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Nationwide population‐based study of the impact of immediate breast reconstruction after mastectomy on the timing of adjuvant chemotherapy

Background Initiation of adjuvant chemotherapy within 6–12 weeks after mastectomy is recommended by guidelines. The aim of this population‐based study was to investigate whether immediate breast reconstruction (IBR) after mastectomy reduces the likelihood of timely initiation of adjuvant chemotherapy. Methods All patients with breast cancer who had undergone mastectomy and adjuvant chemotherapy between 2012 and 2016 in the Netherlands were identified. Time from surgery to adjuvant chemotherapy was categorized as within 6 weeks or after more than 6 weeks, within 9 weeks or after more than 9 weeks, and within 12 weeks or after more than 12 weeks. The impact of IBR on the initiation of adjuvant chemotherapy for these three scenarios was estimated using propensity score matching to adjust for treatment by indication bias. Results A total of 6300 patients had undergone primary mastectomy and adjuvant chemotherapy, of whom 1700 (27·0 per cent) had received IBR. Multivariable analysis revealed that IBR reduced the likelihood of receiving adjuvant chemotherapy within 6 weeks (odds ratio (OR) 0·76, 95 per cent c.i. 0·66 to 0·87) and 9 weeks (0·69, 0·54 to 0·87), but not within 12 weeks (OR 0·75, 0·48 to 1·17). Following propensity score matching, IBR only reduced the likelihood of receiving adjuvant chemotherapy within 6 weeks (OR 0·95, 0·90 to 0·99), but not within 9 weeks (OR 0·97, 0·95 to 1·00) or 12 weeks (OR 1·00, 0·99 to 1·01). Conclusion Postmastectomy IBR marginally reduced the likelihood of receiving adjuvant chemotherapy within 6 weeks, but not within 9 or 12 weeks. Thus, IBR is not contraindicated in patients who need adjuvant chemotherapy after mastectomy.


Introduction
Breast cancer is the most commonly diagnosed malignant cancer among women 1 . Despite advancements in diagnostics and systemic treatment, up to one-third of patients with breast cancer undergo mastectomy as the first surgical treatment to achieve local control 2 . Adjuvant systemic treatment, including chemotherapy, reduces the risk of distant recurrence and breast cancer mortality 3 . In the Netherlands, 6 weeks is the maximum time limit aimed for between surgery and initiation of adjuvant chemotherapy, as recommended by the European Society for Medical Oncology 4 (ESMO) and the Netherlands Society for Plastic Surgery 5,6 . Several studies 7 -12 have reported that delayed initiation of adjuvant chemotherapy is associated with lower overall and recurrence-free survival. The recommended acceptable maximum delay, however, varies from 7 to 12 weeks. There still is no international consensus on the definition of an unacceptable delay, but all guidelines advocate that initiation of adjuvant chemotherapy should not be delayed unnecessarily, as this may have a negative impact on survival, specifically in patients at higher risk of recurrence 9,10,12 .
The addition of immediate breast reconstruction (IBR) to mastectomy could result in preoperative delay owing to more complex logistic coordination of the operation. After surgery, a delay could be the result of longer recovery, as IBR may increase the risk of postoperative complications, even though reports on the risk of adverse events are conflicting 13 -16 . In the past decade, an increasing number of women have undergone IBR after mastectomy 2,17,18 . IBR is generally associated with good aesthetic results and less negative psychological impact on the patient, as it involves fewer operations and hospital admissions compared with breast reconstruction at a later time 19 -21 . Owing to the lack of consensus on timing of adjuvant chemotherapy, physicians remain cautious in recommending IBR when adjuvant chemotherapy is part of the preoperative treatment plan 22 .
Most previous studies 16, 23 on the possible delaying impact of postmastectomy IBR have been single-centre studies with weak methodology and no adjustment for treatment by indication bias. A systematic review 24 from 2015 concluded that IBR does not delay time from surgery to adjuvant chemotherapy to a clinically relevant extent, although the included studies showed strongly contradictory results. Moreover, a cut-off point of 12 weeks to initiation of adjuvant treatment was used, whereas current European guidelines 4 recommend 6 weeks. Furthermore, it seems likely that there may be an underlying reason why some patients have IBR and others do not, giving rise to treatment by indication bias when comparing the outcomes of these two groups.
The aim of the present nationwide population-based study was to investigate the extent to which postmastectomy IBR reduces the likelihood of timely initiation of adjuvant chemotherapy compared with mastectomy alone, while also adjusting for confounding by indication.

