Title:

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Impact of breast surgical procedure on survival in BRCA mutated patients with invasive
breast cancer: mastectomy versus conservative treatment.

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Authors:

Katia MAHIOU1, Clémentine JANKOWSKI1, Laura VINCENT1, Hélène COSTAZ1, Marie-

Martine PADEANO1, Ariane MAMGUEM3, Sandrine DABAKUYO3, Charles COUTANT1,2

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1 Department of Surgical Oncology, Georges François Leclerc Cancer Center -UNICANCER,

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Dijon, France.

2 University of Burgundy-Franche Comté, Dijon, France.

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3 National Quality of Life and Cancer Clinical Research Platform, Georges François Leclerc
Cancer Center -UNICANCER, Dijon, France.
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Corresponding author :

Dr Katia MAHIOU
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Département de Chirurgie Oncologique

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Centre Georges François Leclerc

1 rue du Pr Marion
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21000 Dijon

email : katia.mahiou@gmail.com

Conflict of interest:
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This article has not been published in any other newspaper.

We do not declare any conflict of interest.
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This preprint research paper has not been peer reviewed. Electronic copy available at: https://ssrn.com/abstract=4441934
 Title:

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Impact of breast surgical procedure on survival in BRCA mutated patients with invasive
breast cancer: mastectomy versus conservative treatment.

Abstract:

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Introduction:

Patients with BRCA1/2 mutations have a higher risk of developing breast cancer compared to
the wild-type population. For patients with a BRCA mutation, there are no specific

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recommendations for surgical management. The aim of this study was therefore to

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retrospectively investigate overall survival (OS) and recurrence-free survival (RFS) of BRCA
mutated patients with localized invasive breast cancer, by comparing conservative surgery
versus mastectomy.

Methods:
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This study was based on data from the Côte d'Or breast and gynecological cancer registry.
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Data from patients with a constitutional BRCA1/2 mutation who presented with invasive
breast cancer were collected retrospectively from 1998 to 2018. The Kaplan-Meier method
was used to describe RFS and OS.
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Results:

A total of 104 patients were included in the analysis, of whom 69 had conservative surgery
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and 35 underwent mastectomy. Regarding survival, there was no significant difference in OS

(HR =1.49; 95% confidence interval (CI) [0.76-2.93], p=0.25). Similarly, there was no
significant difference in RFS (HR =1.40; 95% CI [0.81-2.40], p=0.22), survival without
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homolateral recurrence (HR =0.88; 95% CI [0.30-2.61], p=0.89), without contralateral

recurrence (HR =1.50; 95% CI [0.55-4.09], p=0.42), or without distant metastatic recurrence
(HR =1.42, 95% CI [0.69-2.90], p=0.33).
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Conclusion

In invasive breast cancer in a patient with a germline BRCA1/2 mutation, conservative

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surgery, when possible, appears to be a feasible option over total mastectomy, with no
difference in overall survival. However, the patient should be informed of the aggressive
nature of recurrence in this population requiring chemotherapy in most cases.

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 Keywords:

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Breast cancer surgery, BRCA, mastectomy, conservative surgery

Highlights:

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Surgery in BRCA mutated patients

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This research did not receive any specific grant from funding agencies in the public,
commercial, or not-for-profit sectors.

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This preprint research paper has not been peer reviewed. Electronic copy available at: https://ssrn.com/abstract=4441934
 I. Introduction

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There were 58,459 new cases of breast cancer in France in 2018 (1). Only 5 to 10% of breast
cancers are hereditary, i.e. attributable to a genetic mutation, whether known or not. Next
Generation Sequencing (NGS) makes it possible to identify a panel of genes predisposing to

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breast cancer. BRCA2 mutation, followed by BRCA1 mutation are the two most frequent
mutations (2). Patients with BRCA1 and BRCA2 mutations have a higher risk of developing
breast and ovarian cancer compared to the wild-type population. By age 80, the cumulative
risk of developing invasive cancer is estimated to be 72% for patients with a BRCA1 mutation

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and 69% for patients with a BRCA2 mutation (3). At twenty years after a first invasive
cancer, the cumulative risk of developing a contralateral cancer is 40% for BRCA1 mutated

