Grégory Ballas
email: gregory.ballas@umontpellier.fr

Flavia Girard

Yannick Caniven

Roger Soliva

Bernard Célérier

Romain Hemelsdaël

Sylvain Mayolle

Aurélien Gay

Michel Séranne

Hybrid compactive faults formed during burial in micritic limestone (Montpellier area, France)

Keywords: compactive faults, shear localization, pressure-solution, crystallographic preferred orientation, micritic limestone

Introduction

In micritic carbonate rocks, it is generally considered that fault initiate by a combination of various deformation structures such as veins, shearing planes, and/or compactive pressuresolution seams [START_REF] Peacock | Pull-aparts, shear fractures and pressure solution[END_REF][START_REF] Willemse | Nucleation and growth of strike-slip faults in limestones from Somerset, U.K[END_REF][START_REF] Mazzoli | Critical displacement for normal fault nucleation from en-échelon vein arrays in limestones: a case study from the southern Apennines (Italy)[END_REF][START_REF] Crider | Initiation of brittle faults in the upper crust: a review of field observations[END_REF][START_REF] Micarelli | Normal fault terminations in limestones from the SE-Basin (France): implications for fluid flow[END_REF]Delle Piane et al., 2017 and references therein). Faults mainly grow by propagation and segment linkage [START_REF] Kelly | Linkage and evolution of conjugate strike-slip fault zones in limestones of Somerset and Northumbria[END_REF][START_REF] Ferrill | Dilational normal faults[END_REF][START_REF] Soliva | A linkage criterion for segmented normal faults[END_REF][START_REF] Agosta | Inner structure and deformation mechanisms of normal faults in conglomerates and carbonate grainstones (Granada Basin, Betic Cordillera, Spain): Inferences on fault permeability. Fault Zone Structure[END_REF][START_REF] Roche | Architecture and growth of normal fault zones in multilayer systems: A 3D field analysis in the South-Eastern Basin, France[END_REF][START_REF] Ferrill | Fault zone processes in mechanically layered mudrock and chalk[END_REF]Mayolle et al., 2019 among others). Because fine-grained carbonates are generally of low-porosity, fracturing and brecciation are dominant in fault zones, expressing dilation and shear behaviour [START_REF] Micarelli | Structural evolution and permeability of normal fault zones in highly porous carbonate rocks[END_REF][START_REF] Bussolotto | Fault deformation mechanisms and fault rocks in micritic limestones: Examples from Corinth rift normal faults[END_REF][START_REF] Balsamo | Anatomy and paleofluid evolution of laterally restricted extensional fault zones in the Jabal Qusaybah anticline, Salakh arch, Oman[END_REF]. This deformation can progressively evolve into cataclastic processes within the main deformation area called the "fault core" [START_REF] Billi | Grain size distribution and thickness of breccia and gouge zones from thin (<1m) strike-slip fault cores in limestone[END_REF][START_REF] Hausegger | Analysis of the internal structure of a carbonate damage zone: Implications for the mechanisms of fault breccia formation and fluid flow. Faulting and Fracturing of Carbonate Rocks: New Insights into Deformation Mechanisms[END_REF][START_REF] Schröckenfuchs | Rock pulverization and localization of a strike-slip fault zone in dolomite rocks (Salzach-Ennstal-Mariazell-Puchberg fault, Austria)[END_REF][START_REF] Ferraro | Space-time evolution of cataclasis in carbonate fault zones[END_REF]. It can be accompanied by other various processes generally related to seismic events, i.e. clast-cortex grains, calcite crystallographic preferred orientation (CPO), or fluidized layers [START_REF] Delle Piane | Carbonate hosted fault rocks: A review of structural and microstructural characteristic with implications for seismicity in the upper crust[END_REF][START_REF] Demurtas | Development of crystallographic preferred orientation during cataclasis in low-temperature carbonate fault gouge[END_REF]. In such model, compactional processes are generally restricted to specific areas, such as fault dip changes [START_REF] Ferrill | Fault failure modes, deformation mechanisms, dilation tendency, slip tendency, and conduits v. seals[END_REF] or fault tips [START_REF] Rispoli | Stress fields about strike-slip faults inferred from stylolites and tension gashes[END_REF][START_REF] Petit | Palaeostress superimposition deduced from mesoscale structures in limestone: the Matelles exposure, Languedoc, France[END_REF][START_REF] Agosta | Oblique normal faulting along the northern edge of the Majella Anticline, central Italy: Inferences on hydrocarbon migration and accumulation. Faulting and Fracturing of Carbonate Rocks: New Insights into Deformation Mechanisms[END_REF]. Compaction by pervasive pressure-solution can also occur within the cataclastic zone, showing scaly foliation [START_REF] Bullock | Lithological controls on the deformation mechanisms operating within carbonate-hosted faults during the seismic cycle[END_REF][START_REF] Clemenzi | Extensional deformation structures within a convergent orogen: The Val di Lima low-angle normal fault system (Northern Apennines, Italy)[END_REF]. However, fault initiation by compaction processes (mainly pressure-solution pressure-solution but also disaggregation and cataclasis) remains unclear, especially in micritic carbonates [START_REF] Billi | Solution slip and separations on strike-slip fault zones: theory and application to the Mattinata Fault, Italy[END_REF][START_REF] Graham | Formation and growth of normal faults in carbonates within a compressive environment[END_REF][START_REF] Agosta | Architecture and deformation mechanism of a basin-bounding normal fault in Mesozoic platform carbonates, central Italy[END_REF].

Conversely, fault initiation by shear and compaction failures is well known in porous and granular rocks such as sandstones [START_REF] Antonellini | Effect of Faulting on Fluid Flow in Porous Sandstones: Petrophysical Properties1[END_REF][START_REF] Ballas | Control of tectonic setting and large-scale faults on the basin-scale distribution of deformation bands in porous sandstone (Provence, France)[END_REF]Fossen et al., 2018), grainstones [START_REF] Tondi | The role of deformation bands, stylolites and sheared stylolites in fault development in carbonate grainstones of Majella Mountain, Italy[END_REF][START_REF] Cilona | Deformation bands in porous carbonate grainstones: Field and laboratory observations[END_REF][START_REF] Antonellini | First reported occurrence of deformation bands in a platform limestone, the Jurassic Calcare Massiccio Fm., northern Apennines, Italy[END_REF][START_REF] Rotevatn | Sequential growth of deformation bands in carbonate grainstones in the hangingwall of an active growth fault: Implications for deformation mechanisms in different tectonic regimes[END_REF] or chalks [START_REF] Wennberg | Deformation bands in chalk, examples from the Shetland Group of the Oseberg Field, North Sea, Norway[END_REF][START_REF] Kaminskaite | Microstructure and petrophysical properties of deformation bands in high porosity carbonates[END_REF]. In such lithologies, faults initiate by deformation bands showing different micro-mechanisms [START_REF] Fisher | The permeability of faults within siliciclastic petroleum reservoirs of the North Sea and Norwegian Continental Shelf[END_REF][START_REF] Aydin | Failure modes of the lineaments on Jupiter's moon, Europa: Implications for the evolution of its icy crust[END_REF]Fossen et al., 2007) and various ratios of shear to compaction; i.e. pure compaction bands [START_REF] Mollema | Compaction bands: a structural analog for anti-mode I cracks in aeolian sandstone[END_REF][START_REF] Agosta | Oblique normal faulting along the northern edge of the Majella Anticline, central Italy: Inferences on hydrocarbon migration and accumulation. Faulting and Fracturing of Carbonate Rocks: New Insights into Deformation Mechanisms[END_REF][START_REF] Rotevatn | Sequential growth of deformation bands in carbonate grainstones in the hangingwall of an active growth fault: Implications for deformation mechanisms in different tectonic regimes[END_REF], shearenhanced compaction bands [START_REF] Eichhubl | Pure and shear-enhanced compaction bands in Aztec Sandstone[END_REF][START_REF] Ballas | Shear-enhanced compaction bands formed at shallow burial conditions; implications for fluid flow (Provence, France)[END_REF][START_REF] Fossen | Contractional deformation of porous sandstone: Insights from the Aztec Sandstone, SE Nevada, USA[END_REF], compactive-shear bands [START_REF] Saillet | Permeability and flow impact of faults and deformation bands in highporosity sand reservoirs: Southeast Basin, France, analog[END_REF], and shear bands [START_REF] Rotevatn | Slipped deformation bands: A new type of cataclastic deformation bands in Western Sinai, Suez rift, Egypt[END_REF].

Cataclastic processes are dominant and the related grain crushing induces pore collapse and porosity reduction [START_REF] Antonellini | Effect of Faulting on Fluid Flow in Porous Sandstones: Geometry and Spatial Distribution1[END_REF][START_REF] Fossen | Deformation bands and their influence on fluid flow[END_REF][START_REF] Ballas | Factors controlling permeability of cataclastic deformation bands and faults in porous sandstone reservoirs[END_REF] leading to material hardening and shear localization [START_REF] Aydin | Development of faults as zones of deformation bands and as slip surfaces in sandstone[END_REF][START_REF] Schultz | Displacement-length scaling in three dimensions: the importance of aspect ratio and application to deformation bands[END_REF][START_REF] Shipton | A conceptual model for the origin of fault damage zone structures in high-porosity sandstone[END_REF][START_REF] Philit | Clusters of cataclastic deformation bands in porous sandstones[END_REF]. Other micro-mechanisms; such as disaggregation (grain rotation, torsion or displacement), or pressure-solution-recrystallization; are described in deformation bands and faults [START_REF] Cilona | Deformation bands in porous carbonate grainstones: Field and laboratory observations[END_REF][START_REF] Ballas | Shear-enhanced compaction bands formed at shallow burial conditions; implications for fluid flow (Provence, France)[END_REF][START_REF] Philit | Relations between shallow cataclastic faulting and cementation in porous sandstones: First insight from a groundwater environmental context[END_REF]Tavani et al., 2018a;Kaminskaite et al., 2019 among others). However, these processes remain difficult to integrate in mechanical model such as the one developed for cataclastic structures [START_REF] Saillet | Evolution of cataclastic faulting in high-porosity sandstone, Bassin du Sud-Est, Provence, France[END_REF][START_REF] Soliva | A model of strain localization in porous sandstone as a function of tectonic setting, burial and material properties; new insight from Provence (southern France)[END_REF][START_REF] Soliva | Tectonic regime controls clustering of deformation bands in porous sandstone[END_REF][START_REF] Robert | Deformation bands, early markers of tectonic activity in front of a fold-and-thrust belt: Example from the Tremp-Graus basin, southern Pyrenees, Spain[END_REF]Fossen et al., 2018) because of the lack of combined descriptive-mechanical approach on such deformation features.

