Nature Reviews Cancer | Research Highlight
Pancreatic cancer Spotlight on B cells
Sarah Seton-Rogers
Nature Reviews Cancer 16,67(2016)doi:10.1038/nrc.2016.7
Published online 29 January 2016
Three papers published in Cancer Discovery have shown that different subsets of B cells can promote development and progression of pancreatic ductal adenocarcinoma (PDAC).
Pylayeva-Gupta et al. detected B cell infiltrates and the B cell chemoattractant CXCL13 in human pancreatic intraepithelial neoplasia (PanIN) and in PanIN from LSL-KrasG12D;Ptf1a-Cre (hereafter KrasG12D) mice.
A CXCL13-blocking antibody prevented B cell infiltration in KrasG12D mice and in mice orthotopically injected with KrasG12D-expressing pancreatic ductal epithelial cells (PDECs); importantly, it also reduced the growth of orthotopic tumours.
KrasG12D PDECs implanted into mice lacking B cells (μMT mice) had reduced tumour growth compared with tumours grown in wild-type mice, and tumour growth was restored by adoptive transfer of B cells, indicating a direct role for B cells.
Furthermore, the CD19+CD1dhighCD5+ subpopulation of B cells was shown to be crucial for promoting tumour growth via production of interleukin 35 (IL-35), which seems to increase PDEC proliferation.
Lee et al. investigated the contribution of hypoxia-inducible factor 1α (HIF1α) to PDAC. PanINs in KrasG12D mice progress to invasive PDAC, and HIF1α expression and hypoxia were detected at all stages. However, KrasG12D mice with pancreas-specific deletion of HIF1α (KrasG12D;Hif1aKO mice) had increased PanIN and progression to PDAC. Interestingly, overall survival of the two mouse strains was similar, indicating that HIF1α might switch from a protective role to a tumour-promoting role during progression.
HIF1α deletion increased B cell infiltration in PanIN lesions, and human PanIN and PDAC samples also had increased levels of B cells. Examination of B cell subpopulations indicated that pancreata from KrasG12D mice had decreased numbers of B2 cells and increased numbers ofB1 cells compared with wild-type mice, and this ratio shifted further in KrasG12D;Hif1aKO mice. Depletion of B cells in both PDAC models reduced the number of higher grade PanIN lesions. Further experiments suggested that B cells are recruited to HIF1α-deficient tumours through increased expression of B cell chemoattractants, including CXCL13, through a non-tumour-cell-autonomous mechanism.
Gunderson, Kaneda et al. also found that PDACs had high B cell infiltration, as well as infiltration of Fcγ receptor (FcγR)-positive myeloid cells. The authors hypothesized that these two cell types might interact to promote tumorigenesis. PDACs derived from orthotopic implantation of LSL-KrasG12D;Pdx1-Cre cells (a PDAC model similar to LSL-KrasG12D;Ptf1a-Cre) that also lacked Trp53 or Cdkn2a in syngeneic mice had substantial infiltration of B cells, including B1 cells and several other B cell subpopulations. Implantation of these PDAC cells into mice lacking B cells (Igh-J−/− mice) resulted in smaller tumours compared with controls; a similar result was observed in FcγR-deficient mice, indicating that both B cells and myeloid cells are important for PDAC development.
The authors then investigated signalling pathways common to both B cells and macrophages (a subset of myeloid cells).
Activated Bruton's tyrosine kinase (BTK) was present in both B cells and macrophages inhuman and orthotopic mouse PDAC tumours.
Several lines of evidence suggested that the γ-isoform of PI3K (PI3Kγ) activates BTK in macrophages to promote production of immunosuppressive T helper 2 (TH2) cytokines. This TH2 polarization of macrophages occurred following co-culture with PDAC-derived B cells and was blocked by the BTK inhibitor ibrutinib, suggesting that B cells promote the pro-tumorigenic macrophage phenotype, and that BTK signalling is tumour promoting in both cell types.
Ibrutinib and a PI3Kγ inhibitor suppressed orthotopic PDAC growth; a combination of the two drugs had no additional effects. The inhibitors also reduced tumour size in late-stage tumours, which suggests possible therapeutic efficacy.
