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.

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.

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.

Impact of therapeutic strategy on disease-free and overall survival of early-stage cervical cancer: Surgery alone versus preoperative radiation.

BACKGROUND AND OBJECTIVES: There is no international consensus for management of early-stage cervical cancer (ESCC). This study aimed to retrospectively investigate disease-free survival (DFS) and overall survival (OS) in patients with ESCC according to the therapeutic strategy used, surgery alone versus preoperative radiation following by surgery. METHODS: Data were retrospectively collected from 1998 to 2015 using the Gynecological Cancer Registry of the Côte d'Or. The inclusion criteria were FIGO 2018 ≤ IB2; squamous cell carcinoma, adenocarcinoma or adenosquamous type. Survival curves were compared using the log-rank test. RESULTS: One hundred twenty-six patients were included. Median survival was 90 months. There was no significant difference in DFS (HR = 0.91, 95%CI [0.32-2.53], p = 0.858) or in OS between surgery alone versus preoperative radiation following by surgery (HR = 0.97, 95%CI [0.31-2.99], p = 0.961). In the subgroup of patients with stage ≥IB1, there was no significant difference in DFS (HR = 3.26, p = 0.2) or in OS (HR = 3.87, p = 0.2). CONCLUSION: Our study did not identify any difference in survival according to the treatment strategy. Preoperative radiation following by surgery can be an alternative to surgery alone for ESCC.

Impact of complete surgical staging on survival of patients with early-stage (FIGO I or II) ovarian cancer: Data from the Cote d'Or Registry of Gynecological Cancers from 1998 to 2015.

INTRODUCTION: Early-stage ovarian cancer represents 20 to 33% of all ovarian cancers and is thus quite rare in France, with around 1200 new cases per year. No study to date has convincingly demonstrated the utility of lymphadenectomy in early-stage ovarian cancer. We sought to evaluate the impact on overall survival of complete surgical staging in patients management for FIGO stage I and II ovarian cancer. METHODS: We performed a retrospective observational study using data from the Cote d'Or Registry of Gynecological Cancers. We included patients with invasive early stage epithelial ovarian cancer (FIGO stages I and II), diagnosed between 1 January 1998 and 31 December 2015. RESULTS: A total of 179 patients were included in the study. Patients who had lymphadenectomy were younger on average (P<0.001) and had fewer comorbidities (P=0.03). Lymphadenectomy was performed during the first surgery in 59.2% of cases (58 patients) and during a second, re-staging surgery in 40.8% (n=40). When complete surgical staging was performed, the rate of up-staging (to at least FIGO stage III) was 11.2% (11/98). The median follow-up was 8.4 years. At the study, 31.6% patients with complete surgical staging had died and 48.4% patients also died in the group without lymphadenectomy, HR 0.59 CI [0.36-0.97] P<0.04. CONCLUSION: In patients with early-stage ovarian cancer, complete surgical staging appears to yield a benefit in terms of overall survival. In 10 to 15% of cases, it leads to upstaging, with the resultant indication for maintenance therapy, which has also shown a survival benefit.

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.

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.

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.

The transfer of multigene panel testing for hereditary breast and ovarian cancer to healthcare: What are the implications for the management of patients and families?

Until recently, the molecular diagnosis of hereditary breast and ovarian cancer (HBOC) was mostly based on BRCA1/2 testing. Next generation sequencing and the recent discovery of new genes involved in HBOC now permit the transfer of genomic capture targeting multiple candidate genes from research to clinical use. However, the implications for the management of patients and their families have not been extensively studied, in particular since some of these genes are not well-established cancer predisposing genes. We studied 583 consecutive patients from Burgundy (France) fulfilling the criteria for BRCA testing using a next generation sequencing 25-genes panel including 20 well-established high-risk cancer genes as well as more recently identified predisposing HBOC cancer. A pathogenic BRCA1/2 mutation was found in 51 patients (9%). Besides, we found 37 pathogenic or likely pathogenic mutations in 10 different high to low-risk genes in 34 patients (6%). The most frequently mutated genes were CHEK2 (n = 12; 2%), ATM (n = 9; 1.5%), and PALB2 (n = 4; 0.6%). Three patients had a mutation in two different predisposing genes. The analysis of clinical actionability conducted in mutation-positive individuals revealed that additional disease-specific screening and/or prevention measures beyond those based on personal and family history alone had been recommended in 69% of cases. In conclusion, multigene panel testing is a powerful tool to identifying high to low-risk HBOC susceptibility genes. The penetrance and spectrum of cancers with these other genes are sometimes undefined, and further collaborative work is crucial to address this question.

