This report documents the medium term follow-up of 300 women at high-risk of ovarian cancer who have undergone risk-reducing surgery. This study has reinforced the efficacy of this surgery to reduce ovarian cancer risk. No cancers have occurred after surgery, whereas over 15 were expected, and the upper end of the 95% CI are still equivalent to an 81% reduction in risk. This is significantly better than the pooled data from 10 studies, which gave a 79% overall reduction.16
Two peritoneal primaries were reported in a large combined series of 259 BRCA1
/2 mutation carriers undertaking BSO, although 56 ovarian cancers occurred in 292 controls.17
This was equivalent to a 96% reduction in risk. In a smaller study of 170 women, 98 chose risk-reducing salpingo-oophorectomy, and peritoneal cancer was diagnosed in one woman.18
Amongst 72 women who chose surveillance in this study, ovarian cancer occurred in four, and peritoneal cancer in one; this was equivalent to a 75% reduction in risk. Although our report has fewer mutation carriers than the first of these reports from 2002,17
it also includes women from families without proven mutations. Three of the expected cancers and six of those in the controls occurred in women not known to be BRCA1
/2 mutation carriers. A larger combined study from the first two groups on 1079 mutation carriers found an 85% reduction in gynaecological malignancy for BRCA1
Three peritoneal primary cancers occurred in a mean follow-up of 40 months amongst 325 women undertaking surgery.
The potential accuracy of our risk prediction is shown by the control group, although the CIs were still wide. The cancers detected in BRCA1/2 carriers and in non-carriers were virtually identical to that predicted. The control group, although larger, contained a substantial group of women with lower overall predicted risk (). This accounts for the 0.46% annual risk compared with the 0.66% risk predicted in the surgery group. Although we have not carried out a direct matching exercise of cases and controls, the accuracy of the predictions has been bourne out by our analysis.
The rate of occult malignancy is identical to that found in the two earlier reports in mutation carriers.17, 19
A total of 3 of 160 (2%) had occult malignancy in our report compared with 6 of 259 (2.3%) in the larger report.17
A higher rate of occult malignancy has been found if extra pathological examinations are carried out with seven occult malignancies discovered, four in the fallopian tube and three in the ovaries, amongst 76 cases.20
Six of these were microscopic. It is arguable whether we would have detected more cancers with a more thorough protocol, but none of the patients without malignancy detected have gone on to develop signs of invasive disease.
In contrast to the study by Rebbeck et al
which used controls who were not necessarily undergoing surveillance, we have only used controls who were prospectively followed on an active annual surveillance programme. Despite this surveillance, women on an annual programme of CA125 and ovarian ultrasound will still present predominantly with late-stage disease (). This is shown from our own data and a combined analysis from five centres of 63 ovarian tumours in a screening programme with 10-year survival of only 36%.21
As such, 11 ovarian cancer deaths may have been expected out of the 15.79 cancers expected in the surgical group, with one actually dying from a cancer detected at surgery. As such, close to 13 ovarian cancers and 10 ovarian cancer deaths will most likely have already been prevented in the surgery group. With further follow-up, it is likely that this benefit would be greatly increased given the absence of cancers found after surgery. We are not able to comment on any benefit from the prevention of breast cancer or breast cancer death due to the absence of direct matching of cases in this study. It is nonetheless likely that breast cancers will be prevented in women undergoing early BSO with around a 50% reduction in risk.17
Comparison of the oophorectomy and control groups for ovarian and breast cancer incidence and death
The debate as to the frequency of peritoneal malignancy after surgery still pertains. In 324 women who underwent prophylactic BSO in an ovarian cancer family registry, primary peritoneal carcinoma histologically indistinguishable from primary ovarian adenocarcinoma developed in six of them.20
Such malignancy could reflect undetected occult disease removed at surgery or the development of disease in ovarian epithelial tissue lodged during embryological development. In particular, the high rate of tubal malignancy and occult disease in reports22
emphasises the need to remove the fallopian tube in its entirety. Alternatively, epithelial ovarian cells on the surface of the ovaries could be displaced into the peritoneum at the time of surgery. We are aware of one peritoneal cancer occurring in a 56-year-old BRCA1
carrier 4 years after BSO at another centre in our region. An increased risk in the peritoneum is suggested by the apparently higher rates of peritoneal primary disease in mutation carriers after surgery. Only 6 of 244 (2.4%) of ovarian cancers were designated as of peritoneal origin in our mutation carriers, excluding the case found after surgery from another centre. It is possible that some stage 3 or 4 disease is wrongly labelled as starting in the ovaries, nonetheless, the risk reduction of 96% in the paper by Rebbeck et al17
suggests that <10% of the ovarian type risk resides in the peritoneum. Absolute risks of peritoneal cancer in follow-up are still <1% in BSO series.17, 19
The result that no peritoneal cancers were found during follow-up after surgery, may be because of the relatively small number of patients or the length of follow-up. Nonetheless, our data support the careful approach to ovarian risk-reducing surgery carried out by this and many other centres, although direct comparisons of techniques in large numbers of women would be required for proof of benefit.