Denosumab improves trabecular bone score in relationship with decrease in fracture risk of women exposed to aromatase inhibitors.

PURPOSE: Trabecular bone score (TBS) is a gray-level textural metric that has shown to correlate with risk of fractures in several forms of osteoporosis. The value of TBS in predicting fractures and the effects of bone-active drugs on TBS in aromatase inhibitors (AIs)-induced osteoporosis are still largely unknown. The primary objective of this retrospective study was to assess the effects of denosumab and bisphosphonates (BPs) on TBS and vertebral fractures (VFs) in women exposed to AIs. METHODS: 241 consecutive women (median age 58 years) with early breast cancer undergoing treatment with AIs were evaluated for TBS, bone mineral density (BMD) and morphometric VFs at baseline and after 18-24 months of follow-up. During the study period, 139 women (57.7%) received denosumab 60 mg every 6 months, 53 (22.0%) BPs, whereas 49 women (20.3%) were not treated with bone-active drugs. RESULTS: Denosumab significantly increased TBS values (from 1.270 to 1.323; P < 0.001) accompanied by a significant decrease in risk of VFs (odds ratio 0.282; P = 0.021). During treatment with BPs, TBS did not significantly change (P = 0.849) and incidence of VFs was not significantly different from women untreated with bone-active drugs (P = 0.427). In the whole population, women with incident VFs showed higher decrease in TBS vs. non-fractured women (P = 0.003), without significant differences in changes of BMD at any skeletal site. CONCLUSIONS: TBS variation predicts fracture risk in AIs treated women. Denosumab is effective to induce early increase of TBS and reduction in risk of VFs.

[Traumatic events and stress responses: the role of oxytocin and attachment]. / Evénements traumatiques et réponses de stress: le rôle de l'ocytocine et de l'attachement.

Being repeatedly confronted to very difficult situations since childhood influences the way indivuals will later respond to even mildly stressful events. The hypothalamic-pituitary-adrenal axis (HPA) is a complex system implicated in regulating neuroendocrine responses to stress. Its activation produces among others the <

Prognosis and adjuvant treatment effects in selected breast cancer subtypes of very young women (<35 years) with operable breast cancer.

BACKGROUND: There is limited knowledge about prognosis of selected breast cancer subtypes among very young women. PATIENTS AND METHODS: We explored patterns of recurrence by age according to four immunohistochemically defined tumor subtypes: Luminal A and Luminal B (estrogen receptor positive and/or progesterone receptor positive and either human epidermal growth factor receptor 2 (HER2) positive and/or high Ki-67), HER2-positive (and) endocrine receptor absent and Triple Negative, in 2970 premenopausal patients with pT1-3, pN0-3 and M0 breast cancer. RESULTS: Patients <35 years of age (315, 11%) presented a significantly increased risk of recurrence and death [hazards ratio (HR) = 1.65, 95% confidence interval (CI) 1.30-2.10 and HR = 1.78, 95% CI 1.12-2.85, respectively] when compared with older patients (2655, 89%) with similar characteristics of disease. This was true considering patients with Luminal B [HR = 1.62, 95% CI 1.21-2.18 for disease-free survival (DFS) and HR = 2.09, 95% CI 0.96-4.53 for overall survival (OS)] and with Triple Negative (HR = 2.04, 95% CI 1.11-3.72 for DFS and HR = 2.20, 95% CI 1.10-4.41 for OS) breast cancer, observing the highest risk of recurrence in the younger patients with HER2-positive breast cancer (HR = 2.37, 95% CI 1.12-5.02) when compared with older patients. CONCLUSIONS: Very young patients with Triple Negative, Luminal B or HER2-positive breast cancer have a worse prognosis when compared with older patients with similar characteristics of disease.

A risk score to predict disease-free survival in patients not achieving a pathological complete remission after preoperative chemotherapy for breast cancer.

