To the Editor
It is now appreciated that ovarian cancer includes several distinct molecular types, each of which probably requires a different treatment approach. It is also clear that the biology of ovarian cancer changes with treatment as resistant disease develops. Both these factors highlight the importance of obtaining adequate amounts of tissue at diagnosis and relapse for both histologic examination and molecular characterization of a tumor. In ovarian cancer, it is the development of treatment-resistant disease that accounts for the significant mortality rate of ovarian cancer (∼40% 5-year survival), which has not improved in the last 30 years.1 This treatment-resistant ovarian cancer is less well-molecularly characterized. To understand and identify markers of resistance to treatment, translational research is vital. However, obtaining tissue samples from this patient group can present challenges, both in terms of patient safety and technical feasibility.
In recent years, it has been shown that in treatment naive ovarian cancer patients, image-guided needle biopsy is safe and obtains a histologic diagnosis in 87% of cases.2 A further, more recent publication in Cancer described the feasibility and safety of sequential tumor biopsies in 150 patients recruited to 6 clinical trials; 77% of whom had relapsed ovarian cancer.3 Of the patients consented, baseline biopsies were collected from 97% of the patients and second biopsies for 70% of the patients, and the complication rate was low (2%). This is consistent with a complication rate of 1.4% reported in another phase 1 patient cohort with various tumor types.4
Although together these studies provide extremely useful information demonstrating the feasibility and safety of obtaining biopsies for research, the populations that were studied were selected for the presence of a lesion amenable to percutaneous biopsy before inclusion.
To plan the translational aspects of a phase 3 study in relapsed ovarian cancer, where the patient cohort is not preselected for the presence of a lesion amenable to percutaneous biopsy, further information is needed. We therefore undertook the present study to assess the feasibility of obtaining sufficient numbers of biopsies for a translational research project in a phase 3 study cohort where a lesion amenable to biopsy was not an inclusion criterion.
The planned phase 3 study required a target sample size of 230 patients. We estimated that a minimum of 30 (13%) tissue samples would be required to assess the correlation between the molecular marker of interest and the clinical outcome of response.
We assumed that approximately 50% of the trial population would consent to biopsy where this was technically feasible. This feasibility study was designed to distinguish an inadequate biopsy rate (<10%), from an adequate biopsy rate (>25%), using a 2-stage Simon minimax design. A biopsy rate in this range would support addition of a translational component to the planned phase 3 study. The design used had 90% power at a 10% 1-sided level of statistical significance. This required 40 patients, with 7 or more patients being amenable to biopsy indicating a positive outcome.
To test whether the cohort size of the planned phase 3 study would provide an adequate number of lesions amenable to biopsy, we undertook a retrospective assessment of computed tomographic (CT) images from a historic cohort of patients with relapsed ovarian cancer. Patients, previously treated for ovarian cancer, who were undergoing further chemotherapy were identified from a chemotherapy database. Pretreatment CT images were reviewed by a specialized gynecologic oncology radiologist with extensive knowledge of the skills, capabilities, and multimodality access of their regional interventional radiology team. The proportion of patients with lesions amenable to percutaneous, image-guided biopsy was recorded.
Of the 37 patients identified from sequential chemotherapy records with available imaging, 7 patients had lesions suitable for radiologically guided biopsy; further patients were not sought because the threshold for study success had been met. Of the 37 patients, 22 had no lesion amenable to biopsy or cytologic sampling. Eight of the patients with no lesion amenable to biopsy had pleural or ascitic fluid accessible for cytologic sampling. Of the 7 lesions that could be biopsied, 4 patients had metastatic liver deposits, 1 patient had a perisplenic deposit, and 1 patient had an anterior abdominal wall nodule, which were assessed as suitable for ultrasound-guided biopsy, and 1 patient had a liver lesion suitable for CT-guided biopsy.
