Tumour biology, metastatic sites and taxanes sensitivity as determinants of eribulin mesylate efficacy in breast cancer: results from the ERIBEX retrospective, international, multicenter study.

BACKGROUND: Our retrospective, international study aimed at evaluating the activity and safety of eribulin mesylate (EM) in pretreated metastatic breast cancer (MBC) in a routine clinical setting. METHODS: Patients treated with EM for a locally advanced or MBC between March 2011 and January 2014 were included in the study. Clinical and biological assessment of toxicity was performed at each visit. Tumour response was assessed every 3 cycles of treatment. A database was created to collect clinical, pathological and treatment data. RESULTS: Two hundred and fifty-eight patients were included in the study. Median age was 59 years old. Tumours were Hormone Receptor (HR)-positive (73.3 %) HER2-positive (10.2 %), and triple negative (TN, 22.5 %). 86.4 % of the patients presented with visceral metastases, mainly in the liver (67.4 %). Median previous metastatic chemotherapies number was 4 [1-9]. Previous treatments included anthracyclines and/or taxanes (100 %) and capecitabine (90.7 %). Median number of EM cycles was 5 [1-19]. The relative dose intensity was 0.917. At the time of analysis (median follow-up of 13.9 months), 42.3 % of the patients were still alive. The objective response rate was 25.2 % (95 %CI: 20-31) with a 36.1 % clinical benefit rate (CBR). Median time to progression (TTP) and overall survival were 3.97 (95 %CI: 3.25-4.3) and 11.2 (95 %CI: 9.3-12.1) months, respectively. One- and 2-year survival rates were 45.5 and 8.5 %, respectively. In multivariate analysis, HER2 positivity (HR = 0.29), the presence of lung metastases (HR = 2.49) and primary taxanes resistance (HR = 2.36) were the only three independent CBR predictive factors, while HR positivity (HR = 0.67), the presence of lung metastases (HR = 1.52) and primary taxanes resistance (HR = 1.50) were the only three TTP independent prognostic factors. Treatment was globally well tolerated. Most common grade 3-4 toxicities were neutropenia (20.9 %), peripheral neuropathy (3.9 %), anaemia (1.6 %), liver dysfunction (0.8 %) and thrombocytopenia (0.4 %). Thirteen patients (5 %) developed febrile neutropenia. CONCLUSION: EM is an effective new option in heavily pretreated MBC, with a favourable efficacy/safety ratio in a clinical practice setting. Our results comfort the use of this new molecule and pledge for the evaluation of EM-trastuzumab combination in this setting. Tumour biology, primary taxanes sensitivity and metastatic sites could represent useful predictive and prognostic factors.

Female stick insects mate multiply to find compatible mates

Why females of many species mate multiply in the absence of direct benefits remains an open question in evolutionary ecology. Interacting and mating with multiple males can be costly to females in terms of time, resources, predation risk, and disease transmission. A number of indirect genetic benefits have been proposed to explain such behaviors, but the relative importance of these mechanisms in natural systems remains unclear. We tested for several direct and indirect benefits of polyandry in the walking stick Timema cristinae. We found no evidence of direct benefits with respect to longevity or fecundity. However, male x female genotypic interactions affected egg-hatching success and offspring production independent of relatedness, suggesting that mating with certain males benefits females and that the best male may differ for each female. Furthermore, multiply mated females biased paternity toward one or few males, and the extent of this bias was positively correlated to egg-hatching success. Our data, therefore, provide evidence for indirect benefits through compatibility effects in this species. By mating multiply, females may improve their chances of mating with a compatible male if compatibility cannot be assessed before mating. Such compatibility effects can explain the evolution and maintenance of polyandry in Timema and many other species.

Comprehensive Molecular Portraits of Invasive Lobular Breast Cancer.

Invasive lobular carcinoma (ILC) is the second most prevalent histologic subtype of invasive breast cancer. Here, we comprehensively profiled 817 breast tumors, including 127 ILC, 490 ductal (IDC), and 88 mixed IDC/ILC. Besides E-cadherin loss, the best known ILC genetic hallmark, we identified mutations targeting PTEN, TBX3, and FOXA1 as ILC enriched features. PTEN loss associated with increased AKT phosphorylation, which was highest in ILC among all breast cancer subtypes. Spatially clustered FOXA1 mutations correlated with increased FOXA1 expression and activity. Conversely, GATA3 mutations and high expression characterized luminal A IDC, suggesting differential modulation of ER activity in ILC and IDC. Proliferation and immune-related signatures determined three ILC transcriptional subtypes associated with survival differences. Mixed IDC/ILC cases were molecularly classified as ILC-like and IDC-like revealing no true hybrid features. This multidimensional molecular atlas sheds new light on the genetic bases of ILC and provides potential clinical options.

