S. Alran

Validation and Limitations of Use of a Breast Cancer Nomogram Predicting the Likelihood of Non–Sentinel Node Involvement After Positive Sentinel Node Biopsy

BackgroundAxillary lymph node dissection (ALND) for patients with positive sentinel lymph nodes (SLNs) is currently under discussion in the literature. The breast cancer nomogram (BCN), an online tool developed by the Memorial Sloan-Kettering Cancer Center (MSKCC), aims to predict the risk of positive non-SLN in SLN-positive patients. The purpose of this study was to test the accuracy of the nomogram on patients with macrometastatic and micrometastatic SLN-positive biopsy findings.MethodsPatient characteristics, tumor pathology, and positive SLN characteristics were collected on 588 consecutive patients who underwent completion ALND. The MSKCC BCN tool was used to calculate risk of metastases for all 588 cases that included a subgroup of the 213 patients with SLN micrometastases. The BCN was performed for positive SLN biopsy findings regardless of the method of metastasis detection. Evaluation of the BCN was performed by the area under the curve method.ResultsThe BCN applied to all 588 patients achieved an area under the receiver operating characteristic curve (ROC) of .724 (range, .677–.771) compared with .76 in the MSKCC study. When the tool was applied solely to micrometastases found by hematoxylin and eosin staining and metastases found by immunohistochemistry, the area under the ROC was .538 (range, .423–.653).ConclusionsThe MSKCC nomogram has been validated for all the patients having a metastatic SLN at the Institut Curie. However, this model was not reliably predictive for positive non–SLN in cases with micrometastic positive SLN.

The Molecular Subtype Classification Is a Determinant of Sentinel Node Positivity in Early Breast Carcinoma

Introduction Several authors have underscored a strong relation between the molecular subtypes and the axillary status of breast cancer patients. The aim of our work was to decipher the interaction between this classification and the probability of a positive sentinel node biopsy. Materials and Methods Our dataset consisted of a total number of 2654 early-stage breast cancer patients. Patients treated at first by conservative breast surgery plus sentinel node biopsies were selected. A multivariate logistic regression model was trained and validated. Interaction covariate between ER and HER2 markers was a forced input of this model. The performance of the multivariate model in the training and the two validation sets was analyzed in terms of discrimination and calibration. Probability of axillary metastasis was detailed for each molecular subtype. Results The interaction covariate between ER and HER2 status was a stronger predictor (p = 0.0031) of positive sentinel node biopsy than the ER status by itself (p = 0.016). A multivariate model to determine the probability of sentinel node positivity was defined with the following variables; tumour size, lympho-vascular invasion, molecular subtypes and age at diagnosis. This model showed similar results in terms of discrimination (AUC = 0.72/0.73/0.72) and calibration (HL p = 0.28/0.05/0.11) in the training and validation sets. The interaction between molecular subtypes, tumour size and sentinel nodes status was approximated. Discussion We showed that biologically-driven analyses are able to build new models with higher performance in terms of breast cancer axillary status prediction. The molecular subtype classification strongly interacts with the axillary and distant metastasis process.

Dehydroepiandrosterone 7α-hydroxylation in human tissues: Possible interference with type 1 11β-hydroxysteroid dehydrogenase-mediated processes ☆

Dehydroepiandrosterone (DHEA) is 7alpha-hydroxylated by the cytochome P450 7B1 (CYP7B1) in the human brain and liver. This produces 7alpha-hydroxy-DHEA that is a substrate for 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) which exists in the same tissues and carries out the inter-conversion of 7alpha- and 7beta-hydroxy-DHEA through a 7-oxo-intermediary. Since the role of 11beta-HSD1 is to transform the inactive cortisone into active cortisol, its competitive inhibition by 7alpha-hydroxy-DHEA may support the paradigm of native anti-glucocorticoid arising from DHEA. Therefore, our objective was to use human tissues to assess the presences of both CYP7B1 and 11beta-HSD1. Human skin was selected then and used to test its ability to produce 7alpha-hydroxy-DHEA, and to test the interference of 7alpha- and 7beta-hydroxy-DHEA and 7-oxo-DHEA with the 11beta-HSD1-mediated oxidoreduction of cortisol and cortisone. Immuno-histochemical studies showed the presence of both CYP7B1 and 11beta-HSD1 in the liver, skin and tonsils. DHEA was readily 7alpha-hydroxylated when incubated using skin slices. A S9 fraction of dermal homogenates containing the 11beta-HSD1 carried out the oxidoreduction of cortisol and cortisone. Inhibition of the cortisol oxidation by 7alpha-hydroxy-DHEA and 7beta-hydroxy-DHEA was competitive with a Ki at 1.85+/-0.495 and 0.255+/-0.005 microM, respectively. Inhibition of cortisone reduction by 7-oxo-DHEA was of a mixed type with a Ki at 1.13+/-0.15 microM. These findings may support the previously proposed native anti-glucocorticoid paradigm and suggest that the 7alpha-hydroxy-DHEA production is a key for the fine tuning of glucocorticoid levels in tissues.