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patients and 26% for BRCA2 mutated patients (3). Data from the literature confirm that the
presence of a BRCA mutation significantly increases the rate of ipsilateral breast cancer (4,5)
but also the rate of contralateral breast cancer (6).
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The therapeutic management of early-stage breast cancer is based on four main approaches:
surgery, radiotherapy, chemotherapy and hormonal therapy (7). For localized cancers, breast-
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conserving surgery and sentinel lymph node biopsy are performed if the breast volume is
amenable, combined with adjuvant radiotherapy and adjuvant systemic treatments if
necessary. Total mastectomy is performed in cases of contraindication to radiotherapy, in
cases of large tumors or in cases where the breast volume is insufficient to perform
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conservative treatment with a satisfactory aesthetic result, or at the patient's request. In the
literature, there is no significant difference in terms of recurrence-free survival (RFS) or
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overall survival (OS) between conservative surgery with adjuvant radiotherapy versus total
mastectomy in the population with early breast cancer and without known mutation (8-10).

For patients with a BRCA mutation, there are no specific recommendations for surgical
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management. There is currently no prospective randomized study that has compared

conservative surgery versus mastectomy and conducting such a study would not be ethical.
Retrospective studies on this subject are discordant. In the study by Pierce et al., the 15-year
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recurrence rate was significantly higher in the group undergoing conservative surgery and
adjuvant radiotherapy, compared to patients undergoing total mastectomy for the surgical
management of early breast cancer in patients with a BRCA mutation (23.5% vs. 5.5%,
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p<0.0001) (11). In the study by Wan et al. comparing breast cancer severity score (BCSS)
survival between conservative surgery, total mastectomy alone and mastectomy followed by

This preprint research paper has not been peer reviewed. Electronic copy available at: https://ssrn.com/abstract=4441934
 radiation, for BRCA mutated patients, there was no significant difference between the three
treatment strategies (12).

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In this context, the aim of this study was therefore to retrospectively investigate overall
survival (OS) and recurrence-free survival (RFS) of BRCA mutation positive patients with

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localized invasive breast cancer, by comparing conservative surgery versus mastectomy,
using data from the Côte d'Or Registry of Breast and other Gynecological Cancers.

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II.Materials and Methods

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a.Study Population

This retrospective study was based on data from the Côte d'Or breast and gynecological
cancer registry. This registry is the only French registry dealing specifically with breast and
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gynecological cancers. Since 1982, the registry has been collecting data on all cases of breast
and gynecological cancers occurring in residents of the Côte d'Or Departement in Eastern
France. Data from patients with a constitutional BRCA1 or BRCA2 mutation who presented
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with invasive breast cancer were collected retrospectively from 1998 to 2018.

To be included in the present analysis, patients had to meet the following criteria:
constitutional BRCA1 and/or BRCA2 gene mutation, unilateral invasive breast cancer,
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surgery performed in the management, and data available about treatments received (namely
surgery, chemotherapy, radiotherapy, hormone therapy).
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Patients were excluded if they had any one or more of the following criteria: a history of
invasive breast cancer, metastatic breast cancer at diagnosis, bilateral breast cancer, ductal
carcinoma in situ (DCIS) without an invasive component, no identified BRCA mutation or
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mutation of unknown significance, no surgical treatment in the management.

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b.Data collected

The following variables were recorded for all patients: age at diagnosis, BRCA1/2 status, type
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of surgery (conservative surgery or mastectomy), clinical size of the lesion, lymph node
status, histological type, molecular profile of the tumor, treatments performed (neoadjuvant
chemotherapy, adjuvant chemotherapy, adjuvant radiotherapy, adjuvant hormonal therapy),

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 survival data and treatments for recurrence (homolateral, contralateral and distant) and vital
status.

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The mastectomy group comprised patients who had undergone mastectomy as part of the
initial management of invasive cancer, and the conservative surgery group comprised patients

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who had undergone conservative breast surgery.

Breast cancer recurrence was defined as any biopsied lesion identified and histologically
diagnosed as a recurrence of invasive or in situ breast cancer.

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Recurrence-free survival was defined as the time (in months) from the date of initial
histologic diagnosis of the first invasive breast cancer to the date of the first histologically or

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imaging-diagnosed recurrence in a homolateral, contralateral, or distant manner. For
homolateral recurrence, patients who received conservative treatment were censored at the
date of prophylactic homolateral mastectomy. Similarly, for contralateral recurrence, patients
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were censored at the date of contralateral prophylactic mastectomy.

