Increasing opportunities for breast-conserving therapy in multiple ipsilateral breast cancer: Dutch nationwide study

Abstract

Introduction

An increasing number of breast cancer patients undergo breast-conserving surgery (BCS), but multiple ipsilateral breast cancer (MIBC) is still considered a relative contraindication for breast conservation. This study provides an update on trends in the surgical management for MIBC over a 10-year period.

Methods

Nationwide data from the Netherlands Cancer Registration of all patients diagnosed with breast cancer between 2011 and 2021 were analysed. The primary outcomes of this study were the incidence of MIBC and the trend in breast surgery type among patients between 2011 and 2021. Secondary outcomes were the positive resection margin rates in patients treated with BCS, the proportion of patients requiring re-excision and overall survival.

Results

In total, 114 433 patients (83%) with unifocal breast cancer and 23 932 patients (17%) with MIBC were identified. The incidence of MIBC was stable (17%) over the years. Overall BCS rates, both primary and after neoadjuvant chemotherapy, increased in MIBC from 29% in 2011 to 41% in 2021. Re-excision was performed in 1348 patients (n = 8455, 16%). The 5-year OS estimate for patients with MIBC treated with BCS was 93%. The pathological complete response (pCR) in MIBC patients treated with neoadjuvant chemotherapy followed by mastectomy was 23%.

Conclusion

The breast conservation rate in MIBC has increased over the last decade. In addition, 23% of MIBC patients treated with neoadjuvant chemotherapy followed by mastectomy achieved a pCR. This suggests increasing opportunities for even more BCS in MIBC.

Introduction

Breast cancer is the most common type of cancer among women worldwide¹. Although most patients present with unifocal breast cancer, around 10–20% of patients have multiple tumours in the same breast. Multiple ipsilateral breast cancer (MIBC) can be classified as multicentric tumours with more than one tumour in different quadrants of the breast, or multifocal tumours with more than one tumour within the same quadrant of the breast (Fig. 1)^2,3. Increasing numbers of MIBC are being reported, possibly due to the improved quality and application of breast imaging and the more frequent use of MRI in the diagnostic work-up^4–7.

Despite increasing number of breast cancer patients undergoing breast-conserving surgery (BCS), MIBC is still often considered a relative contraindication to BCS due to oncological safety concerns^8–15. Furthermore, maintaining a good aesthetic outcome can be challenging due to an unfavourable tumour-to-breast volume ratio^16,17. Recently published results from the ACOSOG Z11102 trial evaluating the oncological outcome of patients with MIBC treated with BCS followed by adjuvant radiotherapy (RT) showed a 5-year local recurrence rate of 3.1% (95% c.i. 1.3 to 6.4)¹⁸. The ACOSOG Z11102 trial evaluated the primary surgical setting and excluded patients treated with neoadjuvant chemotherapy (NACT). In the current era, NACT is increasingly being used, allowing those initially planned for a mastectomy to undergo BCS when obtaining a good treatment response^11,19–24, as shown here in the example of one such patient (Fig. 1). Only few studies have evaluated the outcome of BCS after NACT in patients with MIBC. These show that BCS may be a favourable alternative to mastectomy when achieving free margins and with adjuvant RT^25–29. Nevertheless, there is a lack of consensus among breast surgeons regarding the safety of BCS for patients with MIBC³⁰. No studies have assessed factors that influence the surgical approach to the breast in MIBC. The present study provides an up-to-date overview of the trend in surgical approach for MIBC in the Netherlands over the past decade and includes patients treated with NACT.

Methods

The Netherlands Cancer Registry

Nationwide data from the Netherlands Cancer Registry (NCR), a database of all cancer patients in the Netherlands, was used³¹. This database is managed by the Dutch Comprehensive Cancer Organization. Data from the NCR include information on patient age, cancer diagnosis, tumour stage at time of diagnosis according to TNM³², tumour location and morphology according to the WHO International Classification of Diseases for Oncology³³ as well as type of treatment.

Data selection and definitions

All data records of women aged 18 years and older diagnosed with invasive breast cancer between 2011 and 2021 in the Netherlands were collected. Exclusion criteria were cT4 cancer including inflammatory breast cancer, metastatic disease, a history of ipsilateral breast cancer and male sex.

Multifocal and multicentric tumours are registered as the same entity by the NCR and are therefore both defined as MIBC in the present study. NACT was defined as treatment with chemotherapy in the neoadjuvant setting that was administered according to Dutch national breast cancer guidelines at the time of treatment. The NCR reports on TNM stage at diagnosis including the pathological TNM after surgery. Pathological complete response (pCR) of the breast after NACT was defined as ypT0. The type of breast surgery was either BCS or mastectomy. Adjuvant RT was defined as local RT to the breast.

