L. Johnson

Institute of Cancer Research, Londinium, England, United Kingdom

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Publications (16)98.27 Total impact

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    ABSTRACT: The ACTION trial was initiated to provide evidence from a randomised trial on the effects of chemotherapy in women aged over 70 years where evidence for risk and benefit are lacking. This was a randomised, phase III clinical trial for high risk, oestrogen receptor (ER) negative/ER weakly positive early breast cancer. The trial planned to recruit 1000 women aged 70 years and older, randomised to receive 4 cycles of anthracycline chemotherapy or observation. The primary endpoint was relapse-free interval. The trial included a pilot phase to assess the acceptability and feasibility of recruitment. The trial opened at 43 UK centres. Information on number of patients approached was available from 38 centres. Of the 43 eligible patients that were approached, 39 were not randomised due to patients declining entry. After 10 months only 4 patients had been randomised and after discussion with the research funder, the trial was closed and funding terminated. Despite widespread support at several public meetings, input from patient groups including representation on the Trial Management Group, the trial failed to recruit due to the inability to convince patients to accept randomisation. It would therefore seem that randomising the patients to receive chemotherapy vs observation is not a viable design in the current era for this patient population.
    British Journal of Cancer 10/2011; 105(9):1260-6. DOI:10.1038/bjc.2011.377 · 4.82 Impact Factor
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    ABSTRACT: The risk of recurrence following surgery in women with early breast cancer varies, depending upon prognostic factors. Adjuvant chemotherapy reduces this risk; however, increasingly effective regimens are associated with higher costs and toxicity profiles, making it likely that different regimens may be cost-effective for women with differing prognoses. To investigate this we performed a cost-effectiveness analysis of four treatment strategies: (1) no chemotherapy, (2) chemotherapy using cyclophosphamide, methotrexate, and fluorouracil (CMF) (a first generation regimen), (3) chemotherapy using Epirubicin-CMF (E-CMF) or fluorouracil, epirubicin, and cyclophosphamide (FEC60) (a second generation regimens), and (4) chemotherapy with FEC60 followed by docetaxel (FEC-D) (a third generation regimen). These adjuvant chemotherapy regimens were used in three large UK-led randomised controlled trials (RCTs). A Markov model was used to simulate the natural progression of early breast cancer and the impact of chemotherapy on modifying this process. The probability of a first recurrent event within the model was estimated for women with different prognostic risk profiles using a parametric regression-based survival model incorporating established prognostic factors. Other probabilities, treatment effects, costs and quality of life weights were estimated primarily using data from the three UK-led RCTs, a meta-analysis of all relevant RCTs, and other published literature. The model predicted the lifetime costs, quality adjusted life years (QALYs) and cost-effectiveness of the four strategies for women with differing prognoses. Sensitivity analyses investigated the impact of uncertain parameters and model assumptions. For women with an average to high risk of recurrence (based upon prognostic factors and any other adjuvant therapies received), FEC-D appeared most cost-effective assuming a threshold of £20,000 per QALY for the National Health Service (NHS). For younger low risk women, E-CMF/FEC60 tended to be the optimal strategy and, for some older low risk women, the model suggested a policy of no chemotherapy was cost-effective. For no patient group was CMF chemotherapy the preferred option. Sensitivity analyses demonstrated cost-effectiveness results to be particularly sensitive to the treatment effect estimate for FEC-D and the future price of docetaxel. To our knowledge, this analysis is the first cost-effectiveness comparison of no chemotherapy, and first, second, and third generation adjuvant chemotherapy regimens for early breast cancer patients with differing prognoses. The results demonstrate the potential for different treatment strategies to be cost-effective for different types of patients. These findings may prove useful for policy makers attempting to formulate cost-effective treatment guidelines in the field of early breast cancer.
