Anticipating changes in the HER2 status of breast tumours with disease progression-towards better treatment decisions in the new era of HER2-low breast cancers.

BACKGROUND: HER2 expression is often negative or low in primary breast cancers (BCs) but its changes with disease progression remain poorly known. We aimed to estimate them between primary and recurrent tumours, and identify predictive factors. METHODS: We compared the HER2 status, and clinical and pathological characteristics by its evolution category (stable or changed), between all primary BCs and matched recurrences registered in our database in 2000-2020 (n = 512). RESULTS: HER2-low tumours were the most prevalent at diagnosis (44.9%), followed by HER2-negative tumours (39.3%). HER2 status significantly changed in 37.3% of recurrences, mainly of HER2-negative and HER2-low tumours. HER2-negative tumours which relapsed as HER2-low significantly more frequently expressed oestrogen receptors (ER) and recurred later than stably HER2-negative tumours. Changed HER2 status in distant metastases correlated with lower proliferation rates and higher ER expression in primary tumours, and among metastases of hormone receptor-positive (HR+) tumours-with weak progesterone receptor (PR) expression in primary tumours. CONCLUSIONS: HER2 status changes with BC progression, with enrichment of HER2-low tumours in advanced stages. The ER+/PR- status, low proliferation index and time to late recurrence correlated with these changes. These findings highlight the need of retesting recurrences, especially of HR + primary tumours, to identify candidates for new anti-HER2 therapies.

Early Locoregional Breast Surgery and Survival in de novo Metastatic Breast Cancer in the Multicenter National ESME Cohort.

OBJECTIVE: The aim was to evaluate the impact of local surgery performed during the year after MBC diagnosis on patients' outcomes from a large reallife cohort. SUMMARY BACKGROUND DATA: Locoregional treatment for patients with MBC at the time of diagnosis remains debated. METHODS: Women with newly diagnosed, de novo stage IV MBC and who started MBC treatment between January 2008 and December 2014 in one of the 18 French Comprehensive Cancer Centers were included (NCT03275311). The impact of local surgery performed during the first year on overall survival (OS) and progression-free survival (PFS) was evaluated by the Cox proportional hazards model in a 12 month-landmark analysis. RESULTS: Out of 16,703 patients in the ESME database, 1977 had stage IV MBC at diagnosis, were alive and progression-free at 12 months and eligible for this study. Among them, 530 (26.8%) had received primary breast cancer surgery within 12 months. A greater proportion of patients who received surgery had less than 3 metastatic sites than the no-surgery group (90.8% vs 78.2%, P < 0.0001). Surgery within 12 months was associated with treatment with chemotherapy, HER2-targeted therapy (89.1% vs 69.6%, P < 0.0001) and locoregional radiotherapy (81.7% vs 32.5%, P < 0.0001). Multivariable analyses showed that surgery performed within 12 months was associated with longer OS and PFS (adjusted HR [95%CI] = 0.75 [0.61-0.92] and 0.72 [0.63-0.83], respectively), which were also affected by pattern and number of metastatic sites, histological subtype, and age. CONCLUSIONS: In the large ESME cohort, surgery within 1 year after de novo MBC diagnosis was associated with a significantly better OS and PFS.

Prognosis of local invasive relapses after carcinoma in situ of the breast: a retrospective study from a population-based registry.

PURPOSE: The prognosis of local invasive recurrence (LIR) after prior carcinoma in situ (CIS) of the breast has not been widely studied and existing data are conflicting, especially considering the specific prognosis of this entity, compared to de novo invasive breast cancer (de novo IBC) and with LIR after primary IBC. METHODS: We designed a retrospective study using data from the specialized Côte d'Or Breast and Gynecological cancer registry, between 1998 and 2015, to compare outcomes between 3 matched groups of patients with localized IBC: patients with LIR following CIS (CIS-LIR), patients with de novo IBC (de novo IBC), and patients with LIR following a first IBC (IBC-LIR). Distant relapse-free (D-RFS), overall survival (OS), clinical, and treatment features between the 3 groups were studied. RESULTS: Among 8186 women initially diagnosed with IBC during our study period, we retrieved and matched 49 CIS-LIR to 49 IBC, and 46 IBC-LIR patients. At diagnosis, IBC/LIR in the 3 groups were mainly stage I, grade II, estrogen receptor-positive, and HER2 negative. Metastatic diseases at diagnosis were higher in CIS-LIR group. A majority of patients received adjuvant systemic treatment, with no statistically significant differences between the 3 groups. There was no significant difference between the 3 groups in terms of OS or D-RFS. CONCLUSION: LIR after CIS does not appear to impact per se on survival of IBC.

