Improvement in 5 Year Survival Race 1975 1989 2014 All 36 38 47 White 35 38 48 African American 42 34 39 Noone AM Howlader N Krapcho M et al eds SEER Cancer Statistics Review 19752015 National Cancer Institute Bethesda MD wwwseercancergovcsr197 ID: 776623
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Slide1
Slide2Ovarian Cancer Incidence/Mortality
Slide3Improvement in 5 Year Survival:
Race197519892014All36%38%47%White35%38%48%African American42%34%39%
Noone
AM,
Howlader
N,
Krapcho
M, et al. (eds). SEER Cancer Statistics Review, 1975-2015, National Cancer Institute, Bethesda, MD, www.seer.cancer.gov/csr/1975_2015/, based on November 2017 SEER data submission, posted to the SEER website April 2018.
Slide4Ovarian Cancer Facts and Figures
5 year overall survival (OS) rate across ALL stages of ovarian cancer: 47%
If diagnosed with advanced disease: 28%
Slide5Ovarian Cancer Risk Factors
Not a comprehensive list of risk factors for ovarian cancer; BRCA = breast cancer susceptibility gene; BMI = body mass index; HRT = hormone replacement therapy.
1. What are the risk factors for ovarian cancer?. Atlanta, GA: American Cancer Society. Last revised February 4, 2016. http://www.cancer.org/cancer/ovariancancer/detailedguide/ovarian-cancer-risk-factors. Accessed July 24, 2017. 2. Wei JJ, et al. Int J
Gynecol
Pathol
.
2011;30:553-568.
Age
Obesity
Genetics
Family history (1
st
degree relatives)
BRCA
Lynch syndrome
Peutz-Jeghers
syndrome
Cowden syndrome
Endometriosis
Medications
Hormone replacement therapy
Protective factors:
Birth control pills, childbirth before age 26, tubal ligation
Slide6~20%–22% of patients with ovarian cancer14%–15% are associated with hereditary germline BRCA1 or BRCA2 mutations (gBRCAmut)1~6%–7% are associated with somatic BRCA mutations (sBRCAmut)1 Risk of Ovarian Cancer among BRCA carriers: 39% of BRCA1 develop ovarian cancer by age 703,411%–17% of BRCA2 develop ovarian cancer by age 703,41% lifetime risk for the general female population1
BRCA Mutations
Konstantinopoulos PA et al.
Cancer Discov.
2015;5:1137-54; Liu JF et al.
Gynecol Oncol
. 2014;133:362-369; Antoniou A et al.
Am J Hum Genet
. 2003;72:1117-1130; Chen S, Parmigiani G.
J Clin Oncol
. 2007;25:1329-1333.
Slide7CA125
Best known marker in ovarian cancer
Present in 79%
90% of advanced cases
50% of early cases
Also elevated in benign conditions
Endometriosis, benign breast changes, inflammatory conditions
Can be elevated in other cancers
Slide8Screening?
Slide9Screening?
NCCN=National Comprehensive Cancer NetworkAmerican Congress of Obstetricians and Gynecologists (ACOG) Committee Opinion. http://www.acog.org/Resources-And-Publications/Committee-Opinions/Committee-on-Gynecologic-Practice/The-Role-of-the-Obstetrician-Gynecologist-in-the-Early-Detection-of-Epithelial-Ovarian-Cancer. Accessed March 24, 2015.