BACKGROUND: We aimed to predict disease-free survival (DFS) in patients who failed to achieve a pathologic complete remission (pCR) after preoperative chemotherapy (PC). PATIENTS AND METHODS: Data from 577 patients treated with PC and operated at the European Institute of Oncology (EIO) were used to develop a nomogram using Cox proportional hazards regression model based on both categorical (pT, positive nodes, human epidermal growth factor receptor 2 (HER2) status, vascular invasion) and continuous histological variables (estrogen receptors and Ki-67 expression) at surgery. The nomogram was tested on a second patient cohort (343 patients) treated in other institutions and subsequently operated at the EIO. RESULTS: The nomogram for DFS based on both categorical and continuous variables had good discrimination in the training and the validation sets (concordance indices 0.73, 0.67). CONCLUSION: The use of a nomogram based on the degree of selected histopathological variables can predict DFS and might help in the adjuvant therapeutic algorithm design.

Minimal axillary lymph node involvement in breast cancer has different prognostic implications according to the staging procedure.

It is still controversial whether the identification of micrometastases and isolated tumor cells in the axillary lymph nodes of patients with breast cancer has any prognostic value. We evaluated the prognostic role of isolated tumor cells and micrometastases in the axillary lymph nodes in 3,158 consecutive patients pT1-2 pN0-N1mi (with a single involved lymph node) and M0, referred to the Division of Medical Oncology after surgery performed at the European Institute of Oncology from April 1997 to December 2002. Median follow-up was 6.3 years (range 0.1-11 years). Sentinel lymph node biopsy (SLNB) and axillary lymph node dissection (ALND) were performed in 2,087 and 1,071 patients, respectively. A worse metastasis-free survival was observed for patients with micrometastatic disease compared to node-negative patients, if staged with ALND (log-rank P < .0001; HR: 3.17; 95% CI 1.72-5.83 at multivariate analysis), but not for patients who underwent SLNB (log-rank P = 0.36). The presence of a single micrometastatic lymph node is associated with a higher risk of distant recurrence as compared to node-negative disease only for patients undergoing ALND for staging purposes. Treatment recommendations for systemic therapy should not take into account the presence of a single micrometastatic lymph node identified during complete serial sectioning of sentinel node(s).

Factors that predict early treatment failure for patients with locally advanced (T4) breast cancer.

Locally advanced breast cancer (LABC) is associated with dire prognosis despite progress in multimodal treatments. We evaluated several clinical and pathological features of patients with either noninflammatory (NIBC, cT4a-c) or inflammatory (IBC, cT4d) breast cancer to identify subset groups of patients with high risk of early treatment failure. Clinical and pathological features of 248 patients with LABC, who were treated with multimodality treatments including neoadjuvant chemotherapy followed by radical surgery and radiotherapy were reassessed. Tumour samples obtained at surgery were evaluated using standard immunohistochemical methods. Overall, 141 patients (57%) presented with NIBC (cT4a-c, N0-2, M0) and 107 patients (43%) with IBC (cT4d, N0-2, M0). Median follow-up time was 27.5 months (range: 1.6-87.8). No significant difference in terms of recurrence-free survival (RFS) (P=0.72), disease-free survival (DFS) (P=0.98) and overall survival (OS) (P=0.35) was observed between NIBC and IBC. At the multivariate analysis, patients with ER- and PgR-negative diseases had a significantly worse RFS than patients with ER- and/or PgR-positive diseases (hazard ratio: 2.47, 95% CI: 1.33-4.59 for overall). The worst RFS was observed for the subgroup of patients with endocrine nonresponsive and HER2-negative breast cancer (2-year RFS: 57% in NIBC and 57% in IBC) A high Ki-67 labelling index (>20% of the invasive tumour cells) and the presence of peritumoral vascular invasion (PVI) significantly correlated with poorer RFS in overall (HR 2.69, 95% CI: 1.61-4.50 for Ki-67>20% and HR 2.27, 95% CI: 1.42-3.62 for PVI). Patients with endocrine nonresponsive LABC had the most dire treatment outcome. High degree of Ki-67 staining and presence of PVI were also indicators of higher risk of early relapse. These factors should be considered in therapeutic algorithms for LABC.

