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Application of next generation sequencing in liquid biopsy analysis
S234 less comfort discussing tamoxifen with the patient (53.4% vs. 62.5%, p ¼ 0.005). There were no differences in comfort managing the patient between GP and SCC prescribers. No differences were apparent for any outcome between the breast cancer risk groups. Compared with respondents unwilling to prescribe, GPs willing to prescribe were more likely to consider the benefits of tamoxifen (87.6% vs. 97.2%, p < 0.001) and less likely to consider its ‘off-licence’ status (91.4% vs. 69.6%, p < 0.001). Conclusion: There is low awareness among GPs of tamoxifen as a preventive agent. A shared care agreement between primary and secondary care may overcome reluctance from GPs to initiate tamoxifen prescriptions. http://dx.doi.org/10.1016/j.ejso.2016.07.071
172. Research study: Continued variation in breast cancer follow up practice Laurie Marlow1, Mike Dixon2, David Montgomery3, Davinder Theti3 1 Pfizer/University of Surrey, UK 2 Western General Hosptial, Edinburgh, UK 3 Pfizer Ltd, UK Background: Provision of follow up care after curative resection for breast cancer is of uncertain value. Practice and agreed purpose, varies widely. More limited follow up, or alternative models, are being explored. Objectives of this research are to establish UK current follow up practice; to establish rationale/evidence underpinning follow up practice; to identify alternative methods and how widespread these are. Method: Questionnaire sent to UK Breast surgeons. Results: Surveys were sent to 202 UK breast surgeons. 92% of respondents were aware of UK guidelines, and 100% had a follow up protocol. Follow up duration varied from 3 to 10 years. Frequency of follow up varied considerably. 75% employed traditional clinic based follow up. This was mostly consultant led, with significant cost implications. For respondents providing follow up for more than 10 years, over 75% reported to have changed method or duration. Drivers for change included studies and research and a general need for service improvement. The perceived aims of follow up varied substantially between clinicians. All respondents conduct mammography annually. 68% of respondents undertake local mammography for 5 years before referral to breast screening. 30% for 10 years and one respondent for longer than 10 years. Conclusion: There remains no consensus in either published guidelines or among the clinicians surveyed here as to the purpose of follow up. Consequently, methodology varies significantly. Inconsistency in point of referral back to breast screening results in substantial variation in mammography frequency. Follow up remains extremely labour intensive, with significant resource implications. Evidence based changes in follow up practices are required. http://dx.doi.org/10.1016/j.ejso.2016.07.072
173. Views on provision of personalised cancer risk information: A qualitative interview study with members of the public Juliet Usher-Smith1, Barbora Silarova1, Artitaya Lophatananon2, Robbie Duschinsky1, Jackie Campbell3, Joanne Warcaba4, Kenneth Muir2 1 University of Cambridge, UK 2 University of Manchester, UK 3 University of Northampton, UK 4 Moulton Surgery, UK
ABSTRACTS Background: It is estimated that nearly 600,000 cancer cases in the UK could have been avoided in the past five years if people had healthier lifestyles. A number of theories of behaviour change suggest that before people will change health behaviours, they must accept that a risk applies to them. This study aimed to explore the views of members of the public on receiving personalised cancer risk information. Method: We conducted 27 interviews with members of the public. Each participant completed a questionnaire to allow calculation of their risk of developing the most common cancers (10 for women, 8 for men). During the interviews we presented their risk using a web-based tool developed for the study and discussions covered their views on receiving that information. Each interview was audio-recorded and then analysed using thematic analysis. Results: Participants generally viewed the concept of personalised cancer risk positively and were keen that it be provided more widely. When presented with their 10-year absolute risk of an individual cancer on a grey scale almost all felt that it was low and not concerning. Views on what constituted a high risk ranged widely, from 0.5 to 60%. When presented in colour, the colour was often more important than the number and dominated their interpretation. All felt seeing the impact of changes in lifestyle on their risk was powerful. For some this led to intentions to change behaviour, but reductions in risk were not always motivating as the risks were considered low and differences small. Conclusion: Provision of personalised cancer risk information was well received and may be a useful adjunct to other cancer prevention initiatives. Further work is needed in particular to address the disparity between typical risk estimates and the general perception of what constitutes a risk high enough to motivate behaviour change. http://dx.doi.org/10.1016/j.ejso.2016.07.073
