Vaysse

Keywords: de novo metastatic breast cancer, surgery, exclusive radiotherapy, locoregional treatment, primary tumor, tumor biology

published or not. The documents may come

Introduction

Breast cancer (BC) is the most frequent cancer among women worldwide. Five to eight percent of patients present with metastasis at initial diagnosis (stage IV) which is known as de novo metastatic breast cancer (dnMBC) [START_REF] Dawood | Trends in survival over the past two decades among white and black patients with newly diagnosed stage IV breast cancer[END_REF][START_REF] Gobbini | Time trends of overall survival among metastatic breast cancer patients in the real-life ESME cohort[END_REF][START_REF] Malmgren | Differential presentation and survival of de novo and recurrent metastatic breast cancer over time: 1990-2010[END_REF]. These patients represent up to 25% of all metastatic breast cancers and have a better prognosis than metastatic relapse [START_REF] Malmgren | Differential presentation and survival of de novo and recurrent metastatic breast cancer over time: 1990-2010[END_REF][START_REF] Den Brok | Survival with metastatic breast cancer based on initial presentation, de novo versus relapsed[END_REF][START_REF] Thomas | Initial Surgery and Survival in Stage IV Breast Cancer in the United States, 1988-2011[END_REF]. In addition, new types of management have led to increased overall survival (OS) with 20 to 40% exceeding 5 years [START_REF] Malmgren | Differential presentation and survival of de novo and recurrent metastatic breast cancer over time: 1990-2010[END_REF][START_REF] Sundquist | Improved survival in metastatic breast cancer 1985-2016[END_REF][START_REF] Pons-Tostivint | Survival Impact of Locoregional Treatment of the Primary Tumor in De Novo Metastatic Breast Cancers in a Large Multicentric Cohort Study: A Propensity Score-Matched Analysis[END_REF]. Therefore, the question of locoregional treatment (LRT) for these patients with an intact primary tumor (PT) has arisen as a means not only to control locoregional evolution but also to increase OS. Although no recommendations exist on this topic except to control palliative symptoms, recent large real-world databases from Europe and USA showed that approximately 40% of women undergo LRT in the context of dnMBC [START_REF] Thomas | Initial Surgery and Survival in Stage IV Breast Cancer in the United States, 1988-2011[END_REF][START_REF] Pons-Tostivint | Survival Impact of Locoregional Treatment of the Primary Tumor in De Novo Metastatic Breast Cancers in a Large Multicentric Cohort Study: A Propensity Score-Matched Analysis[END_REF][START_REF] Lane | Surgical Resection of the Primary Tumor in Women With De Novo Stage IV Breast Cancer[END_REF]. However, this question has been controversial for decades, with many meta-analyses trying to synthesize highly heterogeneous data [START_REF] Harris | Meta-analysis to determine if surgical resection of the primary tumour in the setting of stage IV breast cancer impacts on survival[END_REF][START_REF] Petrelli | Surgery of primary tumors in stage IV breast cancer: an updated meta-analysis of published studies with meta-regression[END_REF][START_REF] Xiao | Primary tumor resection in stage IV breast cancer: A systematic review and meta-analysis[END_REF][START_REF] Headon | Surgical treatment of the primary tumour improves the overall survival in patients with metastatic breast cancer: A systematic review and meta-analysis[END_REF][START_REF] Gera | Locoregional therapy of the primary tumour in de novo stage IV breast cancer in 216 066 patients: A metaanalysis[END_REF].

The question was first addressed from a surgical point of view, leading to the publication of about 10 retrospective studies. The primary aim was to ensure locoregional control, since local evolution of a breast tumor may result in a profound alteration of the quality of life (QoL) [START_REF] Hazard | Surgical resection of the primary tumor, chest wall control, and survival in women with metastatic breast cancer[END_REF]. Before the 2000s, MBC were not separated into different immunohistochemical (IHC) subtypes (based on Human Epidermal Growth Factor Receptor-2 (HER2) and hormonal receptor (HR) status), and no systemic tailored therapeutic options were available, except endocrine therapy. Nowadays, all therapeutic decisions are based on patient-related factors (age, comorbidities), metastatic dissemination (site and number of metastases) and most importantly tumor biology. Tailored systemic therapies, including targeted therapies and immunotherapy, have led to increased OS in subgroups of patients [START_REF] Baselga | Pertuzumab plus Trastuzumab plus Docetaxel for Metastatic Breast Cancer[END_REF][START_REF] Diéras | Trastuzumab emtansine versus capecitabine plus lapatinib in patients with previously treated HER2positive advanced breast cancer (EMILIA): a descriptive analysis of final overall survival results from a randomised, open-label, phase 3 trial[END_REF][START_REF] Schmid | Atezolizumab and Nab-Paclitaxel in Advanced Triple-Negative Breast Cancer[END_REF][START_REF] Sledge | The Effect of Abemaciclib Plus Fulvestrant on Overall Survival in Hormone Receptor-Positive, ERBB2-Negative Breast Cancer That Progressed on Endocrine Therapy-MONARCH 2: A Randomized Clinical Trial[END_REF]. In parallel, radiotherapy (RT) techniques have considerably improved, allowing for the radiation dose to conform more precisely to the three-dimensional shape of the tumor, thus enabling much higher radiation doses and better tumor control with less toxicity [START_REF] Barry | Establishing the Role of Stereotactic Ablative Body Radiotherapy in Early-Stage Breast Cancer[END_REF][START_REF] Onderdonk | The Evolution (and Future) of Stereotactic Body Radiotherapy in the Treatment of Oligometastatic Disease[END_REF].

Consequently, the LRT of the PT in dnMBC is no longer only a surgical challenge, but more the result of a shared medical decision between medical, radiation and surgical oncologists. It is no longer only a question of locoregional control but rather a wider issue of improving OS, due to the possible biological link between PT and metastases. We discuss herein the question of LRT in dnMBC in the current era of BC IHC subtypes and focus on retrospective studies including enough biological and clinical parameters to be transposed to current practice and issues. We then discuss recent results from prospective studies (published and ongoing) and focus on clinical data involving exclusive RT (ERT) as a therapeutic modality, as more data are currently available. We next discuss the biological rationale for LRT in metastatic disease including new pre-clinical data available on the immune system and its interaction with tumor cells. We conclude with a proposed algorithm to select the optimal candidates for LRT.

2. LRT or no LRT: evidence and unresolved questions 2.1 Who are de novo metastatic breast cancer patients in 2020?

Although BC screening largely increased the proportion of small localized tumors at diagnosis, the use of more sensitive diagnostic imagery (computed tomography (CT)-scan or positron emission tomography-CT) allows for better detection of metastatic lesions.

