Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues

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Olaparib (Lynparza™) -Therapy in Ovarian Cancer [C56]

OMIM numbers: 167000, 113705 (BRCA1), 600185 (BRCA2)

Dipl.-Ing. (FH) Tanja Hinrichsen

Scientific Background

Ovarian cancer (OC) is the second most common malignant disease of the female reproductive organs (approximately 8000 cases/year) and the fifth most common cause of cancer deaths in women. Noticeable symptoms commonly become apparent only in later stages of the disease, so that the 5-year survival rate is approximately 40%. Ovarian cancer has epithelial and non-epithelial histotypes. Epithelial OC can be subdivided into 5 subtypes: High-Grade Serous, Low-Grade Serous, Clear Cell, Endometrioid and Mucinous. Although each subtype displays individual clinical presentation (e.g. response to chemotherapy), standard therapy is a combination of a cytoreductive operation and platinum-based chemotherapy. There is significant risk of a recurrence or a resistance to therapy.

Olaparib (Lynparza™) was recently approved by the European Medicines Agency (EMA), for use as a monotherapy under certain conditions (see below), in high-grade serous OC.

Olaparib is a PARP1 (poly (ADP ribose) polymerase1) inhibitor which uses the principle of "synthetic lethality". Olaparib inhibits the repair of DNA single strand breaks by the base excision repair-mechanism (BER). Due to the collapse of the replication fork, these single-strand breaks become double strand breaks, which are repaired in turn by homologous recombination (HR) or non-homologous end joining (NHEJ). If, due to a mutation in one of the HR DNA repair genes such as BRCA1 or BRCA2, HR does not occur, the error-prone NHEJ becomes effective and cell apoptosis occurs.

The following criteria must be met as prerequisites for Olaparib therapy:

  • High-grade serous Ovarian carcinoma (HGS-OC)
  • Platinum sensitive
  • Recurrent tumor
  • Evidence of a disease causing mutation in BRCA1 or BRCA2

Whilst around 10-15% of all epithelial OC carry a germline mutation in BRCA1 or BRCA2, approximately 5% have mutations limited to the tumor (somatic) in BRCA1 or BRCA2. As a high proportion of germline mutations are also expected in sporadic ovarian carcinomas, all patients eligible for Olaparib therapy, and thus a BRCA1/2 mutation examination, should be informed in detail about the potential consequences of a possible mutation being found in the germline and receive genetic counselling. Detection of a germline mutation represents an additional increased risk of tumor for the patient, as well as a risk that children and close relatives will also be carriers of the mutation and thus have an increased disease risk.

A mutation analysis of tumors as well as the germline can be carried out in Martinsried by an interdisciplinary team of pathologists and human geneticists. Genetic counselling is offered to patients in our genetic counselling centers.

In accordance with the Level 3 Guidelines for the Diagnosis, Therapy and Follow-up Care of Breast Cancer, genetic counselling and, if necessary molecular genetic examinations, should be offered when in one line of the family:

  • At least three women have developed breast cancer
  • At least two women have developed breast cancer, one of whom is younger than 51 years old
  • At least one woman has developed breast cancer and one woman has developed ovarian cancer
  • At least two women have developed ovarian cancer
  • At least one woman has developed breast and ovarian cancer
  • At least one women younger than 36 years old has developed breast cancer
  • At least one women has developed bilateral breast cancer before the age of 51
  • At least one man has developed breast cancer and one woman has developed breast or ovarian cancer