Overall survival (OS) was defined as the time (in months) from the date of initial histologic
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diagnosis of invasive breast cancer to the date of death from any cause. Patients who did not
have an event were censored at the date of last report.

Patients were referred for oncogenetic consultation in case of clinico-pathological

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characteristics of their lesion suggestive of a mutation or in case of a family history of breast

and ovarian cancers (13).
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The diagnosis of germline BRCA status was made on a blood sample, confirmed by a second
blood sample. Thus, depending on the personal or family history, the patient and/or the
practitioner may have known about the existence of a BRCA gene mutation before or after the
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diagnosis of invasive cancer.

The histological and molecular profile of the tumors was established initially on diagnostic
biopsy and then confirmed on histological analysis of the surgical specimen. Hormone
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receptor (HR) status was considered positive if the immunohistochemical expression of

estrogen and progesterone receptors in the tumor cells was ≥10%. Human epidermal growth
factor receptor 2 (HER2) status was studied by immunohistochemistry.
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Each patient's file was discussed in a multidisciplinary consultation meeting to decide on the
surgical procedure to be performed and the postoperative adjuvant treatments.

This preprint research paper has not been peer reviewed. Electronic copy available at: https://ssrn.com/abstract=4441934
 ed
c. Statistical analysis

Categorical variables are presented as number and percentage, and quantitative variables as
mean and standard deviation or median and interquartile range. Variables were compared

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using the Chi2 or Fisher’s exact test for qualitative variables and the student’s t-test for
quantitative variables.

The Kaplan-Meier method was used to describe RFS and OS. Survival was determined for the

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entire population and subgroup analysis was performed for homolateral recurrence,
contralateral recurrence, and distant recurrence. Survival curves were compared using the log

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rank test.

A propensity score was constructed from a stepwise top-down logistic regression performed
on the characteristics at diagnosis. The final model on which the score was constructed
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included clinical tumor size and lymph node involvement. Adjusted survival curves were
estimated using the direct adjusted survival method via a Cox model adjusted for BRCA
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status and using the inverse probability treatment weighting method. Test results were
considered significant when the p value was <0.05.

All statistical analyses were performed using RStudio Team (2020) software. RStudio:
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Integrated Development for R. RStudio, PBC, Boston, MA URL http://www.rstudio.com/ and

SAS version 9.4 (SAS institute Inc., Cary, NC, USA).
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III. Results
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a. Characteristics of the study population

Among the 8,022 patients in the Côte d'Or breast cancer registry database with nonmetastatic
invasive breast cancer diagnosed between 1998 and 2018, 106 patients had an identified
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BRCA1/2 mutation (1.3%). Two patients did not have any surgical procedure during their
management. A final total of 104 patients were included in the analysis, of whom 69 had
conservative surgery and 35 underwent mastectomy (Figure 1). Median follow-up was 92.5
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months. BRCA1 mutation was identified in 49% (51/104) of patients and BRCA2 mutation in
51% (53/104). cT2 and cT3 tumors were more frequently represented in the mastectomy

This preprint research paper has not been peer reviewed. Electronic copy available at: https://ssrn.com/abstract=4441934
 group (p=0.02). Similarly, patients in the mastectomy group more often had clinically invaded
lymph nodes (p=0.02). Histological types and molecular profiles were comparable between

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the two groups. Adjuvant radiotherapy was performed more frequently in patients in the
conservative surgery group (p<0.001) (Table 1).

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b. Association between survival and surgical procedure

Regarding survival adjusted for BRCA1/2 status and weighted for clinical tumor size and

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clinical lymph node status, there was no significant difference in OS (HR =1.49; 95%
confidence interval (CI) [0.76-2.93], p=0.25) (Figure 2). Similarly, there was no significant

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difference in RFS (HR =1.40; 95% CI [0.81-2.40], p=0.22) (Figure 3), survival without
homolateral recurrence (HR =0.88; 95% CI [0.30-2.61], p=0.89) (Figure 1, Supplementary
Appendix), without contralateral recurrence (HR =1.50; 95% CI [0.55-4.09], p=0.42) (Figure
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2, Supplementary Appendix), or without distant metastatic recurrence (HR =1.42, 95% CI
[0.69-2.90], p=0.33) (Figure 3, Supplementary Appendix).
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c. Treatments for recurrence

A total of 35 patients experienced recurrence (homolateral, contralateral or metastatic), of

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whom 23 received chemotherapy as part of their treatment (66%), 17 radiotherapy (49%) and
18 (52%) surgery. There was significantly more surgery in the segmentectomy group at
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recurrence (p=0.03) (Table 2).

