Comparison of Treatment Outcome Between Invasive Lobular and Ductal Carcinomas in Patients Receiving Partial Breast Irradiation With Intraoperative Electrons

Accepted Manuscript Comparison of treatment outcome between invasive lobular and ductal carcinomas in patients receiving partial breast irradiation with intraoperative electrons Maria Cristina Leonardi, MD, Patrick Maisonneuve, Dipl.Eng, Mauro Giuseppe Mastropasqua, MD, Federica Cattani, MSc, Giuseppe Fanetti, MD, Anna Morra, MD, Roberta Lazzari, MD, Federica Bazzani, MD, Mariangela Caputo, MD, Nicole Rotmensz, MSc, Marianna Alessandra Gerardi, MD, Rosalinda Ricotti, MSc, Viviana Galimberti, Paolo Veronesi, MD, Samantha Dicuonzo, MD, Giuseppe Viale, MD, Barbara Alicja Jereczek-Fossa, MD, Roberto Orecchia, MD PII:

S0360-3016(17)30854-4

DOI:

10.1016/j.ijrobp.2017.04.033

Reference:

ROB 24233

To appear in:

International Journal of Radiation Oncology • Biology • Physics

Received Date: 14 November 2016 Revised Date:

16 March 2017

Accepted Date: 21 April 2017

Please cite this article as: Leonardi MC, Maisonneuve P, Mastropasqua MG, Cattani F, Fanetti G, Morra A, Lazzari R, Bazzani F, Caputo M, Rotmensz N, Gerardi MA, Ricotti R, Galimberti V, Veronesi P, Dicuonzo S, Viale G, Jereczek-Fossa BA, Orecchia R, Comparison of treatment outcome between invasive lobular and ductal carcinomas in patients receiving partial breast irradiation with intraoperative electrons, International Journal of Radiation Oncology • Biology • Physics (2017), doi: 10.1016/ j.ijrobp.2017.04.033. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT Comparison of treatment outcome between invasive lobular and ductal carcinomas in patients receiving partial breast irradiation with intraoperative electrons

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Short title: APBI in lobular carcinoma Maria Cristina Leonardi1 MD, Patrick Maisonneuve2 Dipl.Eng, Mauro Giuseppe Mastropasqua3 MD, Federica Cattani4 MSc, Giuseppe Fanetti1,5 MD, Anna Morra1 MD, Roberta Lazzari1 MD, Federica

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Bazzani1,5* MD, Mariangela Caputo1,5* MD, Nicole Rotmensz2* MSc, Marianna Alessandra Gerardi1 MD, Rosalinda Ricotti1 MSc, Viviana Galimberti6, Paolo Veronesi5,6 MD, Samantha Dicuonzo1,5

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MD, Giuseppe Viale3 MD, Barbara Alicja Jereczek-Fossa1,5§ MD and Roberto Orecchia5,7 MD 1 Division of Radiation Oncology, European Institute of Oncology, Milan Italy 2 Division of Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy 3 Division of Pathology, European Institute of Oncology, Milan, Italy 4 Medical Physics Unit, European Institute of Oncology, Milan, Italy

5 Department of Oncology and Hemato-oncology, University of Milan, Milan, Italy

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6 Division of Breast Surgery, European Institute of Oncology, Milan, Italy 7 Department of Medical Imaging and Radiation Sciences, European Institute of Oncology, Milan Italy

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Co-last author

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*Affiliation at the time of the study

**Corresponding author: Samantha Dicuonzo, M.D.

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Division of Radiation Oncology, European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy Tel +390257489037; Fax +390294379227 e-mail: samantha.dicuonzo©ieo.it

Conflict of Interest Notification: All the authors declare that there is no actual or potential conflict of interest. Acknowledgements: This work was partially supported by a research grant from Accuray Inc. The sponsor did not play any role in the study design, collection, analysis and interpretation of data, nor in the writing of the manuscript, nor in the decision to submit the manuscript for publication.

ACCEPTED MANUSCRIPT Summary Lobular carcinomas (ILCs) are included in the ASTRO and ESTRO cautionary group for accelerated partial breast irradiation (APBI). We analyzed in- breast tumor reappearance (IBTR)

comparing ductal carcinomas (IDCs) and ILCs.

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rate in patients who received full dose intraoperative radiotherapy with electrons (IORT),

Despite a favorable tumor profile, there was a higher incidence of IBTRs in ILCs compared to

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IDCs: the excess of risk was particularly high for small tumors and elderly patients.

