# Tumor-intrinsic chemosensitivity assessed by KELIM and prognosis by BRCA status in patients with advanced ovarian carcinomas

Ondine Becker, Alice Durand, Marion Chevrier, Laetitia Collet, Laurence Gladieff, Florence Joly, Baptiste Sauterey, Christophe Pomel, Hélène Costaz, Patricia Pautier, et al.

► To cite this version:

Ondine Becker, Alice Durand, Marion Chevrier, Laetitia Collet, Laurence Gladieff, et al. Tumor-intrinsic chemosensitivity assessed by KELIM and prognosis by BRCA status in patients with advanced ovarian carcinomas. International Journal of Gynecological Cancer, 2024, 35 (5), pp.ijgc-2024-005815. 10.1136/ijgc-2024-005815. hal-04828283

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Distributed under a Creative Commons Attribution 4.0 International License
1 Tumour-intrinsic chemosensitivity assessed by KELIM and prognosis by BRCA status in patients

2 with advanced ovarian carcinomas

3

4 Authors : Ondine Becker¹*, Alice Durand²,³*, Marion Chevrier⁴*, Laetitia Collet⁵,⁶, Laurence

5 Gladieff⁷, Florence Joly⁸, Baptiste Sauterey⁹, Christophe Pomel¹⁰, Hélène Costaz¹¹, Patricia

6 Pautier¹², Cécile Guillemet¹³, Thibault de la Motte Rouge¹⁴, Renaud Sabatier¹⁵, Jean-Marc

7 Classe¹⁶, Thierry Petit¹⁷, Eric Leblanc¹⁸, Frédéric Marchal¹⁹, Pierre-Emmanuel Colombo²⁰,

8 Emmanuel Barranger²¹, Aude-Marie Savoye²², Lise Bosquet²³, Isabelle Ray-Coquard⁵,

9 Matthieu Carton⁴, Olivier Colomban²⁴, Benoit You²,²⁴§, Manuel Rodrigues¹,²⁵§

10 *§ These authors contributed equally

11

12 Authors' affiliations

13 ¹ Medical Oncology, Institut Curie, Paris, France

14 ² Medical Oncology, Institut de Cancérologie des Hospices Civils de Lyon (IC-HCL),
15 EPSILYON, Lyon, France

16 ³ Université Claude Bernard Lyon 1, Villeurbane, France

17 ⁴ Biostatistical Unit, Institut Curie, Paris, France

18 ⁵ Medical Oncology, Centre Léon Bérard, Lyon, France

19 ⁶ Breast Cancer Translational Research Laboratory (BCTL), Institut Jules Bordet, Brussels,
20 Belgium

21 ⁷ Medical Oncology, Insitut Claudius Régaud, Toulouse, France

22 ⁸ Medical Oncology, Centre François Baclesse, Caen, France

23 ⁹ Medical Oncology, Institut de Cancérologie de l'Ouest - Centre Paul Papin, Angers, France

24 ¹⁰ Surgical Oncology, Centre Jean Perrin Cancer, Clermont-Ferrand, France

25 ¹¹ Surgical Oncology, Centre Georges-François Leclerc, Dijon, France

26 ¹² Medical Oncology, Gustave Roussy, Villejuif, France
27 ¹³ Medical Oncology, Centre Henri Becquerel Cancer, Rouen, France

28 ¹⁴ Medical Oncology, Centre Eugène Marquis, Rennes, France

29 ¹⁵ Medical Oncology, Paoli-Calmettes Insitute, Marseille, France

30 ¹⁶ Surgical Oncology, Institut de Cancérologie de l'Ouest - Centre René Gauducheau, Saint-Herblain, France

32 ¹⁷ Medical Oncology, ICANS Centre Paul Strauss, Strasbourg, France

33 ¹⁸ Surgical Oncology, Centre Oscar Lambret, Lille, France

34 ¹⁹ Surgical Oncology, Institut de Cancérologie de Lorraine Cancer Institute, Nancy, France

35 ²⁰ Surgical Oncology, Institut regional du Cancer de Montpellier, Montpellier, France

36 ²¹ Surgical Oncology, Centre Antoine-Lacassagne, Nice, France

37 ²² Medical Oncology, Centre Jean Godinot, Reims, France

38 ²³ Health Data and Partnerships Departement, Unicancer, Paris, France

39 ²⁴ Université Claude Bernard Lyon 1, Faculté de Médecine Lyon-Sud, EA 3738 CICLY, Lyon, France

41 ²⁵INSERM U830, DNA Repair and Uveal Melanoma (D.R.U.M.), PSL Research University, Paris, France.
43 Co-corresponding authors :

44 Manuel Rodrigues

45 Medical Oncology Department

46 Institut Curie

47 26 rue d'Ulm

48 75248 Paris Cedex 05

49 France

50

51 INSERM U830: Cancer, Heterogeneity, Instability and Plasticity

52 Institut Curie

53 26 rue d'Ulm

54 75248 Paris Cedex 05

55 France

56 Manuel.rodrigues@curie.fr

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59 Benoit You

60 Medical Oncology Department

61 Institut de Cancérologie des Hospices Civils de Lyon (IC-HCL), CITOHL

62 Centre Hospitalier Lyon-Sud

63 Chemin du Grand Revoyet,

64 69495 Pierre-Benite, France

65

66 Université Claude Bernard Lyon 1

67 EA UCBL/HCL 3738 CICLY

68 Lyon, France

69 benoit.you@chu-lyon.fr

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**ABSTRACT:**

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**Objective:** Treatment of high-grade serous ovarian carcinomas relies on surgery and chemotherapy, potentially followed by bevacizumab and/or PARP inhibitors. The modeled CA-125 ELIMination rate constant K (KELIM) is a pragmatic indicator of the tumor primary chemosensitivity. Although it is well established that the *BRCA* mutations are associated with platinum sensitivity, the relationship between BRCA status and KELIM score have yet to be elucidated. This study aimed to evaluate the interactions between these, and their respective prognostic values.

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**Methods:** We retrospectively collected data from 743 patients with high-grade serous ovarian carcinomas included in a French nationwide registry (NCT03275298), treated with neoadjuvant platinum-based chemotherapy followed by surgery. We analyzed the interactions between *BRCA* and KELIM, and their impacts on progression-free survival and overall survival.

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**Results:** *BRCA*Am patients had higher standardized KELIM than *BRCA*-wild type (BRCAwt) tumors (median, 1.16 vs 1.06, respectively; p=0.001). The prognostic value of KELIM score was independent of *BRCA* in multivariate analyses. KELIM score and *BRCA* could be combined to define three prognostic groups: 1) an unfavorable prognostic group with both BRCAwt and unfavorable KELIM (median progression-free survival, 12.0 months) ; 2) an intermediate prognostic group with either BRCAm and unfavorable KELIM, or BRCAwt and favorable KELIM (median progression-free survival of 16.0 and 18.8 months, respectively; HR, 0.64 compared to the unfavorable group p<0.001); 3) a favorable prognostic group with both BRCAm and favorable KELIM (median progression-free survival 28.8 months ; HR, 0.37 compared to the unfavorable group p<0.001).