How patient-centered do female physicians need to be? Analogue patients' satisfaction with male and female physicians' identical behaviors (Published online: 30 Aug 2014)

Previous research suggests that female physicians may not receive appropriate credit in patients' eyes for their patient-centered skills compared to their male counterparts. An experiment was conducted to determine whether a performance of higher (versus lower) verbal patient-centeredness would result in a greater difference in analogue patient satisfaction for male than female physicians. Two male and two female actors portrayed physicians speaking to a patient using high or low patient-centered scripts while not varying their nonverbal cues. One hundred ninety-two students served as analogue patients by assuming the patient role while watching one of the videos and rating their satisfaction and other evaluative responses to the physician. Greater verbal patient-centeredness had a stronger positive effect on satisfaction and evaluations for male than for female physicians. This pattern is consistent with the hypothesis that the different associations between patient-centeredness and patients' satisfaction for male versus female physicians occur because of the overlap between stereotypical female behavior and behaviors that comprise patient-centered medical care. If this is the case, high verbal patient-centered behavior by female physicians is not recognized as a marker of clinical competence, as it is for male physicians, but is rather seen as expected female behavior.

Clinical utility of a molecular test in adjuvant treatment decision making in women with endocrine-sensitive early stage breast cancer: a retrospective, single center one year experience

Background. Molecular tests for breast cancer (BC) risk assessment are reimbursed by health insurances in Switzerland since the beginning of year 2015. The main current role of these tests is to help oncologists to decide about the usefulness of adjuvant chemotherapy in patients with early stage endocrine-sensitive and human epidermal growth factor receptor 2 (HER2)-negative BC. These gene expression signatures aim at predicting the risk of recurrence in this subgroup. One of them (OncotypeDx/OT) also predicts distant metastases rate with or without the addition of cytotoxic chemotherapy to endocrine therapy. The clinical utility of these tests -in addition to existing so-called "clinico-pathological" prognostic and predictive criteria (e.g. stage, grade, biomarkers status)-is still debated. We report a single center one year experience of the use of one molecular test (OT) in clinical decision making. Methods. We extracted from the CHUV Breast Cancer Center data base the total number of BC cases with estrogen-receptor positive (ER+), HER2-negative early breast cancer (node negative (pN0) disease or micrometastases in up to 3 lymph nodes) operated between September 2014 and August 2015. For the cases from this group in which a molecular test had been decided by the tumor board, we collected the clinicopathologic parameters, the initial tumor board decision, and the final adjuvant systemic therapy decision. Results. A molecular test (OT) was done in 12.2% of patients with ER + HER2 negative early BC. The median age was 57.4 years and the median invasive tumor size was 1.7 cm. These patients were classified by ODX testing (Recurrence Score) into low-, intermediate-, and high risk groups, respectively in 27.2%, 63.6% and 9% of cases. Treatment recommendations changed in 18.2%, predominantly from chemotherapyendocrine therapy to endocrine treatment alone. Of 8 patients originally recommended chemotherapy, 25% were recommended endocrine treatment alone after receiving the Recurrence Score result. Conclusions. Though reimbursed by health insurances since January 2015, molecular tests are used moderately in our institution as per the decision of the multidisciplinary tumor board. It's mainly used to obtain a complementary confirmation supporting the decision of no chemotherapy. The OncotypeDx Recurrence Score results were in the intermediate group in 66% of the 9 tested cases but contributed to avoid chemotherapy in 2 patients during the last 12 months.

Les étudiant(e)s en médecine mènent une recherche dans La communauté [Male/female medical students conduct research in the community].

Pendant quatre semaines, les étudiant(e)s en médecine de 3e année de l'Université de Lausanne mènent une enquête dans la communauté sur le sujet de leur choix. L'objectif de ce module est de faire découvrir aux futurs médecins les déterminants non biomédicaux de la santé, de la maladie et de l'exercice de la médecine : les styles de vie, les facteurs psychosociaux et culturels, l'environnement, les décisions politiques, les contraintes économiques, les questions éthiques, etc. Par groupes de cinq, les étudiant(e)s commencent par définir une question de recherche originale et en explorent la littérature scientifique. Leur travail de recherche les amène à entrer en contact avec le réseau d'acteurs de la communauté concernés, professionnels ou associations de patients dont ils analysent les rôles et influences respectives. Chaque groupe est accompagné par un(e) tuteur(trice), enseignant(e) de la Faculté de biologie et de médecine de l'Université de Lausanne. Les étudiant(e)s présentent la synthèse de leurs travaux pendant un congrès de deux jours à la fin du module. Quatre travaux parmi les plus remarquables ont été choisis pour être publiés dans la Revue Médicale Suisse et Primary Care.