Interestingly, the proportion of dnMBC has remained globally stable over the last decades at around 3 to 8% (2-4), but there are several patterns of dnMBC at diagnosis:

-It could be the early dissemination from the PT, which is sometimes even unknown. Indeed, among dnMBC at diagnosis, 30 to 40% present with a tumor smaller than 5 cm without clinical node involvement in 15-25% [START_REF] Thomas | Initial Surgery and Survival in Stage IV Breast Cancer in the United States, 1988-2011[END_REF][START_REF] Pons-Tostivint | Survival Impact of Locoregional Treatment of the Primary Tumor in De Novo Metastatic Breast Cancers in a Large Multicentric Cohort Study: A Propensity Score-Matched Analysis[END_REF][START_REF] Warschkow | Improved Survival After Primary Tumor Surgery in Metastatic Breast Cancer: A Propensity-adjusted, Population-based SEER Trend Analysis[END_REF]. This suggests dissemination from early transformed lesions and acquisition of important genetic changes at the metastatic site, a phenomenon known as parallel progression [START_REF] Klein | Parallel progression of primary tumours and metastases[END_REF].

-It could be slow growth from a neglected PT, which finally lead to metastatic sites that grow at equal rates (defined as linear progression, since genetic alterations originate mainly from the PT [START_REF] Turajlic | Metastasis as an evolutionary process[END_REF]).

-Finally, it could be a quick and aggressive disease phenotype, with an aggressive locoregional disease with skin nodules on the chest wall that concomitantly develop secondary lesions. Up to 30% of patients with inflammatory BC have metastases at diagnosis [START_REF] Matro | Inflammatory breast cancer management in the national comprehensive cancer network: the disease, recurrence pattern, and outcome[END_REF]. Also, the metastatic burden at diagnosis of dnMBC is heterogeneous and can vary from a mono-metastatic disease to a diffuse multi-metastatic state. A subset of patients are therefore diagnosed with an oligometastatic disease, defined by a limited number and size of metastatic lesions ranging from 1 to 5, not necessarily in the same organ [START_REF] Cardoso | 5th ESO-ESMO internaIonal consensus guidelines for advanced breast cancer (ABC 5) †[END_REF]. Several large studies in a variety of primary tumor types with oligometastatic dissemination have demonstrated prolonged survival associated with local primary (in the de novo metastatic disease) plus metastases loco-regional treatment [START_REF] Gutiontov | Oligometastasis: Past, Present, Future[END_REF]. As discussed below, these highly heterogeneous patients indistinctly included in retrospective studies will certainly affect the indication, the type and the impact of LRT.

Heterogeneous retrospective studies prevent homogeneous recommendations

Most clinical data available come from retrospective studies, including large population-based studies involving thousands of patients and smaller mono/multicenter institutional studies [START_REF] Hazard | Surgical resection of the primary tumor, chest wall control, and survival in women with metastatic breast cancer[END_REF][START_REF] Rapiti | Complete Excision of Primary Breast Tumor Improves Survival of Patients With Metastatic Breast Cancer at Diagnosis[END_REF][START_REF] Babiera | Effect of primary tumor extirpation in breast cancer patients who present with stage IV disease and an intact primary tumor[END_REF][START_REF] Fields | Surgical Resection of the Primary Tumor is Associated with Increased Long-Term Survival in Patients with Stage IV Breast Cancer after Controlling for Site of Metastasis[END_REF][START_REF] Bafford | Breast surgery in stage IV breast cancer: impact of staging and patient selection on overall survival[END_REF][START_REF] Neuman | Stage IV breast cancer in the era of targeted therapy: does surgery of the primary tumor matter?[END_REF][START_REF] Shien | Primary tumor resection improves the survival of younger patients with metastatic breast cancer[END_REF] (main studies are listed in Table 1) [START_REF] Thomas | Initial Surgery and Survival in Stage IV Breast Cancer in the United States, 1988-2011[END_REF][START_REF] Pons-Tostivint | Survival Impact of Locoregional Treatment of the Primary Tumor in De Novo Metastatic Breast Cancers in a Large Multicentric Cohort Study: A Propensity Score-Matched Analysis[END_REF][START_REF] Lane | Surgical Resection of the Primary Tumor in Women With De Novo Stage IV Breast Cancer[END_REF][START_REF] Hazard | Surgical resection of the primary tumor, chest wall control, and survival in women with metastatic breast cancer[END_REF][START_REF] Warschkow | Improved Survival After Primary Tumor Surgery in Metastatic Breast Cancer: A Propensity-adjusted, Population-based SEER Trend Analysis[END_REF][START_REF] Rapiti | Complete Excision of Primary Breast Tumor Improves Survival of Patients With Metastatic Breast Cancer at Diagnosis[END_REF][START_REF] Fields | Surgical Resection of the Primary Tumor is Associated with Increased Long-Term Survival in Patients with Stage IV Breast Cancer after Controlling for Site of Metastasis[END_REF][START_REF] Bafford | Breast surgery in stage IV breast cancer: impact of staging and patient selection on overall survival[END_REF][START_REF] Neuman | Stage IV breast cancer in the era of targeted therapy: does surgery of the primary tumor matter?[END_REF]. Five meta-analyses published over the past two decades suggested that PT surgical resection may improve survival with a hazard ratio (HR) around 0.60 [START_REF] Harris | Meta-analysis to determine if surgical resection of the primary tumour in the setting of stage IV breast cancer impacts on survival[END_REF][START_REF] Petrelli | Surgery of primary tumors in stage IV breast cancer: an updated meta-analysis of published studies with meta-regression[END_REF][START_REF] Xiao | Primary tumor resection in stage IV breast cancer: A systematic review and meta-analysis[END_REF][START_REF] Headon | Surgical treatment of the primary tumour improves the overall survival in patients with metastatic breast cancer: A systematic review and meta-analysis[END_REF][START_REF] Gera | Locoregional therapy of the primary tumour in de novo stage IV breast cancer in 216 066 patients: A metaanalysis[END_REF]. The most recent one published by Gera et al. in 2020 included 42 studies and concluded that surgery would specifically reduce mortality by 36.2% [START_REF] Gera | Locoregional therapy of the primary tumour in de novo stage IV breast cancer in 216 066 patients: A metaanalysis[END_REF]. However, several dozens of studies were performed before the era of high-quality imaging to assess metastatic extension, but also before the current IHC classification and systemic tailored therapies, thus limiting their relevancy in the current thinking. Consequently, differences observed in terms of OS between LRT and no-LRT could result from several biases [START_REF] Bafford | Breast surgery in stage IV breast cancer: impact of staging and patient selection on overall survival[END_REF][START_REF] Cady | Matched Pair Analyses of Stage IV Breast Cancer with or Without Resection of Primary Breast Site[END_REF][START_REF] Dominici | Surgery of the primary tumor does not improve survival in stage IV breast cancer[END_REF], and from heterogeneity between studies including:

-A very long period of recruitment sometimes spanning more than 40 years and consequently different systemic therapy modalities (before and/or after LRT) [START_REF] Shien | Primary tumor resection improves the survival of younger patients with metastatic breast cancer[END_REF].

-Indisputable selection bias: women who received surgery tended to be younger and healthier, to have smaller PT, a lower burden of metastatic disease, and were less likely to have visceral metastases (review in [START_REF] Khan | Surgical Management of de novo Stage IV Breast Cancer[END_REF]).

