Improved tolerability of neratinib in patients with HER2-positive early-stage breast cancer: the CONTROL trial.

BACKGROUND: Neratinib is an irreversible pan-HER tyrosine kinase inhibitor approved for extended adjuvant treatment in early-stage HER2-positive breast cancer based on the phase III ExteNET study. In that trial, in which no antidiarrheal prophylaxis was mandated, grade 3 diarrhea was observed in 40% of patients and 17% discontinued due to diarrhea. The international, open-label, sequential-cohort, phase II CONTROL study is investigating several strategies to improve tolerability. PATIENTS AND METHODS: Patients who completed trastuzumab-based adjuvant therapy received neratinib 240 mg/day for 1 year plus loperamide prophylaxis (days 1-28 or 1-56). Sequential cohorts evaluated additional budesonide or colestipol prophylaxis (days 1-28) and neratinib dose escalation (DE; ongoing). The primary end point was the incidence of grade ≥3 diarrhea. RESULTS: Final data for loperamide (L; n = 137), budesonide + loperamide (BL; n = 64), colestipol + loperamide (CL; n = 136), and colestipol + as-needed loperamide (CL-PRN; n = 104) cohorts, and interim data for DE (n = 60; completed ≥six cycles or discontinued; median duration 11 months) are available. No grade 4 diarrhea was observed. Grade 3 diarrhea rates were lower than ExteNET in all cohorts and lowest in DE (L 31%, BL 28%, CL 21%, CL-PRN 32%, DE 15%). Median number of grade 3 diarrhea episodes was one; median duration per grade 3 episode was 1.0-2.0 days across cohorts. Most grade 3 diarrhea and diarrhea-related discontinuations occurred in month 1. Diarrhea-related discontinuations were lowest in DE (L 20%, BL 8%, CL 4%, CL-PRN 8%, DE 3%). Decreases in health-related quality of life did not cross the clinically important threshold. CONCLUSIONS: Neratinib tolerability was improved with preemptive prophylaxis or DE, which reduced the rate, severity, and duration of neratinib-associated grade ≥3 diarrhea compared with ExteNET. Lower diarrhea-related treatment discontinuations in multiple cohorts indicate that proactive management can allow patients to stay on neratinib for the recommended time period. CLINICALTRIALS.GOV: NCT02400476.

Circulating Tumor Cells (CTC) Are Associated with Defects in Adaptive Immunity in Patients with Inflammatory Breast Cancer.

BACKGROUND: Circulating tumor cells (CTCs) play a crucial role in tumor dissemination and are prognostic in primary and metastatic breast cancer. Peripheral blood (PB) immune cells contribute to an unfavorable microenvironment for CTC survival. This study aimed to correlate CTCs with the PB T-cell immunophenotypes and functions of patients with inflammatory breast cancer (IBC). METHODS: This study included 65 IBC patients treated at the MD Anderson Cancer Center. PB was obtained from patients prior to starting a new line of chemotherapy for CTCs enumeration by CellSearch(®), and T cell phenotype and function by flow cytometry; the results were correlated with CTCs and clinical outcome. RESULTS: At least 1 CTC (≥1) or ≥5 CTCs was detected in 61.5% or 32.3% of patients, respectively. CTC count did not correlate with total lymphocytes; however, patients with ≥1 CTC or ≥5 CTCs had lower percentages (%) of CD3+ and CD4+ T cells compared with patients with no CTCs or <5 CTCs, respectively. Patients with ≥1 CTC had a lower percentage of T-cell receptor (TCR)-activated CD8+ T cells synthesizing TNF-α and IFN-γ and a higher percentage of T-regulatory lymphocytes compared to patients without CTCs. In multivariate analysis, tumor grade and % CD3+ T-cells were associated with ≥1 CTC, whereas ≥5 CTC was associated with tumor grade, stage, % CD3+ and % CD4+ T cells, and % TCR-activated CD8 T-cells synthesizing IL-17. CONCLUSIONS: IBC patients with CTCs in PB had abnormalities in adaptive immunity that could potentially impact tumor cell dissemination and initiation of the metastatic cascade.

Long-term treatment efficacy in primary inflammatory breast cancer by hormonal receptor- and HER2-defined subtypes.