ACCEPTED MANUSCRIPT Introduction

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The greater tendency for invasive lobular carcinoma (ILC) to be multifocal and multicentric

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(1, 2) implies that a limited local therapeutic approach, such as accelerated partial breast

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irradiation (APBI), has always been debatable (3, 4). Moreover, because there is no

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clinically palpable mass and the mammographic appearance is indistinct there can be an

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underestimation of the extent of the disease (5), which is one of the most important APBI

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selection criteria, especially when intraoperative techniques are used. Most of the

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unsuccessful pioneer studies on APBI included ILC (6). Unfortunately, the role of histology

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remains unclear, since these studies rarely performed a multivariate analysis, which would

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have made it possible to weigh the contribution of single parameters. Consequently, the

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American and the European guidelines for the proper use of APBI (6, 7) placed the ILC

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histology in the cautionary group. As the popularity of APBI has increased nearly 10-fold

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over the last decade, the problem of dealing with patients deemed to be sub-optimal

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candidates according to the guidelines is part of daily practice. As a matter of fact, a recent

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survey has shown that the percentage of such patients treated with APBI has increased

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over time (8). ILCs are a challenging subject of debate because their prognostic profile

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appears often favorable, which makes them potentially suitable for APBI. In fact, although

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the mean tumor size of ILCs tends to be slightly larger than in patients with invasive ductal

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carcinoma (IDC), ILCs are found in elderly women, with a low grade and a low proliferation

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index and high levels of hormonal receptors (9,10). The aim of our current study was to

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evaluate in-breast tumor reappearance (IBTR) rate correlated with histology (ILC vs. IDC)

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in our extensive institutional experience of early-stage breast cancers treated with APBI

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using intraoperative electrons (IORT). The role of the histological subtypes of ILC was also

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investigated.

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ACCEPTED MANUSCRIPT Materials and methods

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From 1999 to 2007, 2173 women affected with early stage breast cancer with a lobular or

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ductal histology were treated with breast conserving surgery and IORT (21Gy) as the sole

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treatment. Patient data were entered into the institutional database that included patients

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treated both outside and inside the ELIOT randomized phase III trial (11, 12). Only pure

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IDCs and pure ILCs were considered in this study. Patients with ILC (252, 11.6%) were

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compared to those with IDC (1921, 88.4%) in terms of local control. As per routine, lobular

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histology was further divided into the subtypes according to the World Health Organization

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(WHO) (13): classic, alveolar, solid and trabecular, and a subgroup named ‘‘mixed non-

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classic’’, which includes pleomorphic, signet ring, histiocytoid, and apocrine subtypes

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based on the absolute prevalence (>50%) of a distinct morphologic pattern. In addition,

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patients were grouped according to the surrogate breast cancer molecular subtype,

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estimated by ER/PgR/HER2 receptor status and Ki67 labeling index, as follows: Luminal A

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(ER and/or PgR positive, HER2 negative , Ki-67 <14%); Luminal B-HER2 negative ( ER

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and/or PgR positive, HER2 negative, Ki-67 high) ; Luminal B-HER2 positive (ER and/or

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PgR positive, any Ki-67, HER2 over-expressed or amplified); HER2 positive ( HER2 over-

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expressed or amplified, ER and PgR absent); Triple negative (ER and PgR absent; HER2

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negative) (14).

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The radiation technique employed has already been described (15).

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Systemic therapy, chemotherapy and/or endocrine therapy were tailored to the individual

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patients. All patients were followed up on a regular basis to assess local disease control

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and survival. Clinical examinations were performed at least every year and mammograms

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and ultrasound were required yearly. Magnetic resonance imaging (MRI) was not routinely

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performed.

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ACCEPTED MANUSCRIPT All the patients signed a specific consent for IORT and gave consent for use of

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anonymised data for research and scientific purposes. Some of them were also enrolled in

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the ELIOT trial registered with ClinicalTrials.gov as NCT0184913. This review was

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approved by the Institutional Ethics Committee.