The FDA, US Preventative Services Task Force, American College
of Obstetrics and Gynecologists, Society of Gynecologic Oncology,
and NCCN recommend AGAINST ovarian cancer screening
Slide10Signs and Symptoms:
American Society of Clinical Oncology. https://www.cancer.net/cancer-types/ovarian-fallopian-tube-and-peritoneal-cancer/symptoms-and-signs
Most Common SymptomsBloating Pelvic or abdominal painor pressure Trouble eating or feeling full quickly Urinary symptoms(urgency or frequency)
Other Nonspecific SymptomsFatigue Upset stomach Back pain Constipation Pain with intercourse Menstrual changes Abdominal swelling Weight loss
Slide11Diagnostic Work-up
CA-125 = cancer antigen 125; CT = computed tomography; MRI = magnetic resonance imaging; PET = positron emission tomography. 1. American Society of Clinical Oncology. https://www.cancer.net/cancer-types/ovarian-fallopian-tube-and-peritoneal-cancer/symptoms-and-signs. Accessed Oct 21,2019;
Imaging1Transvaginal ultrasoundCT or MRI scanPET-CT scan Chest imagingPelvic or abdominal ultrasonography
CA-1251Serum tumor markerLow predictive value for detecting ovarian cancer in women without special risk factors2 Nonspecific for ovarian cancer3Along with other tumor markers (e.g. CA 19-9) can be used to aid diagnosis
Summary1Ovarian cancer has largely nonspecific symptoms3 Initial diagnosis is made by: Physical exam Tumor markersLaboratory tests Radiology imaging Biopsy usually done at time of first surgeryStaging is done at the time of surgery
Physical Exam
Abdominal / pelvic exam
Mass
Ascites
Distension
Slide12WHO = World Health Organization.
1. Ehdaivand S. WHO classification of ovarian neoplasms. Pathology Outlines. Revised May 19, 2016. http://www.pathologyoutlines.com/topic/ovarytumorwhoclassif.html. Accessed August 17, 2017. 2. Bodurka DC, et al. Cancer. 2012;118(12):3087-3094. 3. Prat J. Ann Oncol. 2012;23(Suppl 10):x111-117.
Histological Subtypes
Germ cells
Epithelium
Stroma
WHO histological typing of ovarian cancer is based on cell lineage
1
Epithelial cells
Germ cells
Sex chord and stromal cells
Endometrioid 10%
Clear-Cell 10%
Epithelial Ovarian Carcinoma Subtypes
High-grade Serous 70%
Mucinous 3%
Low-grade Serous <5%
Other 2%
Ovarian tumor cell lineage
Slide13Serous ovarian tumors are typically graded using a 2-tier system
2
Slide14FIGO Staging
FIGO=International Federation of Gynecology and Obstetrics.1. Society of Gynecologic Cancer. https://www.sgo.org/wp-content/uploads/2012/09/FIGO-Ovarian-Cancer-Staging_1.10.14.pdf. Accessed July 12, 2016; 2. College of American Pathologists. http://www.cap.org/ShowProperty?nodePath=/UCMCon/Contribution%20Folders/WebContent/pdf/cp-ovary-fallopian-16protocol-1000.pdf. Accessed July 12, 2016.
Histologic grade is included as criteria for staging of all subtypes except clear cell and serous ovarian cancer2
FIGO Stage
1
Description
I
The cancer is confined to the ovaries or fallopian tube(s)
II
The cancer is in one or both of the ovaries and
has spread below the pelvis
III
The cancer
is in one or both of the ovaries and has spread in the peritoneal area outside of the pelvis and surrounding nodes
IV
The cancer has spread
to organs beyond the ovaries and the peritoneal area
Slide155 Year Survival by Stage
Surveillance, Epidemiology, and End Results (SEER) Program Cancer Statistics Factsheets: Ovary Cancer. Bethesda, MA: National Cancer Institute, 2017. http://seer.cancer.gov/statfacts/html/ovary.html. Accessed August 18, 2017.
Majority of ovarian cancer cases are diagnosed at an advanced stage*
Stage at Diagnosis
5-Year Survival by Stage
15
19
6
60
Survival rate
declines as stage at diagnosis increases
92.5
73.0
28.9
25.1
Slide16Despite advances in treatment 85% of those diagnosed with advanced stage Ovarian Cancer will recur.
Slide17Adapted from Ovarian Cancer National Alliance. http://www.ovariancancer.org/about/treatment/. Accessed July 13, 2016. Ushijima K. J Oncol. 2010;2010:497429.
10
30
70-90
90-95
Recurrence Rates by Stage of Diagnosis
~70%
of all patients diagnosed with ovarian cancer (all stages) will have a recurrence
1
Recurrent ovarian cancer is
treatable but not curable
Slide18After Each Subsequent Treatment, Median Progression-Free Survival (PFS) Shortens During Watchful Waiting
*PFS was calculated from the day of randomization (day of first cycle of chemotherapy) to the first disease progression.PFS = progression-free survival; L = line. Hanker LC, et al. Ann Onc. 2012;23:2605-2612. Lorusso D, et al. Int J Surg Oncol. 2012;2012:613980.