Mechanical concepts suggest a potential formation of compactive-shear structures under progressive burial, i.e. out of regional tectonic influence [START_REF] Soliva | A model of strain localization in porous sandstone as a function of tectonic setting, burial and material properties; new insight from Provence (southern France)[END_REF]. However, only few natural examples propose compactive shear localization under gravitational loading [START_REF] Guiraud | Soft-sediment microfaulting related to compaction within the fluviodeltaic infill of the Soria strike-slip basin (northern Spain)[END_REF][START_REF] Wennberg | Deformation bands in chalk, examples from the Shetland Group of the Oseberg Field, North Sea, Norway[END_REF], whereas almost all described compactive-shear structures are related to tectonic stresses. During progressive burial, compaction follows general porosity reduction curves [START_REF] Ehrenberg | Sandstone vs. carbonate petroleum reservoirs: A global perspective on porosity-depth and porosity-permeability relationships[END_REF] but can also localize bed parallel structures, such as compaction bands [START_REF] Aydin | Bed-parallel compaction bands in aeolian sandstone: Their identification, characterization and implications[END_REF][START_REF] Rustichelli | Development and distribution of bedparallel compaction bands and pressure solution seams in carbonates (Bolognano Formation, Majella Mountain, Italy)[END_REF] or stylolites (Laronne [START_REF] Ben-Itzhak | Sedimentary stylolite networks and connectivity in limestone: Large-scale field observations and implications for structure evolution[END_REF]. The part of these localization structures within the whole compaction of sediment remains unclear. A better understanding of compactive-shear structures initiation appears necessary, especially within fine-grained materials and under burial "gravitational" loading.

In such context, we investigate a network of meter-scale compactive-shear structures exposed within micritic continental limestone in the Aumelas -Hérault basin in the South of France (Montpellier area). Detailed fieldwork, natural light, SEM and EBSD (scanning electron microscopy, electron backscatter diffraction) microstructural investigations, and kinematic inversion method have been used to describe the fault systems and discuss the mechanisms and triggers. Theoretical mechanical models are used to discuss the origin of such structures.

Methods

Field observations and measurements

Sedimentological log of the main studied section was done to identify the relationship between the occurrence of fault and bed characteristics. Beds are analyzed following the Dunham classification (M: Mudstone, W: Wackstone, P: Packestone, G: Grainstone, B: Boundstone + C to identify clays). Evidences of subaerial alterations (desiccation, karstification, brecciation) observed on bed surfaces and the beds affected by fault sets (i.e. the location of fault networks in the sedimentary succession) are also reported.

The geometry of the fault network is analyzed from stereographic data collected using compass and digit tablet (FieldMOVE software). These data are reported on stereoplots and histograms of dip and rake, i.e. the angle between the slickenline and the strike direction of individual fault planes. The data are presented after restoring the bedding to horizontal.

Microstructure and rock properties

Nine polished thin-sections were cut from blocks sampled below fault slickensides previously impregnated by epoxy resin. These thin-sections were cut in the dip-slip direction of faults (6 thin-sections) or the strike direction of faults (3 thin-sections) to analyze fault micro-mechanisms and kinematic criteria (evidence and sense of shear). They were analyzed by backscattered electron imagery using a FEI Quanta 200 environmental scanning-electron microscope (SEM).

Mosaics of SEM backscattered electron images, with a gray-scale intensity range from 0 to 255, were obtained and used to observe deformation features and to estimate the porosity of the deformed zones and the host rocks (2D porosity obtained from black areas on SEM images).

Several SEM images were also acquired on 3D blocks to observe grains and slickensides micromorphology. Analyses with optical microscope in natural or cross-polarized light, and cathodoluminescence mode were also used to identify potentially different cement phases.

Electron BackScatter Diffraction (EBSD) analyses were done in the host rocks and along the fault zones, including steps and fault core. This analysis edits a map of the particles form their crystallographic assemblage and allows analyzing their size, shape and crystallographic orientation. Data were collected with the scanning electron microscope CamScan Crystal Probe X500FE and were processed using AZtecHKL software (Oxford Instruments). The acquisition was done with a 0.3-0.4 µm step size at a working distance of 25 mm. Grains were reconstructed from orientation data and their boundaries were defined as having a misorientation angle between neighboring pixels of > 5°. The grain slope (i.e. the angle of the grain longer axis with respect to vertical) was measured on grains showing surface area larger than 5 µm in order to avoid artefact due to the image resolution. These data are represented on rose diagram. Crystallographic orientations are represented on stereographic diagram (equal area, lower hemisphere) and the multiple of the uniform distribution (m.u.d. value) is used to estimate the crystallographic preferred orientation of grains (CPO). Calcite twinning is automatically mapped using the AZtecHKL software.

Fault slip and stress analysis

The state of stress during fault slip is obtained by inversion of the fault and slickenline data [START_REF] Angelier | Tectonic analysis of fault slip data sets[END_REF] with the FSA software that was developed to analyse various aspects of the relationship between fault slips and stresses [START_REF] Tajima | Possible focal mechanism change during reactivation of a previously ruptured subduction zone and stress tensor implications[END_REF][START_REF] Burg | Fault analysis and paleostress evolution in large strain regions: methodological and geological discussion of the southeastern Himalayan fold-and-thrust belt in Pakistan[END_REF][START_REF] Célérier | FSA: Fault & Stress Analysis software[END_REF]. The inversion seeks the stress tensor that best align shear stress with observed slickenlines [START_REF] Wallace | Geometry of Shearing Stress and Relation to Faulting[END_REF][START_REF] Bott | The Mechanics of Oblique Slip Faulting[END_REF] and uses the random search proposed by [START_REF] Etchecopar | An inverse problem in microtectonics for the determination of stress tensors from fault striation analysis[END_REF]. This method allows to invert either the whole dataset in the case of monophase data or only a fraction of the dataset in the case of polyphase data. It yields the principal stress orientations s1, s2, s3, and stress tensor aspect ratio r0 = (σ1-σ2) / (σ1-σ3), where σ1 ≥ σ2 ≥ σ3 are the principal stress magnitudes corresponding to the orientations s1, s2, s3. We use the quality criterion proposed by [START_REF] Heuberger | Paleostress regimes from brittle structures of the Karakoram-Kohistan Suture Zone and surrounding areas of NW Pakistan[END_REF] to distinguish robust solutions from statistical artifacts. It is based on a comparison between the total number of data (Ntotal), the number of data with a rake misfit lower than 15° (Nexp15), and the number of data (N0exp15) that could be obtained below the same misfit by inverting a random dataset of the same size Ntotal. The result of this comparison is summarized by an integer quality index, InvQual, which varies from -1 for barely acceptable solutions to 2 for robust estimates.

Geological Setting

Regional tectonic framework

The Aumelas -Hérault basin is located 20 km to the west of Montpellier city in the South of France (Fig. 1a). This basin form a part of the continental foreland basin developed at the front of the Montpellier thrust (also called North Pyrenean Frontal Thrust) [START_REF] Arthaud | Les structures pyrénéennes du Languedoc et du Golfe du Lion (Sud de la France)[END_REF]. This thrust is related to the Pyrenean orogeny occurring in this area during two main shortening events, during Early Paleocene and Late Eocene. A relatively quiescent phase of tectonic activity occurred during Lower Eocene [START_REF] Debrand-Passard | Synthèse géologique du Sud-Est de la France[END_REF] when carbonate lacustrinepalustrine sequence were deposits [START_REF] Bonnet | Notice de la carte géologique à 1/50 000, feuille Montpellier[END_REF]. However, the accommodation of a 300-500 m thick sedimentary sequence showing locally growth strata (synsedimentary folding) in lacustrine deposits, indicates that some moderate tectonic activity remained during this period.

The studied outcrops are located along the A750 highway, at the "La Taillade" site (Lat. 43°37'36N; Long. 3°35'54"E, Fig. 1a). This area is located in front of the WNW-ESE St Bauzille Thrust (reactivated Mesozoic normal-fault) and close to the change from NE-SW to EW trend of the main Montpellier Thrust. Lacustrine-palustrine limestones were mainly folded and faulted during Late Eocene second shortening phase of the Pyrenean orogeny (Fig. 1b). These strata are now tilted 15-30° to the S and SW (up to 65° in the central part of the section, Fig. 2a), according to their location in the fore-bulge of the Pyrenean thrusts and to the tilting of the NE-trending Hérault half-graben during Oligocene rifting [START_REF] Maerten | Extensional tectonics of the Oligo-Miocene Herault Basin (S. France), Gulf of Lion margin[END_REF]. We note that the maximum burial reached by the studied section is difficult to evaluate due to an uplift (>100 m) and erosion during late Miocene [START_REF] Séranne | Polyphased uplift and erosion of the Cévennes (southern France). An example of slow morphogenesis[END_REF]. However, we consider a maximum burial in an order of magnitude of 100 m since Oligocene sediments are not deposited above the study site (only formed in half-grabens) and the studied limestone section corresponds to the upper part of the Eocene sequence.

Host rock characteristics

The main outcrop lies at the top of the 300 m thick "Lutetian" limestones strata related to a lacustrine-palustrine system [START_REF] Hartenberger | Les gisements de vertébrés de la région montpelliéraine. 1.-Gisements éocènes[END_REF] (Fig. 2). The studied section is limestone dominated and shows a succession of mostly 25-50 cm thick, stacked, tabular carbonate beds (Figs. 2 b,c). The beds are mainly composed of a massive white mudstone including whole or fragments of fossils of continental gastropods (limnea and planorbis) and ostracods bioclasts. We note the presence of a 7 m thick wackestone to packstone interval (particle sizes well above 30 microns meters and often rather millimeters to centimeters). In some places, the mudstone beds are intercalated with few centimeters thick brownish silty marls (Fig. 2d). Such silty marls can also reached 1 m thick at the base of the studied section. The top of the section ends with a 3 m thick marly interval including sandy-carbonate beds. The complete sedimentary succession does not display any particular depositional architecture nor sedimentary structures. The main study section is located down West of the 3 km long exposure along the highway, where the carbonate beds only dip of 25-35° which permits to make measurements (Fig. 2a). A second section is located to the East, at the close vicinity of the Montpellier thrust and the Oligocene La Boissière normal fault (Fig. 2a). This second outcrop of "Lutetian" limestone strata is separated by mapscale strike-slip sinistral faults and cannot be precisely correlated to the whole outcrop as no benchmark beds is observed from both sections.

