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Post-Mastectomy Radiation Therapy in HER-2 Positive Breast Cancer Patients:

Analysis of the HERA Trial

Joseph Abi Jaoude, MD, Evandro de Azambuja, MD, Maha Makki, MS, Hani Tamim,
PhD, Arafat Tfayli, MD, Fady Geara, MD, Martine Piccart, MD, Philip Poortmans, MD,
Youssef H. Zeidan, MD
PII: S0360-3016(19)33904-5
DOI: https://doi.org/10.1016/j.ijrobp.2019.10.022
Reference: ROB 25996

To appear in: International Journal of Radiation Oncology • Biology • Physics

Received Date: 31 July 2019

Revised Date: 7 October 2019
Accepted Date: 14 October 2019

Please cite this article as: Jaoude JA, de Azambuja E, Makki M, Tamim H, Tfayli A, Geara F, Piccart
M, Poortmans P, Zeidan YH, Post-Mastectomy Radiation Therapy in HER-2 Positive Breast Cancer
Patients: Analysis of the HERA Trial International Journal of Radiation Oncology • Biology • Physics
(2019), doi: https://doi.org/10.1016/j.ijrobp.2019.10.022.

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 Post-Mastectomy Radiation Therapy in HER-2 Positive Breast Cancer Patients:
Analysis of the HERA Trial
Joseph Abi Jaoude, MD , Evandro de Azambuja, MD2, Maha Makki, MS3, Hani
1

Tamim, PhD4, Arafat Tfayli, MD5, Fady Geara, MD6, Martine Piccart, MD2, Philip
Poortmans, MD7, Youssef H. Zeidan, MD*6
1
Faculty of Medicine, American University of Beirut, Beirut, Lebanon
2
Institut Jules Bordet and l’Université Libre de Bruxelles (U.L.B), Brussels, Belgium
3
Clinical Research Institute, American University of Beirut Medical Center, Beirut, Lebanon
4
Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon
5
Department of Internal Medicine, Division of Hematology/Oncology, American University of Beirut
Medical Center, Beirut, Lebanon
6
Department of Radiation Oncology, American University of Beirut Medical Center, Beirut, Lebanon
7
Department of Radiation Oncology, Institut Curie & Paris Sciences & Lettres - PSL University; Paris,
France

• Running Head: PMRT in HER-2 Positive Breast Cancer.

• Oral presentation at the 2019 annual meeting of the American Society for
Radiation Oncology (ASTRO), Chicago, IL.

• Research Support: We would like to thank the ROCHE team and the Clinical
Study Data Request (CSDR) team for providing us with the HERA trial data.

• Declaration of interests: The authors declare no conflicts of interest.

• Source of Financial Support: No financial support was offered for this project.

• Acknowledgements: We would like to thank all patients who participated in the

HERA trial and their families.

• Statistical Analysis: Conducted by Hani Tamim, PhD and Maha Makki, MS .

*Corresponding Author:
Youssef H. Zeidan, M.D, Ph.D.
Assistant Professor,
Department of Radiation Oncology
American University of Beirut
Adjunct Assistant Professor
University of Miami
yz09@aub.edu.lb
Tel: +961 1 350000 ext: 5091
Fax: +961 1370795
 Post-Mastectomy Radiation Therapy in HER-2 Positive Breast Cancer Patients:

Analysis of the HERA Trial

• Running Head: PMRT in HER-2 Positive Breast Cancer.

Abstract:

Purpose: Post-mastectomy radiation therapy (PMRT) improves recurrence rates and overall

survival in breast cancer patients. However, it remains unclear whether these findings can be

applied to HER-2 positive patients treated with trastuzumab.

Methods and Materials: The HERA trial is a phase III randomized clinical trial that established

the efficacy of trastuzumab in HER-2 positive early stage breast cancer. The current study is a

retrospective analysis of prospective data of 1633 trial patients treated with mastectomy and

adjuvant trastuzumab. The primary objective of the study was to determine the effect of PMRT on

loco-regional recurrence rates (LRR). Hazard ratios were estimated from Cox models and LRR

curves were generated by the Kaplan-Meier method.

Results: Our analysis included 940 patients (57·6%) who received PMRT and 693 patients

(42·4%) who did not. Patients in the PMRT group had worse prognostic disease characteristics. At

a median follow up of 11 years, no significant difference in LRR was noted after PMRT in node

negative (N0) patients (p-value = 0·96). Patients with 1-3 positive lymph nodes had a LRR-free

survival of 97% in the PMRT group as compared to 90% in the no PMRT group (HR = 0·28, p-

value = 0·004) and a non-significant improved overall survival (OS) after PMRT (HR = 0·63, p-

value = 0·06).