Different outcome of invasive cervical cancer associated with high‐risk versus intermediate‐risk HPV genotype

Human papillomavirus (HPV) DNA sequences are associated with the large majority of invasive cervical carcinoma but the role of specific genotype(s) in the outcome of the disease is still debated. To determine the viral epidemiology in the French population of patients and the prognostic value of HPV genotypes in cervical cancer, we performed a retrospective study in 515 patients treated in our Institution from 1985 to 2005. Ninety‐six percent of the cases were found associated with HPV DNA whereas 4% remained HPV negative. High‐risk HPV 16/18 genotypes were found in 70% of the cases. HPV 18 was more frequently associated with adenocarcinoma (40.6%) than HPV 16 (10.4%) and found in tumours developed in younger women (mean age, 45.8 years) than HPV 16 (48.3 years) or other HPV types (53.6 years). In multivariate analysis, node involvement (p < 0.0001), parametria invasion (p = 0.009), tumour size (p = 0.01) and HPV status (p = 0.02) were associated with disease‐free survival (median follow‐up 95 months). Disease outcome was better in tumours associated with intermediate risk HPV types (HPV 31, 33, 35, 39, 52, 53, 58, 59, 73) than in tumours with high oncogenic types (HPV 16, 18, 45) (p = 0.03). Node status and tumour size remained prognostic factor for overall survival. Our data show that HPV genotype is one of the biological factors associated with the outcome of cervical cancer. One third of invasive carcinoma were not associated with HPV 16/18, indicating that the screening for cervical neoplasia should be maintained after prophylactic vaccination against these HPV genotypes.

Time-Dependent Prognostic Impact of Circulating Tumor Cells Detection in Non-Metastatic Breast Cancer: 70-Month Analysis of the REMAGUS02 Study

Introduction. In non-metastatic breast cancer patients, the REMAGUS02 neoadjuvant study was the first to report a significant impact of circulating tumor cells (CTCs) detection by the CellSearch system on the distant metastasis-free survival (DMFS) and overall survival (OS) endpoints. However, these results were only reported after a short follow-up. Here, we present the updated data, with a longer follow-up. Material and Methods. CTC count was performed before and after neoadjuvant chemotherapy in 118 patients and correlated to survival. Results. CTC count results were available before and/or after neoadjuvant chemotherapy in 115 patients. After a median follow-up of 70 months, detection of ≥1 CTC/7.5 mL before chemotherapy (N = 95) was significantly associated with DMFS (P = 0.04) and OS (P = 0.03), whereas postchemotherapy CTC detection (N = 85) had no significant impact. In multivariable analysis, prechemotherapy CTC and triple negative phenotype were the two independent prognostic factors for survival. We observed that the CTC impact is most significant during the first three years of follow-up. Discussion. We confirm that the detection of CTC is independently associated with a significantly worse outcome, but mainly during the first 3-4 years of follow-up. No prognostic impact is seen in patients who are still relapse-free at this moment.

Human Papillomavirus Mutational Insertion: Specific Marker of Circulating Tumor DNA in Cervical Cancer Patients