In thin section, the matrix of mudstones is composed of an unclear micrite sometimes including initially mud-size crushed bioclastic debris and peloids. The SEM image from 3D samples show micritic euhedral crystals of calcite less than 5 µm in size and few crystals of dolomite (less than 5%) (Fig. 3a). The present-day porosity of the studied mudstones, measured in laboratory on 11 mini cores using the triple weighting method, ranges from 4.4% to 22.3%. These mudstones are therefore qualified as fine-grained and porous carbonate rocks. The dark and homogeneous images from cathodoluminescence microscopy analysis reveal no difference between calcite grains and interstitial cements. We note that the imbricated contacts between calcite particles are observed at microscale disseminated in the material (Fig. 3b). The bed surfaces are affected by pedogenic modifications (i.e. desiccation cracks, micro-karstification, brecciation, iron oxide deposits…) related to shallow palustrine environments (wetlands), and therefore to common exposition to drying conditions and evaporative/groundwater recharge phases [START_REF] Freytet | Continental carbonate sedimentation and pedogenesis-Late Cretaceous and Early Tertiary of southern France[END_REF][START_REF] Alonso-Zarza | Chapter 2 Palustrine Carbonates[END_REF]. The mudstone beds of the second (eastern) outcrop show less evidences of emersion and contain several brecciated beds with higher quartz grains fraction. These specificities suggest a formation of this sedimentary section in a lacustrine domain rather than palustrine environment, or at least a deeper water "lake" setting that records less the evaporative phases compared to the wetland environment of carbonate section of the western outcrop.

Description of faults

Different fault sets are observed along the study outcrop. We focus on meter-scale faults showing specific slickensides (see description section 4.2.) whereas Late Pyrenean or Oligocene fault networks (i.e. faults of several meters to tens meters length, cutting across the whole observable limestone section, with a brecciated fault core, a damage zone with mode I joint systems and calcite fiber along their surface) are not considered in the present study. Studied faults are organized in two different sets: a set of dip-slip normal faults at low-angle with respect to bedding, and a set of strike-slip faults at high-angle to bedding.

Location of faults within the limestone succession

Faults are heterogeneously distributed in the limestone succession. They affect almost all beds within the first 30 m and the last third of the mudstone sequence from 82 to 88 m (Fig. 4). They are mainly absent from 55 m to 75 m, especially in the wackestone-packstone interval. These faults are also observed restricted to specific mudstone beds that are intercalated within beds unaffected by faults from 30 to 55 m and from 75 to 82 m. The faults are only observed in limestone beds thicker than 20 cm (mainly absent in thinner ones). They can be observed whatever the secondary alteration occurring in affected limestone beds during syn-sedimentary subaerial exposure (desiccation, oxidation…) (Fig. 4). However, we note that faults are more abundant in limestone beds showing few secondary alteration (for example the 2 m to 17 m section) whereas they are mainly absent in highly altered limestone beds (for example the 55 m to 75 m section).

Specificity of fault slickensides

The studied faults differ from other fault systems affecting the limestone sections in the area by their morphology and slickenside characteristics (Fig. 5). At the first order, these faults are characterized by the lack of a macroscopic fault core (i.e. fault rock visible at the naked eyes) and the lack of calcite or iron oxide precipitation along their slickensides (Fig. 5a). The slickensides show grooves as frequent as ridges along the fault planes. These grooves and ridges features are of several centimeters length and show U-shape with flat bottom (or flat top) and larger wave length than amplitude (Figs. 5b,c). These grooves are observed at two imbricated scales of width: 1 cm and 100s µm (Figs. 5b,e). The ridges of one wall of the fault plane perfectly fit into the grooves of the other wall, i.e. no fracture porosity or cementation is observed along the fault surface. These grooves show no specific asperity at the lower tip whereas two different morphologies are observed at the upper tip of the groove: (1) V "crescentic" markings and (2) step markings formed by sharp mm to cm-high plane, at high angle to the slickenside (following the classification of Doblas, 1998) (Figs. 5b, c, d andf). These step markings are irregular planes of centimeter to several centimeters length (Fig. 5d). They are uncommonly related to joint below the fault plane but are more generally observed without associated deformation structures. No stylolitic teeth are observed on these step markings.

Normal fault system

The low-angle to bedding faults are generally composed of meter-scale length structures (Fig. 6a). These faults are mainly restricted within single carbonate beds, and rarely affecting 2 or 3 beds. They show a sigmoidal shape (or flat S-shape) in cross-section with a maximum dip in the central part of the beds, progressively decreasing at the top and base of the beds (listric to bed interface) (Figs. 6b,c). Laterally, they form curved and irregular bended surfaces and show connections with surrounding faults. The steps at the upper tip of the grooves along the slickensides suggest a normal-sense kinematic [START_REF] Petit | Morphology and microstructures of hydroplastic slickensides in sandstone[END_REF]) (Fig. 5), but no offset markers or tip folding are observable. These faults form a conjugate system with opposite dip.

After restoration to horizontal, stereographic plots reveal East-West oriented conjugate fault system, with mainly North-South slickenlines (grooves) (Fig. 7a). Each dipping set is crosscutting the other with a dominant observation of South-dipping set cutting the North-dipping one (Figs. 6d,e). These crosscutting zones uncommonly show millimeter-scale normal-sense shear-displacement but no measurable offset is more generally detected along these faults.

Moreover, numerous abutting contacts are observed between both sets (Fig. 6d,e). Few NW or SW-striking slickenlines are also measured. The dip of the faults, measured systematically in the central part of beds, is on average 25° ± 7°, suggesting a high dihedral angle of about 130° between conjugate fault sets (Fig. 7b). The rake data show purely dip-slip motion (Fig. 7c).

Strike-slip fault system

The high-angle to bedding faults show large grooves and ridges similarly to low-angle normal faults (Figs. 8a,b). These faults generally cross-cut several limestone layers (2 to 5 beds). They show numerous centimeter-scale dilational jogs between meter-scale planar fault segments (Fig. 8c). These dilational jogs observed along the fault revealed a shear-displacement of about 1 cm (Fig. 8d). These faults form then a strike-slip system with a dextral set of strike ranging of strike ranging from N°20E to N°50E and a sinistral set striking from N°150E to N°180E (Fig. 9a). The strike-slip faults form a conjugate system with a general dihedral angle between 120° and 140° (similarly to the normal-sense set). These faults are almost vertical after restoration of bedding to horizontal, on average 79° ± 9°, and show mostly horizontal slickenlines (grooves) with a plunge of 11° ± 13° on average (both North or South) (Fig. 9b) and a rake around the 0° and the 180° values (i.e. horizontal) (Fig. 9c).

The strike-slip fault systems generally cross-cut the normal-sense fault system (Fig. 8a), but, a same surface is sometimes observed as laterally evolving from strike-slip to dip-slip slickensides, with a progressive decrease of dip and showing parallel grooves of similar trend (Figs. 10a,b).

We note that both dip-slip and strike-slip systems are commonly observed together (Fig. 10d).

However, a bed-by-bed analysis of fault system within the first 47 beds of the limestone succession reveals 6 beds where only dip-slip normal faults are observed and 3 beds with only strike-slip faults (Fig. 10c). The fault spacing of only few tens centimeters revealed a pervasive distribution of both sets in bed affected by faulting (Fig. 10d). We note that several examples of strike-slip slickensides are observed along the plane of late strike-slip brittle faults (i.e. faults of tens meters length, with a brecciated fault core and calcite fiber along the fault mirror).

Microstructure of faults

The microstructure of the limestone in the wall along the fault plane changes from areas where the grain framework is similar to the host rock (grain size, shape, composition, porosity) into zones where the microporosity is significantly reduced close to the main fault surface (Fig. 11).

The thickness of this low-porosity zone is variable and can reach in the best-case 0.3 mm below the fault plane. These compacted zones are preferentially observed at fault plane irregularities, i.e. where small dip changes occurs and forms compressive jogs along the slickenside (Figs. 11a,c,d). This specific location of compaction is consistent with the kinematics of the faults deduced form field observations. Smooth pressure-solution seams are observed particularly in these zones as sinuous cleavages following grain contacts (Figs. 11c,d). These cleavages are parallel or slightly oblique to the faults and are sometimes open (probably related to thin-section preparation). Concerning step markings located at the upper tip of the groove, these areas show no evidence of compaction. The presence of dilation joint is sometimes observed (Fig. 11e), but several examples show no deformation feature below the step. A sharp plane penetrating the material is often observed in the continuity of the fault plane and could be interpreted as P plane structure (Fig. 11e). No significant grain orientation is observed in the host material (Fig. 12a).

However, compacted areas show a preferential orientation of grains parallel to the fault plane (Figs. 12b,c).

A low-porosity and compacted zone of few tens of micrometers is observed above the main fault plane (Fig. 11b). In this zone, the particles appear smaller than the ones of host material (Fig. 13a). We note that only few grains with microcracks and no hertzian contacts were identified in these structures. This zone is bordered by the main fault slickenside. Several tens µm long planes are also observed within the comminuted zone (Fig. 11b). This comminution is accompanied by a crystallographic preferred orientation (CPO) of grains as revealed by the dominant reddish color of grains within the compacted fault zone (EBSD acquisition showing colors depending on the crystallographic organization of each grains) (Fig. 13a). This CPO shows a maximum m.u.d. value of 4.85 whereas this value nether exceeds 1.70 in the host rock (Fig. 13b). This CPO is observed in the c-axis of calcite grains and is oriented about 70° to the fault plane. We note that twining process is revealed by µm-thick bands showing a different color than the grain they affect (Fig. 14a). These twins are only observed within the compacted area of the fault core or the compactive jogs (Figs. 14b,c) whereas no twins are observed on step marking at the upper tip of grooves (Fig. 14d). This specific location of calcite twins is consistent with the normal-sense kinematic proposed for the fault system at low-angle dip relative to the bedding.

Fault slip and stress analysis

Strike directions of faults are clustered East-West and rakes have 3 modes: a major mode that is pure normal (rake around -90, Fig. 7c) and two minor modes, around pure sinistral (left lateral) and pure dextral (right lateral) (rake around 0 and 180, Fig. 9c). Inverting the restored dataset and taking into account all of the 264 data yields a solution with only three outliers with a rake misfit larger than 160°. This can be due either to discordant movements or to erroneous slip sense determination. It was thus decided to invert for 99% of the data to disable any influence of the outliers on the result. The resulting solution is at the transition between extensional and wrench regime with s3 horizontal and about N°10E (Fig. 15a). In this solution, s1 is vertical and show a very close value with s2 suggested by the r0 = 0.0. This solution also yields a low average angular error (<10°, computed on 99% of the data), a large number of faults with rake misfit below 15° (Nexp15 = 216), and the highest value InvQual = 2 (Fig. 15b). The normal faults are at high angle (≥ 60°) with s1 because of their low (15-30°) dip with respect to bedding. The strike-slip faults are also at high angle with s2, which plays the same role as s1 when r0 = 0.0. As a consequence both types of fault data are located on the right hand side of Mohr's circle (Fig. 15c). The quality of the solution supports the fact that all faults are dynamically consistent.

Multi-beds normal faults

Several multi-beds normal faults (i.e. non-stratabound faults) are observed at the second studied site, eastward of the main study outcrop (Fig. 2a). Because of the specificity of these structures and their absence in the main 2.5 km long outcrop, we decided to describe them separately.

