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. 2022 Mar 7;149(3):1085–1093. doi: 10.1007/s00432-022-03973-8

A propensity score–matched analysis of breast-conserving surgery plus whole-breast irradiation versus mastectomy in breast cancer

Francesca Magnoni 1,✉,#, Giovanni Corso 1,2,#, Patrick Maisonneuve 3, Giulia Massari 1, Luca Alberti 1, Giulia Castelnovo 1, Maria Cristina Leonardi 4, Virgilio Sacchini 5, Viviana Galimberti 1, Paolo Veronesi 1,2
PMCID: PMC11328321  NIHMSID: NIHMS2002762  PMID: 35254519

Abstract

Purpose

Recent observations regarding long-term outcomes among patients with early-stage breast cancer (BC) who underwent breast-conserving surgery (BCS) plus whole-breast irradiation (WBI) or mastectomy are from a small number of registry-based studies. Therefore, these findings may overestimate differences in survival between the two groups, compared with randomized controlled trials conducted in the 1980s. The aim of this study is to compare long-term outcomes and clinicopathologic characteristics between patients treated with BCS + WBI or mastectomy for BC.

Methods

We performed a propensity score–matched analysis in a cohort of 9710 patients aged < 70 years who underwent BCS + WBI or mastectomy without external radiotherapy for a first primary BC (pT1-2, N0-3a) at the European Institute of Oncology between 2000 and 2008. Patients were matched by propensity score.

Results

Median follow-up was 8.4 years (interquartile range 6.5–10.2). The cumulative incidence of axillary lymph node recurrence at 10 years was lower in the BCS + WBI group [2.4% (95% CI, 1.7–3.3%)] than in the mastectomy group [4.4% (95% CI, 3.5–5.5%)] (P = .0005), and the cumulative incidence of contralateral BC was higher in the BCS + WBI group [3.9% (95% CI, 2.8–5.1%)] than in the mastectomy group [2.5% (95% CI, 1.7–3.4%)] (P = .01). Among the 366 patients with HER2 subtype BC, BCS + WBI was associated with a fivefold higher risk [hazard ratio 4.97 (95% CI, 2.28–10.8)] of  ipsilateral breast tumor recurrence (IBTR), compared with mastectomy (P < .0001); however, among patients with other BC subtypes, the rates of IBTR were not statistically significantly different.

Conclusion

Patients with HER2 subtype BC (T1-2, N0-3) who underwent BCS + WBI had a statistically significantly higher risk of IBTR than patients who underwent mastectomy. Survival was not statistically significantly different between the groups.

Supplementary Information

The online version contains supplementary material available at 10.1007/s00432-022-03973-8.

Keywords: Breast cancer, Breast conserving surgery, Mastectomy, Radiotherapy, HER2, Outcome

Introduction

Long-term survival among patients with early-stage breast cancer (BC) treated with breast-conserving surgery (BCS) plus whole-breast irradiation (WBI) has been shown to be noninferior to survival among patients treated with mastectomy, as demonstrated by several randomized studies (Veronesi et al. 1981, 2002; Fisher et al. 2002, 1989). Indeed, BCS was endorsed as the treatment of choice for early-stage BC by the US National Institutes of Health in 1990 (NIH Consensus Conference 1991). Since then, the management of BC has evolved substantially, with improvements in diagnostic assessment and therapeutic approaches, both local and systemic. Likewise, molecular markers, gene-expression profiling, and molecular prognostic indicators have been tailored for the treatment of BC and have enhanced personalized care. This progress has resulted in a steady decline in rates of local recurrence, with reports of risk of recurrence of 2% at 10 years (Gentilini et al. 2017). However, recent studies have demonstrated higher rates of mastectomy (either unilateral or bilateral) in patients with early-stage BC, in particular younger patients with noninvasive cancer, smaller tumor size, and node-negative disease (Kummerow et al. 2015; Wrubel et al. 2021). This has been attributed to several potential factors, including increased use of breast magnetic resonance imaging in diagnostic assessment of BC, patient preferences secondary to fears of local recurrence, increasing use of genetic testing with a consequent increase in prophylactic mastectomies, and improved availability of and advances in reconstructive surgery (Mahmood et al. 2013).