187. Application of next generation sequencing in liquid biopsy analysis Eirini Papadopoulou, Vasiliki Metaxa-Mariatou, Nikolaos Tsoulos, Angeliki Tsirigoti, Chrisoula Efstathiadou, Angela Apessos, Konstantinos Agiannitopoulos, Georgia Pepe, George Nasioulas GeneKor Medical S.A., Greece Background: Nowadays, the presence of cell-free tumor derived DNA (cftDNA/ctRNA) in cancer patients plasma is well documented. cftDNA is considered a “liquid biopsy” since it can be used for the detection of tumor specific alterations in plasma samples of cancer patients. Method: A total of 66 plasma and tumor FFPE samples from Greek patients with newly diagnosed NSCLC were analyzed for mutations in hot spot regions of 15 cancer related genes using a targeted Next Generation Sequencing (NGS) approach. Additionally plasma samples of 10 patients with an EGFR mutation at the time of diagnosis were analysed, following relapse to targeted therapy. NGS was carried out using the NGS platform Ion Proton (ThermoFisher Scientific). The sensitivity of the method was identified using CFDNA reference standards (Horizon Diagnosis). Results: The NGS methodology used was able to identify less than 1% of mutant alleles in a background of wild type DNA content. No mutation was identified in 52 plasma samples whose FFPE tissue was mutation free, indicating a 100% specificity of the assay. Additionally, 8/10 patients with a KRAS mutation and 8/9 patients with an EGFR mutation, in the FFPE sample presented the same mutation in the plasma sample. Thus, there was an 83% concordance between mutations identified in FFPE and plasma samples. Liquid biopsy analysis of 10 patients with EGFR mutated tumors at the time of diagnosis, revealed presence of the primary mutation in 50% of the cases following therapy relapse. Most importantly, 3 patients with a primary EGFR mutation and 1 patient whose primary EGFR mutation was no longer detectable following treatment carried the resistance mutation p.T790M, which is known to confer sensitivity to third generation TKIs.
ABSTRACTS Conclusion: NGS liquid biopsy analysis has a big validity either for mutation detection at the time of diagnosis or for the detection of early molecular relapse following treatment. http://dx.doi.org/10.1016/j.ejso.2016.07.074 191. Malignant bowel obstruction e How can we do better? Sarah Slater, Ros Glasspool, Stephen McKay, Helen MacKay, Nicky Donnelly, Alison Mitchell, Doherty Graeme Beatson West of Scotland Cancer Centre, UK Background: Malignant small bowel obstruction (SBO) affects 20e50% of ovarian cancer patients and has a grave prognosis (Caprotti et al, 2006). There is little evidence to guide optimal management of these patients and they often require prolonged periods in hospital. Surgery is rarely an option as ovarian cancer SBO is characteristically multi-focal. Medical management includes a combination of opioids, antiemetics, glucocorticoids and antisecretory drugs with limited symptomatic response rates. Research suggests that a subpopulation of patients benefit from early intervention with total parenteral nutrition (TPN) and chemotherapy (AbuRustum et al, 1997; Bryan, 2006) but there are currently no established prognostic indicators to identify those patients most likely to benefit from TPN and access to home TPN varies around the country. In December 2015 Health Improvement Scotland published Complex Nutritional Care Standards which require that NHS boards ensure patients are considered for complex nutritional care by a multidisciplinary team (MDT). At the Beatson, West of Scotland Cancer Centre (BWSCC), we have established a MDT to develop new guidelines and pathways for the management of patients with malignant SBO. Method: To inform this process we undertook a retrospective study of current practice and outcomes in ovarian cancer patients with SBO at BWoSCC admitted over two years. Results: We present data on 56 patient admissions, including age, performance status, BMI, stage of disease, presence of ascites, previous and current anti-cancer therapy, laboratory factors including, albumin, white cell count and CA-125 were recorded as well as data on length of stays, use and complications of TPN, resolution of obstruction, place of discharge and survival. The current inpatient journey, specifically referral processes to dieticians, TPN team, surgeons and palliative care team is reviewed. Conclusion: The necessity for a MDT in complex nutrition care of cancer patients is demonstrated. http://dx.doi.org/10.1016/j.ejso.2016.07.075
