gardner miami brca 2019 final -...

4/9/2019

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The BRCA Patient and Gynecologic Options

Ginger J. Gardner, MD

Vice Chair, Department of Surgery for Hospital Operations

Surgical Chair, Institutional Patient Flow Committee

Lead Physician, Gynecology Disease Management Team Alliance

Ovarian Cancer Surgery Section, Gynecology Service, Department of Surgery

• No disclosures

• Identification of the high risk patient

• Ovarian cancer screening

• Risk reduction strategies & controversies

– Role of hysterectomy

– The hormone dilemma

– Salpingectomy

Objectives

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Ovarian Cancer is Not One Disease

High Grade Serous

Clear Cell Endometrioid Mucinous Low Grade Serous

% of CasesFIGO stage I‐IIFIGO stage III‐IV

39%86%

33%2%

22%7%

5%2%

1%3%

Genetic Risk Factors

BRCA 1/2 Lynch Lynch None known

None known

Precursor Lesion SerousTubal Intraepithelial

Carcinoma (STIC)

Endometriosis Endometriosis Unknown Serous Borderline Tumor

Molecular Genetics

p53, BRCA, HR Defects, Tumor

Microenvironment

PI3K, ARID1A, MSI

PTEN, beta‐catenin,

ARID1A, MSI

KRAS, HER2

BRAF, KRAS, NRAS

Bookman et al. J Natl Cancer Inst 2014.

Family History

• Any ovarian cancer

– Treatment details

• Early onset breast cancer

• Male breast cancer

• Multiple primary breast cancer

• Many relatives affected over multiple generations

• Breast and ovarian cancers

• Ashkenazi descent

Breast, Ovarian, Pancreas, Prostate, Uterine*

BRCA1

Breast, Ovarian, Male breast cancer, Prostate, Melanoma

BRCA2

Ovarian BRIP1, RAD51C/D, BARD1*, PALB2*

Breast ATM, CHEK2, PALB2, NBN

Colon, Endometrial, Ovarian, Stomach, Small bowel, Pancreas, GU

Lynch syndrome:MLH1, MSH2, MSH6, PMS2, EPCAM

*data limited

BRCA 1 & 2

Roy et al. Nature Reviews Cancer, 2012.

• Risk of ovarian cancer to age 80 with BRCA 1 or 2 mutation is 20‐40%

– BRCA1

• Highest risk of ovarian cancer ~40%

• Earlier onset

– BRCA2

• Ovarian cancer risk ~20%

• Male breast cancer

Moderate Penetrance Genes

• BRIP1

– Cumulative life time risk 4‐13%

– Crosses population risk age 45‐49

• RAD51C


– Crosses population risk age 55‐59

• RAD51D


• Crosses population risk age 45‐49

Song et al. J Clin Oncol. 2015Loveday C et al. Nat Genet. 2011

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Lynch Syndrome and Gynecologic Cancer

Ryan et al. JAMA Oncol. 2017.Schmeler et al. NEJM 2006.

Lifetime risk of ovarian cancer up to ~15%

Lifetime risk of endometrial cancer up to ~70%

Median age of diagnosis = 46 and 42 years for endometrial and ovarian cancer respectively

The Fallopian Tube hypothesis

Serous Tubal Intraepithelial Carcinoma (STIC)

• Identified in 5 – 15% of women with BRCAmutations undergoing risk‐reducing surgery

• Identified in up to 80% of women with BRCA associated HGSC

• Identified in up to 40‐60% women with sporadic HGSC

• No other ovarian precursor lesion has been identified

Callahan et al, J Clin Oncol. 2007.Lee et al, Int J Gynecol Path. 2013.Przybycin et al, Am J Surg Path. 2010.

Image credit: Carolyn Hrubran, NCI.org.

A Note about Screening:

• High risk women have traditionally been recommended to undergo TVUS and serum CA125 measurements q6 months starting ~age 30

• FDA Statement 9/7/2016

– Recommendation AGAINST using currently offered tests to screen for ovarian cancer for all women, including those at increased risk:

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Uterine Washings as a Novel Screening Tool

Uterine Lavage• Biomarker assessment

• CA125 • YKL‐40• HE4• Mesothelin

• Mutational profile• To characterize the

repertoire of mutations present in uterine washings as compared to matched tumor and normal DNA

• MSK‐IMPACT

Risk‐reducing Salpingo‐oophorectomy (RRSO)

• The most effective risk‐reducing strategy

• Surgeon experienced in risk‐reducing procedures

– Minimally invasive

– Retroperitoneal approach

– Complete excision of the fallopian tube*

• Pathologist experienced in risk‐reducing procedures

– SEE‐FIM (Sectioning and Extensively Examining the Fimbriated end)

• Distal 2cm of tube– Transect from rest of tube

• Cut into 4 pieces longitudinally– Section transversely every 2‐3mm

• Remainder of tube– Section transversely every 2‐3mm

SEE‐FIM: Sectioning and Extensively Examining the Fimbriated end

Crum et al. Curr Opin Obstet Gynecol. 2007.

