BRCA1 and 2 mutations are not frequently observed with LGSC (14, 15), but are observed in as high as 18-47% of women diagnosed with a HGSC of the ovary (15). Lastly, KRAS and BRAF as well as a higher expression of active MAP Kinase are seen with LGSC as well as mucinous carcinoma and endometrioid carcinoma but not in HGSC (22-26) (Table 1). The insulin-like growth factor pathway and downstream effectors, such as phosphatidylinositol 3-kinase (PI3KCA) and AKT, also appear to play an important role in the pathogenesis of low-grade serous ovarian carcinoma, with activating mutations of PIK3CA observed in 40% of tumors, as well as inactivating PTEN mutations (3-8%) and expression of insulin-like growth factor (IGF) receptor.
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Mutations of Low-grade Serous
Driven by activating mutations of: PIK3CA (40%) Inactivating mutations of PTEN (3-8%) Expression of insulin-like growth factor (IGF) receptor Downstream effectors of IGF pathway, including PI3K/AKT/mTOR have well-established roles as mitogens in carcinogenesis Low-grade serous ovarian cancers also appear to be driven by activating mutations of PIK3CA (40%), inactivating mutations of PTEN (3-8%), and expression of insulin-like growth factor receptor, further demonstrating that the PI3K pathway is important in the pathogenesis of low-grade serous ovarian cancer [18, 19]. PIK3CA mutations, like PTEN loss, lead to constitutive activation of PI3K signaling. Further, the insulin-like growth factor (IGF) pathway has emerged as a potential therapeutic target among patients with low-grade serous ovarian cancer. Downstream effectors of the IGF pathway, including PI3K/AKT/mTOR have well-established roles as mitogens in carcinogenesis.
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Epidemiology Low grade serous carcinoma accounts for 10% of all serous ovarian carcinomas 5% of all epithelial ovarian cancers Serous borderline tumor--a precursor lesion to LGSC, which likely originates in the ovary Deleterious BRCA1 and 2 mutations infrequently observed with LGSC, but observed in as high as 18-47% of women diagnosed with HGSC Low-grade serous ovarian cancer is less common and aggressive than the high-grade variety, yet exceptionally difficult to treat when frontline therapy fails Gershenson et al, Gynecol Oncol, 2012 Fader et al, Obstet Gynecol, 2013
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Epidemiology Women w/ LGSC diagnosed at a younger age and have a relatively long overall survival Pooled retrospective data on 5-year survival 40-56% for advanced LGSC versus 9-34% for HGSC LGSC have lower response rates to conventional chemotherapy
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Surgery is the mainstay of therapy!
Without question, surgery is the mainstay in treatment for LGSC, and achieving a maximal cytoreductive effort, when possible, is paramount for women with this disease.
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Survival by Residual Disease After Primary Cytoreductive Surgery: GOG 182
An ancillary analysis of women with stage III-IV epithelial ovarian cancer Treated with primary cytoreductive surgery T/C compared with triplet or sequential doublet regimens 189 had Grade 1 disease (surrogate for low grade) Only residual disease status after primary debulking was independently and significantly associated with survival (p=.006) Studies demonstrate that survival rates improve accordingly when the primary cytoreductive surgical paradigm is aggressive and incorporates radical techniques aimed at achieving microscopic residual disease. Although disease-free survival overall appears to be higher with LGSC than with HGSC, surgical cytoreduction to microscopic residual is critical to achieving this improved survival outcome Fader et al, Obstet Gynecol, 2013
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Survival by Residual Disease After Primary Cytoreductive Surgery: GOG 182
*Grade 1 serous used as a surrogate For low grade N=187 patients P<.001 Fader et al, Obstet Gynecol, 2013
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Neoadjuvant chemotherapy?
Relative chemoresistance also observed in a review of women who received neoadjuvant chemotherapy for advanced stage LGSC 25 patients, median age 45 years Only 4% response rate Half of evaluable patients had a greater than 50% reduction in serum CA 125 levels after chemo--only one patient had an objective response by imaging assessment Schmeler et al, Gynecol Oncol. 2008
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Chemotherapy After Primary Cytoreductive Surgery?