ER-/PR+ breast cancer: A distinct entity, which is morphologically and molecularly close to triple-negative breast cancer.

Determining the status of steroid hormone receptors [oestrogen (ER) and progesterone receptors (PR)] is a crucial part of the breast cancer workup. Thereby, breast cancers can be classified into four subtypes. However, the existence of ER-/PR+ tumours, often reported to be ill-classified due to technical errors, remains controversial. In order to address this controversy, we reviewed the hormone receptor status of 49 breast tumours previously classified as ER-/PR+ by immunohistochemistry, and compared clinical, pathological and molecular characteristics of confirmed ER-/PR+ tumours with those of ER+ and triple-negative tumours. We unequivocally confirmed the ER-/PR+ status in 27 of 49 tumours (0.3% of all breast cancers diagnosed in our institution between 2000 and 2014). We found that ER-/PR+ were morphologically and histologically similar to triple-negative tumours, but very distinct from ER+ tumours, with more aggressive phenotypes and more frequent basal marker expression than the latter. On the molecular level, RNA sequencing revealed different gene expression profiles between the three groups. Of particular interest, several genes controlled by the suppressor of zest 12 (SUZ12) were upregulated in ER-/PR+ tumours. Overall, our results confirm that ER-/PR+ breast cancers are an extremely rare but 'real' tumour subtype that requires careful diagnosis and has distinct features warranting different responsiveness to therapies and different clinical outcomes. Studies on larger cohorts are needed to further characterise these tumours. The likely involvement of SUZ12 in their biology is an interesting finding which may - in a long run - give rise to the development of new therapeutic alternatives.

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.

INTRODUCTION: Improvement in overall survival (OS) by locoregional treatment (LRT) of the primary tumor in de novo metastatic breast cancer (MBC) patients remains controversial. OBJECTIVE: The aim of our study was to evaluate the impact of LRT on OS in a large retrospective cohort of de novo MBC patients, with regard to immunohistochemical characteristics and pattern of metastatic dissemination. METHODS: We conducted a multicentric retrospective study of patients diagnosed with de novo MBC selected from the French Epidemiological Strategy and Medical Economics MBC database (NCT03275311) between 2008 and 2014. Overall, 4276 women were included in the study. LRT comprised either radiotherapy, surgery, or both. RESULTS: LRT was used in 40% of patients. Compared with no LRT, patients who received LRT were younger (p < 0.0001) and were more likely to have only one metastatic site (p < 0.0001) or bone-only metastases (p < 0.0001). LRT was associated with a significantly better OS based on landmark multivariate analysis at 1-year (hazard ratio 0.65, 95% confidence interval 0.55-0.76, p < 0.001). Similar results were observed in all sensitivity analyses, including propensity score matching. In subgroup analysis, LRT was associated with better OS in patients with hormone receptor-positive/human epidermal growth factor receptor 2 (HER2)-negative (61.6 vs. 45.9 months, p < 0.001) and HER2-positive tumors (77.2 vs. 52.6 months, p = 0.008), but not in triple-negative tumors (19 vs. 18.6 months, p = 0.54), and was also associated with a reduction in the risk of death in visceral metastatic patients (p < 0.001). CONCLUSIONS: LRT was associated with a significantly better OS in de novo MBC patients, including patients with visceral involvement at diagnosis; however, LRT did not impact OS in triple-negative MBC.

Multicenter prospective evaluation of the reliability of the combined use of two models to predict non-sentinel lymph node status in breast cancer patients with metastatic sentinel lymph nodes: the MSKCC nomogram and the Tenon score. Results of the NOTEGS study.