RRSO in BRCA mutation carriers

Study Design N (RRSO) Ovarian CancerBreast Cancer

HRStudy

Kauff, et al.NEJM 2002

Prospective 98HR = 0.15

(95% CI: 0.02‐1.31)

HR = 0.32(95% CI: 0.08‐

1.20)

Kauff, et al.NEJM 2002

Rebbeck, et al.NEJM 2002

Retrospective 259HR = 0.04

(95% CI: 0.01‐0.16)

HR = 0.53(95% CI: 0.33‐

0.84)

Rebbeck, et al.NEJM 2002

Rutter, et al.JNCI 2003

Retrospective 251OR = 0.29

(95% CI: 0.12‐0.73)

Rutter, et al.JNCI 2003

Finch, et al.JAMA 2006

Combined 1045HR = 0.20

(95% CI: 0.07‐0.58)

Finch, et al.JAMA 2006

Kauff, et al.JCO 2008

Prospective 881HR = 0.12

(95% CI: 0.03‐0.41)

HR = 0.53(95% CI: 0.29‐

0.96)

Kauff, et al.JCO 2008

Domchek, et al.JAMA 2010

Combined 939HR = 0.14

(95% CI: 0.04‐0.59 )

HR = 0.54 (95% CI: 0.37‐

0.79)

Domchek, et al.JAMA 2010

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Prevention: Recommendations

• BRCA1 mutation carriers

• 11‐21% risk of ovarian cancer by age 50

• Recommend consideration of RRSO beginning at age 35

• If patient chooses to defer (e.g., personal choice, to complete child bearing, etc), should complete by age 40

• BRCA2 mutation carriers

• 2‐3% risk of ovarian cancer by age 50

• Recommend consideration of RRSO beginning at age 40

• If patient chooses to defer (e.g., personal choice, to complete child bearing, etc), should complete by age 45‐50

King MC, et al. Science. 2003Satagopan J, et al. Clin Cancer Res. 2002Rebbeck TR, et al. J Natl Cancer Inst. 1999

Prevention: Moderate penetrance genes

• Data on the impact of RRSO is not yet available

• Consider family history

• Consultation with Clinical Genetics

• Data suggests that mutations in BRIP1, RAD51C, RAD51D, and possibly RAD51B are associated with statistically significant increases in the risk of ovarian cancer (RR>5)

– Most cases were >50 years.

– Discuss the risks and benefits of performing RRSO between ages 45‐50

• Other moderate penetrance genes (e.g. CHEK2, ATM, PALB2, NBN, MRE11A, BARD1)

• There is currently insufficient evidence to recommend RRSO based on germline mutation only

Tung and Robson et al. Nat Rev Clin Oncol. 2017

What is the Role of Hysterectomy? Keep this in mind:

Lifetime Risk of Developing Cancer: Approximately 2.8 percent of women will be diagnosed with endometrial cancer at some point during their lifetime, based on 2012‐2014 data.

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Study N Population Screening BRCA1 BRCA2

Goshen et al., 2000 56 Unselected Canadians

Selected founder/protein truncation

0 0

Levine et al., 2001 199 Ashkenazi Jewish

Ashkenazi founder 1 (0.5%) 2 (1%)

Biron‐Shental et al., 2006 22 Israeli Jewish Ashkenazi founder 3 (13.6%) 3 (13.6%)

Lavie et al., 2010 51 Ashkenazi Jewish

Ashkenazi founder 7 (11.9%) 1 (1.7%)

Pennington et al., 2013 151 Unselected Americans

Comprehensive analysis 3 (2.0%) 0

Is there an Increased Risk of Uterine Cancer with BRCA mutations? Is there an Increased Risk of Uterine Cancer with BRCA mutations?