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**Conclusion:** The KELIM score provides complementary prognostic information with respect to *BRCA*, and discriminates different prognoses within *BRCA*Am or *BRCA*wt patients. Patients with both BRCAwt/unfavorable KELIM have a poor prognosis, underscoring the urgent need for novel therapeutic strategies.
97 KEY MESSAGES

98 What is already known on this topic

99 CA125 elimination, as assessed by the KELIM score during first-line chemotherapy for high-
grade serous ovarian cancer, reflects chemosensitivity and serves as a strong prognostic factor.

101 BRCA mutation status is also a known prognostic marker and indicator of chemosensitivity,
102 but the relationship between KELIM and BRCA has not been previously studied.

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104 What this study adds

105 This study, using data from a French national registry, reveals that BRCA and KELIM are
106 complementary prognostic tools rather than interchangeable. It identifies three distinct
107 prognostic groups: favorable (BRCAm/favorable KELIM), intermediate (BRCAm/unfavorable
108 KELIM or BRCAwt/favorable KELIM), and unfavorable (BRCAwt/unfavorable KELIM).

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110 How this study might affect research, practice, or policy

111 The combined assessment of KELIM score and BRCA status may help identify high-risk
112 patients who could benefit from prioritizing alternative treatment strategies.
113 INTRODUCTION

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High-grade serous ovarian carcinoma is the most common ovarian cancer. Its major risk factor is the presence of a germline mutation in *BRCA1* or *BRCA2* gene ¹. They are frequently associated with high serum levels of CA125 antigen ². Standard management relies on a medical-and-surgical treatment, including a cytoreductive surgery and a platinum-based chemotherapy, followed by a maintenance treatment with bevacizumab and/or PARPi (Poly (ADP-ribose) polymerase inhibitors) ³,⁴. Maintenance treatment relies on the presence of a BRCA mutation, the most important predictive marker of PARPi efficacy through synthetic lethality ⁵⁻⁷. Homologous recombination deficiency can also be found in patients without BRCA mutation and allows prediction of PARPi sensitivity in a larger population⁵,⁶,⁸. In daily routine, this status is assessed with genomic scars assays such as MyChoice® CDx (Myriad Oncology, Salt Lake City, Utah, USA), and other assays being developed ⁹⁻¹¹.

Data have shown that the benefit expected from PARPi maintenance cannot be unequivocally explained by homologous recombination status, and that other biomarkers are useful for treatment decision-making ¹²⁻¹⁴. Among others, the platinum-sensitivity seems to be a relevant predictor of PARPi activity ¹⁵⁻¹⁷. The CA-125 kinetic parameter KELIM is the modeled rate constant of elimination of the CA-125 during the 100 days of chemotherapy, calculated with at least three CA-125 and reflecting the magnitude of its decline with chemotherapy. Datas from more than 18,000 patients treated in first-line showed that patients with standardized KELIM value≥1.0 (favorable KELIM score) have a highly chemosensitive tumor, therefore a better prognosis in term of progression-free survival and overall survival ¹⁸⁻²³. It also serves as a predictive marker. Patients with unfavorable KELIM benefit more from bevacizumab, as shown in two phase III trials, and it could also modestly predict benefit from
the PARP inhibitor veliparib in the VELIA trial, complementing homologous recombination deficient status <sup>24-27</sup>. KELIM could be an additional, more practical, numerical tool to help maintenance treatment decisions, even in the BRCA-mutated (BRCAm) or homologous recombination deficient subgroups. However, the relationships between KELIM and *BRCA* or homologous recombination statuses are still unclear.

The aim of this investigation performed in a French nationwide registry is to investigate the potential interchangeability or complementarity between KELIM score and BRCA mutational status; and in case of complementarity, to combine these two covariates to develop subgroups of patients with distinct prognoses in terms of progression-free survival and overall survival.
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# METHODS

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## Patients selection

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The ESME-OVR database (NCT03275298) is a real-world, retrospective database that centralizes clinical data from more than 10,000 patients treated for ovarian cancer in 18 French cancer centers. We retrospectively collected data from ovarian cancer patients included in this registry and treated in first-line setting. We included adult patients diagnosed with high-grade serous ovarian carcinomas (International Federation of Gynecology and Obstetrics (FIGO) stage III or IV) who received neoadjuvant platinum-based chemotherapy followed by interval debulking surgery as first-line treatment between 2011 and 2017. Patients with an unknown FIGO stage were deemed advanced, as they were treated with neoadjuvant chemotherapy and thus included in this study.

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We selected the patients with at least 3 available CA125 values between 14 days before the first course of chemotherapy until 100 days after, so we could calculate KELIM continuous value (standardized continuous value), and categorize within a KELIM score using a threshold of 1 (KELIM<1.0 as unfavorable score; or KELIM ≥1.0 as favorable score) as previously described <sup>18</sup>. The few patients who received a PARP inhibitor maintenance after the first-line (n=6) were excluded because of the potential bias they could induce in survival. The ESME Ovarian Cancer database (NCT03275298) was authorized by the French data protection authority (CNIL; https://www.cnil.fr/fr; initial authorization no. DE-2017-397 and subsequent amendment in accordance with GDPR) and an independent scientific committee (ESME OC scientific committee) specifically approved the present work during an evaluation meeting held on January 17, 2020. No written dedicated consent was required but patients were informed by the participating centers about the use of their data. Because the homologous recombination status was not available in the ESME cohort due to diagnosis dates, we established an

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independent, retrospective series of 138 BRCAwt patients meeting similar inclusion and
exclusion criteria (Patients with high-grade serous ovarian carcinomas FIGO III/IV, treated
with first-line platinum-based neoadjuvant chemotherapy, with sufficient CA125 values to
calculate the KELIM), from four centers, to assess the distribution of KELIM scores according
to homologous recombination status (deficient or proficient) in patients with BRCAwt tumors.
All studies were conducted in accordance with the Declaration of Helsinki.

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181 Statistical analysis

182 Progression-free survival was defined as the time between the start of the chemotherapy and
183 the date of progression, relapse, death or last news. Overall survival was defined as the time
184 between the start of the chemotherapy and the date of death or last news. They were estimated
185 by the Kaplan-Meier method. Differences between groups were tested with the Student's t test
186 for the quantitative variables and the Chi2 or Fischer test for the qualitative variables. Since
187 KELIM was calculated based on CA125 kinetics within the first 100 days after the start of
188 chemotherapy, a landmark analysis was performed to eliminate events occurring in the first
189 100 days. The impact of possible prognostic factors on survival was analyzed using a
190 univariate Cox model. To consider potential confounders, these factors (BRCA status [wild
type/mutated/non tested], KELIM [favorable/unfavorable], FIGO stage [III/IV], age at
191 diagnosis [≤70 years-old/>70 years-old], bevacizumab [yes/no]) were then included in a
192 multivariate Cox model. Analyses were performed using R software (version 4.0.2). All tests
193 were implemented using a two-sided 0.05 alpha risk. NONMEM 7.5 (ICON Development
194 Solutions, Ellicott City, MD, USA) software was used to calculate patient KELIM values.
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196 **RESULTS**