    European journal of cancer (Oxford, England: 1990) 07/2011; 47(17):2517-30. DOI:10.1016/j.ejca.2011.06.019 · 4.82 Impact Factor
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    ABSTRACT: The neoadjuvant IMPACT trial suggested Ki67 levels after 2 weeks endocrine therapy predicts long-term outcome. Major changes in gene expression have also been seen in ER+ breast cancer after aromatase inhibitor (AI) treatment. POETIC evaluates whether changes in Ki67 level after 2 weeks treatment predicts for relapse-free survival (RFS) more effectively than the baseline value. It also tests whether gene expression profile at this timepoint provides more accurate prognostic and predictive information than the pre-treatment profile. Experimental evidence suggests peri-operative endocrine therapy may improve disease outcome. This hypothesis is also addressed in POETIC. (ISRCTN63882543) With a sample size of 4000, an improvement in 5 year relapse from 10% to 7% could be detected with 91% power (two sided alpha of 5%), as would a 1.3 fold difference in the ability of Ki67 to predict RFS (90% power, two sided 5% significance level). Target recruitment is 4000 patients from 100 UK hospitals over 3-4 years. Methods: Patients are randomised in the ratio of 2:1 to perioperative AI (letrozole 2.5mg or anastrozole 1mg daily) starting 2 weeks before planned surgery until 2 weeks after surgery. FFPE and RNA-later samples are taken prior to trial entry (baseline) and at surgery. Eligible patients are postmenopausal with ER+ invasive breast cancer. Consent to take additional research tissue is sought from patients undergoing diagnostic biopsy. Consenting patients donate tumour tissue in RNA-later and/or a FFPE research sample and enter POETIC following diagnosis of ER+ breast cancer. Matching tumour tissue is taken at surgery. Where an RNA-later sample at baseline is unavailable, consenting patients may undergo a further biopsy for research tissue immediately before study entry. Where consent procedures at diagnosis present logistical challenges, sites may provide FFPE tissue left over from diagnosis only. The 1st patient was entered in September 2008, and by January 2011 102 UK hospitals open and 1200 patients were entered. 182 optional RNA-later samples at both timepoints are available. Current success is due to a flexible approach to tissue sample collection and overcoming local and national logistical challenges.
    2011 ASCO Annual Meeting, Chicago, USA; 06/2011
  • EJC Supplements 03/2010; 8(3):184-184. DOI:10.1016/S1359-6349(10)70454-7 · 9.39 Impact Factor
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    ABSTRACT: Aim: To determine the relationship between ER and HER2 expression according to HER2 amplification status.Background: ER and HER2 are the most commonly measured biomarkers in breast cancer and are important targets for therapy. It is known that ER and HER2 positivity are inversely correlated and that among ER+ tumours ER expression is higher in HER2 non-overexpressing (–ve) than HER2 overexpressing (+ve) disease (Konecny et al, JNCI 2003, 95: 142-53). There are however, very few data on the quantitative relationship between ER and HER2 expression in HER2–ve tumours. We therefore measured the expression of ER and HER2 at both the mRNA and protein level in HER2 +ve and –ve breast carcinomas.Methods: ER and HER2 levels were assessed by IHC (6F11 antibody and HercepTest, respectively) on tissue microarrays and q-RT-PCR in formalin-fixed primary breast cancers from 429 patients in the tamoxifen arm of the ABC Trial (ABC Trialists, JNCI 2007, 99: 506-15). HER2 amplification status was assessed with the PathVysion 2-probe FISH test. ER IHC was H-scored. Transcript levels for ER and HER2 from 1139 HER2–ve TransATAC tumours were available from the Oncotype DX test (Dowsett et al, Cancer Res 2009, 69suppl: 75s).Results: Matched results were available from all analyses for 257 ABC patients except for 25 cases where HER2 was by IHC or FISH. HER2 was amplified in 14.4% and equivocal in 1.3% of cases. ER was +ve in 67% of cases. The expected negative correlation between levels of ER and HER2 expression was found in HER2 +ve tumours (r=-0.45, p=0.0028). In contrast in HER2-ve tumours (ER+ve and ER-ve combined) there was a significant POSITIVE correlation between ER and HER2 mRNA levels (r=0.43, p<0.0001). As a result in HER2–ve tumours the quantitative level of HER2 was higher in ER+ve than ER–ve tumours (mean fold difference 1.74, p<0.0001). There was a mean 5.8-fold higher HER2 transcript levels in HER2+ve vs HER2–ve tumours in ER+ve disease and 12.9-fold higher in ER–ve disease. The positive correlation though weaker was maintained in the ER+ve HER2–ve group (r=0.24, p=0.0023) and was present to a similar extent in that subgroup in TransATAC (r=0.25, p<0.00001). The positive association was also significant in ER IHC analyses in ABC: mean±95%CI H-scores were 90±19 and 134±19 in the 0 and 1+ HER2 IHC categories, respectively (p=0.0013).Conclusions: ER and HER2 expression are positively correlated at both protein and transcript levels in HER2–ve breast cancer in contrast to their negative correlation in HER2+ve disease. The distinction between HER2+ve and HER2–ve is greater in ER–ve than ER+ve disease and this may lead to greater diagnostic uncertainties in ER+ve patients. These findings may also have importance for signaling pathways and application of targeted therapy in HER2–ve disease.*Acknowledgement: We are grateful to the ABC Trial Working and Biological Studies Groups, the ATAC Trialists and Cancer Research UK for funding.