Of the 35 patients who had a recurrence, 27 recurred with a lesion identical to the initial
lesion and 8 patients had a new cancer. In the segmentectomy group, 18/23 patients (78.3%)
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had a locoregional recurrence and 5/23 (21.7%) had a new cancer. In the mastectomy group,
9/12 patients (75%) had locoregional recurrence and 3/12 (25%) had new cancer.
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This preprint research paper has not been peer reviewed. Electronic copy available at: https://ssrn.com/abstract=4441934
 ed
8022 women in the Côte d'Or Breast Cancer Registry
database with non-metastatic invasive breast cancer

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diagnosed between 1998 and 2018

7916 tumors without BRCA 1 or

2 genetic mutation

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106 women with tumors diagnosed after 1998 and

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before 2018 BRCA positive (1.3%)

2 patients who did not have

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104 patients included

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Conservative surgery (n=69) Mastectomy (n=35)

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a. Figure 1 : Flow-chart
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 ed
Overall population Conservative Mastectomy p=
(n=104) surgery (n=69) (n=35)
Age at diagnosis, years, mean (±SD) 44.6 (±11.8) 45.2 (±11.5) 43.5 (±12.4) 0.52

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Median follow-up, months (Q1,Q3) 92.5 (69.8-147.3) 109 (72-169) 81 (48-104.5)<0.001
Mutation BRCA 0.02
BRCA1 51 (49%) 40 (58%) 11 (31%)
BRCA2 53 (51%) 29 (42%) 24 (69%)
Menopause 0.82
Yes 28 (27%) 17 (24%) 11 (31%)
No 67 (64%) 44 (64%) 23 (66%)

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Unknown 9 (9%) 8 (12%) 1 (3%)
Clinical size 0.02

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cT1 72 (69%) 53 (77%) 19 (54%)
cT2 30 (29%) 16 (23%) 14 (40%)
cT3 2 (2%) 0 (0%) 2 (6%)
Clinical lymph node status 0.02
cN0 78 (75%) 57 (83%) 21 (60%)
cN1 24 (23%) 11 (16%) 13 (37%)
cN2
cN3
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1 (1%)
1 (1%)
0 (0%)
1 (1%)
1 (3%)
0 (0%)
Histologically positive nodes 0.13
Yes 36 (35%) 20 (29%) 16 (46%)
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No 68 (65%) 49 (71%) 19 (54%)
Histological type 0.17
Ductal 91(87%) 60 (87%) 31(89%)
Lobular 7 (7%) 4 (6%) 3 (8%)
Ductal+lobular 1 (1%) 0 (0%) 1 (3%)
Other 5 (5%) 5 (7%) 0 (0%)
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Molecular profile
HR+ 61 (59%) 36 (52%) 25 (71%) 0.09
HR+/HER2 positive 6 (10%) 4 (11%) 2 (8%)
HR+/HER2 negative 55 (90%) 32 (89%) 23 (92%)
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Triple negative 43 (41%) 33 (48%) 10 (29%) 0.99

Treatments
Neoadjuvant chemotherapy 20 (19%) 9 (13%) 11 (31%) 0.03
Adjuvant chemotherapy 66 (64%) 44 (64%) 22 (63%) 0.55
Adjuvant radiation therapy 91 (87%) 68 (99%) 23 (66%) <0.001
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Adjuvant hormone therapy 52 (50%) 29 (42%) 23 (66%) 0.04

Relapse 35 (34%) 23 (33%) 12 (34%) 0.22
SD: standard deviation, BRCA: BReast CAncer, HR: Hormone Receptor, HER2: human epidermal growth factor receptor 2.
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Table 1: Characteristics of the study population

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b. Figure 2 : Overall Survival

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c. Figure 3 : Overall recurrence-free survival (homolateral, contralateral or

metastatic)
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 ed
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Total
Treatments for Segmentectomy Mastectomy

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population p value
recurrence n=23 n=12
n=35

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Chemotherapy 23 (66%) 15 8 p=1

Radiotherapy 17 (49%) er 11 6 p=1

Surgery 18 (52%) 15 3 p=0.03

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Table 2: Treatments for recurrence
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III. Discussion:

In this single-center, retrospective cohort study, there was no difference in OS or RFS

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between conservative surgery and total mastectomy in BRCA1/2 germline mutation patients
managed for unilateral invasive breast cancer.
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These results in terms of OS are consistent with the systematic review by Co et al. and the
study by Wan et al. (12, 14). On the other hand, contrary to the systematic review of Co et al.,
there was no significant difference in homolateral local recurrence in our study according to
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the surgical treatment performed. This may be due to a lack of power of our study linked to
the low number of events (only 10 local homolateral recurrences after surgery).

