Distinguishing Low-Grade Serous Ovarian Cancer From Other Ovarian Cancer Types

Despite low-grade serous ovarian cancer’s characterization as an epithelial ovarian cancer subtype, which is predominated by high-grade serous ovarian cancer, their molecular profiles differ, requiring different targeted treatment strategies, according to Kathleen N. Moore, MD, MS.

CancerNetwork® spoke with Moore, Virginia Kerley Cade Endowed Chair of Cancer Development, associate director of Clinical Research at the Stephenson Cancer Center, director of the Oklahoma TSET Phase I Program and professor in the Section of Gynecologic Oncology the University of Oklahoma Health Sciences Center, about identifying and distinguishing low-grade serous ovarian cancer from other types of ovarian cancer.

Moore first explained that despite both being epithelial ovarian cancer subtypes, low-grade and high-grade serous ovarian cancer were molecularly different and required different targeted therapy strategies. She further expressed that low-grade serous ovarian cancer typically occurs in younger patients than high-grade but highlighted that patients of any age can be diagnosed.

Furthermore, Moore stated that the precursor lesions associated with low-grade serous disease were typically low malignant potential, contrasted with serous tubal intraepithelial carcinoma (STIC) lesions and TP53 alterations in hybrid serous ovarian cancer. She further iterated that some low-grade serous ovarian cancer did not have an identified precursor lesion but emphasized that many have low malignant potential lesions.

Low-grade serous ovarian cancers typically do not have TP53 alterations, instead, Moore suggested that they are characterized more by MAPK alterations. Specifically, in almost 40% of low-grade serous ovarian cancer tumors, RAS alterations are observed.

Additionally, Moore expressed that she has observed BRAF V600E mutually exclusive with KRAS alterations but that she also has observed [class] 3 BRAF mutations to a lesser extent. She concluded by stating that her institution was considering whether or not to target BRAF V600E and class 3 BRAF mutations differently.

Transcript:

Low-grade serous ovarian cancer is a rare subtype of epithelial ovarian cancer. The classification of epithelial ovarian cancer is predominated by high-grade serous ovarian cancer. We have an increasing understanding that they are vastly different tumors, molecularly, from one another, and are starting, as best we can, to try and target in molecular ways or in targeted ways, our therapies. BRCA [mutations] in high-grade serous [ovarian cancer] is the best example.

We are [primarily] working on clear cell [ovarian cancer], and low grade is another place where we are trying to pull those out and develop therapy specifically for them because they are... different in a number of ways. Epidemiologically, they tend to happen at a younger age range than high-grade serous [ovarian cancer], although it’s important to note that you can see low-grade serous ovarian cancer at any age. The median age is about a decade earlier than we see with hybrid serous ovarian cancer, even more so.

You will see the precursor lesions tend to be quite a bit different. For hybrid serous [ovarian cancer] we focus on the STIC lesions and TP53 alterations of the fallopian tubes. In low-grade serous ovarian cancers, the precursor lesion that we believe is there are these tumors that we used to call borderline tumors, or low malignant potential, although I will say that not all low grade serous [ovarian cancers] have at least an identified precursor lesion, but certainly we have evidence that these low malignant potential or borderline serous tumors can progress to low-grade serous ovarian cancer.

They tend not to have TP53 alterations. You can sometimes see a mixed picture, but that is one of the dichotomizations that you can see between high-grade and low-grade, and they tend to be characterized more by MAPK alterations. You look at the molecular profile, and you will see almost 40% RAS alterations, predominantly KRAS, but you can see HRAS and NRAS. You can see BRAF V600E that tends to be mutually exclusive with KRAS––but type 3 BRAF is uncommon. Whether or not we target those differently is something we are thinking about.