Development of primary early-onset colorectal cancers due to biallelic mutations of the FANCD1/BRCA2 gene.

Fanconi anaemia (FA) is characterized by progressive bone marrow failure, congenital anomalies, and predisposition to malignancy. In a minority of cases, FA results from biallelic FANCD1/BRCA2 mutations that are associated with early-onset leukaemia and solid tumours. Here, we describe the clinical and molecular features of a remarkable family presenting with multiple primary colorectal cancers (CRCs) without detectable mutations in genes involved in the Mendelian predisposition to CRCs. We unexpectedly identified, despite the absence of clinical cardinal features of FA, a biallelic mutation of the FANCD1/BRCA2 corresponding to a frameshift alteration (c.1845_1846delCT, p.Asn615Lysfs*6) and a missense mutation (c.7802A>G, p.Tyr2601Cys). The diagnosis of FA was confirmed by the chromosomal analysis of lymphocytes. Reverse transcriptase (RT)-PCR analysis revealed that the c.7802A>G BRCA2 variation was in fact a splicing mutation that creates an aberrant splicing donor site and results partly into an aberrant transcript encoding a truncated protein (p.Tyr2601Trpfs*46). The atypical FA phenotype observed within this family was probably explained by the residual amount of BRCA2 with the point mutation c.7802A>G in the patients harbouring the biallelic FANCD1/BRCA2 mutations. Although this report is based in a single family, it suggests that CRCs may be part of the tumour spectrum associated with FANCD1/BRCA2 biallelic mutations and that the presence of such mutations should be considered in families with CRCs, even in the absence of cardinal features of FA.

Time to deterioration in quality of life score as a modality of longitudinal analysis in patients with breast cancer.

PURPOSE: This prospective multicenter study explored different definitions of time to deterioration (TTD) in quality of life (QoL) scores, according to different cutoffs of the minimal clinically important difference (MCID) as a modality for longitudinal QoL assessment in breast cancer patients. METHODS: QoL was assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 and BR-23 before surgery, after surgery, and 6 and 12 months later. The global health score, arm symptoms score (BRAS), and breast symptoms score were analyzed. For a given baseline score, QoL was considered to have deteriorated if this score decreased by ≥5 points at any time point after baseline. Analyses were repeated using an MCID of 10 points and taking the score after surgery as the reference score (to explore the occurrence of response shift). TTD was calculated using the Kaplan-Meier method and Cox regression was used to identify independent factors associated with TTD. RESULTS: Two hundred thirty-five patients underwent axillary lymph node dissection (ALND), 222 underwent sentinel lymph node biopsy (SLNB), and 61 underwent SLNB plus ALND. Patients who underwent SLNB had a significantly longer TTD for the BRAS dimension than those who underwent ALND. Cox multivariate analyses showed that treatment using SLNB and age >59 years were independently associated with longer TTD for the BRAS, whereas surgery elsewhere than at the Centre Georges François Leclerc was associated with a shorter TTD. CONCLUSION: Exploration of different definitions of TTD in QoL provides meaningful longitudinal QoL results for clinicians.

[Brenner tumour of the vagina]. / Tumeur de Brenner vaginale.

Vaginal tumours are rare, and Brenner tumour is one of the most infrequent vaginal lesions. Brenner tumour is a transitional tumour that typically arises in the ovaries. Some cases have been reported in the broad ligament, uterus and paratesticular structures. Only five cases have been reported in the vagina. We report a sixth case and discuss the histogenesis of this tumour, as well as the differential diagnosis with the mixed tumour of the vagina.