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Statistical methods

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The primary endpoint was the incidence of IBTRs, either within the tumor bed, true

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recurrence, or in the other ipsilateral breast quadrants, new ipsilateral tumors, as first

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event during follow-up. The cumulative incidence of IBTRs was calculated from the date of

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surgery to the date of breast cancer-related first event or the date of the last follow-up,

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whichever occurred first, and was evaluated using the Kaplan-Meier method. The log-rank

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test was used to assess the difference in the incidence of IBTRs in patients with pure IDC

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and pure ILC. Five-year and 10-year event rates, with respective 95% confidence

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intervals, were obtained from actuarial survival analysis. We also calculated the average

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annual IBTR incidence among patients with ILC and IDC, dividing the number of events

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observed by the number of person-years of follow-up in each group. Univariate and

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multivariable Cox proportional hazard regression models were used to assess the

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influence of clinical and tumor characteristics on the development of IBTRs. In the

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multivariable analysis, ER, PgR, Ki67 and HER2 expression were represented by

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molecular subtype. A “reduced” multivariable model was then built using only those

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parameters that were statistically significant in the fully adjusted model. The multivariable-

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adjusted hazard ratio for the risk of IBTR in patients with ILC compared to those with IDC

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in different patients subgroups was graphically represented by a forrest plot. In addition, a

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propensity score matching analysis was performed in a group of ILC patients matched with

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an equivalent group of IDC patients having similar characteristics. The propensity score

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was built via a multivariable logistic regression model considering all the variables listed in

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Table 1, and the IBTR rates in the two matched groups were compared by Kaplan-Meier analysis. All analyses were performed with the SAS software version 9.2 (Cary, NC). All p-

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values were two-sided.

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Results

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Median follow-up was 6.2 years (range 0-14 years). Table 1 summarizes the clinical and

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pathological characteristics by histology. The median age of patients was 59 years for the

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ILC group and 58 years for the IDC group. Compared to the IDC group, patients with ILC

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were older (≥70 years, 20.2% vs. 11.5%), with less lymph node involvement (pN0, 80.2%

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vs. 70.3%), lower grade (G1-2, 86.5% vs. 71.8%), less peritumoral vascular invasion

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(1.6% vs. 18.7%), higher hormonal receptor status (ER+, 97.2% vs. 88.6%), greater HER2

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negativity (96.0% vs. 89.2%), lower proliferative index (Ki67≥20%, 23.8% vs. 44.1%) and

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were more likely to have close or positive margins (5.6% vs. 2.8%). Technical IORT

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parameters did not differ between the subgroups. ILC patients were more likely to receive

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hormonal therapy alone than were IDC ones because of their low–risk profile and high

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hormonal responsiveness.

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The 5- and 10-year IBTR rates were 7.5% (95% CI 4.7-11.8) and 21.8% (95% CI

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14.1-32.9) for ILC patients versus 5.5% (95% CI 4.5-6.7) and 14.4% (95% CI 11.8-17.4)

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for IDC patients (log-rank p=0.03) (Figure 1).The corresponding annual rate of IBTRs was

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1.99% for the ILC group and 1.34% for the IDC group (Table 2). After adjustment for

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potential confounding factors (tumor size, surgical margins, nodal status, tumor grade and

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molecular subtype), the risk of IBTR for ILC versus IDC patients was HR=1.70 (95% CI

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1.13-2.54, p= 0.01) (supplementary table 1).

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We further investigated whether the excess risk of IBTR in patients with ILC varied

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according to clinical or pathological characteristics (Table 2). In a stratified multivariable

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analysis, the adjusted risk of IBTR for ILC versus IDC was particularly high for patients

ACCEPTED MANUSCRIPT with tumor ≤1cm (HR=2.24; 95% CI 1.03-7.85; p=0.04), aged 60-69 years (HR=2.27; 95%

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CI 1.11-4.63; p=0.02),and ≥70 years (HR=3.28; 95% CI 1.08-10.0; p=0.04), with well

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differentiated (G1) tumors (HR=3.50; 95% CI 1.05-11.7; p=0.04) and with Luminal A breast

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cancer subtype (HR=3.18; 95% CI 1.49-6.77; p=0.003). On the contrary, the risk of IBTR

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was not significantly high in subgroups of patients with less favorable characteristics

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(young age, large tumor size, close/positive margin, multifocality, presence of in-situ

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component and vascular invasion, nodal positivity, grade 3 and molecular subtypes other

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than Luminal A) (Table 2; Figure 1).

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Among the 758 patients with Luminal A breast cancer, the excess risk of IBTR in ILC

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versus IDC patients was present in most of the subgroups studied, but was particularly

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important for those irradiated with small (3-4 cm) collimators (HR=6.98; 95% CI 2.96-16.5;

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p<.0001) (Supplementary table 2).