200. SPORT high-risk trial: A randomised feasibility study evaluating stereotactic prostate radiotherapy in high-risk localised prostate cancer with or without elective nodal irradiation Ciara Lyons1, Conor McGarry2, Alan Hounsell2, Sharon Hynds2, Kevin Prise3, Joe O’Sullivan3, Suneil Jain3 1 Centre for Cancer Research and Cell Biology, UK 2 Northern Ireland Cancer Centre, Belfast Health and Social Care Trust, UK 3 Centre for Cancer Research and Cell Biology, Queen’s University Belfast, UK Background: Prostate Cancer (PC) has a low alpha-beta ratio, making it sensitive to hypofractionated radiotherapy. Stereotactic ablative radiotherapy (SABR) provides an opportunity for dose escalation beyond that achievable with conventional radiotherapy. Additionally, there is a lack of novel biomarkers in use in the management of localized PC. Method: Thirty men with high-risk node-negative PC (at least one of PSA > 20 ng/mL, T3a, Gleason score 4 + 3) will be randomized on a 1:1 basis to receive SABR to the prostate (P) and proximal seminal vesicles (SV) alone (36.25 Gy/5#) or to the addition of elective
S235 pelvic nodal irradiation (ENI) (25 Gy/5#). All men will be treated using a volumetric arc therapy solution with intra-prostatic fiducial markers, a prostate-rectal spacer device and cone-beam CT-based image-guidance. Results: The primary objective of this study is to demonstrate the feasibility of performing a randomised trial comparing P/SV SABR to the addition of ENI SABR in men with high-risk localised PC. This will be measured via distinct endpoints: adequate recruitment rate (30 patients in 24 months), number of plans delivered as planned and on schedule, and quantification of acute toxicity to enable calculation of the sample size for a subsequent Phase II trial (CTCAE v4.03). Secondary objectives include quantification of late toxicity and quality of life scores and assessment of PC outcomes post-SABR. Tertiary and exploratory outcomes include the biobanking of clinically annotated tissue, a health economic analysis, assessment of multiple biomarker candidates, measurement of fatigue, and assessment of the impact of prostate spacer placement. Conclusion: SABR provides scope for dose escalation in men with high-risk localized PC. The role of ENI has not been determined. Furthermore, this trial offers an additional opportunity for novel biomarker investigation in localized PC. http://dx.doi.org/10.1016/j.ejso.2016.07.076
207. The extent and impact of musculoskeletal dysfunction on women following breast reconstruction using the latissimus dorsi muscle: A questionnaire survey Nicole Blackburn, Iseult Wilson, Joseph McVeigh, Eilis McCaughan Ulster University, UK Background: Quality of life is becoming more important in regard to breast cancer as treatment advances extend the period of survivorship. Breast reconstruction following mastectomy is an important management option in breast cancer, therefore the functional implications associated with this surgery must be considered. The latissimus dorsi (LD) flap is one the most widely used surgical procedures for women with breast cancer undergoing reconstructive surgery. To date, literature has mainly focused on body image and wound healing with little indepth investigation of the impact of this surgery on shoulder function. Few studies have specifically investigated the musculoskeletal impact of surgery and of those that have, findings have varied regarding the impact and extent. Method: A postal survey design was used to gather detailed and personal information from women who had LD breast reconstruction. All eligible women who underwent LD flap surgery through the Northern Ireland Health and Social Care Trusts were included in the study. A range of validated outcome measures were included in order to determine both the physical and psychosocial implications of LD breast reconstruction in women following mastectomy for breast cancer. Results: A total of 159 women, (mean age ¼ 46.8 7.9 years; mean time since surgery ¼ 4.3 2.9 years) completed the survey. The results from the validated outcome measure scores demonstrated low to moderate dysfunction among the group. Subgroup analysis revealed that auxiliary node removal significantly impacted disability scores (p ¼ .036) as per DASH and quality of life scores regarding mobility (p ¼ .008) and selfcare (p ¼ .030) as per EuroQol. Conclusion: The findings from this study indicate that LD breast reconstruction has an impact on the functional ability of patients undergoing this specific procedure, with the results from the validated outcome measure scores demonstrating low to moderate dysfunction among the group. http://dx.doi.org/10.1016/j.ejso.2016.07.077