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198 **Cohort characteristics**

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200 A total of 10263 patients with a diagnosis of ovarian cancer were included in the ESME registry. Among these, 743 patients met the inclusion criteria, corresponding to high-grade serous ovarian carcinomas patients treated with first-line neoadjuvant platinum-based chemotherapy presenting with sufficient CA125 values to assess KELIM (Supp Figure 1). For these 743 patients, the median follow-up was 50.3 months with median progression-free survival and overall survival of 15.7 months (95% Confidence Interval (CI) [13.7; 16.8]) and 50.7 months (95%CI [44.8; 55.7]), respectively. Patient's characteristics are described in Table 1. Of these 743 patients, 223 were not tested for *BRCA* mutation (30.0%: *BRCA*Ant), whilst 449 had available *BRCA* status (60.4%) including 125 patients carrying a *BRCA* mutation (16.8% of all patients, 27.8% of tested patients; BRCAm), 81 with a *BRCA1* mutation (*BRCA1*m; 18.0% of tested patients), 43 with a *BRCA2* mutation (*BRCA2*m 9.6% of tested patients), and one unspecified case (Supp Table 1). Notably, *BRCA* sequencing in France is universally accessible for high-grade serous ovarian carcinomas patients, thus its testing in this cohort was guided by medical necessity only. As expected, *BRCA* tested patients were younger than untested (median 62 *versus* 69 years; Kruskal-Wallis p<0.001) and more frequently diagnosed after 2013 (64.1% *versus* 46.6%, respectively; Khi-2 p<0.001).

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217 **Relationships between KELIM values, BRCA and homologous recombination status**

218 Our first goal was to determine whether KELIM score and BRCA status were interchangeable. Among patients with available *BRCA* status (n=449), the median standardized KELIM value was slightly higher in BRCAm patients compared to BRCAwt patients (median

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1.16, (range; 0.37-2.24) versus 1.06 (range; 0.29-4.3); Kruskal-Wallis p=0.001; **Figure 1A**) but
this small difference is insufficient for using KELIM as a reliable predictor of BRCA status.
Patients with a BRCA mutation seemed more likely to have a favorable KELIM score ≥1.0
compared to patients with BRCAwt: 63.2% versus 53.1%, but the difference was not significant
(Khi-2 p=0.053). We observed a potential bimodal distribution of standardized KELIM values
in BRCAm patients (**Figure 1B**), corresponding to *BRCA1m* (median of 1.15; range, 0.46-2.17)
and to *BRCA2m* patients (median 1.21; range; 0.37-2.24) (Kruskal-Wallis p=0.56).

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We also observed a bimodal distribution of KELIM values in BRCAwt suggesting the
presence of two sub-populations (**Figure 1B**). As the homologous recombination status was
unavailable in this database, we analyzed another series of 138 patients with BRCAwt high-
grade serous ovarian carcinomas treated in four centers (**Supplementary Table 2**).
Standardized KELIM values tended to be higher in patients with homologous recombination
deficient cancers (n=36) compared to those with homologous recombination proficient disease
(n =102): median 1.06 (range; 0.38-1.97) versus 0.73 (range; 0.21-2.34; Mann Whitney
p=0.017) (**Figure 1C**), which may explain the bimodal distribution of KELIM in BRCAwt
patients.

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239 **Prognostic value of the KELIM score and BRCA status**

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Our second goal was to assess the prognostic value of KELIM according to BRCA
status. In the ESME cohort of 743 patients, both KELIM score (favorable *versus* unfavorable)
and *BRCA* status were associated with progression-free survival and overall survival in
univariate and multivariate analysis, together with FIGO stage (**Table 2**). Information on
completeness of debulking surgery was known for 52.5% of patients. A sensitivity analysis on

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this population confirmed that *BRCA* status and KELIM score were still associated with
progression-free survival and overall survival in multivariate analysis, as was surgical
completeness (**Supplementary table 3**).

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In the 743 patients, median progression-free survival was 11.0 and 20.0 months in patients with unfavorable and favorable KELIM score, respectively (Hazard Ratio (HR) = 0.55; 95%CI [0.47; 0.65]; log-rank p<0.001; **Figure 2A**). The median progression-free survival was 30.7, 21.1, 15.9 and 9.8 months in patients with *BRCA2m*, *BRCA1m*, *BRCAwt* and *BRCAnt* tumors, respectively (log-rank for comparison between *BRCAm* versus *BRCAwt*, p<0.001; HR=0.63; 95%CI [0.49;0.8]; **Figure 2B**). Furthermore, a favorable KELIM score was associated with a significantly improved progression-free survival, regardless of the *BRCA* mutation status: *BRCAwt* population, median progression-free survival 18.8 months for favorable KELIM score versus 12.0 months for unfavorable KELIM score (HR=0.63 95%CI [0.49 ; 0.81] ; log-rank p<0.001); *BRCAm* population, median progression-free survival 28.8 months for favorable KELIM score versus 16.0 months for unfavorable KELIM score (HR=0.50 95%CI [0.32 ; 0.76] ; log-rank p=0.002; **Figure 2C**). Same results were identified in terms of overall survival: for the *BRCAwt* population, median overall survival of 61.3 months versus 45.4 months (HR = 0.58 95%CI [0.41 ; 0.81] ; log-rank p=0.001), and for the *BRCAm* population, median overall survival of 115.6 months versus 53.9 months (HR=0.39 95%CI [0.2 ; 0.75] ; log-rank p=0.006; **Figure 3**).

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For the *BRCA* tested population, when KELIM score and *BRCA* status were combined,
three prognostic groups were delineated with significantly different progression-free survival:
1) an unfavorable prognostic group composed of patients with both *BRCAwt* tumors and
unfavorable KELIM (median 12.0 months) ; 2) an intermediate prognostic group composed of
patients with either a *BRCAwt* and favorable KELIM tumor, or a *BRCAm* and unfavorable
271 KELIM score (median 18.8 and 16.0 months, respectively; log-rank p-value for comparison
272 with unfavorable group p<0.001 ; HR=0.64 ; 95%CI [0.51-0.8]) ; 3) a favorable prognostic
273 group composed of patients with BRCAm tumors and a favorable KELIM (median 28.8 months
274 ; log-rank p-value for comparison with unfavorable group <0.001 ; HR=0.37 ; 95%CI [0.27-
275 0.51]; Figure 2C).
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# DISCUSSION

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## Summary of Main Results

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The present work directly addresses the relationships between KELIM and *BRCA/homologous recombination status*, along with their complementary prognostic values, in a large real-world, nationwide registry of patients treated in neo-adjuvant setting. The present study confirms that *BRCA* mutation, *BRCA2* especially, are associated with higher KELIM values than *BRCA* wild-type. Beyond *BRCA* mutation, a homologous recombination deficient status (i.e. high genomic instability score) was also associated with higher KELIM value compared to a homologous recombination proficient status in patients with *BRCA* wild-type tumors. Also, we found that KELIM score and *BRCA* status are not interchangeable but provide complementary prognostic information. Both covariates exhibited significant prognostic value on progression-free survival and overall survival in univariate and multivariate analysis. Furthermore, they could be combined to generate three prognostic groups with large progression-free survival differences: 1) an unfavorable prognostic group with BRCAwt and unfavorable KELIM (median 12.0 months); 2) an intermediate prognostic group including patients with either BRCAm and unfavorable KELIM, or BRCAwt and favorable KELIM (median 16.0 months and 18.8 months, respectively); and 3) a favorable prognostic group with patients with BRCAm and favorable KELIM (median of 28.8 months).

