Ovary Part 5

Ovarian Cancer
Written By Sydney Oesch

Episode Notes

  1. Epidemiology

    1. Less common epithelial ovarian cancers (LCEOC) make up 15-20% of all epithelial ovarian cancers.

      1. Low grade serous: <5%

  2. Workup/Evaluation

    1. FIGO staging system is the same for all ovarian cancers, and staging procedures mimic staging for HGSOC.

    2. Many less common epithelial ovarian cancers are diagnosed postoperatively; refer back to Ovary Part 1 for a review of how to stage these patients

    3. Fertility sparing approaches to treatment can be considered for clinical stage 1 epithelial tumors and borderline tumors

      1. Fertility sparing surgery in clear cell ovarian carcinoma is controversial

      2. Fertility sparing surgery is NOT recommended for ovarian carcinosarcoma/malignant mixed mullerian tumors

  3. Low Grade Serous Ovarian Cancer

    1. Majority (90%) are stage II-IV at time of diagnosis and majority (60%) are associated with serous borderline tumors

    2. Classic mutations include MAPKinase pathway, with KRAS and BRAF mutations

    3. Less chemoresponsive than high grade serous tumors, and NACT typically not employed. Primary debulking surgery is preferred.

    4. Adjuvant therapy

      1. Observation appropriate for stage I disease, with inconclusive recommendations for chemotherapy for stage IC disease

      2. Stage II+ disease recommended for systemic therapy with carbo/taxol +/- bevacizumab with consideration of hormonal therapy

        1. NRG-GY019 study is ongoing evaluation up front carbo/taxol/letrozole vs. letrozole monotherapy for treatment of LGSOC

      3. Maintenance after primary therapy

        1. Retrospective study (Gershenson et al 2017) demonstrated a 40m benefit in PFS for patients treatment with maintenance hormonal therapy (AI vs. SERM); based on this study, some routinely prescribe maintenance hormonal therapy after completion of up front systemic therapy

    5. Recurrent/persistent disease

      1. Consider secondary cytoreduction

      2. Systemic cytotoxic therapy options are similar to HGSOC

      3. Targeted therapies

        1. MEK inhibitors: trametinib and binimetinib. GOG281 evaluated trametinib vs. SOC chemotherapy for recurrent disease; PFS benefit in the ITT population was 13m vs. 7.2m, with improved response in patients with KRAS, BRAF, and NRAS mutations.

        2. BRAF inhibitors: Dabrafenib (specifically targets BRAFV600E mutation). NCI-MATCH study led to FDA approval of dabrafenib and trametinib combination therapy for patietns with BRAFV600E mutations.

      4. Hormonal therapy is an option for treatment of recurrent LGSOC

  4. Borderline tumors

    1. Previously called low malignant potential tumors, true borderline tumors do not invade the basement membrane. Most are serous or mucinous. 

    2. >80% 5 year survival, bilateral 50% of time. 

    3. Subclasses

      1. Ovarian microinvasion: <5mm focus of ovarian stromal invasion. Not associated with increased recurrence/cancer risk, treated as borderline

      2. Microinvasive implants outside of the ovary. 30% risk of recurring with invasive disease

        1. Controversy regarding classification and management: NCCN and ESGO > treat as borderline/not invasive LGSOC; WHO>treat as metastatic low grade serous carcinoma

      3. Micropapillary features also increase risk of recurrence

    4. Management: surgery. LN evaluation not necessary as does not improve prognosis. Omentectomy and peritoneal biopsies recommended. 

  5. Mucinous ovarian carcinoma

    1. Most mucinous tumors in the ovary are metastatic! Crucial to differentiate primary mucinous ovarian carcinoma from mucinous carcinoma metastatic to the ovary.

    2. GI evaluation should be performed to rule out GI disease. CA 19-9 and CEA can be helpful, as can some pathologic stains.

    3. Primary mucinous ovarian carcinomas 

      1. Often have KRAS mutations, p53 mutations, and may have HER2 mutations

      2. Infiltrative subtypes more aggressive, expansile subtypes less aggressive

    4. Staging: 

      1. Consider appendectomy, can defer if appendix grossly normal

      2. Lymphadenectomy: can be omitted if no clinically enlarged nodes, some perform for infiltrative subtypes

    5. Early stage ovarian mucinous carcinomas have a good prognosis, but metastatic mucinous carcinomas have very poor prognosis (median PFS 10.5m after primary treatment, median OS 17m)

    6. Adjuvant therapy: 

      1. GI regimens often preferred over ovarian ca regimens (carbo/taxol) due to retrospective data demonstrating improved outcomes: 5-FU/leucovorin/oxaliplatin (FOLFOX) or capecitabine/oxaliplatin (CAPOX). Consider addition of bevacizumab, which increases toxicity.