Tamoxifen as a confounder

• Prospective cohort study of 857 women with BRCA mutations

– 6 endometrial cancers (1.13 expected): SIR 5.3 (p=0.0011)

• 4 of 6 had a history of Tamoxifen use

• In those with history of Tamoxifen use, SIR 11.6 (p=0.0004)

• In those with no history of Tamoxifen use, risks were not significantly elevated SIR 2.7 (p=0.17)

• Prospective cohort of 4456 BRCA+ women

– 17 endometrial cancers: Cumulative risk 2.8 %

• 13 BRCA1 carriers SIR 1.91 (p=0.03)

• 4 BRCA2 carriers SIR 1.75 (p=0.2)

• Risks NOT controlled for Tamoxifen use

– Cumulative risk in pts with Tamoxifen use 4.3%

Beiner et al. Gynecol Oncol 2007Segev et al. Gynecol Oncol. 2013.

• Prospective multi‐site cohort of 1083 BRCA+ women s/p RRSO

– Increased incidence of uterine cancer compared to age specific SEER rates

• 8 new uterine cancers (4.3 expected)

– 5 were serous or serous‐like (4 BRCA1, 1 BRCA2)

• Risk of serous ca by age 70 for BRCA1: 2.6 – 4.7%

• 7‐13 years after RRSO

• Tumor analysis confirmed loss of wild‐type BRCA1 gene/protein in all 3 of the available BRCA1 serous ca

Statistically Significant or Clinically Significant?

Study Limitations:• Conclusions based on only 4 cases • Confounding by breast cancer history

and/or tamoxifen use• SEER misclassification/underreporting of

rare EC subtypes

Shu, et al JAMA Oncol 2016Hysterectomy is Cost‐Effective

• Cost‐effectiveness analysis of hysterectomy with RRSO for prevention of serous‐like endometrial cancers in BRCA1 mutation carriers

– Used conservative risk from Shu paper 2.6%

– 40 yo undergoing hysterectomy/BSO gains 4.9 additional months survival vs RRSO alone

– RRSO alone $9013 versus hyst/RRSO $8803

RRSO/hysterectomy dominant strategy

Havrilesky et al. Gynecol Oncol. 2017..

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Perspective

• In the most widely referenced study on this subject, there would have been 135 hysterectomies done to prevent one case of endometrial cancer

• It’s not “just” about the BRCA‐related risk of uterine cancer. Evaluate non‐BRCA related issues of uterus and cervix:

– Presence of large fibroids

– Recurrent cervical dysplasia

– Prolapse

• Empower patients to make a decision that is best for them

Hysterectomy = Safer Hormone Replacement

• Estrogen + Progesterone in postmenopausal women with a uterus increases breast ca incidence and death from breast cancer

– Increase persists post‐intervention

– 16608 women randomized, median intervention 5.6 years

• Estrogen alone in postmenopausal women with prior hysterectomy reduces breast cancer incidence and deaths from breast cancer

– Effect persists for several years post‐intervention, but is lost in late post‐intervention

– 10739 women randomized, median intervention 7.2 years

Chelebowski, et al. JAMA Oncol. 2015Chelebowski, et al. JNCI. 2015

• Prospective cohort study of BRCA carriers in 80 countries

• 872 BRCA1 carriers with a mean f/u of 7.6 years

– HRT use after RRSO was not associated with increased breast cancer risk (HR 0.97, 95% CI 0.62 – 1.52)

• Estrogen alone incidence 12%

• Estrogen + progesterone 22% (P=.04)

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What is the role of salpingectomy in high risk women?

Premature Menopause is Unacceptable to Some Women

• Quality of life post‐RRSO

– Vaginal dryness (52.1%), reduced interest in sex (50.0%), sleep disturbances (46.7%), impaired sex life (43.9%), hot flashes (42.9%).

• Health implications: CV disease, bone health, lipid levels, etc

• Most women continue to experience some degree of menopausal symptoms despite HRT

• Many women will delay, or even decline, RRSO

– In GOG199, 36% opted for screening

– Only 60‐70% of BRCA mutation carriers are estimated to have undergo RRSO and only 43% of those <40 years

Bradbury Genet Med 2008.Campfield Bonadies, Fam Cancer 2011Madalinska J Clin Oncol 2006

PROS

• Risk reduction without added morbidity of menopause

• Opportunity to inspect peritoneal cavity

• Pathologic evaluation of fallopian tubes

• If a STIC is identified, completion oophorectomy

CONS

• Degree of protection is unknown

• Diminished breast cancer risk‐reduction

• Need for 2 operations

• Possibility that women will declined completion oophorectomy

Interval Salpingectomy with Delayed Oophorectomy (ISDO) What About the Breast Protection?

