Clonal expansion and linear genome evolution through breast cancer progression from pre-invasive stages to asynchronous metastasis

Evolution of the breast cancer genome from pre-invasive stages to asynchronous metastasis is complex and mostly unexplored, but highly demanded as it may provide novel markers for and mechanistic insights in cancer progression. The increasing use of personalized therapy of breast cancer necessitates knowledge of the degree of genomic concordance between different steps of malignant progression as primary tumors often are used as surrogates of systemic disease. Based on exome sequencing we performed copy number profiling and point mutation detection on successive steps of breast cancer progression from one breast cancer patient, including two different regions of Ductal Carcinoma In Situ (DCIS), primary tumor and an asynchronous metastasis. We identify a remarkable landscape of somatic mutations, retained throughout breast cancer progression and with new mutational events emerging at each step. Our data, contrary to the proposed model of early dissemination of metastatic cells and parallel progression of primary tumors and metastases, provide evidence of linear progression of breast cancer with relatively late dissemination from the primary tumor. The genomic discordance between the different stages of tumor evolution in this patient emphasizes the importance of molecular profiling of metastatic tissue directing molecularly targeted therapy at recurrence

Switching between intravenous and subcutaneous trastuzumab: safety results from the PrefHer trial

Aim: To assess the safety and tolerability of switching between subcutaneous (SC) and intravenous (IV) trastuzumab in the PrefHer study (NCT01401166). Patients and methods: Patients with HER2-positive early breast cancer completed (neo)adjuvant chemotherapy and were randomised to receive four cycles of SC trastuzumab, via single-use injection device (SID; Cohort 1) or hand-held syringe (Cohort 2), followed by four cycles of IV, or vice versa (the crossover period presented here) as part of their 18 standard cycles of adjuvant trastuzumab treatment. Adverse events (AEs) were reported using standard criteria. Results: Overall, fewer AEs were reported during the IV treatment periods, regardless of administration sequence (IV→SC or SC→IV). Differences in AEs between the SC and IV periods were partly due to variances in grade 1 and 2 local injection site reactions (ISRs) and systemic administration-related reactions (ARRs) and these occurred mainly during SC treatment, as expected. When ISRs and ARRs were excluded, rates of AEs were higher during the first treatment period, compared with the second, in both treatment sequences; otherwise there was no clear pattern in the type of AEs reported. Rates of clinically important events, including grade ≥3 AEs, serious AEs, AEs leading to study drug discontinuation and cardiac AEs, were low and similar between treatment arms (<5%). There were no grade 4 or 5 AEs. No new safety signals for trastuzumab were observed. Conclusions: PrefHer revealed that switching from IV to SC trastuzumab (hand-held syringe or SID) or vice versa did not impact the known safety profile of trastuzumab

Genomic Analyses of Breast Cancer Progression Reveal Distinct Routes of Metastasis Emergence

A main controversy in cancer research is whether metastatic abilities are present in the most advanced clone of the primary tumor or result from independently acquired aberrations in early disseminated cancer cells as suggested by the linear and the parallel progression models, respectively. The genetic concordance between different steps of malignant progression is mostly unexplored as very few studies have included cancer samples separated by both space and time. We applied whole exome sequencing and targeted deep sequencing to 26 successive samples from six patients with metastatic estrogen receptor (ER)-positive breast cancer. Our data provide support for both linear and parallel progression towards metastasis. We report for the first time evidence of metastasis-to-metastasis seeding in breast cancer. Our results point to three distinct routes of metastasis emergence. This may have profound clinical implications and provides substantial novel molecular insights into the timing and mutational evolution of breast cancer metastasis

Wind-Solar-Wärmepumpenquartiere: Praxiserfahrungen und Planungshilfen für den erneuerbaren Betrieb von Wärmepumpenquartieren mit minimiertem Primärenergiebedarf

