th
56
Annual Ob-Gyn Update
Ovarian Cancer:
Finally
We Can Start To Talk About
Prevention!
Walter Kinney M.D.
Division of Gynecologic Oncology
The Permanente Medical Group
Clinical Professor of Ob/Gyn, U.C. Davis
Sacramento, California
Uncompensated Colleagues
Dr. Helen Dinkelspiel
Gyn Oncology Fellow
Columbia University
First edition of this talk
Dr. Bethan Powell
Gynecologic Oncologist
KP San Francisco
Slide designs and images!
Why Not Screening?
Prevention
Requires a “detectable preclinical phase” of long
duration (like colon and cervix). We have now
identified a preclinical phase for some of the serous
cancers (STIC) but presently there is no screening
test that can detect this.
Mortality Reduction
Diagnosis at earlier stage. Requires long stage
duration. Stage duration for high grade serous
(HGS) ovarian cancer is measured in weeks or
months
Why Not Screening?
PLCO Trial – General Population
•Large, federally funded, prospective randomized
controlled clinical trial of annual CA-125 and
ultrasound: 78,216 women, age 55-74, median
followup 13 years
•Outcome – Screening arm experienced:
– No change in rate of occurrence of
ovarian/peritoneal/fallopian tubal cancer (hereafter
“ovarian cancer” or “HGS cancer”)
– No change in stage distribution
– No survival advantage
– 1080 surgeries including 163 “serious complications”
Buys SS, JAMA 2011 305:2295-2303
Why Not Screening?
UKFOCSS – High Risk Women
•Annual CA-125, and TVUS for abnormals
•3663 women with >=10% lifetime risk
•Women diagnosed with cancer who were screened
in the preceding year before diagnosis: 26% Stage
IIIC+ versus 86.7% Stage IIIC+ and OS 72 versus 48
months BUT
•60% of Stage I were Lynch syndrome; BRCA
associated cancers were 7/8 Stage IIIC+ AND
•Only 2/13 incident screen detected cancers were
early stage
•Conclusion – screening interval changed to 4
months and CA-125 interpretation changed
Long KC, JCO 2013 31:8-10 and Rosenthal AN, JCO 2013 31:49-57
Why Not Screening?
Symptoms and p53 on Pap
•Value of symptom triggered diagnostic evaluation
for ovarian cancer
– 5012 women age 40+; 241 positive symptom screen
(4.8%)
– 6 surgeries for ovarian masses, 2 cancers diagnosed
with 6 months, one stage 1A, symptom negative and
one Stage III+, symptom positive
•Cells from most endometrial cancers and some
HGS pelvic cancers in liquid Pap specimens
– Pap screening for p53?
– Untested for screening or more importantly for
precursor detection
Anderson MR Ob Gyn 2015;123:73-9, and Kunde, Sci Transl Med 2013; 5:167
Important Insights
• Screening is ineffective for High Grade Serous
cancer in the pelvis. There are no effective tests
for early stage disease and the stage duration is
too short
• Ovarian cancer is several (probably many)
diseases in two general categories: HGS (70%)
and everything else
• New data suggests 70% of HGS carcinomas may
originate in the fallopian tube
• A precursor state is identifiable (STIC)
• Explosion in the world of genetics: panel testing
now available and about 25% of ovarian cancer is
related to an inherited gene.
Classic thinking….
Germ Cell
(3%-5%)
Sex Cord-Stromal
(2%-3%)
Secondary
(Metastatic)
(5%)
Figure modified from Gartner, L.P. & Hiatt, J.L. eds. In Color Atlas of Histology.
3rd ed. (2000) Lippincott Williams & Wilkins: Philadelphia, PA.
