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Background: Breast cancer biological characteristics change as age advances. Today, there is a lack of knowledge regarding age-specific molecular alterations that characterize breast tumours, notably in elderly patients. The vast majority of studies that aimed at exploring breast cancer in function of age are based on clinico-pathological data. Gene-expression signatures (GES), which in some ways capture biological information in a non-reductionist manner, represent powerful tools able to explore tumour heterogeneity. Methods: Twenty-five GES were used for functional annotation of breast tumours in function of age: five for molecular subtyping, seven for immune response, three for metabolism, seven for critical pathways in cancer and three for prognosis. Affymetrix® genomics datasets were exclusively used to avoid cross-platform normalization issues. Available corresponding clinico-pathological data were also retrieved and analysed. Results: Fifteen publicly available datasets were pooled for a total of 2378 breast cancer patients (whole cohort), out of whom 1413 were of Caucasian origin. Three age groups were defined: ≤ 40 years (AG1), > 40 to < 70 years (AG2) and ≥ 70 years (AG3). We confirmed that age influenced the incidence of molecular subtypes. We found a significant growing incidence of luminal B and a decreasing kinetics for basal-like in function of age. We showed that AG3 luminal B tumours were less aggressive than AG1 luminal B tumours based on different GES (iron metabolism, mitochondrial oxidative phosphorylation and reactive stroma), recurrence score prognostic GES and histological grade (SBR). Contrary to tumours of young patients, tumours of elderly patients concentrated favourable GES scores: high oestrogen receptor and mitochondrial oxidative phosphorylation, low proliferation, basal-like, glycolysis, chromosomal instability and iron metabolism, and low GES prognostic scores (van't Veer 70-GES, genomic grade index and recurrence score). Conclusions: Functional annotation of breast tumours by means of 25 GES demonstrated a decreasing aggressiveness of breast tumours in function of age. This strategy, which can be strengthened by increasing the number of representative GES to gain more insight into biological systems involved in this disease, provides a framework to develop rational therapeutic strategies in function of age. [ABSTRACT FROM AUTHOR]

Background: Metastatic prostate cancer remains a common cause of death in Europe, and improvements in management of the disease are urgently needed. The advent of positron-emission tomography (PET) imaging enhanced with fluorocholine has led to the identification of a new sub-group of metastatic prostate cancer patients: those with so-called oligometastatic disease. Presenting with a low burden of metastatic disease (≤5 lesions), this new sub-group lies between true metastatic prostate cancer patients for whom androgen- deprivation therapy (ADT) is the mainstay of treatment, and patients with a rising PSA, but no visible lesion on conventional imaging, in whom intermittent ADT has been shown to be no less effective than continuous ADT. One might conclude that intermittent ADT would also be the standard of care for oligometastatic prostate cancer patients, but radical strategies such as extensive lymphadenectomy or high-dose radiotherapy have been suggested as another means to delay the need for ADT, and increase its effectiveness once initiated. This study will explore the role of salvage pelvic image-guided intensity-modulated radiation therapy (IMRT) combined with ADT administered for 6 months in pelvic oligometastatic patients in prolonging the failure-free interval between two consecutive ADT courses, or even to cure selected patients with limited metastatic burden.Methods/design: We plan to assess the two year outcome in oligometastatic prostate cancer patients (1-5 pelvic oligometastases) treated concomitantly with high-dose IMRT (54 Gy, 30 fractions to the pelvis and 66 Gy, 30 fractions to the lymph nodes) and ADT for six months.Discussion: This multicenter prospective phase II study will yield new data regarding the safety and efficacy of high-dose radiotherapy combined with ADT and will provide a basis for a larger phase III study to examine the role of radiotherapy in this population currently treated only with hormone therapy.Trial Registration: NCT02274779 , date of registration: 23/10/14. [ABSTRACT FROM AUTHOR]