• Prospective analysis of 3700 BRCA+ women RRSO was not associated with risk of breast cancer

– HR 0.96 (95% CI = 0.73 to 1.26, P = 76) for BRCA1

– HR 0.65 (95% CI = 0.37 to 1.16, P = 14) for BRCA2

– In stratified analysis, RRSO was associated with decreased risk in BRCA2carriers diagnosed prior to age 50 (HR = 0.18, 95% CI = 0.05 to 0.63, P = 007), but not in BRCA1 carriers (HR = 0.79, 95% CI = 0.55 to 1.13, P = 51)

• Breast cancer protection likely overestimated in prior studies

Kotsopoulos et al. JNCI report, 2017.

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Women choosIngSurgical Prevention (WISP) Trial

• Two‐arm, non‐randomized multi‐center clinical trial

– Premenopausal women between age 30 – 50 with a deleterious mutation in BRCA 1 or any of the 9 other known ovarian cancer genes

– Patient choice: ISDO vs RRSO

• To determine if ISDO is a safe and acceptable prevention strategy that can improve sexual functioning and other measures of psychosocial well‐being compared to RRSO.

WISP Accrual, November 2018

4 5 8 12 15 16 1823

3843 46 48 52

6069

7787

105114

124131 135

143149

154163

168180

0

20

40

60

80

100

120

140

160

180

200

Jul‐16

Aug‐16

Sep‐16

Oct‐16

Nov‐16

Dec‐16

Jan‐17

Feb‐17

Mar‐17

Apr‐17

May‐17

Jun‐17

Jul‐17

Aug‐17

Sep‐17

Oct‐17

Nov‐17

Dec‐17

Jan‐18

Feb‐18

Mar‐18

Apr‐18

May‐18

Jun‐18

Jul‐18

Aug‐18

Sep‐18

Oct‐18

Number of E

nrolled Patients

Month‐Year

Cumulative Accrual By Month

Women choosIng Surgical Prevention (WISP) Trial

3324

30

1523

43

7 5

180

17 14 127

18 18

3 2

91

1610

188 5

25

4 3

89

0

20

40

60

80

100

120

140

160

180

200

MD Anderson

(June 2016)

Mayo Clinic

(September2016)

University of

Washington(October 2016)

University of

Chicago(October 2016)

DFCI (January

2017)

MSKCC

(January 2017)

NYU

(September2017)

Upenn

(September2018)

TOTAL

WISP Accrual by Site

All ISDO Arm RRSO Arm


WISP Accrual, November 2018

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Lu K et al, SGO 2019


Lu K et al, SGO 2019

Women choosIngSurgical Prevention (WISP) Trial Risk‐Reduction at MSK

• 6/2015 – 4/2018

– 615 high risk unaffected patients were seen in consultation to discuss risk‐reducing surgical options (~18/month)

N (%)

BRCA1BRCA2Moderate PenetranceNo mutation identified/FH alone

235 (38%)219 (36%)10 (2%)152 (25%)

Consult only 259 (42%)

Surgical Risk‐ReductionRR SORR SO + hysterectomyISDO

356 (58%)240 (67%)95 (28%)18 (5%)

Filippova & Long Roche, 2018, submitted.

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Risk‐Reduction at MSK

• In those undergoing salpingo‐oophorectomy (N=345):

N (%)

Post‐menopausal 104 (30%)

Premenopausal 241 (70%)

Menopause discussion documentedMenopause management discussion documented

Eligible for HRTRx given for HRTNon‐hormonal therapyReferral to other provider for menopause management

200 (83%)165 (69%)

130 (54%)33 (25%)7 (5%)84 (65%)

* Of the 33 patients given HRT, 22 (67%) BRCA1, 11 (33%) BRCA215 (45%) had a hysterectomy and were treated with estrogen alone

Filippova & Long Roche, 2018, submitted.

• Seize the opportunity to prevent ovarian cancer

– Genetic testing

– Incremental testing if indicated

– Fallback on family history

– Referral for risk‐reduction

• Continue work on early detection

• Improve risk‐reducing options while valuing quality of life

– Salpingectomy with delayed oophorectomy on trial

– Better menopausal management

– Inform patients and discuss their individual options

Moving Forward

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Thank You

TEAM OVARY

• Dennis Chi

• Kara Long‐Roche

• Yukio Sonoda

• Oliver Zivanovic

• NadeemAbu‐Rustum

• Vance Broach

• Carol Brown

• Deborah Goldfrank

• Elizabeth Jewell

• Mario Leitao

• Jenny Mueller

• Carol Aghajanian

• Gyn Surgery Fellows

• Olga Filippova

And endless thanks to the brave women and families affected by

ovarian cancer.

gardner miami brca 2019 final -...

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