Genetics of ovarian cancer- an overview

SASGO September 2016

Mainstay of treatment

Cytoreductive surgery Chemotherapy

Familial

• BRCA, Lynch syndrome

• Autosomal dominant

• Incidence 5-10% of all ovarian cancers

• Historically: younger age of onset and family history of cancer

Serous ovarian cancer origin

Kurman et al. Am J Surg Pathol 2010; 34:433-443

Serous ovarian cancer

High grade serous Low grade serous ovarian

• 10-15% of serous carcinoma of ovary

• Completely different clinical entity

• 85-90% of serous carcinomas

• Median age 64 years

• Immunohistochemistry:

CK7+, WT1+, CK20-

• Tumour protein P53+ in 96% of cases

A step back

• 44% had no previous family history

• Germ line BRCA mutations found in 22% of women with high grade serous ovarian cancer

• Approximately 25% BRCA mutation carriers were older than 60 years of age!

Journal of Clinical Oncology 2012; 30(21): 2654-2663

BRCA: the facts

JAMA 2012;307(4): 382-390

Novel agents

The essence of BRCA!

BRCA- like behaviour

• In sporadic ovarian cancer

• No BRCA germline mutation

• Also homolousrecombination repair deficiency (HRD)

• Susceptibility to platinum chemotherapy and other DNA damaging agents

Impact of BRCA/ BRCA- like status

• Incidence

• Survival

• Chemo sensitivity

• Targeted agents

Recent recommendations

• SGO (March 2014):

Women diagnosed with epithelial ovarian, tubal and peritoneal cancers should be considered for genetic counseling and testing, even in the absence of a family history

• NCCN (February 2014):

Epithelial ovarian cancer at any age

• Australia national guidelines( July 2013):

Women <70 years of age with ovarian cancer can receive genetic testing for BRCA1/2 mutations regardless of family history

• Europe: no standardized guidelines ( vary country by country)

Germany: BRCA testing in HGSC without family history

Our setting in AFRICA

• Ovarian cancer NOT the commonest gynaecological cancer yet highest case fatality ratio

• Diversity of Africa: no studies yet

• Not at a place where we can offer similar recommendations YET due to– patient education and empowerment

– Genetic counselling load

– Cost/ targeted therapy

Low grade serous ovarian cancer ( LGSOC)

• Rare histiotype

• Pathogenic continuum: LGSOC arises from serous borderline tumours

• Crucial role of KRAS, BRAF mutations

• Usually diagnosed in a younger population

• Indolent clinical behaviour, longer survival

• Poor chemosensitivity

LGSOC: clinical relevance

• Due to rarity of disease , all data retrospective

• Treatment is a dilemma/ controversial

– Adjuvant treatment in early stage disease

– Recurrences

– Advanced disease

• KRAS/BRAF/MAPK signaling abberations

• More studies required ( targeted agents)

Endometriod

• Account for 10% of all ovarian cancers

• Composed of glands that resemble endometrial epithelium

• Association with endometriosis

• Immunohistochemistry:– CK7+, Estrogen+ and progesterone+, WT1- and CK20-

• Mutations: PTEN, ARID1A,PIK3CA

• Often seen when ovarian cancers occur in LYNCH syndromes

Clear cell

• 6% of ovarian cancers

• Immunohistochemistry:– CK7+, CK20-, Estrogen and progestrone negative and WT1-

• Association with endometriosis

• Mutations: PIK3CA, KRAS, ARID1A

• Poor response to chemotherapy

Mucinous

• Only 2-3% of ovarian cancers

• Difficulty : identifying whether primary or metastasis from gastro-intestinal or pancreatobiliar tumours

• KRAS mutations in 60-86% of cases

• Immunohistochemistry– CK7+, CK20 less diffuse, hormones and WT1 negative

Key points

• Ovarian cancer is a HETEROGENOUS disease.

• Understanding the molecular pathways and genetics of each subtype is crucial in determining treatment planning and prognosis

• The role of the pathologist cannot be overestimated.

Thank you