Tumor biology has become an ever more important factor in personalizing and tailoring treatments for BC. Furthermore, modern surgical approaches for BC increasingly minimize surgical extent and maximize consideration of cosmetic outcomes, thanks to the development of oncoplastic techniques in BCS (Margenthaler et al. 2021). Several recent retrospective studies of large cohorts of women with early-stage BC (T1-2, N0-1) drawn from national registries or the SEER database have even suggested that BCS is associated with superior overall survival (OS) and BC-specific survival (BCSS), compared with mastectomy (Wrubel et al. 2021; Hwang et al. 2013; Agarwal 2014; van Maaren et al. 2016a; van Maaren et al. 2016b; Hartmann-Johnsen et al. 2015; Lagendijk et al. 2018). Given the nonrandomized, observational nature of these studies (Hwang et al. 2013; Agarwal 2014; van Maaren et al. 2016a; van Maaren et al. 2016b; Hartmann-Johnsen et al. 2015; Lagendijk et al. 2018; Vila et al. 2015; Chen et al. 2015), further research is needed to define outcomes between BCS and mastectomy.

The aim of the present study was to compare long-term outcomes between BCS + WBI and mastectomy. A propensity score–matched design was used to account for differences in characteristics between the groups.

Methods

Study design and patients

We retrospectively analyzed a cohort of patients who received treatment for invasive BC at the European Institute of Oncology between January 1, 2000, and December 31, 2008. Data on 9710 consecutive patients aged < 70 years who underwent BCS + WBI or mastectomy without postmastectomy radiation therapy for a first primary BC (pT1-2, N0-3a) were identified from the prospectively maintained European Institute of Oncology BC database. Women who received intraoperative irradiation of the nipple area complex during nipple-sparing mastectomy were eligible. Women who either received neoadjuvant treatment or presented with metastatic breast disease at the time of admission or within 3 months after surgery were excluded. All patients gave informed consent. The study was approved in accordance with the 1964 Helsinki Declaration and its later amendments. The study followed the Strengthening the Reporting of Observational Studies in Epidemiology reporting guidelines (von Elm et al. 2007).

Clinical data and outcomes

Factors considered in the analysis included age at diagnosis, T and N pathologic classification (updated to the seventh edition of the AJCC staging manual), concomitant in situ disease, multifocal or multicentric tumor, tumor grade, estrogen receptor (ER) status, progesterone receptor (PgR) status, HER2 status, Ki-67 proliferative index, peritumoral vascular invasion (PVI), molecular subtype, systemic therapy, and radiotherapy. The study endpoints included the incidence of ipsilateral breast tumor recurrence (IBTR; defined as the reappearance of carcinoma either at the site of the surgical intervention or as any new carcinoma appearing in the other quadrants of the same breast), axillary lymph node recurrence (ALNR), distant metastasis (DM), and contralateral BC (CBC) and BCSS and OS. BCSS was defined from the date of BC surgery to death attributable to BC or last follow-up. OS was defined from the date of surgery to death from any cause or last contact.

Statistical analysis

Patients were divided in two groups: BCS + WBI and mastectomy. To account for differences in clinicopathologic characteristics between the two groups (Online Resource Table 1), patients who underwent mastectomy were matched using propensity scores for age group (< 35, 35–49, 50–69 years), period of surgery (within 3 years), histologic subtype (ductal, lobular, mixed ductal and lobular, other), tumor size (pT1, pT2), in situ component (absent, present), multifocality (absent, present), lymph node status (pNx, sentinel node negative, pN0, 1–3 positive lymph nodes, 4–9 positive lymph nodes, > 10 positive lymph nodes), tumor grade (G1, G2, G3, unknown), PVI (absent, present), Ki-67 (continuous), HER2 status (0/ + / +  + , +  +  + , unknown), surrogate molecular subtype (luminal A–like, luminal B–like, HER2, triple-negative), and adjuvant systemic therapy (none, endocrine therapy alone, chemotherapy alone, endocrine therapy plus chemotherapy). An equal number of patients who underwent BCS + WBI and mastectomy were included.

Table 1.