Conclusions: PMRT delivery in HER-2 positive breast cancer patients with 1-3 positive lymph

nodes decreases the risk of LRR. Although the magnitude of PMRT benefit is lower than historical

1
studies, the current findings are in favor of PMRT for HER-2 positive breast cancer patients with

1-3 involved nodes. Future studies are needed to determine which HER-2 positive breast cancer

patients benefit the most from PMRT.

Keywords:

Breast Cancer

HER-2

Trastuzumab

Post-mastectomy radiation therapy

2
Introduction

Post-mastectomy radiation therapy (PMRT) is offered to women considered to be at a high risk of

loco-regional recurrence (LRR). Through targeting tissues harboring occult disease within the

chest wall and regional lymphatics, radiation therapy improves local disease control. Previously,

three large randomized trials showed a survival and local control benefit for post-mastectomy

radiation therapy [1-3]. In general, these studies show a 10-year absolute reduction in rates of LRR

by 20% and death by 10%. A meta-analysis by the Early Breast Cancer Trialists Collaborative

Group (EBCTCG), largely driven by those trials, further confirmed the role of PMRT by showing

8% reduction in breast cancer mortality at 20 years follow-up [4]. Hence, such trials highlighted

the importance of PMRT in managing breast cancer patients, and shaped the role of radiation

therapy in the post-mastectomy setting.

Advances in systemic therapies, diagnostic tools and surgical techniques coupled to increased

knowledge of tumor biology have led to improvements in both local and systemic breast cancer

disease control [5]. Recent studies report lower rates of LRR after mastectomy, in comparison to

the early randomized PMRT trials [6-9]. Clinical judgment is needed in recommending PMRT,

particularly in women with N1 disease. Analysis of the Danish 82b and c trials uncovered

heterogeneity in PMRT outcomes according to tumor subtype [2, 3, 10]. However, randomized

trials assessing the role of PMRT according to tumor subtypes are lacking.

Historically, expression of HER-2 has been linked to treatment resistance including

radioresistance. Targeted therapies, such as the HER-2 monoclonal antibody trastuzumab,

3
markedly improve outcomes of HER-2 positive breast cancer. The HERA trial is an international

multicenter trial, with 11 years of median follow up, that established the benefit of trastuzumab in

HER-2 positive patients [11, 12]. We aim to analyze the effect of PMRT in HER-2 positive breast

cancer patients treated with trastuzumab, based on a subgroup analysis of a nested cohort within

the HERA trial.

Patients and Methods

Study Population

The following study is a retrospective analysis of prospective data. Clinical data was collected

from the Herceptin Adjuvant (HERA) trial creating a nested cohort of 1633 patients. The Clinical

Study Data Request (CSDR) team granted access to the HERA trial data. The full description of

the HERA trial is provided in the original publication [11]. Briefly, the HERA (BIG 1-

01/BO16348) trial is an international, inter-group, open-label, phase III randomized trial studying

the efficacy and safety of trastuzumab in HER-2 positive breast cancer patients. The trial originally

enrolled 5099 female patients from all ages, with HER-2 positive breast cancer between December

2001 and March 2005. Women with T4 tumors, supraclavicular nodes or distant disease were

excluded. Patients completed loco-regional therapy using surgery with or without post-mastectomy

radiation therapy. For patients undergoing breast-conserving surgery, whole breast radiation

therapy followed. Patients also received a minimum of four courses of chemotherapy. Patients

were recruited and randomly assigned to either observation, 1 or 2 years of trastuzumab in a 1:1:1

ratio. Patients were followed up with a median follow up of 11 years. The study showed an

improvement in disease free-survival favoring trastuzumab [11]. No significant differences in

clinical outcomes were noted between patients receiving trastuzumab for 1 year or 2 years [12].

4
Figure 1 shows the flow diagram of the nested cohort in the present analysis. Eligible patients were

females with HER-2 positive breast cancer after mastectomy who received 1 or 2 years of

trastuzumab, excluding patients assigned to the observation arm and those who underwent breast-

conserving surgery. In order to study the effect of PMRT, patients were divided into two groups:

PMRT (940 patients) and no PMRT (693 patients) (Table 1). Patient and tumor-related

characteristics including age, tumor size, grade, estrogen receptor (ER)/progesterone receptor (PR)

status, number of positive lymph nodes and anthracycline/taxane therapy were recorded.