1L
RECURRENCE
Diagnosed with ovarian cancer
2L
6L
3L
4L
5L
RECURRENCE
RECURRENCE
RECURRENCE
RECURRENCE
Median PFS
~18
mo
Median PFS*
10.2
mo
(9.6–10.7)
Median PFS*
6.4
mo
(5.6–7.0)
Median PFS*
5.6
mo
(4.8–6.2)
Median PFS*
4.4
mo
(3.7–4.9)
Median PFS*
4.1
mo
(3.0–5.1)
Ovarian cancer recurs, receives active line of treatment
Slide19Overview of Ovarian Cancer Treatment
Systemic Treatment
-before surgery (neoadjuvant)
Goal
Reduce tumor burden prior to surgery
Surgery
-Staging
-Primary debulking surgery (PDS)
-Interval debulking surgery (pre and post chemo)
Goal-Curative intent-Reduce tumor burden
Systemic Treatment
-First-line/adjuvant therapy -Recurrence therapy-Maintenance therapy-Clinical trialsGoal-Curative intent-Control symptoms-improve QOL
Supplemental Therapy
-Observation – “watch and wait” -Maintenance therapyGoalExtend platinum –sensitivityExtend chemotherapy-free interval-Extend disease-free int.
National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines) Ovarian Cancer Including Fallopian Tube Cancer and Primary Peritoneal Cancer (Version 2.2019). Accessed Oct. 2019.
Slide20NCCN Guidelines: First-line Treatment
*Stage IA or IB, Grade 1;
†Stage IA or IB, Grade 3 or Stage IC, any grade. Stage IA or IB, Grade 2 has choice of either no treatment (observation) or adjuvant chemotherapy.Chemo=chemotherapy; CR=complete response; NCCN=National Comprehensive Cancer Network; PD=progressive disease; PR=partial response; SD=stable disease; SOC=standard of care.National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines) Ovarian Cancer Including Fallopian Tube Cancer and Primary Peritoneal Cancer (Version 2.2018)
Ovarian cancer classification
Current SOC
Less commonly used
Clinical trial
Observation
OR
Achieved CR
OR
Persistent or Recurrent Disease
PR, SD or PD
Clinical relapse
Surgery
Neoadjuvant therapy
Locally Advanced
Stages II & III
Metastatic
Stage IV
Primary (adjuvant) chemo
“Interval debulking”
Surgery
Adjuvant chemo
No treatment (observation)
Low grade*
High grade
†
Localized
Stage I
Monitoring & follow-up
M
aintenance
therapy
Slide21Surgery
Slide22Chemotherapy
Neoadjuvant
Adjuvant
Metastatic
Intraperitoneal
Slide23First-line Treatment: Stage I
Intraperitoneal/Intravenous Regimen Level of Evidence/RecommendationIntravenous regimensPaclitaxel + Carboplatin day 1. Repeat q3wk × 3-6 cycles (preferred)Category 2ACarboplatin + pegylated liposomal doxorubicin every 4 weeks for 3-6 cyclesCategory 2ADocetaxel + Carboplatin day 1. Repeat q3wk × 6 cycles Category 2A
NCCN=National Comprehensive Cancer Network;
IV=intravenous; IP=intraperitoneal; q3wk=every 3 weeks.