Characteristics of patients in the matched cohort

Characteristic MT alone BCS + WBI P value
All patients 1970 (100) 1970 (100)
Age, year
  < 35 132 (6.7) 125 (6.3)
 35–49 1048 (53.2) 1059 (53.8)
 50–69 790 (40.1) 786 (39.9) 0.88
Histologic subtype
 Ductal 1569 (79.6) 1597 (81.1)
 Lobular 216 (11.0) 207 (10.5)
 Other 110 (5.6) 82 (4.2)
 Mixed 75 (3.8) 84 (4.3) 0.17
pT
pT1 970 (49.2) 941 (47.8)
pT2 1000 (50.8) 1029 (52.2) 0.36
pT (is)
 Absent 1340 (68.0) 1355 (68.8)
 Present 630 (32.0) 615 (31.2) 0.61
pT (m)
 Absent 1327 (67.4) 1343 (68.2)
 Present 643 (32.6) 627 (31.8) 0.59
Nodal status
 SN- 687 (34.9) 699 (35.5)
 pN0 227 (11.5) 234 (11.9)
 1–3 positive nodes 718 (36.4) 689 (35.0)
 4–9 positive nodes 245 (12.4) 250 (12.7)
 10 + positive nodes 84 (4.3) 88 (4.5)
 Missing 9 (0.5) 10 (0.5) 0.96
Tumor grade
 G1 227 (11.5) 211 (10.7)
 G2 852 (43.2) 856 (43.5)
 G3 665 (33.8) 684 (34.7)
 Missing 226 (11.5) 219 (11.1) 0.81
ER status
 Positive 1621 (82.3) 1632 (82.8)
 Negative 349 (17.7) 338 (17.2) 0.64
PgR status
 Positive 1374 (69.7) 1398 (71.0)
 Negative 595 (30.2) 572 (29.0)
 Missing 1 (0.1) – 0.42
HER2 status
 Negativea 1502 (76.2) 1508 (76.5)
 Positiveb 468 (23.8) 462 (23.5) 0.82
Ki-67, %
  < 14 511 (25.9) 535 (27.2)
 14–20 380 (19.3) 344 (17.5)
 20–50 919 (46.6) 934 (47.4)
 50 +  160 (8.1) 157 (8.0) 0.48
 Missing – –
PVI
 Absent 1333 (67.7) 1361 (69.1)
 Present 637 (32.3) 609 (30.9) 0.34
Molecular subtype
 Luminal A 731 (37.1) 721 (36.6)
 Luminal B 896 (45.5) 916 (46.5)
 HER2 192 (9.7) 174 (8.8)
 Triple negative 151 (7.7) 159 (8.1) 0.71
 Missing – –
Systemic therapy
 None 73 (3.7) 76 (3.9)
 HT only 916 (46.5) 905 (45.9)
 CT only 298 (15.1) 290 (14.7)
 HT + CT 661 (33.6) 679 (34.5)
 Missing 22 (1.1) 20 (1.0) 0.97
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Data are no. (%)

BCS breast-conserving surgery, CT chemotherapy, ER estrogen receptor, HT hormone therapy, is in situ, m multifocality, MT mastectomy, PgR progesterone receptor, PVI peritumoral vascular invasion, SN sentinel node, WBI whole-breast Irradiation

aImmunohistochemical scores 0, 1 + , and 2 + not amplified

bImmunohistochemical score 3 + or amplified

The cumulative incidence of BC-related events (IBTR, ALNR, DM, CBC) was calculated from the date of BC surgery to the date of any first event and was estimated in accordance with the method of Kalbfleisch and Prentice, with accounting for competing events (including any first BC-related event, second nonbreast cancer, and death as first event). Gray’s test was used to assess differences in the cumulative incidence of specific events between the two groups. Survival plots were drawn using Kaplan–Meier methods, and the log-rank test was used to assess differences in survival between the two groups. The cumulative incidence of events and OS were assessed at 5 and 10 years of follow-up. Hazard ratios (HRs) for the development of any event or death in the mastectomy group versus the BCS + WBI group were determined using univariate Cox proportional hazards regression models. The proportional hazards assumption was tested by introducing a constructed time-dependent variable, and statistical significance was determined. Statistical analyses were performed using SAS software (version 9.4, SAS Institute, Cary, NC). Statistical significance was defined as 2-tailed P < 0.05.

Results

Study population

The original cohort comprised 9710 eligible patients with BC, of whom 2289 (23.6%) underwent mastectomy alone and 7421 (76.4%) underwent BCS + WBI (Online Resource 1). Mastectomy was more common than BCS + WBI in women aged < 50 years and in women with less favorable pathologic characteristics (lobular histologic subtype, more-advanced stage, positive lymph nodes, multifocal or multicentric tumor or tumor with extensive in situ component, PVI, HER2-positive or triple-negative subtype). After propensity score matching, 1970 of the 2289 patients who underwent mastectomy (86.1%) were successfully matched to 1970 patients who underwent BCS + WBI (Table 1).

