Neoadjuvant chemotherapy and trastuzumab versus neoadjuvant chemotherapy followed by post-operative trastuzumab for patients with HER2-positive breast cancer

Neoadjuvant chemotherapy plus trastuzumab (NCT) increases the rate of pathological complete response (pCR) and event-free survival (EFS) compared to neoadjuvant chemotherapy (NC) alone in women with HER2 positive breast cancer (BC). pCR in this setting is associated with improved EFS. Whether NCT preferentially improves EFS in comparison to NC followed by adjuvant trastuzumab initiated postoperatively (NCAT) has not been addressed. Using clinical data from women with HER2 positive BC treated at 7 European institutions between 2007 and 2010 we sought to investigate the impact on breast cancer outcomes of concomitant (NCT) versus sequential (NCAT) treatment in HER2 positive early BC. The unadjusted hazard ratio (HR) for event free survival with NCT compared with NCAT was 0.63 (95% CI 0.37–1.08; p = 0.091). Multivariable analysis revealed that treatment group, tumour size and ER status were significantly associated with EFS from diagnosis. In the whole group NCT was associated with a reduced risk of an event relative to NCAT, an effect that was confined to ER negative (HR: 0.25; 95% CI, 0.10–0.62; p = 0.003) as opposed to ER positive tumours (HR: 1.07; 95% CI, 0.46–2.52; p = 0.869). HER2 positive/ER negative BC treated with NC gain greatest survival benefit when trastuzumab is administered in both the neoadjuvant and adjuvant period rather than in the adjuvant period alone. These data support the early introduction of targeted combination therapy in HER2 positive/ER negative BC

An Association of Cancer Physicians' strategy for improving services and outcomes for cancer patients.

The Association of Cancer Physicians in the United Kingdom has developed a strategy to improve outcomes for cancer patients and identified the goals and commitments of the Association and its members.The ACP is very grateful to all of its members who have expressed views on the development of the strategy and to the sponsors of our workshops and publications, especially Cancer Research UK and Macmillan Cancer SupportThis is the final version of the article. It was first available from Cancer Intelligence via http://dx.doi.org/10.3332/ecancer.2016.60

Neoadjuvant chemotherapy and trastuzumab versus neoadjuvant chemotherapy followed by post-operative trastuzumab for patients with HER2-positive breast cancer

Neoadjuvant chemotherapy plus trastuzumab (NCT) increases the rate of pathological complete response (pCR) and event-free survival (EFS) compared to neoadjuvant chemotherapy (NC) alone in women with HER2 positive breast cancer (BC). pCR in this setting is associated with improved EFS. Whether NCT preferentially improves EFS in comparison to NC followed by adjuvant trastuzumab initiated postoperatively (NCAT) has not been addressed. Using clinical data from women with HER2 positive BC treated at 7 European institutions between 2007 and 2010 we sought to investigate the impact on breast cancer outcomes of concomitant (NCT) versus sequential (NCAT) treatment in HER2 positive early BC. The unadjusted hazard ratio (HR) for event free survival with NCT compared with NCAT was 0.63 (95% CI 0.37–1.08; p = 0.091). Multivariable analysis revealed that treatment group, tumour size and ER status were significantly associated with EFS from diagnosis. In the whole group NCT was associated with a reduced risk of an event relative to NCAT, an effect that was confined to ER negative (HR: 0.25; 95% CI, 0.10–0.62; p = 0.003) as opposed to ER positive tumours (HR: 1.07; 95% CI, 0.46–2.52; p = 0.869). HER2 positive/ER negative BC treated with NC gain greatest survival benefit when trastuzumab is administered in both the neoadjuvant and adjuvant period rather than in the adjuvant period alone. These data support the early introduction of targeted combination therapy in HER2 positive/ER negative BC

Long term efficacy of first-line afatinib and the clinical utility of ctDNA monitoring in patients with suspected or confirmed EGFR mutant non-small cell lung cancer who were unsuitable for chemotherapy.