-Sensitivity to systemic therapy (ST), which could influence the decision to propose LRT and thus local therapy, may serve as a surrogate of systemic response. Clearance of metastases after ST was unknown in retrospective studies, and it is impossible to determine why women went to surgery. Some studies only included patients with a systemic response, while others included all patients at diagnosis. Patients who did not respond to first-line ST would be more likely included in the no-LRT group, thereby biasing this subgroup with a poor prognosis.

-Different treatment modalities between patients within the same study or between studies regarding surgical timing, resection margins, axillary dissection, radiation therapy, primary induction ST and the type of induction therapy.

Identifying the clinical pattern involved in retrospective studies is very challenging, even with robust statistic methods including multivariate regression analysis and/or, in recent years, the addition of propensity analysis [START_REF] Pons-Tostivint | Survival Impact of Locoregional Treatment of the Primary Tumor in De Novo Metastatic Breast Cancers in a Large Multicentric Cohort Study: A Propensity Score-Matched Analysis[END_REF][START_REF] Warschkow | Improved Survival After Primary Tumor Surgery in Metastatic Breast Cancer: A Propensity-adjusted, Population-based SEER Trend Analysis[END_REF][START_REF] Gnerlich | Surgical removal of the primary tumor increases overall survival in patients with metastatic breast cancer: analysis of the 1988-2003 SEER data[END_REF][START_REF] Vohra | Primary tumor resection in metastatic breast cancer: A propensity-matched analysis, 1988-2011 SEER data base[END_REF][START_REF] Mudgway | The Impact of Primary Tumor Surgery on Survival in HER2 Positive Stage IV Breast Cancer Patients in the Current Era of Targeted Therapy[END_REF]. To limit this bias, it is necessary to select only the patients who had an objective response or a stable disease to the first line of ST and to exclude those who died or progressed quickly after diagnosis [START_REF] Pons-Tostivint | Survival Impact of Locoregional Treatment of the Primary Tumor in De Novo Metastatic Breast Cancers in a Large Multicentric Cohort Study: A Propensity Score-Matched Analysis[END_REF][START_REF] Lane | Surgical Resection of the Primary Tumor in Women With De Novo Stage IV Breast Cancer[END_REF][START_REF] Wang | Metastatic pattern discriminates survival benefit of primary surgery for de novo stage IV breast cancer: A real-world observational study[END_REF]. The largest study that specifically tried to control this bias by selecting patients who survived at least 1 year was published in 2019 [START_REF] Lane | Surgical Resection of the Primary Tumor in Women With De Novo Stage IV Breast Cancer[END_REF]. Nearly 25000 patients were included: 56% received ST alone, 19% underwent PT surgery before ST and 25% underwent PT surgery after ST. The authors concluded that surgical resection of the PT was associated with improved survival, regardless of the treatment sequence (HR=0.72 and HR=0.58 before and after ST, respectively).

Unfortunately, HER2 status was not available in this database.

However, since the prognosis of dnMBC is first linked to metastases, clinical oncologists now widely agree that it is better to initiate a ST, which also has the advantage of testing for sensitivity of the tumor and therefore selecting the optimal patients. Moreover, most of the retrospective studies did not include information about two major indispensable criteria for therapeutic decision-making today: pattern of metastatic disease and IHC profile, both of which have been largely reported as prognostic factors in dnMBC [START_REF] Dawood | Trends in survival over the past two decades among white and black patients with newly diagnosed stage IV breast cancer[END_REF][START_REF] Dawood | Prognosis of women with metastatic breast cancer by HER2 status and trastuzumab treatment: an institutional-based review[END_REF][START_REF] Bertaut | Stage IV breast cancer: a population-based study about prognostic factors according to HER2 and HR status[END_REF]. Patients diagnosed with oligometastatic disease were mostly not identified, and potential local ablative treatments on metastatic lesions were not reported.

Superiority of tumor biology over anatomic dissemination for decision-making: an evolving paradigm

The 5th ESO (European School of Oncology)-ESMO (European Society of Medical Oncology) international consensus guidelines for advanced breast cancer (ABC5) suggested that a multimodal approach, including LRT with curative intent, should be considered for selected metastatic BC patients, especially for the subset of patients with bone-only disease [START_REF] Cardoso | 5th ESO-ESMO internaIonal consensus guidelines for advanced breast cancer (ABC 5) †[END_REF]. Recent real-world observational studies showed that bone was the most common site of metastasis (around 45% of patients) and up to 30% of patients were diagnosed with bone-only metastases [START_REF] Pons-Tostivint | Survival Impact of Locoregional Treatment of the Primary Tumor in De Novo Metastatic Breast Cancers in a Large Multicentric Cohort Study: A Propensity Score-Matched Analysis[END_REF][START_REF] Wang | Metastatic pattern discriminates survival benefit of primary surgery for de novo stage IV breast cancer: A real-world observational study[END_REF]. A recent, large real-world observational study based on the SEER (Surveillance, Epidemiology, and End Results) database including 8000 patients investigated the survival benefit of PT resection according to metastatic pattern at diagnosis [START_REF] Wang | Metastatic pattern discriminates survival benefit of primary surgery for de novo stage IV breast cancer: A real-world observational study[END_REF]. They found that local breast surgery of bone-only metastasis patients offered a significant survival improvement (HR=0.83, p<0.05), which was not found for patients with other single-organ locations. Another retrospective study suggested that the subset of patients with bone-only metastases, even when they were multiple, could benefit from LRT [START_REF] Rapiti | Complete Excision of Primary Breast Tumor Improves Survival of Patients With Metastatic Breast Cancer at Diagnosis[END_REF]. For oligometastatic disease, some retrospective and prospective series demonstrated that local treatment of all metastases, when feasible, was significantly associated with prolonged survival [START_REF] Trovo | Radical radiation therapy for oligometastatic breast cancer: Results of a prospective phase II trial[END_REF]. Patients with oligometastatic bone-only MBC treated with stereotactic radiotherapy had better clinical outcomes than other sites of metastases [START_REF] Milano | Oligometastatic breast cancer treated with hypofractionated stereotactic radiotherapy: Some patients survive longer than a decade[END_REF]. In a study from the SEER database, after stratification based on the distant organ involved, authors found that local breast surgery was associated with a better survival in patients with only one distant organ involved (such as bone, liver or lung) excepted for brain-only metastasis [START_REF] Li | Locoregional surgical treatment improves the prognosis in primary metastatic breast cancer patients with a single distant metastasis except for brain metastasis[END_REF]. This asks the question of the adequate timing for each local treatment (PT and metastases) which is still unknown and should be discussed in multidisciplinary concertation. Two ongoing prospective phase III trials (NCT02089100, NCT02364557) are evaluating the role of metastases local ablation (Stereotactic Body Radiation therapy (SBRT) or surgery) with curative intent in oligometastatic breast cancer. In dnMBC patients, the PT has to have been treated with curative intent. Interestingly, NCT02089100 study excluded patients with TN tumors. Indeed, one major limitation of the retrospective studies was that IHC profile was not available, although each subtype of BC has a preferential site for metastasis: HR-positive tumors tend to metastasize to bone, whereas both HER2-positive and TN tumors are at high risk of developing visceral and brain metastases [START_REF] Leone | Prognostic impact of metastatic pattern in stage IV breast cancer at initial diagnosis[END_REF][START_REF] Lee | Implications of bone-only metastases in breast cancer: favorable preference with excellent outcomes of hormone receptor positive breast cancer[END_REF][START_REF] Smid | Subtypes of breast cancer show preferential site of relapse[END_REF]. In addition, each IHC profile has a distinct prognosis with the availability of tailored therapies. Indeed, the survival trend in metastatic patients with HER2-positive tumors treated before the advent of anti-HER2 treatment was similar to that in women with TN tumors [START_REF] Bertaut | Stage IV breast cancer: a population-based study about prognostic factors according to HER2 and HR status[END_REF]. Therefore, disregarding the IHC profile and the advent of anti-HER2 therapies when considering LRT induces a severe bias.