172. Research study: Continued variation in breast cancer follow up practice Laurie Marlow1, Mike Dixon2, David Montgomery3, Davinder Theti3 1 Pfizer/University of Surrey, UK 2 Western General Hosptial, Edinburgh, UK 3 Pfizer Ltd, UK Background: Provision of follow up care after curative resection for breast cancer is of uncertain value. Practice and agreed purpose, varies widely. More limited follow up, or alternative models, are being explored. Objectives of this research are to establish UK current follow up practice; to establish rationale/evidence underpinning follow up practice; to identify alternative methods and how widespread these are. Method: Questionnaire sent to UK Breast surgeons. Results: Surveys were sent to 202 UK breast surgeons. 92% of respondents were aware of UK guidelines, and 100% had a follow up protocol. Follow up duration varied from 3 to 10 years. Frequency of follow up varied considerably. 75% employed traditional clinic based follow up. This was mostly consultant led, with significant cost implications. For respondents providing follow up for more than 10 years, over 75% reported to have changed method or duration. Drivers for change included studies and research and a general need for service improvement. The perceived aims of follow up varied substantially between clinicians. All respondents conduct mammography annually. 68% of respondents undertake local mammography for 5 years before referral to breast screening. 30% for 10 years and one respondent for longer than 10 years. Conclusion: There remains no consensus in either published guidelines or among the clinicians surveyed here as to the purpose of follow up. Consequently, methodology varies significantly. Inconsistency in point of referral back to breast screening results in substantial variation in mammography frequency. Follow up remains extremely labour intensive, with significant resource implications. Evidence based changes in follow up practices are required. http://dx.doi.org/10.1016/j.ejso.2016.07.072
173. Views on provision of personalised cancer risk information: A qualitative interview study with members of the public Juliet Usher-Smith1, Barbora Silarova1, Artitaya Lophatananon2, Robbie Duschinsky1, Jackie Campbell3, Joanne Warcaba4, Kenneth Muir2 1 University of Cambridge, UK 2 University of Manchester, UK 3 University of Northampton, UK 4 Moulton Surgery, UK
ABSTRACTS Background: It is estimated that nearly 600,000 cancer cases in the UK could have been avoided in the past five years if people had healthier lifestyles. A number of theories of behaviour change suggest that before people will change health behaviours, they must accept that a risk applies to them. This study aimed to explore the views of members of the public on receiving personalised cancer risk information. Method: We conducted 27 interviews with members of the public. Each participant completed a questionnaire to allow calculation of their risk of developing the most common cancers (10 for women, 8 for men). During the interviews we presented their risk using a web-based tool developed for the study and discussions covered their views on receiving that information. Each interview was audio-recorded and then analysed using thematic analysis. Results: Participants generally viewed the concept of personalised cancer risk positively and were keen that it be provided more widely. When presented with their 10-year absolute risk of an individual cancer on a grey scale almost all felt that it was low and not concerning. Views on what constituted a high risk ranged widely, from 0.5 to 60%. When presented in colour, the colour was often more important than the number and dominated their interpretation. All felt seeing the impact of changes in lifestyle on their risk was powerful. For some this led to intentions to change behaviour, but reductions in risk were not always motivating as the risks were considered low and differences small. Conclusion: Provision of personalised cancer risk information was well received and may be a useful adjunct to other cancer prevention initiatives. Further work is needed in particular to address the disparity between typical risk estimates and the general perception of what constitutes a risk high enough to motivate behaviour change. http://dx.doi.org/10.1016/j.ejso.2016.07.073