BACKGROUND: The purpose of this study was to prospectively evaluate the combined use of The Memorial Sloan Kettering Cancer Center nomogram and Tenon score to select, in patients with metastatic sentinel lymph node (SN), those at low risk of metastatic non-SN for whom additional axillary lymph node dissection (ALND) could be avoided. METHODS: From January 2011 to July 2012, a prospective non-interventional nationwide study was conducted (NCT01509963). We sought to identify the false reassurance rate (FRR, a negative test result is false) in patients with both a ⩽10% probability of metastatic non-SN with the MSKCC nomogram and a Tenon score ⩽3.5 (low risk): the proportion of patients with metastatic non-SN at additional ALND. Our hypothesis was that these patients would have a FRR⩽5%. RESULTS: Data on 2822 patients with breast cancer from 53 institutions were prospectively recorded. At least one SN was metastatic (isolated tumour cells, micro- or macrometastases) in 696 patients (24.7%). Among patients with ALND and complete data to calculate combined risk (n=504), 67 and 437 patients had low and high combined risk, respectively. Patients at low risk had less ALND (47%) compared to patients at high risk (P<0.001). This study did not meet its primary objective because the FRR in patients with low risk was 16.4% (11 out of 67) (95% confidence interval (CI): 9.7-23.1%). In the high-risk group, 33.9% (148 out of 437) (95% CI: 29.6-38.4%) had non-SN metastases (P=0.004). CONCLUSIONS: In this controlled prospective study, metastatic SN patients with both a ⩽10% probability of metastatic non-SN with the MSKCC nomogram and a Tenon score ⩽3.5 failed to identify patients at low risk of metastatic non-SN when completion ALND was not systematic.

Predictive factors of pathologic complete response of HER2-positive breast cancer after preoperative chemotherapy with trastuzumab: development of a specific predictor and study of its utilities using decision curve analysis.

PURPOSE: The aim of this study was to assess the Institut Gustave Roussy/M.D. Anderson Cancer Center (IGR/MDACC) nomogram in predicting pathologic complete response (pCR) to preoperative chemotherapy in a cohort of human epidermal growth factor receptor 2 (HER2)-positive tumors treated with preoperative chemotherapy with trastuzumab. We then combine clinical and pathological variables associated with pCR into a new nomogram specific to HER2-positive tumors treated by preoperative chemotherapy with trastuzumab. PATIENTS AND METHODS: Data from 270 patients with HER2-positive tumors treated with preoperative chemotherapy with trastuzumab at the Institut Curie and at the Georges François Leclerc Cancer Center were used to assess the IGR/MDACC nomogram and to subsequently develop a new nomogram for pCR based on multivariate logistic regression. Model performance was quantified in terms of calibration and discrimination. We studied the utility of the new nomogram using decision curve analysis. RESULTS: The IGR/MDACC nomogram was not accurate for the prediction of pCR in HER2-positive tumors treated by preoperative chemotherapy with trastuzumab, with poor discrimination (AUC = 0.54, 95% CI 0.51-0.58) and poor calibration (p = 0.01). After uni- and multivariate analysis, a new pCR nomogram was built based on T stage (TNM), hormone receptor status, and Ki67 (%). The model had good discrimination with an area under the curve (AUC) at 0.74 (95% CI 0.70-0.79) and adequate calibration (p = 0.93). By decision curve analysis, the model was shown to be relevant between thresholds of 0.3 and 0.7. CONCLUSION: To the best of our knowledge, ours is the first nomogram to predict pCR in HER2-positive tumors treated by preoperative chemotherapy with trastuzumab. To ensure generalizability, this model needs to be externally validated.

Impact of the withdrawal of macrotextured implant on reconstruction practices.

