Selection criteria for early breast cancer patients in the DBCG proton trial – The randomised phase III trial strategy

Background and purpose Adjuvant radiotherapy of internal mammary nodes (IMN) improves survival in high-risk early breast cancer patients but inevitably leads to more dose to heart and lung. Target coverage is often compromised to meet heart/lung dose constraints. We estimate heart and lung dose when target coverage is not compromised in consecutive patients. These estimates are used to guide the choice of selection criteria for the randomised Danish Breast Cancer Group (DBCG) Proton Trial.Materials and methods 179 breast cancer patients already treated with loco-regional IMN radiotherapy from 18 European departments were included. If the clinically delivered treatment plan did not comply with defined target coverage requirements, the plan was modified retrospectively until sufficient coverage was reached. The choice of selection criteria was based on the estimated number of eligible patients for different heart and lung dose thresholds in combination with proton therapy capacity limitations and dose-response relationships for heart and lung.Results Median mean heart dose was 3.0 Gy (range, 1.1-8.2 Gy) for left-sided and 1.4 Gy (0.4-11.5 Gy) for right-sided treatment plans. Median V17Gy/V20Gy (hypofractionated/normofractionated plans) for ipsilateral lung was 31% (9-57%). The DBCG Radiotherapy Committee chose mean heart dose ≥ 4 Gy and/or lung V17Gy/V20Gy ≥ 37% as thresholds for inclusion in the randomised trial. Using these thresholds, we estimate that 22% of patients requiring loco-regional IMN radiotherapy will be eligible for the trial.Conclusion The patient selection criteria for the DBCG Proton Trial are mean heart dose ≥ 4 Gy and/or lung V17Gy/V20Gy ≥ 37%

Genomic copy number alterations in poorly differentiated breast cancer

This project was designed to assess clinical and biological parameters of prognosis in high grade breast cancer (BC). The first approach aimed to define Clinicoepidemiological parameters associated with poor survival in a retrospective BC cohort of 1339 non-metastatic patients presenting at Singleton Hospital, South Wales, UK. Median follow-up was 5.4 years (range 0.09-10.14 years). Results of this analysis supported the role of histological grade (HG) as a prognostic factor and a tumour classifier. HG stood as one of the main variables associated with OS, DDFS and DFS with only N3 disease conferring worse prognosis. This analysis contributed with clinical information and survival data required for sample selection for subsequent comparative genomic hybridisation (CGH) studies. Array Comparative genomic hybridisation (aCGH) was performed in 78 cases (67 HG3 and 11 HG2) cases aiming to identify copy number alterations (CNA) associated with poor survival. aCGH protocol optimisation was required to obtain reproducible results and a new simplified aCGH protocol was described. A region of chromosomal gain in Chromosome 5 (5q35.1 to 5q35.2) was significantly associated with Cancer-specific survival (CSS; FDR<0.2). DUSP-1 and MSX2 genes were among those candidate genes validated In-silico for poorer prognosis in BC. FINALLY, THE ISSUE OF TAMOXIFEN RESISTANCE WAS ADDRESSED BY ATTEMPTING TO IDENTIFY CNA IN OESTROGEN RECEPTOR (ER) POSITIVE/TAMOXIFEN TREATED PATIENTS ASSOCIATED WITH EARLY RELAPSE/DEATH ≤5 YEARS (TAMRG) COMPARED WITH A SUB-GROUP OF PATIENTS ALIVE AND WELL AFTER 5 YEARS ON FOLLOW-UP (TAMCG). A REGION OF GAIN ON CHROMOSOME 7 (188219-6234052) WAS ASSOCIATED WITH TMACG (P:0.05) WHICH WAS ALSO ASSOCIATED WITH SIGNIFICANT OVER-EXPRESSION OF SNX8 USING IN-SILICO VALIDATION IN LOI ET AL DATASET. RESULTS FROM THIS STUDY CONTRIBUTE TOWARDS THE IDENTIFICATION OF CANDIDATE PROGNOSTIC GENES IN BC. BIOLOGICAL VALIDATION OF THESE RESULTS IS RECOMMENDED. FURTHER RESEARCH IS NEEDED TO ASSESS THE FUNCTIONAL RELEVANCE OF THESE CANDIDATE GENES