187. Application of next generation sequencing in liquid biopsy analysis Eirini Papadopoulou, Vasiliki Metaxa-Mariatou, Nikolaos Tsoulos, Angeliki Tsirigoti, Chrisoula Efstathiadou, Angela Apessos, Konstantinos Agiannitopoulos, Georgia Pepe, George Nasioulas GeneKor Medical S.A., Greece Background: Nowadays, the presence of cell-free tumor derived DNA (cftDNA/ctRNA) in cancer patients plasma is well documented. cftDNA is considered a “liquid biopsy” since it can be used for the detection of tumor specific alterations in plasma samples of cancer patients. Method: A total of 66 plasma and tumor FFPE samples from Greek patients with newly diagnosed NSCLC were analyzed for mutations in hot spot regions of 15 cancer related genes using a targeted Next Generation Sequencing (NGS) approach. Additionally plasma samples of 10 patients with an EGFR mutation at the time of diagnosis were analysed, following relapse to targeted therapy. NGS was carried out using the NGS platform Ion Proton (ThermoFisher Scientific). The sensitivity of the method was identified using CFDNA reference standards (Horizon Diagnosis). Results: The NGS methodology used was able to identify less than 1% of mutant alleles in a background of wild type DNA content. No mutation was identified in 52 plasma samples whose FFPE tissue was mutation free, indicating a 100% specificity of the assay. Additionally, 8/10 patients with a KRAS mutation and 8/9 patients with an EGFR mutation, in the FFPE sample presented the same mutation in the plasma sample. Thus, there was an 83% concordance between mutations identified in FFPE and plasma samples. Liquid biopsy analysis of 10 patients with EGFR mutated tumors at the time of diagnosis, revealed presence of the primary mutation in 50% of the cases following therapy relapse. Most importantly, 3 patients with a primary EGFR mutation and 1 patient whose primary EGFR mutation was no longer detectable following treatment carried the resistance mutation p.T790M, which is known to confer sensitivity to third generation TKIs.
ABSTRACTS Conclusion: NGS liquid biopsy analysis has a big validity either for mutation detection at the time of diagnosis or for the detection of early molecular relapse following treatment. http://dx.doi.org/10.1016/j.ejso.2016.07.074 191. Malignant bowel obstruction e How can we do better? Sarah Slater, Ros Glasspool, Stephen McKay, Helen MacKay, Nicky Donnelly, Alison Mitchell, Doherty Graeme Beatson West of Scotland Cancer Centre, UK Background: Malignant small bowel obstruction (SBO) affects 20e50% of ovarian cancer patients and has a grave prognosis (Caprotti et al, 2006). There is little evidence to guide optimal management of these patients and they often require prolonged periods in hospital. Surgery is rarely an option as ovarian cancer SBO is characteristically multi-focal. Medical management includes a combination of opioids, antiemetics, glucocorticoids and antisecretory drugs with limited symptomatic response rates. Research suggests that a subpopulation of patients benefit from early intervention with total parenteral nutrition (TPN) and chemotherapy (AbuRustum et al, 1997; Bryan, 2006) but there are currently no established prognostic indicators to identify those patients most likely to benefit from TPN and access to home TPN varies around the country. In December 2015 Health Improvement Scotland published Complex Nutritional Care Standards which require that NHS boards ensure patients are considered for complex nutritional care by a multidisciplinary team (MDT). At the Beatson, West of Scotland Cancer Centre (BWSCC), we have established a MDT to develop new guidelines and pathways for the management of patients with malignant SBO. Method: To inform this process we undertook a retrospective study of current practice and outcomes in ovarian cancer patients with SBO at BWoSCC admitted over two years. Results: We present data on 56 patient admissions, including age, performance status, BMI, stage of disease, presence of ascites, previous and current anti-cancer therapy, laboratory factors including, albumin, white cell count and CA-125 were recorded as well as data on length of stays, use and complications of TPN, resolution of obstruction, place of discharge and survival. The current inpatient journey, specifically referral processes to dieticians, TPN team, surgeons and palliative care team is reviewed. Conclusion: The necessity for a MDT in complex nutrition care of cancer patients is demonstrated. http://dx.doi.org/10.1016/j.ejso.2016.07.075