INTRODUCTION: On 22 November 2018, the French Society for Plastic, Reconstructive and Aesthetic Surgery recommended that Allergan® macrotextured breast implants be recalled, a decision endorsed by the French national health products safety agency (ANSM) on 2nd April 2019. At the Georges-François Leclerc Cancer Center (CGFL) in Dijon, we decided to stop using macrotextured implants as of November 2018 in favor of smooth implants. The purpose of this study is to evaluate the impact of the recall of macrotextured implants on breast reconstruction surgical practices and their complications. METHODS: This is a single-centre, retrospective study performed at the CGFL in Dijon, France. Reconstruction techniques and complications were compared between two periods, i.e. before the recall of macrotextured breast implants (period 1: 1st September 2017-November 22, 2018) and after the recall (period 2: 23 November 2018-31st March 2020). All patients who underwent breast reconstruction for the first time were included. RESULTS: Data were collected from 168 reconstructions in period 2, and 159 in period 2. The rate of use of breast implants during reconstructions decreased significantly in period 2 (53.6% vs. 23.9%; P<0.001). The rate of autologous reconstructions increased significantly for muscle sparing latissimus dorsi (2.4% vs. 12.6%; P<0.001) and exclusive fat grafting (9.5% vs. 21.5%; P<0.01). Clavien-Dindo Stage IIIb complications decreased in period 2 (10% vs. 18.4%; P=0.04). CONCLUSION: Since the recall of macrotextured breast implants, the reconstruction rate has decreased in our centre in favor of autologous techniques with lower complication rates.

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

INTRODUCTION: Patients with BRCA1/2 mutations have a higher risk of developing breast cancer compared to the wild-type population. For patients with a BRCA mutation, there are no specific recommendations for surgical management. The aim of this study was therefore to retrospectively investigate overall survival (OS) and recurrence-free survival (RFS) of BRCA mutated patients with localized invasive breast cancer, by comparing conservative surgery versus mastectomy. METHODS: This study was based on data from the Côte d'Or breast and gynecological cancer registry. Data from patients with a constitutional BRCA1/2 mutation who presented with invasive breast cancer were collected retrospectively from 1998 to 2018. The Kaplan-Meier method was used to describe RFS and OS. RESULTS: A total of 104 patients were included in the analysis, of whom 69 had conservative surgery and 35 underwent mastectomy. Regarding survival, there was no significant difference in OS (HR =1.49; 95 % confidence interval (CI) [0.76-2.93], p = 0.25). Similarly, there was no significant difference in RFS (HR =1.40; 95 % CI [0.81-2.40], p = 0.22), survival without homolateral recurrence (HR =0.88; 95 % CI [0.30-2.61], p = 0.89), without contralateral recurrence (HR =1.50; 95 % CI [0.55-4.09], p = 0.42), or without distant metastatic recurrence (HR =1.42, 95 % CI [0.69-2.90], p = 0.33). CONCLUSION: In invasive breast cancer in a patient with a germline BRCA1/2 mutation, conservative surgery, when possible, appears to be a feasible option over total mastectomy, with no difference in overall survival. However, the patient should be informed of the aggressive nature of recurrence in this population requiring chemotherapy in most cases.

HER2-Low Luminal Breast Carcinoma Is Not a Homogenous Clinicopathological and Molecular Entity.

BACKGROUND: With the development of some new antibody-drug conjugates, the HER2 classification of breast carcinomas now includes the HER2-low (H2L) category: IHC 1+, 2+ non-amplified by ISH, and double-equivocal carcinomas, mostly luminal, expressing hormone receptors (HR+). METHODS: We analyzed mutational status and transcriptomic activities of three HER2 effector pathways: PI3K-AKT, MAPK, and JAK-STAT, in association with clinicopathologic features, in 62 H2L carcinomas compared to 43 HER2-positive and 20 HER2-negative carcinomas, all HR+. RESULTS: H2L carcinomas had significantly lower histoprognostic grades and mitotic and Ki67 proliferation indexes than HER2-positive carcinomas. Their PIK3CA mutation rates were close to those of HER2-negative and significantly higher than in HER2-positive carcinomas, contrary to TP53 mutations. At the transcriptomic level, we identified three distinct groups which did not reflect the new HER2 classification. H2L and HER2-negative carcinomas shared most of clinicopathological and molecular characteristics, except HER2 membrane expression (mRNA levels). The presence of a mutation in a signaling pathway had a strong pathway activation effect. PIK3CA mutations were more prevalent in H2L carcinomas, leading to a strong activation of the PI3K-AKT signaling pathway even in the absence of HER2 overexpression/amplification. CONCLUSION: PIK3CA mutations may explain the failure of conventional anti-HER2 treatments, suggesting that new antibody-drug conjugates may be more effective.