The primary outcome was the trend in the type of breast surgery in patients with MIBC from 2011 to 2021. Secondary outcomes were the rate of positive resection margins in patients treated with BCS, the proportion of patients requiring re-excision and overall survival (OS). Resection margins were considered focally non-radical if the area of the involved margin was less than 4 mm. If more than 4 mm of the margin was involved, the margin was considered as more than focally non-radical. According to Dutch National guidelines, only focally non-radical margins do not require a re-excision. However, re-excision (BCS or mastectomy) is indicated in patients with more than focally non-radical (>4 mm) margins³⁴, in the presence of ductal carcinoma in situ (DCIS) at the margin or multifocality in patients that have undergone a diagnostic lumpectomy.

Statistical analysis

Descriptive analyses were used for patient, tumour and treatment characteristics and trends stratified for unifocal breast cancer and MIBC. Survival estimates were calculated using the Kaplan–Meier method and compared with the log rank test. All statistical analyses were performed with IBM SPSS Statistics (SPSS for Windows version 29.0; SPSS Inc., Chicago, IL).

Results

Between 2011 and 2021, a total of 151 262 patients with breast cancer were registered, of which 138 365 patients were included in the present analyses (Fig. S1). In total, 114 433 patients (83%) had unifocal breast cancer and 23 932 patients (17%) MIBC, defined as more than one tumour lesion in the same breast. Although an increase in the use of MRI was observed, the proportion of MIBC relative to unifocal breast cancer has remained stable at approximately 17% (Fig. 2).

Baseline

Overall, the mean age was 60 years (s.d. 13). Most patients had cT1 (n  = 84 115, 61%) and cN0 (n  = 115 115, 83%) cancers. Most patients’ cancers were of no specific type at histology (n = 107 513, 83%), without a DCIS component (n  = 72 322, 52%) and hormone receptor positive (+)/human epidermal growth factor 2 (HER-2) negative (−) (n  = 103 738, 75%). Most patients were not treated with NACT (n  = 113 104, 82%) and the majority underwent BCS (n  = 92 505, 67%). Thirty per cent of patients operated with a mastectomy underwent immediate breast reconstruction (n = 12 032). Most patients received adjuvant RT (n  = 101 811, 74%). Baseline characteristics are listed in Table 1.

Trends and type of breast surgery in multiple ipsilateral breast cancer

Of all patients with MIBC, 16 804 underwent primary surgery (70%) and 7128 patients were treated with NACT followed by surgery (30%). Treatment with NACT in MIBC increased from 15% in 2011 to 39% in 2021. Although most patients with MIBC underwent a mastectomy (n  = 15 477, 65%), an increase in BCS rates was observed (29% in 2011 compared to 41% in 2021). This increase was observed both in the group operated directly and among those operated after NACT (29% to 41% and 32% to 42% respectively). Primary mastectomy rates for MIBC decreased from 61% in 2011 to 36% in 2021. In univariate and multivariable regression analyses, NACT was positively associated with BCS in MIBC (OR 2.71, 95% c.i. 2.48 to 2.94, P < 0.001; Table S1).

Margin involvement and neoadjuvant chemotherapy treatment response

A total of 8455 patients with MIBC underwent BCS of whom 5737 (68%) had primary surgery and 2718 (32%) were operated after NACT. Table 2 shows the surgical outcome in patients with MIBC treated with BCS. Information on surgical margins was missing for 198 patients. Resection margins were more than focally non-radical in 7% of patients with primary BCS (n = 401) and in 6% of patients operated with BCS after NACT (n = 162). In total, re-excision was performed in 1348 patients (16%). Of these, 632 patients underwent a second BCS (7%) and 716 patients underwent mastectomy (8%). Definitive surgery was BCS in 7642 patients (90%) and mastectomy in 813 patients (10%).

Overall, pCR was achieved in 25% of patients (n  = 1774). The pCR rate of patients undergoing BCS following NACT was 28% (n = 755) and in patients undergoing mastectomy this was 23% (n = 1019; Table S2).

Overall survival in multiple ipsilateral breast cancer

The 5-year estimated OS for unifocal breast cancer and MIBC, at a median follow-up of 58 months (i.q.r. 30–92), is demonstrated in Fig. 3. The 5-year OS for unifocal breast cancer + BCS was 92%, for unifocal breast cancer + mastectomy 80%, for MIBC + BCS 93% and for MIBC + mastectomy 87% (Fig. 3).

