Streamlining Decision Making in Contralateral Risk-Reducing Mastectomy: Impact of PREDICT and BOADICEA Computations

Of 272 consecutive patients identified who underwent ABR, 20 were excluded for the following reasons: 5 (1.8%) had synchronous BC, 13 (4.8%) had ductal carcinoma in situ (DCIS) only, one was male, and one was aged > 80 years, factors that precluded CLBCR estimation. After exclusions, 252 patients with a mean age of 53 years (SD 16.8) were included in the final analysis.

Table 1 illustrates the outcomes of gene testing for the entire cohort in the context of UM or BM and ABR. Of patients undergoing CPM, 14 (37.8%) had BOADICEA scores > 30%, tested gene positive, and appropriately underwent CPM and ABR. Hence, decisions for CPM were not based on genetic mutation status for the majority of patients (62.2%). Of the patients undergoing UM, only five were found to have BOADICEA scores > 30%, of whom four tested gene positive. One patient had a BOADICEA score of 30.7% and was not referred for genetic testing. Interestingly, all five of these patients at higher CLBCR were not offered CPM.

There was no correlation between BODICEA and PREDICT 10-year survival estimate scores (p = 0.735). As illustrated in Fig. 2, a substantial proportion of women not at high-risk of CLBC underwent CPM (20/37 [54%]). Of those who had a BODICEA score < 30%, eight (21.6%) were performed with no documented reason or at the patient’s request, five (13.5%) had contralateral non-invasive disease (DCIS, lobular carcinoma in situ [LCIS], or papilloma) with or without a FH of BC, four (10.8%) had FH, and three (8%) had ipsilateral cancer recurrence. As anticipated, the majority of patients undergoing UM had CLBCR scores < 30%. However, as seen in Fig. 3, 2.3% (5/215) of patients were identified as not undergoing CPM despite a high CLBCR score (> 30%) and ‘good’ prognosis.

The mean (SD) 5- and 10-year predicted survival for the entire cohort without any treatment was 77% (16.8%) and 60.75% (21.9%), respectively. Analysis of BOADICEA scores demonstrated the mean (SD) probability of having BRCA1 and BRCA2 mutations was 5% (19.5%) and 4% (16.1%), respectively, and the likelihood of no mutation was 91% (24.6%). Of the total 252 patients, 215 underwent UM and 37 received CPM. Table 2 highlights differences in CLBCR and survival estimates for patients undergoing unilateral versus bilateral surgery, depicting no significant difference in age (53 ± 9.6 years vs. 59 ± 9.1 years; p = 0.49) or 5-year (87.05 vs. 87.12; p = 0.21) and 10-year (75.3 vs. 79.4; p = 0.73) PREDICT survival estimates. The mean (SD) lifetime CLBCR in the unilateral and bilateral groups was 13.2% (15.5%) and 33.4% (26.6%), respectively. Interestingly, of patients undergoing CPM (n = 37), 15 (40.5%) had BRCA/P53 mutation, and 2 (5.4%) had a BOADICEA score > 30%.

Regarding resource implications, patients undergoing CPM had significantly increased hospital stay (mean ± SD: unilateral 6.2 ± 2.6 days vs. CPM 7.6 ± 4.4 days; p = 0.002). There was no significant difference in operative time [mean (SD): CPM 520.1 min (123.8) vs. unilateral 452.0 min (116.0); p = 0.45] (Table 2). As highlighted in Table 2, complication rates were modestly elevated in the CPM group (37% vs. 30%) and patients were twice as likely to require surgical re-intervention in the CPM group (33% vs. 17%).

This study demonstrates that in the absence of formal prospective CLBCR scores, a significant proportion of low-risk women undergo CPM, arguably without significant risk attenuation, and a small proportion of high-risk women are not offered CPM. Critically, a substantial proportion of patients receiving CPM have either low CLBCR and/or relatively poor prognosis from index disease, and are hence unlikely to have witnessed contralateral recurrence across their lifetime. Presently, approximately one-fifth of patients receiving CPM are classified as ‘low risk’, with a lifetime CLBCR estimate below the 30% NICE threshold. Conversely, a smaller proportion (approximately 2%) with high CLBCR and good prognosis are not receiving CPM.