Slickensides of the multi-beds normal-faults show closely similar morphology than the bedrestricted faults, i.e. grooves and ridges, marking steps, no calcite precipitation, and curved planes (Fig. 16a). The specificity of such slickensides is the presence of visible indentations at lower tip of grooves interpreted as slickolites (i.e. sheared pressure-solution zone, [START_REF] Arthaud | Exemples de stylolites d'origine tectonique dans le Languedoc, leurs relations avec la tectonique cassante[END_REF]) (Fig. 16b). The height of these faults is at least 10 m and their horizontal length is about several tens of meters. They are mainly trending EW and dip exclusively to the South (Fig. 16c).

Their average dip is 23° ± 7° (after bedding restored to horizontal). The fault throw can reach few centimeters (Fig. 16d, see the evidence of footwall bed marks on the fault slickenside). We note evidences of reactivation in reverse-sense motion on one of these faults, i.e. fine and regular striation oblique to the main normal slickenlines, consistently with a reactivation during late Eocene Pyrenean shortening. No multi-bed normal fault dipping to the North was observed at this site. Brittle-like (late) strike-slip structures are observed with brecciated fault core, calcite fiber along the fault plane, and mode I fracture damage zone (joints), but no strike-slip slickensides were clearly identified.

Discussion

Model of fault formation

The low intergranular porosity zones having wavy cleavage observed close to the fault planes (Fig. 11), the comminution, CPO and twinning observed in the fault core, as well as the high dihedral angle between conjugate faults (130° to the shortening axis) reveals that the deformation mechanism is hybrid between compaction and shear, and not controlled by a standard Coulomb type frictional strength law. These characteristics expressing failure on the right hand side of the Mohr's circle (Fig. 15c) are consistent with shear-enhanced compaction and pore collapse modes observed in porous granular material having yield envelope with elliptical end cap [START_REF] Wong | The brittle-ductile transition in porous rock: A review[END_REF][START_REF] Cilona | The effects of rock heterogeneity on compaction localization in porous carbonates[END_REF] (Fig. 17a). Indeed, studied limestones are composed of micritic grains of calcite with relatively high interstitial porosity (up to 22%; we note that these faults are very rarely or never observed in wackestone or packstone carbonate beds). They probably behaved similarly to other porous and fine granular carbonates such as chalk [START_REF] Risnes | Deformation and yield in high porosity outcrop chalk[END_REF][START_REF] Risnes | Water weakening of chalk-Mechanical effects of water-glycol mixtures[END_REF] or marine limestones [START_REF] Vajdova | Compaction, dilatancy, and failure in porous carbonate rocks[END_REF][START_REF] Wong | The brittle-ductile transition in porous rock: A review[END_REF] and references therein). The size of such yield envelopes is mainly controlled by the porosity and the grain size of the host material (if grain fragmentation is involved) as well as particle cementation (e.g. [START_REF] Estrada | Yield surfaces and plastic potentials of cemented granular materials from discrete element simulations[END_REF][START_REF] Soliva | A model of strain localization in porous sandstone as a function of tectonic setting, burial and material properties; new insight from Provence (southern France)[END_REF]). This mechanical model implies that the faults were formed along the cap under low ratios between applied shear and normal stress (Fig. 17a).

The stress state leading to fault formation can be obtained under a progressive increase of burial with a high coefficient of Earth pressure at rest (K0 the ratio of vertical to horizontal stresses in oedometric conditions, i.e. no horizontal remote stress). This ratio ranges from 0.5 to 1 in very fine-grained materials [START_REF] Goulty | Reservoir stress path during depletion of Norwegian chalk oilfields[END_REF][START_REF] Mitchell | Fundamentals of soil behavior[END_REF] but is not constrained for continental unlithified micritic carbonate muds to your knowledge. The occurrence of both sub-synchronous normal-sense and strike-slip systems suggests that vertical (σv) and horizontal (σΗEW) stresses are very close. This fault pattern and the occurrence of faults in an unconsolidated material argue for a high K0 context since no evidence of EW regional (tectonic) contraction is observed in this area.

We here consider a range of K0 from 0.7 to 0.9 to estimate stress paths leading to faults formation (Fig. 17a). All these observations and mechanical considerations allow considering these faults as formed by burial driven compaction during the increase of burial depth. The presence of faults within the top of the sequence suggests that structures can form under a burial of only few tens meters depth (Fig. 4). Their curved and irregular geometry is consistent with subsurface conditions of formation in poorly lithified rocks [START_REF] Guiraud | Soft-sediment microfaulting related to compaction within the fluviodeltaic infill of the Soria strike-slip basin (northern Spain)[END_REF]. We note that faults are generally observed in the limestone succession showing less evidences of subaerial exposure (karstification, desiccation…) (Fig. 4). Subaerial exposure, by its impact on the host material rheology, would probably prevent the formation of such faults. However, it is not common to localize shear plane in such mechanical context favourable to compaction banding with more or less shear component [START_REF] Schultz | A general framework for the occurrence and faulting of deformation bands in porous granular rocks[END_REF][START_REF] Baud | Shear-enhanced compaction and strain localization: Inelastic deformation and constitutive modeling of four porous sandstones[END_REF][START_REF] Soliva | A model of strain localization in porous sandstone as a function of tectonic setting, burial and material properties; new insight from Provence (southern France)[END_REF]. In these cited examples, the compaction and the pore collapse mainly occurred by cataclasis, leading to pervasive network of compactive cataclastic bands [START_REF] Solum | Characterization of deformation bands associated with normal and reverse stress states in the Navajo Sandstone, Utah[END_REF][START_REF] Saillet | Evolution of cataclastic faulting in high-porosity sandstone, Bassin du Sud-Est, Provence, France[END_REF][START_REF] Ballas | Factors controlling permeability of cataclastic deformation bands and faults in porous sandstone reservoirs[END_REF][START_REF] Soliva | Tectonic regime controls clustering of deformation bands in porous sandstone[END_REF][START_REF] Cavailhes | Deformation bands in volcaniclastic rocks -Insights from the Shihtiping tuffs, Coastal Range of Taiwan[END_REF][START_REF] Robert | Deformation bands, early markers of tectonic activity in front of a fold-and-thrust belt: Example from the Tremp-Graus basin, southern Pyrenees, Spain[END_REF] and uncommonly conduct to shear plane localization following the strain hardening model of [START_REF] Aydin | Development of faults as zones of deformation bands and as slip surfaces in sandstone[END_REF] (e.g. [START_REF] Rotevatn | Slipped deformation bands: A new type of cataclastic deformation bands in Western Sinai, Suez rift, Egypt[END_REF][START_REF] Tueckmantel | Fault seal prediction of seismicscale normal faults in porous sandstone: A case study from the eastern Gulf of Suez rift, Egypt[END_REF]. The fault mechanism described in the present study differs from this model of localization as a combination of processes is involved, i.e. grain rotation, pressure-solution, comminution, and a dynamic recrystallization as revealed by the crystallographic preferred orientation (CPO) of grains [START_REF] Smith | Coseismic recrystallization during shallow earthquake slip[END_REF][START_REF] Delle Piane | Carbonate hosted fault rocks: A review of structural and microstructural characteristic with implications for seismicity in the upper crust[END_REF]. By this way, it is interesting to compare the characteristics of these planes to the slickensides described in C-S structures in crystalline rocks at the deep brittle-ductile transition [START_REF] Berthé | Orthogneiss, mylonite and non coaxial deformation of granites: the example of the South Armorican Shear Zone[END_REF][START_REF] Lin | Importance of differentiating ductile slickenside striations from stretching lineations and variation of shear direction across a high-strain zone[END_REF]. In such contexts, slickensides share similar characteristics than the presently studied structures: grooves and ridges morphology without noticeable downslip ends, and slickenlines (grooves) of several centimeters length for a fault of cm-scale sheardisplacement (e.g. [START_REF] Means | A newly recognized type of slickenside striation[END_REF]. To explain this strain localization in a ductile context, a plastic behaviour of material which is not related to a frictional sliding process is proposed by [START_REF] Lin | The origin of ridge-in-groove slickenside striae and associated steps in an S-C mylonite[END_REF]. As expressed by [START_REF] Will | Experimentally produced slickenside lineations in pyrophyllitic clay[END_REF] from analog laboratory experiments: "the excess length and the nesting between footwall and hanging wall ridges and grooves is therefore a product of this plastic deformation".

We propose that quite similar hybrid and evolving processes occurred under sub-surface conditions in response of plastic processes followed by shear localization and an early blocking of the fault movement. The fault initiation starts by disaggregation and grain comminution within 10s µm thick zones (Fig. 17b, stage 1). The process triggering the grain comminution remains unclear. No evidence of significant cataclasis was observed even if this process cannot be totally excluded. However, the grain comminution is accompanied by a dynamic recrystallization of calcite as revealed by the CPO within the comminuted zone. The potential hardening induced by the grain comminution [START_REF] Schultz | A general framework for the occurrence and faulting of deformation bands in porous granular rocks[END_REF][START_REF] Wibberley | The mechanics of fault distribution and localization in highporosity sands, Provence, France[END_REF] evolves contemporaneously with a softening behaviour induced by the dynamic recrystallization [START_REF] Smith | Coseismic recrystallization during shallow earthquake slip[END_REF], which conducts to shear localization. This shear localization seems initiated by segments of hundreds µm to several mm long, and is developed within or, more frequently, along the comminuted-recrystallized zone (Fig. 17b, stage 2). We note that grain rotation and pressuresolution evidences are generally observed within compressive jogs and are not observed all along the fault plane. This specific location suggests that these processes acts as secondary mechanisms related to the fault plane heterogeneities and then mainly occurred after the fault localization (Fig. 17b, stage 3). However, these processes reveal a compactive behaviour during the last stage of the fault evolution which certainly triggers an early blocking of the fault movement as expressed by the very low shear displacement measured along the fault slickensides.

The formation of two sub-synchronous conjugate systems rather than radial or random patterns is quite unexpected considering that this mechanism of faulting is triggered by compaction and burial context. This particularity in the fault pattern can be explained by a decrease of the NS (σ3) stress induced by the syn-burial tilting of sedimentary layers since they are located in the extrados of a very smooth antiform associated with the flexure of the foreland basin (foreland bulge, Fig. 17c) (e.g. [START_REF] Ferrill | The fold-thrust belt stress cycle: Superposition of normal, strike-slip, and thrust faulting deformation regimes[END_REF]. In this particular setting, a conjugate system of E-W oriented normal-sense faults formed consistently with the polarization of horizontal stresses (NS s3), impeding more random pattern formation. The strike-slip faults generally crosscut the low-angle normal faults whereas their connection may be a local reactivation of the normal system. The strike-slip system could then initiate slightly later, consistently with a close value of σ1 and σ2 [START_REF] Morris | The importance of the effective intermediate principal stress (σ′2) to fault slip patterns[END_REF], and could be linked to local stress release induced by the formation of the normal-sense system. More precisely, the softening occurring during the shear plane localization of normal-sense faults could be enough to imply simultaneously the permutation between a vertical s1 to a horizontal and East-West s1 (local stress perturbation due to fault slip), especially if we considered a high K0 value. We underline that the similarity between dihedral angles for both the strike-slip and normal fault sets (130°), suggests that the material had the same behaviour during normal faulting and strike-slip faulting, and also that no significant vertical compaction occurred after fault formation (i.e. vertical compaction would have only increased the dihedral angle between normal faults). This observation suggests that the material reaches its maximum mechanical compaction during the development of the studied faults.