Ovarian cancer: different diseases
Grade
1
Serous
Endometrio Mucinou
id
s
3.5%
10%
Transitional
Undifferentiat
ed
4%
Grade
2
Grade
3
Clear
cell
70%
10%
2% NOS
EOC Grouping reflects epidemiology, germline genetics, somatic
genetics, animal models, clinical presentation and response to
therapy
Gilks, Mod Path 2008
Kurman and Shih, July 2011
Origin of ovarian cancer: Paradigm
shift
•
•
•
•
•
•
TYPE 1
Clear cell,low grade
endometrioid
Low-grade serous
Mucinous
Molecular Markers: BRAF,
KRAS, PTEN, MEK, MAPK,
Beta-catenin
Early changes and
precancer surrounds
cancer
Chemotherapy resistent
•
•
•
•
•
TYPE II
High grade serous,
endometrioid,
carcinosarcoma.
Molecular markers: P53,
CCNE2, Ki-67, MIB-!,
PAX2, PAX8, PIK3CA, WT-1
Fallopian tube markers
Most late stage, rapidly
growing.
Chemotherapy sensitive
Timeline: Origin of serous cancer
in the FT
1993
2004 Progression of
BRCA1
p53 signature to STIC
Today:
Clinical
1997
2007
Implications of FT
FTCA assoc
70% of PSC involve tube
origin
with BRCA
2010
2001
Tubal dysplasia P53 mutations match,
molecular genetics match
In RRSO
Bowtell et al, Nat Rev Can 2011
Crum, Clin Med 2007
Kurman et al, Human Path 2011
Stepwise Progression: Precursor
Lesions
Levanon JCO 2008, Lee et al
P53 Signature
P53 Signature – Possible Precursor Lesion
STIC and cancer in proximity
Pathology Review of 150 RRSO Cases
Performed at UCSF
Case
Ovary
FT
Side
Size
Met
Stage
FU
1
Serous
Neg
Uni
0.9 mm
None
IA
PP, 7y
2
Neg
Serous, TIC, I
Uni
8.2 mm
None
IA-0
NED, 7y
3
Neg
Serous, TIC, F
Uni
2.0 mm
+ Cyto
IC
NED, 4y
4
CIS,
surface
TIC, F
Uni
1.0 mm
None
0
NED, 3y
5
Serous
Neg
Bi
11, 3 mm
LN
IIIC
AWT, 2y
6
Neg
TIC, F
Uni
1 mm
None
0
NED,
1.5y
7
Neg
TIC, F
Uni
2 mm
+ Cyto
IC
NED, 1y
8
Neg
TIC, I
Uni
2 mm
None
0
R
Serous, TIC, F
Ovary Bi
FT Uni
Ovary 13, 5.5
mm
FT 6 mm
LN
+ Cyto
IIIC
R
9
Serous
STIC and invasive Ca at RRSO
• STIC found in 3% of 2035 RRSOs
– Median age 50
– 70% BRCA1
• Invasive Ca in 2.7% of 3030 RRSOs
– 71% of tubal origin
– Median age 51
– 79% BRCA1
Powell, Gyn Onc 2014
Evidence compelling that some if not most
HGS cancers originate in the fallopian tube
• Consistent with epidemiology
• Precursor lesion in tube, not in ovary
• Mullerian molecular markers: PAX8, not
calretinin
• Molecular markers match, P53 mutation in
>80%
• STIC or tube involved in 70% of PSC in
sporadic and BRCA related cancer.
• Mouse model
Genetics: Who Gets Referred?
