1. 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

2. 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

3. 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

4. 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

5. 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)

6. 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

7. Ovarian Cancer
Ovarian cancer diagnosed in approximately 23,000 women annually in the United States
Nearly 90% of ovarian malignancies are epithelial ovarian tumors

8. 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

9. 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?

10. 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

11. 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

13. 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

14. 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

15. 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

16. 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

17. 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

18. 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.

19. 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

20. 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

21. 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

22. 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.

23. A Developing Industry

24. Profiling Report

25. 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

26. 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

27. 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

28. 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.

29. 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

30. 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

31. Advances in Ovarian Cancer Screening

34. Circulating Tumor DNA

35. 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

36. 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%

37. 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

38. 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

39. 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

40. Standard treatment for epithelail ovarian cancer: NCCN
Debulking surgery
Carbo/taxol or cisplatin/taxol therapy, either IV or IV/IP

41. 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

42. Rare Epithelial Ovarian Cancer Subtypes
Low-grade serous carcinoma
Clear cell carcinoma
Mucinous carcinoma
Endometrioid carcinoma

43. 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

44. 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, .

45. 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.

46. 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.

47. 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

48. 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

49. 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.

50. 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

51. 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

52. 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

53. 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

54. 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

55. N=52 patients
Farley et al, Lancet Oncol. 2013

56. 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

57. 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

58. 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

59. 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

60. Hormonal Therapy and Low Grade Serous
MD Anderson: 1° CRSC/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° CRShormonal 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

61. 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

62. 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

63. Response to Letrozole

64. NCCN Ovarian Cancer Guidelines
After primary CRS…
Allows for platinum/taxane-based therapy followed by maintenance hormonal therapy OR
Hormonal monotherapy

65. 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

66. 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

67. 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

68. 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

69. 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!

70. Thank You!