Cartherics’ Dr Ian Nisbet (Chief Operating Officer) and Kathy Skoff (Clinical Trials Manager) recently attended an ovarian cancer symposium in Sydney, organised by Ovarian Cancer Australia and sponsored by AstraZeneca and GSK.  It was an excellent event, with an exceptional panel of speakers who provided overviews of the different types of ovarian cancer along with current and emerging treatment options.  The session closed with an informative panel discussion of two case studies.

One of the key messages from the symposium was that ovarian cancer is not ovarian cancer – rather it’s a mixture of quite distinct diseases with different origins, mutational profiles and prognoses.

Subtypes of ovarian cancer

Around 90% of ovarian cancers are epithelial in origin (adenocarcinomas). Epithelial ovarian cancers (EOC) have historically been treated as a homogenous group in the clinic, despite clear histopathological and molecular data showing that distinct subgroups exist:

Subtype	Incidence
High grade serous ovarian carcinoma (HGSOC)	70%
Clear cell ovarian carcinoma (CCOC)	10%
Endometrial ovarian carcinoma (EOC)	10%
Low grade serous ovarian carcinoma (LGSOC)	3 -5%
Mucinous ovarian carcinoma (MOC)	3 -5%

High-grade serous and low-grade serous carcinomas comprise distinct groups, while endometrioid and clear cell histologies are different again from serous but with some overlapping genetic events. It is now clear that these molecular distinctions reflect differences in site of origin, with high-grade serous cancers now thought to arise from the fallopian tube fimbriae, low grade serous cancer from the ovarian epithelium, and clear cell and endometrioid cancers arising from endometriosis, which itself is derived from the endometrium. However, the origin of the mucinous group remains controversial. Many mucinous ovarian carcinomas (MOCs), formerly classified as primary, are now recognized to have been mis-diagnosed metastases from predominantly gastrointestinal or endocervical sites. However, some mucinous cancers do appear to be ovarian primaries, particularly benign and borderline cancers, which generally have a good prognosis not consistent with a metastatic cancer.

High grade serous ovarian carcinoma (HGSOC) originates from the ovary or fallopian tubes. HGSOC shares features with triple negative breast cancer including TP53 mutation, BRACA 1 and BRACA 2 homologous recombination deficiency (HRD).  Cyclin E1 gene amplification and protein over-expression is a marker of platinum resistance in HGSOC. Patients with recurrent platinum resistant HGSOC, fallopian tube and primary peritoneal cancer typically have low response rates to chemotherapy and poor overall survival. Addition of bevacizumab has improved response rates and progression free survival (PFS) but more effective, ideally personalized therapies, are urgently needed.

Clear cell ovarian carcinoma (CCOC) is a histological subtype of ovarian cancer that is more frequent in Asian countries (~25% of ovarian cancers) than in US/European countries (less than 10%). The origin of CCOC is retrograde menstruation. CCOC is refractory to conventional platinum-based chemotherapy. Notably, deleterious mutations in SWI/SNF chromatin remodelling genes, such as ARID1A, are common in CCOC but rare in HGSOC. Because this complex regulates multiple cellular processes, including transcription and DNA repair, molecularly targeted therapies that exploit the consequences of SWI/SNF deficiency may have clinical efficacy against CCOC. Three such strategies have been proposed to date: prioritizing a gemcitabine-based chemotherapeutic regimen; synthetic lethal therapy targeting vulnerabilities conferred by SWI/SNF deficiency; and immune checkpoint blockade therapy that exploits the high mutational burden of ARID1A-deficient tumors. Thus, ARID1A deficiency has potential as a biomarker for precision medicine of ovarian cancer.

The links between endometriosis and CCOC are well established, with the loss of ARID1A function thought to be an early event in the transformation from endometriosis into CCOC.

There are two major subtypes of CCOC – Classic-CCOC (83% of cases) and HGSOC (17% of cases).  The Classic-CCOC group is relatively platinum resistant, making it a target group for investigational front-line therapies.