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Most IBTRs were true local relapses (123 in IDC and 23 in ILC), while the rest were

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considered new ipsilateral tumors (35 in IDC and 8 in ILC). In multivariable analysis, ILC

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was associated with significant excess of true local relapse (HR=1.63; 95% CI 1.02-2.60),

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but not of new ipsilateral breast cancer (HR=1.98; 95% CI 0.88-4.47) (Supplementary

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figure 1). Because the ILC and IDC groups differed significantly in terms of prognostic risk

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factors, the risk estimates obtained from the multivariable analysis could still be subject to

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residual confounding. Therefore, we performed a case-control study in which the 252

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patients with ILC were matched with 252 patients with IDC and otherwise similar

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characteristics, using propensity-score matching based on all variables listed in table 1

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(Supplementary table 3).The analysis confirmed an excess risk of IBTR in ILC patients

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(HR=2.08; 95% CI 1.12-3.86; p=0.02), particularly in those with luminal A breast cancer

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subtype (HR=2.60; 95% CI 1.01-6.70; p=0.004) (Supplementary figure 2). Again, no

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significant excess risk was observed for patients with luminal B, HER2 positive or Triple

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negative subtypes.

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ACCEPTED MANUSCRIPT ILCs were further subtyped into several variants. Most of the ILCs were defined as classic

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(42.1%)(Supplementary table 4). Taking the classic subtype as reference with its IBTR

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rate/100–year of 1.65, local control was significantly worse for signet ring cell and solid

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variants (IBTR rate/100-year of 10.5 and 4.24, p=0.009), but the small number of patients

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in each subgroup limited this aspect of the analysis. Grouping all the non-classic variants

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together, no difference was seen compared to the classic subtype with regard to local

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control (p=0.53). No difference in the rate of IBTRs was seen between low and high grade

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ILCs (p=0.37) (Supplementary Table 4).

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Discussion

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This is, to our knowledge, the largest series of ILC patients treated with APBI in which a

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comparison is made with IDC patients with a median follow-up of more than 6 years. Our

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findings showed that ILCs, when treated with IORT, had higher rate of IBTRs compared to

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IDCs.

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In the setting of APBI especially, the predictive role played by lobular histology for IBTR has hardly been addressed so far, due to the paucity of data. Given the expected

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pattern of multifocality, most of the current guidelines are cautious about treating ILCs with

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APBI outside of clinical trials (6, 7). In addition, the negative results from the Christie

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Hospital trial, which reported ILC as a predictor for IBTR in a multivariable analysis, gave

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grounds for excluding it in normal clinical routine (16).

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Some modern APBI phase III trials hold the same opinion. The RAPID, the IMPORT

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LOW, the NRG Oncology/RTOG 9517, the TARGIT (17, 18) trials and the National

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Institute of Oncology Hungarian study (19), which recently demonstrated an excellent long-

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term outcome with APBI , did not include ILC in the eligibility criteria.

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Conversely, some other modern APBI phase III trials, such as the IRMA, the GECESTRO (17, 20), the NSABP B-39- RTOG 0413 and the University of Florence enrolled

ACCEPTED MANUSCRIPT patients with ILC (21). The latter did not show any significant association between

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histology and local failure, but ILCs accounted for 11.2% of the study population. In the

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IORT series, lobular histology was not clearly associated with higher IBTR rate, (11,12),

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even if a trend was seen when a deeper analysis was made (22).

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Many reports on APBI suffered from some limitations concerning the number of ILCs and

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the length of follow-up. In a series from the William Beaumont Hospital, 16 patients with

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ILC and 410 with IDC did not differ with regard to IBTRs (0% vs. 2.5%) with a median

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follow-up of only 3.8 years for those with ILC (23). In the study by McHaffie et al., the

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predictive value of ILC as seen on univariate analysis was not confirmed on multivariate

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analysis, given the small absolute number of IBTRs (24).