The occurrence of fault sets within specific beds or beds section of the limestone succession (Fig. 4) suggests that additional factors affect the fault formation. Low-porosity and/or early cementation as well as the rock texture (distribution of grain size and nature of grains) in beds may certainly impede the initiation of such hybrid compactive faults, similarly to the well-known conditioning parameters described for deformation bands occurrence in porous sandstones (Fossen et al., 2018a and references therein). Moreover, external larger-scale factors such the sedimentation rate controlling the overloading stress or the tectonic features (tilting and slope, regional stresses) can also periodically create favourable or unfavourable conditions for fault initiation.

The specific case of multi-beds faults

The specificity of multi-beds faults remains elusive. Most of their characteristics argue for a similar mechanical context of formation by compaction processes, under the influence of a NS trending s3. These multi-beds faults cannot be considered as the evolution of bed-restricted ones as their slickensides show any evidences of segment connection and cut across several limestone beds without marked plan bending. We propose that these multi-beds faults formed in an area of higher sedimentation rate consistently with the lack of significant emersion and the presence of several sedimentary breccias (debris flow from the thrust relief). This higher sedimentation rate coupled with less marked mechanical stratigraphy (fewer differences between rheology of limestone beds compared to more fluctuating palustrine environment) is proposed to explain the occurrence of such large-scale slickensides. The apparent absence of the conjugate set is also interpreted to be linked with a larger influence of the slope during fault formation. We note that these faults are not significantly reactivated during late Eocene Pyrenean shortening despite of their EW orientation and their location in front of the main thrust system. This suggests that these faults, from their deformation mechanisms, morphology, and diagenetic origin, are not suitable to form preferential plane of weakness.

Comparison with other fault systems

Other fault systems share several geometrical attributes with the fault system described in the present study. For example, distributed patterns of compactive faults have already been described as cataclastic shear-enhanced compaction bands in porous sandstones [START_REF] Eichhubl | Pure and shear-enhanced compaction bands in Aztec Sandstone[END_REF][START_REF] Ballas | Shear-enhanced compaction bands formed at shallow burial conditions; implications for fluid flow (Provence, France)[END_REF][START_REF] Fossen | Contractional deformation of porous sandstone: Insights from the Aztec Sandstone, SE Nevada, USA[END_REF] and porous limestones [START_REF] Rustichelli | Development and distribution of bedparallel compaction bands and pressure solution seams in carbonates (Bolognano Formation, Majella Mountain, Italy)[END_REF][START_REF] Rotevatn | Sequential growth of deformation bands in carbonate grainstones in the hangingwall of an active growth fault: Implications for deformation mechanisms in different tectonic regimes[END_REF][START_REF] Kaminskaite | Microstructure and petrophysical properties of deformation bands in high porosity carbonates[END_REF], or as deformation bands with particles reorientationtorsion in clayey materials [START_REF] Ujiie | Origin of deformation bands in argillaceous sediments at the toe of the Nankai accretionary prism, southwest Japan[END_REF][START_REF] Milliken | Multiple causes of diagenetic fabric anisotropy in weakly consolidated mud, Nankai accretionary prism[END_REF]. Furthermore, meterscale shear structures showing both cataclasis and pressure-solution were described in porous limestones [START_REF] Tondi | The role of deformation bands, stylolites and sheared stylolites in fault development in carbonate grainstones of Majella Mountain, Italy[END_REF][START_REF] Rotevatn | Sequential growth of deformation bands in carbonate grainstones in the hangingwall of an active growth fault: Implications for deformation mechanisms in different tectonic regimes[END_REF]Tavani et al., 2018b), chalk [START_REF] Kaminskaite | Microstructure and petrophysical properties of deformation bands in high porosity carbonates[END_REF] or undetermined carbonate [START_REF] Marshak | Mesoscopic fault array of the northern Umbrian Apennine fold belt, Italy: Geometry of conjugate shear by pressure-solution slip[END_REF]. These examples and the fault system described in the present study complete the range of localized deformation structures observed along end cap yield envelop of porous materials (Fossen et al., 2018b;[START_REF] Ferrill | The fold-thrust belt stress cycle: Superposition of normal, strike-slip, and thrust faulting deformation regimes[END_REF].

However, these cited examples of pervasive compactional structures differ from our fault system as there are mainly deformation bands without localization of slickensides and they are mainly related to regional contractional stress fields.

Compaction of sediment during burial conditions is mainly diffuse across the entire material [START_REF] Ehrenberg | Sandstone vs. carbonate petroleum reservoirs: A global perspective on porosity-depth and porosity-permeability relationships[END_REF]. The compaction can also take place in discontinuity such as bedparallel pressure-solution seams [START_REF] Toussaint | Stylolites: A review[END_REF][START_REF] Meng | Origins of non-tectonic fractures in shale[END_REF] or compaction bands [START_REF] Tondi | The role of deformation bands, stylolites and sheared stylolites in fault development in carbonate grainstones of Majella Mountain, Italy[END_REF][START_REF] Aydin | Bed-parallel compaction bands in aeolian sandstone: Their identification, characterization and implications[END_REF]. However, the participation of shear discontinuities in the sediment compaction remains mainly not considered although polygonal fault patterns observed worldwide in offshore sediments [START_REF] Cartwright | The genesis of polygonal fault systems: a review[END_REF][START_REF] Gay | Polygonal faults-furrows system related to early stages of compaction -upper Miocene to recent sediments of the Lower Congo Basin[END_REF][START_REF] Cartwright | Diagenetically induced shear failure of fine-grained sediments and the development of polygonal fault systems[END_REF][START_REF] Gay | Are polygonal faults the keystone for better understanding the timing of fluid migration in sedimentary basins[END_REF] are discussed to be triggered during sediment burial and diagenesis. In chalks, [START_REF] Hibsch | Normal faulting in chalk: tectonic stresses vs. compaction-related polygonal faulting[END_REF] described polygonal faulting where shearing is associated with decrease of porosity by pressure solution and cementation. Conversely, [START_REF] Wennberg | Deformation bands in chalk, examples from the Shetland Group of the Oseberg Field, North Sea, Norway[END_REF] described cataclastic compaction bands triggered by vertical loading during burial (no information of the fault pattern). In our study, faults appear to be a hybrid system between these two previously cited examples as cataclasis, pressure-solution and dynamic recrystallization is observed.

We note that the polygonal faults described by [START_REF] Tewksbury | Polygonal faults in chalk: Insights from extensive exposures of the Khoman Formation, Western Desert, Egypt[END_REF] show calcite mineralization along the fault plane which implies a dominant dilatant behaviour. The meterscale compactive normal faults described by [START_REF] Guiraud | Soft-sediment microfaulting related to compaction within the fluviodeltaic infill of the Soria strike-slip basin (northern Spain)[END_REF] in clayey sediments are also related to water-escape structures during sediment compaction (their low-angle to bedding and their slickenside morphology are quite similar to our study faults). These examples reveal that different micro-mechanisms can occur within the shear discontinuities initiated during sediment compaction. These structures participate to sediment compaction by compactive mechanisms within the shear structures (cataclasis, pressure-solution) or by dilatant behaviour which permits fluid expulsion and diffuse compaction of the host material.

Conclusion

Compactive faults showing hybrid micromechanisms of deformation are described in micritic porous limestones from the South of France. These faults are organized in distributed patterns of meter-scale structures and form two sub-synchronous conjugate sets: a set composed of lowangle normal faults and a set composed of subvertical strike-slip faults. Their curve plane, incipient shear offset, high angle relative to s1, and porosity reduction argues for a dominant compaction behaviour during faulting. Comminution, dynamic recrystallization (revealed by the crystallographic preferred orientation from EBSD acquisitions), pressure-solution and grain rotation are observed in these structures initiated during early sediment burial and basin flexure. These faults complete the range of compactive structures formed along the end cap yield envelop of porous materials. This example underlines the complexity of deformation processes occurring under compaction and early burial context, especially in such poorly consolidated carbonate material. The reported geological map is modified form the 1/50 000 maps of Montpellier [START_REF] Bonnet | Notice de la carte géologique à 1/50 000, feuille Montpellier[END_REF] and Lodève [START_REF] Alabouvette | Carte géologique de Lodève[END_REF]. Main bed dip values are reported for the three main parts of the outcrop. The main studied section is located westward. A second studied outcrop is located eastward but is potentially disconnected form the other studied green, 30-180° grey. The procedure is detailed in Appendix 1 of Burg et al. (1995). Ntotal: Total number of fault slip data. Pinv: Proportion of slip data used in the inversion. ∆λαv: Average angular misfit of the rake; this average is computed on the Pinv lowest misfits only [START_REF] Etchecopar | An inverse problem in microtectonics for the determination of stress tensors from fault striation analysis[END_REF]. Nexp15: Number of fault slip data with rake misfit < 15°. N0exp15: Number of fault slip data with rake misfit < 15° that could be obtained from a random sample. InvQual: Quality index as in [START_REF] Heuberger | Paleostress regimes from brittle structures of the Karakoram-Kohistan Suture Zone and surrounding areas of NW Pakistan[END_REF].

Caption List

Fig. 1 .

 1 Fig. 1. (a) Schematic geological map of the study area modified from the 1/1 000 000 geological map of France. (b) SSW-NE Structural cross-section within the Aumelas -La Boissière basin using field cartographic measurements and the St Bauzille Well data. La Taillade is the study site.

Fig. 2 .

 2 Fig. 2. (a) Aerial pictures (GoogleEarth) showing the location of the studied outcrop along the A750 highway. The reported geological map is modified form the 1/50 000 maps of Montpellier

  exposures by map-scale sinistral faults. (b) Field view of the main studied limestone-dominated section. (c) Details of the studied outcrop showing mudstone beds. (d) Example of brownish silty marl deposits intercalated in mudstone beds.

Fig. 3 .

 3 Fig. 3. Host rock microstructure observed from SEM images. (a) 3D mudstone sample showing micritic euhedral crystals of calcite less than 5 µm in size. (b) Image from thin-section showing imbricated contact between calcite particles.

Fig. 4 .

 4 Fig. 4. Sedimentological log of the main studied section showing location of studied faults along the succession. Evidence of pedogenetic alterations (desiccation, karstification, brecciation) observed on bed surfaces are also reported. Beds are draw following the Dunham classification (M: Mudstone, W: Wackstone, P: Packestone, G: Grainstone, B: Boundstone + C to identify clays). Studied fault symbol represents indifferently both normal-sense and strike-slip fault sets.