National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines) Ovarian Cancer Including Fallopian Tube Cancer and Primary Peritoneal Cancer (Version 2.2018)
Slide24First-line Treatment: Stage II-IV
Intraperitoneal/Intravenous Regimen Level of Evidence/RecommendationIntraperitoneal/Intravenous regimensPaclitaxel IV day 1; Cisplatin IP day 2 after IV Paclitaxel; Paclitaxel IP day 8. Repeat q3wk × 6 cycles Category 2AIntravenous regimensPaclitaxel + Carboplatin day 1. Repeat q3wk × 6 cycles Category 2ADose-dense Paclitaxel days 1, 8, and 15, followed by Carboplatin day 1.Repeat q3wk × 6 cycles Category 2APaclitaxel + Carboplatin day 1. Weekly for 18 weeks Category 2ADocetaxel + Carboplatin day 1. Repeat q3wk × 6 cycles Category 2ACarboplatin + pegylated liposomal doxorubicin every 4 weeks for 6 cyclesCategory 2ABevacizumab-containing regimens per ICON-7 and GOG-218Paclitaxel IV + Carboplatin IV + bevacizumab IV day 1. Repeat q3wk × 5–6 cycles. Continue bevacizumab up to 12 additional cycles for maintenance Category 2APaclitaxel IV + Carboplatin IV day 1. Repeat q3wk × 6 cycles Starting day 1 of cycle 2, give bevacizumab IV q3wk up to 22 cycles Category 2A
NCCN=National Comprehensive Cancer Network;
IV=intravenous; IP=intraperitoneal; q3wk=every 3 weeks.
National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines) Ovarian Cancer Including Fallopian Tube Cancer and Primary Peritoneal Cancer (Version 2.2018)
Slide25Intraperitoneal chemotherapy HIPEC - Hyperthermic
Most of OC have spread to peritoneum by the time of diagnosis Intraperitoneal (IP) chemotherapy prolonged survival time and reduced the risk of death. Higher rate of adverse events and the frequency of discontinuation hampered adoption Abdominal pain, Nausea, Vomiting, Fatigue, Infection, IleusHyperthermia enhanced cancer cell destruction HIPEC-based regimens might PFS and OS for patients with advanced primary ovarian cancer. Benefit still under debate
Zhang, G., Zhu, Y., Liu, C.
et al.
The prognosis impact of
hyperthermic
intraperitoneal chemotherapy (HIPEC) plus cytoreductive surgery (CRS) in advanced ovarian cancer: the meta-analysis.
J Ovarian Res
12,
33 (2019) doi:10.1186/s13048-019-0509-1
Slide26Definition of Response to First-Line Chemotherapy: NCCN Guidelines
CT=computed tomography; ULN=upper limit of normal.National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines) Ovarian Cancer Including Fallopian Tube Cancer and Primary Peritoneal Cancer (Version 2.2018); Nishino M et al. AJR Am J Roentgenol. 2010;195:281-289.
Complete response (CR):
Negative physical exam
Negative CA-125 Negative CT with <1cm lymph nodes
Partial response (PR)
:
≥ 30% reduction in the sum of diameters compared to baseline Persistence of 1 or more non-target lesions AND/ORCA-125 above ULN
Progressive disease (PD)
:
≥ 20% increase in the sum of diameters of target lesions
The sum must demonstrate an absolute increase of
≥ 5mm
OR
Appearance of one or more new lesions
Slide27Then what???
Slide28BRCA mutation in Ovarian Cancer
BRCA is tumor suppressor gene involved in repair of DNA double strand breaks
When mutated that mechanism is damaged
Germ-line BRCA (
gBRCAmut
)
improved PFS and OS
In relapse setting: improved response to 2
nd
line therapy even if early relapse
Platinum and non platinum
Non
gBRCAmut
who respond to multiple lines likely to have somatic BRCA mutation (
sBRCAmut
) or other mutations
Slide29Genetic Mutations Beyond BRCA Mutations May Lead to Homologous Recombination Deficiency (HRd)
OTHER (may be HR deficient via upregulation of miRNAs or other mechanisms)
HR DEFICIENT
HR PROFICIENT
POSSIBLY HR DEFICIENT
HR=homologous recombination; NER=nucleotide excision repair; MMR=mismatch repair; PTEN=phosphatase and tensin homolog.
Konstantinopoulos PA et al.
Cancer Discov
. 2015;5:1137-54; Liu JF et al.
Gynecol Oncol
. 2014;133:362-369; Antoniou A et al.
Am J Hum Genet
. 2003;72:1117-1130; Chen S, Parmigiani G.
J Clin Oncol
. 2007;25:1329-1333.