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 Regardless of BRCA status, the choice of surgical treatment between conservative treatment
associated with radiotherapy or treatment by total mastectomy depends on clinical and

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pathological criteria, such as the tumor size, the ratio of tumor size to overall breast volume,
the location of the lesion and the aesthetic results of possible conservative treatment by
oncoplasty, the multifocality of the lesions and their relationship to the aero-mammary plate,

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the existence of a contraindication to radiotherapy, the administration in some cases of neo-
adjuvant chemotherapy and the personal choice of the patient.

In our population, most patients had triple negative or luminal cancer. Although for a similar

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lesion size the molecular profile does not systematically influence the surgical procedure, it
would be interesting to study the safety of conservative surgery according to the histology of

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the lesion. Due to the small number of patients in our study, we were unable to perform this
analysis.

Only risk-reducing surgeries (prophylactic bilateral mastectomy and bilateral adnexectomy)

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are recommended. Thus, for patients with BRCA1/2 mutation, prophylactic bilateral
mastectomy can be proposed from the age of 30 years and prophylactic adnexectomy is
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recommended between 35-40 years for BRCA1 and 40-45 years for BRCA2 carriers (15).

When invasive breast cancer is found in a patient with a germline BRCA1/2 mutation, several
factors may influence management. Knowledge of the presence of a BRCA1/2 mutation by
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the patient and/or the practitioner managing the patient may have an effect on the choice of
surgery. In the article by Park et al. among 164 patients, there was a significant difference in
the surgery performed depending on whether or not the patient knew of her BRCA status,
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with total mastectomy being performed in preference to other surgeries when the mutation
was known (p=0.017) (16). However, there was no difference in terms of homolateral
(p=0.765) or contralateral (p=0.69) recurrence. In our study, we were not able to obtain
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information on the date of diagnosis of the BRCA germline mutation for all patients. We also
could not ascertain whether the mutation was identified in the patient being managed for
breast cancer or whether it was previously identified in an index case.
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Age at diagnosis and risk of homolateral and contralateral recurrence of the incident cancer
must be considered. Patients with BRCA mutation have a greater risk of homolateral and
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contralateral recurrence compared to patients without mutation (4-6). In a first case of

unilateral invasive cancer, the question of prophylactic management of the contralateral
unaffected breast should be discussed with the patient. Indeed, in the study by Van den Broek

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This preprint research paper has not been peer reviewed. Electronic copy available at: https://ssrn.com/abstract=4441934
 et al, the cumulative risk of contralateral cancer was reported to be greater in BRCA1/2
mutated patients compared to a non-mutated population (6). The cumulative 10-year risk of

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contralateral breast cancer is 21.1% for BRCA1 mutated and 10.8% for BRCA2 mutated
patients, two to three times higher than for non-mutated patients (HR 3.31 for BRCA1 and
HR 2.17 for BRCA2). This difference is also influenced by the age at diagnosis of unilateral

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invasive cancer in mutated patients (cumulative 10-year risk of contralateral breast cancer:
24% for BRCA1/2 mutants for a cancer diagnosed before the age of 41 and 13% for a first
cancer diagnosed between 40 and 49 years). There was no subgroup analysis in this study
concerning the impact of the surgical procedure on survival. Due to the lack of events in our

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study, we were unable to study the impact of age at surgical management on survival.

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When conservative treatment is performed, it should always be combined with radiotherapy.
Adjuvant radiotherapy in patients with BRCA mutation has not been shown to cause excess
toxicity compared to the population without mutation (17, 18). On the other hand, the
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cosmetic impact of radiation must be taken into account, and it must be noted that in case of
prophylactic secondary mastectomy, this history of radiotherapy may create significant
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cosmetic harm.