Fig. 5 .

 5 Fig. 5. Slickenside morphology. (a) example of slickenside from a normal-sense fault. (b), (c), and (d) Detailed observations of grooves and ridges morphology and tips. (e) SEM image showing slickenlines morphology at the microscale. (f) SEM image showing the 3D morphology of a step marking on a slickenside. Thick arrows show the sense of displacement of the absent wall.

Fig. 6 .

 6 Fig. 6. Normal fault system. (a) Limestone layers containing constrained normal-sense faults. (b) and (c) S-Shape of faults. (d) and (e) Cross-section of limestone beds showing the conjugate system of faults. White arrows show the fault kinematic. S0 is the bedding (base of the succession at the bottom of the photography).

Fig. 7 .Fig. 8 .

 78 Fig. 7. Stereographic analysis of normal-sense fault set. (a) Stereograms showing projection of fault planes and slickenlines. (b) Histogram of fault dip. (c) Histogram of fault rake. (Restored data)

Fig. 9 .Fig. 10 .

 910 Fig. 9. Stereographic analysis of strike-slip fault set. (a) Stereograms showing projection of fault planes and slickenlines (grooves). (b) Histogram of fault dip. (c) Histogram of fault rake. (Restored data)

Fig. 11 .

 11 Fig. 11. Microstructure of faults. (a) Mosaic of SEM images showing the rock microstructure below the fault slickensides and photograph of the block sample (see the orientation and dip of the fault). (b) Focus on the compacted zone above the main fault plane. (c) Example of the compressive jog showing compaction and evidences of enhanced pressure-solution. (d) Other example of the compacted zone below the fault plane. (e) Example of fault step marking at the upper tip of groove. This example illustrates the presence of dilation joint and the lack of compaction.

Fig. 12 .

 12 Fig. 12. Grain framework reconstruction maps form EBSD acquisition and rose diagram of grain slope (angle from the image top) in (a) the host rock, (b) and (c) the compressive jogs along the fault plane. The color of grain indicates the angle of their crystallographic preferred orientation with the different calcite crystallographic axis (0001: c-axis; 0110 and 1010: a-axes).

Fig. 13 .

 13 Fig. 13. Crystallographic preferred orientation (CPO) in the fault zone, EBSD acquisitions. (a) Grain framework reconstruction maps from EBSD acquisition showing deformation zone above

Fig. 14 .

 14 Fig. 14. (a) EBSD acquisitions showing example of calcite twinning within the fault core. Maps of calcite twins detected at the fault core (b), a compressive jog (c), and a step marking (d). The calcite twins are draw by red lines. High concentration of calcite twins is observed in the fault core and along the compressive jog whereas no twins are observed in the host rocke and at marking dilatant step.

Fig. 15 .

 15 Fig. 15. Stress state during fault formation. (a) Stereogram projection showing state of stress determination by inversion method. (r0: stress tensor aspect ratio; s1, s2, s3, principal stress orientations). (b) Table showing stress inversion parameters. (c) Reduced Mohr circle. The faults are color coded as a function of their angular misfit range: 0-5° blue, 5-15° magenta, 15-30°

Fig. 16 .

 16 Fig. 16. Multi-beds normal faults. (a) Exposure of such fault. (b) Detail of slickenside morphology showing slickolites (teeth evidencing pressure-solution at the down-slip ends of grooves). (c) Stereographic data showing faults organization (bedding restored to horizontal). (d) Example of such faults with their estimated shear-displacement. White arrows show the fault kinematic. S0 is the bedding. ds is the apparent shear displacement.

Fig. 17 .

 17 Fig. 17. Conceptual model of faults formation. (a) Differential Stress (Q) -Mean Effective Stress (P) space diagram showing location of faults formation using yield envelops of porous carbonates (Risnes et al. 2005) and estimated stress path (Ko : coefficient of Earth Pressure at Rest; blue lines: estimated stress paths). (b) The successive stages of faults formation: comminuted zone with dynamic recrystallization (stage 1), shear localization (stage 2), and early blocking of fault movement by grain rotation and pressure-solution processes (stage 3). (c) 3D schematic bloc diagram showing the location of fault in the basin and the influence of the slope.

Acknowledgements

We acknowledge Pierre Azémard, Patrick Demange, Jean-Christophe Merzeau and all the team from CEI Montarnaud to give us access and support along A750 Highway. We are grateful to Doriane Delmas and Christophe Nevado for the high quality thin-sections and, Frédéric Fernandez and Fabrice Barou for the help on the SEM and EBSD devices. We also thank Michel Lopez, Alfredo Taboada, and Didier Loggia for constructive discussions about the fault formation. We acknowledge Andrea Billi and David Ferrill for their constructive reviews which improve the manuscript.

Funding information

This work relied on basic support from the Geosciences Montpellier Laboratory and on the Tellus Program of CNRS/INSU.


Arthur Petat

Eric Dansin

Fabien Calcagno

Laurent Greillier

Eric Pichon

Mallorie Kerjouan

Christelle Clement-Duchene

Bertrand Mennecier

Virginie Westeel

François Thillays

Xavier Quantin

Youssef Oulkhouir

Luc Thiberville

Charles Ricordel

Vincent Thomas De Montpreville

Lara Chalabreysse

Véronique Hofman

Thierry Molina

Pierre Fournel

Laurence Bigay Game

Benjamin Besse

Nicolas Girard
email: nicolas.girard2@curie.fr

Treatment strategies for thymic carcinoma in a real-life setting. Insights from the RYTHMIC network

Keywords:

de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

INTRODUCTION

Thymic carcinomas are a subset of thymic epithelial tumors that represent a heterogeneous group of rare intrathoracic malignancies, which are aggressive and difficult to treat [START_REF] Girard | Thymoma: a focus on current therapeutic management[END_REF].

Contrary to thymomas, that usually present with local and regional disease progression, thymic carcinomas have a higher risk of advanced or metastatic presentation at diagnosis [START_REF] Ruffini | Thymic carcinoma: a cohort study of patients from the European society of thoracic surgeons database[END_REF][START_REF] Hishida | Long-term outcome and prognostic factors of surgically treated thymic carcinoma: results of 306 cases from a Japanese Nationwide Database Study[END_REF][START_REF] Wei | Preoperative induction therapy for locally advanced thymic tumors: a retrospective analysis using the ChART database[END_REF][START_REF] Ahmad | Thymic carcinoma outcomes and prognosis: results of an international analysis[END_REF][START_REF] Meurgey | Assessment of the ITMIG Statement on the WHO Histological Classification and of the Eighth TNM Staging of Thymic Epithelial Tumors of a Series of 188 Thymic Epithelial Tumors[END_REF]. While the historical Masaoka-Koga staging system was primarily designed for thymomas [START_REF] Detterbeck | The Masaoka-Koga stage classification for thymic malignancies: clarification and definition of terms[END_REF], the recent implementation of TNM staging allows a better recognition of the actual invasiveness of thymic carcinomas [START_REF] Brierly | Thymic Tumors[END_REF].

Treatment strategy of thymic carcinomas is based on whether surgical resection may be achieved, what represents the most significant favorable prognostic factor on survival [START_REF] Ruffini | Thymic carcinoma: a cohort study of patients from the European society of thoracic surgeons database[END_REF][START_REF] Hishida | Long-term outcome and prognostic factors of surgically treated thymic carcinoma: results of 306 cases from a Japanese Nationwide Database Study[END_REF][START_REF] Wei | Preoperative induction therapy for locally advanced thymic tumors: a retrospective analysis using the ChART database[END_REF][START_REF] Ahmad | Thymic carcinoma outcomes and prognosis: results of an international analysis[END_REF].

Meanwhile, most of the current knowledge on those tumors rely on the one hand on retrospective, surgically-oriented databases focusing on early-stage disease, that may not reflect the actual burden of non-resectable tumors [START_REF] Ruffini | Thymic carcinoma: a cohort study of patients from the European society of thoracic surgeons database[END_REF][START_REF] Hishida | Long-term outcome and prognostic factors of surgically treated thymic carcinoma: results of 306 cases from a Japanese Nationwide Database Study[END_REF][START_REF] Wei | Preoperative induction therapy for locally advanced thymic tumors: a retrospective analysis using the ChART database[END_REF][START_REF] Ahmad | Thymic carcinoma outcomes and prognosis: results of an international analysis[END_REF]; on the other hand, small prospective, singlearm trials have been conducted in metastatic thymic carcinomas, mostly in a refractory, lateline setting [START_REF] Ko | Prognostic Factors and Efficacy of First-Line Chemotherapy in Patients with Advanced Thymic Carcinoma: A Retrospective Analysis of 286 Patients from NEJ023 Study[END_REF][START_REF] Giaccone | Pembrolizumab in patients with thymic carcinoma: a single-arm, single-centre, phase 2 study[END_REF][START_REF] Cho | Pembrolizumab for Patients With Refractory or Relapsed Thymic Epithelial Tumor: An Open-Label Phase II Trial[END_REF][START_REF] Thomas | Sunitinib in patients with chemotherapy-refractory thymoma and thymic carcinoma: an open-label phase 2 trial[END_REF]. In a routine practice setting, the management of patients with thymic carcinoma raises multiple questions, from the transposability of strategies established for thymomas, including primary/induction chemotherapy and surgery for advanced disease, to the actual value of recommendations such as postoperative chemotherapy and the treatment of recurrences [START_REF] Girard | Systemic Treatment in Advanced Thymic Epithelial Tumors. Insights From a Prospective Cohort of 1000 Patients enrolled in RYTHMIC. International Association for the Study of Lung Cancer[END_REF].

"Réseau tumeurs THYMiques et Cancer" (RYTHMIC) is the nationwide network for TET in France, which was established in 2012 [START_REF] Girard | Systemic Treatment in Advanced Thymic Epithelial Tumors. Insights From a Prospective Cohort of 1000 Patients enrolled in RYTHMIC. International Association for the Study of Lung Cancer[END_REF]. Within the network, the management of any patient diagnosed with thymic epithelial tumor has to be systematically discussed on a real-time basis at a national multidisciplinary tumor board; it is also recommended to discuss the patient at any step of disease progression, allowing a prospective follow-up with multidisciplinary quality control. A database is hosted by the French Thoracic Cancer Intergroup (IFCT) and collects information for all consecutive patients. For this study, we took advantage of this unique prospective database to describe baseline characteristics, analyze treatment strategies in light of existing guidelines, and provide landmark patient outcomes data with regards to response and survival of patients in a real-life clinical practice setting.