“B cells might contribute to PDAC progression in different ways”
Overall, these data suggest that B cells might contribute to PDAC progression in different ways, depending on the biological context.
Understanding the complete immune environment of these tumours and further dissecting the roles of B cells will be important for the development of effective immunotherapies for PDAC.
References
Pylayeva-Gupta, Y. et al. IL-35 producing B cells promote the development of pancreatic neoplasia. Cancer Discov. http://dx.doi.org/10.1158/2159-8290.CD-15-0843 (2015)
Lee, K. E. et al. Hif1α deletion reveals pro-neoplastic function of B cells in pancreatic neoplasia. Cancer Discov. http://dx.doi.org/10.1158/2159-8290.CD-15-0822 (2015)
Gunderson, A. J., Kaneda, M. M. et al. Bruton's Tyrosine Kinase (BTK)-dependent immune cell crosstalk drives pancreas cancer. Cancer Discov. http://dx.doi.org/10.1158/2159-8290.CD-15-0827 (2015)
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Alopecia in patients treated with molecularly targeted anticancer therapies
Alopecia in patients treated with molecularly targeted anticancer therapies
V. R. Belum1, K. Marulanda2, C. Ensslin3, L. Gorcey4, T. Parikh5, S. Wu6,7, K. J. Busam8, P. A. Gerber9 and M. E. Lacouture1,*
Received April 7, 2015.
Revision received September 8, 2015.
Accepted September 13, 2015.
Abstract
Background
The introduction of molecularly targeted anticancer therapies presents new challenges, among which dermatologic adverse events are noteworthy. Alopecia in particular is frequently reported, but the true incidence is not known.
Patients and methods
We sought to ascertain the incidence and risk of developing alopecia during treatment with approved inhibitors of oncogenic pathways and molecules [anaplastic lymphoma kinase, breakpoint cluster region-abelson, B-rapidly accelerated fibrosarcoma, Bruton's tyrosine kinase, cytotoxic T-lymphocyte antigen-4, epidermal growth factor receptor, human epidermal growth factor receptor-2, Janus kinase, MAPK/ERK (extracellular signal-regulated kinase) Kinase, mammalian target of rapamycin, smoothened, vascular endothelial growth factor, vascular endothelial growth factor receptor, platelet derived growth factor receptor; proteasomes; CD20, CD30, CD52]. Electronic database (PubMed, Web of Science) and ASCO meeting abstract searches were conducted to identify clinical trials reporting alopecia. Meta-analysis was conducted utilizing fixed- or random-effects models.
Results
The calculated overall incidence of all-grade alopecia was 14.7% [95% confidence interval (CI) 12.6% to 17.2%]—lowest with bortezomib, 2.2% (95% CI 0.4% to 10.9%), and highest with vismodegib, 56.9% (95% CI 50.5% to 63.1%). There was an increased risk of all-grade alopecia [relative risk (RR), 7.9 (95% CI 6.2–10.09, P ≤ 0.01)] compared with placebo, but when compared with chemotherapy, the risk was lower [RR, 0.32 (95% CI 0.2–0.55, P ≤ 0.01)].
Conclusions
Targeted therapies are associated with an increased risk of alopecia.
V. R. Belum1, K. Marulanda2, C. Ensslin3, L. Gorcey4, T. Parikh5, S. Wu6,7, K. J. Busam8, P. A. Gerber9 and M. E. Lacouture1,*
Received April 7, 2015.
Revision received September 8, 2015.
Accepted September 13, 2015.
Abstract
Background
The introduction of molecularly targeted anticancer therapies presents new challenges, among which dermatologic adverse events are noteworthy. Alopecia in particular is frequently reported, but the true incidence is not known.
Patients and methods
We sought to ascertain the incidence and risk of developing alopecia during treatment with approved inhibitors of oncogenic pathways and molecules [anaplastic lymphoma kinase, breakpoint cluster region-abelson, B-rapidly accelerated fibrosarcoma, Bruton's tyrosine kinase, cytotoxic T-lymphocyte antigen-4, epidermal growth factor receptor, human epidermal growth factor receptor-2, Janus kinase, MAPK/ERK (extracellular signal-regulated kinase) Kinase, mammalian target of rapamycin, smoothened, vascular endothelial growth factor, vascular endothelial growth factor receptor, platelet derived growth factor receptor; proteasomes; CD20, CD30, CD52]. Electronic database (PubMed, Web of Science) and ASCO meeting abstract searches were conducted to identify clinical trials reporting alopecia. Meta-analysis was conducted utilizing fixed- or random-effects models.