Unfortunately, studies focusing on the role of LRT on survival outcomes in the light of IHC profile are limited. The first study was conducted between 2000 and 2004 by Neuman et al. but included only 186 patients [START_REF] Neuman | Stage IV breast cancer in the era of targeted therapy: does surgery of the primary tumor matter?[END_REF]. The authors reported that surgery was not associated with improved OS in patients with TN tumors, whereas it was associated with improved survival in patients with either HR or HER2-positive tumors when hormonal therapy and trastuzumab were used. Results were confirmed in other studies for patients with HER2positive tumors who received trastuzumab, and for those with HR-positive tumors [START_REF] Mudgway | The Impact of Primary Tumor Surgery on Survival in HER2 Positive Stage IV Breast Cancer Patients in the Current Era of Targeted Therapy[END_REF][START_REF] Lambertini | Patterns of Care and Clinical Outcomes of HER2-positive Metastatic Breast Cancer Patients With Newly Diagnosed Stage IV or Recurrent Disease Undergoing First-line Trastuzumabbased Therapy: A Multicenter Retrospective Cohort Study[END_REF][START_REF] Chen | Locoregional therapy in luminal-like and HER2-enriched patients with de novo stage IV breast cancer[END_REF].

In contrast, Dominici et al. did not found that surgery improve survival after adjusting for trastuzumab therapy, but patients who had surgery in the earlier time period (1997)(1998)(1999)(2000)(2001)(2002)(2003)(2004) could negatively biased the study [START_REF] Dominici | Surgery of the primary tumor does not improve survival in stage IV breast cancer[END_REF]. A recent multicenter French retrospective study involving more than 4000 patients between 2008 and 2014 demonstrated that LRT was associated with a better OS in patients with HR-positive (62 vs 46 months, n=2356) and HER2-positive (77 vs 53 months, n=918) tumors, but not in TN tumors (19 vs 19 months, n=495) [START_REF] Pons-Tostivint | Survival Impact of Locoregional Treatment of the Primary Tumor in De Novo Metastatic Breast Cancers in a Large Multicentric Cohort Study: A Propensity Score-Matched Analysis[END_REF]. In this study, all patients received adapted hormonal and/or targeted therapy (excepted cyclin-dependent kinase 4/6 inhibitors). Interestingly, the IHC subtype along with the efficacy of tailored therapy seemed to impact the benefit of LRT more than the pattern of metastatic dissemination [START_REF] Pons-Tostivint | Survival Impact of Locoregional Treatment of the Primary Tumor in De Novo Metastatic Breast Cancers in a Large Multicentric Cohort Study: A Propensity Score-Matched Analysis[END_REF]. Conversely, a study conducted between 2010 and 2013 on the SEER database and including more than 9000 patients (1311 patients with TN tumors) found that the survival benefit was similar regardless of IHC, but the median follow-up was very short (only 13 months), so no conclusions could be drawn [START_REF] Wu | The survival benefits of local surgery in stage IV breast cancer are not affected by breast cancer subtypes: a population-based analysis[END_REF].

To conclude with IHC tumor profiles, without effective tailored ST as is the case for TN tumors, LRT seems to provide no benefit other than for palliative purposes. However, a recent study focused specifically on the impact of PT resection in patients with dnMBC TN tumors (n=1737 from 2010 to 2016) [START_REF] Wang | A Risk Stratification Model for Predicting Overall Survival and Surgical Benefit in Triple-Negative Breast Cancer Patients With de novo Distant Metastasis[END_REF]. The authors proposed a predictive nomogram based on seven independent risk factors which included demographic features (age and marital status) and clinicopathological variables (T stage and bone/brain/liver/lung metastases). The total score of an individual classified the patient into one of three risk-groups. The conclusion was that surgery could improve survival only in highly selected low-and intermediate-risk groups. Therefore, prospective studies including metastatic dissemination along with tailored adapted systemic therapies taking IHC profile into account are needed to enlighten the debate concerning LRT in dnMBC.

Lessons learned from prospective studies

In the last four years, three prospective phase III randomized studies have been published, all with OS as primary objective, with divergent results (Table 2). The first trial was a monocenter Indian study conducted between 2005 and 2013 [START_REF] Badwe | Locoregional treatment versus no treatment of the primary tumour in metastatic breast cancer: an open-label randomised controlled trial[END_REF]. Patients with singlemetastasis amenable to a treatment with a curative intent were excluded. Patients first received induction ST and only those who responded were next randomized to surgery +/-RT, vs no LRT. Importantly, following induction therapy, if response or stable disease was obtained, ST was not maintained but only resumed after progression. This means that if the local treatment accelerated the growth of metastatic lesions (concept of "surgical wounding" described in part 4.2), it was not controlled with additional ST. Moreover, patients did not receive ST according to BC IHC subtypes, so no comparison with current standard of care was possible. The median OS was not improved by LRT (20.5 vs 19.2 months between the LRT / no-LRT groups). However, LRT was associated with a significant improvement in locoregional disease control compared to no LRT (p<0.0001).

The two other prospective trials randomized patients before any ST prior to LRT. This time, ST included chemotherapy, anti-HER2 and hormonal therapy according to IHC subtypes. The MF07-01 trial from Turkey (73) suggested a potential benefit after the fifth year of follow-up (41.6% of the patients were alive in the LRT group vs 24.4% in the no-LRT group (p = 0.005)), that was not observed in a previous report after only 3 years (60% vs 51% of survival between both groups, p=0.10). Unplanned subgroup analysis suggested a potential benefit in patients with an HR-positive, HER2-negative tumor, younger than 55 years, and with a metastatic disease limited to a solitary bone lesion. On the other hand, patients with multiple liver/pulmonary metastases had a significantly worse prognosis with initial surgery.

For patients with TN tumors, the median OS was not different between the groups (17.5 vs 18 months in the LRT / no-LRT group). The third study was an Austrian study (POSYTIVE, ABCSG 28) that failed to demonstrate any benefit associated with LRT [START_REF] Fitzal | Impact of Breast Surgery in Primary Metastasized Breast Cancer: Outcomes of the Prospective Randomized Phase III ABCSG-28 POSYTIVE Trial[END_REF]. Due to poor recruitment, the study was stopped prematurely (after the inclusion of only 90 patients out of the 254 needed), so the results should be interpreted with caution. Stratification was done according to tumor grade, IHC, visceral vs bone-only metastases, and planned first-line ST.