Discussion

This large population-based study shows a clear increase in BCS rates for patients with MIBC diagnosed in the Netherlands between 2011 and 2021. Currently, MIBC is a commonly used term in the literature to define the group of patients with multifocal and multicentric breast lesion and therefore used in the present study^28,29. The present study highlights evolving trends regarding surgical treatment in patients with MIBC, including those treated with NACT prior to surgery, and thus provides an overview of the current status of surgical treatment in MIBC patients.

Over this 10-year period, a stable percentage of MIBC (17%) was observed. An increase in the use of MRI was noted, rising from 35% in 2011 to 54% in 2021. However, this increase in MRI use did not contribute to higher MIBC rates as has been reported in previous studies^35,36.

More patients were also operated after NACT and this strategy was significantly associated with BCS in MIBC (OR 2.71), with an increase in BCS rates for MIBC after NACT from 32% in 2011 to 42% in 2021. This trend is consistent with the trend of more BCS after NACT in unifocal breast cancer¹⁹. Not surprisingly, BCS rates after NACT remain lower in patients with MIBC compared to those with unifocal breast cancer²⁰.

Overall, 25% of patients with MIBC treated with NACT achieved a pCR, which is comparable to results in unifocal breast cancer^11,37,38. At the same time, the present study shows that 23% of patients with MIBC treated with NACT still underwent a mastectomy, despite a pCR of the breast, suggesting that further de-escalation of surgery can be achieved.

Currently, there is no consensus on the surgical treatment of MIBC. Massanat et al. recently published their results of an international survey among 743 physicians from 100 countries evaluating the surgical management of MIBC³⁰. They concluded that there is no unanimous agreement on the definition of MIBC. The survey, however, clearly indicated that there is substantial support within the international breast surgical community for BCS also in multifocal breast cancer. There was heterogeneity in the marking of lesions prior to surgery. Most respondents only mark the tumours needed to delineate the extent of disease (40.4%), whereas only 15.6% mark every lesion preoperatively. Unfortunately, this survey did not cover the surgical management of MIBC after NACT. In the case of NACT, marking of multiple lesions is preferred, especially in triple negative breast cancer and HER2+ patients in line with the high pCR rates³⁸.

Despite the clinician support for BCS, relatively few studies have reported on the oncological safety of BCS in MIBC and most studies exclude NACT-treated patients^18,39,40. The 5-year OS for BCS in both unifocal breast cancer and MIBC was comparable (92% and 93%) in the present study. Patients with unifocal breast cancer treated with mastectomy were shown to have the worst survival. It should, however, be emphasized that this is OS and not breast cancer-specific survival. The explanation may thus be that the group with highest co-morbidity and disease stage receive the simplest treatment. This group does not, however, differ in age (Table 1), and thus co-morbidity, for which we have no data, may play a role. Unfortunately, further data on oncological safety in terms of locoregional recurrence and disease-free survival (DFS) were not available. Oh et al. published their results regarding loco-regional control, DFS and OS in 97 patients with MIBC treated with NACT and BCS plus adjuvant RT compared to patients with unifocal disease²⁶. They reported no significant differences in loco-regional control (94% versus 89%, P = 0.92), 5-year DFS (86% versus 78%, P = 0.16) and 5-year OS (86% versus 83%) compared to unifocal disease. These findings were supported by Ataseven et al., who in 2015 published their results in 134 patients on local recurrence-free survival (LRFS), DFS and OS in patients with MIBC treated with NACT. They showed that the LRFS, DFS and OS of MIBC were not inferior to those of patients with unifocal breast cancer, provided that pCR was achieved²⁵. The recently published study by Di Lena et al. evaluated 544 patients (80.5% unifocal breast cancer, 19.5% MIBC), all of whom underwent BCS after NACT. The local recurrence rate at 55 months of follow-up (i.q.r. 32–83) was 4.8% in the unifocal group compared to 4.7% in the MIBC group (P = 0.97)²⁸.

The results of the present study suggest that there are increasing opportunities for BCS in MIBC, especially in patients treated with NACT. Around 23% of patients with a pCR still underwent a mastectomy. With current techniques there are increasingly possibilities to use BCS and oncoplastic breast conserving surgery instead of mastectomy. By training breast surgeons in oncoplastic surgical techniques, will allow be for BCS also in patients with MIBC who would otherwise have been treated with a mastectomy.

Funding

The authors have no funding to declare.

Disclosure

The authors declare no conflict of interest.

Supplementary material

Supplementary material is available at BJS online.

Data availability

The data presented in this study are available in this article.

References