METHODS

Study design

RYTHMIC is a nationwide network dedicated to the management of thymic malignancies in France. It was appointed in 2012 by the French Institut National du CAncer (INCA) as part of its rare cancer initiative [START_REF] Girard | Systemic Treatment in Advanced Thymic Epithelial Tumors. Insights From a Prospective Cohort of 1000 Patients enrolled in RYTHMIC. International Association for the Study of Lung Cancer[END_REF][START_REF] Bluthgen | Updated incidence of thymic epithelial tumors (TET) in France and clinical presentation at diagnosis[END_REF]. The network aims at a territorial coverage by 15 regional expert centres, the dissemination of the highest standards for diagnosis and treatment, and the promotion of collaborative research. The RYTHMIC multidisciplinary tumor board takes place twice a month using web-based conferencing system and characteristics of all patients, treatments, and follow-up are prospectively collected in the network database. Systematic pathological review of cases is conducted by an international panel of expert pathologists based on the standard WHO classification [START_REF] Travis | WHO histological classification of tumours of the thymus[END_REF][START_REF] Marx | The 2015 World Health Organization Classification of Tumors of the Thymus: Continuity and Changes[END_REF] Registration of all patients diagnosed with thymic malignancies is recommended as a part of good clinical practice for oncologists. From January 2012 to April 2019, a total of 2723 patients were enrolled Based on national epidemiological data, the RYTHMIC network is estimated to cover 95% of newly diagnosed patients in France [START_REF] Thomas | Sunitinib in patients with chemotherapy-refractory thymoma and thymic carcinoma: an open-label phase 2 trial[END_REF]. The current analysis was approved by the steering and ethics committee of the RYTHMIC network.

Identification of patients

Inclusion criteria for this analysis were the following: 1) histologically-confirmed thymic carcinomas -excluding neuroendocrine tumors-after pathological review by the RYTHMIC pathology panel, 2) discussion of the case at the RYTHMIC multidisciplinary tumor board, 3) at least one active treatment modality. Patient were identified using the RYTHMIC prospective database, hosted by the French Thoracic Cancer Intergroup (IFCT) according to ongoing legal requirements. The inclusion period was from January 2012 to April 2019. Follow-up was obtained in all cases and was censored on December 30 th , 2020.

Data collection

The data (including patients baseline characteristics, histology, stage, chemotherapy regimen, dates of treatment initiation and discontinuation, dates of progression) were collected after a review of patient's medical records and multidisciplinary tumor board reports, especially for analyses of treatment sequences. Masaoka-Koga stage was assessed according to the International Thymic Malignancy Interest Group (ITMIG) recommendations, using clinical, imaging, and pathological findings [START_REF] Detterbeck | The Masaoka-Koga stage classification for thymic malignancies: clarification and definition of terms[END_REF]; given the period of this study, we did not prospectively use the 8th American Joint Committee on Cancer / Union for International Cancer Control TNM system [START_REF] Brierly | Thymic Tumors[END_REF]. Best response to systemic treatment was assessed by treating physicians, according to ITMIG recommendations adopted by the RYTHMIC/ESMO guidelines [START_REF] Girard | Thymic epithelial tumours: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up[END_REF][START_REF] Huang | Standard outcome measures for thymic malignancies[END_REF].

Definitions for chemotherapy and radiotherapy treatments

According to definitions and policies of the ITMIG [START_REF] Girard | Chemotherapy definitions and policies for thymic malignancies[END_REF], chemotherapy for thymic malignancies includes: 1/ primary chemotherapy, delivered as induction treatment for unresectable locally-advanced tumors at time of diagnosis, with the intent of subsequent surgical resection or definitive radiotherapy; 2/ postoperative chemotherapy, delivered after surgery in the absence of macroscopic residual disease or tumor progression; 3/ exclusive chemotherapy, in advanced tumors with no plan for surgery or radiotherapy, e.g. in patients with metastatic disease; 4/ chemotherapy for recurrence after surgery or radiotherapy, or disease progression after exclusive chemotherapy; multiple lines of chemotherapy may be administered for second, third, and if possible subsequent recurrences. In this study, we analyse the modalities and outcomes of chemotherapy and other systemic treatments using the framework of those definitions.

Similarly, as for radiotherapy, ITMIG recommendations distinguish 1/ postoperative radiotherapy delivered after surgery, 2/ definitive radiotherapy, alone or combined with chemotherapy, in the setting of non-metastatic tumors non amenable to surgery, and 3/ radiotherapy for recurrence [START_REF] Gomez | Radiation therapy definitions and reporting guidelines for thymic malignancies[END_REF].

Statistical analyses

All patients were included in the statistical calculations. Categorical variables were compared using the Chi-square or Student 's test, and continuous variables by the Mann-Whitney nonparametric test. Survival was assessed using the Kaplan-Meier method. For patients who were operated on, disease-free survival (DFS) was calculated from the date of surgery. For patients who received primary chemotherapy, time-to-progression (TTP) was calculated from the date of initiation of chemotherapy to the date of relapse, with censoring at the date of last follow-up if the patient had not presented with disease progression. For patients who received exclusive chemotherapy or chemotherapy for recurrence, progression-free survival (PFS) was calculated from the date of initiation of chemotherapy to the date of progression, with censoring at the date of last follow-up if the patient had not presented with disease progression. Overall survival (OS)

was calculated from diagnosis to the date of death, censoring at the last follow-up date if the patient was alive. Relevant parameters were studied for influence on survival by univariate analysis using the Log Rank test. The differences were considered as statistically significant at the 0.05 level. All analyses were performed using the SPSS software program (Chicago, IL), version 25.0. With regards to treatment strategies, 60 (28%) patients were considered as surgical candidates upfront, 91 (43%) received primary chemotherapy, and 62 (29%) received exclusive chemotherapy.

RESULTS

Patients characteristics

A

Treatment strategies

Upfront surgery was performed for 60 patients (Figure 1

Overall survival

Median OS in the whole cohort of 213 patients was 49.2 months (IC95%: 34.8-63.6) (Figure 4); OS was significantly longer in patients with a lower stage at diagnosis (p<0.001), who were operated on upfront, as opposed to patients who received primary or exclusive chemotherapy (p<0.001). Surgery, conducted upfront or after primary chemotherapy, was significantly associated with more prolonged OS (p<0.001); complete resection and postoperative radiotherapy were also predictors of better outcome (p=0.018 and p=0.051, respectively).

In the 60 patients who were operated on upfront, median OS was 79.1 months (IC95%: 60.1-98.0). Only Masaoka-Koga stage was a significant predictor of OS in our cohort (p=0.039). The following factors were not significantly associated with OS: age, gender, smoking, histological subtype, resection completeness, or delivery of postoperative treatment.

In the 91 patients who received induction chemotherapy, median OS was 36.9 months (IC95%:

28.8-45.1); significant predictors of more prolonged OS were lower Masaoka-Koga stage (p=0.027), response to primary chemotherapy (p=0.007), and delivery of postoperative radiotherapy (p=0.017). Interestingly, the following factors were not significantly associated with OS: age, gender, smoking, histological subtype, chemotherapy regimen, surgery of the primary tumor, or resection completeness.

In patients who had exclusive chemotherapy, median OS was 32.9 months (IC95%: 20.6-45.1).

Response to first-line chemotherapy and squamous histology were the only significant predictors of OS (p=0.002 and p=0.040, respectively); chemotherapy regimens were not associated with OS.

DISCUSSION

Taking advantage of the RYTHMIC network infrastructure, our analysis is the first to our knowledge, to analyse the treatment strategies for thymic carcinoma in a real-life setting, with no selection based on the actual recruitment of patients as we used a prospective nationwide cohort of consecutive patients, in the unique setting of systematic discussion at an expert MTB at each step of the management of patients, based on established clinical practice guidelines.

First, this unique process allows the analysis of data based on the actual intent of the treatment, what had not been made possible in the majority of previously reported retrospective or prospective studies which combined patients receiving surgery or systemic treatment in a curative and in a palliative intent, or patients treated in various lines of treatment [START_REF] Ruffini | Thymic carcinoma: a cohort study of patients from the European society of thoracic surgeons database[END_REF][START_REF] Hishida | Long-term outcome and prognostic factors of surgically treated thymic carcinoma: results of 306 cases from a Japanese Nationwide Database Study[END_REF][START_REF] Wei | Preoperative induction therapy for locally advanced thymic tumors: a retrospective analysis using the ChART database[END_REF][START_REF] Ahmad | Thymic carcinoma outcomes and prognosis: results of an international analysis[END_REF]. While we confirm the major prognostic impact of surgery, our data highlight the need for optimized multidisciplinary management and innovative therapies as the survival of patients remains limited.

Our results clearly indicate the peculiar characteristics of patients with thymic carcinoma, that are mostly never smokers; this is a major point to consider as misdiagnosis with primary lung carcinoma may be frequent in the setting of a tumor arising in the mediastinum, and as in our study, is associated with lung lesions and lymph nodes. Immunohistochemistry using CD5 and CD117 helps to distinguish both entities, and should be systematically assessed in such clinical situations. This is even more relevant now that immunotherapy using anti-PD-1 checkpoint inhibitors are routinely used in lung carcinoma, while it may be associated with higher risk of autoimmune adverse events in thymic carcinomas [START_REF] Giaccone | Pembrolizumab in patients with thymic carcinoma: a single-arm, single-centre, phase 2 study[END_REF][START_REF] Cho | Pembrolizumab for Patients With Refractory or Relapsed Thymic Epithelial Tumor: An Open-Label Phase II Trial[END_REF].

Our data indicate that only a limited number of patients with thymic carcinoma are actually eligible to upfront surgical resection, 28% of patients in our cohort. Pre-operative biopsy was available for a majority of patients, even in the setting of a decision of upfront surgery, given the tumor invasion at imaging. Meanwhile, complete resection was not achieved in 37% of patients. As per ESMO clinical practice guidelines recommendation, a majority of patients received postoperative radiotherapy [START_REF] Girard | Thymic epithelial tumours: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up[END_REF]. As in previously reported surgical cohorts of patients, postoperative radiotherapy was associated with a more prolonged overall survival, what may be related to the high rate of R1 or R2 status. Interestingly, our data show that the recommendation of postoperative chemotherapy was actually applied to only 7 patients, mostly in the setting of incomplete resection and stage IV disease. More detailed studies on the location of R1 or R2 would be of interest to understand the pre-and per-operative decision making of the surgical teams. A high rate of incomplete resection has to be expected for patients with T4 disease, while debulking may be valuable to facilitate subsequent therapies and decrease the symptom burden. Accurate preoperative imaging may help to better assess the tumor invasion.