BACKGROUND: Here we present long-term outcomes of first line afatinib in comorbid patients with suspected or confirmed EGFR mutant NSCLC otherwise considered unsuitable for chemotherapy, and the clinical utility of serial ctDNA monitoring. METHODS: TIMELY (NCT01415011) was a multicentre, single arm, phase II trial conducted in the UK. Patients aged ≥18 were treated with daily oral afatinib (40 mg) until disease progression or unacceptable toxicity. Blood samples for ctDNA analysis were obtained at baseline and 12-weekly until treatment discontinuation. The primary endpoint was PFS. RESULTS: Thirty-nine patients were enrolled between March 2013 and August 2015. Median follow-up was 98 months (range 69-101). Median PFS was 7.9 months (95% CI 4.6-10.5). Seven patients (18%) continued afatinib beyond 18 months, 3 beyond 36 months and 2 were still on treatment at last follow-up 101 months post-treatment initiation. Analysis of baseline ctDNA samples identified 8 EGFR mutant cases that were not identified by tissue genotyping and ctDNA clearance was associated with improved PFS and OS. CONCLUSION: Afatinib is a viable treatment option for tissue or ctDNA-detected EGFR mutant NSCLC comorbid patients, with a proportion achieving long-term clinical benefit. Plasma ctDNA testing improved EGFR mutant identification and its clearance predicted improved PFS and OS

Long term efficacy of first-line afatinib and the clinical utility of ctDNA monitoring in patients with suspected or confirmed EGFR mutant non-small cell lung cancer who were unsuitable for chemotherapy.

This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made.Background: Here we present long-term outcomes of first line afatinib in comorbid patients with suspected or confirmed EGFR mutant NSCLC otherwise considered unsuitable for chemotherapy, and the clinical utility of serial ctDNA monitoring. Methods: TIMELY (NCT01415011) was a multicentre, single arm, phase II trial conducted in the UK. Patients aged ≥18 were treated with daily oral afatinib (40 mg) until disease progression or unacceptable toxicity. Blood samples for ctDNA analysis were obtained at baseline and 12-weekly until treatment discontinuation. The primary endpoint was PFS. Results: Thirty-nine patients were enrolled between March 2013 and August 2015. Median follow-up was 98 months (range 69-101). Median PFS was 7.9 months (95% CI 4.6-10.5). Seven patients (18%) continued afatinib beyond 18 months, 3 beyond 36 months and 2 were still on treatment at last follow-up 101 months post-treatment initiation. Analysis of baseline ctDNA samples identified 8 EGFR mutant cases that were not identified by tissue genotyping and ctDNA clearance was associated with improved PFS and OS. Conclusion: Afatinib is a viable treatment option for tissue or ctDNA-detected EGFR mutant NSCLC comorbid patients, with a proportion achieving long-term clinical benefit. Plasma ctDNA testing improved EGFR mutant identification and its clearance predicted improved PFS and OS

Mesothelioma and Radical Surgery 2 (MARS 2): protocol for a multicentre randomised trial comparing (extended) pleurectomy decortication versus no (extended) pleurectomy decortication for patients with malignant pleural mesothelioma.

INTRODUCTION: Mesothelioma remains a lethal cancer. To date, systemic therapy with pemetrexed and a platinum drug remains the only licensed standard of care. As the median survival for patients with mesothelioma is 12.1 months, surgery is an important consideration to improve survival and/or quality of life. Currently, only two surgical trials have been performed which found that neither extensive (extra-pleural pneumonectomy) or limited (partial pleurectomy) surgery improved survival (although there was some evidence of improved quality of life). Therefore, clinicians are now looking to evaluate pleurectomy decortication, the only radical treatment option left. METHODS AND ANALYSIS: The MARS 2 study is a UK multicentre open parallel group randomised controlled trial comparing the effectiveness and cost-effectiveness of surgery-(extended) pleurectomy decortication-versus no surgery for the treatment of pleural mesothelioma. The study will test the hypothesis that surgery and chemotherapy is superior to chemotherapy alone with respect to overall survival. Secondary outcomes include health-related quality of life, progression-free survival, measures of safety (adverse events) and resource use to 2 years. The QuinteT Recruitment Intervention is integrated into the trial to optimise recruitment. ETHICS AND DISSEMINATION: Research ethics approval was granted by London - Camberwell St. Giles Research Ethics Committee (reference 13/LO/1481) on 7 November 2013. We will submit the results for publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBERS: ISRCTN-ISRCTN44351742 and ClinicalTrials.gov-NCT02040272

Investigating the role of genomic drivers of MET pathway dysregulation in the heterogeneity of Pleomorphic Lung Carcinoma