Results
The calculated overall incidence of all-grade alopecia was 14.7% [95% confidence interval (CI) 12.6% to 17.2%]—lowest with bortezomib, 2.2% (95% CI 0.4% to 10.9%), and highest with vismodegib, 56.9% (95% CI 50.5% to 63.1%). There was an increased risk of all-grade alopecia [relative risk (RR), 7.9 (95% CI 6.2–10.09, P ≤ 0.01)] compared with placebo, but when compared with chemotherapy, the risk was lower [RR, 0.32 (95% CI 0.2–0.55, P ≤ 0.01)].
Conclusions
Targeted therapies are associated with an increased risk of alopecia.
Abiraterone acetate, exemestane or the combination in postmenopausal patients with estrogen receptor-positive metastatic breast cancer†
Abiraterone acetate, exemestane or the combination in postmenopausal patients with estrogen receptor-positive metastatic breast cancer†
J. O'Shaughnessy1,*, M. Campone2, E. Brain3, P. Neven4, D. Hayes5, I. Bondarenko6, T. W. Griffin7, J. Martin8, P. De Porre9, T. Kheoh7, M. K. Yu7, W. Peng7 and S. Johnston10
Received May 4, 2015.
Revision received September 28, 2015.
Accepted September 30, 2015.
Abstract
Background Androgen receptor (AR) signaling and incomplete inhibition of estrogen signaling may contribute to metastatic breast cancer (MBC) resistance to a nonsteroidal aromatase inhibitor (NSAI; letrozole or anastrozole). We assessed whether combined inhibition of androgen biosynthesis with abiraterone acetate plus prednisone and estradiol synthesis with exemestane (E) may be of clinical benefit to postmenopausal patients with NSAI-pretreated estrogen receptor-positive (ER+) MBC.
Patients and methods
Patients
(N = 297) were stratified by the number of prior therapies for metastatic disease (0–1 versus 2) and by prior NSAI use (adjuvant versus metastatic), and randomized (1 : 1 : 1) to receive oral once daily 1000 mg abiraterone acetate plus 5 mg prednisone (AA) versus AA with 25 mg E (AAE) versus 25 mg E alone (E). Each treatment arm was well balanced with regard to the proportion of patients with AR-positive breast cancer. The primary end point was progression-free survival (PFS). Secondary end points included overall survival, clinical benefit rate, duration of response, and overall response rate.
Results
There was no significant difference in PFS with AA versus E (3.7 versus 3.7 months; hazard ratio [HR] = 1.1; 95% confidence interval [CI] 0.82–1.60; P = 0.437) or AAE versus E (4.5 versus 3.7 months; HR = 0.96; 95% CI 0.70–1.32; P = 0.794). Increased serum progesterone concentrations were observed in both arms receiving AA, but not with E. Grade 3 or 4 treatment-emergent adverse events associated with AA, including hypokalemia and hypertension, were less common in patients in the E (2.0% and 2.9%, respectively) and AA arms (3.4% and 1.1%, respectively) than in the AAE arm (5.8% for both).
Conclusions
Adding AA to E in NSAI-pretreated ER+ MBC patients did not improve PFS compared with treatment with E. An AA-induced progesterone increase may have contributed to this lack of clinical activity.
ClinicalTrials.gov NCT01381874.
J. O'Shaughnessy1,*, M. Campone2, E. Brain3, P. Neven4, D. Hayes5, I. Bondarenko6, T. W. Griffin7, J. Martin8, P. De Porre9, T. Kheoh7, M. K. Yu7, W. Peng7 and S. Johnston10
Received May 4, 2015.
Revision received September 28, 2015.
Accepted September 30, 2015.