200. SPORT high-risk trial: A randomised feasibility study evaluating stereotactic prostate radiotherapy in high-risk localised prostate cancer with or without elective nodal irradiation Ciara Lyons1, Conor McGarry2, Alan Hounsell2, Sharon Hynds2, Kevin Prise3, Joe O’Sullivan3, Suneil Jain3 1 Centre for Cancer Research and Cell Biology, UK 2 Northern Ireland Cancer Centre, Belfast Health and Social Care Trust, UK 3 Centre for Cancer Research and Cell Biology, Queen’s University Belfast, UK Background: Prostate Cancer (PC) has a low alpha-beta ratio, making it sensitive to hypofractionated radiotherapy. Stereotactic ablative radiotherapy (SABR) provides an opportunity for dose escalation beyond that achievable with conventional radiotherapy. Additionally, there is a lack of novel biomarkers in use in the management of localized PC. Method: Thirty men with high-risk node-negative PC (at least one of PSA > 20 ng/mL, T3a, Gleason score 4 + 3) will be randomized on a 1:1 basis to receive SABR to the prostate (P) and proximal seminal vesicles (SV) alone (36.25 Gy/5#) or to the addition of elective
S235 pelvic nodal irradiation (ENI) (25 Gy/5#). All men will be treated using a volumetric arc therapy solution with intra-prostatic fiducial markers, a prostate-rectal spacer device and cone-beam CT-based image-guidance. Results: The primary objective of this study is to demonstrate the feasibility of performing a randomised trial comparing P/SV SABR to the addition of ENI SABR in men with high-risk localised PC. This will be measured via distinct endpoints: adequate recruitment rate (30 patients in 24 months), number of plans delivered as planned and on schedule, and quantification of acute toxicity to enable calculation of the sample size for a subsequent Phase II trial (CTCAE v4.03). Secondary objectives include quantification of late toxicity and quality of life scores and assessment of PC outcomes post-SABR. Tertiary and exploratory outcomes include the biobanking of clinically annotated tissue, a health economic analysis, assessment of multiple biomarker candidates, measurement of fatigue, and assessment of the impact of prostate spacer placement. Conclusion: SABR provides scope for dose escalation in men with high-risk localized PC. The role of ENI has not been determined. Furthermore, this trial offers an additional opportunity for novel biomarker investigation in localized PC. http://dx.doi.org/10.1016/j.ejso.2016.07.076
207. The extent and impact of musculoskeletal dysfunction on women following breast reconstruction using the latissimus dorsi muscle: A questionnaire survey Nicole Blackburn, Iseult Wilson, Joseph McVeigh, Eilis McCaughan Ulster University, UK Background: Quality of life is becoming more important in regard to breast cancer as treatment advances extend the period of survivorship. Breast reconstruction following mastectomy is an important management option in breast cancer, therefore the functional implications associated with this surgery must be considered. The latissimus dorsi (LD) flap is one the most widely used surgical procedures for women with breast cancer undergoing reconstructive surgery. To date, literature has mainly focused on body image and wound healing with little indepth investigation of the impact of this surgery on shoulder function. Few studies have specifically investigated the musculoskeletal impact of surgery and of those that have, findings have varied regarding the impact and extent. Method: A postal survey design was used to gather detailed and personal information from women who had LD breast reconstruction. All eligible women who underwent LD flap surgery through the Northern Ireland Health and Social Care Trusts were included in the study. A range of validated outcome measures were included in order to determine both the physical and psychosocial implications of LD breast reconstruction in women following mastectomy for breast cancer. Results: A total of 159 women, (mean age ¼ 46.8 7.9 years; mean time since surgery ¼ 4.3 2.9 years) completed the survey. The results from the validated outcome measure scores demonstrated low to moderate dysfunction among the group. Subgroup analysis revealed that auxiliary node removal significantly impacted disability scores (p ¼ .036) as per DASH and quality of life scores regarding mobility (p ¼ .008) and selfcare (p ¼ .030) as per EuroQol. Conclusion: The findings from this study indicate that LD breast reconstruction has an impact on the functional ability of patients undergoing this specific procedure, with the results from the validated outcome measure scores demonstrating low to moderate dysfunction among the group. http://dx.doi.org/10.1016/j.ejso.2016.07.077