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## Results in the Context of Published Literature

In patients with advanced high-grade serous ovarian carcinomas, there is a need for tools to guide treatment decision-making regarding the maintenance treatment or surveillance (i.e. more intensive surveillance for patients with poor prognosis). While essential, *BRCA* and homologous recombination deficiency statuses are sometimes insufficient to predict response to PARP inhibitors⁵,⁷, therefore considering the tumor primary chemosensitivity assessed by
301 KELIM score as a potential complementary tool is relevant. KELIM has been reported as a
302 strong pragmatic indicator of platinum-sensitivity, and a potential predictor of bevacizumab
303 benefit in post hoc analyses of large international phase III trials. Additionally, a post-hoc
304 exploratory analysis of the VELIA trial suggested that a favorable KELIM was associated with
305 a trend toward greater progression-free survival benefit from veliparib in patients with BRCAm
306 or homologous recombination deficient tumors compared to those with unfavorable KELIM
307 <sup>13,26</sup>. However, these findings are preliminary and need confirmation in larger, purpose-
308 designed studies.
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310 BRCAm patients had higher value of standardized KELIM, what was expected
311 considering the well-known relationships between platinum-sensitivity and PARPi activity <sup>15-17</sup>.
312 But this study raises the question of the biology behind the poorer prognosis of the patients
313 exhibiting unfavorable KELIM despite a <i>BRCA</i> mutation. Several hypotheses can be raised to
314 explain these “bad” <i>BRCA</i> mutations. As recently reported, they could be due to specific <i>BRCA</i>
315 deleterious mutations resulting in lower sensitivity to platinum salts (such as <i>BRCA1</i> mutations
316 in exon 11 or abrogating the RING domain), or to early secondary reversion mutations restoring
317 <i>BRCA</i> function <sup>28-30</sup>. Unfortunately, the type of <i>BRCA</i> mutation was not reported in our
318 database. These results should urge to develop new studies for identifying an optimal treatment
319 for these patients less sensitive to platinum salts, and potentially less sensitive to maintenance
320 by PARP inhibitors alone.
321

## Strengths and Weaknesses

322 Our study is the first to study the link between KELIM and BRCA status and was made
323 in a large nationwide registry including a large group of patients. We confirmed the prognostic
324 value of KELIM in multivariate analysis, and the three prognostic groups that we identified
325 could be useful in daily-practice.
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Our study includes several limitations. The retrospective essence of real-life databases
induces some potential biases due to the heterogeneity of the population, especially for
prognostic analyses. On the other hand, it contributes to make outcomes more applicable to the
patients seen in our daily clinical practice. Moreover, we did not have information on
completeness of the cytoreductive surgery in the whole cohort but our sensitivity analysis in
more than half of the population confirmed that *BRCA* and KELIM were independent
prognostic factors. *BRCA* mutation data and homologous recombination status were missing
for many patients. In addition, because this study was derived from retrospective real-world
data, germline *BRCA* testing was influenced by factors such as age, date of diagnosis, and
possibly recurrence (as patients with recurrence could benefit from PARP inhibitors), thereby
potentially biasing the BRCA-tested population versus the untested population. However, we
mitigated this bias by integrating this variable (tested or not) in our multivariate analysis. In our
second small cohort, we found an association between KELIM value and homologous
recombination status but although this association was statistically significant, there were only
a small number of patients and the magnitude of the association is currently not sufficient to
consider a potential substitution of homologous recombination deficiency assays by KELIM
score. Finally, we could not assess the prognostic value of *BRCA* status and KELIM score
regarding the efficacy of PARPi, since patients receiving PARPi maintenance on first line were
excluded due to their small number (n=6). Investigating this aspect in new cohorts will be
crucial to ascertain the reproducibility of these three prognostic groups in a population treated
with first-line PARPi.

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## Implications for Practice and Future Research

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Despite these limitations, the present study provides new data about the relationships
between *BRCA* status and KELIM, that appear to be complementary prognostic factors. We

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identified three prognostic groups according to BRCA status and KELIM score ; and KELIM score may identify the patients with a poor prognosis despite carrying a BRCA mutation. Of note, the improved prognosis in the favorable group with BRCAm and favorable KELIM patients should not justify therapeutic de-escalation. Indeed, these patients would potentially have an increased sensitivity to PARPi and even better survival with these treatments. KELIM is now recognized as a useful tool for ovarian cancer management by the French guidelines and by ESMO-ESGO recommendations³,³¹. The ongoing NIRVANA-1 (NCT05183984) and AGO-OVAR28/ENGOT-ov57 (NCT05009082) trials could provide insight into the differential responses to PARPi or bevacizumab among the three prognostic groups. Additionally, the SALVOVAR trial (NCT06476184), which evaluates the efficacy of adjusting neoadjuvant chemotherapy to a weekly-dense regimen in patients with unfavorable KELIM score, will provide valuable information on the prognostic values of BRCA and homologous recombination deficiency in these patients.

## CONCLUSION

CA125 decrease assessed by KELIM provides pivotal information on tumor-intrinsic chemosensitivity, including in the BRCA-mutated population. KELIM and BRCA status are not interchangeable but rather two complementary prognostic tools in patients with high-grade serous ovarian carcinomas.
370 DATA AVAILABILITY STATEMENT

371 Data may be obtained from a third party and are not publicly available.

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373 FUNDING

374 This work was supported by R&D UNICANCER. The ESME ovarian cancer database is
375 supported by an industrial consortium (AstraZeneca and GlaxoSmithKline). Data collection,
376 analyses and publications are totally managed by UNICANCER independently of the industrial
377 consortium. MR was supported by the Interface INSERM program.

378

379 ACKNOWLEDGMENTS

380 We thank the 18 participating French Comprehensive Cancer Centres for providing the data
381 and each ESME local coordinator for managing the project at the local level: Institut Curie,
382 Paris/Saint-Cloud; Gustave Roussy, Villejuif; Cancérologie de l'Ouest, Angers/Nantes; Centre
383 Francois Baclesse, Caen; Institut régional du Cancer de Montpellier, Montpellier; Centre Leon
384 Bérard, Lyon; Centre Georges-François Leclerc, Dijon; Centre Henri Becquerel, Rouen; Institut
385 Claudius Regaud, Toulouse; Centre Antoine-Lacassagne, Nice; Institut de Cancérologie de
386 Lorraine, Nancy; Centre Eugene Marquis, Rennes; Institut Paoli-Calmettes, Marseille; Institut
387 Jean Perrin, Clermont-Ferrand; Institut Bergonié, Bordeaux; Centre Paul Strauss, Strasbourg;
388 Institut Jean Godinot, Reims; Centre Oscar Lambret, Lille. The authors would also like to thank
389 the patients, their family members as well as all doctors, clinical research assistants and staff
390 implicated in the ESME program. Moreover, we thank the all members of ESME Strategic
391 /Scientific Committees for their ongoing support.