Background: Several randomized trials and meta-analyses confirmed a wide benefit of radiotherapy (RT), both after breast conserving surgery (BCS) and mastectomy. However, many elderly women don't receive RT. Hypofractionated (HF) RT allows « simplified » and more accessible treatments with equivalent results to classic RT in three large randomized trials. However, there are few available data on HF-RT for nodal irradiation, as well as for the boost. Methods: We evaluated patients treated for IBC by HF-RT between 2004 and 2012 in two regional cancer centres. We used an original scheme delivering 45 Gy in 15 fractions three times a week, both after BCS or mastectomy, with or without nodal irradiation. After BCS, a 9 Gy boost in 3 fractions was delivered. Local, regional and distant recurrences were assessed, as well as acute and late cutaneous, cardiac or pulmonary toxicities. Results: 205 patients were analysed, 116 after BCS (57 %) and 89 after mastectomy (43 %). Median age was 81 years (range: 52-91); 44 % had axillary nodal involvement (pN+). The Nottingham Prognostic Index (NPI) scored 0, 1, 2 and 3 in 10 %, 27 %, 44 % and 19 % of the cases. A nodal HF-RT was delivered in 65 patients (32 %) and boost in 98 patients (84 % of BCS) by 9 Gy/3 fr scheme. Fifty (24 %) patients underwent chemotherapy and 156 (75 %) hormonal treatment. With a 49-month median follow-up, 3/116 (2.6 %) patients and 4/89 (4.5 %) had local recurrence (LR) after BCS and mastectomy, respectively. The overall 5-year LR rate was 4.4 %. In univariate and multivariate analysis, LR risk factors were: high NPI (HR 5.46; p = 0.028), and triple negative tumour (HR 9.78; p = 0.006). Only 8 (4.5 %) patients had grade III skin toxicity; 29 (14 %) late fibrosis and 16 (8 %) telangiectasia. No pulmonary or cardiac toxicity was observed. Conclusion: Our HF-RT scheme (with or without nodal irradiation) confirms in elderly patients the data from randomized trials, both after BCS or mastectomy. Toxicity seems very acceptable but requires a longer follow-up. A larger evaluation is still ongoing in several other centres in France. [ABSTRACT FROM AUTHOR]

Introduction: Triple-negative breast cancers need to be refined in order to identify therapeutic subgroups of patients Methods: We conducted an unsupervised analysis of microarray gene-expression profiles of 107 triple-negative breast cancer patients and undertook robust functional annotation of the molecular entities found by means of numerous approaches including immunohistochemistry and gene-expression signatures. A triple-negative external cohort (n = 87) was used for validation. Results: Fuzzy clustering separated triple-negative tumours into three clusters: C1 (22.4%), C2 (44.9%) and C3 (32.7%). C1 patients were older (mean = 64.6 years) than C2 (mean = 56.8 years; P = 0.03) and C3 patients (mean = 51.9 years; P = 0.0004). Histological grade and Nottingham prognostic index were higher in C2 and C3 than in C1 (P < 0.0001 for both comparisons). Significant event-free survival (P = 0.03) was found according to cluster membership: patients belonging to C3 had a better outcome than patients in C1 (P = 0.01) and C2 (P = 0.02). Event-free survival analysis results were confirmed when our cohort was pooled with the external cohort (n = 194; P = 0.01). Functional annotation showed that 22% of triple-negative patients were not basal-like (C1). C1 was enriched in luminal subtypes and positive androgen receptor (luminal androgen receptor). C2 could be considered as an almost pure basal-like cluster. C3, enriched in basal-like subtypes but to a lesser extent, included 26% of claudin-low subtypes. Dissection of immune response showed that high immune response and low M2-like macrophages were a hallmark of C3, and that these patients had a better event-free survival than C2 patients, characterized by low immune response and high M2-like macrophages: P = 0.02 for our cohort, and P = 0.03 for pooled cohorts. Conclusions: We identified three subtypes of triple-negative patients: luminal androgen receptor (22%), basal-like with low immune response and high M2-like macrophages (45%), and basal-enriched with high immune response and low M2-like macrophages (33%). We noted out that macrophages and other immune effectors offer a variety of therapeutic targets in breast cancer, and particularly in triple-negative basal-like tumours. Furthermore, we showed that CK5 antibody was better suited than CK5/6 antibody to subtype triple-negative patients. [ABSTRACT FROM AUTHOR]

