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New research led by Dana-Farber Cancer Institute scientists may soon enable doctors to determine which patients with high-grade serous ovarian cancer (HGSOC) – the most common cancer of the ovary – are most likely to benefit from a certain class of drugs.
Using technology able to pick out abnormalities in single units of the genetic code, the researchers sorted tumor samples from HGSOC patients into three subtypes based on the extent of a particular kind of genetic damage within the cells. Patients in the subtype with the highest levels of damage – representing one-third to one-half of all HGSOC patients – were the slowest to develop resistance to platinum chemotherapy treatment such as carboplatin. Overall, these patients lived longer without having their disease worsen than more did patients in the two other groups.
"Our findings suggest that, for the first time, we can determine which patients have the best chance of responding to specific categories of drugs for high-grade serous ovarian cancer," says Dana-Farber's Ursula Matulonis, MD, one of the senior authors of the study, which has been published online by the journal Clinical Cancer Research. "For this disease, one of the most difficult to treat of all gynecologic cancers, the study is an important step forward."
J. Dirk Iglehart, MD, of Dana-Farber and Brigham and Women's Hospital, is the paper's other senior author, and Zhigang Wang, MD, PhD, of Dana-Farber, is the first author.
HGSOC cells have a high degree of "genomic instability," their nuclei littered with large numbers of extra or missing chromosomes or chromosome fragments. One of the consequences of this havoc is a process known as loss of heterozygosity (LOH). LOH occurs in cells that lack the usual complement of two normal copies of each gene, having instead a normal and mutant copy of certain genes. When the normal gene in these mismatched pairs becomes inactive or mutated, the cell has no normal copy of the gene left – and is said to have lost heterozygosity.
In the study, investigators used single nucleotide polymorphism (SNP) arrays – technology that reads the elements of the genetic code one by one – to probe HGSOC tissue samples for instances of LOH. The samples tested fell neatly into three groups based on the patterns of LOH within them.
One of these groups was distinguished by a high level of LOH and a deleted segment of chromosome 13. When researchers reviewed the medical records of patients in this group, they found the patients were slow to develop resistance to chemotherapy drugs.
"Patients with the greatest burden of LOH had the longest progression-free survival – the period of time after treatment when their disease is not advancing," says Wang. "This is the group which stands to derive the most from treatment with certain classes of drugs."
LOH hampers cancer cells' ability to survive, rendering the cells particularly dependent on proteins that repair damaged chromosomes. Drugs that target those repair proteins, including a class of agents known as PARP inhibitors, may be especially effective against HGSOC cells with high levels of LOH, the study authors assert.
The authors also found that LOH patterns in HGSOC were similar to those in triple-negative breast cancer, a form of breast cancer also characterized by a high level of chromosomal instability. The discovery suggests that agents effective in treating HGSOC might be effective against this type of breast cancer as well, the authors claim.
Principal funding for the study was provided by the Breast Cancer Foundation.
In addition to Matulonis, Iglehart and Wang, the study's other authors are Aedin Culhane, PhD, Aquila Fatima, Ruiyang Tian, PhD, Matthew Schwede, Kathryn Daniels, Joyce Liu, MD, Alexander Miron, PhD, and John Quackenbush, PhD, of Dana-Farber; Nicolai Juul Birkbak, PhD, of Dana-Farber and the Technical University of Denmark; Ronny Drapkin, MD, PhD, of Dana-Farber and Brigham and Women's Hospital; Kathryn Alsop, Dariush Etemadmoghadam, PhD, Gillian Mitchell, PhD, and David Bowtell, PhD, of the University of Melbourne, Australia; Huiying Piao, MD, and Ross Berkowitz, MD, of Brigham and Women's Hospital; Helga Salvesen, MD, PhD, of the University of Bergen, Norway; and Anna DeFazio, PhD, of the University of Sydney, Australia.
Ovarian cancer is treated at the Gynecologic Cancer Treatment Center at Dana-Farber/Brigham and Women's Cancer Center.