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Apparently, ILC presents such a low-risk profile that it is considered to be an ideal

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candidate for APBI. In comparison to IDC, ILC was characterized by lower grade, lower

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proliferative activity, absence of vascular invasion, positive expression of hormone

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receptors, greater HER2 negativity, and occurrence in older patients. Notwithstanding this

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more favorable profile, IBTR incidence for ILC was higher than that for IDC. Regarding the

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biomolecular classification, ILCs showed a higher proportion of the Luminal A subtype than

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did the IDCs. Again, despite the good prognosis typically associated with this subtype,

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Luminal A ILCs presented a significantly higher rate of IBTRs compared to the IDCs. On

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the contrary, no difference between the ILCs and the IDCs was found regarding the other

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molecular subtypes. Compared to the IDC counterparts, Luminal A ILCs tended to relapse

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mostly as true recurrence; new ipsilateral tumors were less frequent, but still statistically

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significant. A similar observation was also reported by Braunstein et al. (25). In their

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series, in the Luminal A population, the local outcome after whole breast radiotherapy

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(WBI) was worse for ILCs than for IDCs, although not significantly (3.4% vs. 2.6% at 10

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years, p=0.12). Surprisingly, the excess risk of IBTR for ILC compared to IDC was higher

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for very small ILCs (≤1 cm), for which the intraoperative technique should in theory provide

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ACCEPTED MANUSCRIPT adequate tumor bed coverage. The IBTR rate was more than double that of IDCs of the

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same size (1.93 vs. 0.83 per 100 persons per year, p=0.04). Small collimators (4 cm in

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diameter was chosen in 57% of ILCs and 54% of IDCs, while 3 cm-collimator size was

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used exceptionally) appeared quite sufficient to ensure local control in the case of IDCs,

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but they were clearly not adequate in the case of ILCs. One hypothesis could be that ILCs

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carry a higher microscopic neoplastic burden surrounding the primary tumor than do IDCs

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and even small tumors need larger radiation fields. This explains the similarity in local

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behavior between IDCs and ILCs in many series when WBI (26,27) or APBI with larger

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target volumes were performed (20,21). Interstitial brachytherapy (BRT), as well as

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external radiotherapy, can modulate the size of the radiation field in order to better cover

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the volume at risk. The American Brachytherapy Society (28) included ILC in the updated

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guidelines for APBI. Concerning interstitial BRT, no difference in local control was

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observed between ILC and non-ILC patients at a median follow-up of 63 months (29) in

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the German–Austrian phase II study and the GEC-ESTRO phase III randomized trial did

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not report any correlation with efficacy and tumor characteristics, as well (20). However, in

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the study by Johansson et al. (30), in which the median irradiated volume with BRT was as

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large as 31% of the total breast volume, it is worth noting that ILC was the cause of one

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out of three IBTRs at a median follow-up of 86 months. The strategy of delivering

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subsequent additional WBI in the case of ILC in the TARGIT trial was adopted because

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the irradiation of small volumes with low-energy X rays was considered inadequate for

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local control (18). Our data showed that extent of radiation in the context of APBI matters,

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as the difference in local outcome between ILC and IDC leveled out as the collimator

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diameter increased. In a study assessing the maximum radial extension of residual

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carcinoma from the surgical margins, a 10 mm clinical target volume (CTV) was

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considered adequate in 97.4% of cases, but the adequacy of coverage increased to 98.5%

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ACCEPTED MANUSCRIPT when ILC and nodal involvement were excluded from the analysis (31), showing how

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important it is for the radiation volume to cover the adjacent residual neoplastic foci.

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Few patients of the study underwent preoperative MRI, therefore subgroup analysis

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regarding the impact on outcome could not have been performed. A growing body of

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literature underlined the role of MRI in altering APBI recommendations by detecting

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mammographically occult multifocal/multicentric disease (32). This high sensitivity might

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be used to guide the extension of local excision and radiation field.

The prognosis for the ILC variants is shown to be heterogeneous throughout the

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literature, but generally the classic type has a more favorable outcome, while the

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prognosis of the ‘non-classic’ subtype is less so (33).

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A histopathological assessment of the ILC variants might allow excluding from APBI those likely to have a poorer outcome. In the study by Krishnan et al. (34), patients with

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the non-classical type of ILC were not given APBI with 192Ir. No IBTR was reported at a

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median follow-up of 47 months, but the small number of patients enrolled, with only three

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ILCs out of 24 stage I breast cancers, make it impossible to draw any major conclusions.