Abstract
Background Androgen receptor (AR) signaling and incomplete inhibition of estrogen signaling may contribute to metastatic breast cancer (MBC) resistance to a nonsteroidal aromatase inhibitor (NSAI; letrozole or anastrozole). We assessed whether combined inhibition of androgen biosynthesis with abiraterone acetate plus prednisone and estradiol synthesis with exemestane (E) may be of clinical benefit to postmenopausal patients with NSAI-pretreated estrogen receptor-positive (ER+) MBC.
Patients and methods
Patients
(N = 297) were stratified by the number of prior therapies for metastatic disease (0–1 versus 2) and by prior NSAI use (adjuvant versus metastatic), and randomized (1 : 1 : 1) to receive oral once daily 1000 mg abiraterone acetate plus 5 mg prednisone (AA) versus AA with 25 mg E (AAE) versus 25 mg E alone (E). Each treatment arm was well balanced with regard to the proportion of patients with AR-positive breast cancer. The primary end point was progression-free survival (PFS). Secondary end points included overall survival, clinical benefit rate, duration of response, and overall response rate.
Results
There was no significant difference in PFS with AA versus E (3.7 versus 3.7 months; hazard ratio [HR] = 1.1; 95% confidence interval [CI] 0.82–1.60; P = 0.437) or AAE versus E (4.5 versus 3.7 months; HR = 0.96; 95% CI 0.70–1.32; P = 0.794). Increased serum progesterone concentrations were observed in both arms receiving AA, but not with E. Grade 3 or 4 treatment-emergent adverse events associated with AA, including hypokalemia and hypertension, were less common in patients in the E (2.0% and 2.9%, respectively) and AA arms (3.4% and 1.1%, respectively) than in the AAE arm (5.8% for both).
Conclusions
Adding AA to E in NSAI-pretreated ER+ MBC patients did not improve PFS compared with treatment with E. An AA-induced progesterone increase may have contributed to this lack of clinical activity.
ClinicalTrials.gov NCT01381874.
CDX2 as a Prognostic Biomarker in Stage II and Stage III Colon Cancer
Original Article
CDX2 as a Prognostic Biomarker in Stage II and Stage III Colon Cancer
Piero Dalerba, M.D., Debashis Sahoo, Ph.D., Soonmyung Paik, M.D., Xiangqian Guo, Ph.D., Greg Yothers, Ph.D., Nan Song, Ph.D., Nate Wilcox-Fogel, M.S., Erna Forgó, M.D., Pradeep S. Rajendran, B.S., Stephen P. Miranda, B.A., Shigeo Hisamori, M.D., Ph.D., Jacqueline Hutchison, Tomer Kalisky, Ph.D., Dalong Qian, M.D., Norman Wolmark, M.D., George A. Fisher, M.D., Ph.D., Matt van de Rijn, M.D., Ph.D., and Michael F. Clarke, M.D.
N Engl J Med 2016; 374:211-222January 21, 2016DOI: 10.1056/NEJMoa1506597
Background
The identification of high-risk stage II colon cancers is key to the selection of patients who require adjuvant treatment after surgery. Microarray-based multigene-expression signatures derived from stem cells and progenitor cells hold promise, but they are difficult to use in clinical practice.
Methods
We used a new bioinformatics approach to search for biomarkers of colon epithelial differentiation across gene-expression arrays and then ranked candidate genes according to the availability of clinical-grade diagnostic assays. With the use of subgroup analysis involving independent and retrospective cohorts of patients with stage II or stage III colon cancer, the top candidate gene was tested for its association with disease-free survival and a benefit from adjuvant chemotherapy.
Results
The transcription factor CDX2 ranked first in our screening test.
A group of 87 of 2115 tumor samples (4.1%) lacked CDX2 expression.
In the discovery data set, which included 466 patients, the rate of 5-year disease-free survival was lower among the 32 patients (6.9%) with CDX2-negative colon cancers than among the 434 (93.1%) with CDX2-positive colon cancers (hazard ratio for disease recurrence, 3.44; 95% confidence interval [CI], 1.60 to 7.38; P=0.002).
In the validation data set, which included 314 patients, the rate of 5-year disease-free survival was lower among the 38 patients (12.1%) with CDX2 protein–negative colon cancers than among the 276 (87.9%) with CDX2 protein–positive colon cancers (hazard ratio, 2.42; 95% CI, 1.36 to 4.29; P=0.003).
