Results in the Context of Published Literature
The comparison of tumor dissemination patterns revealed that patients with
BRCAmut disease showed a more aggressive course of disease during pOC, with significantly more extensive involvement of the mid-abdomen compared with the
BRCAwt group. However, this phenomenon vanishes throughout the course of disease and no significant differences could be determined during rOC stages. This was confirmed by Marchetti et al., who examined the tumor dissemination pattern between patients with
BRCAmut and
BRCAwt disease and could not detect any significant differences at recurrence.
25
Interestingly, even though patients with
BRCAmut disease showed more extrapelvic tumor involvement in pOC, surgical effort to achieve maximum reduction of tumor mass did not differ in both groups, at either the primary or recurrent stage. Additionally, patients with
BRCAmut disease showed higher rates of complete cytoreduction at all times. Although the difference in patients with pOC disease with complete tumor resection did not reach statistical significance compared with the
BRCAwt group, optimal debulking was significantly more often achieved during rOC surgery in the
BRCAmut cohort. In a recently published study by Ataseven et al., these findings were largely confirmed in a great population of 1221 patients with pOC disease.
26 Similarly to our findings, the
BRCAmut cohort showed higher rates of complete tumor resection compared with their
BRCAwt counterparts but did not reach statistical significance, and surgical complexity was not significantly different between both groups. However, median follow-up was considerably shorter, at 31 months, and the study focused only on treatment in the pOC situation. To conclude, it is conceivable that, owing to biologic characteristics of
BRCAmut OC cells, primary occurrence of disease is earlier, but tumor invasion at recurrence seems to be less aggressive. Therefore, surgery followed by an adequate adjuvant treatment line is still very effective, even during rOC, and should be the treatment modality pursued.
As already described in previous studies, we confirmed significantly younger age at primary diagnosis in patients with
BRCAmut disease.
27,28 Moreover, the
BRCAmut cohort showed significantly prolonged OS, which is also consistent with existing published literature.
29,30 However, it has been a topic of international debate whether improved survival, operability, and response rates to therapy among the
BRCAmut group are solely caused by the fact that these patients are younger, or whether other tumor characteristics play an important role in that process as well.
Multivariate analysis to predict complete macroscopic tumor resection in our pOC cohort revealed that only age at diagnosis had a significant effect. This finding is in line with data by Hyman et al., where patient’s age was found to be a significant predictor for surgical outcome at primary debulking, whereas
BRCA mutation status was not.
31 The impact of
BRCA status on surgical outcome in rOC, however, has not been sufficiently investigated. In this study, multivariate analysis detected that
BRCA mutation status is the only significant predictive factor for complete resection in rOC. This is in line with Estati et al., who also validated
BRCAmut status to significantly promote complete macroscopic resection in recurrence.
32 The rate of complete secondary resection in their study was 89.5% in the
BRCAmut group and 65.2% in the
BRCAwt group.
32 This indicates that especially patients with
BRCAmut rOC disease show altered tumor biology and consecutively treatment response that cannot just be explained by younger age. Therefore, we suggest that
BRCA mutation status should be taken into account as a parameter when selecting patients eligible for secondary debulking surgery aiming for complete macroscopic resection.
Surgery in patients with first rOC disease has been proven to significantly prolong PFS and OS in the DESKTOP III trial only if macroscopic tumor clearance could be achieved.
3 If there was still residual tumor mass left, patients showed worse survival compared with those treated with chemotherapy alone. Two further prospective randomized clinical trials confirmed better PFS rates in patients with rOC disease if complete macroscopic tumor resection could be achieved, but the GOG trial failed to show a significant OS benefit in patients from the surgery cohort.
33,34 One crucial difference between the GOG trial and the DESKTOP III and SOC-1 trials is the lack of a scoring system to select patients who will more likely benefit from secondary tumor debulking. These findings underline that reliable criteria to assess eligibility of individual patients for surgical treatment are indispensable. Implementation of the AGO criteria into this decision-making process has already been proven to be a very helpful tool in clinical practice, although only complete resection rates of 67–75.5% of patients with rOC and AGO positive score were reported in recent studies.
3,4 Conversely, complete macroscopic resection was still achievable in 48.5% patients with an AGO negative score.
4 Hence, identifying new selection criteria for secondary tumor debulking is mandatory, especially in borderline decision cases to identify those patients in whom maximal rOC surgery is feasible without harming those patients who would not benefit from it. In this context, we suggest implementing
BRCAmut status as a favorable factor for surgical therapy in patients with rOC disease. To our understanding, the combination of effective cytoreductive surgery with chemotherapy followed by effective maintenance therapy such as PARP inhibitors can be a key factor to achieve prolonged survival in a larger cohort of patients with
BRCAmut OC disease. The superiority of this treatment combination has already been proven in a recent study by Marchetti et al.
35 Additional factors, such as further homologous recombination deficiencies, need to be investigated in future studies to estimate predictive value for complete macroscopic tumor resection during primary and recurrent OC.
In our study cohort, we confirmed
BRCAmut status to be a predictive factor for patient survival. Although patients with
BRCAmut disease showed longer PFS at all times, a significant difference could only be measured during recurrence. Additionally, patients with
BRCAmut disease showed a median OS benefit of 24.3 months compared with the
BRCAwt group. These findings are partially in line with the clinical trial conducted by Bookman et al., which investigated the impact of platinum-free interval and
BRCA mutation status on treatment and survival of patients with rOC. One major finding was that patients with
BRCAmut disease showed a prolonged OS without reaching statistical significance.
23 However, it has to be stated that, in the mentioned study, median follow-up was 25 months and, therefore, the observation period was possibly not long enough to detect long-term effects of
BRCA mutation status on survival. In our study, median follow-up after first-line treatment was considerably longer, at 51.7 months, and effects of
BRCA positivity on OS were significant. Another trial by Jorge et al. had a similar median follow-up of 49.3 months and compared survival of patients with
BRCA1 and
BRCA2 mutated OC disease treated with surgery and platinum-based chemotherapy. They calculated a median OS of 76.2 months from diagnosis for patients with positive
BRCA1 and 82.0 months for patients with positive
BRCA2 disease, which is in line with our finding of 80.6 months for the
BRCAmut cohort.
24