Methods
Prospectively collected data from the NABON Breast Cancer Audit (NBCA) database were used. The NBCA was started in 2011 and is an initiative from the National Breast Cancer Organization Netherlands (NABON), the Netherlands Comprehensive Cancer Organization and the Dutch Institute for Clinical Auditing. The NBCA collects anonymized data on clinicopathological characteristics, diagnostics and treatment modalities in a database from all hospitals in the Netherlands. It includes all patients diagnosed with ductal carcinoma in situ (DCIS) or invasive breast cancer treated surgically since 2012. The NBCA aims to monitor the quality of breast cancer care and to provide feedback to participating hospitals to stimulate and facilitate quality improvement 25 . No formal consent is required for this type of study from an ethics committee in the Netherlands according to Central Committee on Research involving Human Subjects.

Patient population
All women diagnosed with invasive breast cancer between 2012 and 2016 who had undergone primary mastectomy with or without IBR followed by adjuvant chemotherapy were identified from the NBCA database. IBR was defined as a reconstruction performed by a plastic surgeon on the same day as the mastectomy. Women who had received systemic neoadjuvant treatment, had undergone lumpectomy as initial surgery or had a re-excision were excluded from the analysis. Patients who had received another adjuvant therapy before the initiation of adjuvant chemotherapy, and those with a missing date of operation or adjuvant chemotherapy were also excluded.

Outcomes
The primary outcome was whether the patient received adjuvant chemotherapy within a specific time interval after surgery. Time to adjuvant chemotherapy was analysed with three different cut-off values: within 6 weeks or after more than 6 weeks, within 9 weeks or after more than 9 weeks, and within 12 weeks or after more than 12 weeks. These cut-offs were chosen based on the currently recommended starting point according to Dutch and ESMO guidelines, and on previous literature demonstrating that a clinical impact is found when adjuvant chemotherapy is started later than 7-12 weeks, indicating the importance of initiating adjuvant chemotherapy at least within this time period 4,7 -12 .

Confounders
Potential confounders included in analyses were year of diagnosis, age, WHO performance status 26 , presence of DCIS, histological type, receptor status, tumour stage according to the seventh edition of AJCC 27 , sentinel node biopsy, axillary lymph node dissection (ALND), hospital transfer between site for surgery and that for adjuvant chemotherapy, and annual number of patients operated on for breast cancer at the hospital (hospital volume). Data regarding reconstruction at a later time, rather than IBR, are not registered in the NBCA and could therefore not be included.

Statistical analysis
Statistical differences for all possible confounders between women who had mastectomy alone and those who had mastectomy plus IBR were determined using χ 2 tests. All tests were two-sided, and P < 0⋅050 was considered statistically significant. Multivariable logistic regression analysis was used to determine the likelihood that women who had undergone IBR received adjuvant chemotherapy within 6, 9 and 12 weeks, when adjusted for the confounders. There may, however, be an underlying reason why patients have IBR, so that not all women are equally likely to receive IBR, for example because of a different type of tumour or age of the patient, introducing a treatment by indication bias. Thus, propensity score matching (PSM) was performed, including all available patient and tumour characteristics to adjust for treatment by indication bias. Use of PSM ensures that patients from both cohorts are matched and have the same likelihood of receiving IBR, given certain patient and tumour characteristics. For each pair, one patient did and one did not undergo IBR; this is essential to estimate the true treatment effect on an outcome in observational studies 28,29 . Statistical analyses were performed with SPSS ® version 24 (IBM, Armonk, New York, USA).