Genetics: Germline mutations in
ovarian cancer
• Approximately 24% of ovarian cancers have a
germ line mutation, 17% BRCA and 7% nonBRCA
(18+ other genes)
• Lynch is a small contributor to the total: 8/1890
cases (0.4%) sequences by UW or GOG
• 31% -44% have no family history and 40% are
>age 60 at diagnosis
• Approximately 12% of women alive in 2013, with
ovarian cancer diagnosed in the last 5 years have
been tested for BRCA1 and BRCA2
Walsh, PCOS 2012, myriad annual
report 2013
Not your mother’s BRCA: Gene Panels
•
•
•
•
•
•
BRCA 1 ,BRCA 2
MLH1, MSH2,
MSH6, PMS2, EPCAM
STK11
TP53
CHEK2, BRIP1, RAD50,
RAD51C, RAD51D,
• PALP2, ATM,
• TP53, BARD1, NBN,
MRE11A
Genetics: Germline mutations in
ovarian cancer
• Approximately 24% of ovarian cancers have a
germ line mutation, 17% BRCA and 7% nonBRCA
(18+ other genes)
• Lynch is a small contributor to the total: 8/1890
cases (0.4%) sequences by UW or GOG
• 31% -44% have no family history and 40% are
>age 60 at diagnosis
• Approximately 12% of women alive in 2013, with
ovarian cancer diagnosed in the last 5 years have
been tested for BRCA1 and BRCA2
Walsh, PCOS 2012, myriad annual
report 2013
Genetics: Who gets referred?
March 2014 SGO Statement on
Genetic testing
All women with ov/ft/pp cancer should considered
for genetic counseling and testing in the absence of
family history.
All women with endometrial cancer should undergo
a clinical or molecular evaluation for lynch
syndrome with molecular tumor evaluation the
preferred method.
Genetics: Germline mutations in
ovarian cancer
• Approximately 24% of ovarian cancers have a
germ line mutation, 17% BRCA and 7% nonBRCA
(18+ other genes)
• Lynch is a small contributor to the total: 8/1890
cases (0.4%) sequences by UW or GOG
• 31% -44% have no family history and 40% are
>age 60 at diagnosis
• Approximately 12% of women alive in 2013, with
ovarian cancer diagnosed in the last 5 years have
been tested for BRCA1 and BRCA2
Walsh, PCOS 2012, myriad annual
report 2013
Compliance with referral to genetic
counseling
• 59% with breast cancer were referred while only 21%
with ovarian cancer were referred (p<0.0001).
• Opportunity missed in ovarian cancer due to death.
• Attrition every additional step to testing.
• Family history and ethnicity were difficult to interpret
with very few documented Jewish women in cohort.
Powell Int J Gyn Cancer, 2011
All guidelines recommend: Risk
Reducing salpingo-oophorectomy for
BRCA mutation carriers
90 % effective in reducing ovarian cancer
50% reduction in breast cancer if performed before
age 50
Increase life expectancy 6.6-11.7 years for
combined BSO, mastectomy.
Microsectioning the tubes and ovaries
.
Medeiros et al, Am J Surg Path, 2006
Sectioning of RRSO Specimens
BRCA Risk of Ovarian Cancer
AGE
BRCA1
BRCA2
40
2.2%
<1%
50
8.7%
1.9%
60
22%
7.4%
Chen et al, JCO 2007
Oophorectomy reduces
Breast Cancer Risk in BRCA
mutation carriers
Risk reduction if performed by age 40
• BRCA 1: 56% (OR= 0.44;95% CI 0.29,0.66)
• BRCA 2: 46% (OR=0.57;95% CI 0.28,1.15),
Domchek JAMA, 2010
Eisen et al, J Clin Oncol, 2005
Compliance with NCCN guidelines in a
community based health care system
• 305 women with BRCA mutations in KPNC
• Mean age at BRCA test: 47!
• 74% elected RRSO
• 17% of these women <40yrs
• Median time 6 mos from test date to surgery date
Garcia, C et al Gyn Onc
2013
Oral contraceptives reduce
Ovarian Cancer Risk in BRCA
mutation carriers
Cancer risk reduction:
• Ovary: OR= 0.58; 95% CI 0.46-0.73)
• Breast: OR=1.21; 95% CI 0.93-1.58),
Moorman PG, J Clin Oncol 2013 31:4188
Adherence to Cancer Screening Among
Women With BRCA1 or 2 Who Retained
Tubes and Ovaries
Garcia, Powell, et al, WAGO, 2013
NCCN guidelines for BRCA mutation
carriers
Early Menopause
• Remove the tubes and
ovaries when between
the age of 35-40 or
when completed
childbearing.