Introduction In most cases of cervical cancers, HPV DNA is integrated into the genome of carcinoma cells. This mutational insertion constitutes a highly specific molecular marker of tumor DNA for every patient. Circulating tumor DNA (ctDNA) is an emerging marker of tumor dynamics which detection requires specific molecular motif. To determine whether the sequence of the cell-viral junction could be used in clinical practice as a specific marker of ctDNA, we analyzed a series of cervical cancer patient serums. Methods and Findings Serum specimens of 16 patients diagnosed with HPV16/18-associated cervical cancer, and for which the viral integration locus had been previously localized, were analyzed. Sequential serum specimens, taken at different times during the course of the disease, were also available for two of these cases. ctDNA was found in 11 out of 13 patients with tumor size greater than 20 mm at diagnosis, and analysis of sequential serum specimens showed that ctDNA concentration in patients serum was related to tumor dynamics. Conclusions We report that HPV mutational insertion constitutes a highly specific molecular marker of ctDNA in HPV-associated tumor patients. Using this original approach, ctDNA was detected in most cervical cancer patients over stage I and ctDNA concentration was found to reflect tumor burden. In addition to its potential prognostic and predictive value, HPV mutation insertion is likely to constitute a new molecular surrogate of minimal residual disease and of subclinical relapse in HPV-associated tumor. This is of major importance in the perspective of specific anti-HPV therapy.

Disseminated tumor cells and the risk of locoregional recurrence in nonmetastatic breast cancer

BACKGROUND In early breast cancer patients, bone marrow (BM)-disseminated tumor cells (DTCs) were associated with distant metastasis and locoregional recurrence. Our aim was to determine whether BM DTC detection could be related to specific locoregional dissemination of cancer cells, according to radiotherapy volumes. PATIENTS AND METHODS The relationship between locoregional recurrence-free survival (LRFS) and DTC detection was evaluated according to the various locoregional volumes irradiated after surgery. RESULTS BM DTCs were detected in 94 of 621 stage I-III breast cancer patients (15%) and were not associated with axillary node status. Eighteen patients (2.9%) experienced locoregional recurrence (median follow-up 56 months), of whom eight (44%) were initially BM DTC positive. BM DTC detection was the only prognostic factor for LRFS [P = 0.0005, odds ratio = 5.2 (2.0-13.1), multivariate analysis]. In BM DTC-positive patients, a longer LRFS was observed in those who were given adjuvant hormone therapy (P = 0.03) and radiotherapy to supraclavicular nodes (SCNs)/internal mammary nodes (IMNs) (P = 0.055) (multivariate analysis; interaction test: P = 0.028). CONCLUSIONS The presence of DTC in BM may be associated with a different pattern of locoregional cancer cell dissemination and influences LRFS. The possible reseeding of the primary cancer area by DTC could be prevented by systemic hormone therapy but also by SCN/IMN irradiation.

Vaginal birth after cesarean section: X-ray pelvimetry at term is informative.

Abstract Objective: To examine whether X-ray pelvimetry data to evaluate the likelihood of vaginal birth after previous cesarean section. Design: Retrospective study Setting: University hospital Population: Patients with a previous cesarean delivery who underwent X-ray pelvimetry and gave birth at gestational age 37 weeks during a seven-year period. Methods: 1190 patients with a scarred uterus were compared with 15,189 patients without a scarred uterus. In the scarred uterus group, 760 patients with a transverse pelvic diameter ≥12 cm were compared with 430 patients with a transverse pelvic diameter <12 cm. Main outcome measures: The obstetrical outcomes were spontaneous or induced labor, and mode of delivery. The maternal morbidity outcomes were hemorrhage requiring transfusion of packed red cells, uterine rupture, bladder injury, and hysterectomy due to hemorrhage. The neonatal morbidity outcomes were the 5-min Apgar score, transfer to intensive care, and intubation. Results: Patients with a scarred uterus had a significantly higher rate of cesarean section (35.5%) than those with no prior cesarean section (9%). Among patients with a scarred uterus who were selected for vaginal delivery, 81% delivered vaginally when the transverse diameter (TD) of the pelvic inlet was greater than 12 cm, 68% when the TD was between 11.5 and 12 cm, and 58% when the TD was less than 11.5 cm. Maternal morbidity was significantly higher in the patients with a scarred uterus. The neonatal results were comparable in the different groups. Conclusion: X-ray pelvimetry tailors the information given to each patient about the likelihood of having a vaginal delivery. It can also be used to optimize the selection of patients allowed to enter labor.

