*The picture above: figure shows homologous recombination repair marker, RAD51 (red), in high-grade serous ovarian cancer tumor cell nuclei (blue).
Researchers at the Universities of Helsinki and Turku have developed a test to identify those ovarian cancer patients who benefit from traditional platinum-based chemotherapy as well as from a newer type of cancer drugs, PARP inhibitors. The developed test provides a valuable tool to support clinical decision-making.
Ovarian cancer has the worst prognosis and highest mortality among gynecological cancers. For decades, the cornerstone for ovarian cancer treatment has been platinum-based chemotherapy. Recently, another class of cancer drugs, PARP inhibitors, have entered clinical use with significant benefit to many patients. PARP inhibitors have revolutionized the treatment of ovarian cancer, but due to considerable side effects and high cost, they should be targeted to patients who are most likely to benefit from them.
The newly-developed test takes advantage of a well-known Achilles heel of ovarian cancer: DNA damage repair deficiency.
“Both platinum-based chemotherapy and PARP inhibitors induce damage to the cell’s DNA. This type of DNA damage is normally neutralized by a DNA repair mechanism called homologous recombination. Approximately half of ovarian cancers are deficient in this DNA repair mechanism,” says Associate Professor Liisa Kauppi, the corresponding author of the study.
DNA damage caused by platinum and by PARP inhibitors can be repaired in tumors with high homologous recombination capacity. Thus, these tumors are resistant to DNA damaging treatments and such patients could in the future be channeled for other treatment regimens.
Overcoming the drawbacks of previously developed tests
Existing homologous recombination deficiency (HRD) tests, currently used in clinics, rely on information obtained from tumor DNA. These DNA-based assays have limitations which the new assay overcomes.
DNA-based HRD tests report on “historical”, but not necessarily current homologous recombination capacity of the tumor. That is, if a tumor was homologous recombination deficient sometime during its development, even if that is not the case anymore, DNA-based assays will classify the tumor as HRD. This poses a problem because restoration of homologous recombination occurs at an appreciable frequency in tumor cells.
“Our test detects a key homologous recombination repair protein, RAD51, in action, allowing us to quantify homologous recombination capacity of each tumor,” says doctoral researcher Sanna Pikkusaari.
“Our test measures, in real-time, whether homologous recombination is functional in the sampled tumor tissue. If RAD51, the protein that marks homologous recombination is detected, this means that homologous recombination was active in the tumor at the time of surgery,” says Pikkusaari.
Another caveat of DNA-based tests is that they typically require relatively high tumor content in the sample in order to reliably quantify homologous recombination capacity. This poses a problem especially for patients who have received chemotherapy prior to surgery.
“Tumor samples from ovarian cancer patients are often obtained from patients who have already undergone several treatment cycles of platinum-based chemotherapy. If a patient has good response to this neoadjuvant chemotherapy, at the time of surgery there will only be a limited number of tumor cells left. These are precisely the patients most likely to benefit from PARP inhibitor treatment also, but because of low amounts of tumor cells, their tumor’s homologous recombination capacity cannot be quantified with DNA-based assays,” Kauppi says.
“The developed assay overcomes the issue of tumor content, because in tissue sections with visible markers, tumor cells can be located and homologous recombination capacity quantified in those cells only. Even just a few hundred tumor cells in the specimen are enough to obtain a result,” Kauppi concludes.
The study was primarily funded by the Academy of Finland, the iCAN Digital Precision Cancer Medicine Flagship (iCAN-OVCA sub-project), the Finnish Cancer Foundation and the Sigrid Jusélius Foundation.
Sanna Pikkusaari, Manuela Tumiati, Anni Virtanen, Jaana Oikkonen, Yilin Li, Fernando Perez-Villatoro, Taru Muranen, Matilda Salko, Kaisa Huhtinen, Anna Kanerva, Heidi Koskela, Johanna Tapper, Riitta Koivisto-Korander, Titta Joutsiniemi, Ulla-Maija Haltia, Heini Lassus, Sampsa Hautaniemi, Anniina Färkkilä, Johanna Hynninen, Sakari Hietanen, Olli Carpén, Liisa Kauppi; Functional homologous recombination assay on FFPE specimens of advanced high-grade serous ovarian cancer predicts clinical outcomes. Clin Cancer Res. Feb 2023.
Liisa Kauppi, Associate Professor, University of Helsinki