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395 CONFLICTS OF INTEREST

396 JM. Classe reports personal fees from AstraZeneca, Roche, Vifor, Clovis, GlaxoSmithKline
397 and Merck Sharp and Dohme, outside the submitted work. L. Collet reports non-financial
398 support from Pharmamar and GSK, outside the submitted work. PE. Colombo reports
399 personal fees from Merck Sharp and Dohme, AstraZeneca and GlaxoSmithKline, outside the
400 submitted work. A. Durand reports non-financial support from Monaco Age Oncologie,
401 outside the submitted work. T. De La Motte Rouge reports personal fees from Pfizer,
402 AstraZeneca, GlaxoSmithKline, Clovis Oncology, Roche, Merck Sharp and Dohme, Mylan,
403 Tesaro and Norvartis, Grants from Pfizer, Merck Sharp and Dohme and Seagen, non-financial
404 advisory role for French national cancer institute, Arcagy and Unicancer, outside the
405 submitted work. L. Gladieff reports personal fees from Viatris, Roche, Merck Sharp and
406 Dohme, Clovis, GlaxoSmithKline and AstraZeneca, outside the submitted work. F.Joly
407 reports personal fees from Amgen, Astellas, AstraZeneca, Byaer, EISAI, GlaxoSmithKline,
408 Ipsen, Janssen, Merck Sharp and Dohme, Novartis, Novocure, Pfizer, Seagen and Viatris,
409 non-financial support from Astellas, AstraZeneca, Bristol-Meyer Squibb, GlaxoSmithKline,
410 Janssen, Merck Sharp and Dohme, Ipsen, EISAI and Chugai, outside the submitted work. E.
411 Leblanc reports personal fees from Strycker, outside the submitted work. P. Pautier reports
412 personal fees from GlaxoSmithKline, Merck Sharp and Dohme, PharmaMar and Roche,
413 outside the submitted work. C.Pomel reports personal fees from Roche, GlaxoSmithKline,
414 Pharmamar and Merck Sharp and Dohme, outside the submitted work. R. Sabatier reports
415 grants from AstraZeneca, personal fees from GlaxoSmithKline, EISAI, Seagen and Novartis,
416 non-financial support from Merck Sharp and Dohme, GlaxoSmithKline and Novartis, outside
417 the submitted work. I. Ray-Coquard reports personal fees from Agenus, Amgen, AstraZeneca,
418 Clovis, Deciphera, GlaxoSmithKline, Macrogenics, Merck Sereno, Mersena, Novartis,
419 Oxnea, Roche, Bristol-Meyer Squibb and Merck Sharp and Dohme, outside the submitted
420 work. M. Rodrigues reports non-financial support from AstraZeneca, grants from Merck

421 Sharp and Dohme, Daiichi Sankyo and Bristol-Meyer Squibb, personal fees from

422 AstraZeneca, Immunocore, Merck Sharp and Dohme and GlaxoSmithKline, outside the

423 submitted work. B. You reports personal fees from Merck Sharp and Dohme, AstraZeneca,

424 GSK-TESARO, Bayer, Roche-Genentech, ECS Progastrine, Novartis, LEK, Amgen, Clovis

425 oncology, Merck Serono, Bristol-Meyer Squibb, Seagen, Myriad, Menarini, Gilead and