Long-Term Prognostic Performance of Ki67 Rate in Early Stage, pT1-pT2, pN0, Invasive Breast Carcinoma

Background Molecular signatures may become of use in clinical practice to assess the prognosis of breast cancers. However, although international consensus conferences sustain the use of these new markers in the near future, concerns remain about their degree of discordance and cost-effectiveness in different international settings. The present study aims to validate Ki67 as prognostic factor in a large cohort of early-stage (pT1–pT2, pN0) breast cancer patients. Methods 456 patients treated in 1995–1996 were identified in the Institut Curie database. Ki67 (MIB1) was retrospectively assessed by immunohistochemistry for all cases. The prognostic value of this index was compared to that of histological grade (HG), Estrogen receptor (ER) and HER2 status. Distant disease free interval, loco-regional recurrence, time-lapse from first metastatic diagnosis to death were analyzed. Results All 456 patients were treated by lumpectomy plus axillary dissection and radiotherapy. 27 patients (5.9%) received systemic treatment. Tumors were classified as HG1 in 35%, HG2 in 42% and HG3 in 23% of cases. ER was expressed in 86% of the tumors, HER2 in 5% and 14% were triple negative. The median follow-up was 151 [5–191] months. Distant and loco-regional disease recurrences were observed in 16% and 18%, respectively. High (>20%) Ki67 rate [HR = 3 (1.8–4.8), p<10e−06] and HG3 [HR = 4.4 (2.2–8.6), p = 0.00002] were associated with an increased rate of distant relapse. In multivariate analysis, the Ki67 remained the only significant prognostic factor in the subgroups of ER positive HER2 negative [HR = 2.6 (1.5–4.6), p = 0.0006] and ER positive HER2 negative HG2 tumors [HR = 2.2 (1.01–4.8), p = 0.04]. Conclusions We validate the prognosis value of the Ki67 rate in small size node negative breast cancer. We conclude that Ki67 is a potential cost-effective decision marker for adjuvant therapy in early-stage HG2, pT1–pT2, pN0, breast cancers.

Cost comparison of axillary sentinel lymph node detection and axillary lymphadenectomy in early breast cancer. A national study based on a prospective multi-institutional series of 985 patients ‘on behalf of the Group of Surgeons from the French Unicancer Federation’

BACKGROUND Our objective was to assess the global cost of the sentinel lymph node detection [axillary sentinel lymph node detection (ASLND)] compared with standard axillary lymphadenectomy [axillary lymph node dissection (ALND)] for early breast cancer patients. PATIENTS AND METHODS We conducted a prospective, multi-institutional, observational, cost comparative analysis. Cost calculations were realized with the micro-costing method from the diagnosis until 1 month after the last surgery. RESULTS Eight hundred and thirty nine patients were included in the ASLND group and 146 in the ALND group. The cost generated for a patient with an ASLND, with one preoperative scintigraphy, a combined method for sentinel node detection, an intraoperative pathological analysis without lymphadenectomy, was lower than the cost generated for a patient with lymphadenectomy [€ 2947 (σ = 580) versus € 3331 (σ = 902); P = 0.0001]. CONCLUSION ASLND, involving expensive techniques, was finally less expensive than ALND. The length of hospital stay was the cost driver of these procedures. The current observational study points the heterogeneous practices for this validated and largely diffused technique. Several technical choices have an impact on the cost of ASLND, as intraoperative analysis allowing to reduce rehospitalization rate for secondary lymphadenectomy or preoperative scintigraphy, suggesting possible savings on hospital resources.BACKGROUND Our objective was to assess the global cost of the sentinel lymph node detection [axillary sentinel lymph node detection (ASLND)] compared with standard axillary lymphadenectomy [axillary lymph node dissection (ALND)] for early breast cancer patients. PATIENTS AND METHODS We conducted a prospective, multi-institutional, observational, cost comparative analysis. Cost calculations were realized with the micro-costing method from the diagnosis until 1 month after the last surgery. RESULTS Eight hundred and thirty nine patients were included in the ASLND group and 146 in the ALND group. The cost generated for a patient with an ASLND, with one preoperative scintigraphy, a combined method for sentinel node detection, an intraoperative pathological analysis without lymphadenectomy, was lower than the cost generated for a patient with lymphadenectomy [€2947 (σ = 580) versus €3331 (σ = 902); P = 0.0001]. CONCLUSION ASLND, involving expensive techniques, was finally less expensive than ALND. The length of hospital stay was the cost driver of these procedures. The current observational study points the heterogeneous practices for this validated and largely diffused technique. Several technical choices have an impact on the cost of ASLND, as intraoperative analysis allowing to reduce rehospitalization rate for secondary lymphadenectomy or preoperative scintigraphy, suggesting possible savings on hospital resources.