Post-Mastectomy Radiation Therapy

Delivery of PMRT was not randomized and performed according to physician discretion. PMRT

was completed prior to trastuzumab treatment. Table 1 shows the patients, tumor and treatment

characteristics. Overall, patients who received PMRT were younger, had larger tumors, more nodes

involved, and received more chemotherapy. PMRT treatment parameters are provided in

supplementary Table 1. On average, patients received a total radiation dose of 48·8 Gy, divided

over 25 fractions. Radiation therapy was planned using 3 dimensional CT-based treatment

planning. Radiation targets (supplementary Table 1) included the ipsilateral chest wall (90% of

fields) the supraclavicular region (58%), and the axilla (42%). Internal mammary nodes were

included according to the local protocol in around 12% of the PMRT cases. Only a minority of

patients received surgical scar radiation boost (3.8%).

Outcomes

The primary endpoint of the study was loco-regional recurrence (LRR), defined as any local or

regional recurrence, as reported previously [11]. Local recurrence refers to recurrence in the breast

5
surgical scar or ipsilateral chest wall. Regional recurrence refers to the regional lymph nodes

(ipsilateral axillary, infraclavicular or internal mammary lymph nodes). Supraclavicular nodal

recurrence, although currently considered as part of regional recurrence, was considered as distant

recurrence in the HERA trial, and coded under “distant lymph nodes” with no location

specification [11]. The trial’s case report form (CRF) considered such recurrences part of distant

metastases, as per the original published results [11]. Secondary endpoints of the study were

overall survival (OS), distant recurrence and disease-free-survival (DFS). Disease-free-survival

was defined as time from randomization to the first occurrence of any of the following: recurrence

of breast cancer at any site, the development of ipsilateral or contralateral breast ductal carcinoma

in situ, the development of second non-breast malignant disease (except basal-cell or squamous-

cell carcinoma of the skin or carcinoma in situ of the cervix), or death from any cause. Time-to-

event end point definitions are in line with the DATECAN classification [13].

Statistical Analysis

Univariate analyses were conducted to describe the present cohort. Categorical variables are

presented as frequencies and percentages. Differences in such variables between patients from the

PMRT and no PMRT groups were assessed with the likelihood ratio Chi-Square. Continuous

variables are presented as means with corresponding standard deviations and medians with

corresponding ranges. Differences here were assessed with the t test.

Multivariate regression was used to evaluate the association between PMRT and LRR, OS, distant

recurrence and DFS. Survival data were analyzed using Kaplan Meier curves. Cox proportional

hazards regression was used to generate adjusted hazard ratios (HR) with their corresponding 95%

6
confidence interval (CI). The reported HRs are for the comparison of PMRT versus no PMRT. All

adjusted hazard ratios were adjusted for age, tumor size, tumor grade and anthracycline/taxane

therapy. Factors considered for inclusion in the multivariate analyses were dependent on statistical

significance of the bivariate analyses, as well as clinical significance and implications. Nodal status

and ER/PR expression were used for subgroup analyses. Finally, binary logistic regression was

used to calculate adjusted odds ratio (OR) for the association between patients/tumors

characteristics and loco-regional recurrence in our multivariate analysis.

Statistical significance was set at an alpha of 5% for a two-sided p-value. All analyses were

conducted using SAS 9·4 (SAS Institute, Cary, NC).

Results

Study Population

Of the 5099 patients originally enrolled in the HERA trial, 1633 patients met our inclusion criteria

(Fig 1). Table 1 presents the baseline characteristics of the patients, tumors and treatment. Of those

patients, 940 (57·6%) received PMRT, and 693 (42·4%) did not. Patients in the PMRT group were

slightly younger than those in the no PMRT group (49 and 50 respectively). Patients receiving

PMRT were more likely to have involved lymph nodes, especially more than 3 (62·98% vs.

5·19%). Tumor size was significantly larger in the PMRT group (p<0·0001). Most patients had

ductal carcinoma subtypes (93·6%) that were moderately differentiated (grade 2) tumors (60·5%).

Estrogen receptor positivity was similar between the two groups (PMRT: 42·34%; no PMRT:

41·56%). Patients in the PMRT group received more anthracycline (95·74% vs. 88·6%) and taxane

(32·23% vs. 12·41%) based chemotherapy as compared to those in the no PMRT group. Endocrine

7
therapy and receipt of trastuzumab were similar between the two groups. Baseline characteristics

of patients with N1 disease are presented in supplementary Table 2.