Preoperative bevacizumab combined with letrozole and chemotherapy in locally advanced ER- and/or PgR-positive breast cancer: clinical and biological activity.

The antiangiogenic agent bevacizumab showed synergistic effects when combined with chemotherapy in advanced breast cancer. We presently investigated the activity of bevacizumab in combination with chemotherapy, including capecitabine and vinorelbine, and endocrine therapy, including letrozole (+triptorelin in premenopausal women), as primary therapy for patients with ER and/or PgR > or =10% T2-T4a-c, N0-N2, M0 breast cancer. Biological end point included the proliferative activity (Ki67), whereas clinical end points were clinical response rate, pathological complete response (pCR) and tolerability. Circulating endothelial cells (CECs) and their progenitors, as surrogate markers of antiangiogenic activity, were measured at baseline and at surgery.Thirty-six women are evaluable. A clinical response rate of 86% (95% CI, 70-95) and no pCR were observed; Ki67 was significantly decreased by 71% (interquartile range, -82%, -62%). Toxicity was manageable: two grade 3 hypertension, four grade 3 deep venous thrombosis and no grade >2 proteinuria were observed. Treatment significantly decreased the percentage of viable CECs and prevented the chemotherapy-induced mobilisation of circulating progenitors. Basal circulating progenitors were positively associated with clinical response. In conclusion, bevacizumab is feasible and active in association with primary chemoendocrine therapy for ER-positive tumours in terms of proliferation inhibition, clinical response and antiangiogenic activity.

Expression of ER, PgR, HER1, HER2, and response: a study of preoperative chemotherapy.

PURPOSE: To identify the role of estrogen (ER), progesterone (PgR), epidermal growth factor 1 (HER1), and HER2 receptors in predicting response to preoperative chemotherapy. MATERIALS AND METHODS: We reviewed the pretreatment biopsies of 485 patients with locally advanced breast cancer (cT2-T4, N0-2, M0) treated with preoperative chemotherapy. The incidence of pathological complete remission (pCR) and outcome were assessed with respect to clinical and pathological findings including ER/PgR status (absent versus expressed), HER1 (absent versus expressed) and HER2 (overexpressed versus none) expression. RESULTS: Patients with ER/PgR-absent tumors were 12.0 times [95% confidence interval (CI) 4.93-29.28] more likely to achieve a pCR (P < 0.0001). Predictors of disease-free survival (DFS) at the univariate analysis included HER1 [hazards ratio (HR) 1.6, 95% CI 1.04-2.32, P = 0.03] and HER2 (HR 1.6, 95% CI 1.08-2.38, P = 0.02) expression. A statistically significant difference in DFS was confirmed at the multivariate analysis for patients with ER/PgR-absent disease (HR 2.1, 95% CI 1.41-2.99, P = 0.0002). CONCLUSIONS: The pCR rate is higher and outcome worse for patients with ER/PgR-absent tumors. HER1 and HER2 expression may have a prognostic role in locally advanced breast cancer and warrant further studies.

Premenopausal endocrine-responsive early breast cancer: who receives chemotherapy?

BACKGROUND: The role of chemotherapy in addition to combined endocrine therapy for premenopausal women with endocrine-responsive early breast cancer remains an open question, yet trials designed to answer it have repeatedly failed to adequately accrue. The International Breast Cancer Study Group initiated two concurrent trials in this population: in Premenopausal Endocrine Responsive Chemotherapy (PERCHE), chemotherapy use is determined by randomization and in Tamoxifen and Exemestane Trial (TEXT) by physician choice. PERCHE closed with inadequate accrual; TEXT accrued rapidly. METHODS: From 2003 to 2006, 1317 patients (890 with baseline data) were randomly assigned to receive ovarian function suppression (OFS) plus tamoxifen or OFS plus exemestane for 5 years in TEXT. We explore patient-related factors according to whether or not chemotherapy was given using descriptive statistics and classification and regression trees. RESULTS: Adjuvant chemotherapy was chosen for 64% of patients. Lymph node status was the predominant determinant of chemotherapy use (88% of node positive treated versus 46% of node negative). Geography, patient age, tumor size and grade were also determinants, but degree of receptor positivity and human epidermal growth factor receptor 2 status were not. CONCLUSIONS: The perceived estimation of increased risk of relapse is the primary determinant for using chemotherapy despite uncertainties regarding the degree of benefit it offers when added to combined endocrine therapy in this population.