• Screening with CA 125
and ultrasound q 6
months.
Cognitive
impairment
Hot flashes
Cardiac mortality
sexuality
osteoporosis
Salpingectomy in mutation carriers
Pros
• Some cancer risk reduction
• Avoid premature
menapause
• Maintain option for IVF
pregnancy
• Option for those
unwilling to have
BSO
Cons
• Two stages to surgery
• Delay of removing the
ovaries
• May not be as effective
• No Breast cancer risk
reduction
Cost Effectiveness Model
Average
Discounted Costs
(Can $)
Avg Life
Expectancy
Gain
Avg QALY
Expectancy
Gain
Incremental
C-E Ratio (cost per
QALY)
BSO @ 40
$25,987
21.15
17.56
---
Tubes @ 40
$38,208
20.74
18.17
$20,050
Tubes @ 40,
Ov @ 50
$41,577
20.83
18.26
$37,805
BSO @40
$16,932
22.62
18.87
---
Tubes @ 40
$33,150
22.08
19.51
$25,658
Tubes @ 40,
Ov @ 50
$37,686
22.14
19.56
$89,680
BRCA1
BRCA2
Delayed oophorectomy with the greatest QALY
Kwon et al, Obstet Gynecol 2013
Why leave the tube in women at
average risk?
In US 30% women undergo hysterectomy, 50% have
ovaries and fallopian tube left in situ
~20% of women who develop ovarian cancer have
had a prior hysterectomy
Up to 20% of ovarian cancer patients have had a
tubal ligation
Most women with inherited risk are unidentified.
Walsh et al, PNAS 2011
Davis et al, J La Soc 2003
Removal of the tube at hysterectomy
• No detrimental effect on:
ovarian function
hormonal levels
blood supply to the ovary
• If tube is left in situ, incidence of hydrosalpinx: 28%,
requiring surgery 7.8%
Dar et al, 2000 Sezik et al, 2007 Ghezzi et al, 2009,
Morse et al, 2006 Morelli 2013, Findley 2013
Salpingectomy Instead of tubal ligation
or at time of any pelvic surgery
Pros
• Decreased tubal pathology,
• Decreased ectopic rate
• Improved sterilization
efficacy
• Potential cancer risk
reduction
Cons
• Requires surgery
• May be difficult to access
tube
• Potential for bleeding
• May require additional
equipment/incision/cost
• Uncommon cancer
Salpingectomy versus Tubal Ligation
• Effect of tubal sterilization on risk of serous epithelial
or primary peritoneal cancer
• Nested case control, 194 cases and 388 controls
• Controlled for prior hyst or SO, oral contraceptive
use, endometriosis, infetility, gravidity and parity
• HGS cancer risk
– Any tubal sterilization OR 0.59 (0.29-1.17) p = 0.13
– Salpingectomy
OR 0.36 (0.13-1.02) p = 0.054
Lessard-Andersen, Gyn Onc 2014; 135:423-7
Technique
BRCA 1 or 2 mutation
• Inspect entire abdomen
• Peritoneal cytology
• Remove adjacent ovarian
capsule (fimbria ovarica)
• Remove all the tube
• Place in an endoscopic bag
• Pathology: microsectioning
entire tubes
No known genetic risk
• Preserve the utero-ovarian
ligament
• Remove or cauterize any
attachments to the ovary
• If the entire fallopian tube
cannot be removed,
consider removing the tubal
fimbrial end
• Pathology: examine the
fimbrae in 2-3 cassettes.
Ovarian Cancer Prevention
• Improve compliance with referral guidelines to
genetic counseling for women at hereditary
risk
• RRSO for mutation carriers: big change in
overall survival
• OCs or preferably salpingectomy for a bad
family history and negative testing or
mutation carriers who are not disposed to
consider RRSO
• Opportunistic salpingectomy