In the present study, 7 (19%) of the 37 reviewed CT scans demonstrated relapsed ovarian cancer amenable to biopsy (80% confidence interval, 12%–28%). Although this indicates that it would be feasible to attain an adequate number of tissue samples to draw meaningful conclusions in the planned phase 3 study, the biopsy rate demonstrated in this unselected population is much lower than the successful biopsy rates reported by Lee et al3 and others. Caution is therefore required when planning and powering translational studies in relapsed ovarian cancer because only a proportion of patients will have a lesion deemed amenable to image-guided, percutaneous biopsy. Many studies of biologic agents now require mandatory biopsies for study entry. Based on our findings, these studies will exclude a significant number of patients with relapsed ovarian cancer and may also bias the population and tumor types included.
With the increased requirement for knowledge of the molecular pathogenesis of a particular cancer and the development of targeted therapies, there will be a need for robust mechanisms for selecting particular therapies for individual patients. Furthermore, repeated testing may be required before successive lines of therapy because tumors evolve with treatment. There is, therefore, a need for improvements in cancer imaging and biopsy techniques5 to increase the number of patients who can undergo biopsy, but our study also indicates the need to develop and validate other methods of assessment such as evaluation of circulating tumor cells and circulating DNA. Not only will these “liquid biopsy” techniques be less invasive for patients, but they may also go some way to circumvent the problem of tumor heterogeneity because they will capture the predominant mutational spectrum rather than the particular tumor area that was examined through biopsy. In studies requesting an optional biopsy, only 4.4% of the patients underwent biopsy, and the authors highlighted poor infrastructure and a lack of funding as the causes.4 Importantly, there did not appear to be a lack of patient willingness to undergo biopsies. This is consistent with feedback from patient groups that, with a clear explanation of the rationale for the research, many women are happy to take part in studies that require biopsies. In our experience, the additional cost of image-guided research biopsies and the pressure of work in the routine clinical service have been major factors limiting the addition of biopsy studies to clinical trials, so in addition to investment in imaging and biopsy techniques, further investment is also needed to build supportive infrastructure for research biopsies to take place, at the same time as developing other methods of assessment for patients where biopsy is not technically feasible. It is vital that studies are designed so that sufficient biopsies are collected to address the hypotheses in question to avoid exposing women to additional risk for no benefit. We are currently involved in a multicenter study assessing the feasibility and safety of collecting 300 research biopsies in women with relapsed high-grade serous ovarian cancer. Such collaborative efforts are challenging but essential if we are to further our understanding of treatment resistance.
Patricia Roxburgh, PhD, MRCP,
The Beatson West of Scotland Cancer
Centre, Glasgow, United Kingdom
University of Glasgow, Glasgow
Gordon W. Cowell, MBChB
Victoria Infirmary, Glasgow
Rosalind M. Glasspool, PhD, MRCP,
The Beatson West of Scotland Cancer
Centre, Gartnavel Hospital, University of
Glasgow, Glasgow, United Kingdom
The authors declare no conflicts of interest.
1. Vaughan S, Coward JI, Bast RC Jr, et al. Rethinking ovarian cancer: recommendations for improving outcomes. Nat Rev Cancer. 2011; 11: 719–725.
2. Griffin N, Grant LA, Freeman SJ, et al. Image-guided biopsy in patients with suspected ovarian carcinoma: a safe and effective technique? Eur Radiol. 2009; 19: 230–235.
3. Lee JM, Hays JL, Noonan AM, et al. Feasibility and safety of sequential research-related tumor core biopsies in clinical trials. Cancer. 2013; 119: 1357–1364.
4. El-Osta H, Hong D, Wheler J, et al. Outcomes of research biopsies in phase I clinical trials: the MD anderson cancer center experience. Oncologist. 2011; 16: 1292–1298.
5. Marshall D, Laberge JM, Firetag B, et al. The changing face of percutaneous image-guided biopsy: molecular profiling and genomic analysis in current practice. J Vasc Interv Radiol. 2013; 24: 1094–1103.