Clinical Outcomes in N0 and Node Positive Patients

A total of 93 LRR events were recorded among the 1633 patients analyzed (5·7%). 49 of those

happened in the PMRT group (5·21% of PMRT patients), and 44 happened in the no PMRT group

(6·35% of no PMRT patients). Patients with N0 disease did not benefit from the addition of PRMT

(HR = 1·03, p-value = 0·96) (Fig. 2A). In contrast, patients with N1 disease who underwent PMRT

had a significantly higher 10-year LRR-free survival of 97% (CI = [95%-99%]), vs. 90% (CI =

[86%-94%]) for no PMRT (HR= 0·28, CI = [0·12-0·67], p-value = 0·004) (Fig. 2B). Additionally,

the benefit of PMRT was validated using multivariate analysis, where patients who underwent

PMRT had less LRR events as compared to those who did not undergo PMRT (OR = 0.30, CI =

[0.13-0.68], p-value = 0.003) (Supplementary Table 3).

Next, we investigated LRR in N1 patients according to hormonal receptor expression. In ER and/or

PR positive patients, LRR-free survival was observed in 97% of patients undergoing PMRT vs.

89% in the no PMRT group (HR = 0·26, CI = [0·08-0·79], p-value = 0·02) (Fig. 3A). On the other

hand, no significant difference in loco-regional control was detected in ER/PR negative patients

with 1-3 positive lymph nodes (97% vs. 91%; HR = 0·28, p-value = 0·07) (Fig. 3B).

Of the 93 LRR events, approximately half were local recurrences (53/93) (Table 2). Sites of local

recurrence were the ipsilateral chest wall (22/93), and the surgical scar (31/93). Regional

8
recurrences were mainly in the ipsilateral axillary lymph nodes (18/93). Supraclavicular recurrence

was considered as distant failure and not recorded separately in the HERA trial dataset.

Clinical outcomes of N1 patients according to receipt of PMRT are shown in Table 3. A total of

535 disease-free-survival events were recorded, with 356 being death events. PMRT showed a DFS

benefit with an absolute difference of 7% (77% vs 70%; HR = 0·64, CI = [0·45; 0·92], p=0·01). A

trend towards improved OS was noted in N1 patients receiving PMRT however the difference did

not reach statistical significance (87% (CI = [83%; 91%] vs. 82% (CI = [78%; 87%], HR = 0·63, p-

value = 0·06). Distant recurrence events were not significantly different between the two groups

(HR = 0·75, p-value = 0·19).

As shown in Table 1, 628 patients had 4 or more positive lymph nodes. The vast majority of those

patients (592 patients, 94·3%) received PMRT, while only 36 patients did not. As such, analyzing

the effect of PMRT in this nodal group is limited. Thus, we report the clinical outcomes of patients

with 4 or more positive lymph nodes who received PMRT (Supplementary Table 4). In this

population, at 10 years, LRR-free survival was 93% (CI = [90%; 95%]), distant metastasis free

survival was 60% (CI = [56%; 64%]), disease free survival was 51% (CI = [47%; 56%]) and

overall survival was 63% (CI = [59%; 67%)]).

Discussion

Postmastectomy radiation therapy is an essential component of the multidisciplinary management

of breast cancer. In this article, we examine the impact of PMRT in HER-2 positive breast cancer

patients treated in the HERA phase III trial. Our results show a significant improvement in loco-

9
regional control after PMRT in women with N1 disease, with increased benefit noted in patients

with hormone receptor positive disease. However, the addition of PMRT did not have a significant

impact on distant recurrence or OS.

Early randomized trials published in the 1990’s established the importance of PMRT in reducing

the risk of loco-regional failure and eradicating any residual microscopic disease. Since then the

benefit of PMRT in cases with 4 or more positive nodes is widely recognized, however routine use

of PMRT in women with 1-3 positive nodes remains controversial [14]. The Danish 82b and c

trials showed that women with 1-3 positive nodes who received PMRT had improved LRR (4% vs.

27%) and OS (57% vs. 48%) at 15 years [15]. In a later update from the Danish cooperative group,

Kyndi et al. investigated PMRT outcomes according to biological subtype. The study reported a

27% loco-regional control benefit for PMRT in HER-2 positive patients at 15 years [10]. Improved

OS after PMRT was noted in select patients with better prognostic factors such as positive

hormone receptor status. The use of PMRT is further supported by the EORTC 22922/10925 and

NCIC MA20 trials highlighting the importance of adding regional nodal irradiation to whole-breast

or thoracic wall irradiation in high-risk patients [16, 17].