In both these groups, these findings were independent of the patient’s age, sex, and tumor stage and grade. Among patients with stage II cancer, the difference in 5-year disease-free survival was significant both in the discovery data set (49% among 15 patients with CDX2-negative tumors vs. 87% among 191 patients with CDX2-positive tumors, P=0.003) and in the validation data set (51% among 15 patients with CDX2-negative tumors vs. 80% among 106 patients with CDX2-positive tumors, P=0.004). In a pooled database of all patient cohorts, the rate of 5-year disease-free survival was higher among 23 patients with stage II CDX2-negative tumors who were treated with adjuvant chemotherapy than among 25 who were not treated with adjuvant chemotherapy (91% vs. 56%, P=0.006).
Conclusions
Lack of CDX2 expression identified a subgroup of patients with high-risk stage II colon cancer who appeared to benefit from adjuvant chemotherapy. (Funded by the National Comprehensive Cancer Network, the National Institutes of Health, and others.)
CDX2 as a Prognostic Biomarker in Stage II and Stage III Colon Cancer
Piero Dalerba, M.D., Debashis Sahoo, Ph.D., Soonmyung Paik, M.D., Xiangqian Guo, Ph.D., Greg Yothers, Ph.D., Nan Song, Ph.D., Nate Wilcox-Fogel, M.S., Erna Forgó, M.D., Pradeep S. Rajendran, B.S., Stephen P. Miranda, B.A., Shigeo Hisamori, M.D., Ph.D., Jacqueline Hutchison, Tomer Kalisky, Ph.D., Dalong Qian, M.D., Norman Wolmark, M.D., George A. Fisher, M.D., Ph.D., Matt van de Rijn, M.D., Ph.D., and Michael F. Clarke, M.D.
N Engl J Med 2016; 374:211-222January 21, 2016DOI: 10.1056/NEJMoa1506597
Background
The identification of high-risk stage II colon cancers is key to the selection of patients who require adjuvant treatment after surgery. Microarray-based multigene-expression signatures derived from stem cells and progenitor cells hold promise, but they are difficult to use in clinical practice.
Methods
We used a new bioinformatics approach to search for biomarkers of colon epithelial differentiation across gene-expression arrays and then ranked candidate genes according to the availability of clinical-grade diagnostic assays. With the use of subgroup analysis involving independent and retrospective cohorts of patients with stage II or stage III colon cancer, the top candidate gene was tested for its association with disease-free survival and a benefit from adjuvant chemotherapy.
Results
The transcription factor CDX2 ranked first in our screening test.
A group of 87 of 2115 tumor samples (4.1%) lacked CDX2 expression.
In the discovery data set, which included 466 patients, the rate of 5-year disease-free survival was lower among the 32 patients (6.9%) with CDX2-negative colon cancers than among the 434 (93.1%) with CDX2-positive colon cancers (hazard ratio for disease recurrence, 3.44; 95% confidence interval [CI], 1.60 to 7.38; P=0.002).
In the validation data set, which included 314 patients, the rate of 5-year disease-free survival was lower among the 38 patients (12.1%) with CDX2 protein–negative colon cancers than among the 276 (87.9%) with CDX2 protein–positive colon cancers (hazard ratio, 2.42; 95% CI, 1.36 to 4.29; P=0.003).
In both these groups, these findings were independent of the patient’s age, sex, and tumor stage and grade. Among patients with stage II cancer, the difference in 5-year disease-free survival was significant both in the discovery data set (49% among 15 patients with CDX2-negative tumors vs. 87% among 191 patients with CDX2-positive tumors, P=0.003) and in the validation data set (51% among 15 patients with CDX2-negative tumors vs. 80% among 106 patients with CDX2-positive tumors, P=0.004). In a pooled database of all patient cohorts, the rate of 5-year disease-free survival was higher among 23 patients with stage II CDX2-negative tumors who were treated with adjuvant chemotherapy than among 25 who were not treated with adjuvant chemotherapy (91% vs. 56%, P=0.006).
Conclusions
Lack of CDX2 expression identified a subgroup of patients with high-risk stage II colon cancer who appeared to benefit from adjuvant chemotherapy. (Funded by the National Comprehensive Cancer Network, the National Institutes of Health, and others.)