Prognostic stratification ability of the CPS+EG scoring system in HER2-low and HER2-zero early breast cancer treated with neoadjuvant chemotherapy.

BACKGROUND: The CPS+EG scoring system was initially described in unselected early breast cancer (eBC) patients treated with neoadjuvant chemotherapy (NAC), leading to refined prognostic stratification, and thus helping to select patients for additional post-NAC treatments. It remains unknown whether the performance is the same in new biological breast cancer entities such as the HER2-low subtype. PATIENTS AND METHODS: Outcomes (disease-free (DFS) and overall survival OS)) of 608 patients with HER2-non amplified eBC and treated with NAC were retrospectively analyzed according to CPS-EG score. We compared the prognostic stratification abilities of the CPS+EG in HER2-low and HER2-0 eBC, analyzing ER+ and ER- tumors separately. RESULTS: In ER+ eBC, the CPS+EG scoring system seems to retain a prognostic value, both in HER2-low and HER2-0 tumors, by distinguishing populations with significantly different outcomes (good: score 0-1, poor: score 2-3, and very poor: score 4-5). Using C-indices for DFS and OS, CPS+EG provided the highest prognostic information in ER+ eBC, especially in HER2-0 tumors. In contrast, in ER- eBC, the CPS+EG does not appear to be able to distinguish different outcome groups, either in HER2-low or HER2-0 tumors. In ER- eBC, C-indices for DFS and OS were highest for pathological stage, reflecting the predominant prognostic importance of residual disease in this subtype. CONCLUSIONS: HER2-low status does not influence the prognostic performance of the CPS+EG score. Our results confirm the usefulness of the CPS+EG score in stratifying the prognosis of ER+ eBC after NAC, for both HER2-0 and HER2-low tumors. For ER- eBC, HER2-low status does not influence the performance of the CPS+EG score, which was lower than that of the pathological stage alone.

The exportability of the ACOSOG Z0011 criteria for omitting axillary lymph node dissection after positive sentinel lymph node biopsy findings: a multicenter study.

PURPOSE: To determine the exportability of the criteria defined by the American College of Surgeons Oncology Group Z0011 trial for selecting patients who are eligible for omitting completion axillary lymph node dissection (cALND) after a positive sentinel lymph node (SLN) biopsy result and to investigate whether not following the Z0011 criteria might affect patient outcomes. METHODS: From a multicenter database, we selected 188 patients with positive SLNs and then excluded patients with positive SLNs on immunohistochemistry only. We retrospectively applied the Z0011 criteria and grouped the patients as eligible or ineligible for omitting cALND. The eligible group was compared with the cohort included in the Z0011 trial and with the ineligible group. Kaplan-Meier survival curves were calculated for each group, and univariate analyses assessed associations between the groups and clinicopathological variables. RESULTS: The final analysis involved 125 patients with positive SLNs. Eighty-seven patients (69.6 %) were potentially eligible for omitting cALND. The estrogen receptor status, T stage, grade, and number of positive non-SLNs were not statistically different between the eligible group and the Z0011 cohort. The ineligible group had significantly more positive non-SLNs (P = 0.01) and a lower 5-year overall survival rate than the eligible group (P < 0.001). CONCLUSIONS: The similarity of clinical characteristics between the Z0011 trial cohort and our eligible group confirms the exportability of these criteria to another population. The worse prognosis of patients who did not meet the Z0011 criteria suggests prudence before disregarding or enlarging broadening the indications for omitting cALND.

Axillary pathologic response after neoadjuvant chemotherapy and surgery according to breast cancers subtypes and survival impact.