Genomic copy number alterations in poorly differentiated breast cancer

This project was designed to assess clinical and biological parameters of prognosis in high grade breast cancer (BC). The first approach aimed to define Clinicoepidemiological parameters associated with poor survival in a retrospective BC cohort of 1339 non-metastatic patients presenting at Singleton Hospital, South Wales, UK. Median follow-up was 5.4 years (range 0.09-10.14 years). Results of this analysis supported the role of histological grade (HG) as a prognostic factor and a tumour classifier. HG stood as one of the main variables associated with OS, DDFS and DFS with only N3 disease conferring worse prognosis. This analysis contributed with clinical information and survival data required for sample selection for subsequent comparative genomic hybridisation (CGH) studies. Array Comparative genomic hybridisation (aCGH) was performed in 78 cases (67 HG3 and 11 HG2) cases aiming to identify copy number alterations (CNA) associated with poor survival. aCGH protocol optimisation was required to obtain reproducible results and a new simplified aCGH protocol was described. A region of chromosomal gain in Chromosome 5 (5q35.1 to 5q35.2) was significantly associated with Cancer-specific survival (CSS; FDR<0.2). DUSP-1 and MSX2 genes were among those candidate genes validated In-silico for poorer prognosis in BC. FINALLY, THE ISSUE OF TAMOXIFEN RESISTANCE WAS ADDRESSED BY ATTEMPTING TO IDENTIFY CNA IN OESTROGEN RECEPTOR (ER) POSITIVE/TAMOXIFEN TREATED PATIENTS ASSOCIATED WITH EARLY RELAPSE/DEATH ≤5 YEARS (TAMRG) COMPARED WITH A SUB-GROUP OF PATIENTS ALIVE AND WELL AFTER 5 YEARS ON FOLLOW-UP (TAMCG). A REGION OF GAIN ON CHROMOSOME 7 (188219-6234052) WAS ASSOCIATED WITH TMACG (P:0.05) WHICH WAS ALSO ASSOCIATED WITH SIGNIFICANT OVER-EXPRESSION OF SNX8 USING IN-SILICO VALIDATION IN LOI ET AL DATASET. RESULTS FROM THIS STUDY CONTRIBUTE TOWARDS THE IDENTIFICATION OF CANDIDATE PROGNOSTIC GENES IN BC. BIOLOGICAL VALIDATION OF THESE RESULTS IS RECOMMENDED. FURTHER RESEARCH IS NEEDED TO ASSESS THE FUNCTIONAL RELEVANCE OF THESE CANDIDATE GENES.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Radiotherapy to regional nodes in early breast cancer: an individual patient data meta-analysis of 14324 women in 16 trials

BackgroundRadiotherapy has become much better targeted since the 1980s, improving both safety and efficacy. In breast cancer, radiotherapy to regional lymph nodes aims to reduce risks of recurrence and death. Its effects have been studied in randomised trials, some before the 1980s and some after. We aimed to assess the effects of regional node radiotherapy in these two eras.MethodsIn this meta-analysis of individual patient data, we sought data from all randomised trials of regional lymph node radiotherapy versus no regional lymph node radiotherapy in women with early breast cancer (including one study that irradiated lymph nodes only if the cancer was right-sided). Trials were identified through the EBCTCG's regular systematic searches of databases including MEDLINE, Embase, the Cochrane Library, and meeting abstracts. Trials were eligible if they began before Jan 1, 2009. The only systematic difference between treatment groups was in regional node radiotherapy (to the internal mammary chain, supraclavicular fossa, or axilla, or any combinations of these). Primary outcomes were recurrence at any site, breast cancer mortality, non-breast-cancer mortality, and all-cause mortality. Data were supplied by trialists and standardised into a format suitable for analysis. A summary of the formatted data was returned to trialists for verification. Log-rank analyses yielded first-event rate ratios (RRs) and confidence intervals.FindingsWe found 17 eligible trials, 16 of which had available data (for 14 324 participants), and one of which (henceforth excluded), had unavailable data (for 165 participants). In the eight newer trials (12 167 patients), which started during 1989–2008, regional node radiotherapy significantly reduced recurrence (rate ratio 0·88, 95% CI 0·81–0·95; p=0·0008). The main effect was on distant recurrence as few regional node recurrences were reported. Radiotherapy significantly reduced breast cancer mortality (RR 0·87, 95% CI 0·80–0·94; p=0·0010), with no significant effect on non-breast-cancer mortality (0·97, 0·84–1·11; p=0·63), leading to significantly reduced all-cause mortality (0·90, 0·84–0·96; p=0·0022). In an illustrative calculation, estimated absolute reductions in 15-year breast cancer mortality were 1·6% for women with no positive axillary nodes, 2·7% for those with one to three positive axillary nodes, and 4·5% for those with four or more positive axillary nodes. In the eight older trials (2157 patients), which started during 1961–78, regional node radiotherapy had little effect on breast cancer mortality (RR 1·04, 95% CI 0·91–1·20; p=0·55), but significantly increased non-breast-cancer mortality (1·42, 1·18–1·71; p=0·00023), with risk mainly after year 20, and all-cause mortality (1·17, 1·04–1·31; p=0·0067).InterpretationRegional node radiotherapy significantly reduced breast cancer mortality and all-cause mortality in trials done after the 1980s, but not in older trials. These contrasting findings could reflect radiotherapy improvements since the 1980s.<br/