At the time of the initial PMRT trials, adjuvant systemic therapies included CMF chemotherapy in

premenopausal women and tamoxifen in postmenopausal women. In a meta-analysis of 22 trials,

the EBCTCG showed a reduction of 16.7% in LRR and 7.9% in breast cancer mortality after

PMRT [4]. However, the applicability of these results to patients with one to three positive nodes

in the current era is questionable. Advances in local and distant control due to more effective

adjuvant systemic therapy and improved surgical techniques resulted in attenuated benefit for

10
PMRT over the past two decades. With the improvement of axillary staging, the advent of modern

chemotherapy regimens and the use of aromatase inhibitors, the absolute risk of recurrence has

significantly decreased and the benefit of PMRT has become questionable [6]. The emerging

literature is reflected in current expert consensus statements calling for clinical judgment in making

recommendations regarding PMRT in N1 patients [18, 19]. Clinicians often consider various

clinicopathologic factors including tumor subtype, in such recommendations. Our current study is

the largest of its kind to address the benefit of PMRT in the HER-2 positive patient population

treated with modern systemic therapy.

Although historically regarded to have poor prognosis, outcomes of HER-2 positive breast cancer

have been revolutionized with the introduction of targeted therapies. However, little is known

about the impact of PMRT in this patient population in the current era. Our results show no benefit

for the addition of PMRT in patients with N0 disease. Recent studies showed excellent loco-

regional recurrence and disease free survival rates in node negative patients receiving effective anti

HER-2 therapy [20]. At a median follow up of 10 years, we detected 26 LRR events in the no

PMRT group and 7 recurrences in the PMRT group, in HER-2 positive patients with N1 disease.

Interestingly, PMRT had a trend to improve OS (OS: 87% in the PMRT group vs. 82% in the no

PMRT group, p-value = 0·06). Our results show a smaller loco-regional control benefit for PMRT

in HER-2 positive patients when compared to that reported by Kyndi et al. [10]. In fact, the latter

study was conducted prior to adoption of anti HER-2 therapies, which probably explains the

relatively higher magnitude of PMRT benefit compared to our study. Other recent studies reported

LRR rates of 0·26% to 1·7 % at 5 years, for HER-2 positive patients treated with modern

11
approaches [21, 22]. Furthermore, the radiation therapy technique (electrons vs photons) and

sequencing of trastuzumab relative to PMRT might impact locoregional disease control [23, 24].

Our results highlight the importance of tumor hormonal receptor status in PMRT response.

Hormone receptor positive N1 patients have a higher magnitude of loco-regional control (97% at

10 years) after PMRT. We believe that administration of more effective systemic treatments for

high risk patients decreases mortality due to distant metastasis hence increasing the importance of

optimal locoregional disease control [25]. This is in contrast to ER/PR negative patients where

differences in LRR did not reach statistical significance, which may be related to the lower number

of patients in this subgroup. This finding is in line with the subtype analysis in the Danish trials,

which reported diminished loco-regional control benefit for PMRT in ER/PR negative HER-2

positive subtype [2, 3]. Biologically, this can be explained by the radiosensitivity conferred by ER

signaling through accelerating the G1/S phase transition and diminishing DNA repair [26, 27].

Therefore, dose escalation or radiosensitisation approaches are reasonable future considerations in

patients with negative hormone receptor status [28].

The current analysis carries some limitations that are worth mentioning. First, our study is an

unplanned subgroup analysis based on prospectively collected data from the HERA trial that

originally randomized patients based on trastuzumab receipt. As such, in our study, PMRT was not

randomized, and the volumes of radiation therapy were not pre-specified. The decision to deliver

PMRT was based on institutional preferences. Thus, as one would expect, the PMRT group

displayed more unfavorable characteristics: younger age, more involved nodes and larger tumors

which could diminish the benefit of PMRT (Table 1). This observation, added to the current

12
controversy in PMRT literature, prompted us to focus our analysis on N1 patients. Future

randomized controlled phase III trials, with clear protocols for PMRT administration are still

needed to better assess the role of PMRT in HER-2 positive breast cancer patients. Second,

supraclavicular recurrence was considered as distant recurrence and coded under “distant lymph

nodes” in the HERA trial, while it is currently considered to be a regional recurrence. Third, extra-

capsular extension and lympho-vascular invasion were not recorded in the HERA trial and

therefore were not analyzed in our study. Finally, our results do not apply to HER-2 positive breast

cancer patients receiving neoadjuvant therapy, a question to be addressed by other modern trials.