PURPOSE: To retrospectively assess the rate of pathologic complete response in the axilla according to breast cancer biologic subtypes, and to study the impact of nodal response on survival. METHODS: Inclusion criteria were all T-stage breast cancers with initial lymph node involvement, non-metastatic, treated with neoadjuvant chemotherapy followed by surgery with axillary lymph node dissection, managed at the George-François Leclerc Cancer Center in Dijon, France, between 2000 and 2018. RESULTS: Among 437 patients included, the rate of complete nodal response rate varied according to tumor subtypes: 69.4% in Hormone Receptors (HR)-/HER2-positive, 47.4% in HR-/HER2-negative, 46.7% in HR+/HER2-positive, 8.5% in HR+/HER2-negative. By multivariate analysis, the factors significantly associated with complete nodal response were HER2-positive profile (OR 4.48 [2.14-9.65], P<0.001 if HR+; OR 8.02 [3.54-18.74], P<0.001 if HR-), triple negative tumors (OR 3.01 [1.40-6.58], P=0.005), SBRIII grade (OR 6.85 [2.28-29.58], P=0.002) and breast complete response (OR 18.69 [9.67-38.53], P<0.001). Five-year recurrence rates were 15.7% in ypN0, 23% in ypN1, 41.2% in ypN2, 50% in ypN3 patients (P<0.001). Five-year overall survival rates were 92.2% in ypN0, 85.7% in ypN1, 72.2% in ypN2, 65.4% in ypN3 patients (P<0.001). CONCLUSION: The impact of nodal response on survival was significant. Pathologic complete response in the axilla appears to be a good surrogate marker of long-term outcome in patients treated for these cancers.

HER2-positive invasive lobular carcinoma: a rare breast cancer which may not necessarily require anti-HER2 therapy. A population-based study.

BACKGROUND: HER2-positive (HER2 +) invasive lobular breast cancer (ILC) is rare and poorly characterised. In particular, patient outcomes compared to those associated with HER2 + invasive ductal cancer (IDC) and HER2-negative (HER2 -) ILC, as well as the benefits of anti-HER2 therapy, are not well established. METHODS: We analysed the data from the Côte d'Or Registry of Breast and Gynaecological Cancers (France) for all patients diagnosed with early-stage HER2 + ILC (62 cases), HER2 + IDC (833 cases) and HER2 - ILC (685 cases) between 1998 and 2015 to compare overall and disease-free survival (OS and DFS) between these groups in correlation with anti-HER2 therapy. RESULTS: ILCs were associated with older age, larger tumours, lower histological grades, higher hormonal receptor positivity rates and multifocality, and more common endocrine therapy. OS and DFS between the three groups did not differ. We found that anti-HER2 therapy was associated with a survival benefit in patients with HER2 + IDC. In contrast, the survival of HER2 + ILC patients was not improved by anti-HER2 treatment, remaining close to that of HER2 - ILC patients. CONCLUSION: HER2 + ILC seems not to be associated with better outcomes than HER2 + IDC but may not differ from HER2 - ILC in terms of survival.

Pathologic complete response and survival in HER2-low and HER2-zero early breast cancer treated with neoadjuvant chemotherapy.

BACKGROUND: Breast cancers without HER2 amplification but still expressing this membrane protein constitute a new entity called HER2-low tumors. It is important to characterize them in terms of sensitivity to treatment and prognosis. PATIENTS AND METHODS: To investigate chemosensitivity and long-term prognosis of HER2-low early breast cancer (eBC), compared to HER2-0 tumors, we retrospectively retrieved clinicopathological characteristics, response to treatment, and survival data from 511 patients treated for eBC with neoadjuvant chemotherapy (NAC) in a French cancer center between 2007 and 2018. Factors associated with the achievement of pathologic complete response (pCR) and survival were studied among hormone receptor positive (HR+) and negative (HR-) eBC. RESULTS: A total of 280 HR+ (61% HER2-low), and 231 HR- (28% HER2-low) eBC were included. We found classical clinicopathological factors usually associated with chemosensitivity and prognosis, in both HR+ and HR- eBC. By uni- and multivariable analysis, HER2 status (low vs 0) was not independently associated with pCR, either in HR+ or HR- eBC. Relapse free (RFS) and overall survival (OS) were not significantly different between HER2-low and HER2-0 among HR+ tumors. In contrast, among HR- negative tumors, RFS and OS were slightly better in HER2-0 eBC by univariable but not by multivariable analysis. CONCLUSIONS: In eBC patients treated with NAC, taking into account HR expression subtype and other current clinicopathological features, HER2-low tumors did not appear to have different chemosensitivity or prognosis, compared to their HER2-0 counterparts.