Of the patients in the matched series, 53.2% (MT) and 53.8% (BCS + WBT) were aged 35–49 years, 11% and 10.5% had lobular BC, 3.8% and 4.3% had mixed ductal and lobular BC, and 5.6% and 4.2% had other histologic subtypes. Approximately half of these patients had pT2 tumors or positive lymph node(s) on pathologic examination. One-third had multicentric or multifocal tumor or an extensive in situ component. On the basis of ER, PgR, HER2, and Ki-67 status, a surrogate BC subtype was defined as luminal in 83%, HER2 in 9%, and triple-negative in 8% of patients. PVI was present in 32% of cases (Table 1). Patients who received intraoperatory radiotherapy of the tumor bed after BCS were excluded; however, 705 of the 1970 patients who underwent mastectomy (35.8%) had nipple-sparing surgery with intraoperatory radiotherapy of the nipple-areola complex.

Outcomes

At a median follow-up of 8.4 years (interquartile range, 6.5–10.2), 248 patients developed IBTR, 122 developed ALNR, 539 developed DM, and 104 developed CBC (Table 2). More patients in the BCS + WBI group (n = 131) than in the mastectomy group (n = 117) developed IBTR, but the difference was not statistically significant (Gray’s test P = 0.12) (Fig. 1A). The 10-year cumulative incidence of IBTR was 8.0% (95% CI, 6.5–9.6%) in the BCS + WBI group and 6.7% (95% CI, 5.5%-8.0%) in the mastectomy group (Table 2). On subgroup analyses, presence of in situ component, poor differentiation, ER-negative status, PgR-negative status, and HER2-positive status were statistically significantly different between the two groups (Fig. 2, Online Resource 1). In particular, among the 366 patients with HER2 subtype BC, those in the BCS + WBI group had a fivefold higher risk [HR 4.97 (95% CI, 2.28–10.8)] of developing IBTR, compared with those in the mastectomy group (P < 0.0001) (Fig. 2 and Online Resource 4). Patients who received adjuvant therapy with trastuzumab [HR 5.00 (95% CI, 2.06–12.2)] and patients diagnosed earlier who did not receive trastuzumab [HR 4.26 (95% CI, 0.85–21.3)] had a similar risk of developing IBTR (Online Resource 5).

Table 2.

Five-year and 10-year event rates in the MT and BCS + WBI groups

Event MT alone BCS + WBI
Events 5-year 10-year Events 5-year 10-year
Ipsilateral breast tumor recurrence 117 3.72 (2.94–4.63) 6.66 (5.45–8.02) 131 3.65 (2.87–4.55) 7.95 (6.50–9.58)
Lymph node recurrence 82 2.89 (2.21–3.71) 4.40 (3.50–5.46) 40 1.19 (0.78–1.76) 2.41 (1.72–3.29)
Distant recurrence 277 9.31 (8.07–10.7) 15.3 (13.6–17.1) 262 9.51 (8.25–10.9) 16.2 (14.2–18.2)
Contralateral breast cancer 45 0.62 (0.34–1.06) 2.46 (1.73–3.40) 59 1.30 (0.87–1.89) 3.85 (2.82–5.13)
Breast cancer-related death 229 5.32 (4.38–6.38) 12.1 (10.6–13.8) 214 5.07 (4.16–6.12) 14.1 (12.1–16.2)
Any death 248 5.57 (4.61–6.66) 13.0 (11.4–14.7) 236 5.57 (4.61–6.65) 15.6 (13.5–17.8)
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Data are no. or percent rate (95% confidence interval)

BCS breast-conserving surgery, MT mastectomy, WBI whole-breast irradiation

Fig. 1.

Fig. 1

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Patient outcomes by type of surgery. BCS breast-conserving surgery, HR hazard ratio, WBI whole-breast irradiation

Fig. 2.