Lifetime and intergenerational fitness consequences of harmful male interactions for female lizards.

Male mating behaviors harmful to females have been described in a wide range of species. However, the direct and indirect fitness consequences of harmful male behaviors have been rarely quantified for females and their offspring, especially for long-lived organisms under natural conditions. Here, lifetime and intergenerational consequences of harmful male interactions were investigated in female common lizards (Lacerta vivipara) using field experiments. We exposed females to male harm by changing the population sex ratio from a normal female-biased to an experimental male-biased sex ratio during the first experimental year. Thereafter, females and their first generation of offspring were monitored during two additional years in a common garden with a female-biased sex ratio. We found strong immediate fitness costs and lower lifetime reproductive success in females subjected to increased male exposure. The immediate fitness costs were partly mitigated by direct compensatory responses after exposure to male excess, but not by indirect benefits through offspring growth, offspring survival, or mating success of offspring. These results support recent empirical findings showing that the direct costs of mating are not outweighed by indirect benefits.

Identification of Propionibacterium avidum from a breast abscess: an overlooked etiology of clinically significant infections.

We report the case of a 37-year-old previously healthy woman diagnosed with a breast abscess due to Propionibacterium avidum after breast reduction surgery. This case emphasizes the potential pathogenicity and morbidity associated with this commensal skin organism.

Female common lizards (Lacerta vivipara) do not adjust their sex-biased investment in relation to the adult sex ratio.

Sex allocation theory predicts that facultative maternal investment in the rare sex should be favoured by natural selection when breeders experience predictable variation in adult sex ratios (ASRs). We found significant spatial and predictable interannual changes in local ASRs within a natural population of the common lizard where the mean ASR is female-biased, thus validating the key assumptions of adaptive sex ratio models. We tested for facultative maternal investment in the rare sex during and after an experimental perturbation of the ASR by creating populations with female-biased or male-biased ASR. Mothers did not adjust their clutch sex ratio during or after the ASR perturbation, but produced sons with a higher body condition in male-biased populations. However, this differential sex allocation did not result in growth or survival differences in offspring. Our results thus contradict the predictions of adaptive models and challenge the idea that facultative investment in the rare sex might be a mechanism regulating the population sex ratio.

Environmentally induced changes in carotenoid-based coloration of female lizards: a comment on Vercken et al.

Colouration may either reflect a discrete polymorphism potentially related to life-history strategies, a continuous signal related to individual quality or a combination of both. Recently, Vercken et al. [J. Evol. Biol. (2007) 221] proposed three discrete ventral colour morphs in female common lizards, Lacerta vivipara, and suggested that they reflect alternative reproductive strategies. Here, we provide a quantitative assessment of the phenotypic distribution and determinants of the proposed colour polymorphism. Based on reflectance spectra, we found no evidence for three distinct visual colour classes, but observed continuous variation in colour from pale yellow to orange. Based on a 2-year experiment, we also provide evidence for reversible colour plasticity in response to a manipulation of the adult population sex ratio; yet, a significant portion of the colour variation was invariant throughout an adult female's life. Our results are thus in agreement with continuous colour variation in adults determined by environmental factors and potentially also by genetic factors.

Continuous quantification of HER2 expression by microfluidic precision immunofluorescence estimates HER2 gene amplification in breast cancer.

Chromogenic immunohistochemistry (IHC) is omnipresent in cancer diagnosis, but has also been criticized for its technical limit in quantifying the level of protein expression on tissue sections, thus potentially masking clinically relevant data. Shifting from qualitative to quantitative, immunofluorescence (IF) has recently gained attention, yet the question of how precisely IF can quantify antigen expression remains unanswered, regarding in particular its technical limitations and applicability to multiple markers. Here we introduce microfluidic precision IF, which accurately quantifies the target expression level in a continuous scale based on microfluidic IF staining of standard tissue sections and low-complexity automated image analysis. We show that the level of HER2 protein expression, as continuously quantified using microfluidic precision IF in 25 breast cancer cases, including several cases with equivocal IHC result, can predict the number of HER2 gene copies as assessed by fluorescence in situ hybridization (FISH). Finally, we demonstrate that the working principle of this technology is not restricted to HER2 but can be extended to other biomarkers. We anticipate that our method has the potential of providing automated, fast and high-quality quantitative in situ biomarker data using low-cost immunofluorescence assays, as increasingly required in the era of individually tailored cancer therapy.

Effects of oral supplementation of iron on hepcidin blood concentrations among non-anaemic female blood donors: a randomized controlled trial.