Despite these limitations, our study is the largest to date to examine the effect of PMRT in HER-2

positive patients treated with modern therapy and followed over an average of 11 years.

In conclusion, PMRT in HER-2 positive breast cancer patients shows improvement in loco-

regional control and disease free survival in patients with 1-3 positive lymph nodes, even after

trastuzumab treatment. These findings are particularly evident in patients with either estrogen or

progesterone receptor expression. However, the magnitude of PMRT benefit is lower than that

recorded in historical studies. Future studies, including analysis of real-life data or possibly

randomized trials, are needed to better assess the role of PMRT in HER-2 positive breast cancer

patients.

13
References:

1. Ragaz J, Jackson SM, Le N et al. Adjuvant radiotherapy and chemotherapy in

node-positive premenopausal women with breast cancer. N Engl J Med 1997; 337:
956-962.
2. Overgaard M, Jensen MB, Overgaard J et al. Postoperative radiotherapy in
high-risk postmenopausal breast-cancer patients given adjuvant tamoxifen: Danish
Breast Cancer Cooperative Group DBCG 82c randomised trial. Lancet 1999; 353:
1641-1648.
3. Overgaard M, Hansen PS, Overgaard J et al. Postoperative radiotherapy in
high-risk premenopausal women with breast cancer who receive adjuvant
chemotherapy. Danish Breast Cancer Cooperative Group 82b Trial. N Engl J Med
1997; 337: 949-955.
4. Ebctcg, McGale P, Taylor C et al. Effect of radiotherapy after mastectomy and
axillary surgery on 10-year recurrence and 20-year breast cancer mortality: meta-
analysis of individual patient data for 8135 women in 22 randomised trials. Lancet
2014; 383: 2127-2135.
5. Wright JL, Parekh A. Updates in Postmastectomy Radiation. Surg Oncol Clin
N Am 2017; 26: 383-392.
6. McBride A, Allen P, Woodward W et al. Locoregional recurrence risk for
patients with T1,2 breast cancer with 1-3 positive lymph nodes treated with
mastectomy and systemic treatment. Int J Radiat Oncol Biol Phys 2014; 89: 392-398.
7. Tendulkar RD, Rehman S, Shukla ME et al. Impact of postmastectomy
radiation on locoregional recurrence in breast cancer patients with 1-3 positive lymph
nodes treated with modern systemic therapy. Int J Radiat Oncol Biol Phys 2012; 83:
e577-581.
8. Zeidan YH, Habib JG, Ameye L et al. Postmastectomy Radiation Therapy in
Women with T1-T2 Tumors and 1 to 3 Positive Lymph Nodes: Analysis of the Breast
International Group 02-98 Trial. Int J Radiat Oncol Biol Phys 2018; 101: 316-324.
9. Muhsen S, Moo TA, Patil S et al. Most Breast Cancer Patients with T1-2
Tumors and One to Three Positive Lymph Nodes Do Not Need Postmastectomy
Radiotherapy. Ann Surg Oncol 2018; 25: 1912-1920.
10. Kyndi M, Sorensen FB, Knudsen H et al. Estrogen receptor, progesterone
receptor, HER-2, and response to postmastectomy radiotherapy in high-risk breast
cancer: the Danish Breast Cancer Cooperative Group. J Clin Oncol 2008; 26: 1419-
1426.
11. Piccart-Gebhart MJ, Procter M, Leyland-Jones B et al. Trastuzumab after
adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 2005; 353:
1659-1672.
12. Cameron D, Piccart-Gebhart MJ, Gelber RD et al. 11 years' follow-up of
trastuzumab after adjuvant chemotherapy in HER2-positive early breast cancer: final
analysis of the HERceptin Adjuvant (HERA) trial. Lancet 2017; 389: 1195-1205.
13. Gourgou-Bourgade S, Cameron D, Poortmans P et al. Guidelines for time-to-