BACKGROUND: Subtypes defined by hormonal receptor (HR) and HER2 status have not been well studied in inflammatory breast cancer (IBC). We characterized clinical parameters and long-term outcomes, and compared pathological complete response (pCR) rates by HR/HER2 subtype in a large IBC patient population. We also compared disease-free survival (DFS) and overall survival (OS) between IBC patients who received targeted therapies (anti-hormonal, anti-HER2) and those who did not. PATIENTS AND METHODS: We retrospectively reviewed the records of patients diagnosed with IBC and treated at MD Anderson Cancer Center from January 1989 to January 2011. Of those, 527 patients had received neoadjuvant chemotherapy and had available information on estrogen receptor (ER), progesterone receptor (PR), and HER2 status. HR status was considered positive if either ER or PR status was positive. Using the Kaplan-Meier method, we estimated median DFS and OS durations from the time of definitive surgery. Using the Cox proportional hazards regression model, we determined the effect of prognostic factors on DFS and OS. Results were compared by subtype. RESULTS: The overall pCR rate in stage III IBC was 15.2%, with the HR-positive/HER2-negative subtype showing the lowest rate (7.5%) and the HR-negative/HER2-positive subtype, the highest (30.6%). The HR-negative, HER2-negative subtype (triple-negative breast cancer, TNBC) had the worst survival rate. HR-positive disease, irrespective of HER2 status, had poor prognosis that did not differ from that of the HR-negative/HER2-positive subtype with regard to OS or DFS. Achieving pCR, no evidence of vascular invasion, non-TNBC, adjuvant hormonal therapy, and radiotherapy were associated with longer DFS and OS. CONCLUSIONS: Hormone receptor and HER2 molecular subtypes had limited predictive and prognostic power in our IBC population. All molecular subtypes of IBC had a poor prognosis. HR-positive status did not necessarily confer a good prognosis. For all IBC subtypes, novel, specific treatment strategies are needed in the neoadjuvant and adjuvant settings.

Circulating tumor cells in immunohistochemical subtypes of metastatic breast cancer: lack of prediction in HER2-positive disease treated with targeted therapy.

BACKGROUND: Circulating tumor cells (CTCs) are associated with inferior prognosis in metastatic breast cancer (MBC). We hypothesized that the relationship between CTCs and disease subtype would provide a better understanding of the clinical and biologic behavior of MBC. PATIENTS AND METHODS: We retrospectively analyzed 517 MBC patients treated at a single institution. Subtypes of primary tumors were analyzed by immunohistochemical (IHC) or fluorescent in situ hybridization analyses and CTCs were enumerated by CellSearch(®) at starting a new therapy. Overall survival (OS) and progression-free survival durations for each IHC subtype were determined. RESULTS: At a median follow-up of 24.6 months, 276 of 517 (53%) patients had died. The median OS for patients with <5 and ≥ 5 CTCs were 32.4 and 18.3 months, respectively (P < 0.001). Except in HER2+ patients, the prognostic value of CTCs was independent of disease subtype and disease site. CONCLUSIONS: In this large retrospective study, CTCs were strongly predictive of survival in all MBC subtypes except HER2+ patients who had been treated with targeted therapy. Our results clearly demonstrate the value of enumerating CTCs in MBC and strongly suggest an interesting biological implication in the HER2+ subset of patients that need to be further explored.

Superovulatory response of zebu cows treated with pFSH in a single subcutaneous injection followed by an additional intramuscular sub-dose 48 h later.

The aim of this study was to evaluate whether an additional intramuscular (im) injection of pFSH would increase the embryo production in zebu cows superovulated with a single subcutaneous (sc) pFSH injection. Twenty-one Nelore cows were treated with a progesterone vaginal implant (Controlled Internal Drug Relased - CIDR B) and injected im with 2.5 mg estradiol benzoate. Four days later, cows were assigned randomly into three groups and superovulated with pFSH. Groups A and B received single sc injections of 400 and 320 IU, respectively; Group C received multiple im injections of 400 IU in decreasing doses at 12-h intervals over 4 days. In the morning (07:00 am) of day 3 after starting superovulation, cows received im 150 mcg cloprostenol and Group B was additionally injected im with 80 IU of pFSH. CIDR-B was withdrawn in the afternoon (07:00 pm). Cows were inseminated 48 and 62 h after the cloprostenol injection. Embryo collection and corpora lutea (CL) estimation were done 7 days after insemination. Alternation of treatments (crossover design) occurred at a 60-day interval. There was no significant difference (p > 0.05) of CL counts among treatments. The total (transferable and no transferable) number of recovered embryos from Group A (6.9 +/- 1.5) was not different from Group C (9.8 +/- 1.2), whereas Group B (5.7 +/- 1.5) was lower than Group C (p < 0.05). The number of transferable embryos from Groups A (2.4 +/- 0.7) and B (1.7 +/- 0.6) was lower (p < 0.05) than Group C (4.6 +/- 1.2). Lesser (p < 0.05) embryo production from Group B was related to lower recovery rate (46.4%), compared with Groups A (65.1%) and C (81.7%). It was concluded that an additional im subdose of pFSH, injected 48 h after a single subcutaneous (sc) dose of pFSH, does not improve the embryo production in zebu cows.

Transfer of bovine blastocysts derived from short-term in vitro culture of low quality morulae produced in vivo.