426 EISAI, outside the submitted work. E. Barranger O. Becker, L. Bosquet, M. Carton, M.

427 Chevrier, O. Colomban, H. Costaz, C. Guillemet, F. Marchal, T.Petit, B. Sauterey AM.

428 Savoye have nothing to disclose.

429
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<table><caption>**Table 1: Characteristics of the patients.** ESME population includes 71 patients for which the BRCA status could not be retrieved</caption><thead><tr><th>Characteristics</th><th>BRCA tested (449)</th><th>BRCA mutated (125)</th><th>BRCA wild type (324)</th><th>BRCA non tested (223)</th><th>ESME Population (743)</th></tr></thead><tbody><tr><td>Median age at diagnostic - year (range)</td><td>62 (19 - 86)</td><td>58 (34 - 81)</td><td>64 (19 - 86)</td><td>69 (29 - 90)</td><td>645 (19 - 90)</td></tr><tr><td>Median follow-up - months (range)</td><td>52 (8 - 243.4)</td><td>58.8 (8 - 124.3)</td><td>49.4 (8 - 124.3)</td><td>48.6 (5.3 - 97.1)</td><td>50.3 (5.3 - 243.4)</td></tr><tr><td>International FIGO stage - no (%)</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>III</td><td>198 (44.1%)</td><td>57 (45.6%)</td><td>141 (43.5%)</td><td>86 (38.6%)</td><td>321 (43.2%)</td></tr><tr><td>IV</td><td>151 (33.6%)</td><td>43 (34.4%)</td><td>108 (33.3%)</td><td>75 (33.6%)</td><td>249 (33.5%)</td></tr><tr><td>NA</td><td>100 (22.3%)</td><td>25 (20%)</td><td>75 (23.2%)</td><td>62 (27.8%)</td><td>173 (23.3%)</td></tr><tr><td>First line platinum-based therapy - no (%)</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Platinum-based therapy with Taxanes</td><td>431 (96.0%)</td><td>118 (94.4%)</td><td>313 (96.6%)</td><td>188 (84.3%)</td><td>686 (92.3%)</td></tr><tr><td>Other platinum-based therapy</td><td>18 (4.0%)</td><td>7 (5.6%)</td><td>11 (3.4%)</td><td>35 (15.7%)</td><td>57 (7.7%)</td></tr><tr><td>Bevacizumab</td><td>204 (45.4%)</td><td>56 (44.8%)</td><td>148 (45.7%)</td><td>55 (24.7%)</td><td>291 (39.2%)</td></tr><tr><td>CA125 level</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Median number of values (range)</td><td>4 (3 - 10)</td><td>4 (3 - 10)</td><td>4 (3 - 10)</td><td>4 (3 - 10)</td><td>4 (3 - 12)</td></tr><tr><td>Median level at day 0 (range)</td><td>634 (4 - 34534)</td><td>634 (4 - 25000)</td><td>634 (4 - 34534)</td><td>552 (4 - 38176)</td><td>597 (3.5 - 38176)</td></tr><tr><td>Median level at cycle 4 (range)</td><td>47 (3 - 8523)</td><td>34 (4 - 4300)</td><td>51 (3 - 8523)</td><td>58 (4 - 9900)</td><td>48 (3 - 19000)</td></tr></tbody></table>
<table><caption>**Table 2 : Cox regression univariate and multivariate analysis of Progression Free Survival and overall survival.** This analysis includes only patients with available data for BRCA status, KELIM score, FIGO stage, age, and bevacizumab treatment status.</caption><thead><tr><th colspan="5">Progression Free Survival</th><th colspan="5">Overall survival</th></tr><tr><th rowspan="2">Covariates</th><th colspan="3">Univariate analysis</th><th colspan="2">Multivariate analysis</th><th colspan="3">Univariate analysis</th><th colspan="2">Multivariate analysis</th></tr><tr><th>N</th><th>HR (CI95)</th><th>P value</th><th>HR (CI95)</th><th>P value</th><th>N</th><th>HR (CI95)</th><th>P value</th><th>HR (CI95)</th><th>P value</th></tr></thead><tbody><tr><td><strong>BRCA status</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td><strong>BRCA wild-type</strong></td><td>241</td><td>1</td><td rowspan="3">&lt; 0.001</td><td>1</td><td rowspan="3">&lt; 0.001</td><td>249</td><td>1</td><td rowspan="3">&lt;0.001</td><td>1</td><td rowspan="3">&lt;0.001</td></tr><tr><td><strong>BRCA mutated</strong></td><td>98</td><td>0.55<br/>[0.42 ; 0.72]</td><td>0.56<br/>[0.42 ; 0.74]</td><td>100</td><td>0.41<br/>[0.27 ; 0.64]</td><td>0.45<br/>[0.29 ; 0.69]</td></tr><tr><td><strong>BRCA non tested</strong></td><td>157</td><td>1.27<br/>[1.02 ; 1.59]</td><td>1.13<br/>[0.89 ; 1.43]</td><td>161</td><td>2.46<br/>[1.87 ; 3.24]</td><td>2.42<br/>[1.84 ; 3.19]</td></tr><tr><td><strong>KELIM</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td><strong>KELIM&lt;1 unfavorable</strong></td><td>237</td><td>1</td><td rowspan="2">&lt; 0.001</td><td>1</td><td rowspan="2">&lt; 0.001</td><td>249</td><td>1</td><td rowspan="2">&lt;0.001</td><td>1</td><td rowspan="2">&lt;0.001</td></tr><tr><td><strong>KELIM≥ 1.0 favorable</strong></td><td>259</td><td>0.51<br/>[0.41 ; 0.62]</td><td>0.56<br/>[0.45 ; 0.68]</td><td>261</td><td>0.46<br/>[0.35 ; 0.6]</td><td>0.54<br/>[0.41 ; 0.7]</td></tr><tr><td><strong>FIGO stage</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td><strong>FIGO III</strong></td><td>278</td><td>1</td><td rowspan="2">&lt;0.001</td><td>1</td><td rowspan="2">0.002</td><td>284</td><td>1</td><td rowspan="2">&lt;0.001</td><td>1</td><td rowspan="2">0.006</td></tr><tr><td><strong>FIGO IV</strong></td><td>218</td><td>1.45<br/>[1.17 ; 1.76]</td><td>1.398<br/>[1.13 ; 1.69]</td><td>226</td><td>1.57<br/>[1.21 ; 2.03]</td><td>1.44<br/>[1.11 ; 1.87]</td></tr><tr><td><strong>Age at diagnosis</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td><strong>≤ 70 years-old</strong></td><td>350</td><td>1</td><td rowspan="2">0.008</td><td>1</td><td rowspan="2">0.21</td><td>362</td><td>1</td><td rowspan="2">0.003</td><td>1</td><td rowspan="2">0.66</td></tr><tr><td><strong>&gt; 70 years-old</strong></td><td>146</td><td>1.35<br/>[1.09 ; 1.68]</td><td>1.16<br/>[0.92 ; 1.46]</td><td>148</td><td>1.55<br/>[1.17 ; 2.05]</td><td>1.07<br/>[0.8 ; 1.44]</td></tr><tr><td><strong>Bevacizumab</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td><strong>No</strong></td><td>292</td><td>1</td><td rowspan="2">0.19</td><td>1</td><td rowspan="2">0.06</td><td>304</td><td>1</td><td rowspan="2">0.59</td><td></td><td></td></tr><tr><td><strong>Yes</strong></td><td>204</td><td>0.87<br/>[0.71 ; 1.07]</td><td>0.82<br/>[0.66 ; 1.01]</td><td>206</td><td>0.93<br/>[0.71 ; 1.22]</td><td></td><td></td><td></td></tr></tbody></table>
**Figure 1: Distribution of standardized KELIM values.** in *BRCA* wild-type and *BRCA*-mutated from the ESME cohort (A), in *BRCA* wild-type, *BRCA1*-mutated, and *BRCA2*-mutated from the ESME cohort (B) and in *BRCA* wild-type according to HRD status in an independent cohort of 138 patients (C). HRD: homologous repair deficiency; ns: non significant.

<figure><img src="image_2.png" /></figure>
<figure><img src="image_3.png" /><figcaption>**Figure 2 :** Kaplan–Meier Estimates of Progression-free Survival, according to KELIM score (A), *BRCA* status (B), *BRCA* status (in the 121 patients with known *BRCA1/BRCA2* status) and KELIM score (C). *BRCAnt:* *BRCA* non tested; *BRCAwt:* *BRCA* wild-type.</figcaption></figure>
Figure 3 : Kaplan-Meier Estimates of overall survival according to BRCA status and KELIM score

<figure><img src="image_4.png" /></figure>
<figure><img src="image_5.png" /><figcaption>**Supplementary Figure 1 : Study Flow-Chart.**</figcaption></figure>
**Supplementary Table 1 : BRCA mutation testing.**

BRCA status n = 743

BRCA wild-type 324 (43.6%)

BRCA mutated 125 (16.8%)

BRCA1 81

BRCA2 43

Unknown 1

BRCA not tested 223 (30%)

NA 72 (9.6%)

Type of genetic analysis for BRCA1/BRCA2 positive (124)

Constitutional 95 (76.6%)

Tumoral 17 (13.7%)

