Therapeutic options for mucinous ovarian carcinoma

Abstract

Objective: Mucinous ovarian carcinoma (MOC) is an uncommon ovarian cancer histotype that responds poorly to conventional chemotherapy regimens. Although long overall survival outcomes can occur with early detection and optimal surgical resection, recurrent and advanced disease are associated with extremely poor survival. There are no current guidelines specifically for the systemic management of recurrent MOC. We analyzed data from a large cohort of women with MOC to evaluate the potential for clinical utility from a range of systemic agents.

Methods: We analyzed gene copy number (n = 191) and DNA sequencing data (n = 184) from primary MOC to evaluate signatures of mismatch repair deficiency and homologous recombination deficiency, and other genetic events. Immunohistochemistry data were collated for ER, CK7, CK20, CDX2, HER2, PAX8 and p16 (n = 117-166).

Results: Molecular aberrations noted in MOC that suggest a match with current targeted therapies include amplification of ERBB2 (26.7%) and BRAF mutation (9%). Observed genetic events that suggest potential efficacy for agents currently in clinical trials include: KRAS/NRAS mutations (66%), TP53 missense mutation (49%), RNF43 mutation (11%), ARID1A mutation (10%), and PIK3CA/PTEN mutation (9%). Therapies exploiting homologous recombination deficiency (HRD) may not be effective in MOC, as only 1/191 had a high HRD score. Mismatch repair deficiency was similarly rare (1/184).

Conclusions: Although genetically diverse, MOC has several potential therapeutic targets. Importantly, the lack of response to platinum-based therapy observed clinically corresponds to the lack of a genomic signature associated with HRD, and MOC are thus also unlikely to respond to PARP inhibition.

Keywords: Genomic; Molecular targeted therapy; Ovarian cancer; Precision oncology; Sequencing; Therapy.

Fig. 1.

Prevalence of DNA damage repair pathways. A. Homologous recombination deficiency was measured as in Marquard et al. [11] (HRD Score) and shows that MOC rarely have a score above that used to predict response to platinum or PARP inhibitors (BRCA-deficient median and blue zone indicating HRD Score >42 that may respond to platinum from Telli et al. [13]). Black diamond is the mean HRD Score. B. Mismatch repair deficiency is also rare, as indicated by the mutation burden: Mutations per Mb, log10 transformed, black diamond is the mean, dashed line is a suggested threshold for mismatch-repair deficiency detection from Nowak et al. [14]. Arrow, MOC with MSH6 mutation, arrowheads, extra-ovarian metastases (EOM) with MMR gene mutations, *, MOC with MSH6 mutation that is likely non-pathogenic. BEN, benign mucinous tumor, MBT, mucinous borderline tumor. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 2.

Targetable events in mucinous ovarian cancer. A. Genetic events potentially targetable in MOC. MBT = mucinous borderline tumor n = 27, G1 MOC n = 83, G2 MOC n = 78, G3 MOC n = 24. Mutation type: Amp = Amplification (ERBB2 only); HomDel = Homozygous deletion (CDKN2A only). B. ER immunohistochemistry status by MOC grade. C. ERBB2 amplification and HER2 immunohistochemistry. Case 15417 showing concordance of 3+ staining and high-level amplification (Scale bar 100 μm). Case IC392 showing HER2 heterogeneity (Scale bar 200 μm). Arrows indicate location of ERBB2 gene. D. Percentage of cases with the number of genes (from A) affected by mutation or copy number.

Fig. 3.

Clinical pathway for therapy choice in MOC. We suggest that high-risk disease (grade 3/advanced stage/infiltrative subtype) should be pre-emptively tested for genomic events using a suitable panel method, since these are unlikely to respond completely to the adjuvant chemotherapy that will be offered while genomic testing is performed. On recurrence of non-high risk disease, genomic testing should also be performed, preferably on recurrence tumor tissue if this is available through surgical debulking or biopsy. If not, primary tumor tissue could be used. ER, estrogen receptor; HRD, homologous recombination deficiency; TMB, tumor mutational burden; “i”, inhibitor. TKi, tyrosine kinase inhibitor.