Ovarian Cancer and Contraception for Women with Known Hereditary Risk

Kelly M. Joy, MS, MSPAS, PA-C A 36 yo WF calls her GYN clinic requesting a refill of oral :

Case Study • Non-smoker

• Mother with history of breast cancer x 2

• Patient and mother test positive for BRCA 2 gene

• Patient is recently post-op from elective prophylactic double • Patient declines prophylactic bilateral - (BSO) as she desires fertility • Patient is not currently married or in a relationship and has no immediate plans to conceive Genetic Testing and Counseling

-With expanded genetic testing more and more women are being identified as carriers prior to the onset of

-Research shows that many patients testing positive for high-risk hereditary • FDA-authorized Direct-To-Consumer BRCA Test conditions receive ineffective counseling • Self-collected saliva sample for management • Online results • Low cost  Too much information  Complex terminology  Information perceived as not relevant by Ineffective the patient Counseling  Poor patient engagement  Vague discussions of screening and recommendations  As primary care providers...

What can we -We can expect more women with known hereditary risk for ovarian cancer in our clinics expect?

-We can expect that they will be confused/uninformed about their management options

...even about something as simple as contraception 1. Review common theories regarding the development of ovarian cancer

2. Review the most common hereditary syndromes with ovarian cancer in their pedigrees (HBOC and Lynch syndrome)

Objectives 3. Discuss contraception options for those patients without a personal history of cancer but with a known hereditary risk for ovarian cancer who decline prophylactic

4. Discuss how these contraception methods effect other aspects of HBOC and Lynch syndrome, specifically the risk for breast and endometrial cancer Ovarian Cancer (OC)

- Fifth most common cause of cancer death in women -Leading cause of mortality from gynecologic malignancy -Symptoms are vague or absent -No adequate protocol for screening -Often diagnosed at an advance stage, therefore low rate of survival "Incessant ovulation"

Theories of  Ovarian Retrograde menstruation Carcinogenesis Transplantation from the fallopian tubes Incessant Ovulation -Repetitive minor trauma -Subsequent acute inflammation -Exposure of the ovarian surface to estrogen

Fathalla 1971  Risk factors for OC: -nulliparity Support for -early menarche the Role of -late menopause Ovulation in OC  Decreased OC risk: -parity Development  Provide physiologic rest from ovulation -breastfeeding -oral contraceptive use Retrograde Menstruation -OC forms as a result of the retrograde transport of carcinogenic substances from the vagina and uterus to the peritoneal cavity Support for the Role of  Endometrioid and clear cell ovarian tumors have been Retrograde associated with endometriosis which is typically Menstruation thought to result from retrograde menstruation in OC Development Cell Transplantation from Fallopian Tubes Support for the Role of  Histological studies of fallopian tubes from women with a genetic predisposition for the development of Malignant Cell OC (having prophylactic BSO) have shown in situ and Transplantation small early invasive tubal carcinomas in OC Development Hereditary Breast- Hereditary ~10% of Ovarian Cancer Nonpolyposis Colorectal Syndrome (HBOC) Cancer (HNCC) or Lynch ovarian Syndrome cancers are  90% of the ovarian cancers  Syndrome caused by are positve for mutation in mutations in MMR genes associated BRCA1 or BRCA2 genes  Risk of developing ovarian with a  Risk of developing ovarian cancer 9-12% by age 70 cancer 39-46% by age 70 for hereditary BRCA1 mutation carriers and  Endometrial cancer risk 10-27% by age 70 for BRCA2 genetic mutation carriers mutation  Breast cancer risk  Presents at a younger age than sporadic ovarian cancer

 Due to the early age of onset, lethality of the disease, Hereditary and the lack of adequate screening protocols focus is OC directed to primary prevention

 For patients with known hereditary risk primary prevention is accomplished through prophylactic BSO National Comprehensive Cancer Network (NCCN): Clinical Practice Guidelines in Oncology For BRCA mutation carriers without a personal history of cancer:

• Risk-reducing BSO is recommended for women who have completed child-bearing.

• BSO is recommended between the ages of 35 and 40 but may be individualized based on reproductive plans and the age at onset of ovarian cancer in the family.

• It may be reasonable to delay BSO in BRCA2 mutation carriers to 40-45 years of age as cancer onset tends to be 8-10 years later in these patients compared to BRCA1 mutation carriers. NCCN: Clinical Practice Guidelines in Oncology For Lynch Syndrome:

• with BSO is recommended as a risk-reducing option for women who have completed childbearing.

• Timing should be individualized to the patient based on reproductive plans, menopause status, comorbidities, family history, and the type of gene mutation, as risk varies by mutated gene.

• Ovarian cancer risk- the mean age of onset for MLH1 and MSH2 mutations is between 43 and 45 years of age.

• Endometrial cancer risk- the mean age of onset across all mutations is between 48 and 62 years of age. What are the contraception options for women without a personal history of cancer but with an identified hereditary ovarian cancer predisposition wishing to preserve fertility or delay menopause?

Is there something we can provide that could mitigate ovarian cancer risk? Off-label Prescribing

Most birth control methods are only approved by the FDA for contraception purposes.