Fig. 2

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Stratified analysis of the risk of ipsilateral breast cancer recurrence between BCS + WBI and MT alone according to specific clinicopathological characteristics, with attention to statistically significant correlations with HER2-positive status. BCS breast-conserving surgery, HR hazard ratio, IBTR ipsilateral breast tumor recurrence, is in situ, m multifocality, MT mastectomy, PVI peritumoral vascular invasion, SN sentinel node, WBI whole-breast irradiation

The incidence of ALNR was statistically significantly lower in the BCS + WBI group than in the mastectomy group [HR, 0.51 (95% CI, 0.35–0.75); P = 0.0005] (Fig. 1B). The cumulative incidence of ALNR at 10 years was 2.4% (95% CI, 1.7–3.3%) in the BCS + WBI group, compared with 4.4% (95% CI, 3.5–5.5%) in the mastectomy group (Table 2). The lower risk of ALNR among patients who received WBI was observed in all subgroups examined (Online Resource 2).

The 10-year cumulative incidence of DM was not statistically significantly different between the two groups (P = 0.84) (Fig. 1C): 16.2% (95% CI, 14.2–18.2%) in the BCS + WBI group and 15.3% (95% CI, 13.6–17.1%) in the mastectomy group (Table 2). The risk of CBC was higher in the BCS + WBI group [HR 1.61 (95% CI, 1.09–2.38); P = 0.01] (Fig. 1D); the 10-year cumulative incidence of CBC was 3.9% (95% CI, 2.8–5.1%) in the BCS + WBI group and 2.5% (95% CI, 1.7–3.4%) in the mastectomy group (Table 2). The higher risk of CBC in the BCS + WBI group was observed in all subgroups examined (Online Resource 3).

At the end of follow-up, 484 patients (12.3%) had died, including 443 (91.5%) who died of BC. BCSS (log-rank P = 0.46) and OS (log-rank P = 0.29) were not statistically significantly different between the two groups (Fig. 1E and Fig. 1F).

Discussion

In this study, OS and BCSS were not statistically significantly different between BCS + WBI and mastectomy alone (Fig. 1E, F). Among patients with HER2-positive disease, BCS + WBI was associated with a higher rate of IBTR, compared with mastectomy; BCS + WBI was also associated with a higher rate of IBTR among patients with HER2-positive disease treated with or without trastuzumab (Fig. 2, Online Resource 1, Online Resource 5). Moreover, ALNR was more prevalent in the mastectomy group (Fig. 1, Online Resource 2), and CBC was more prevalent in the BCS + WBI group (Fig. 1, Online Resource 3).

Recent findings have challenged the axiom that BCS is associated with noninferior OS and BCSS, compared with mastectomy (Wrubel et al. 2021, Hwang et al. 2013; Agarwal 2014; van Maaren et al. 2016a; van Maaren et al. 2016b; Hartmann-Johnsen et al. 2015; Lagendijk et al. 2018; Vila et al. 2015; Chen et al. 2015). The results of our large cohort study, however, diverge from the contemporary evidence, confirming a statistical overlap in OS and BCCS between the two treatment approaches. Findings from large, retrospective studies also suggest that tumor biology and relative adjuvant treatment are associated with BCSS (Wrubel et al. 2021, Hwang et al. 2013; Agarwal 2014; van Maaren et al. 2016a; van Maaren et al. 2016b; Hartmann-Johnsen et al. 2015; Lagendijk et al. 2018; Vila et al. 2015; Chen et al. 2015). Furthermore, some studies included patients with major nodal involvement, as in the present study (van Maaren et al. 2016a; Chen et al. 2015). We performed a propensity score–matched analysis to evaluate closely matched patient populations, since this approach provides simulation of randomization in a context in which a randomized controlled trial would not be plausible (Wrubel et al. 2021). In several studies that similarly stratified patients with early-stage BC by clinicopathologic factors, BCS + WBI was associated with superior OS, compared with mastectomy (Wrubel et al. 2021; Kim et al. 2021; Wang et al. 2018).

Many of the previous cancer registry studies, with the exception of a few recent ones (Wrubel et al. 2021; Kim et al. 2021; Wang et al. 2018), did not include HER2/Neu receptor status as a variable, as we did in the present study. Our results suggest that HER2 is a decisive biologic marker that confers potential resistance to radiation (Fig. 2, Online Resources 1, 4, and 5); furthermore, our findings support the notion that HER2 positivity is associated with unfavorable locoregional outcomes. HER2-positive BC remains an aggressive disease—in our study, the rate of IBTR was higher in the BCS + WBI group regardless of trastuzumab treatment status (Online Resource 5).