    San Antonio Breast Cancer Symposium, San Antonio, Texas, USA; 12/2009
  • The Breast 03/2009; 18. DOI:10.1016/S0960-9776(09)70209-7 · 2.58 Impact Factor
  • Cancer Research 02/2009; 69(2 Supplement):6106-0. DOI:10.1158/0008-5472.SABCS-6106 · 9.28 Impact Factor
  • EJC Supplements 04/2008; 6(7):196-196. DOI:10.1016/S1359-6349(08)70806-1 · 9.39 Impact Factor
  • EJC Supplements 04/2008; 6(7):47-48. DOI:10.1016/S1359-6349(08)70315-X · 9.39 Impact Factor
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    ABSTRACT: Questionnaires were circulated to UK patients and health care professionals (HCPs) participating in the Taxotere as Adjuvant ChemoTherapy (TACT) trial in autumn 2004 asking if and how trial results, when available, should be conveyed to patients. A total of 1431 (37% of surviving UK TACT patients) returned questionnaires. In all, 30 (2%) patients did not want results. In all, 554 (40%) patients preferred to receive them via their hospital; 664 (47%) preferred results posted directly to their home, 177 (13%) preferred a letter providing a telephone number to request results. Six hundred and twelve patients thought results should come directly from the trials office. One hundred and seventy-six HCPs from 89 UK centres (86%) returned questionnaires. In all, 169 out of 176 patients (96%) thought results should be written in lay terms for patients. Seventy (41%) preferred patients to receive results via their hospital; 64 (38%) preferred a letter providing a telephone number to request results, and 32 (19%) preferred results posted directly to patients. Thirty-one HCPs (18%) thought results to patients should come directly from the trials office. A total of 868 (61%) patients thought next of kin of deceased patients should receive results, 543 (38%) did not; 47 (27%) HCPs thought they should; 118 (68%) did not.
    British Journal of Cancer 02/2008; 98(1):34-8. DOI:10.1038/sj.bjc.6604119 · 4.82 Impact Factor
  • Critical Reviews in Oncology/Hematology 11/2007; 64:S41. DOI:10.1016/S1040-8428(13)70191-4 · 4.05 Impact Factor
  • Clinical Oncology 11/2007; 19(8):593-5. DOI:10.1016/j.clon.2007.06.016 · 2.83 Impact Factor
  • Critical Reviews in Oncology/Hematology 11/2006; 60:S29–S30. DOI:10.1016/S1040-8428(13)70087-8 · 4.05 Impact Factor
  • L. Johnson, Barrett-Lee, P. Ellis, J. Bliss
    EJC Supplements 03/2006; 4(2):84-84. DOI:10.1016/S1359-6349(06)80164-3 · 9.39 Impact Factor
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    L Johnson, P Ellis, J M Bliss
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    ABSTRACT: Randomised clinical trials that exceed anticipated recruitment rates will by definition have the necessary precision to answer the research question within the expected time, thus ensuring the timely release of data that will inform future clinical practice. In addition, the national or international momentum generated brings with it a collective sense of achievement. Such trials, however, may also identify logistical and scientific problems that researchers should be aware of and for which provision needs to be made. The logistical problems relate to the rapid identification of the extra resources required to allow continued excellence in day-to-day management and monitoring of trial governance (both in participating centres and in coordinating trials units). The scientific/clinical problems include managing issues such as unexpected toxicities and suboptimal compliance, and the lack of time available in a rapidly recruiting trial to address them. A related issue concerns the lack of time available to initiate substudies (e.g. biological substudies), the relevance of which may only become apparent as the trial progresses. Many of these challenges were highlighted by recent experience with the Cancer Research UK Taxotere as Adjuvant Chemotherapy trial.
    British Journal of Cancer 06/2005; 92(9):1679-83. DOI:10.1038/sj.bjc.6602574 · 4.82 Impact Factor
  • EJC Supplements 09/2003; 1(5). DOI:10.1016/S1359-6349(03)90448-4 · 9.39 Impact Factor