Background: Considerable variation in intravenous 5-fluorouracil (5-FU) metabolism can occur due to the wide range of dihydropyrimidine dehydrogenase (DPD) enzyme activity, which can affect both tolerability and efficacy. The oral fluoropyrimidine tegafur-uracil (UFT) is an effective, well-tolerated and convenient alternative to intravenous 5-FU. We undertook this study in patients with locally advanced rectal cancer to evaluate the efficacy and tolerability of UFT with leucovorin (LV) and preoperative radiotherapy and to evaluate the utility and limitations of multicenter staging using pre- and post-chemoradiotherapy ultrasound. We also performed a validated pretherapy assessment of DPD activity and assessed its potential influence on the tolerability of UFT treatment. Methods: This phase II study assessed preoperative UFT with LV and radiotherapy in 85 patients with locally advanced T3 rectal cancer. Patients with potentially resectable tumors received UFT (300 mg/m/2/day), LV (75 mg/ day), and pelvic radiotherapy (1.8 Gy/day, 45 Gy total) 5 days/week for 5 weeks then surgery 4-6 weeks later. The primary endpoints included tumor downstaging and the pathologic complete response (pCR) rate. Results: Most adverse events were mild to moderate in nature. Preoperative grade 3/4 adverse events included diarrhea (n = 18, 21%) and nausea/vomiting (n = 5, 6%). Two patients heterozygous for dihydropyrimidine dehydrogenase gene (DPYD) experienced early grade 4 neutropenia (variant IVS14+1G > A) and diarrhea (variant 2846A > T). Pretreatment ultrasound TNM staging was compared with postchemoradiotherapy pathology TN staging and a significant shift towards earlier TNM stages was observed (p < 0.001). The overall downstaging rate was 42% for primary tumors and 44% for lymph nodes. The pCR rate was 8%. The sensitivity and specificity of ultrasound for staging was poor. Anal sphincter function was preserved in 55 patients (65%). Overall and recurrence-free survival at 3 years was 86.1% and 66.7%, respectively. Adjuvant chemotherapy was administered to 36 node-positive patients (mean duration 118 days). Conclusion: Preoperative chemoradiotherapy using UFT with LV plus radiotherapy was well tolerated and effective and represents a convenient alternative to 5-FU-based chemoradiotherapy for the treatment of resectable rectal cancer. Pretreatment detection of DPD deficiency should be performed to avoid severe adverse events. [ABSTRACT FROM AUTHOR]

Background: Anti-apoptotic signals induced downstream of HER2 are known to contribute to the resistance to current treatments of breast cancer cells that overexpress this member of the EGFR family. Whether or not some of these signals are also involved in tumor maintenance by counteracting constitutive death signals is much less understood. To address this, we investigated what role anti- and pro-apoptotic Bcl-2 family members, key regulators of cancer cell survival, might play in the viability of HER2 overexpressing breast cancer cells., Methods: We used cell lines as an in vitro model of HER2-overexpressing cells in order to evaluate how anti-apoptotic Bcl-2, Bcl-xL and Mcl-1, and pro-apoptotic Puma and Bim impact on their survival, and to investigate how the constitutive expression of these proteins is regulated. Expression of the proteins of interest was confirmed using lysates from HER2-overexpressing tumors and through analysis of publicly available RNA expression data., Results: We show that the depletion of Mcl-1 is sufficient to induce apoptosis in HER2-overexpressing breast cancer cells. This Mcl-1 dependence is due to Bim expression and it directly results from oncogenic signaling, as depletion of the oncoprotein c-Myc, which occupies regions of the Bim promoter as evaluated in ChIP assays, decreases Bim levels and mitigates Mcl-1 dependence. Consistently, a reduction of c-Myc expression by inhibition of mTORC1 activity abrogates occupancy of the Bim promoter by c-Myc, decreases Bim expression and promotes tolerance to Mcl-1 depletion. Western blot analysis confirms that naïve HER2-overexpressing tumors constitutively express detectable levels of Mcl-1 and Bim, while expression data hint on enrichment for Mcl-1 transcripts in these tumors., Conclusions: This work establishes that, in HER2-overexpressing tumors, it is necessary, and maybe sufficient, to therapeutically impact on the Mcl-1/Bim balance for efficient induction of cancer cell death.