Evaluation of multiple transcriptomic gene risk signatures in male breast cancer

Marcadors pronòstics; Biomarcadors tumoralsMarcadores pronósticos; Biomarcadores tumoralesPrognostic markers; Tumour biomarkersMale breast cancer (BCa) is a rare disease accounting for less than 1% of all breast cancers and 1% of all cancers in males. The clinical management is largely extrapolated from female BCa. Several multigene assays are increasingly used to guide clinical treatment decisions in female BCa, however, there are limited data on the utility of these tests in male BCa. Here we present the gene expression results of 381 M0, ER+ve, HER2-ve male BCa patients enrolled in the Part 1 (retrospective analysis) of the International Male Breast Cancer Program. Using a custom NanoString™ panel comprised of the genes from the commercial risk tests Prosigna®, OncotypeDX®, and MammaPrint®, risk scores and intrinsic subtyping data were generated to recapitulate the commercial tests as described by us previously. We also examined the prognostic value of other risk scores such as the Genomic Grade Index (GGI), IHC4-mRNA and our prognostic 95-gene signature. In this sample set of male BCa, we demonstrated prognostic utility on univariate analysis. Across all signatures, patients whose samples were identified as low-risk experienced better outcomes than intermediate-risk, with those classed as high risk experiencing the poorest outcomes. As seen with female BCa, the concordance between tests was poor, with C-index values ranging from 40.3% to 78.2% and Kappa values ranging from 0.17 to 0.58. To our knowledge, this is the largest study of male breast cancers assayed to generate risk scores of the current commercial and academic risk tests demonstrating comparable clinical utility to female BCa.This work has been funded by the Breast Cancer Research Foundation (BCRF) with additional funding provided by the Government of Ontario to the Ontario Institute of Cancer Research (OICR). This work was funded by the Breast Cancer Research Foundation (BCRF), the Susan G. Komen for the Cure Foundation and the Ontario Institute of Cancer Research (OICR). Funding for OICR is provided by the Government of Ontario

Postoperative radiotherapy in women with early operable breast cancer (Scottish Breast Conservation Trial): 30-year update of a randomised, controlled, phase 3 trial

Background Breast-conserving surgery, adjuvant systemic therapy, and radiotherapy are the standard of care for most women with early breast cancer. There are few reports of clinical outcomes beyond the first decade of follow-up of randomised trials comparing breast-conserving surgery with or without radiotherapy. We present a 30-year update of the Scottish Breast Conservation Trial. Methods In this randomised, controlled, phase 3 trial across 14 hospitals in Scotland, women aged younger than 70 years with early breast cancer (tumours ≤4 cm [T1 or T2 and N0 or N1]) were included. They underwent breast-conserving surgery (1 cm margin) with axillary node sampling or clearance. Oestrogen receptor (ER)-rich patients (≥20 fmol/mg protein) received 20 mg oral tamoxifen daily for 5 years. ER-poor patients (&lt;20 fmol/mg protein) received chemotherapy (cyclophosphamide 600 mg/m2, methotrexate 50 mg/m2, and fluorouracil 600 mg/m2 every 21 days intravenously in eight courses). Stratification was by menstrual status (within or more than 12 months from last menstrual period) and ER status (oestrogen concentration ≥20 fmol/mg protein, &lt;20 fmol/mg protein, or unknown) and patients were randomly assigned (1:1) to high-dose (50 Gy in 20–25 fractions) local or locoregional radiotherapy versus no radiotherapy. No blinding was possible due to the nature of the treatment. We report the primary endpoint of the original trial, ipsilateral breast tumour recurrence, and the co-primary endpoint, overall survival. Clinical outcomes were compared by the log-rank test. Hazard ratios (HRs) are reported, with no radiotherapy as the reference group. Failures of the proportional hazards assumption are reported if significant. All analyses are by intention to treat. Findings Between April 1, 1985, and Oct 2, 1991, 589 patients were enrolled and randomly assigned to the two treatment groups (293 to radiotherapy and 296 to no radiotherapy). After exclusion of four ineligible patients (two in each group), there were 291 patients in the radiotherapy group and 294 patients in the no radiotherapy group. Median follow-up was 17·5 years (IQR 8·4–27·9). Ipsilateral breast tumour recurrence was significantly lower in the radiotherapy group than in the no radiotherapy group (46 [16%] of 291 vs 107 [36%] of 294; HR 0·39 [95% CI 0·28–0·55], p&lt;0·0001). Although there were differences in the hazard rate for ipsilateral breast tumour recurrence in the first decade after treatment (HR 0·24 [95% CI 0·15–0·38], p&lt;0·0001), subsequent risks of ipsilateral breast tumour recurrence were similar in both groups (0·98 [0·54–1·79], p=0·95). There was no difference in overall survival between the two groups (median 18·7 years [95% CI 16·5–21·5] in the no radiotherapy group vs 19·2 years [16·9–21·3] in the radiotherapy group; HR 1·08 [95% CI 0·89–1 ·30], log-rank p=0·43). Interpretation Our findings suggest that patients whose biology predicts a late relapse a decade or more after breast-conserving surgery for early breast cancer might gain little from adjuvant radiotherapy.</div