Developmental delay in communication among toddlers and its relationship to caregiving behavior among violence-exposed, posttraumatically stressed mothers.

OBJECTIVES: This study aimed to understand if maternal interpersonal violence-related posttraumatic stress disorder (IPV-PTSD) is associated with delayed language development among very young children ("toddlers"). METHODS: Data were collected from 61 mothers and toddlers (ages 12-42 months, mean age = 25.6 months SD = 8.70). Child expressive and receptive language development was assessed by the Ages and Stages Questionnaire (ASQ) communication subscale (ASQCS) that measures language acquisition. Observed maternal caregiving behavior was coded from videos of 10-min free-play interactions via the CARE-Index. Correlations, Mann-Whitney tests, and multiple linear regression were performed. RESULTS: There was no significant association between maternal IPV-PTSD severity and the ASQCS. Maternal IPV-PTSD severity was associated with continuous maternal behavior variables (i.e. sensitive and controlling behavior on the CARE-Index) across the entire sample and regardless of child gender. Maternal sensitivity was positively and significantly associated with the ASQCS. Controlling behavior was negatively and significantly associated with the ASQCS. CONCLUSIONS: Results are consistent with the literature that while maternal IPV-PTSD severity is not associated with child language delays, the quality of maternal interactive behavior is associated both with child language development and with maternal IPV-PTSD severity. Further study is needed to understand if the level of child language development contributes to intergenerational risk or resilience for relational violence and/or victimization.

Prognostic role of the extent of peritumoral vascular invasion in operable breast cancer.

BACKGROUND: The clinical relevance of the degree of peritumoral vascular invasion (PVI) in patients with no or limited involvement of the axillary nodes is unknown. MATERIALS AND METHODS: 2606 consecutive patients with pT1-3, pN0 (1586)-1a (1020) and M0, operated and counseled for medical therapy from 1/2000 to 12/2002, were prospectively classified according to the degree of PVI: absent (2017, 77.4%), focal (368, 14.1%), moderate (51, 2.0%) and extensive (170, 6.5%). RESULTS: Patients with extensive PVI were more likely to be younger, to have larger tumors, high tumor grade, axillary-positive nodes, high Ki-67 expression and HER2/neu over-expression compared with patients having less PVI (P for trend, <0.0001). In patients with node-negative disease a statistically significant difference in disease-free survival (DFS), risk of distant metastases and overall survival (OS) was observed at the multivariate analysis for extensive PVI versus no PVI (hazard ratios: 2.11, 95% CI, 1.02 to 4.34, P = 0.04 for DFS; 4.51, 95% CI, 1.96 to 10.4, P< 0.001 for distant metastases; 3.55, 95% CI, 1.24 to 10.1, P = 0.02 for OS). CONCLUSIONS: The extent of vascular invasion should be considered in the therapeutic algorithm in order to properly select targeted adjuvant treatment.

A phase II study of primary dose-dense sequential doxorubicin plus cyclophosphamide and docetaxel in cT4 breast cancer.

BACKGROUND: Dose-dense chemotherapy with anthracyclines and taxanes has improved either disease free survival or overall survival in high risk patients with early breast cancer. PATIENTS AND METHODS: The activity and safety of a dose-dense schedule (q14 days) of adriamycin 60 mg/sqm and cyclophosphamide 600 mg/sqm (AC) x 4 cycles followed by docetaxel 75 mg/sqm for 4 cycles with hematopoietic support in patients with stage IIIB breast cancer was explored. Patients with ER > or =10% tumors received concomitant endocrine therapy with 3-month triptorelin and letrozole. RESULTS: Fifteen patients with histologically proven cT4b (three patients) and cT4d (twelve patients) M0 breast cancer were enrolled. Median age was 48 years (range 25-66). Eight clinical responses including one pathological complete remission (pCR), three stable disease (including minor responses) and four progression of disease, one during AC and three during taxotere, were observed. Four patients had grade 3-4 non hematological toxicities and all except one discontinued treatment. CONCLUSION: Due to the high rate of progressive disease, this schedule should not represent a standard option in cT4 breast cancer.

