Gynecologic Oncology update

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1 Gynecologic Oncology update Park City Utah Postgraduate Course in the Department of Obstetrics and Gynecology University of Utah/Huntsman Cancer Institute Andrew P. Soisson, MD Division of Gynecologic Oncology

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3 Endometrial Cancer/Incidence:

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5 Introduction: ACS estimates an incidence of approximately 60,000 cases of endometrial cancer in The increased incidence appears to be occurring primarily in postmenopausal women. Since 2002, increased incidence of 2.5% for women age compared to 1.1% for women age Sheikh and associates estimate that by 2030 there will be a 55% increase in cases of endometrial cancer. SEER data suggests that approximately 15 20% of women with endometrial cancer will be less than age 50 at the time of diagnosis. 2% will be less than age 40. Endometrial Cancer/Incidence:

6 Young women with EMC, are they unique: Most investigations show that women less than 40 with EMC are obese and nulliparous. Most investigations show that young women with EMC have a better prognosis. Several authors note that young women with EMC have a greater tendency for synchronous ovarian tumors. Does not appear to be an increased incidence of Lynch Syndrome in young women with EMC. Some authors suggest that young women with EMC who are not obese have a poor prognosis. Endometrial Cancer/Incidence:

7 Criteria for treatment with progesterone: Women less than age 40. Grade 1 or II malignancies/endometriod type. No evidence of myometrial invasion, ovarian metastases, retroperitoneal adenopathy. Compliant and likely to undergo follow up. Endometrial Cancer/Fertility sparing treatment:

8 Conservative treatment types. Oral continuous medoxyprogesterone acetate (Provera) mg. Oral continuous megesterol (Megace) mg. Progesterone containing IUD. Letrozole. GnRH agonists. Metformin. Tamoxifen. Endometrial Cancer/Fertility sparing treatment:

9 Progestin therapy outcomes: Author # PTS Response Recurrence Pregnancy Chen EIN = 16 EMC = 37 EIN = 75% EMC = 73% EIN = 19% EMC = 22% EIN = 40% EMC = 14% Baek EIN = 18 EMC = 13 EIN = 89% EMC = 54% EIN = 10% EMC = 31% Falcone EMC= 28 90% 8% EMC = 87% Laurelli EMC = 21 86% 10% EMC = 83% Pronin EIN = 38 EMC = 32 EIN = 92% EMC = 72% EIN = 2% EMC = 6% Simpson EIN = 19 EMC = 25 55% Shan EIN/EMC = 26 81% Gonthier EIN/EMC = 40 Obese=67% Non obese=75% Obese=20% Non obese =12% Obese=13% Non obese=48% Gong EIN = 21 EMC = 9 EIN = 86% EMC = 56% EIN = 57% EMC = 50% EIN = 48% EMC = 44% Ohyagi EIN = 11 EMC = 16 EIN + 82% EMC = 69% EMC = 82% EIN = 75 92% EMC = 54 90% EIN = 2 57% EMC = 6 82% N = 10 EIN = 48 87% EMC = 14 87%

10 Conservative treatment types. 55 women less than age 40 with EIN or EMC at IHC and the University of Utah/HCH Number (%) Megace 35 64% Provera 13 24% Mirena 6 11% Norethindrone 1 2% Endometrial Cancer/Fertility sparing treatment:

11 55 women less than age 40 with EIN or EMC at IHC and the University of Utah/HCH Number (%) Cancer 17 31% Hyperplasia 38 69% G % Hispanic 12 22% Asian 2 4% Pacific Islander 7 13% Middle Eastern 1 2% Caucasian 33 60% BMI 40 Referral to REI 23 36% Endometrial Cancer/Fertility sparing treatment:

12 55 women less than age 40 with EIN or EMC at IHC and the University of Utah/HCH Number (%) Response 31 56% Non response 24 44% Recurrence/pers 20 istence 36% Pregnancy 20% 11 REI + pregnancy 22% No REI + pregnancy 19% Endometrial Cancer/Fertility sparing treatment:

13 Progestin therapy outcomes/ University of Utah/IHC: 18 women with EMC who elect to undergo fertility sparing treatment. 72% are nulligravid. Response rate = 27% 83% develop recurrence or persistence of disease, 72% ultimately have hysterectomy. No patients achieve pregnancy, 50% consult REI. No difference in BMI responders versus non responders. Endometrial Cancer/Fertility sparing treatment:

14 Conservative treatment types/anastrozole. Letrozole shown to have anti proliferation effects on endometrial cancer cell lines. 16 women treated with preoperative anastrozole prior to hysterectomy: decreased cellular proliferation, decreased expression of ER and AR. Case report of 2 women with EMC treated with provera and anastrozole. We have treated 4 women with progesterone and anastrozole. Endometrial Cancer/Fertility sparing treatment:

15 Conservative treatment types. Type of progesterone has not been well studied, most studies utilize medoxyprogesterone acetate (Provera) or megesterol (Megace) with a wide range of doses. Dose varies in multiple studies: GOG studied 200 mg versus 1,000 mg of Provera with no difference in response: in breast cancer recurrence 800mg of Megace better than 160mg. Route of administration: Randomized trial in EIN showed 100% response with IUD compared to 96% for continuous oral progesterone and 69% for cyclic oral progesterone. Side effects: Cholakian demonstrated less weight gain and systemic side effects with IUD versus oral progesterone. Endometrial Cancer/Fertility sparing treatment:

16 Recommended treatment of EIN/EMC. Candidates for fertility sparing treatment should be less than 40 with a grade I or II endometriod cancer. MRI with no MI, ovarian metastases, or retroperitoneal adenopathy. Pretreatment hysteroscopy with resection of visible tumor and D&C. Treatment with progestin IUD for 6 12 months. Consider anastrozole if morbidly obese. Follow up hysteroscopy and D&C to asses response. Close follow up as recurrence rates are high. Endometrial Cancer/Fertility sparing treatment:

17 Rationale for oophorectomy during hysterectomy: Estrogen sensitive tumor and preservation of the ovaries will compromise cure and increase the risk of recurrence of tumor. Risk of synchronous ovarian cancer. Risk of metastases to the ovary. Increased risk of subsequent epithelial ovarian cancer. 3 5% of women with endometrial cancer have the Lynch Syndrome. Endometrial Cancer/Ovarian preservation:

18 Ovarian preservation: survival Author # Patients Survival outcome Lau 17 ND Lee 175 ND Li 20 ND Sun 20 ND Wright 402 ND Wright 1121 ND Matsuo 4109 ND Gu 1419 ND Koska 184 ND N= ND Endometrial Cancer/Ovarian preservation:

19 Ovarian preservation: Incidence of synchronous and metastatic tumors. Author # PTS Incidence synchronous tumors Incidence metastatic tumors Walsh % 3% Lee 260 3% 5% Pan 976.3% 2% Navarria % Kinjyo 48 5%.3 23% 2 5% Endometrial Cancer/Ovarian preservation

20 Universal screening for Lynch: Incidence in the general population to Approximately 2 3% of CRC associated with HNPCC syndrome, 3 10% for women less than 50. Approximately 3 5% of EMC associated with HNPCC. 3 relatives with CRC or Lynch syndrome associated cancer. Endometrial hyperplasia in women less than 50 years of age should not be an indication for HNPCC screening. Physicians do a poor job screening patients for potential risk of HNPCC. Endometrial Cancer/Lynch Syndrome screening.

21 Universal screening for Lynch: Median age = 48 years of age % life time risk of EMC, 20% less than age % risk of OVCA/median age = 45, similar histology. 80% have endometriod histology, MMT and papillary serous tumors reported. OVCA: presents at early age, early stage, and non serous histology. Risk of EMC is 26% within 10 years of diagnosis of CRC. Over half have no family history. Risk increased if less than 50 and obese. Endometrial Cancer/Lynch Syndrome screening.

22 Universal screening for Lynch: Three or more relatives with histologically verified Lynch syndrome associated cancers (CRC, cancer of the endometrium or small bowel, transitional cell carcinoma of the ureter or renal pelvis), one of whom is a first degree relative of the other two and in whom familial adenomatous polyposis (FAP) has been excluded. Lynch syndrome associated cancers involving at least two generations. One or more cancers were diagnosed before the age of 50 years. Endometrial Cancer/Lynch Syndrome screening.

23 Universal screening for Lynch: MMR genes associated with mismatch repair system Gene name Frequency Chromosome MLH % 3p21.3 MSH % 2p22-p21 MSH6 7-10% 2p16 PMS1 unknown 2q31-q33 PMS2 <5% 7p22 MSH3 0% 5q11-q12 MLH3 0% 14q24.3 Endometrial Cancer/Lynch Syndrome screening.

24 Universal screening for Lynch: Risk of malignancy Life time risk for females CA site MLH1 MSH2 MSH6 Any 50 76% 38 78% 65% CR 50 53% 39 68% 18 30% EMC 60% 21% 30% OV 20% 24% 1% GU.4% 9% 1% PMS % 15% 15% Endometrial Cancer/Lynch Syndrome screening.

25 Universal screening for Lynch: Analysis of 272 women with EMC/universal Lynch testing University of Utah/HCH Parameter Abnormal IHC staining MLH1/PSM2 # 87 (32%) 67 Methylation + 63 Methylation 4 MSH6 + 5 MSH2/MSH PSM2 +MSH2 + 2 Candidates for sequencing 2 DNA sequencing 24 DNA sequencing + 22 Total number with Lynch 9 (3%)

26 Cost associated with universal Screening for the Lynch Syndrome. Parameter # tested Cost IHC staining 272 $54,440 DNA methylation 67 $19,765 Counseling 24 $1,364 Letters 287 $6,314 Phone calls 42 $462 DNA sequencing 22 $ Total $148,005 Cost/patient $16,445 Endometrial Cancer/Lynch Syndrome screening.

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