More recently, an association between locoregional recurrence (LRR) and BC molecular subtype was observed; HER2 status is known to be a strong predictor of relapse (Corso G et al. 2020; Gillon et al. 2017). The rate of LRR for HER2 subtype BC (not treated with trastuzumab) and triple-negative subtype BC has been reported to be 15–30%, suggesting that radiation alone might be insufficient for some patients with specific molecular subtypes of BC (Torres-Roca 2015). The contribution of trastuzumab to local control in patients who underwent radiation is controversial, with reports of no effect (Sanpaolo et al. 2011), persistence of higher risk after WBI (Fodor et al. 2021), and statistically significant improvements in rates of local control in patients with pN1 tumors after postmastectomy radiation therapy (Abi Jaoude et al. 2020). It is not clear whether tumors that overexpress HER2 should be treated using a dose-escalation program.

By developing a gene-expression molecular signature to measure cellular radiosensitivity, Torres-Roca et al. found that hormonal receptor–negative/HER2-positive tumors were less likely to benefit from an increased dose of radiation, compared with luminal tumors, suggesting that HER2 status might represent a molecular signature (Torres-Roca 2015) that is indicative of potential resistance to radiation. Thorat et al. recently highlighted the prognostic and predictive role of HER2 in ductal carcinoma in situ (DCIS) as well, reporting the higher in situ recurrence risk in HER2-positive DCIS, but associated with a benefit due to radiotherapy (Thorat et al. 2021). However, although impressive progress has been made in defining the role of molecular variables in outcomes of patients with BC, which biologic determinants have an effect on the efficacy of radiotherapy remain to be determined (Torres-Roca et al. 2015; EBCTCG Group 2011).

The extensive lymph nodes involvement in patients submitted to BCS + WBI, compared to mastectomy, would appear instead not significantly correlated with IBTR, as observed in Fig. 2, likely explained by the protective role of radiation performed after conservative surgery.

In our study, the risk of CBC was higher in the BCS + WBI group than in the mastectomy group [HR, 1.61 (95% CI, 1.09–2.38); P = 0.01] (Fig. 1, Online Resource 3). Clinical evidence has demonstrated that a survivor of BC has a higher risk of developing a second breast tumor, either ipsilateral or contralateral, than a healthy woman has of developing a first BC (Corso et al. 2018; Hayat et al. 2007; Goldstein et al. 2003). Several factors may underlie this finding. Among patients with luminal A subtype BC, the risk of CBC was higher for patients treated with BCS + WBI than mastectomy [HR 2.10 (95% CI, 1.00–4.43); P = 0.04] (Online Resource 4), with a pointed difference in risk after the 6 year of follow-up. On the basis of this finding, the cessation of endocrine therapy at 5 years in patients who underwent BCS + WBI might play a role in the observed higher risk. Indeed, in a retrospective cohort of 15,168 patients with BC, incidence of CBC was associated with a family history of BC or ovarian cancer, older age, and advanced-stage BC, thus confirming the protective effect of endocrine therapy on risk of CBC [HR, 0.43 (95% CI, 0.30–0.60); P < 0.0001] (Corso et al. 2018). Data on family history of BC and presence of genetic mutations were not available for our cohort, but both factors likely played a role in the higher incidence of CBC after BCS + WBI, as contralateral mastectomy might have been used more frequently among patients with high-risk BC in the mastectomy group.

A family history of BC might imply a greater susceptibility to radiation-induced CBC as well, due to the DNA damage repair pathway, and it may have an additive effect on the risk of CBC. Overall, the use of radiotherapy for the treatment of BC is controversial (Burt et al. 2017; Billena et al. 2021). Since the risk of radiation-induced CBC appears to have a linear dose-response relationship, great care must be taken to minimize the scattered dose to the contralateral breast (Hooning et al. 2008).

A contralateral BC is usually considered a de novo tumor with diverse histopathologic and biologic traits (Corso et al. 2018; Banelli et al. 2010); only a small percentage of CBCs represent metastasis from the index BC, as revealed by recent genomic analysis (Begg et al. 2008). Moreover, prognosis for BC appears to be influenced by anthropometric factors, such as high body mass index and, consequently, breast size, which have been reported to be associated with a worse prognosis in both pre- and postmenopausal patients (Markkula et al. 2012; Jansen et al. 2014). Although data on BMI and breast size are not available for our cohort, it could be speculated that higher BMI and larger breast size are associated with an increased risk of CBC, with a consequently higher rate of BCS in patients with cT1-T2 disease.