Computational approaches to support comparative analysis of multiparametric tests: Modelling versus Training.

Multiparametric assays for risk stratification are widely used in the management of breast cancer, with applications being developed for a number of other cancer settings. Recent data from multiple sources suggests that different tests may provide different risk estimates at the individual patient level. There is an increasing need for robust methods to support cost effective comparisons of test performance in multiple settings. The derivation of similar risk classifications using genes comprising the following multi-parametric tests Oncotype DX® (Genomic Health.), Prosigna™ (NanoString Technologies, Inc.), MammaPrint® (Agendia Inc.) was performed using different computational approaches. Results were compared to the actual test results. Two widely used approaches were applied, firstly computational "modelling" of test results using published algorithms and secondly a "training" approach which used reference results from the commercially supplied tests. We demonstrate the potential for errors to arise when using a "modelling" approach without reference to real world test results. Simultaneously we show that a "training" approach can provide a highly cost-effective solution to the development of real-world comparisons between different multigene signatures. Comparisons between existing multiparametric tests is challenging, and evidence on discordance between tests in risk stratification presents further dilemmas. We present an approach, modelled in breast cancer, which can provide health care providers and researchers with the potential to perform robust and meaningful comparisons between multigene tests in a cost-effective manner. We demonstrate that whilst viable estimates of gene signatures can be derived from modelling approaches, in our study using a training approach allowed a close approximation to true signature results

Adjunctive statistical standardization of quantitated adjuvant HER2 and ultra-low HER2 in Canadian Cancer Trials Group MA.27 trial of exemestane versus anastrozole

Purpose: Statistically standardized estrogen receptor (ER) and progesterone receptor (PgR) differentiated prognosis. Here we examined statistically standardized human epidermal growth receptor 2 (HER2). Methods: CCTG MA.27 (NCT00066573) was an adjuvant phase III trial of exemestane versus anastrozole in postmenopausal women with ER + and/or PgR + tumors. We centrally quantitated machine-image immunohistochemical HER2, defined American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) dual-probe FISH HER2/CEP17 categories, determined ultra-low HER2 (IHC 0 with (0,10%] 1 + stain), and standardized HER2 to mean 0, standard deviation 1. Univariate distant disease-free survival (DDFS) was described with Kaplan–Meier plots and examined with Wilcoxon (Peto-Prentice) test statistic. Adjusted Cox multivariable regressions 2-sided Wald tests had nominal significance p &lt; 0.05. Results: Of 7576 women, 2900 had ER results; 2726, PgR; 2680, HER2; and 2325, ER/PgR/HER2 for multivariable investigations. ASCO/CAP categorization significantly differentiated univariate DDFS (p = 0.01), although not values of IHC 0 (N = 864) and ultra-low HER2 (N = 1143). Statistical standardization did not differentiate univariate DDFS (p = 0.08–0.27); however, (natural logarithm-) standardized values ≤ − 1.0 (ultra-low 1 + /2 + /3 + HSCORE, or % +, &lt; 0.1) were similar to &gt; 1.0 (HSCORE &gt; 19; % + &gt; 14). Neither ASCO/CAP, nor statistically standardized, ER (p = 0.65–0.94) or HER2 (p = 0.20–0.97) were associated with DDFS in models with PgR; higher PgR had better DDFS (p ≤.003). Conclusions: ASCO/CAP categories significantly differentiated DDFS, while statistical standardization did not. Patients with ultra-low HER2 and IHC 0 without stain had similar 5-year DDFS, while standardization indicated similar prognosis for very low 1 + /2 + /3 + and highest HER2 stain. We caution about assessment of ultra-low, or very low, HER2 due to HER2 assay dynamic range.</p