While our previous results reported in thymoma highlighted the need for distinguishing primary -induction before surgical resection of definitive radiotherapy -vs. exclusive -first-line for disease ineligible to focal treatment -chemotherapy, as clinicians' expectations may differ regarding response rates, ranging from 79% to 35%, respectively, data from this larger cohort of patients with thymic carcinoma indicate similar response rates in those situations, 56% and 53%, respectively. Those figures are still in line with historical studies [START_REF] Ko | Prognostic Factors and Efficacy of First-Line Chemotherapy in Patients with Advanced Thymic Carcinoma: A Retrospective Analysis of 286 Patients from NEJ023 Study[END_REF]. Thymomas are known to be more sensitive to chemotherapy, what may partly be related to a "lympholytic effect" of cytotoxic agents and steroids in type B thymomas. PFS was actually limited -8.1 months -in the setting of advanced thymic carcinoma, receiving chemotherapy alone. Besides histologic type, metastatic thymic tumors may present with more aggressive biological features leading to a lower sensitivity to first-intent systemic treatment, as compared with locallyadvanced tumors; virtually no data regarding the molecular features of advanced TETs have been made available so far, as the majority of comprehensive genomic studies were conducted in treatment-naïve, surgically resected tumors.

Meanwhile, distinguishing first-intent -primary or exclusive -treatment from recurrences provides with an insight in treatment sequences along with the management of patients; while PAC regimen is used upfront for the majority of patients -62% to 66% of patients -, carboplatin and paclitaxel, sunitinib, and single agent chemotherapies are preferred regimens for recurrences, based phase II studies that provided the evidence for the development of the ESMO clinical practice guidelines, which have then been applied in our cohort [START_REF] Girard | Thymic epithelial tumours: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up[END_REF].

Still, our results indicate that multiple lines of systemic therapy may be delivered beyond firstintent treatment, providing patients with an opportunity of clinically relevant median PFS, around 8 months in the setting of recurrent disease; indeed, patients presenting with thymic carcinomas are usually young, in a good medical condition with no co-morbidities. The impact of potential cumulative side effects of systemic treatments was not assessed in our study, as toxicities are not captured in the prospective RYTHMIC database; the increased use of noncytotoxic agents in late lines of treatment suggests those aspects, especially performance status and history of hematological toxicities, were taken into account during discussions at the MTB.

One limitation of our study is the absence of blinded radiological review of imaging to assess objective response; still, the RYTHMIC MTB includes the review of available imaging that is shared to the multi-disciplinary panel -that includes a thoracic radiologist -through a using web-based conferencing system. Despite such a unique, nation-wide multidisciplinary approach, that includes a discussion of each case with a minimum of 3 experienced surgical teams together with medical oncologists and radiation oncologists, our results highlight the major challenges in defining and predicting the resectability of thymic carcinoma tumors, and the need for clarifying the actual role for primary/induction chemotherapy to increase the chance of complete resection. Ultimately, the assessment of objective response and tumor invasion remains challenging in TETs given the frequent occurrence of pleural and mediastinal tumor targets for which standardization of measurements is debated.

Overall, our data indicate a median OS in the whole cohort of 213 patients as long as 49.2 months (IC95%: 34.8-63.6); while this is more prolonged than in patients with other thoracic malignancies, this is mainly driven by patients who are operated on, either upfront or after induction chemotherapy. Multimodal treatment is actually key, as shown by the significant prognostic value of postoperative radiotherapy and also the opportunity to achieve complete surgical resection after induction chemotherapy.

Ultimately, as no randomized or even prospective comparative study has ever been conducted to assess chemotherapy or other systemic agents in those clinical situations, there is paucity of prospective data regarding the outcome of patients; our real-life data provide with landmark OS, PFS and response rates that are needed when designing clinical trials assessing innovative agents, especially in the setting of single-arm phase II studies, that have been available for immune checkpoint inhibitors [START_REF] Giaccone | Durable Response in Patients With Thymic Carcinoma Treated With Pembrolizumab After Prolonged Follow-Up[END_REF], or new targeted agents, such as lenvatinib [START_REF] Sato | Lenvatinib in patients with advanced or metastatic thymic carcinoma (REMORA): a multicentre, phase 2 trial[END_REF]. Ultimately, the RYTHMIC nation-wide MTB offers the opportunity of systematically identifying patients who are potentially eligible for such clinical trials.

To conclude, our data provide with a unique insight into systemic treatment strategies for thymic carcinomas, highlighting the value of the ITMIG definitions and policies to distinguish primary, exclusive, and recurrence settings, the relevance of ESMO clinical practice guidelines, and the benefit of multimodal treatment in the setting of multidisciplinary discussion.

Figure 1 :

 1 Figure 1: Treatment strategies in 60 patients with upfront surgical resection of the tumor,

Figure 2 :

 2 Figure 2: Treatment strategies in 91 patients who received preoperative chemotherapy (A),

Figure 3 :

 3 Figure 3: Systemic treatment regimens in 62 patients who received first-line exclusive

Figure 4 :

 4 Figure 4: Overall survival (OS) in the whole cohort of 213 patients (A). OS according to

Figure 1 :

 1 Figure 1: Treatment strategies in 60 patients with upfront surgical resection of the tumor,

Figure 2 :

 2 Figure 2: Treatment strategies in 91 patients who received preoperative chemotherapy (A),

Figure 3 :

 3 Figure 3: Systemic treatment regimens in 62 patients who received first-line exclusive

Figure 4 :

 4 Figure 4: Overall survival (OS) in the whole cohort of 213 patients (A). OS according to

  , in 5 patients, chemotherapy -combination of platinum and etoposide or paclitaxel or adriamycin-cyclophosphamide-in 10 patients, and sunitinib in 2 patients. Best objective response to systemic treatment was partial response in 5 patients, stable disease in 5 patients, and 2 progression in 2 patients.After a median follow-up of 25 months, 53 (58%) patients who receive primary chemotherapy presented with recurrence; sites of first recurrence were the mediastinal pleura in 12 patients, mediastinal lymph nodes in 12 patients, the liver in 14 patients, the bone in 10 patients, the lung in 7 patients, and the brain in 2 patients. Median DFS was 21.0 months (IC95%: 5.9-36.1); surgical resection (p=0.023) and delivery of postoperative radiotherapy (p=0.026) were significant predictors of more prolonged DFS. Gender, age, smoking, histological type, stage, response to primary chemotherapy, resection completeness did not significantly predict DFS.

	thoracoscopy for 1 (3%) patients. Surgical resection included resection of mediastinal
	structures, including great vessels, lung, pericardium, in all patients. Resection status was R0
	in 22 (55%) patients, R1 in 13 (33%) patients, and R2 in 5 (13%) patients. Incomplete resection
	mostly occurred in patients with stage T3 (10 out of 28 patients) or T4 (8 out of 12 patients).
	Postoperative radiotherapy was delivered to 27 (72%) patients, and postoperative chemo-
	radiotherapy to 7 (12%) patients, consisting of platinum and etoposide in 5 patients, and
	). A preoperative biopsy was available platinum and docetaxel in 2 patients; all the 5 patients with a R2 resection received
	for 49 patients. ; surgical approach consisted of median sternotomy for 49 (82%) patients, postoperative chemoradiotherapy. Overall, 51 patients who were deemed not to be surgical
	thoracotomy for 6 (10%) patients, and thoracoscopy for 5 (8%) patients. Surgical resection candidates, received definitive radiotherapy to a median dose of 60 Gy.
	included resection of mediastinal structures, including great vessels, lung, pericardium, in 50
	(83%) patients. Resection status was R0 in 38 (63%) patients, R1 in 18 (30%) patients, and R2
	After a median follow-up of 27 months, 41 (66%) patients who received a first-line of exclusive
	chemotherapy did received second-line treatment, mostly consisting of carboplatin and
	paclitaxel (61% of patients) (Figure 3). Best objective response was partial response in 9 (22%)
	Primary/induction chemotherapy with intent for subsequent local treatment -surgery or patients, stable disease in 14 (34%) patients, and progression in 18 (44%) of patients. Median
	radiation therapyt-was delivered to 91 patients. All patients had a preoperative biopsy. PAC Recurrences PFS was 8.1 months (IC95%: 5.2-11.1). Predictors of more prolonged PFS were squamous
	regimen was the most frequently delivered, to 56 (62%) patients (Figure 2A); median number After a median follow-up of 36 months, 17 (28%) of the 60 patients who were operated upfront, histologic subtype (p=0.048) and response (p<0.001). A total of 30 (48%) patients did receive
	of cycles was 4 (range 2-6). Objective response was observed in 51 (56%) patients, stable presented with disease recurrence. Sites of recurrences were the following: lung in 8 patients, third-line treatment, consisting of sunitinib or other multikinase, VEGFR inhibitors, in 17
	disease in 29 (32%), and progression disease in 9 (10%) patients; 2 patients were not assessable pleura in 6 patients, mediastinum in 4 patients, liver in 2 patients, and bone in 1 patient. Median (57%) patients. Best objective response was partial response in 6 (20%) patients, stable disease
	for response. Surgery was ultimately performed for 40 patients (Figure 2B); surgery was more DFS was 52.0 months (IC95%: 39.0-65.0); none of the following factors were not significantly in 11 (37%) patients, and progression in 13 (43%) of patients. Median PFS was 3.0 months
	frequently performed in responders to primary chemotherapy (p<0.001). Surgical approach (IC95%: 2.2-3.8).
	consisted of median sternotomy for 36 (90%) patients, thoracotomy for 3 (8%) patients, and

in 4 (7%) patients. Incomplete resection occurred in patients with stage T2 (2 out of 18 patients), T3 (14 out of 34 patients) and T4 (6 out of 8 patients). Postoperative radiotherapy was delivered to 43 (72%) patients, and postoperative chemotherapy to 7 (12%) patients, consisting of platinum and etoposide in 4 patients, platinum and adriamycin and cyclophosphamide (PAC) in 3 patients.

Exclusive chemotherapy was delivered to 62 patients, who all received platinum-based regimen as first-line treatment (Figure

3

); PAC regimen was delivered to 66% of patients. Median number of cycles was 6 (range-2-9). Best objective response to first-line chemotherapy was partial response in 33 (53%) patients, stable disease in 15 (24%) patients, and progression in 14 (23%) of patients. Median PFS was 8.0 months (IC95%: 5.0-11.1); while regimen was not a predictor of PFS, histologic type (squamous vs. other) and response were significantly associated with longer PFS (p<0.001 and p=0.001, respectively). associated with OS: age, gender, smoking, histological subtype, stage, resection completeness, or delivery of postoperative treatment. Treatment consisted of surgical resection, mostly for pleural recurrencesTreatment for recurrence consisted of chemotherapy in 36 patients and radiotherapy or other local ablative therapy in 4 patients (Figure 2); 7 patients did not receive treatment for recurrence, and treatment was unknown in 6 patients.

TABLE 1 :

 1 Patients characteristics

	n	%

TABLE 1 :

 1 Patients characteristics

	n	%

Meanwhile, in the setting of a rare cancer with limited opportunities for the development of randomized clinical trials, systematic discussion at an expert MTB coupled with a prospective database offers the opportunity to ensure equal access to high quality care to all patients, with the opportunity of continuous assessment of treatment options.

ACKNOWLEDGEMENTS

We thank Pascale MISSY from the Intergroupe Francophone de Cancérologie Thoracique, Paris, France.