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The analysis made by Iorfida et al. found a statistically significant difference in the

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outcome for patients with non-classic compared to those with classic ILC (35). Taking the

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classic variant as baseline, our study did not find any difference in the rate of IBTRs

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compared to non–classic ILC. Some variants seemed to be highly aggressive locally, but

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analysis was not meaningful due to the small number of patients. Although it might be

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reasonable to exclude the higher–risk profile variants from treatment with APBI, the current

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amount of data is not sufficient to formulate the recommendations. Again, the biology of

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the tumor variants could be more important than the type of treatment.

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Conclusion

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ACCEPTED MANUSCRIPT Our analysis helps to increase the body of literature on the role of APBI in lobular

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histology, since many of the studies performed so far did not present the results arranged

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by histology. The strength of the analysis is based on the length of the follow-up period

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and on the number of patients with ILC who were included. A limitation of the study may

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be that only a part of the analysis was made within the randomized ELIOT trial, which did

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not have any preplanned categorization according to risk factors. While we are awaiting

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the results of the other APBI trials that have included ILC in the eligibility criterion, our

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relatively large institutional experience suggests that it can be used with caution. When

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treating with intraoperative APBI, local control may be improved by doing a more accurate

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diagnostic work-up to help rule out multicentricity, and by increasing the irradiated volume

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by using larger collimators.

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ACCEPTED MANUSCRIPT Figure/table captions

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Table 1. Clinical, pathologic, and treatment related characteristics for the ILC and IDC groups

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Table 2. IBRT rate between ILC and IDC patients, according to clinical, pathologic, and treatment

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related characteristics (stratified analysis)

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Figure 1. IBTR rate between ILC and IDC patients, overall and according to molecular tumor

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subtype

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Supplementary Table 1. Univariate and multivariate analyses of factors associated with IBTR

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Supplementary Table 2. IBTR rate between Luminal A ILC and IDC patients, according to

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clinical, pathologic, and treatment related characteristics

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Supplementary Table 3. Clinical, pathologic, and treatment related characteristics of the matched

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ILC and IDC patients included in the PROPENSITY analysis

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Supplementary Table 4. IBTR rate in ILC group, according to morphologic subtype

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Supplementary Figure 1. Breakdown of IBTR rate into true local relapse and new ipsilateral

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breast tumor for ILC and IDC patients

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Supplementary Figure 2. IBTR rate for the ILC and IDC matched groups, overall and according to

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molecular tumor subtype* in the PROPENSITY analysis

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13. Ellis IO, Schnitt SJ, Sartre-Garau X, et al. Invasive breast carcinoma. In: Tavassoli FA, Devilee P (eds) World Health Organization classification of tumors. Pathology and genetics of tumors of the breast and female genital organs. IARC Press Lyon, pp 23-26 (2003).

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15. Veronesi U, Gatti G, Luini A, et al. Intraoperative radiation therapy for breast cancer: technical notes. Breast J 2003;9:106-112.

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16. Magee B, Swindell R, Harris M, et al. Prognostic factors for breast recurrence after conservative breast surgery and radiotherapy: results from a randomised trial. Radiother Oncol 1996;39:223-227.

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17. Leonardi MC, Ricotti R, Dicuonzo S, et al . From technological advances to biological understanding: The main steps toward high-precision RT in breast cancer. Breast. 2016;29:213-22

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18. Vaidya JS, Wenz F, Bulsara M, et al. Risk-adapted targeted intraoperative radiotherapy versus whole-breast radiotherapy for breast cancer: 5-year results for local control and overall survival from the TARGIT-A randomised trial. Lancet 2014;383:603-613.

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19. Polgár C, Fodor J, Major T, et al. Breast-conserving therapy with partial or whole breast irradiation: ten-year results of the Budapest randomized trial. Radiother Oncol 2013;108:197202.

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29. Strnad V, Hildebrandt G, Potter R, et al. Accelerated partial breast irradiation: 5-year results of the german-austrian multicenter phase ii trial using interstitial multicatheter brachytherapy alone after breast-conserving surgery. Int J Radiat Oncol Biol Phys 2011;80:17-24.

