"True" Genomic Drivers of Ovarian Cancer Not Yet Identified, NCI Researcher Says

Christina M. Annunziata, MD, PhD

OncLive: What are the main limitations of the current treatment paradigm for ovarian cancer?

What are the major somatic molecular drivers of ovarian cancer?

What have genome-wide studies taught us about ovarian cancer?

Has this been translated to any therapeutic advances in the clinic?

What are the most significant unanswered questions or hurdles to our understanding of the genomic background of ovarian cancer?

Christina M. Annunziata, MD, PhD, has been instrumental in the genomic profiling of ovarian cancers and in elucidating the molecular pathways that are central to this disease. She is principal investigator and clinical director as well as head of the Translational Genomics Section at the Women’s Malignancies Branch of the National Cancer Institute in Bethesda, Maryland.Annunziata: The current standard of care for women with newly diagnosed ovarian cancer is surgery and chemotherapy with platinum and taxane. This approach is applied to all women regardless of age, family history, histology, or other molecular diagnoses. There are no tools to predict who will remain in remission and who will relapse soon after completing therapy.There are currently no true “drivers” of ovarian cancer that have been identified. Several consistent genetic aberrations have been associated with particular types of ovarian cancer, such as p53 mutations or deletions in high-grade serous cancer, ARID1A loss in clear cell or endometrioid cancer, KRAS or BRAF mutations in low-grade serous cancer. These may all be instrumental in the development of cancers, but are not yet proven to be independent “drivers” of cancer growth and spread.Genome-wide studies have taught us important aspects of the biology of ovarian cancer. For example, we have learned that the high-grade serous type of ovarian cancer has a lot of genomic instability, and this causes cells to have high or low numbers of particular areas of the chromosomes. This could include regions of genes that become overexpressed, such as cyclin E. We also learned that certain types of cancers have hallmark mutations.These findings have resulted in the development of focused clinical trials that intend to target these genetic aberrations. For example, PARP inhibitors are being tested in women with high-grade serous ovarian cancer in attempt to selectively kill the cancer cells that have high genomic instability. Diagnostic tests are under development to identify the cancers with high genomic instability and are incorporated into some of these clinical trials.The genomic instability of ovarian cancer presents several hurdles to both understanding the genomic background and treating the disease. It appears that the cancer is not only different between individual women, but can be different depending on the anatomical site of the tumor; that is, tumor growing in the ovary, versus tumor spread to the lymph node, versus tumor spread to the liver, etc.

Moreover, the cells on the outside of a tumor can be different from those on the inside of the same tumor. And, the composition of the tumors may change over time, especially after exposure to different chemotherapies. This presents a challenge in both understanding what genomic alterations are driving the cancer, what treatments would best treat the cancer, and when to use the treatments.