Median OS was 34.6 months in the LRT group vs 54.8 months in the no-LRT group. Time to local progression (including breast and lymph nodes) was similar between both arms (HR=0.93). Post hoc analysis suggested that luminal A patients had worse results after upfront surgery (HR=0.3 (0.1-0.8)). Other subgroups were insignificant. A QoL analysis revealed no difference between both groups.

In conclusion, based on the prospective available studies, different approaches at the time of randomization (before or after primary ST) and different availabilities of modern ST (including targeted therapies), the results are divergent. Therefore, no definitive conclusions can be drawn about the benefits of breast surgery. As testimony to the difficulty of resolving this question, other studies failed to be ended. One randomized trial from the Netherlands was closed in 2014 due to poor enrolment (SUBMIT, NCT01392586), and one from Thailand was withdrawn (NCT01906112).

Fortunately, results from other prospective trials will soon be available (Table 3). In a Japanese Clinical Oncology Group study (JCOG 1017) and an American Eastern Clinical Oncology Group (ECOG 2108) study, after a first line of the most up-to-date ST according to their IHC status, women were randomized to undergo surgery or no (+/-RT). ST were continued [START_REF] Shien | The eligibility of primary tumor resection for de novo stage IV breast cancer patients[END_REF][START_REF] Shien | A randomized controlled trial comparing primary tumour resection plus systemic therapy with systemic therapy alone in metastatic breast cancer (PRIM-BC): Japan Clinical Oncology Group Study JCOG1017[END_REF]. These two studies have now completed the enrolment. First results of the phase III ECOG were presented at the ASCO (American Society of Clinical Oncology) congress 2020 and reported no survival benefit of surgery and radiotherapy of the PT, with no differences according to IHC status in terms of OS. Subgroup analysis according to the metastatic site has not been presented yet. Before drawing any proper conclusion, we are waiting for the publication of the study. A third prospective, non-randomized study should begin soon in France (PALATINE, NCT03870919), evaluating the combination of palbociclib plus letrozole with LRT (surgery +/-RT, or ERT) after six months of ST. This study is particularly interesting as it also investigates the type of LRT, which is also an important issue.

3. Metastatic breast cancer, a disease where survival and comfort matter: which LRT?

3.1 Surgery: an old candidate Surgery of the PT in dnMBC has been performed for decades but the preferential type of surgery in this singular context remains unknown. We will not discuss this topic in an exhaustive manner as it is the focus of a specific review [START_REF] Khan | Surgical Management of de novo Stage IV Breast Cancer[END_REF]. We will only address some key points.

First, concerning the type of surgery, few studies have compared the OS benefit between radical treatment and conservative treatment. Whereas studies reported no difference in OS between the two types of surgery, complete excision with clear surgical margins reduced the risk of death significantly [START_REF] Rapiti | Complete Excision of Primary Breast Tumor Improves Survival of Patients With Metastatic Breast Cancer at Diagnosis[END_REF][START_REF] Khan | Does aggressive local therapy improve survival in metastatic breast cancer?[END_REF][START_REF] Kommalapati | A prognostic scoring model for survival after locoregional therapy in de novo stage IV breast cancer[END_REF][START_REF] Nguyen | Can Locoregional Treatment of the Primary Tumor Improve Outcomes for Women With Stage IV Breast Cancer at Diagnosis[END_REF]. In another study, however, OS was better in the mastectomy group, but 26% had positive margins in the lumpectomy group vs only 3% in the case of total mastectomy (p <0.001) [START_REF] Mcguire | Factors associated with improved outcome after surgery in metastatic breast cancer patients[END_REF]. Therefore, it seems that if surgery of the PT is considered for dnMBC other than for palliative reasons, it should be planned with the intent of obtaining negative margins [START_REF] Cardoso | 5th ESO-ESMO internaIonal consensus guidelines for advanced breast cancer (ABC 5) †[END_REF]. To date, the benefit of axillary dissection on survival has not been demonstrated, and it is particularly morbid [START_REF] Mclaughlin | Prevalence of lymphedema in women with breast cancer 5 years after sentinel lymph node biopsy or axillary dissection: objective measurements[END_REF]. Therefore, it is to date not indicated but it can be discussed on a multidisciplinary basis, associated with optimal breast surgery, for patients with initial axillary lymph node involvement.

Because it has existed for decades, LRT is often only thought of in terms of surgery. However, only a few studies have investigated the benefit of ERT, yet it is far from lacking value.

Exclusive RT (ERT): data on overall survival

Only a few studies (summarized in Table 4) have evaluated survival outcome in patients who received ERT [START_REF] Nguyen | Can Locoregional Treatment of the Primary Tumor Improve Outcomes for Women With Stage IV Breast Cancer at Diagnosis[END_REF][START_REF] Scodan | Breast Cancer With Synchronous Metastases: Survival Impact of Exclusive Locoregional Radiotherapy[END_REF][START_REF] Bourgier | Breast radiotherapy as part of loco-regional treatments in stage IV breast cancer patients with oligometastatic disease[END_REF][START_REF] Pons-Tostivint | Radiation therapy to the primary tumor for de novo metastatic breast cancer and overall survival in a retrospective multicenter cohort analysis[END_REF]. However, it appears that up to 40% of physicians propose it in clinical practice [START_REF] Pons-Tostivint | Radiation therapy to the primary tumor for de novo metastatic breast cancer and overall survival in a retrospective multicenter cohort analysis[END_REF]. All these studies are retrospective as none of the prospective studies terminated or ongoing (Tables 2 and3) included an ERT group. The most important limitation is that all studies except one stopped recruiting patients long before new systemic therapeutic advances in MBC became available, especially anti-HER2 targeted therapies. Moreover, they do not give much information concerning the different techniques of RT. Two studies were monocenter, both recruiting until 2003/2004 [START_REF] Scodan | Breast Cancer With Synchronous Metastases: Survival Impact of Exclusive Locoregional Radiotherapy[END_REF][START_REF] Bourgier | Breast radiotherapy as part of loco-regional treatments in stage IV breast cancer patients with oligometastatic disease[END_REF]. The first compared an LRT group in which 78% patients received ERT (n=249/320) to a non-LRT group (n=261) [START_REF] Scodan | Breast Cancer With Synchronous Metastases: Survival Impact of Exclusive Locoregional Radiotherapy[END_REF]. The authors demonstrated that LRT was associated with a significantly better OS (HR=0.70 [0.58; 0.85]), and ERT was an independent factor for OS in multivariate analysis. The other monocenter study compared ERT (n=147) with surgery-based LRT (n=92, combined with RT for 70% of them) [START_REF] Bourgier | Breast radiotherapy as part of loco-regional treatments in stage IV breast cancer patients with oligometastatic disease[END_REF]. Results were similar for OS between both modalities (HR=1.05 [0.72; 1.73]), without comparison with a non-LRT group.

