Survival in epithelial ovarian cancer: a multivariate analysis incorporating BRCA mutation status and platinum sensitivity
May 2011
Associate Professor Clare Scott
The article:
Gallagher DJ., Konner JA., Bell-McGuinn KM., et al. Survival in epithelial ovarian cancer: a multivariate analysis incorporating BRCA mutation status and platinum sensitivity. Ann Oncol 2011 22(5):1127-32.
The reviewer:
Associate Professor Clare Scott is Medical Oncologist at the Royal Melbourne Hospital and Laboratory Head at the Walter and Eliza Hall Institute of Medical Research.
Abbreviations
Disease Free Survival (DFS), Overall Survival (OS)
Summary
Study Design
This analysis examined the impact of prognostic factors on disease-free survival (DFS) and overall survival (OS) in patients with known BRCA mutation status. One-hundred and ten stage III-IV ovarian cancer patients [36 BRCA (+), 74 BRCA (-)], treated between December 1996 and September 2006 and tested on protocol for BRCA mutations, were included in the study. Impact on DFS and OS was determined by Kaplan-Meier analysis and a Cox proportional hazards model.
Findings
Thirty-one of 36 (86%) BRCA (+) and 60 of 74 (81%) BRCA (-) patients had platinum-sensitive disease (p=0.60). After a median follow-up of 41 months, twenty-four (67%) BRCA (+) and 54 (73%) BRCA (-) patients had relapsed. Five (14%) BRCA (+) and 26 (35%) BRCA (-) patients had died of disease. Median OS was longer for BRCA (+) than for BRCA (-) patients (not reached vs. 67.8 months; p=0.02), while DFS was similar (26.9 months vs. 24.0 months, p=0.3).
On univariate analysis, presence of a BRCA mutation, platinum sensitive disease, and CA125 nadir <20 were significantly associated with improved OS after first-line therapy. On multivariate analysis, OS independently correlated with primary platinum sensitivity and BRCA (+) mutation status but not with CA125 nadir <20 (Table 1).
Table 1: Univariate and multivariate analyses for OS
| Variable | HR (95% CI) | p-value |
| Univariate analysis | ||
| BRCA mutation | 0.34 (0.13-0.89) | 0.016 |
| Platinum-sensitive disease | 0.14 (0.06-0.30) | <0.001 |
| Optimal debulking surgery | 0.88 (0.43-1.82) | 0.85 |
| Consolidation treatment | 0.85 (0.41-1.78) | 0.60 |
| Age ≥60 years | 1.67 (0.81-3.44) | 0.13 |
| CA125 nadir ≥20 | 2.33 (1.10-4.94) | 0.044 |
| Histology (serous vs. non-serous) | 1.49 (0.69-3.23) | 0.29 |
| Multivariate analysis | ||
| BRCA mutation | 0.33 (0.12-0.86) | 0.023 |
| Platinum-sensitive disease | 0.15 (0.06-0.34) | <0.001 |
| CA125 nadir ≥20 | 1.21 (0.54-2.73) | 0.64 |
After second-line therapy, on univariate analysis, presence of a BRCA mutation (p=0.028), platinum-sensitive disease (following first-line therapy) (p = 0.005), and age <60 years (p=0.017) were significantly associated with improved survival from time of recurrence. Only BRCA (+) mutation status (HR = 0.36; 95% CI 0.14–0.93) and age ≥60 years (HR = 2.30; 95% CI 1.01–5.21) remained significantly associated with survival on multivariate analysis, and there was a suggestion that primary platinum sensitivity was also associated with improved survival (HR = 0.47; 95% CI 0.22–1.03; p=0.058).
Conclusion
The authors concluded that the study confirmed improved survival is associated with BRCA-associated ovarian cancer, and since BRCA mutation status predicted OS independent of primary platinum sensitivity, underlying tumour biology may contribute to disease outcome and be worthy of consideration in future clinical trial design.
Commentary
What does this article add to existing clinical evidence in this area?
This article confirms findings in previous studies, which have shown that patients with stage III/IV epithelial ovarian cancer who are carriers of BRCA1 or BRCA2 mutations have improved survival following chemotherapeutic treatment (median overall survival p=0.02) and increased primary sensitivity to platinum agents (p<0.001). In particular, the authors suggest that biologic differences beyond platinum-sensitivity associated with loss of BRCA function, may contribute to the improved survival observed. This study did show that BRCA status was predictive of survival, independent of primary platinum sensitivity, but as details of second-line systemic therapy were not included, it remains possible that platinum-sensitivity post-first line could be responsible for the survival advantage observed. Platinum response may well be a surrogate for a range of biologic factors, but the contribution of non-platinum related factors is not proven by this study.
This study contributes a modest increase in the number of BRCA1 or BRCA2 mutation carriers who have now been included in studies of stage III/IV epithelial ovarian cancer outcome following treatment. Of the 110 patients in this study, only 36 had deleterious mutations in BRCA1/2 (20 in BRCA1 and 16 in BRCA2). In two other relevant studies, outcomes were described for 22 patients with BRCA1/2 mutations (17 BRCA1 and 5 BRCA2)1 and for 229 patients with BRCA1/2 mutations (172 BRCA1 and 57 BRCA2).2
How adequate was the methodology used in addressing the aim of this study?