Omitting axillary lymph node dissection after positive sentinel lymph node in the post-Z0011 era: Compliance with NCCN and ASCO clinical guidelines and Z0011 criteria in a large prospective cohort.

PURPOSE: In the ACOSOG Z0011 trial, patients with primary breast cancer and 1-2 tumor-involved sentinel lymph nodes (SLNs) undergoing breast-conserving surgery had no oncological outcome benefit after axillary lymph node dissection (ALND), despite a relevant rate of non-SLN metastases of 27%. According to the St Gallen expert consensus, and NCCN and ASCO clinical guidelines, ALND may be avoided in patients who meet all ACOSOG Z0011 inclusion criteria. This recommendation can also be extended to patients undergoing mastectomy, with 1 or 2 positive SLNs and an indication for chest wall radiation, in whom axillary radiotherapy can be proposed as an alternative to completion ALND. The aim of this study was to assess non-compliance with the NCCN and ASCO clinical guidelines and Z0011 criteria, namely the rate of performance of completion ALND when it was not recommended, and the rate of failure to perform completion ALND when recommended. METHODS: Data were prospectively analysed from T1-2 N0 breast cancer patients undergoing an SLN procedure and treated at the Georges-François Leclerc Cancer Center between November 2015 and May 2017. Factors associated with non-compliance treatment decisions were identified using logistic regression. RESULTS: Among 563 patients included, 122 (21.7%) had at least one positive SLN. ALND was not recommended for 76 patients (62.3%), and was recommended in 46 patients (37.7%). The rate of non-compliant treatment was 32% (39/122) overall: ALND was performed despite not being recommended in 16/76 patients (21.1%) and was not performed in 50% of patients in whom it was recommended (23/46). By multivariate analyses, lymphovascular invasion ((Odds Ratio (OR)=6.1; 95% confidence interval (CI): 1.4-26.7; P=0.02)) and only one SLN removed (OR=9.1; 95%CI: 2.2-33.3; P=0.002) were associated with performance of completion ALND when not recommended. Conversely, >1 SLN removed (OR=5.1; 95%CI: 1.2-22.2; P=0.03) was associated with the failure to perform completion ALND when recommended. CONCLUSION: Almost one third of patients with invasive breast cancer receive treatment that is not in compliance with recommendations regarding completion ALND.

What Are Young Women Living Conditions after Breast Cancer? Health-Related Quality of Life, Sexual and Fertility Issues, Professional Reinsertion.

In recent decades, the living conditions of young breast cancer (BC) survivors have garnered increasing attention. This population-based study aimed to identify the clinical, social and economic determinants of Health-Related Quality of Life (HRQoL), and to describe other living conditions of young long-term BC survivors. Women with non-metastatic BC diagnosed between 2006 and 2015, aged 45 years and younger at the time of diagnosis, were identified through the Breast and Gynecologic Cancer Registry of the Côte d'Or, France. Participants completed self-report questionnaires including standardized measures of HRQoL, anxiety, depression, social deprivation, social support and sexuality. Fertility and professional reintegration issues were also assessed. The determinants of HRQoL were identified using mixed regression model. In total, 218 BC survivors participated in the survey. The main determinants of poor HRQoL were anxiety, depression, comorbidities, social deprivation and menopausal status. Among 72% of women who did not receive information about fertility preservation, 38% of them would have liked to have been informed. Finally, 39% of survivors reported a negative impact of BC on their professional activity. This study showed that BC stage or treatments did not have an impact on HRQOL of young long-term BC survivors. Fertility, sexuality and professional reintegration remained the main concerns for survivors. Specific interventions in these population should focus on these issues.

[Strategies in case of metastatic sentinel lymph node in breast cancer]. / Stratégies en cas de positivité du ganglion sentinelle dans les cancers du sein.