Background: Pleomorphic Lung Carcinoma (PC) is a rare lung cancer that is aggressive and poorly responsive to treatments. It is a highly heterogenous tumour and unique as it has at least 10% dedifferentiated sarcomatoid component alongside its epithelial components. Recent data have demonstrated a high frequency of mutations in the MET receptor that may support epithelial to mesenchymal transition (EMT) as an important pathway in PCs oncogenesis. The hypothesis was that MET, along with other key components of the MET pathway, would be dysfunctional and exhibit damaging aberrations. Methods: 80 cases of PC were identified from the biobank and diagnostic archives of the Royal Brompton Hospital and Imperial College Healthcare NHS trusts. FFPE sections were obtained and DNA was isolated from histologically distinct areas and epithelial and sarcomatoid areas. Differences in the mutational and expression profiles of a select set of genes/proteins of these areas were determined. Correlative analyses were performed with the genetic and expression profiles against clinicopathological features. Biomarkers of the MET pathway were evaluated with immunohistochemistry and MET copy number was determined with ddPCR. Ultra-deep next generation sequencing was performed on a gene panel selected from earlier findings in PC or that play a role in MET signalling (including MET, KRAS, CBL and HGF). Results: This cohort was comparable to that of other PC studies in terms of patient survival and other clinical characteristics. Median OS was poor (16.3 months) and predicted by tumour size, nodal status and composite stage (P=0.04; 0.008; 0.01). The most commonly mutated genes were TP53 (55%) and KRAS (27%). PCs with paired samples from across both phenotypic components shared oncogenic drivers although differing frequencies of TP53 LOH and KRAS activating mutations were observed. KRAS mutations were mutually exclusive to MET mutations (P=0.03). MET pathway aberrations were present in 44% of cases where there was an increase in MET copy number or MET mutations. MET copy number was significantly higher in the sarcomatoid component (P=0.046). Novel CBL deletions were present in 9.6% of PCs and HGF mutations were present in 8.2% of PCs, albeit at low frequency. There was a significant increase in PD-L1 expression across PCs with higher expression in the sarcomatoid components (p = 0.001). Conclusions: The frequency of alleles with TP53 and KRAS mutations supports the development of PC from an early totipotent progenitor with potential to develop into an epithelial or sarcomatoid tumour. PCs have frequent aberrations of the MET pathway and novel CBL deletions and HGF mutations that warrant further investigation.Open Acces

Machinability properties of particleboards made with addition of raspberry stem chips (Rubus idaeus L.)

The article describes vulnerability to machinability particleboards with addition raspberry stem chips (Rubus idaeus L.). Machinability can be analyzed with using of numerous machinability indicators. In this article was assumed as machinability criterions, cutting resistance during milling and drilling regards to percentage contribution of raspberry stem chips. The addition of alternative raw material didn’t deteriorated machinability properties based on axial forces during drilling and cutting force during milling. However, at higher amount of mentioned above raw material, increase of torque. </jats:p

Machinability properties of particleboards made with addition of raspberry stem chips (Rubus idaeus L.)

The article describes vulnerability to machinability particleboards with addition raspberry stem chips (Rubus idaeus L.). Machinability can be analyzed with using of numerous machinability indicators. In this article was assumed as machinability criterions, cutting resistance during milling and drilling regards to percentage contribution of raspberry stem chips. The addition of alternative raw material didn’t deteriorated machinability properties based on axial forces during drilling and cutting force during milling. However, at higher amount of mentioned above raw material, increase of torque.Podatność na obróbkę skrawaniem płyt wiórowych z dodatkiem łodyg maliny właściwej (Rubus idaeus L.). Istnieje wiele kryteriów oceny skrawalności materiałów drewnopochodnych. Jednym z nich są opory skrawania. Artykuł opisuje wpływ dodatku alternatywnego surowca na opory skrawania podczas wiercenia i frezowania. Przeanalizowano zarówno opory skrawania podczas obróbki frezowaniem jak i wierceniem w zależności od zawartości surowca pochodzącego z łodyg maliny właściwej. Dodatek alternatywnego surowca nie spowodował pogorszenia skrawalności określonej na podstawie siły osiowej rejestrowanej podczas wiercenia i sił skrawania występujących podczas frezowania. Zauważono natomiast, że przy wyższej zawartości wspomnianego wcześniej surowca alternatywnego wzrosła wartość momentu obrotowego podczas wiercenia