Results
In the selected time interval, 6300 women were diagnosed with invasive breast cancer and met the eligibility criteria. Of these, 4600 patients (73⋅0 per cent) underwent mastectomy alone and 1700 patients (27⋅0 per cent) had postmastectomy IBR. Of the women who had IBR, 91⋅2 per cent had received an implant-based reconstruction (including tissue expanders).
The proportion of women who had postmastectomy IBR decreased with patient age and increased over time (Fig. 1). Patients who underwent IBR were younger at diagnosis, more often had a WHO status of 0, or were diagnosed with no special type of histology, DCIS component and tumour stage I than women who had mastectomy alone ( Table 1). There was no difference in receptor status or differentiation grade between the two groups. Of women who had postmastectomy IBR, the proportions that underwent sentinel node biopsy, transferred hospital between surgery and adjuvant chemotherapy, or were treated in a hospital with surgical volume exceeding 250 patients annually were also higher compared with those of women who had mastectomy alone. However, the proportion that had ALND was lower in women who underwent postmastectomy IBR ( Table 1).

Time to adjuvant chemotherapy
The median (i.q.r.) time from surgery to adjuvant chemotherapy in women who had postmastectomy IBR was 36 (29-47) days, compared with 34 (28-44) days in those who had mastectomy alone ( Table 2). Adjuvant chemotherapy was initiated within 6 weeks in more than two-thirds of patients, and the vast majority received adjuvant chemotherapy within 9 and 12 weeks. The total proportion of patients who received adjuvant chemotherapy within 6, 9 and 12 weeks did not differ over time (2012-2016: P = 0⋅282, P = 0⋅128 and P = 0⋅052 respectively) (Fig. 2).
Although not the focus of this study, analyses of predictive confounders demonstrated that, amongst other factors, patients who had a sentinel node biopsy or ALND were less likely to receive adjuvant chemotherapy within 6 and 9 weeks, as well as within 12 weeks for ALND ( Table 3).