event end point definitions in breast cancer trials: results of the DATECAN initiative
(Definition for the Assessment of Time-to-event Endpoints in CANcer trials)dagger.
Ann Oncol 2015; 26: 873-879.
14. Curigliano G, Burstein HJ, Winer EP et al. Reply to “The St. Gallen
International Expert Consensus on the Primary Therapy of Early Breast Cancer 2017:
the point of view of an International Panel of Experts in Radiation Oncology” by
Kirova et al. Annals of Oncology 2017; mdx543-mdx543.
14
15. Overgaard M, Nielsen HM, Overgaard J. Is the benefit of postmastectomy
irradiation limited to patients with four or more positive nodes, as recommended in
international consensus reports? A subgroup analysis of the DBCG 82 b&c
randomized trials. Radiother Oncol 2007; 82: 247-253.
16. Poortmans PM, Collette S, Kirkove C et al. Internal Mammary and Medial
Supraclavicular Irradiation in Breast Cancer. N Engl J Med 2015; 373: 317-327.
17. Whelan TJ, Olivotto IA, Parulekar WR et al. Regional Nodal Irradiation in
Early-Stage Breast Cancer. N Engl J Med 2015; 373: 307-316.
18. Recht A, Comen EA, Fine RE et al. Postmastectomy Radiotherapy: An
American Society of Clinical Oncology, American Society for Radiation Oncology,
and Society of Surgical Oncology Focused Guideline Update. Ann Surg Oncol 2017;
24: 38-51.
19. Curigliano G, Burstein HJ, E PW et al. De-escalating and escalating
treatments for early-stage breast cancer: the St. Gallen International Expert Consensus
Conference on the Primary Therapy of Early Breast Cancer 2017. Ann Oncol 2017;
28: 1700-1712.
20. Bellon JR, Guo H, Barry WT et al. Local-regional recurrence in women with
small node-negative, HER2-positive breast cancer: results from a prospective multi-
institutional study (the APT trial). Breast Cancer Res Treat 2019; 176: 303-310.
21. Panoff JE, Hurley J, Takita C et al. Risk of locoregional recurrence by
receptor status in breast cancer patients receiving modern systemic therapy and post-
mastectomy radiation. Breast Cancer Res Treat 2011; 128: 899-906.
22. Tseng YD, Uno H, Hughes ME et al. Biological Subtype Predicts Risk of
Locoregional Recurrence After Mastectomy and Impact of Postmastectomy Radiation
in a Large National Database. Int J Radiat Oncol Biol Phys 2015; 93: 622-630.
23. Boulle G, Saint-Martin C, De La Lande B et al. Photons Without Bolus
Versus Electrons With Bolus After Upfront Mastectomy Without Immediate
Reconstruction in Breast Cancer Patients. Int J Radiat Oncol Biol Phys 2019; 104:
877-884.
24. Jacob J, Belin L, Pierga JY et al. Concurrent administration of trastuzumab
with locoregional breast radiotherapy: long-term results of a prospective study. Breast
Cancer Res Treat 2014; 148: 345-353.
25. Poortmans P. Postmastectomy radiation in breast cancer with one to three
involved lymph nodes: ending the debate. Lancet 2014; 383: 2104-2106.
26. Prall OW, Sarcevic B, Musgrove EA et al. Estrogen-induced activation of
Cdk4 and Cdk2 during G1-S phase progression is accompanied by increased cyclin
D1 expression and decreased cyclin-dependent kinase inhibitor association with
cyclin E-Cdk2. J Biol Chem 1997; 272: 10882-10894.
27. Sutherland RL, Prall OW, Watts CK, Musgrove EA. Estrogen and progestin
regulation of cell cycle progression. J Mammary Gland Biol Neoplasia 1998; 3: 63-
72.
28. Langlands FE, Horgan K, Dodwell DD, Smith L. Breast cancer subtypes:
response to radiotherapy and potential radiosensitisation. Br J Radiol 2013; 86:
20120601.