The aim of this study was to evaluate if blastocysts arising from in vitro culture of Grade 3 bovine morulae produced in vivo can promote acceptable pregnancy rates when transferred into recipients. Embryos of different stages and qualities were recovered from superovulated Bos taurus and B. indicus donors. Grade 3 morulae were cultured in either Holding Plus or TCM-199 (supplemented with 10% bovine fetal serum) media for 24 h at 38.5 degrees C. After this culture period, the resulting blastocysts were morphologically classified (Grades 1, 2 and 3) and transferred into recipients previously synchronized with the donors. Non-cultured Grades 1 and 3 morulae were used as control. Pregnancy diagnosis was carried out 60 days after embryo transfer and the data were analysed by logistic regression, considering variables, such as embryo quality (Grade), donor breed, culture medium, donor-recipient synchrony and seasonality. Embryo quality was the only variable, showing significant effect on the pregnancy rate. Pregnancy rates for non-cultured Grade 1 and 3 morulae, and blastocysts arising from cultured Grade 3 morulae were 58.1% (n = 31), 17.1% (n = 35) and 51.1% (n = 47), respectively (p < 0.05). There were no statistical differences between non-cultured Grade 1 morulae and cultured blastocysts. Pregnancy rates for Grades 1 (65.0%) and 2 (60.0%) were higher than Grade 3 (29.4%) cultured blastocysts (p < 0.05). It was concluded that short-term in vitro culture is a very convenient method of identifying morphologically low quality morulae with higher chances of continuing development after the transfer into recipients.

Efeito do líquido folicular bovino tratado com carväo ativado na secreçäo de FSH em novilhas pré-púberes intatas e ovariectomizadas / Effect of charcoal-treated bovine follicular fluid on the secretion of FSH in ovariectomized and intact prepubertal heifers

O presente trabalho objetivou determinar o efeito do líquido folicular bovino tratado com carväo ativado (LFb) na secreçäo do hormônio folículo estimulante (FSH) de novilhas pré-púberes ovariectomizadas ou intatas. A aplicaçäo de LFb (quatro injeçöes de 10 ml com intervalo de 8 horas) provocou uma queda de aproximadamente 44 por cento na concentraçäo plasmática de FSH nas novilhas ovariectomizadas, mas näo teve efeito nas novilhas intatas. Näo foi observada hipersecreçäo de FSH após o término da aplicaçäo do LFb. Esses resultados sugerem que proteínas presentes no LFb atuam ao nível hipofisiário para inibir a secreçäo de FSH e, diferentemente das intatas, as novilhas ovariectomizadas constituem um modelo adequado para evidenciar esse efeito, particularmente quando o LFb possui reduzida atividade supressora do FSH

Perfis endócrinos e taxa de ovulaçäo de vacas superovuladas com FSH após imunizaçäo passiva contra líquido folicular bovino livre de esteróides / Endocrine profiles and ovulation rate of cow superovulated with FSH following passive immunization against steroid free-bovine follicular fluid

Dez vacas multíparas, secas, foram distribuídas aleatoriamente em dois grupos de cinco animais cada. Nos dias 8 a 12 do diestro, o primeiro grupo recebeu 100 ml de anti-soro contra líquido folicular livre de esteróides (anti-LFb) produzido em ovelhas ovariectomizadas. O segundo grupo (controle) recebeu 100 ml de soro de ovelhas näo-imunizadas. Seis horas após a aplicaçäo, os dois grupos foram superovulados com FSH (18 NIH-FSH-S1 unidades) e LH (0,29 NIH-LH-S1 unidades) administrados em quantidades decrescentes durante quatro dias. Na manhä do terceiro dia, foi administrada uma dose luteolítica de cloprostenol. Duas inseminaçöes foram realizadas 48 e 60 horas após. Os embriöes foram recuperados pelo método cervical 7 dias após a primeira inseminaçäo. Amostras de sangue foram coletadas durante todo o período experimental para determinar, por radioimunoensaio, as concentraçöes plasmáticas de FSH, LH e progesterona. Todas as vacas do grupo imunizado e 3 do grupo controle apresentaram mais de 2 CL. Näo existiu diferença significativa (p>0,05) na taxa de ovulaçäo entre os grupos imunizado e controle (14,4 e 9,9, respectivamente). O número de embriöes recuperado näo foi significativamente diferente (p>0,05) entre os grupos, embora o grupo imunizado tenha apresentado maior número de embriöes transferíveis (3,4 ñ 1,0 versus 0,8 ñ 0,4, p<0,05). As concentraçöes de gonadotrofinas plasmáticas näo foram correlacionadas com a taxa de ovulaçäo ou com o número de embriöes recuperados. As concentraçöes de progesterona plasmática foram positivamente correlacionadas (r = 0,88, p<0,01) com a taxa de ovulaçäo. Os resultados sugerem que o anti-LFb, aplicado antes da superovulaçäo, näo reduz a variabilidade da resposta ovariana