  6. Endometrioid carcinoma

    1. Accounts for 10% of all ovarian carcinomas. Often diagnosed at early stage. Chemo-responsive. Associated with endometriosis.

      1. 15-20% will have concurrent endometrioid endometrial carcinoma; important and difficult to determine primary site

    2. Characterized by PTEN, CTNNB1 mutations. Usually ER+.

    3. Adjuvant therapy

      1. Recommended for stage IC+

      2. Treatment recommendations follow same algorithm in NCCN as LGSOC.

  7. Clear cell carcinoma

    1. Very small fraction of ovarian cancer in the U.S., but up to 25% of all ovarian cancers in Japan

    2. Characterized by ARID1a mutations. Associated with endometriosis.

    3. Unique presentation: associated with thrombosis and hypercalcemia

    4. Not recommended for fertility sparing surgery

    5. Adjuvant therapy: recommended for all stages of disease! Carbo/taxol +/- bevacizumab

  8. Carcinosarcoma

    1. Previously known as malignant mixed mullerian tumors

    2. Most aggressive ovarian neoplasm, thought to be a variant of poorly differentiated epithelial ovarian cancer

    3. Not recommended for fertility sparing surgery

    4. Adjuvant therapy: recommended for all stages of disease! Carbo/taxol +/- bevacizumab

Ovary Part 5 Reference List

 1.    Gershenson DM, Bodurka DC, Coleman RL, Lu KH, Malpica A, Sun CC. Hormonal Maintenance Therapy for Women With Low-Grade Serous Cancer of the Ovary or Peritoneum. J Clin Oncol. 2017;35(10):1103-1111. doi:10.1200/JCO.2016.71.0632

2.       Monk BJ, Grisham RN, Banerjee S, et al. MILO/ENGOT-ov11: Binimetinib Versus Physician’s Choice Chemotherapy in Recurrent or Persistent Low-Grade Serous Carcinomas of the Ovary, Fallopian Tube, or Primary Peritoneum. J Clin Oncol. 2020;38:3753-3762. doi:10.1200/JCO.20

3.       Grisham RN, Vergote I, Banerjee S, et al. Molecular Results and Potential Biomarkers Identified from the Phase 3 MILO/ENGOT-ov11 Study of Binimetinib versus Physician Choice of Chemotherapy in Recurrent Low-Grade Serous Ovarian Cancer. Clinical Cancer Research. 2023;29(20):4068. doi:10.1158/1078-0432.CCR-23-0621

4.       Gershenson DM, Miller A, Brady WE, et al. Trametinib versus standard of care in patients with recurrent low-grade serous ovarian cancer (GOG 281/LOGS): an international, randomised, open-label, multicentre, phase 2/3 trial. Lancet. 2022;399(10324):541. doi:10.1016/S0140-6736(21)02175-9

5.       Manning-Geist BL, Gordhandas SB, Giri DD, et al. Phase II study of enzalutamide in androgen receptor positive, recurrent, high- and low-grade serous ovarian cancer. Gynecol Oncol. 2022;164(1):12-17. doi:10.1016/J.YGYNO.2021.10.087

6.       Salama AKS, Li S, Macrae ER, et al. Dabrafenib and Trametinib in Patients With Tumors With BRAFV600E Mutations: Results of the NCI-MATCH Trial Subprotocol H. J Clin Oncol. 2020;38(33):3895-3904. doi:10.1200/JCO.20.00762

7.       Ottenbourgs T, van Gorp T, Kridelka F, et al. A phase II, multicenter, open-label study of abemaciclib and letrozole in patients with estrogen receptor-positive rare ovarian cancer: ALEPRO trial. Int J Gynecol Cancer. Published online March 6, 2024:ijgc-2023-005189. doi:10.1136/IJGC-2023-005189

8.       Schmeler KM, Tao X, Frumovitz M, et al. Prevalence of lymph node metastasis in primary mucinous carcinoma of the ovary. Obstetrics and gynecology. 2010;116(2 Pt 1):269-273. doi:10.1097/AOG.0B013E3181E7961D

9.       Iii WEW, Maxwell GL, Tian C, et al. Prognostic Factors for Stage III Epithelial Ovarian Cancer: A Gynecologic Oncology Group Study. Published online 2007. doi:10.1200/JCO.2006.10.2517

10.     Grisham RN, Slomovitz BM, Andrews N, et al. Low-grade serous ovarian cancer: expert consensus report on the state of the science. International Journal of Gynecological Cancer. 2023;33(9):1331. doi:10.1136/IJGC-2023-004610

Sydney Oesch
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