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Table

ACCEPTED MANUSCRIPT Table 1. Clinical, pathologic, and treatment related characteristics for the ILC and IDC groups

50 (19.8) 202 (80.2)

0.08

325 (16.9) 746 (38.8) 629 (32.7) 221 (11.5)

40 (15.9) 91 (36.1) 70 (27.8) 51 (20.2)

trend 0.05

637 (33.2) 653 (34.0) 349 (18.2) 271 (14.1) 11 ( 0.6)

80 (31.8) 85 (33.7) 53 (21.0) 34 (13.5) 0 ( 0.0)

1866 (97.1) 50 ( 2.6) 5 ( 0.3)

238 (94.4) 12 ( 4.8) 2 ( 0.8)

0.04

1872 (97.5) 49 ( 2.5)

236 (93.7) 16 ( 6.3)

0.003

1597 (83.1) 321 (16.7) 3 ( 0.2)

193 (76.6) 58 (23.0) 1 ( 0.4)

1350 (70.3) 451 (23.5) 117 ( 6.1) 3 ( 0.2)

202 (80.2) 36 (14.3) 14 ( 5.6) 0 ( 0.0)

501 (26.1) 879 (45.8) 524 (27.3) 17 ( 0.9)

47 (18.7) 171 (67.9) 32 (12.7) 2 ( 0.8)

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trend 0.63

RI PT

p-value

SC

480 (25.0) 1441 (75.0)

0.02

0.003

<0.0001

1562 (81.3) 359 (18.7)

248 (98.4) 4 ( 1.6)

218 (11.4) 1702 (88.6) 1 ( 0.1)

6 ( 2.4) 245 (97.2) 1 ( 0.4)

<0.0001

442 (23.0) 1477 (76.9) 2 ( 0.1)

47 (18.7) 204 (91.0) 1 ( 0.4)

0.12

1713 (89.2) 200 (10.4) 8 ( 0.4)

242 (96.0) 9 ( 3.6) 1 ( 0.4)

0.0005

641 (33.4) 427 (22.2) 847 (44.1) 6 ( 0.3)

131 (52.0) 60 (23.8) 60 (23.8) 1 ( 0.4)

629 (32.7) 934 (48.6) 139 ( 7.2) 61 ( 3.2) 154 ( 8.0) 4 ( 0.2)

129 (51.2) 108 (42.9) 8 ( 3.2) 1 ( 0.4) 5 ( 2.0) 1 ( 0.4)

1426 (74.2) 205 (10.7) 245 (12.7) 45 ( 2.3)

224 (88.9) 6 ( 2.4) 17 ( 6.7) 5 ( 2.0)

1046 (54.5) 686 (35.7) 149 ( 7.8) 40 ( 2.1)

145 (57.5) 89 (35.3) 14 ( 5.6) 4 ( 1.6)

trend 0.29

533 (27.8) 789 (41.1) 557 (29.0) 42 ( 2.2)

67 (26.6) 118 (46.8) 60 (23.8) 7 ( 2.8)

trend 0.70

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Patients series Trial Out-trial Age <50 years 50-59 years 60-69 years ≥70 years Pathological size ≤1.0 cm 1.0-1.5 cm 1.5-2.0 cm >2.0 cm Missing Surgical margins Negative Close Positive Multifocality Unifocal Multifocal In-situ component No Yes Missing Nodal status 0 1-3 ≥4 Missing Tumor grade G1 G2 G3 Missing Peritumoral vascular invasion Absent Present Estrogen Receptor Absent Present Missing Progesterone receptor Absent Present Missing HER2 Not over-expressed (0/+/++) Over-expressed (+++) Missing Proliferative index (Ki-67) <14% 14-19% ≥20% Missing Molecular Subtype Luminal A Luminal B (HER2-neg) Luminal B (HER2-pos) HER2 positive Triple negative Missing Adjuvant treatment Endocrine therapy alone Chemotherapy alone Endocrine and chemotherapy Control IORT collimator size 3-4 cm 5 cm 6-8 cm Unknown Electron energy ≤6 7-8 9-10 Unknown Breast gland thickness

ILC N (col %) 252 (100)

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IDC N (col %) 1921 (100)

EP

Characteristics*

<0.0001

<0.0001

<0.0001

<0.0001

ACCEPTED MANUSCRIPT <1.0 cm 1.0-1.5 cm 1.5-2.0 cm ≥2.0 cm Unknown

103 ( 5.4) 680 (35.4) 648 (33.7) 437 (22.8) 53 ( 2.8)

9 ( 3.6) 90 (35.7) 101 (40.1) 48 (19.1) 4 ( 1.6)

trend 0.98

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IDC: Invasive Ductal Carcinoma; ILC: Invasive Lobular Carcinoma; IORT: intraoperative radiotherapy