The results of several randomized trials confirm that utility of radiotherapy for patients undergoing BCS and for patients with high-risk, node-positive BC undergoing mastectomy, as it has been shown to be associated with longer BCSS and OS (EBCTCG Group 2011; Cady 2007; Clarke et al. 2005).

In our cohort, the rate of ALNR was statistically significantly higher in the mastectomy group than in the BCS + WBI group (Fig. 1, Online Resources 2 and 4), and no patients received postmastectomy radiotherapy, even if approximately half had pN1a-2a-3a disease. The lack of use of postmastectomy radiotherapy was justified by the institutional policy in force during the period of the study, which spared women with any pathologic axillary lymph node involvement from postmastectomy radiotherapy. However, the difference in the rate of ALNR appeared not associated with OS or BCSS in the mastectomy group (Fig. 1). An association between BCS + WBI and a lower risk of axillary recurrence was recently observed (Gentilini et al. 2017), as was an association between specific biologic and pathologic parameters and a higher risk of LRR in patients with BC with pathologically involved lymph nodes (Botteri et al. 2012). Recent findings from our institute suggest that postmastectomy radiotherapy has a benefit for selected patients with high-risk BC (both N0 and N1) who undergo mastectomy; Ki-67 ≥ 20%, young age, and lymphovascular invasion were associated with LRR (10-year cumulative incidence: Ki-67 ≥ 20% plus young age, 8.8%; Ki-67 ≥ 20% plus lymphovascular invasion, 10.9%, after a median follow-up of 8.2 years). In the matched-pair analysis, WBI was associated with a lower rate of nodal recurrence and a higher rate of distant control, without an effect on survival (Leonardi et al. 2021).

Limitations

Our study has several limitations. The treatment of BC has progressively changed during the course of the study. To minimize any possible risk of bias, we considered a large population of patients with BC by use of a matched approach, with a long-term follow-up of > 8 years. A stage-matched comparison by subtype may be underpowered to detect small differences in recurrence or survival. As our population is not recent, patients did not receive anti-HER2 therapy in a neoadjuvant approach. Lack of specific data on radiation’s dose performed after BCS may affect the interpretation of the findings related to CBC. Finally, during the study period, our patients with BC did not receive postmastectomy radiation, and this may have affected rates of LRR, although there was no observed effect on OS.

Conclusion

In this study, which included a large matched cohort of patients with T1-2, N0-3 BC, OS and BCSS were not statistically significantly different between patients who underwent BCS + WBI and patients who underwent mastectomy. However, rates of CBC were higher in the BCS + WBI group, and rates of ALNR were higher in the mastectomy group. We suggested that HER2 molecular subtype is a synonym for biologic aggressiveness and can play a role in predicting response to radiotherapy. In light of the continued evolution of targeted therapies and improved selection of patients for appropriate treatment, our findings require further investigation.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 1547 kb) (1.5MB, docx)

Acknowledgements

We acknowledge David B. Sewell of the Memorial Sloan Kettering Cancer Center Department of Surgery for his editorial and writing assistance and Claudia Sangalli of the European Institute of Oncology, Data Management Division, for her contribution to the manuscript.

Author contributions

All authors made substantial contributions to the design of the work and interpretation of data; -drafted the work and revised it critically for important intellectual content;-approved the version to be published; -and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This research has been registered on www.clinicaltrials.gov: assigned Unique Identifying Number (UIN): NCT05126667.

Funding

This work was partially supported by the Italian Ministry of Health with Ricerca Corrente and 5 × 1000 funds and NIH/NCI Cancer Center Support Grant P30 CA008748 (Dr. Virgilio Sacchini).

Availability of data and materials

The datasets analysed during the current study are available in the European Institute of Oncology repository of Milan, Italy.

Declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Code availability

None.

Footnotes

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Francesca Magnoni and Giovanni Corso contributed equally.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplementary file1 (DOCX 1547 kb) (1.5MB, docx)

Data Availability Statement

The datasets analysed during the current study are available in the European Institute of Oncology repository of Milan, Italy.

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