Evidence to date suggests that LGSC relatively resistant to first-line chemotherapy MD Anderson: Review of 112 patients with newly diagnosed stage II-IV LGSC treated with primary surgery and platinum-based chemotherapy Median age 43 Treatment not as successful as expected given high frequency of persistent disease at completion of therapy and low negative second-look rate Only 52% of patients were disease-free after primary surgery and completion of platinum-based chemo Gershenson et al, Gynecol Oncol. 2008
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MEK Inhibition: GOG 239 Selumetinib: potent, selective, orally-available, and non-ATP competitive small molecule inhibitor of mitogen-activated protein (MAP) kinase kinase, MEK-1/2 Primary objectives: Determine response rate of patients and toxicity of selumetinib A landmark Phase II GOG study by Farley et al. demonstrated promising results utilizing Selumetinib, a selective non-ATP competitive small molecule inhibitor of MEK 1/ 2 (an important player in the MAP Kinase pathway) in the setting of recurrent LGSC. It was an efficacious and tolerable oral treatment option for recurrent LGCS (32), with a 15.5% response rate and 65% stable disease rate, for an overall clinical benefit of 80.5%. This is comparable to the response rate observed in a retrospective study of recurrent LGSC treatment with aromatase inhibition Farley et al, Lancet Oncol. 2013
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N=52 patients Farley et al, Lancet Oncol. 2013
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Chemotherapy for Recurrence: Appraisal
Variable Chemo Hormonal Therapy Selumetinib No. Patients 58 64 52 CR (%) 1 7 2 PR (%) 2.8 13.5 SD (%) 60.2 62 65 % Clinical Benefit 71 80.5 Median PFS 7.3 mo. 7.4 mo. 11 mo. % PFS >6 mos. 61 63 This table compares the results of this GOG trial with historic info regarding treatment with platinum-based chemotherapy or hormonal therapy. Given the modest responses from chemotherapy and hormonal therapy, exploring agents that target the MAP kinase, IGF 1 pathways are of particular interest Farley et al, Lancet Oncol. 2013; Gershenson et al, Gynecol Oncol. 2012; Gershenson, et al Gynecol Oncol. 2009
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Ongoing Studies: NRG/GOG 281
At the cooperative group level, a randomized phase II/III study to assess the efficacy of Trametinib (MEK inhibitor) compared to standard chemo or hormone therapy in patients with recurrent or progressive low grade serous was activated in February 2014 240/240 patients have accrued
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MILO Study (MEK Inhibitor in Low-grade Serous Ovarian Cancer)
Phase 3 study for recurrent or persistent disease Investigational MEK inhibitor, MEK162, compared to a chemotherapy chosen by the physician Liposomal doxorubicin Paclitaxel Topotecan Letrozole NCT
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The Johns Hopkins Experience
Since 2011, we have treated women with advanced low grade serous after radical primary debulking surgery with hormonal therapy alone (no chemotherapy) Aromatase inhibition—arimidex or letrozole Continue therapy indefinitely until disease progression or toxicity No difference in outcomes compared to chemo
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Hormonal Therapy and Low Grade Serous
MD Anderson: 1° CRSC/T +/- HMT (n=203) 70 received Hormonal therapy maintenance (HMT) after C/T Median PFS carbo/taxol/OBS vs. carbo/taxol/HMT=26.4 vs mos (p<0.001) Letrozole most common therapy JHH/Cleveland Clinic 1° CRShormonal monotherapy (n=27) Only 22% recurred after median follow-up of 41 months Median PFS and OS not reached but 2 year PFS 82.8% and OS 96.3%. Optimal treatment unknown Gershenson et al, J Clin Oncol, 2016; Fader et al, Gynecol Oncol, 2016
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Patient Case 38 year old w/ Stage IV LGSC—extensive liver metastases and abdominal/intestinal metastases Carbo/Taxol x2—disease progression and SBO Debulk surgery with total colectomy, diaphragm, spleen, ileostomy—July 1, 2014 Optimal <1 cm residual but tiny parenchymal liver mets could not be debulked
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Patient Case Tumor Estrogen Receptor +90% Progesterone Receptor +40%
Letrozole 6 months w/ regression of most liver mets 12 & 18 months, with shrinking, asymptomatic w/ tiny, stable liver mets No disease progression for 30 months, now alive with disease on treatment
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Response to Letrozole
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NCCN Ovarian Cancer Guidelines
After primary CRS… Allows for platinum/taxane-based therapy followed by maintenance hormonal therapy OR Hormonal monotherapy
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NRG-GY019 A Randomized Phase III, Two-Arm Trial of Paclitaxel, Carboplatin, & Maintenance Letrozole Versus Letrozole Monotherapy in Patients with Stage II-IV, Primary Low-Grade Serous Carcinoma of the Ovary or Peritoneum
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Hypothesis Letrozole monotherapy/maintenance will be non-inferior to IV paclitaxel/carboplatin and maintenance letrozole with respect to PFS in women with stage II-IV primary low-grade serous carcinoma of the ovary or peritoneum after primary surgical cytoreduction
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Study Schema Newly dx Stage II-IV low-grade serous ovarian or peritoneal carcinoma post 1o cytoreductive surgery 1:1 RANDOMIZATION Arm 2 Letrozole x 6 cycles Arm 1 Carboplatin + paclitaxel x 6 cycles Letrozole until disease progression
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Conclusions Ovarian cancer is not a single disease, it consists of multiple entities that require a nuanced, individualized approach to treatment Personalized medicine allows for individualization of potential prevention and treatment strategies for women with ovarian cancer based on differences in molecular, genetic and lifestyle In its nascent stages—not all mutations or proteins are “actionable” and have a treatment Significant progress hain the last decade with treatment and outcome of women with rare ovarian tumors
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Conclusions Care from a gynecologic oncologist and with medical oncologists with expertise in gynecologic cancers are vital to achieving the best survival outcomes! Be your own advocate in talking with your health care provider about novel treamtents and research advances in the field!
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Thank You!
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