But often they are prescribed off- label when there are data indicating efficacy for other conditions. Off-label uses for birth control: • Irregular menses • Menorrhagia • Dysmenorrhea • Acne • Premenstrual dysphoric disorder (PMDD)  Ovarian Cancer Prevention The Most  Oral contraception Commonly  Female sterilization (ex. tubal ligation) Used  Male condom  Long-acting reversible contraception (LARC- exs. Contraceptive subdermal implants and intrauterine devices) Methods

*2011–2013 National Survey of Family Growth, CDC Oral  Many studies have demonstrated a decreased risk of ovarian cancer with oral contraceptive Contraception use Trends in Oral Contraceptive Pill (OCP) Use -US Cancer Surveillance Epidemiology, and End Results (SEER) data -1957 the pill approved by the FDA for severe menstrual disorders -1960 the pill is approved for contraception -1965 ~6.5million women are on the pill

Webb et al. 2017 Trends in Oral Contraceptive Pill (OCP) Use -1968 Pope Paul VI declares opposition to the pill in the Humanae Vitae encyclical -1969 Barbara Seaman publishes The Doctor's Case Against the Pill which exposed the potential side effects of the pill including the risk of blood clots, heart attacks, strokes, etc... -1979 Sales of the pill drop by 24% in 4 years due to publicity

Webb et al. 2017 Adjustments are made to pill dosage and formula Trends in Oral Contraceptive Pill (OCP) Use -1988 original high dose pills are taken off the market and an FDA study shows the benefits of newer pills including a decreased risk for Fe def anemia, PID and.... Ovarian Cancer

-1990's- Norplant, Depo Provera, Plan B -2000's- Ortho Evra, NuvaRing, Implanon, Essure

Webb et al. 2017  The pill was approved as contraception in 1960

Ovarian Cancer Incidence by Birth Cohort -Ovarian cancer rates were increasing until the US cohort born in 1918 who were the first to use OCP -Ovarian cancer rates decreased dramatically across cohorts -The ovarian cancer risk rates for the 1968 cohort were ~½ those of women born 45 years earlier Webb et al. 2017  The protective effects of oral contraception have been observed across all major epithelial OC types  Estimated 30% risk reduction for any patient that has ever used OCP Oral  Risk reduction increases to ~50% for those using the Contraception drugs >10years  Risk reducing effects against OC may persist for ~20 and OC Risk years and do NOT seem to be associated with a particular drug formula  Additionally, historical use of OCP seems to confer a more favorable prognosis in patients diagnosed with OC OCP and OC HBOC Lynch Syndrome

 Studies suggest similar risk  Use is relevant due to ovarian reduction for BRCA1/BRCA2 cancer risk reduction in the OCP and as in the general population general population Hereditary OC Risk  Maximum benefit ≥5years for  Additionally, OCP has been BRCA1 and ≥3years use for associated with reduced BRCA2 mutation carriers rates of colorectal and endometrial cancer which increases its relevance in these patients  So, why isn't OCP recommended as chemoprevention?

Breast Cancer Risk

• The use of OCP in BRCA mutation carriers could increase their risk for breast cancer

• It has been recommended that BRCA1 mutation carriers avoid OCP for the prevention of OC before the age of 25

• Studies suggest the risk is mostly due to the estrogen component

• No link in Lynch Syndrome  Levonorgestrel is a second- generation progestin and a common component of oral contraception

Levonorgestrel-  A device placed in the uterus releasing to prevent pregnancy for up to 5 years Intrauterine Devices  Like OCP these devices are effective in decreasing (LRG-IUD) menstrual flow

 The most common on the US market are Mirena®, Skyla®, Kyleena®, Liletta®  A cohort study of Finnish women in 2016 demonstrated a 41% ovarian cancer risk reduction with the use of LRG-IUD's in the general population LRG-IUD and  The decreased risk was observed in all the main OC Risk histologic OC types

 It has been proposed that a high local progestin effect could be responsible for modifying ovarian cancer risk LRG-IUD and OC HBOC Lynch Syndrome

 Use is relevant due to  Use is relevant due to ovarian ovarian cancer risk reduction cancer risk reduction in the in the general population general population LRG-IUD and Hereditary OC Risk  Studies of progestin-only  There are data to support contraception in the general decreased endometrial population have shown no proliferation with the use of increased risk of breast progestin-only contraception cancer in Lynch syndrome patients Tubal Ligation (TL) and Salpingectomy -Banded -Tied and cut -Cauterized -Section Removed  The Nurses' Health Study of 2014 demonstrated that TL conferred a 24% risk reduction for ovarian cancer

 Association was not stronger among women who had the procedure before the age of 35 TL and OC  No association based on years since TL

 A separate meta-analysis demonstrated a profound reduction noted for endometrioid OC -Endometrioid and clear -Some ovarian cancers may cell ovarian tumors have develop from the been associated with transplantation of malignant endometriosis which is cells from the to typically thought to result the ovary from retrograde menstruation  The proposed mechanism for OC prevention with TL is the formation of a mechanical barrier to prevent the transport of carcinogenic substances to the peritoneal cavity

 An obvious limitation is its lack of effect on the distal TL and OC fallopian tube where high risk epithelial OC is known to originate

 Opportunistic/prophylactic salpingectomy has been proposed for OC prevention, but ACOG has recommended more research "to support the validity of this approach"  While unequivocal evidence is lacking, research has demonstrated trends that support the protective effect of TL in women with a hereditary risk of OC TL and  Caution should be used for BRCA1 and BRCA2 Hereditary mutation carriers as research is suggesting that OC OC Risk may originate in the distal fallopian tube in these patients  With expanded DNA testing the number of patients with an identified hereditary risk of ovarian cancer is increasing

 Due to ineffective counseling routine management of these patients will likely fall to those of us in primary care

 Management focus is on prevention Conclusions  BSO/hysterectomy after child bearing is complete

 Contraception options exist for those patients delaying prophylactic surgery to preserve fertility or delay menopause

 OCP, LRG-IUD, and TL are all associated with a decreased risk for OC Questions? References

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