Systemic Therapy for Non-Serous Ovarian Carcinoma

Yanin Chávarri-Guerra; Eduardo González-Ochoa; Héctor De-la-Mora-Molina; Enrique Soto-Perez-de-Celis


Chin Clin Oncol. 2020;9(4):52 

In This Article

Endometrioid Ovarian Carcinoma

Endometrioid carcinoma accounts for 10% of EOC.[1] This tumor type presents most frequently in women aged 40–50 years, with a mean age at diagnosis of 56 years.[3] Compared with serous tumors, endometrioid carcinomas are more commonly identified at earlier stages and tend to be relatively sensitive to chemotherapy, translating into a better prognosis.[3] In a Canadian cohort of 533 patients with EOC[9] (18% endometrioid and 81% serous), 5-year OS was significantly better for those with endometroid tumors (81% vs. 35%), translating in a significantly lower risk of death (HR 0.41, 95% CI: 0.26–0.66).[9] The most widely known risk factor for this type of tumor is endometriosis, which increases the risk of by approximately 14% [odds ratio (OR) 2.04, 95% CI: 1.67–2.48].[35] Endometrioid carcinoma has also been found in women with Lynch syndrome, accounting for 10–15% of hereditary EOC, with the lifetime risk being higher for women with mutations in MLH1 (20%) or MSH2 (24%) genes.[36]

Macroscopically, endometrioid tumors are cystic, solid or hemorrhagic, without papillary formations.[10] High-grade endometrioid carcinomas have similar profiles to high grade serous carcinomas, with expression of p53, p16, and WT1.[11] Ovarian endometrioid carcinomas most frequently harbor alterations in ARID1A (33%), PTEN (32%), CTNNB1 (28%), PIK3CA (26%) and KRAS (26%).[11]

Primary treatment includes complete cytoreductive surgery with comprehensive staging followed by adjuvant treatment or observation. Fertility-sparing surgery is an option for stage IA-IC1 tumors, with half of recurrences in these cases occurring in the contralateral ovary and therefore amenable to rescue by subsequent surgery.[24] Evidence of the role of adjuvant chemotherapy in stage I is scarce. Data from a retrospective Surveillance, Epidemiology and End Results (SEER) cohort[37] including 3,552 patients with FIGO stage I endometrioid ovarian cancer showed that 5-year OS was 90% in patients who received adjuvant chemotherapy versus 89% for those who did not (P=0.80). Only in the subgroup of patients with FIGO IC, grade 3 tumors chemotherapy was associated with an improvement in 5-year OS (81% vs. 62%; HR, 0.58, P=0.03).[37] Based on this data, it is fair to say that women with stage IA/IB, grade 1/2, tumors who have had complete surgical staging have a 5-year disease-free survival (DFS) of over 90% and do not require adjuvant chemotherapy. Patients with grade 3 (any stage) and stage IC-II tumors have a less favorable prognosis, and adjuvant platinum-based chemotherapy should be considered.[38]

The optimal duration of chemotherapy is not well defined. The GOG-157 trial[39] evaluated three versus six cycles of adjuvant carboplatin (AUC 7.5) and paclitaxel (175 mg/m2) every 3 weeks in high risk early stage EOC, including 25% patients with endometrioid histology. The risk of recurrence was found to be lower for patients receiving six cycles (HR 0.76; P=0.18), although longer treatment duration was associated with more toxicity.[39] Therefore, six cycles of standard carboplatin plus paclitaxel +/− bevacizumab is the recommended therapy for stage II/IV endometrioid carcinomas, as well as for high grade serous carcinoma.

Similar to breast cancer, the majority of EOC express estrogen receptors (ER).[40] Several preclinical models have demonstrated the role of estrogen in terms of tumor proliferation and progression in EOC through direct [tumor vascular endothelial growth factor (VEGF) production via ER signaling] and indirect (increased cell migration via protein kinase signaling) pathways.[41] Sieh and colleagues[42] reported a tissue-microarray-based analysis of ER and progesterone receptor (PR) expression in 2,933 women with invasive EOC and found significant receptor expression in endometrioid tumors (77% ER and 67% PR). The expression of one or both independently was associated with improved survival (HR 0.33, P=0.001). Furthermore, receptor expression was also associated with lower grade tumors (P=0.007) and absence of macroscopic residual disease after surgery (P=0.041).[42]

Since 1982, more than 50 trials have evaluated the use of endocrine therapy in EOC, but no RCT have been reported to date. Almost all trials included patients with prior treatments. Overall, studies have large variabilities in the type of endocrine agent used (tamoxifen, letrozole, anastrozole, exemestane, etc.), and poorly defined histological subtype/ER expression thresholds, which may explain the inconsistent results. However, positive hormone receptor status and histologic subtype seem to be relevant when it comes to response to endocrine therapy.[40] In a meta-analysis involving 2,490 patients, Paleari and collegues[43] found a clinical benefit rate of 41% in patients with EOC treated with endocrine therapy, suggesting that there is subgroup of patients with tumor biology that responds well to treatment. Tamoxifen showed the highest clinical benefit rate (43%), compared with 39% for aromatase inhibitors. Based on this evidence, NCCN guidelines recommend hormonal therapy in the adjuvant and recurrent setting in patients with Grade 1 endometrioid tumors (2B recommendation).[29]