NA 12 (9.6%)
<table><caption>Supplementary Table 2 : Patients of the second cohort</caption><thead><tr><th>Patients</th><th>FIGO</th><th>Chemotherapy</th><th>BRCA status</th><th>Center*</th><th>Homologous Recombination status</th><th>Standardized KELIM values</th><th>KELIM Score</th></tr></thead><tbody><tr><td>1</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>1</td><td>Proficient</td><td>1,33</td><td>favorable</td></tr><tr><td>2</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>1</td><td>Proficient</td><td>0,279</td><td>unfavorable</td></tr><tr><td>3</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>1</td><td>Proficient</td><td>0,358</td><td>unfavorable</td></tr><tr><td>4</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>1</td><td>Proficient</td><td>0,643</td><td>unfavorable</td></tr><tr><td>5</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>1</td><td>Proficient</td><td>1,2</td><td>favorable</td></tr><tr><td>6</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>1</td><td>Proficient</td><td>1,54</td><td>favorable</td></tr><tr><td>7</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>1</td><td>Proficient</td><td>0,478</td><td>unfavorable</td></tr><tr><td>8</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>1</td><td>Proficient</td><td>0,208</td><td>unfavorable</td></tr><tr><td>9</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>1</td><td>Proficient</td><td>0,458</td><td>unfavorable</td></tr><tr><td>10</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>1</td><td>Proficient</td><td>1,29</td><td>favorable</td></tr><tr><td>11</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>1</td><td>Proficient</td><td>1,11</td><td>favorable</td></tr><tr><td>12</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>1</td><td>Proficient</td><td>0,923</td><td>unfavorable</td></tr><tr><td>13</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>1</td><td>Proficient</td><td>0,818</td><td>unfavorable</td></tr><tr><td>14</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>1</td><td>Proficient</td><td>0,579</td><td>unfavorable</td></tr><tr><td>15</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>1</td><td>Proficient</td><td>1,14</td><td>favorable</td></tr><tr><td>16</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>1</td><td>Proficient</td><td>1,14</td><td>favorable</td></tr><tr><td>17</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>1</td><td>Proficient</td><td>0,858</td><td>unfavorable</td></tr><tr><td>18</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>1</td><td>Proficient</td><td>0,491</td><td>unfavorable</td></tr><tr><td>19</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>1</td><td>Proficient</td><td>0,403</td><td>unfavorable</td></tr><tr><td>20</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>1</td><td>Proficient</td><td>0,515</td><td>unfavorable</td></tr><tr><td>21</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>1</td><td>Proficient</td><td>1,04</td><td>favorable</td></tr><tr><td>22</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>1</td><td>Proficient</td><td>0,41</td><td>unfavorable</td></tr><tr><td>23</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>1</td><td>Proficient</td><td>0,406</td><td>unfavorable</td></tr><tr><td>24</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>1</td><td>Proficient</td><td>0,534</td><td>unfavorable</td></tr><tr><td>25</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>1</td><td>Proficient</td><td>1,2</td><td>favorable</td></tr><tr><td>26</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>1</td><td>Proficient</td><td>0,507</td><td>unfavorable</td></tr><tr><td>27</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>1</td><td>Proficient</td><td>1,24</td><td>favorable</td></tr><tr><td>28</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>1</td><td>Proficient</td><td>0,363</td><td>unfavorable</td></tr><tr><td>29</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>1</td><td>Proficient</td><td>0,742</td><td>unfavorable</td></tr><tr><td>30</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>1</td><td>Proficient</td><td>0,418</td><td>unfavorable</td></tr><tr><td>31</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>1</td><td>Proficient</td><td>0,645</td><td>unfavorable</td></tr><tr><td>32</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>2</td><td>Proficient</td><td>1,27</td><td>favorable</td></tr><tr><td>33</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>2</td><td>Proficient</td><td>2,34</td><td>favorable</td></tr><tr><td>34</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>2</td><td>Proficient</td><td>0,951</td><td>unfavorable</td></tr><tr><td>35</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>2</td><td>Proficient</td><td>2,05</td><td>favorable</td></tr><tr><td>36</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>2</td><td>Proficient</td><td>0,712</td><td>unfavorable</td></tr><tr><td>37</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>2</td><td>Proficient</td><td>2,15</td><td>favorable</td></tr><tr><td>38</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>2</td><td>Proficient</td><td>0,657</td><td>unfavorable</td></tr><tr><td>39</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>2</td><td>Proficient</td><td>0,633</td><td>favorable</td></tr><tr><td>40</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>2</td><td>Proficient</td><td>1,17</td><td>favorable</td></tr><tr><td>41</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>2</td><td>Proficient</td><td>0,391</td><td>unfavorable</td></tr><tr><td>42</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>2</td><td>Proficient</td><td>0,718</td><td>unfavorable</td></tr></tbody></table>
<table><tr><td>43</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>2</td><td>Proficient</td><td>0,585</td><td>unfavorable</td></tr><tr><td>44</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>2</td><td>Proficient</td><td>1,69</td><td>favorable</td></tr><tr><td>45</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>2</td><td>Proficient</td><td>1,13</td><td>favorable</td></tr><tr><td>46</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>2</td><td>Proficient</td><td>1,78</td><td>favorable</td></tr><tr><td>47</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>3</td><td>Proficient</td><td>1,23</td><td>favorable</td></tr><tr><td>48</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>3</td><td>Proficient</td><td>1,61</td><td>favorable</td></tr><tr><td>49</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>3</td><td>Proficient</td><td>1,4</td><td>favorable</td></tr><tr><td>50</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>3</td><td>Proficient</td><td>1,10</td><td>favorable</td></tr><tr><td>51</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>3</td><td>Proficient</td><td>2,02</td><td>favorable</td></tr><tr><td>52</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>3</td><td>Proficient</td><td>0,405</td><td>unfavorable</td></tr><tr><td>53</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>3</td><td>Proficient</td><td>1,2</td><td>favorable</td></tr><tr><td>54</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>3</td><td>Proficient</td><td>1,01</td><td>favorable</td></tr><tr><td>55</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>3</td><td>Proficient</td><td>1,21</td><td>favorable</td></tr><tr><td>56</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>3</td><td>Proficient</td><td>1,86</td><td>favorable</td></tr><tr><td>57</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>3</td><td>Proficient</td><td>0,551</td><td>unfavorable</td></tr><tr><td>58</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>3</td><td>Proficient</td><td>0,708</td><td>unfavorable</td></tr><tr><td>59</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>3</td><td>Proficient</td><td>0,339</td><td>unfavorable</td></tr><tr><td>60</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>3</td><td>Proficient</td><td>0,369</td><td>unfavorable</td></tr><tr><td>61</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>3</td><td>Proficient</td><td>0,376</td><td>unfavorable</td></tr><tr><td>62</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>3</td><td>Proficient</td><td>1,05</td><td>favorable</td></tr><tr><td>63</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>3</td><td>Proficient</td><td>0,458</td><td>unfavorable</td></tr><tr><td>64</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>3</td><td>Proficient</td><td>0,370</td><td>unfavorable</td></tr><tr><td>65</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>3</td><td>Proficient</td><td>0,497</td><td>unfavorable</td></tr><tr><td>66</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>3</td><td>Proficient</td><td>1,08</td><td>favorable</td></tr><tr><td>67</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>3</td><td>Proficient</td><td>0,476</td><td>unfavorable</td></tr><tr><td>68</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>3</td><td>Proficient</td><td>0,923</td><td>unfavorable</td></tr><tr><td>69</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