Analytical validation of a standardised scoring protocol for Ki67 immunohistochemistry on breast cancer excision whole sections: an international multicentre collaboration

Aims The nuclear proliferation marker Ki67 assayed by immunohistochemistry has multiple potential uses in breast cancer, but an unacceptable level of interlaboratory variability has hampered its clinical utility. The International Ki67 in Breast Cancer Working Group has undertaken a systematic programme to determine whether Ki67 measurement can be analytically validated and standardised among laboratories. This study addresses whether acceptable scoring reproducibility can be achieved on excision whole sections. Methods and results Adjacent sections from 30 primary ER+ breast cancers were centrally stained for Ki67 and sections were circulated among 23 pathologists in 12 countries. All pathologists scored Ki67 by two methods: (i) global: four fields of 100 tumour cells each were selected to reflect observed heterogeneity in nuclear staining; (ii) hot-spot: the field with highest apparent Ki67 index was selected and up to 500 cells scored. The intraclass correlation coefficient (ICC) for the global method [confidence interval (CI) = 0.87; 95% CI = 0.799-0.93] marginally met the prespecified success criterion (lower 95% CI >= 0.8), while the ICC for the hot-spot method (0.83; 95% CI = 0.74-0.90) did not. Visually, interobserver concordance in location of selected hot-spots varies between cases. The median times for scoring were 9 and 6 min for global and hot-spot methods, respectively. Conclusions The global scoring method demonstrates adequate reproducibility to warrant next steps towards evaluation for technical and clinical validity in appropriate cohorts of cases. The time taken for scoring by either method is practical using counting software we are making publicly available. Establishment of external quality assessment schemes is likely to improve the reproducibility between laboratories further

Analytical validation of a standardized scoring protocol for Ki67: phase 3 of an international multicenter collaboration

Pathological analysis of the nuclear proliferation biomarker Ki67 has multiple potential roles in breast and other cancers. However, clinical utility of the immunohistochemical (IHC) assay for Ki67 immunohistochemistry has been hampered by unacceptable between-laboratory analytical variability. The International Ki67 Working Group has conducted a series of studies aiming to decrease this variability and improve the evaluation of Ki67. This study tries to assess whether acceptable performance can be achieved on prestained core-cut biopsies using a standardized scoring method. Sections from 30 primary ER+ breast cancer core biopsies were centrally stained for Ki67 and circulated among 22 laboratories in 11 countries. Each laboratory scored Ki67 using three methods: (1) global (4 fields of 100 cells each); (2) weighted global (same as global but weighted by estimated percentages of total area); and (3) hot-spot (single field of 500 cells). The intraclass correlation coefficient (ICC), a measure of interlaboratory agreement, for the unweighted global method (0.87; 95% credible interval (CI): 0.81–0.93) met the prespecified success criterion for scoring reproducibility, whereas that for the weighted global (0.87; 95% CI: 0.7999–0.93) and hot-spot methods (0.84; 95% CI: 0.77–0.92) marginally failed to do so. The unweighted global assessment of Ki67 IHC analysis on core biopsies met the prespecified criterion of success for scoring reproducibility. A few cases still showed large scoring discrepancies. Establishment of external quality assessment schemes is likely to improve the agreement between laboratories further. Additional evaluations are needed to assess staining variability and clinical validity in appropriate cohorts of samples