Two larger multicenter studies also evaluated ERT. The first one was from the British Columbia Database and was conducted between 1996 and 2005 [START_REF] Nguyen | Can Locoregional Treatment of the Primary Tumor Improve Outcomes for Women With Stage IV Breast Cancer at Diagnosis[END_REF]. It was not specifically designed to analyze an ERT group, but rather to compare LRT (n=378) vs no-LRT (n=355).

However, ERT represented a significant number of patients (22%, n=82), whereas surgery alone and both treatments represented 67% (n=255) and 11% (n=41), respectively. LRT, regardless of the modality, was associated with a significantly better OS in multivariate analysis (HR=0.78 [0.64; 0.94]). Finally, the most recent and largest multicenter study was conducted between 2008 and 2014 and included 1965 patients from 18 French Cancer Centers [START_REF] Pons-Tostivint | Radiation therapy to the primary tumor for de novo metastatic breast cancer and overall survival in a retrospective multicenter cohort analysis[END_REF]. The impact of each LRT modality on OS was analyzed separately compared to a no-LRT group: 366 patients (41%) underwent exclusive RT, 122 (14%) exclusive surgery and 403 (45%) a combination of both. To limit the selection bias described above, only patients free from progression at least one year after diagnosis were included. After adjustment on confounding factors, ERT was significantly associated with a 37% reduction in the risk of death (HR=0.63 [0.49, 0.80]), in the same range as surgery associated with RT (39%, HR=0.61 [0.47, 0.78]) compared to no-LRT [START_REF] Pons-Tostivint | Radiation therapy to the primary tumor for de novo metastatic breast cancer and overall survival in a retrospective multicenter cohort analysis[END_REF].

Reasons for the choice of the type of LRT were probably associated strongly with the clinical context, which is not specified in retrospective studies. Patients who received ERT vs surgery-based treatment had larger PT size and a greater tumor burden [START_REF] Bourgier | Breast radiotherapy as part of loco-regional treatments in stage IV breast cancer patients with oligometastatic disease[END_REF][START_REF] Pons-Tostivint | Radiation therapy to the primary tumor for de novo metastatic breast cancer and overall survival in a retrospective multicenter cohort analysis[END_REF]. Regarding IHC, TN and HER2-positive tumors were more often treated with ERT, whereas HR+/HER2negative tumors more often received a combined therapy with surgery plus RT [START_REF] Pons-Tostivint | Radiation therapy to the primary tumor for de novo metastatic breast cancer and overall survival in a retrospective multicenter cohort analysis[END_REF]. It seems that patients with more indolent diseases (luminal) are more likely to benefit from a "complete" LRT.

Exclusive RT: a credible alternative to surgery for locoregional control?

The literature is sparse regarding ERT as an alternative to breast surgery for locoregional control, but there is some proof that it could be an effective means of control in selected patients. It has been studied mostly in localized disease, for elderly people who are often associated with disabling disease, making oncologists or the patients themselves reluctant for surgery. For example, hypofractioned RT (which is not the current standard) was analyzed in 115 elderly non-metastatic patients (after 3-6 months of hormonal therapy for HR+ patients) [START_REF] Courdi | Long-term results of hypofractionated radiotherapy and hormonal therapy without surgery for breast cancer in elderly patients[END_REF]. The 5-year local PFS was 78% (included 33% ≥ T3). Local failure was not correlated with tumor size or nodal status. Chargari et al. [START_REF] Chargari | The impact of the loco-regional treatment in elderly breast cancer patients: hypo-fractionated exclusive radiotherapy, single institution long-term results[END_REF] studied 29 patients with localized T1-T2 invasive tumors, N0 for 62% of them, who received ERT (32.5 Gy/5 fractions/5 weeks followed by a 13 Gy boost) concomitantly to hormonal therapy. With a median 7-year followup, locoregional control was 95.8% and cause-specific survival was 96.4%.

The retrospective studies listed in Table 4 provide additional information regarding local disease control with ERT in dnMBC. RT doses and fields, when available, are described in the table. Bourgier et al. [START_REF] Bourgier | Breast radiotherapy as part of loco-regional treatments in stage IV breast cancer patients with oligometastatic disease[END_REF] found that only 8/147 (5.4%) patients developed a local recurrence after a median follow-up of 6.5 years [1-15.4]. In the Canadian study [START_REF] Nguyen | Can Locoregional Treatment of the Primary Tumor Improve Outcomes for Women With Stage IV Breast Cancer at Diagnosis[END_REF], patients who received LRT (but only 22% received ERT) had significantly improved locoregional PFS compared to no-LRT patients, from 46% to 72% at 5 years (p<0.001). Another study, without a comparative arm, found a local PFS at 5 years of 67.3%, but half of the patients (67/125) also received surgery plus RT [START_REF] Mauro | Effects of locoregional radiotherapy in patients with metastatic breast cancer[END_REF]. The French multicenter study found a significant decrease in the risk of progression compared to no-LRT: 31% for ERT (HR=0.69 [0.59; 0.81]) and 35% for combined modalities (HR=0.65 [0.55; 0.76]) [START_REF] Pons-Tostivint | Radiation therapy to the primary tumor for de novo metastatic breast cancer and overall survival in a retrospective multicenter cohort analysis[END_REF]. However, they did not differentiate local and distant progression, so it was impossible to draw any firm conclusions.

Surgery, radiotherapy, or both: is it ethical to risk toxicity without evidence of efficacy?

Optimal management of dnMBC should maintain the highest QoL for patients since the disease is incurable [START_REF] Cardoso | 5th ESO-ESMO internaIonal consensus guidelines for advanced breast cancer (ABC 5) †[END_REF]. However, breast conservative surgery, mastectomy, axillary dissection, RT, and sometimes the combination of all these modalities may alter the image of the body and require hospitalization, anesthesia, and several trips back to the hospital. In addition, there are few data in the literature regarding the efficacy of LRT, and even less regarding its toxicity. Surgery could lead to complications such as hematoma, lymphedema, and infection. Moreover, questions arise about breast reconstruction after mastectomy, which could increase the risk of surgical complications [START_REF] Barry | Delay of adjuvant chemotherapy after elective mastectomy and immediate reconstruction in breast-conservation candidates: a matched-pair analysis[END_REF]. Nor is RT without side-effects, such as early skin reactions and esophageal toxicities, or later ones such as subcutaneous fibrosis, telangiectasia, and lymphedema. The combination of ST and RT may cause cumulative sideeffects, especially cardiotoxic effects or pulmonary fibrosis. On the other hand, QoL may also be impaired by an uncontrolled chest wall, thereby justifying medical procedures [START_REF] Hazard | Surgical resection of the primary tumor, chest wall control, and survival in women with metastatic breast cancer[END_REF].

Moreover, palpation of a residual tumor may result in high anxiety, altering QoL, and inviting patients themselves to ask for removal of the PT to feel better.