Radiotherapy to regional nodes in early breast cancer: an individual patient data meta-analysis of 14 324 women in 16 trials

Background: Radiotherapy has become much better targeted since the 1980s, improving both safety and efficacy. In breast cancer, radiotherapy to regional lymph nodes aims to reduce risks of recurrence and death. Its effects have been studied in randomised trials, some before the 1980s and some after. We aimed to assess the effects of regional node radiotherapy in these two eras. Methods: In this meta-analysis of individual patient data, we sought data from all randomised trials of regional lymph node radiotherapy versus no regional lymph node radiotherapy in women with early breast cancer (including one study that irradiated lymph nodes only if the cancer was right-sided). Trials were identified through the EBCTCG's regular systematic searches of databases including MEDLINE, Embase, the Cochrane Library, and meeting abstracts. Trials were eligible if they began before Jan 1, 2009. The only systematic difference between treatment groups was in regional node radiotherapy (to the internal mammary chain, supraclavicular fossa, or axilla, or any combinations of these). Primary outcomes were recurrence at any site, breast cancer mortality, non-breast-cancer mortality, and all-cause mortality. Data were supplied by trialists and standardised into a format suitable for analysis. A summary of the formatted data was returned to trialists for verification. Log-rank analyses yielded first-event rate ratios (RRs) and confidence intervals. Findings: We found 17 eligible trials, 16 of which had available data (for 14 324 participants), and one of which (henceforth excluded), had unavailable data (for 165 participants). In the eight newer trials (12 167 patients), which started during 1989-2008, regional node radiotherapy significantly reduced recurrence (rate ratio 0·88, 95% CI 0·81-0·95; p=0·0008). The main effect was on distant recurrence as few regional node recurrences were reported. Radiotherapy significantly reduced breast cancer mortality (RR 0·87, 95% CI 0·80-0·94; p=0·0010), with no significant effect on non-breast-cancer mortality (0·97, 0·84-1·11; p=0·63), leading to significantly reduced all-cause mortality (0·90, 0·84-0·96; p=0·0022). In an illustrative calculation, estimated absolute reductions in 15-year breast cancer mortality were 1·6% for women with no positive axillary nodes, 2·7% for those with one to three positive axillary nodes, and 4·5% for those with four or more positive axillary nodes. In the eight older trials (2157 patients), which started during 1961-78, regional node radiotherapy had little effect on breast cancer mortality (RR 1·04, 95% CI 0·91-1·20; p=0·55), but significantly increased non-breast-cancer mortality (1·42, 1·18-1·71; p=0·00023), with risk mainly after year 20, and all-cause mortality (1·17, 1·04-1·31; p=0·0067). Interpretation: Regional node radiotherapy significantly reduced breast cancer mortality and all-cause mortality in trials done after the 1980s, but not in older trials. These contrasting findings could reflect radiotherapy improvements since the 1980s. Funding: Cancer Research UK, Medical Research Council