BACKGROUND AND OBJECTIVES: Hepcidin is the main hormone that regulates iron balance. Its lowering favours digestive iron absorption in cases of iron deficiency or enhanced erythropoiesis. The careful dosage of this small peptide promises new diagnostic and therapeutic strategies. Its measurement is progressively being validated and now its clinical value must be explored in different physiological situations. Here, we evaluate hepcidin levels among premenopausal female donors with iron deficiency without anaemia. MATERIALS AND METHODS: In a preceding study, a 4-week oral iron treatment (80 mg/day) was administered in a randomized controlled trial (n = 145), in cases of iron deficiency without anaemia after a blood donation. We subsequently measured hepcidin at baseline and after 4 weeks of treatment, using mass spectrometry. RESULTS: Iron supplementation had a significant effect on plasma hepcidin compared to the placebo arm at 4 weeks [+0·29 nm [95% CI: 0·18 to 0·40]). There was a significant correlation between hepcidin and ferritin at baseline (R(2) = 0·121, P < 0·001) and after treatment (R(2) = 0·436, P < 0·001). Hepcidin levels at baseline were not predictive of concentration changes for ferritin or haemoglobin. However, hepcidin levels at 4 weeks were significantly higher (0·79 nm [95% CI: 0·53 to 1·05]) among ferritin responders. CONCLUSIONS: This study shows that a 4-week oral treatment of iron increased hepcidin blood concentrations in female blood donors with an initial ferritin concentration of less than 30 ng/ml. Apparently, hepcidin cannot serve as a predictor of response to iron treatment but might serve as a marker of the iron repletion needed for erythropoiesis.

Breast implant-associated anaplastic large cell lymphoma: two distinct clinicopathological variants with different outcomes.

BACKGROUND: ALK-negative anaplastic large cell lymphoma associated with breast implant (i-ALCL) has been recently recognized as a distinct entity. Among 43 830 lymphomas registered in the French Lymphopath network since 2010, 300 breast lymphomas comprising 25 peripheral T-cell lymphomas (PTCL) were reviewed. Among PTCL, ALK-negative ALCL was the most frequent and all of them were associated with breast implants. PATIENTS AND METHODS: Since 2010, all i-ALCL cases were collected from different institutions through Lymphopath. Immuno-morphologic features, molecular data and clinical outcome of 19 i-ALCLs have been retrospectively analyzed. RESULTS: The median age of the patients was 61 years and the median length between breast implant and i-ALCL was 9 years. Most implants were silicone-filled and textured. Implant removal was performed in 17 out of 19 patients with additional treatment based on mostly CHOP or CHOP-like chemotherapy regimens (n = 10/19) or irradiation (n = 1/19). CHOP alone or ABVD following radiation without implant removal have been given in two patients. The two clinical presentations, i.e. effusion and less frequently tumor mass correlated with distinct histopathologic features: in situ i-ALCL (anaplastic cell proliferation confined to the fibrous capsule) and infiltrative i-ALCL (pleomorphic cells massively infiltrating adjacent tissue with eosinophils and sometimes Reed-Sternberg-like cells mimicking Hodgkin lymphoma). Malignant cells were CD30-positive, showed a variable staining for EMA and were ALK negative. Most cases had a cytotoxic T-cell immunophenotype with variable T-cell antigen loss and pSTAT3 nuclear expression. T-cell receptor genes were clonally rearranged in 13 out of 13 tested cases. After 18 months of median follow-up, the 2-year overall survival for in situ and infiltrative i-ALCL was 100% and 52.5%, respectively. CONCLUSIONS: In situ i-ALCLs have an indolent clinical course and generally remain free of disease after implant removal. However, infiltrative i-ALCLs could have a more aggressive clinical course that might require additional therapy to implant removal.

A Preclinical Model for ERα-Positive Breast Cancer Points to the Epithelial Microenvironment as Determinant of Luminal Phenotype and Hormone Response.

Seventy-five percent of breast cancers are estrogen receptor α positive (ER(+)). Research on these tumors is hampered by lack of adequate in vivo models; cell line xenografts require non-physiological hormone supplements, and patient-derived xenografts (PDXs) are hard to establish. We show that the traditional grafting of ER(+) tumor cells into mammary fat pads induces TGFβ/SLUG signaling and basal differentiation when they require low SLUG levels to grow in vivo. Grafting into the milk ducts suppresses SLUG; ER(+) tumor cells develop, like their clinical counterparts, in the presence of physiological hormone levels. Intraductal ER(+) PDXs are retransplantable, predictive, and appear genomically stable. The model provides opportunities for translational research and the study of physiologically relevant hormone action in breast carcinogenesis.