ERT may offer satisfactory local control, without undergoing surgery. In addition, RT can be performed on an outpatient basis, without the need for anesthesia or a surgical block, which can be important in older or frail patients. A recent observational study evaluated the feasibility and the toxicity of helical tomotherapy to control locoregional tumors in dnMBC and locally advanced BC [START_REF] Thery | Use of helical tomotherapy in locally advanced and/or metastatic breast cancer for locoregional treatment[END_REF]. 39% had undergone surgery before RT, and ST was administered concurrently in 91% of cases. RT led to significant clinical improvement in 75% of cases with tumor involving skin (n=19 patients), with a positive impact on QoL. In seven of eight patients with locally advanced tumors, there was tumor regression. At the other hand, these series have shown that patients treated for metastatic disease who responded to ST had better OS after locoregional RT, in comparison with those who were presented with locally advance BC without metastasis, but who were bad responders to ST [START_REF] Thery | Use of helical tomotherapy in locally advanced and/or metastatic breast cancer for locoregional treatment[END_REF].

Moreover, whatever the LRT, it should not result in delayed administration of ST, which remains the mainstay of treatment for metastatic disease. Interestingly, for HER2positive patients, the combination of anti-HER2 therapies along with radiotherapy shows no serious adverse events [START_REF] Jacob | Concurrent administration of trastuzumab with locoregional breast radiotherapy: long-term results of a prospective study[END_REF][START_REF] Mignot | Concurrent administration of anti-HER2 therapy and radiotherapy: Systematic review[END_REF]. Similarly, for HR-positive patients, CDK4/6 inhibitors in association with radiotherapy also seem well tolerated, as suggested by the latest studies [START_REF] Ippolito | Concurrent radiotherapy with palbociclib or ribociclib for metastatic breast cancer patients: Preliminary assessment of toxicity[END_REF][START_REF] Chowdhary | Safety and Efficacy of Palbociclib and Radiation Therapy in Patients With Metastatic Breast Cancer: Initial Results of a Novel Combination[END_REF]. However, although neutropenia is rapidly reversible, it is nonetheless the most frequent adverse event reported with these therapies so the risk of infection should be borne in mind, especially after surgery.

What evidence do we have from benchside research?

Since cancer cells in dnMBC disease have already disseminated throughout the systemic circulation and colonized distant organs, researchers have explored the rationale for PT resection. So far, knowledge regarding interactions between the PT and metastatic sites is very limited. We have synthesized the biological hypothesis that could explain the pro and cons of the systemic effect of a local treatment (Fig 1 .).

Tumor debulking

It has been suggested that the PT is not a homogeneous mass of cells. Rather, some PT cells with a major genomic instability might undergo a clonal progression and mutate, thereby becoming more aggressive and more likely to induce metastases [START_REF] Klein | Parallel progression of primary tumours and metastases[END_REF]. The rationale for surgery is to reduce not only the global tumor burden to increase the efficacy of ST but also the source of tumor stem cells with enhanced metastatic potential. This tumor debulking strategy has been demonstrated in various solid tumors (renal, colorectal, ovarian and gastric). Indeed, the metastatic process has been described as a multidirectional process called "tumor self-seeding" whereby cancer cells from the PT can colonize distant sites as well as their primary site of origin [START_REF] Kim | Tumor selfseeding by circulating cancer cells[END_REF][START_REF] Comen | Clinical implications of cancer self-seeding[END_REF]. It is easy to picture tumor cells preferentially seeding their primary mass of origin, as all the tissue-specific factors that allowed their growth in the first place are concentrated there. However, self-seeding selects for highly aggressive tumor cells, as they have undergone selection for movement into and survival in the circulation.

Therefore, PT may foster the expansion of potentially very aggressive metastatic progenies [START_REF] Norton | Is cancer a disease of self-seeding?[END_REF]. Tumor self-seeding by circulating tumor cells (CTC) enhances tumor progression and metastatic dissemination. Three of the ongoing prospective studies cited above (ECOG, JCOG and MSKCC trial) are currently evaluating CTC burden between a surgery and a nonsurgery group, and whether PT resection influences the number of CTC and correlates with survival. Lastly, tumor debulking by surgery or radiotherapy reduces the systemic immunosuppressive activity of malignant cells, as discussed in part 4.3.

Surgical wounding

Surgical wounding after tumor resection can trigger the outgrowth of tumors at distant anatomical sites and contribute to escape from dormancy. This was first suggested by Fisher et al. 30 years ago when they hypothesized that PT resection may promote the progression of distant metastases by the secretion of growth-stimulating factors [START_REF] Fisher | Presence of a growth-stimulating factor in serum following primary tumor removal in mice[END_REF]. Much more recently, Krall et al. demonstrated in a mouse model that surgical wounding induced the release of cytokines and an elevation of the myeloid cell population in the circulation, which could break immune-imposed dormancy and enable tumor outgrowth of dormant metastases [START_REF] Krall | The systemic response to surgery triggers the outgrowth of distant immune-controlled tumors in mouse models of dormancy[END_REF][START_REF] Murthy | Postoperative wound complications and systemic recurrence in breast cancer[END_REF]. Moreover, wound repair following breast surgery could stimulate residual neoplastic cells to acquire the tools for epithelial-to-mesenchymal transition, thus promoting dissemination. Concordant with these pre-clinical data, early BC patients whose tumors expressed a wound-response gene expression signature had worse OS and metastasis-free survival than those with tumors that did not [START_REF] Chang | Robustness, scalability, and integration of a wound-response gene expression signature in predicting breast cancer survival[END_REF]. Thus, if surgical wounding has potential negative effects, one potential benefit of exclusive RT would be to avoid it.

A retrospective clinical study analyzed the relationship between wound complications occurring after surgery of a primary BC and the development of systemic recurrence. Patients who had wound complications, defined as any wound breakdown that needed surgical debridement, dressing or packing, had a significantly greater risk of developing systemic recurrence (HR=2.52 [1.69; 3.77] [START_REF] Murthy | Postoperative wound complications and systemic recurrence in breast cancer[END_REF]. Interestingly, the TATA Memorial's prospective study (part 2.4) concluded that surgical LRT was associated with a significant detriment in distant PFS compared to no-LRT (11.3 vs 19.8 months) [START_REF] Badwe | Locoregional treatment versus no treatment of the primary tumour in metastatic breast cancer: an open-label randomised controlled trial[END_REF]. As a reminder, further ST was not administered after LRT in that trial. Similarly, the POSYTIVE trial identified a trend towards worse results for luminal A patients after upfront surgery. However, these results should be interpreted carefully because numerous biases were present in the TATA trial, and the POSYTIVE trial was stopped prematurely (part 2.4).

Potentiate anti-tumoral immune response

Another major argument to treat the PT comes from the relationship between the immune system and the PT. Experimental studies evaluated the impact of PT resection on metastatic sites, and especially on global immunosuppression. It was demonstrated in a murine model with transplantable tumors that immunosuppression is reversed following PT removal, by comparing immune responses in mice with intact PT vs mice whose PTs have been removed but which had established metastatic disease. Interestingly, the presence of PT suppresses Tcell and antibody responses [START_REF] Demaria | Immune-Mediated Inhibition of Metastases after Treatment with Local Radiation and CTLA-4 Blockade in a Mouse Model of Breast Cancer[END_REF]. Another study concluded likewise by demonstrating with fibrosarcoma cells that PT resection unmasked a population of primed T cells able to mediate protective immunity (100).