Crop Updates 2001 - Cereals

This session covers forty two papers from different authors: PLENARY 1. Planning your cropping program in season 2001, Dr Ross Kingwell, Agriculture Western Australia and University of Western Australia WORKSHOP 2. Can we produce high yields without high inputs? Wal Anderson, Centre for Cropping Systems, Agriculture Western Australia VARIETIES 3. Local and interstate wheat variety performance and $ return to WA growers, Eddy Pol, Peter Burgess and Ashley Bacon, Agritech Crop Research CROP ESTABLISHMENT 4 Soil management of waterlogged soils, D.M. Bakker, G.J. Hamilton, D. Houlbrooke and C. Spann, Agriculture Western Australia 5. Effect of soil amelioration on wheat yield in a very dry season, M.A Hamza and W.K. Anderson, Agriculture Western Australia 6. Fuzzy tramlines for more yield and less weed, Paul Blackwell1 and Maurice Black2 1Agriculture Western Australia, 2Harbour Lights Estate, Geraldton 7. Tramline farming for dollar benefits, Paul Blackwell, Agriculture Western Australia NUTRITION 8. Soil immobile nutrients for no-till crops, M.D.A. Bolland1, R.F. Brennan1,and W.L. Crabtree2, 1Agriculture Western Australia, 2Western Australian No-Tillage Farmers Association 9. Burn stubble windrows: to diagnose soil fertility problems, Bill Bowden, Chris Gazey and Ross Brennan, Agriculture Western Australia 10. Calcium: magnesium ratios; are they important? Bill Bowden1, Rochelle Strahan2, Bob Gilkes2 and Zed Rengel2 1Agriculture Western Australia, 2Department of Soil Science and Plant Nutrition, UWA 11. Responses to late foliar applications of Flexi-N, Stephen Loss, Tim O’Dea, Patrick Gethin, Ryan Guthrie, Lisa Leaver, CSBP futurefarm 12. A comparison of Flexi-N placements, Stephen Loss, Tim O’Dea, Patrick Gethin, Ryan Guthrie, Lisa Leaver, CSBP futurefarm 13. What is the best way to apply potassium? Stephen Loss, Tim O’Dea, Patrick Gethin, Ryan Guthrie, CSBP futurefarm 14. Claying affects potassium nutrition in barley, Stephen Loss, David Phelps, Tim O’Dea, Patrick Gethin, Ryan Guthrie, Lisa Leaver, CSBP futurefarm 15. Nitrogen and potassium improve oaten hay quality, Stephen Loss, Tim O’Dea, Patrick Gethin, Ryan Guthrie, Lisa Leaver, CSBP futurefarm AGRONOMY 16. Agronomic responses of new wheat varieties in the northern wheatbelt, Darshan Sharma and Wal Anderson, Agriculture Western Australia 17. Wheat agronomy research on the south coast, Mohammad Amjad and Wal Anderson, Agriculture Western Australia 18. Influence of sowing date on wheat yield and quality in the south coast environment, Mohammad Amjadand Wal Anderson, Agriculture Western Australia 19. More profit from durum, Md.Shahajahan Miyan and Wal Anderson, Agriculture Western Australia 20. Enhancing recommendations of flowering and yield in wheat, JamesFisher1, Senthold Asseng2, Bill Bowden1 and Michael Robertson3 ,1AgricultureWestern Australia, 2CSIRO Plant Industry, 3CSIRO Sustainable Ecosystems 21. When and where to grow oats, Glenn McDonald, Agriculture Western Australia 22. Managing Gaidner barley for quality, Kevin Young and Blakely Paynter, Agriculture Western Australia PESTS AND DISEASES 23. Strategies for leaf disease management in wheat, Jatinderpal Bhathal1, Cameron Weeks2, Kith Jayasena1 and Robert Loughman1 ,1Agriculture Western Australia. 