Effect of the synthetic retinoid fenretinide on dark adaptation and the ocular surface.

BACKGROUND: Fenretinide, a synthetic derivative of retinoic acid, is under study in clinical trials for the prevention of breast, skin basal cell, bladder, and oral cancer in patients at risk. Although fenretinide is well tolerated even after prolonged use, it does lower plasma retinol levels and thus may affect night vision. PURPOSE: The purpose of this study was to measure changes in dark adaptation resulting from fenretinide administration, to compare the measured results with the patient's subjective perception, to define the association with plasma retinol levels, to assess the reversibility of alterations in night vision, and to assess the effects of fenretinide on the surface of the eye. METHODS: The study involved 65 women who had been operated on for stage I breast cancer. Of the study group, 34 received 200 mg daily of fenretinide for a median of 32 months, while 31 control subjects did not. Dark adaptation was studied with the Goldmann-Weekers adaptometer and with a subjective questionnaire. Plasma retinol levels were measured at each test of dark adaptation. Effects of fenretinide on the ocular surface were evaluated through conjunctival impression cytology. RESULTS: Of the patients on fenretinide, eight (23.5%) showed mild and nine (26.5%) showed moderate alterations of measured dark adaptability, compared with just two controls (6.5%) with mild alterations (cumulative odds ratio = 15.4; P = .0008). A significant inverse correlation exists between the final sensitivity threshold of dark-adaptometry and plasma retinol levels, with mild alterations arising below 16 micrograms/dL and moderate alterations below 10 micrograms/dL. Abnormal rod function improved significantly after 7 days and normalized 1 month after use of fenretinide was stopped or vitamin A supplementation was begun, while the conventional 3-day drug suspension, or drug half dose, did not allow sufficient recovery. Alterations of conjunctival cytology were slightly higher in patients receiving fenretinide, but no clinical disorders of the ocular surface were observed. CONCLUSIONS: The women treated with 200 mg fenretinide daily showed a relatively high incidence of mild-to-moderate alterations of dark-adaptometry as measured with the Goldmann-Weekers adaptometer. However, the real-life implication of the measurements is an open question, for the questionnaire shows that 50% of the patients with altered dark adaptometry were asymptomatic.

The synthetic retinoid fenretinide lowers plasma insulin-like growth factor I levels in breast cancer patients.

We studied the effect of fenretinide [N-(4-hydroxyphenyl)retinamide (4-HPR)], a synthetic analogue of retinoic acid, on plasma insulin-like growth factor I (IGF-I) levels in a consecutive cohort of stage I breast cancer patients belonging to a randomized phase III trial of breast cancer chemoprevention. Thirty-two women receiving 4-HPR 200 mg/daily and 28 untreated controls entered the study. IGF-I levels were determined after acid-ethanol extraction, on plasma obtained at randomization and after a mean time of 10.8 +/- 0.3 months. At baseline, there was no difference in IGF-I levels between the two groups [152.9 +/- 9.4 versus 159.2 +/- 7.0 ng/ml in treated and control group (P = 0.59), respectively]. After follow-up time, while plasma IGF-I levels were unchanged in control patients (163.3 +/- 7.4 ng/ml; P = 0.5), they were significantly reduced to 134.6 +/- 8.1 ng/ml in the patients treated with 4-HPR (P = 0.003 and P = 0.011 versus baseline and control values, respectively). Multiple regression analysis showed that treatment was the only determinant of IGF-I decline. Moreover, the interaction between treatment and age was significant, in that the decrease of IGF-I levels induced by 4-HPR administration was much more pronounced in younger patients, while an age-related decline was observed in controls. We conclude that the synthetic retinoid 4-HPR lowers circulating IGF-I levels in early breast cancer patients. Although the importance of this observation for the clinical prevention of breast cancer remains to be established, it further substantiates the rationale of the combination of 4-HPR with tamoxifen, which is known to decrease IGF-I as well and to act synergistically with the retinoid in preclinical models.