This prompts the question ‘what could be driving CPM rates in patients whose estimated risk is below the CPM threshold?’ (Prior literature suggests age below 50 years,12 White ethnicity,12 higher socioeconomic status,14 private insurance,14 lobular histology,12 preoperative genetic testing,14,15 and MRI).12,14,29 In our series, low CLBCR cases justified CPM on the basis of FH or local relapse in a previously conserved breast now requiring mastectomy, most likely secondary to perceived high risk of further disease relapse. Decisions made during periods of heightened anxiety associated with initial cancer treatment lead to inflation of perceived risk and fear of recurrence.9,30,31 Our belief, supported by current evidence, is that CLBCR is poorly estimated and/or crudely calculated (e.g. 0.7% per annum), and we would argue in favor of objective risk scoring to augment clinical decision making, and better counsel patients considering CPM based on risk. The challenge is to conduct complex risk estimates ‘on the fly’ since computations using BOADICEA and PREDICT are not trivial. Indeed, here each BOADCIEA computation required 25–35 min, and hence the entire analysis took approximately 160 h. Therefore, an expedited surrogate calculation of CLBCR incorporating age, biology of the index BC, and FH to best approximate BOADICEA risk estimates is required. Similarly, survival estimates (PREDICT) are conducted postoperatively, and yet, for improved decision making, it would be valuable to use preoperative data to predict 10-year survival. Put simply, further work is required to consider how surrogate estimates of survival and CLBCR could be utilized prospectively to improve CPM decisions.

While, in our view, CLBCR should be the primary driver for CPM, we accept, as per both US7 and UK guidelines,6 that certain circumstances may justify CPM with CLBCR; for example, patients in whom contralateral surveillance is challenging, such as those with extremely dense breasts, and recall fatigue due to multiple further core biopsies, so called ‘screen cripples’. Arguably, more controversial are grounds for reconstructive symmetry and alleviation of psychological morbidity in risk-averse patients. Indeed, DIEP flaps may be viewed as a ‘one-off opportunity’ to achieve immediate reconstructive symmetry. A survey carried out by Montgomery and colleagues32 identified that the most frequent reasons for CPM is achieving symmetry.32 This, coupled with improvements in reliability and access to reconstructive microsurgery, may contribute to increased CPM uptake.16,17 However, in the context of increased hospital stay and psychological morbidity demonstrated in this study and by others,5,19,20 it is challenging to accept reconstructive symmetry as acceptable grounds for CPM in low-risk patients. Treating anxiety, depression, or fear of relapse with surgery is equally controversial, especially given the postoperative psychological morbidity disappointment and regret experienced by some women following CPM.8,21,32 Critically, we failed to identify patients, albeit retrospectively, in whom reconstructive symmetry or risk aversion were cited as the grounds for CPM, and yet it is challenging to conceive how these factors did not contribute to decision making in low-risk patients.

The implications of CPM decisions are being felt both in human and economic terms. On average, patients undergoing CPM stay 1.5 more days in hospital, are at increased risk of perioperative complications, and are twice as likely to require further re-intervention than patients undergoing UM and reconstruction. The increased risks of physical morbidity associated with bilateral surgery are not unique to our series. Indeed, others have observed that CPM doubles the risk.7,33,34 For example, Miller et al.33 observed that CPM patients were 2.7 times more likely to experience a major complication (odds ratio [OR] 2.66, 95% confidence interval 1.37–5.19; p = 0.004).33 Similarly, Silva et al.34 found that CPM was associated with increased rates of reoperation (OR 1.15, p = 0.029) and wound disruption (OR 2.51, p = 0.015).34 Notwithstanding the physical morbidity of surgery, many patients who undergo CPM experience regret, dissatisfaction, and disappointment with the results of surgery.32,35

Finally, compared with UM reconstruction, simultaneous CPM reconstruction has significant resource implications. Patients undergoing BM required, on average, 68 min of additional operating room (OR) time. This is valuable OR time that could have been released to operate on BCs. Moreover, in our institution, bilateral cases require two teams of attending physicians in breast oncologic surgery and plastic and reconstructive surgery, with impact on outpatient clinics and ward services. Finally, the UK financial reimbursement schedule fails to reflect the additional workload. In the National Health Service (NHS), the Health Resource Group (HRG) code for UM and ABR (HRG code = JA36Z, = £10,627, = $15,141),36,37 which compares unfavorably to BM (HRG code = JA37Z, = £13,083, $18,639).37 Ideally, additional resources required to reduce risk through CPM should be traded off against the longitudinal costs saved in eliminating surveillance, and indeed treating CLBC downstream.36

Calculations of CLBCR and 10-year survival estimates exposes a substantial proportion of patients who are not at high-risk of contralateral cancer but in whom CPM is performed. CPM in low-risk patients is difficult to justify considering the physical morbidity, negligible survival advantage, and rationing of decisions in the current austere climate of the NHS.