This study included retrospective chart review of a relatively small number of informative patients (36 BRCA1/2 mutation carriers). Genetic testing was carried out about one year following initial diagnosis, so it is possible that poor prognosis patients were not available for testing at that time. However, this would have been expected to influence both groups equally.
Because the patients had very varied post-first line treatments, no analysis of 2nd- or 3rd-line responses was included. Therefore, it was not possible to address whether the improved survival noted for BRCA1/2 mutation status, was in fact accounted for by ongoing platinum sensitivity (2nd, 3rd and possibly even 4th line), whereas this was addressed by Tan et al.1
As pointed out by the authors, the BRCA (+) group were slightly younger than the BRCA (-) group, as might be expected given that ovarian cancer can occur earlier in mutation carriers. As young age has been reported in prior studies to be a good prognostic factor, it is possible that in this study, age may be a surrogate for having a BRCA1/2-associated ovarian cancer, explaining the lack of statistical advantage for young age after first line treatment in this study.
No information was provided about family history of breast and ovarian cancer, of particular relevance for the non-mutation carrier group included in this study. Of 808 patients treated for high-grade ovarian cancer during the 10 year period, 110 were tested for mutations in BRCA1/2. No indication was given as to the severity of family history of cancer for the 74 patients referred to a genetics clinic and not found to carry a mutation. A family history of breast/ovarian cancer not accounted for by BRCA1/2 (assuming only 3-5% mutations missed by not completing MLPA testing) may not represent the same biology as that of a true “sporadic” non-BRCA1/BRCA2 mutation cohort of ovarian cancer cases. This important information would have added to the clinical interpretation of the cohorts studied.
Of importance, the number of patients with non-Ashkenazi mutations studied for treatment outcome remains small: 13 patients (36%) in this study, 16 patients (73%), Tan et al1 and 0 patients, Chetrit et al (only Ashkenazi mutations were tested for).2 With treatment outcomes for only 29 carriers of non-Ashkenazi mutations reported to date (and further subdivided into BRCA1 and BRCA2), it is formally possible that findings from Ashkenazi mutation carriers might be not be applicable to carriers of non-Ashkenazi mutations. Published studies including BRCA1/2 carriers other than those described above have significantly greater study design flaws.
What are the implications of this study for clinical practice in Australia?
Since BRCA status is a prognostic factor indicative of improved survival following therapy, determination of whether a patient carries a mutation in BRCA1/2 is an important consideration for all patients with stage III or IV epithelial ovarian cancer.
Platinum response remains an important prognostic factor, especially in carriers of BRCA1/2 mutations: ovarian cancers associated with BRCA1/2 mutations may continue to respond to platinum for longer (and do not appear to respond any better to non-platinum therapies) than do non-BRCA1/2 ovarian cancers.1 Therefore, every effort should be made to continue patients on platinum-based therapies, for example, until they become resistant on platinum therapy. If anything, response to platinum becomes even more impressive in 2nd and 3rd line BRCA1/2 associated ovarian cancers, compared with 1st line, suggesting possible enrichment for platinum-responders within the BRCA1/2 mutation carriers who go on to receive 2nd and 3rd line platinum-based regimens.1 In particular, a desensitization program in the event of apparent hypersensitivity to platinum should be undertaken as carefully as possible, as response to non-platinum agents is inadequate.
As additional biomarkers for subsets of BRCA1/2 mutation-associated ovarian cancer become available, response to platinum and to other novel treatments, such as oral PARP inhibitors, may be better predicted than currently.
Editor's note:
Data on BRCA1/2 mutation status in a large Australian cohort of invasive ovarian cancer patients was presented recently at the Australia New Zealand Gynaecological Oncology Group meeting by Professor D Bowtell, and will be the subject of a forthcoming publication.
References
- Tan DS, Rothermundt C, Thomas K, et al. "BRCAness" syndrome in ovarian cancer: a case-control study describing the clinical features and outcome of patients with epithelial ovarian cancer associated with BRCA1 and BRCA2 mutations. J Clin Oncol. 2008 Dec 1;26(34):5530-6
- Chetrit Hirsh-Yechezkel G, Ben-David Y, et al. Effect of BRCA1/2 mutations on long-term survival of patients with invasive ovarian cancer: the national Israeli study of ovarian cancer. J Clin Oncol 2008 Jan 1;26(1):20-5
Editor: Dr Anne Nelson, Evidence Review and Research Leader, National Breast and Ovarian Cancer Centre.
Clinical Update - Ovarian Cancer Editorial Committee: Prof Michael Friedlander – Medical Oncologist, Prof Neville Hacker – Gynaecological Oncologist, Ms Kim Hobbs – Social Worker, Dr Gillian Mitchell – Medical Oncologist, Dr Deborah Neesham – Gynaecological Oncologist, Ms Georgie Richter – Gynaecological Nurse.
Disclaimer
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