A large study of the genetic mechanisms of chemoresistance in high-grade serous ovarian carcinoma reveals new clues on why the deadliest and most common form of ovarian cancer so often returns after initially successful chemotherapy.
Resistance to chemotherapy is a major factor in the poor survival rate of women who develop high-grade serous ovarian carcinoma (HSC), the most malignant form of ovarian cancer.
HSC accounts for 70% of all ovarian cancers, and 60% of deaths related to the disease. Every year, around 80,000 women worldwide die of HSC, a figure that has barely altered in recent decades.
The new study is published in the journal Nature.
Co-senior author and professor David Bowtell, of the Peter MacCallum Cancer Centre in Melbourne, Australia, says our current knowledge is not good enough to make effective clinical decisions about how to deal with ovarian cancer that returns after treatment:
“For decades clinicians around the world have watched HSCs shrink under attack from chemotherapy, before returning aggressively months or years later.”
In their paper, he and his colleagues describe how they completely sequenced the genomes of 114 HSC samples from 92 patients and found several clues about how the aggressive cancer changes from initially being vulnerable, to eventually becoming highly resistant to chemotherapy.
The samples were collected from the patients at various stages in disease progression – some at diagnosis, some following successful and unsuccessful treatment, and others immediately after death.
Prof. Bowtell explains that by completely sequencing the genomes from samples taken at different stages of the disease, for the first time we have a map of how HSC evolves under the selective pressure of the chemotherapy.
The results reveal at least four genetic changes that the cancer undergoes to evade initially effective chemotherapy. Prof. Bowtell describes them:
“In two of the mechanisms, cancer cells find a way of restoring their ability to repair damaged DNA and thereby resist the effects of chemotherapy; in another, cancer cells ‘hijack’ a genetic switch that enables them to pump chemotherapy drugs out of harm’s way.
A further mechanism sees the molecular structure of the cancer tissue shift and reshape, such that sheets of ‘scar tissue’ appear to block chemotherapy from reaching its target.”
The researchers say this is the first time that the complex disease has been mapped at this level of detail, and believe their findings point to a range of new strategies that could be used to improve prospects for patients with recurrent ovarian cancer.
For example, they could help anticipate which drugs are likely to be ineffective, and thus avoid wasting time using them in the first place.
Funds for the study came from the National Health and Medical Research Council (Australia), Worldwide Cancer Research, Cancer Australia, Ovarian Cancer Action (UK) and Ovarian Cancer Australia.
The research was enabled by the Australian Ovarian Cancer Study (AOCS), the largest molecular epidemiological study of ovarian cancer in the world. The AOCS collects ovarian cancer tissue samples from donors.
The study follows another MNT reported earlier this year about the discovery of a new biomarker that should improve prospects for HSC ovarian cancer patients by indicating how their bodies are likely to respond to chemotherapy.