Endometrial ovarian cancer (EOC) accounts for 10% of ovarian cancers, and shows an association with endometriosis and Lynch syndrome. The origin of EOC (and CCOC) is retrograde menstruation. EOC is often accompanied by synchronous endometrial carcinoma (EC) and typically diagnosed at an early stage. It is estimated that 84-95% of EOC cases are diagnosed at grades I and II, allowing for earlier treatment and better prognosis than for other types of ovarian cancer.

Low-grade serous ovarian carcinoma (LGSOC) development starts from tubal epithelia, which invaginate into ovarian stroma to form ovarian epithelial inclusions (OEI). Further growth of OEI forms serous cystadenoma, serous borderline tumour, and LGSOC in a step-wise fashion. The most common molecular changes including KRAS, BRAF, or ERBB2 mutations are increased in this process. RAS/RAF mutations are seen in ~50% of LGSOG. Chromosomal changes are more common prior to the development of LGSOC. About 10% or less LGSOCs can develop into HGSOC upon acquiring p53 mutation. Over 80% of LGSOC are positive for estrogen receptor (ER) and /or progesterone receptor (PR) expression.

The estimated number of new cases is 90 p.a. in Australia and 15,000 p.a. globally. LGSOC patients are younger diagnosis (median age 55 yrs), but there are no reports of a genetic disposition. Most LGSOC patients present at stage III disease. Adjuvant platinum/taxane post debulking surgery is the standard care in advanced stage LGSOC, although no OS benefit was observed in retrospective analysis. In recurrent disease, chemotherapy response is 10% or less. Hormone therapy (letrazole) has been tried as first line maintenance therapy in ER+/PR+ patients – it provided a PFS benefit but did not improve overall survival (OS).

Mucinous ovarian carcinoma (MOC) is a distinct disease among the EOC subtypes and it is different from GI mucinous carcinoma. MOC is a rare histotype of ovarian cancer, with a low response to platinum-based therapy observed clinically, corresponding to the lack of a genomic signature associated with HRD; MOC is thus also unlikely to respond to PARP inhibition. There is a very poor survival for patients diagnosed at advanced stage (5-year survival ~25%). Key drivers of progression identified are TP53 mutation and copy number aberrations.

MOC is diagnosed as stage 1 in 80% of cases. Prognosis is better in early disease, but worse in the advanced stage, compared to HGSOC, which is mainly due to inadequate response to platinum-based chemotherapy. Around 80% of mucinous carcinomas of the ovary are metastatic. The most frequent primary sites that metastasize to the ovary are: 45% from the gastrointestinal tract, 20% from the pancreas, 18% from the cervix and endometrium, and 8% from the breast. MOC is usually a heterogeneous tumor.  It encompasses benign, borderline, and carcinoma components, which indicate a stepwise progression to carcinoma.

Implications

Over the course of the past two decades, the emergence of powerful tools for assessing mutational pathways and the parallel development of targeted therapies, has seen cancer treatment progressively move away from “one size fits all” to more personalised treatments.  This progression is clearly relevant for the treatment of ovarian cancer, where it has become increasingly obvious that the label covers multiple different diseases.  While standard-of-care platinum plus taxane chemotherapy will remain a core component of the treatment paradigm, it is being supplemented with targeted and immune therapies relevant to specific OC subtypes.

More recently, immune cell therapies (CAR-T cells, CAR-NK cells) have begun to emerge in clinical trials for the treatment of ovarian cancer patients. While the potential efficacy of such therapies should not be limited to particular OC subtypes (depending on the nature of the CAR target), development of immune cell products still needs to take subtype differences into account. For these products to have the best chance of clinical success they need to be directed towards patients who are at greatest risk of not responding to current treatments but who are also not in the very late stages of disease. This is a key challenge for companies like Cartherics, which anticipates having two immune cell products in clinical trials in ovarian cancer in the 2024-25 time horizon.”

Dr Ian Nisbet is the COO and Kathy Skoff is the Clinical Trials Manager of Cartherics, an Australian biotech company developing immune cell therapies for the treatment of solid cancers.