ACCEPTED MANUSCRIPT Table 2. IBRT rate between ILC and IDC patients, according to clinical, pathologic, and treatment related characteristics (stratified analysis)

Annual rate (%)

Adjusted risk of IBTR in patients with ILC compared to IDC

158/1921 1.34

31/252

1.99

114/1441 1.36 44/480 1.28

24/202 7/50

2.01 1.90

35/325 60/746 46/629 17/221

1.79 1.27 1.17 1.42

4/40 10/91 10/70 7/51

1.52 1.66 2.35 2.60

33/637 55/653 34/349 35/271

0.83 1.32 1.62 2.39

10/80 9/85 6/53 6/34

1.93 1.76 1.74 3.21

152/1866 1.32 3/50 1.10 3/5 11.54

26/238 4/12 1/2

1.76 5.48 7.14

152/1872 1.32 6/49 2.03

28/236 3/16

136/1597 1.38 22/321 1.12

24/193 6/58

94/1350 43/451 20/117

1.12 1.53 3.33

24/202 5/36 2/14

18/501 69/879 69/524

0.55 1.27 2.27

5/47 21/171 5/32

117/1562 1.21 41/359 1.91 24/629 86/934 18/139 9/61 21/154

71/1046 63/686 18/149

HR (95% CI) 1.70 (1.13-2.54)

RI PT

ILC IBTR/ patients

Annual rate (%)

Pvalue 0.01 0.02 0.26

0.79 (0.27-2.35) 1.51 (0.72-3.17) 2.27 (1.11-4.63) 3.28 (1.08-10.0)

0.67 0.28 0.02 0.04

2.24 (1.03-4.85) 1.52 (0.73-3.17) 1.34 (0.51-3.47) 1.56 (0.59-4.16)

0.04 0.26 0.55 0.37

1.57 (1.02-2.41) 3.62 (0.09-141.) -

0.04 0.49

1.92 2.86

1.70 (1.12-2.59) 0.05 (0.00-1.37)

0.01 0.08

2.03 1.62

1.64 (1.04-2.58) 1.91 (0.68-5.37)

0.03 0.22

1.88 2.59 2.22

2.00 (1.24-3.22) 1.91 (0.74-4.90) 0.96 (0.18-5.05)

0.005 0.18 0.96

1.72 1.94 2.78

3.50 (1.05-11.7) 1.76 (1.06-2.92) 1.29 (0.50-3.32)

0.04 0.03 0.60

30/248 1/4

1.95 4.00

1.83 (1.20-2.81) 1.38 (0.15-12.5)

0.005 0.77

0.59 1.51 2.36 2.37 2.39

15/129 12/108 2/8 0/1 2/5

1.89 1.75 4.88 0.00 7.69

3.18 (1.49-6.77) 1.17 (0.63-2.16) 1.28 (0.16-9.97) 2.30 (0.51-10.5)

0.003 0.63 0.82 0.28

1.11 1.54 1.76

19/145 10/89 2/14

2.13 1.83 1.89

1.74 (1.00-3.02) 1.55 (0.77-3.13) 1.17 (0.22-6.16)

0.05 0.22 0.86

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1.76 (1.10-2.81) 1.64 (0.70-3.85)

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All patients Series Out-trial Trial Age <50 years 50-59 years 60-69 years ≥70 years Pathological size ≤1.0 cm 1.0-1.5 cm 1.5-2.0 cm >2.0 cm Surgical margins Negative Close Positive Multifocality Unifocal Multifocal In-situ component No Yes Nodal status 0 1-3 ≥4 Tumor grade G1 G2 G3 PVI Absent Present Molecular Subtype Luminal A Luminal B (HER2-neg) Luminal B (HER2-pos) HER2 positive Triple negative IORT collimator size 3-4 cm 5 cm 6-8 cm

IDC IBTR/ patients

EP

Stratification variable

0.2 0.5 1 2 3 5 10 Hazards Ratio IDC: Invasive ductal carcinoma; ILC: Invasive lobular carcinoma; PVI: Peritumoral vascular invasion; IBTR: in-breast tumor reappearance Annual IBTR incidence rates obtained dividing the number of events observed by the number of person-years of follow-up. * Hazards ratio (HR) and 95% confidence intervals (CI) obtained from multivariable analysis adjusted for pathological tumor size, surgical margins, nodal status, tumor grade and molecular subtype.

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ACCEPTED MANUSCRIPT