>3</td><td>Proficient</td><td>0,646</td><td>unfavorable</td></tr><tr><td>70</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>3</td><td>Proficient</td><td>0,411</td><td>unfavorable</td></tr><tr><td>71</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>3</td><td>Proficient</td><td>0,535</td><td>unfavorable</td></tr><tr><td>72</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>3</td><td>Proficient</td><td>1,2</td><td>favorable</td></tr><tr><td>73</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>3</td><td>Proficient</td><td>0,659</td><td>unfavorable</td></tr><tr><td>74</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>3</td><td>Proficient</td><td>0,384</td><td>unfavorable</td></tr><tr><td>75</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>4</td><td>Proficient</td><td>0,345</td><td>unfavorable</td></tr><tr><td>76</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>4</td><td>Proficient</td><td>1,87</td><td>favorable</td></tr><tr><td>77</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>4</td><td>Proficient</td><td>0,776</td><td>unfavorable</td></tr><tr><td>78</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>4</td><td>Proficient</td><td>0,72</td><td>unfavorable</td></tr><tr><td>79</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>4</td><td>Proficient</td><td>0,837</td><td>unfavorable</td></tr><tr><td>80</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>4</td><td>Proficient</td><td>1,55</td><td>favorable</td></tr><tr><td>81</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>4</td><td>Proficient</td><td>0,948</td><td>unfavorable</td></tr><tr><td>82</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>4</td><td>Proficient</td><td>1,3</td><td>favorable</td></tr><tr><td>83</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>4</td><td>Proficient</td><td>0,643</td><td>unfavorable</td></tr><tr><td>84</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>4</td><td>Proficient</td><td>0,596</td><td>unfavorable</td></tr><tr><td>85</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>4</td><td>Proficient</td><td>0,493</td><td>unfavorable</td></tr><tr><td>86</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>4</td><td>Proficient</td><td>0,464</td><td>unfavorable</td></tr><tr><td>87</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>4</td><td>Proficient</td><td>0,609</td><td>unfavorable</td></tr><tr><td>88</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>4</td><td>Proficient</td><td>0,512</td><td>unfavorable</td></tr></table>
<table><tr><td>89</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>4</td><td>Proficient</td><td>2,28</td><td>favorable</td></tr><tr><td>90</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>4</td><td>Proficient</td><td>0,999</td><td>unfavorable</td></tr><tr><td>91</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>4</td><td>Proficient</td><td>1,08</td><td>favorable</td></tr><tr><td>92</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>4</td><td>Proficient</td><td>1,18</td><td>favorable</td></tr><tr><td>93</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>4</td><td>Proficient</td><td>1,98</td><td>favorable</td></tr><tr><td>94</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>4</td><td>Proficient</td><td>1,33</td><td>favorable</td></tr><tr><td>95</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>4</td><td>Proficient</td><td>1,45</td><td>favorable</td></tr><tr><td>96</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>4</td><td>Proficient</td><td>0,619</td><td>unfavorable</td></tr><tr><td>97</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>4</td><td>Proficient</td><td>1,22</td><td>favorable</td></tr><tr><td>98</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>4</td><td>Proficient</td><td>0,78</td><td>unfavorable</td></tr><tr><td>99</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>4</td><td>Proficient</td><td>0,277</td><td>unfavorable</td></tr><tr><td>100</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>4</td><td>Proficient</td><td>0,537</td><td>unfavorable</td></tr><tr><td>101</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>4</td><td>Proficient</td><td>0,489</td><td>unfavorable</td></tr><tr><td>102</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>4</td><td>Proficient</td><td>0,551</td><td>unfavorable</td></tr><tr><td>103</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>1</td><td>Deficient</td><td>1,1</td><td>favorable</td></tr><tr><td>104</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>1</td><td>Deficient</td><td>1,32</td><td>favorable</td></tr><tr><td>105</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>1</td><td>Deficient</td><td>0,727</td><td>unfavorable</td></tr><tr><td>106</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>1</td><td>Deficient</td><td>0,55</td><td>unfavorable</td></tr><tr><td>107</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>1</td><td>Deficient</td><td>1,15</td><td>favorable</td></tr><tr><td>108</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>1</td><td>Deficient</td><td>1,23</td><td>favorable</td></tr><tr><td>109</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>1</td><td>Deficient</td><td>1,03</td><td>favorable</td></tr><tr><td>110</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>1</td><td>Deficient</td><td>1,06</td><td>favorable</td></tr><tr><td>111</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>1</td><td>Deficient</td><td>1,22</td><td>favorable</td></tr><tr><td>112</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>1</td><td>Deficient</td><td>0,6</td><td>unfavorable</td></tr><tr><td>113</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>2</td><td>Deficient</td><td>1,57</td><td>favorable</td></tr><tr><td>114</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>2</td><td>Deficient</td><td>0,384</td><td>unfavorable</td></tr><tr><td>115</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>2</td><td>Deficient</td><td>1,17</td><td>favorable</td></tr><tr><td>116</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>2</td><td>Deficient</td><td>0,816</td><td>unfavorable</td></tr><tr><td>117</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>2</td><td>Deficient</td><td>1,01</td><td>favorable</td></tr><tr><td>118</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>2</td><td>Deficient</td><td>1,89</td><td>favorable</td></tr><tr><td>119</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>2</td><td>Deficient</td><td>0,812</td><td>unfavorable</td></tr><tr><td>120</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>2</td><td>Deficient</td><td>1,04</td><td>favorable</td></tr><tr><td>121</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>2</td><td>Deficient</td><td>0,694</td><td>unfavorable</td></tr><tr><td>122</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>2</td><td>Deficient</td><td>1,13</td><td>favorable</td></tr><tr><td>123</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>2</td><td>Deficient</td><td>1,81</td><td>favorable</td></tr><tr><td>124</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>3</td><td>Deficient</td><td>0,669</td><td>unfavorable</td></tr><tr><td>125</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>3</td><td>Deficient</td><td>0,429</td><td>unfavorable</td></tr><tr><td>126</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>3</td><td>Deficient</td><td>1,15</td><td>favorable</td></tr><tr><td>127</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>3</td><td>Deficient</td><td>0,796</td><td>unfavorable</td></tr><tr><td>128</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>3</td><td>Deficient</td><td>1,21</td><td>favorable</td></tr><tr><td>129</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>3</td><td>Deficient</td><td>1,06</td><td>favorable</td></tr><tr><td>130</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>4</td><td>Deficient</td><td>0,91</td><td>unfavorable</td></tr><tr><td>131</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>4</td><td>Deficient</td><td>1,16</td><td>favorable</td></tr><tr><td>132</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>4</td><td>Deficient</td><td>0,933</td><td>unfavorable</td></tr><tr><td>133</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>4</td><td>Deficient</td><td>1,31</td><td>favorable</td></tr><tr><td>134</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>4</td><td>Deficient</td><td>1,81</td><td>favorable</td></tr></table>
<table><tr><td>135</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>4</td><td>Deficient</td><td>1,06</td><td>favorable</td></tr><tr><td>136</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>4</td><td>Deficient</td><td>1,97</td><td>favorable</td></tr><tr><td>137</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>4</td><td>Deficient</td><td>1,71</td><td>favorable</td></tr><tr><td>138</td><td>III/IV</td><td>Neoadjuvant</td><td>WT</td><td>4</td><td>Deficient</td><td>0,461</td><td>unfavorable</td></tr></table>

*Center : 1 = Institut Curie ; 2 = Center Leon Berard (Lyon) ; 3 = IUCT Oncopole (Toulouse) ; 4 = Hospital Lyon Sud HCL
WT = Wild-type