Discussion
This large population-based study, analysing patients from all hospitals treating breast cancer in the Netherlands, found that, compared with mastectomy alone, IBR after mastectomy reduced the likelihood of receiving adjuvant chemotherapy within 6 weeks of surgery, as recommended by Dutch 6 and European 4,5 guidelines, but not within 9 or 12 weeks. This suggests that postmastectomy IBR is not necessarily contraindicated in patients who need adjuvant chemotherapy, because in general IBR does not delay its initiation to a clinically relevant extent.
Previous studies on the impact of IBR on time to adjuvant chemotherapy reported a large variation in time to adjuvant chemotherapy, ranging from 21 to 80 days for those who had mastectomy alone and from 31 to 97 days for patients who received IBR 30 -34 , with reported differences between these cohorts of 14-27 days 24 . However, this large variation may have been the result of the small single-centre studies, weak methodology and biases, such as the lack of adjusting for treatment by indication bias.
The findings of the present study are not in line with the recently published results from a large multicentre study of Jabo and colleagues 35 in the USA, which suggested that IBR delays time from diagnosis to treatment but not from surgery to adjuvant chemotherapy. This discrepancy may be explained by differences in the statistical approach, as these authors used time as a continuous value, compared with a categorical value in the present study. Moreover, Jabo and co-workers 35 compared time from surgery to adjuvant chemotherapy with non-parametric tests without adjusting for confounders, because the latter was not the main focus of their study. It is noteworthy that their reported time from surgery to adjuvant chemotherapy was considerably longer than that found in the present study, both for patients who had mastectomy alone (40 versus 34 days respectively) and those who underwent IBR (42 versus 36 days) 35 .
The present study suggests that patients who had sentinel node biopsy or ALND were less likely to receive adjuvant chemotherapy within the predefined cut-off points, confirming the previously reported delaying impact of ALND 34 . In the present study, postoperative complications may have occurred more frequently in patients who underwent ALND combined with postmastectomy IBR, and thereby potentially could have delayed chemotherapy 36 -38 . Postoperative complications, such as axillary seroma, are common after mastectomy combined with ALND. The present study suggests that the associated risk of postoperative complications after sentinel node biopsy and ALND may increase the likelihood of delay. The risk of seroma formation can be reduced by minimizing dead space through quilting sutures or an axillary drain 39 . Complications, and strategies to prevent their occurrence, are not collected in the NBCA database and could therefore not be studied as a potential explanatory factor.
The present study has shown that patients diagnosed with triple-negative breast cancer, human epidermal growth factor receptor 2-positive breast cancer and higher stage disease were more likely to receive adjuvant chemotherapy within 6 weeks. It is reassuring that these tumour characteristics were predictive of timely initiation of adjuvant chemotherapy, as previous studies 7, 10 have shown that delay is of particular relevance in women with these more aggressive types of cancer.
It was expected that the impact of IBR on time to adjuvant chemotherapy would change after adjusting for treatment by indication bias, as the present results and a previous Dutch study 40 both showed that patients undergoing IBR differ in many characteristics from those undergoing mastectomy alone.
The majority of patients in the present study underwent a two-stage implant IBR with a tissue expander. This type of IBR is the most common approach in patients eligible for postoperative radiotherapy in most industrialized countries 41 . Despite autologous reconstructions being used increasingly in the last decade 18 , the proportions of different types of IBR were comparable between the predefined cut-off points (data not shown). Nonetheless, the number of women who had IBR using autologous tissue with or without a prosthesis was low (less than 8 per cent), reflecting practice in the past. Therefore, a future study with more patients receiving IBR using autologous tissue could investigate whether this will affect the results.
Patients who changed hospital after surgery were less likely to receive adjuvant chemotherapy within 6 weeks, but not within 9 or 12 weeks. Although this concerned only 3⋅2 per cent of all patients, the association corroborates the theory that hospital transfer delays treatment, as shown by previous studies 34,42,43 .
The present results are inconclusive regarding the association between hospital volume and time to adjuvant chemotherapy. On the one hand, higher volume reduced the likelihood of receiving adjuvant chemotherapy within 6 weeks, but on the other hand, lower volume reduced the likelihood of receiving adjuvant chemotherapy within 9 weeks. A recent study by Schreuder and co-workers 44 demonstrated that hospital volume only partly explains the use of IBR in the Netherlands. Presumably, other hospital related factors such as theatre availability or number of medical specialists have more impact on time to adjuvant chemotherapy after IBR than just hospital volume.
The number of patients aged 70 years or above seems lower in the present study than in previous studies. This might be explained by the fact that adjuvant chemotherapy is used less frequently in these older women in the Netherlands 45 . Furthermore, postmastectomy IBR is used less frequently in this patient group in the Netherlands 40 .
There were several limitations to the present study. First, it was observational, using PSM to adjust for confounding as best as possible. However, matching may be improved by adding other factors potentially associated with delay of adjuvant chemotherapy or the type of surgery (such as radiotherapy, BMI, travel distance). Unfortunately, it was not possible to include these factors as these are not registered in the NBCA database. Insurance coverage was probably not important in the present study, in contrast to studies from the USA, because all Dutch patients are obliged to have basic insurance coverage, providing equal access to breast cancer treatment and breast reconstruction. Second, treatment delay or choice for a specific type of surgery can also be the result of patient preference, such as seeking a second opinion or personal scheduling limitations. Third, this study focused on the time between surgery and initiation of adjuvant chemotherapy, and was therefore not able to assess the potential delaying impact of IBR in the preoperative phase owing to organizational factors such as planning.
The results of the present study in a population-based setting, which were adjusted for confounding and treatment by indication bias, add to the evidence in current literature that IBR is not contraindicated in patients who require a mastectomy and adjuvant chemotherapy, because it does not generally delay time to adjuvant chemotherapy to a clinically relevant extent.

Disclosure
The authors declare no conflict of interest.