Wärmepumpen (WP) bieten großes Potenzial zur Reduzierung des Primärenergiebedarfs und der CO2-Emissionen im Wärmesektor. Besonders hoch fallen diese Reduzierungen aus, wenn der Strom für die Wärmepumpen aus erneuerbaren Energiequellen wie Windenergie oder Photovoltaikanlagen stammt. Bei der Planung und Umsetzung der Wärmeversorgung von einzelnen Gebäuden und ganzen Quartieren mittels Wärmepumpe ergeben sich auf verschiedenen Ebenen allgemeine und technische Fragestellungen. Diese Fragestellungen wurden im Rahmen des Forschungsprojekts Wind-Solar-Wärmepumpenquartier an Hand von Messungen in realen Wärmepumpen-Quartieren und mittels Simulationsstudien untersucht. Die Ergebnisse sind in diesem Bericht zusammengefasst und sollen Hilfestellungen sowie Anregungen zur Planung und Umsetzung von regenerativ betriebenen Wärmepumpenquartieren geben. Dabei gliedert sich der Bericht in die drei folgenden Themenbereiche: Lernen aus der Praxis: Im Rahmen des Projekts wurden zwei Wärmepumpenquartiere untersucht, die sich im Wesentlichen in der Art der Wärmequelle und in ihrem Baujahr unterscheiden. Die bis zu 20-jährigen Betriebserfahrungen und Messdaten aus den Wärmepumpenquartieren liefern umfangreiche Erkenntnisse. Diese lassen eine Bewertung zu, ob innovative Konzepte auch langfristig effizient betrieben werden können und wo noch Handlungsbedarf besteht. Wie können Wärmepumpenquartiere mit erneuerbaren Energien versorgt und Primärenergie (PE) eingespart werden? Bei der Planung von Wärmepumpenquartieren ergeben sich viele Fragestellungen: Welche Wärmequelle ist die beste für die Wärmeversorgung im Quartier? Wie kann der Strombedarf der Wärmepumpen aus erneuerbaren Energieanlagen wie Windenergie und Photovoltaik gedeckt werden? Was sind die relevanten Parameter für eine optimale Auslegung der Windenergie- und Photovoltaik-Anlagen? Welchen Beitrag können Betriebsstrategien und thermische oder elektrische Speicher für einen erneuerbaren Betrieb leisten? Auf Basis von Simulationsstudien werden diese Fragestellungen hinsichtlich der Primärenergieeinsparung untersucht und anhand ihrer Wirksamkeit bewertet. Welche Anforderungen stellen erneuerbar betriebene Wärmepumpenquartiere an die elektrischen Verteilnetze? Wie wirkt sich der Wärmepumpenbetrieb auf die Netzauslastung aus? Welchen Einfluss haben Photovoltaikanlagen auf den Netzbetrieb? Welche weiteren Belastungsfaktoren lassen sich identifizieren? An Hand von verschiedenen Belastungsszenarien wird aufgezeigt, welche Verbraucher und Erzeuger wichtig für die Auslegung der Netze sind und welchen Einfluss die Wahl der Wärmequelle und der Betriebsstrategien der Wärmepumpen auf die Auslastung des Netzes haben

Independent prognostic value of angiogenesis and the level of plasminogen activator inhibitor type 1 in breast cancer patients

Tumour angiogenesis and the levels of plasminogen activator inhibitor type I (PAI-I) are both informative prognostic markers in breast cancer. In cell cultures and in animal model systems, PAI-I has a proangiogenic effect. To evaluate the interrelationship of angiogenesis and the PAI-I level in breast cancer, we have evaluated the prognostic value of those factors in a total of 228 patients with primary, unilateral, invasive breast cancer, evaluated at a median follow-up time of 12 years. Microvessels were immunohistochemically stained by antibodies against CD34 and quantitated by the Chalkley counting technique. The levels of PAI-I and its target proteinase uPA in tumour extracts were analysed by ELISA. The Chalkley count was not correlated with the levels of uPA or PAI-I. High values of uPA, PAI-I, and Chalkley count were all significantly correlated with a shorter recurrence-free survival and overall survival. In the multivariate analysis, the uPA level did not show independent prognostic impact for any of the analysed end points. In contrast, the risk of recurrence was independently and significantly predicted by both the PAI-I level and the Chalkley count, with a hazard ratio (95% CI) of 1.6 (1.01-2.69) and 1.4 (1.02-1.81), respectively. For overall survival, the Chalkley count, but not PAI-I, was of significant independent prognostic value. The risk of death was 1.7 (1,30-2.15) for Chalkley counts in the upper tertile compared to the lower one. We conclude that the PAI-I level and the Chalkley count are independent prognostic markers for recurrence-free survival in patients with primary breast cancer, suggesting that the prognostic impact of PAI-I is not only based on its involvement in angiogenesis. (C) 2003 Cancer Research UK

Patients' preferences for subcutaneous trastuzumab versus conventional intravenous infusion for the adjuvant treatment of HER2-positive early breast cancer: final analysis of 488 patients in the international, randomized, two-cohort PrefHer study

PrefHer revealed compelling and consistent patient preference for subcutaneous (s.c.) trastuzumab, regardless of delivery by single-use injection device or hand-held syringe. s.c. trastuzumab was well-tolerated and safety data, including immunogenicity, were consistent with previous reports. No new safety signals were identified compared with the known intravenous trastuzumab profile in early breast cance