RT has also demonstrated effects on systemic immune response, and particularly on tumor-induced immunosuppression (101). Thus, the use of RT on tumor cells to boost antitumor response is attractive. Accumulated evidence showed that besides a direct cytotoxic effect, ionizing RT is a powerful inducer of apoptosis in tumor cells, and induces a specific death modality called "immunogenic cell death" (102,103). Therefore, it can enhance the release of "danger" signals, and thus promote anti-tumor T cell priming. It could also facilitate the penetration of antigen-presenting cells and effector T cells into tumors [START_REF] Demaria | Immune-Mediated Inhibition of Metastases after Treatment with Local Radiation and CTLA-4 Blockade in a Mouse Model of Breast Cancer[END_REF]104,105). Another immune-related RT is called the abscopal effect, i.e. the reduction of the tumor growth by RT outside the field of radiation (105-107), owing to local activation of systemic antitumor immunity. This concept has been demonstrated in pre-clinical mice transplanted models, where the irradiation of one tumor site resulted in tumor growth inhibition at the other non-irradiated site [START_REF] Demaria | Immune-Mediated Inhibition of Metastases after Treatment with Local Radiation and CTLA-4 Blockade in a Mouse Model of Breast Cancer[END_REF]105). In dnMBC, a case report described a patient with a high tumor burden who presented a dramatic regression of metastatic lesions after an exclusive treatment with RT (of the PT and some of the bone metastases) (108).

However, in view of numerous disappointing studies, the abscopal effect is the subject of much debate (104,109).

Because we are on the cusp of a new therapeutic era in solid oncology with immune checkpoint inhibitors (ICI), especially in TN subtypes for MBC patients [START_REF] Schmid | Atezolizumab and Nab-Paclitaxel in Advanced Triple-Negative Breast Cancer[END_REF], pre-clinical studies have combined RT with ICI, and several clinical studies are ongoing (reviewed in (104)). It was demonstrated in a poorly immunogenic transplantation mouse model that when RT of the PT in metastatic breast disease was combined with ICI, CD8+ T-cell-dependent antitumor immunity was elicited and it inhibited the growth of metastases [START_REF] Demaria | Immune-Mediated Inhibition of Metastases after Treatment with Local Radiation and CTLA-4 Blockade in a Mouse Model of Breast Cancer[END_REF]. However, when taken individually, each treatment was ineffective: RT alone to the PT significantly delayed the growth of the primary irradiated tumor but had no impact on survival rate. RT increased tumor-infiltrating lymphocytes CD8+ and expanded the TCR repertoire of T cells, whereas ICI narrowed it and drove the expansion of a limited number of clones. This therefore explained why the combination of RT and ICI could induce metastatic tumor rejection, by the clonal expansion of specific tumor T-cell clones (110). Importantly, most pre-clinical studies used injected subcutaneous tumor mouse models [START_REF] Demaria | Immune-Mediated Inhibition of Metastases after Treatment with Local Radiation and CTLA-4 Blockade in a Mouse Model of Breast Cancer[END_REF]105,111), which is far removed from the clinical situation of a dnMBC patient.

Conclusion

In the era of modern systemic and locoregional therapies, the question of LRT in dnMBC is a multidisciplinary challenge involving surgeons, radiation oncologists, medical oncologists and the patients themselves. To date, guidelines have suggested that the removal of the PT could be considered only in highly selected patients, as it has not been associated with a high level of evidence that it increases survival significantly [START_REF] Cardoso | 5th ESO-ESMO internaIonal consensus guidelines for advanced breast cancer (ABC 5) †[END_REF]. Age should not be a limitation, provided that global health status and life expectancy is not limited by another pathology. The biology of the disease, the pattern of metastatic disease and sensitivity to first-line ST could thus help in proposing the best loco-therapeutic option, although the type, order and timing of treatments are left to the multidisciplinary team's judgment. However, one should recall that the goal of care in the metastatic setting should always be to maintain the highest QoL while optimizing disease control and that discussion with the patient about the risk/benefit balance is crucial.

LRT should be discussed after checking that ST controls metastatic disease, except in cases where its objective is to control palliative symptoms. Here are three clinical situations that could occur after first-line ST (Graph. Abstract):

-First resistance to ST and metastatic disease evolution. In this case, priority should be given to systemic control and LRT should be considered only if the PT becomes symptomatic.

-Both local and distant sites are well controlled, with or without complete clinical response in the breast and other organs. LRT could be proposed, especially in HER2positive and HR-positive/HER2-negative patients, where there has been dramatic improvement in PFS and OS with the latest targeted therapies. The LRT modalities need to be discussed by clinicians and patients: ERT, surgery, or a combination of surgery plus RT could be proposed.

-Both local and distant sites are well controlled, with a complete resectable metastatic disease. This situation, known as oligometastatic disease, has emerged as a recent concept [START_REF] Gutiontov | Oligometastasis: Past, Present, Future[END_REF]. If available, inclusions in clinical trials should be proposed. Two prospective phase III trials (NCT02089100, NCT02364557) are currently enrolling patients and will help us determine the best strategy in this situation. In the meantime, guidelines recommend considering a multimodal approach including optimal LRT of the PT and metastatic sites with curative intent for these patients [START_REF] Cardoso | 5th ESO-ESMO internaIonal consensus guidelines for advanced breast cancer (ABC 5) †[END_REF].

When available, clinical trial addressing the value of LRT, the best candidates and best timing should be proposed.

Tables and figures

Table 1: Observational studies comparing LRT (surgery +/-radiotherapy) with no-LRT in dnMBC patients, classified by years of recruitment.

Figure 1 :

 1 Figure 1: Biological effects of loco-regional treatment in dnMBC.Graphical abstract: Decision algorithm to select the optimal candidates for LRT in dnMBC.

Table 2 :

 2 Prospective completed randomized trials which evaluated efficacy on overall survival of primary tumor resection in dnMBC.

Table 4 :

 4 On-going prospective trials evaluating locoregional treatment in dnMBC.

Table 3 :

 3 Retrospective studies evaluating exclusive radiation therapy as locoregional treatment in dnMBC.

Table 1 :

 1 Observational studies comparing LRT (surgery +/-radiotherapy) with no-LRT in dnMBC patients, classified by years of recruitment.

	Study	No. of patients	Selection period	Patients with single-organ metastases (%)	Patients with visceral metastases* (%)	Patients who underwent LRT (%)	Median OS (months) Hazard ratio OS LRT No LRT	P value
	Cady Ann. Surg.	622	1970-2002	NA	NA	38	31	20	NA	<.0001
	Oncol 2008

Abbreviations: dnMBC= de novo metastatic breast cancer; OS= overall survival; ER=estrogen receptor; HER2=human epidermal growth factor 2; BCS=breast conservative surgery; RT=radiation therapy; M+=metastasis.