Factors affecting plasma retinol decline during long-term administration of the synthetic retinoid fenretinide in breast cancer patients.

Administration of the synthetic retinoid Fenretinide lowers circulating retinol and may thus affect night vision. We have recently shown that plasma retinol levels below 100 ng/ml are associated with moderate alterations of the dark adaptometry test. To identify which patients are more likely to experience a decrease of plasma retinol under this threshold, we measured plasma levels of retinol, Fenretinide, and its metabolite 4-MPR in a cohort of 28 women receiving Fenretinide at the daily dose of 200 mg and studied their relationship with clinical characteristics such as age, menstrual status, body mass index, and time on treatment. Our results show that patients aged over 55 years with a higher percentage of adipose tissue had higher plasma concentrations of 4-MPR, which turned out to be the major determinant of the retinol decrease. This subgroup may thus deserve careful ophthalmological surveillance.

Randomized trial of fenretinide in superficial bladder cancer using DNA flow cytometry as an intermediate end point.

Retinoids have shown a potential activity in preventing tumor recurrence in superficial bladder cancer. We assessed the activity of the synthetic retinoid fenretinide in superficial bladder cancer using DNA flow cytometry and conventional cytology as surrogate biomarkers. A total of 99 subjects with resected superficial bladder cancer (pTa, pT1) were randomized to either fenretinide (200 mg day p.o. for 24 months) or no intervention. Cystoscopy and bladder washing for DNA flow cytometry end points (proportion of DNA aneuploid histograms, hyperdiploid fraction, and percentage of apoptotic cells) and proportion of abnormal cytological examinations were repeated every 4 months for up to 36 months. The primary study end point was the proportion of DNA aneuploid histograms after 12 months. This figure was 48.9% in the fenretinide arm and 41.9% in the control arm (odds ratio, 1.16; 95% confidence interval, 0.44-3.07). There was no difference in any other response biomarker between the two groups up to 36 months, nor was any biomarker able to predict recurrence risk. Recurrence-free survival was comparable between the arms (27 events in the fenretinide arm versus 21 in the control arm; P = 0.36). Twelve subjects in the fenretinide arm complained of diminished dark adaptability, and nine subjects in the fenretinide arm versus one control subject had mild dermatological alterations. We conclude that fenretinide showed a lack of effect on the DNA content distribution and the morphology of urothelial cells obtained in serial bladder washings. Recurrence-free survival was comparable between groups. Because our data are hampered by the lack of predictivity of the selected biomarkers, additional studies are necessary to assess the activity of fenretinide in preventing bladder cancer.

Long-term effects of fenretinide on retinal function.

The long-term effects of the synthetic retinoid fenretinide (4-HPR) on retinal function were studied by electroretinogram (ERG) in 24 women treated for a median of 30.5 months and in 18 untreated controls belonging to a phase III intervention trial. The six outcome measures were: a wave implicit time, peak-to-peak amplitude and implicit time of b wave following both cone stimulation and maximal cone-rod stimulation in the dark-adapted eye. Multivariate analysis of covariance was applied to evaluate the joint effect on the whole set of ERG measures taking into account their inter-relationship. Predictive factors with a significant effect on ERG measures were: (1) a qualitative interaction between age and treatment duration and (2) the squared (parabolic) function of plasma retinol. Individually, the b wave implicit time following cone stimulation was the only ERG measure significantly influenced by the predictors, indicating a primary effect of 4-HPR on retinal photoreceptor sensitivity without significant alterations of the inner nuclear layer. Thus, in contrast to previous reports at higher dose, administration of 4-HPR at 200 mg/day seems to exert subtle alterations of retinal function as measured by ERG.