Management strategy of micro or macro metastatic sentinel lymph node(s) (SLNs) in breast cancer has dramatically changed over the past ten years and the publication of five randomized trials results: ACOSOG Z0011, IBCSG 23-01, and AATRM comparing axillary lymph node dissection (ALND) versus SLNs biopsy alone; and AMAROS and OTOASOR comparing ALND versus axillary radiotherapy. Despite methodological limitations of several of these trials, notably ACOSOG Z0011, the international recommendations (ASCO, NCCN) and the expert consensus of St Gallen do not recommend the performance of a complementary ALND in case of macro or micro metastatic SLN, if all ACOSOG Z0011 inclusion criteria are met. Moreover, in the context of a mastectomy, with one or two positive SLN and a wall irradiation indication, an axillary radiotherapy can be proposed as an alternative to ALND. Additionally, ALND is also indicated in extracapsular involvement or when three or more SLNs are metastatic. This change in strategy led to a significant decrease on the number of ALNDs performed and resulted on the abandon of SLNs extemporaneous examination. In France, there are no national recommendations on axillary management in the context of SLN involvement. Moreover, a multitude of different local guidelines, led to very heterogeneous practices in our country. The next evolution on axillary management strategy will be the implementation of a SLNs procedure after neoadjuvant chemotherapy (NAC) for patients with lymph node involvement proven before NAC and for whom NAC has allowed axillary downstaging.

Monitoring HSP70 exosomes in cancer patients' follow up: a clinical prospective pilot study.

Exosomes are nanovesicles released by all cells that can be found in the blood. A key point for their use as potential biomarkers in cancer is to differentiate tumour-derived exosomes from other circulating nanovesicles. Heat shock protein-70 (HSP70) has been shown to be abundantly expressed by cancer cells and to be associated with bad prognosis. We previously showed that exosomes derived from cancer cells carried HSP70 in the membrane while those from non-cancerous cells did not. In this work, we opened a prospective clinical pilot study including breast and lung cancer patients to determine whether it was possible to detect and quantify HSP70 exosomes in the blood of patients with solid cancers. We found that circulating exosomal HSP70 levels, but not soluble HSP70, reflected HSP70 content within the tumour biopsies. Circulating HSP70 exosomes increased in metastatic patients compared to non-metastatic patients or healthy volunteers. Further, we demonstrated that HSP70-exosome levels correlated with the disease status and, when compared with circulating tumour cells, were more sensitive tumour dissemination predictors. Finally, our case studies indicated that HSP70-exosome levels inversely correlated with response to the therapy and that, therefore, monitoring changes in circulating exosomal HSP70 might be useful to predict tumour response and clinical outcome.

Radiation therapy to the primary tumor for de novo metastatic breast cancer and overall survival in a retrospective multicenter cohort analysis.

BACKGROUND: The impact of locoregional treatment (LRT) on overall survival (OS) in de novo metastatic breast cancer (dnMBC) is still under debate, with very few data available regarding exclusive radiotherapy (ERT) as a therapeutic modality. METHODS: We evaluated the impact of ERT, exclusive surgery, or a combination of surgery plus radiotherapy (bimodality therapy, BMT) on survival outcomes in a national real-life dnMBC cohort. The primary and secondary end points were OS and progression free survival (PFS) according to LRT (ERT, exclusive surgery, BMT) and no LRT. Sensitivity analyses were performed using propensity score matched analyses. RESULTS: From 2008 to 2014, 4507 dnMBC patients were identified. Only patients alive and free from progression under systemic therapy at least 1 year after diagnosis were included (n = 1965). Forty-five percent of patients (891/1965) underwent LRT: 41.1% (n = 366) ERT, 13.7% (n = 122) exclusive surgery, and 45.2% (n = 403) BMT. OS adjusted for major prognostic factors was significantly longer in the ERT and BMT group compared with no-LRT group, but not exclusive surgery (hazard ratio (HR) = 0.63, 95% confidence interval (CI) [0.49, 0.80], p < 0.001, HR = 0.61, 95%CI [0.47, 0.78], p < 0.001 and HR = 0.87, 95%CI [0.61, 1.26], p = 0.466 respectively). Results were similar after matching on a propensity score. ERT, surgery and BMT were all associated with a significantly better PFS in multivariable analysis. CONCLUSION: ERT was significantly associated with better OS in dnMBC, in the same magnitude as BMT, compared with no-LRT. However, even with statistical models adjusted for known prognostic factors and propensity score analysis, selection biases cannot be eliminated from observational studies.