Slide30Homologous Recombination (HRd)
DNA errors in replication common
DNA damage repair through the highest fidelity mechanism = homologous recombination
HRd
or
HRp
In
BRCAmut
: part of the mechanism is absent =
HRd
PARPs required
Slide31PARP inhibitors
Poly ADP ribose polymerase - enzymes involved in DNA repair through
HR
Single strand DNA breaks
PARP inhibitors block the ability of PARPs to participate in DNA damage repair
Most effective in
BRCAmut
and
HRd
Oral agents: dosed
qd
or bid
Slide32PARP inhibitors
QOL similar between PARP and placebo
Side effects depend on which PARP
Nausea / vomiting
Fatigue
Thrombocytopenia, neutropenia, anemia
Slide33HRd
HRp
HRd
HRd
+ PARP
Slide34Maintenance
Avastin in maintenance if used with 1L
PARPs Previously indicated after recurrence and subsequent chemotherapy
Stretched the PFS after 2L in special populations
Some for
gBRCA
Some for
gBRCA
or
tBRCA
(same as
sBRCA
)
Some for
HRd
Some showed activity in
HRp
Newest data shows advantage in 1L maintenance
Goal: to maintain platinum sensitivity, increase PFS
Slide35Goal: Increase PFS with each subsequent line
*PFS was calculated from the day of randomization (day of first cycle of chemotherapy) to the first disease progression.PFS = progression-free survival; L = line. Hanker LC, et al. Ann Onc. 2012;23:2605-2612. Lorusso D, et al. Int J Surg Oncol. 2012;2012:613980.
1L
Diagnosed with ovarian cancer
2L
3L
RECURRENCE
RECURRENCE
Median PFS
Median PFS*
Ovarian cancer recurs, receives active line of treatment
Slide36NCCN Guidelines: Maintenance Therapy
†Pazopanib is recommended as single-agent maintenance therapy if complete clinical remission following primary therapy for stage II-IV disease, if no prior bevacizumab (category 3).*Rucaparib, Olaparib, Niraparib are approved in the US for a non-maintenance indication. Ledermann JA, Raja FA, Fotopoulou C, et al. Annals of Oncology. 2013;24(Supp 6):vi24-vi32; Ledermann JA, Sessa C, Colombo N. eUpdate-Ovarian Cancer Treatment Recommendations. Updated on: Sep. 21, 2016; http://www.esmo.org/Guidelines/Gynaecological-Cancers/Non-Epithelial-Ovarian-Cancer/eUpdate-Treatment-Recommendations; National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines) Ovarian Cancer Including Fallopian Tube Cancer and Primary Peritoneal Cancer (Version 2.2018).
For those with platinum-sensitive disease who have completed two or more lines of platinum-based therapy, consider niraparib maintenance therapy if partial or complete response
For those with BRCA1/2 mutations who have completed
one or more lines of platinum-based therapy, consider olaparib maintenance therapy if partial or complete response
For platinum-sensitive recurrent disease, if response after chemotherapy, bevacizumab can be continued as maintenance therapy until disease progression or unacceptable toxicity
Niraparib
Olaparib
Bevacizumab
For those with platinum-sensitive disease who have completed two or more lines of platinum-based therapy, consider rucaparib maintenance therapy if partial or complete response
Rucaparib*
Slide37Clinicaltrials.gov
2,498 Ovarian Cancer Trials
764 Phase I
1,011 Phase II
233 Phase III
Slide38What about check point inhibitors?
Slide39Ovarian Cancer Clinical Trials
Ovarian cancer thought to be “cold” tumor
Can it be “warmed up”?
Combination trials with
PARPi
+ immunotherapy agents
Combination trials of
avastin
+
PARPi
Trials on
rechallenging
with a PARP +
Slide40Paradigm Shift
2011: 2 trials showed benefit of bevacizumab with first line therapy
2018: SOLO1 trial showed benefit of
PARPi
in
gBRCAmut
in 1L maintenance
Only 44% adopted
2019: ESMO – 3 trials showing benefit of
PARPi
in 1L maintenance in various populations (high risk,
HRd
,
HRp
, adding to chemo upfront and then following with maintenance, adding to
bev
)
“PARPs Made the biggest splash”
“Game changer”
PARPs in 1L treatment, 1L maintenance, 2L maintenance, 3+L treatment.
Slide41Thank You!