Conservative surgery may be favored by neoadjuvant treatments. In our study we could not
study, the rate of mastectomies that went unperformed thanks to a good response to
neoadjuvant therapies. In certain cases, neoadjuvant chemotherapy can increase the rate of
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conservative surgery by decreasing the lesion burden. This was notably the case in the
BrighTNess study, where neoadjuvant chemotherapy combining paclitaxel, carboplatin and
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velaparib in BRCA mutated patients with triple negative cancer increased the rate of
conservative treatment by more than 50% (19).

Some studies have suggested an increased risk of homolateral recurrence with conservative
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surgery combined with radiotherapy (20). In our study, we censored patients at the date of
homolateral prophylactic mastectomy performed at their request to limit the risk of bias.
Mastectomy with immediate breast reconstruction (IBR) is a feasible option in cancer to limit
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the risk of homolateral recurrence. There are no specific recommendations for BRCA-mutated
patients regarding IBR. There are numerous techniques for IBR for non-mutated patients and
they can also be offered to patients with a mutation without increasing the oncologic risk.
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This is notably the case of mastectomy with preservation of the skin cover (21, 22).
Concerning the complications of these techniques, in the same way as in non-mutated

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 patients, smoking is the main risk factor for postoperative complications (23, 24). In our
study, only four patients underwent IBR by total dorsalis major flap or retropectoral

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prosthesis.

Concerning contralateral surgery, it must take into account the risk of recurrence of the

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incident cancer, the perception of this risk by the patient, the age of onset of the cancer, the
adjuvant treatments performed (hormone therapy, chemotherapy, radiotherapy, bilateral
adnexectomy), the perception of the disease through the family experience and the number of
cases of cancer, the type and conditions of uni- or bilateral IBR and the possible desire for

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symmetrization. In our study, we censored patients at the time of prophylactic contralateral
mastectomy, whether in the same operation or at a later time, and there was no significant

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difference in terms of recurrence between these two groups (HR =1.50; 95%CI [0.55-4.09],
p=0.42).

Measures to reduce the risk of contralateral breast cancer are diverse, and simple surveillance
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is often preferred by patients over prophylactic mastectomy, which is an invasive method that
can alter quality of life (25, 26). Contralateral prophylactic radiotherapy is a less invasive
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technique that can significantly reduce contralateral breast cancer, but it is currently not
routinely recommended (27).

In this study, we excluded cases of in situ breast cancer because the therapeutic strategy and
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the surgical procedure performed may be influenced, particularly in the direction of

conservative treatment.
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At the time of recurrence, 66% of the patients included had chemotherapy as a treatment,
testifying to the aggressiveness of the infiltrating lesions at recurrence. Due to the small
number of patients concerned, we were unable to identify a difference in the proportion of
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chemotherapy.

This study has some limitations, including its retrospective nature and the lack of certain data,
particularly regarding whether or not the BRCA status was known at the time of surgery, and
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the precise date of the prophylactic bilateral adnexectomy compared with the surgery
performed, which may influence the incidence of breast cancer (28).
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To limit selection bias, survival was adjusted for BRCA status and weighted via the inverse
weight method. We were not able to make a propensity score matching due to the small
population and the loss of power that this could have caused. Whether or not neoadjuvant

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 chemotherapy was performed was not included in the weighting because it does not
systematically contribute to the choice of surgical technique. Similarly, the use of adjuvant

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radiotherapy was not included in the weighting.

Finally, drug treatments targeting BRCA and other homologous recombination gene

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mutations show significant impacts on survival, regardless of the surgical procedure
performed. This is notably the case for olaparib in adjuvant treatment in the OlympiA trial
(29) and talazoparib in first-line metastatic disease in the EMBRACA trial (30). European
recommendations on genetic testing for the diagnosis of BRCA germline mutations currently

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remain limited to codified family or personal histories. In the coming years, BRCA status
testing will be a major asset in the management of breast cancer, particularly with the

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development of PARP inhibitor treatments (13). The question of the oncologic safety of
conservative or non-conservative surgery will therefore be a central issue in the management
of BRCA mutated patients. er
V.Conclusion

In invasive breast cancer in a patient with a germline BRCA1/2 mutation, conservative

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surgery, when possible, appears to be a feasible option over total mastectomy, with no
difference in overall survival. However, the patient should be informed of the possible higher
risk of local recurrence with conservative treatment and should be informed of the
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possibilities of IBR, as well as the aggressive nature of recurrence in this population requiring
chemotherapy in most cases.
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Acknowledgements :
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We thank the registry statistics team for their assistance throughout this work.
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 ed
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iew
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