2Mingenew-Irwin Group Inc 24. Strategies for leaf disease management in malting barley, K. Jayasena1, Q. Knight2 and R. Loughman1, 1Agriculture Western Australia, 2IAMA Agribusiness 25. Cereal disease diagnostics, Dominie Wright and Nichole Burges, Agriculture Western Australia 26. The big rust: Did you get your money back!! Peter Burgess, Agritech Crop Research 27. Jockey – winning the race against disease in wheat, Lisa-Jane Blacklow, Rob Hulme and Rob Giffith, Aventis CropScience 28. Distribution and incidence of aphids and barley yellow dwarf virus in over-summering grasses in WA wheatbelt, Jenny Hawkes and Roger Jones, CLIMA and Agriculture Western Australia 29. Further developments in forecasting aphid and virus risk in cereals, Debbie Thackray, Jenny Hawkes and Roger Jones, Agriculture Western Australia and Centre for Legumes in Mediterranean Agriculture 30. Effect of root lesion nematodes on wheat yields in Western Australia, S. B. Sharma, S. Kelly and R. Loughman, Crop Improvement Institute, Agriculture Western Australia 31. Rotational crops and varieties for management of root lesion nematodes in Western Australia, S.B. Sharma, S. Kelly and R. Loughman, Crop Improvement Institute, Agriculture Western Australia WEEDS 32. Phenoxy herbicide tolerance of wheat, Peter Newman and Dave Nicholson, Agriculture Western Australia 33. Tolerance of wheat to phenoxy herbicides,Harmohinder S. Dhammu, Terry Piper and Mario F. D\u27Antuono, Agriculture Western Australia 34. Herbicide tolerance of durum wheats, Harmohinder S. Dhammu, Terry Piper and David Nicholson, Agriculture Western Australia 35. Herbicide tolerance of new wheats, Harmohinder S. Dhammu, Terry Piper and David F. Nicholson, Agriculture Western Australia BREEDING 36. Towards molecular breeding of barley: construction of a molecular genetic map, Mehmet Cakir1, Nick Galwey1, David Poulsen2, Garry Ablett3, Reg Lance4, Rob Potter5 and Peter Langridge6,1Plant Sciences, Faculty of Agriculture, UWA, 2Queensland Department of Primary Industries, Qld, 3Centre for Plant Conservation Genetics Southern Cross University, Lismore NSW, 5SABC Murdoch University, WA, 6Department of Plant Science University of Adelaide, Glen Osmond SA 37. Toward molecular breeding of barley: Identifying markers linked to genes for quantitative traits, Mehmet Cakir1, Nick Galwey1, David Poulsen2, Reg Lance3, Garry Ablett4, Greg Platz2, Joe Panozzo5, Barbara Read6, David Moody5, Andy Barr7 and Peter Langridge7 , 1Plant Sciences, Faculty of Agriculture, UWA, 2Queensland Department of Primary Industries, Warwick, QLD,3Agriculture Western Australia, 4Centre for Plant Conservation Genetics, Southern Cross University, Lismore NSW, 5VIDA Private Bag 260, Horsham VIC, 6NSW Dept. of Agriculture, Wagga Wagga NSW, 7Department of Plant Science, University of Adelaide, Glen Osmond SA 38. Can we improve grain yield by breeding for greater early vigour in wheat? Tina Botwright1, Tony Condon1, Robin Wilson2 and Iain Barclay2, 1CSIRO Plant Industry, 2Agriculture Western Australia MARKETING AND QUALITY 39. The Crop Improvement Royalty, Howard Carr, Agriculture Western Australia 40. GrainGuardÔ - The development of a protection plan for the wheat industry, Greg Shea, Agriculture Western Australia CLIMATE 41. Rainfall – what happened in 2000 and the prospects for 2001, Ian Foster, Agriculture Western Australia 42. Software for climate management issues, David Tennant,Agriculture Western Australia CONTRIBUTING AUTHOR CONTACT DETAIL