Short summary

The long-term survival of ovarian cancer (OC) patients is particularly dependent on the result after surgery as well as stage at time of diagnosis and varies in Denmark between 25 and 87 % (FIGO stage IV-II respectively).

The aim of this study is to monitor methylated HOXA9 in blood samples during neoadjuvant treatment in patients with epithelial OC with the purpose of investigating if HOXA9 methylated circulating tumor DNA (ctDNA) can predict the outcome of the operation.

Rationale

Ovarian cancer (OC) remains the most lethal disease among gynecological malignancies. The majority of patients are diagnosed in an advanced stage and exhibit resistance to standard chemotherapy. 

The treatment of OC is primary surgical debulking followed by adjuvant chemotherapy or neoadjuvant chemotherapy and interval debulking surgery followed by chemotherapy in around 50%.

By this approach 60-80% of patients will achieve clinical complete or partial response. However, 70-80% of the patients will experience recurrence of disease, most within two years after completion of chemotherapy. 

Potential biomarkers that could contribute to the management of OC by monitoring response to treatment, detecting recurrence, distinguishing benign from malignant pelvic masses and attempting to detect disease at an earlier stage has therefore been of major interest, but no reliable marker has been found yet. The currently used biomarker CA125 does not meet the criteria of an ideal marker as both the sensitivity and specificity is poor and a large proportion of OC has little or no expression of CA125.

Aberrant DNA methylation in ovarian cancer is observed in early cancer development. It can be detected in circulating tumor DNA (ctDNA) in the blood and hence provides the promise of a non-invasive detection test. HOXA9 promoter methylation has been observed in a large proportion of patients with high grade serous OC and methylation of HOXA9 is associated with poorer outcome. 

The clinical potential of HOXA9 methylated ctDNA with respect to prognosis, prediction and treatment monitoring is not well investigated. 

Study hypothesis:

HOXA9 methylation can be used for monitoring the effect of neoadjuvant chemotherapy and select patients for radical operation. 

The potential better selection of patients based on HOXA9 status before the comprehensive operation is of major clinical interest as residual tumor is the greatest prognostic factor.

Patients with insufficient treatment effect of neoadjuvant chemotherapy will not achieve major benefit from interval debulking surgery. A preoperative marker to select which patients should be offered interval surgery would therefore have major clinical impact and spare some patients surgical complications.

Description of the cohort

Patients with advanced primary inoperable ovarian cancer allocated for neoadjuavnt chemotherapy at Vejle Hospital before interval debulking surgery. 

Data and biological material

Blood samples.

The blood samples are drawn before start of chemotherapy, 15 days after the first cycle and prior to each of the three planned neoadjuvant chemotherapy cycles with a further sample one month after surgery. 

Collaborating researchers and departments

Department of Oncology, Vejle Hospital

• Professor Karina Dahl Steffensen, PhD, MD

Department of Pathology, Vejle Hospital

• Marianne Waldstrøm, MD, MPM, 

Department of Biochemistry and Immunology, Vejle Hospital

• Molecular biologist Rikke Fredslund Andersen, PhD