15
Figure Legends:

Figure 1. Flow diagram of the study cohort.

Figure 2. Kaplan-Meier curves showing loco-regional recurrence free survival in node

negative patients (A) and 1-3 positive lymph nodes patients (B). LRRFS, Loco-regional

recurrence-free survival; HR, Hazard ratio.

Figure 3. Kaplan-Meier curves showing loco-regional recurrence free survival among

patients with 1-3 positive lymph nodes having either estrogen and/or progesterone

receptor expression (A) or no expression for both estrogen and progesterone receptors

(B). LRRFS, Loco-regional recurrence-free survival; HR, Hazard ratio.

Table 1. Baseline Characteristics of the Patients, Tumors, and Primary Treatments.

Table 2. Loco-Regional Recurrence Sites.

Table 3. Clinical Outcomes of Patients with 1-3 Positive Lymph Nodes.

16
Table 1. Baseline Characteristics of the Patients, Tumors, and Primary Treatments.

PMRT (n=940) No PMRT (n=693) P-Value

Median Age [Min; Max] 49 [25 - 78] 50 [25 - 76]

Age – no. (%)
<35 82 (8·7) 36 (5·2) 0·0456
35-49 421 (44·8) 310 (44·7)
50-59 300 (32·0) 235 (34·0)
>59 137 (14·6) 112 (16·1)
Menopause – no. (%)
Premenopausal 421 (44·8) 310 (44·7) 0·9591
Postmenopausal 129 (13·7) 92 (13·3)
Uncertain 390 (41·5) 291 (42·0)
Nodal Status – no. (%)
N0 98 (10·4) 390 (56·3) <0·0001
1-3 Positive Lymph Nodes 250 (26·6) 267 (38·5)
≥4 Positive Lymph Nodes 592 (63·0) 36 (5·2)
Tumor Size – no. (%)
0-2 cm 254 (27·1) 299 (43·7) <0·0001
2-5 cm 543 (58·1) 370 (54·1)
>5 cm 137 (14·7) 15 (2·2)
Estrogen Receptor (ER) Positive – no.
398 (42·3) 288 (41·6) 0·7517
(%)
Progesterone Receptor (PR) Positive –
346 (36·8) 217 (31·3) <0·0001
no. (%)
Hormone Receptor Status – no. (%)
ER Negative an PR Negative 456 (48·5) 363 (52·4) <0·0001
ER Positive and PR Positive 288 (30·6) 184 (26·6)
Histological Grade – no. (%)
1 (Well differentiated) 282 (30·0) 238 (34·3) 0·1124
2 (Moderately differentiated) 595 (63·3) 393 (56·7)
3 (Poorly differentiated) 40 (4·3) 38 (5·5)
Not Assessed 16 (1·7) 16 (2·3)
Histology – no. (%)
Ductal 878 (93.4) 651 (93·9) 0·6616
Other 62 (6·6) 42 (6·1)
Surgery – no. (%)
Radical Mastectomy 86 (9·2) 64 (9·2) 0·9524
Modified Radical Mastectomy 781 (84·0) 571 (82·4) 0·7151
Simple Mastectomy 74 (7·9) 61 (8·8) 0·5
Anthracycline-Taxane – no. (%)
No Anthracycline No Taxane 38 (4·0) 78 (11·3) <0·0001
Anthracycline and Taxane 301 (32·0) 85 (12·3)
Taxane, No Anthracycline 2 (0·2) 1 (0·1)
Anthracycline, No Taxane 599 (63·7) 529 (76·3)
 Endocrine Therapy Received – no. (%) 433 (46·1) 307 (44·3) 0·4792
Years on Trastuzumab – no. (%)
1 Year 473 (50·3) 341 (49·2) 0·6567
2 Years 467 (49·7) 352 (50·8)

Breast Cancer Laterality – no. (%)

Left 411 (53.8) 594 (51.3) 0.28
Right 353 (46.2) 564 (48.7)
- Bolded and Italic p-values indicate statistical significance.
Table 2. Loco-Regional Recurrence Sites.

Event PMRT (N=940) No PMRT (N=693) p-value

Local 29 (3·1) 24 (3·5) 0.67
Breast Surgical Scar 10 (1·1) 11 (1·6) 0.35
Ipsilateral Anterior Chest Wall 19 (2·0) 13 (1·9) 0.83
Regional 12 (1·3) 15 (2·2) 0.17
Ipsilateral Axillary 7 (0·7) 11 (1·6) 0.11
Infraclavicular 5 (0·5) 4 (0·6) 0.91
Loco-Regional Missing 8 (0·9) 5 (0·7) 0.77

- Values are numbers (percentage).

Table 3. Clinical Outcomes of Patients with 1-3 Positive Lymph Nodes.

Event Free Proportion at 10 years with 95% CI

PMRT no PMRT HR p-value
LRRFS 0·97 (0·95 – 0·99) 0·90 (0·86 – 0·94) 0.28 (0·12 – 0·67) 0·004
DMFS 0·83 (0·79 – 0·88) 0·80 (0·75 – 0·85) 0.75 (0·49 – 1·16) 0·19
DFS 0·77 (0·72 – 0·83) 0·70 (0·64 – 0·75) 0.64 (0·45 – 0·92) 0·01
OS 0·87 (0·83 – 0·91) 0·82 (0·78 – 0·87) 0.63 (0·39 – 1·02) 0·06
Abbreviations: LRRFS: Loco-regional recurrence-free survival, DMFS = Distant

Metastasis Free Survival, DFS = Disease Free Survival, OS = Overall Survival, CI =

Confidence Interval, HR = Hazard Ratio.

- HRs were adjusted for patient’s age, tumor size, tumor grade and anthracycline/taxane

administration.

- Bolded and Italic p-values indicate statistical significance.