56 th Annual Ob-Gyn Update Ovarian Cancer: Finally We Can Start To Talk About Prevention! Walter...
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Transcript of 56 th Annual Ob-Gyn Update Ovarian Cancer: Finally We Can Start To Talk About Prevention! Walter...
56th Annual Ob-Gyn UpdateOvarian Cancer:
Finally We Can Start To Talk About
Prevention!
Walter Kinney M.D.Division of Gynecologic OncologyThe Permanente Medical Group
Clinical Professor of Ob/Gyn, U.C. DavisSacramento, California
Dr. Bethan Powell
Gynecologic OncologistKP San Francisco
Slide designs and images!
Uncompensated Colleagues
Dr. Helen Dinkelspiel Gyn Oncology Fellow
Columbia University First edition of this talk
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 ReductionDiagnosis 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….
Epithelial (EOC)(90%)
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.
Serous
Endometrioid
Mucinous
Clear cell
Transitional
Undifferentiated
Grade 1 3.5%
10%
Grade 2
4%
Grade 3 70%
10%
2% NOS
EOC Grouping reflects epidemiology, germline genetics, somatic genetics, animal models, clinical presentation and response to therapy
Ovarian cancer: different diseases
Gilks, Mod Path 2008Kurman 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
1993BRCA1
1997 FTCA assoc with BRCA
2001Tubal dysplasiaIn RRSO
2004 Progression ofp53 signature to STIC
200770% of PSC involve tube
2010P53 mutations match, molecular genetics match
Today:Clinical Implications of FTorigin
Bowtell et al, Nat Rev Can 2011 Crum, Clin Med 2007 Kurman et al, Human Path 2011
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
4CIS,
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
9 Serous Serous, TIC, F
Ovary BiFT Uni
Ovary 13, 5.5 mmFT 6 mm
LN+
CytoIIIC R
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: 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 cancer50% reduction in breast cancer if performed before age 50Increase life expectancy 6.6-11.7 years for combined BSO, mastectomy.
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, 2010Eisen 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
• 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.
Hot flashes
Cognitive impairment
sexualityosteoporosis
Cardiac mortality
Early Menopause
Salpingectomy in mutation carriers
Pros• Some cancer risk reduction• Avoid premature
menapause• Maintain option for IVF
pregnancy• Option for those unwilling to haveBSO
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)
BRCA1
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
BRCA2
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
Kwon et al, Obstet Gynecol 2013Delayed oophorectomy with the greatest QALY
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