Strategies to reduce the socioeconomic gradient of uptake in the English NHS Bowel Cancer Screening Programme
Effects of evidence-based strategies to reduce the socioeconomic gradient of uptake in the English NHS Bowel Cancer Screening Programme (ASCEND): four cluster-randomised controlled trials
Prof Jane Wardle, PhD*†
, Dr Christian von Wagner, PhD*correspondenceemail , Ines Kralj-Hans, PhD , Stephen P Halloran, FRCPath , Samuel G Smith, PhD , Lesley M McGregor, PhD , Gemma Vart, PhD
, Rosemary Howe, BSc , Julia Snowball, BSc , Graham Handley, PhD , Richard F Logan, FRCP , Sandra Rainbow, PhD , Steve Smith, PhD , Mary C Thomas, MSc , Nicholas
Counsell, MSc , Steve Morris, PhD , Stephen W Duffy, MSc, Allan Hackshaw, MSc, Sue Moss, PhD, Wendy Atkin, PhD, Rosalind Raine, PhD*Joint first authors †Jane Wardle died in October, 2015
Published Online: 08 December 2015
Open Access Article has an altmetric score of 69
DOI: http://dx.doi.org/10.1016/S0140-6736(15)01154-X |
Open access funded by Medical Research Council
showArticle Info
This article can be found in the following collections: Gastrointestinal cancer
Summary
Background
Uptake in the national colorectal cancer screening programme in England varies by socioeconomic status. We assessed four interventions aimed at reducing this gradient, with the intention of improving the health benefits of screening.
Methods
All people eligible for screening (men and women aged 60–74 years) across England were included in four cluster-randomised trials. Randomisation was based on day of invitation.
Each trial compared the standard information with the standard information plus the following supplementary interventions: trial 1 (November, 2012), a supplementary leaflet summarising the gist of the key information; trial 2 (March, 2012), a supplementary narrative leaflet describing people's stories; trial 3 (June, 2013), general practice endorsement of the programme on the invitation letter; and trial 4 (July–August, 2013) an enhanced reminder letter with a banner that reiterated the screening offer.
Socioeconomic status was defined by the Index of Multiple Deprivation score for each home address. The primary outcome was the socioeconomic status gradient in uptake across deprivation quintiles. This study is registered, number ISRCTN74121020.
Findings
As all four trials were embedded in the screening programme, loss to follow-up was minimal (less than 0·5%). Trials 1 (n=163 525) and 2 (n=150 417) showed no effects on the socioeconomic gradient of uptake or overall uptake. Trial 3 (n=265 434) showed no effect on the socioeconomic gradient but was associated with increased overall uptake (adjusted odds ratio [OR] 1·07, 95% CI 1·04–1·10, p<0·0001). In trial 4 (n=168 480) a significant interaction was seen with socioeconomic status gradient (p=0·005), with a stronger effect in the most deprived quintile (adjusted OR 1·11, 95% CI 1·04–1·20, p=0·003) than in the least deprived (1·00, 0·94–1·06, p=0·98). Overall uptake was also increased (1·07, 1·03–1·11, p=0·001).
Interpretation
Of four evidence-based interventions, the enhanced reminder letter reduced the socioeconomic gradient in screening uptake, but further reducing inequalities in screening uptake through written materials alone will be challenging.
Funding
National Institute for Health Research.
Prof Jane Wardle, PhD*†
, Dr Christian von Wagner, PhD*correspondenceemail , Ines Kralj-Hans, PhD , Stephen P Halloran, FRCPath , Samuel G Smith, PhD , Lesley M McGregor, PhD , Gemma Vart, PhD
, Rosemary Howe, BSc , Julia Snowball, BSc , Graham Handley, PhD , Richard F Logan, FRCP , Sandra Rainbow, PhD , Steve Smith, PhD , Mary C Thomas, MSc , Nicholas
Counsell, MSc , Steve Morris, PhD , Stephen W Duffy, MSc, Allan Hackshaw, MSc, Sue Moss, PhD, Wendy Atkin, PhD, Rosalind Raine, PhD*Joint first authors †Jane Wardle died in October, 2015
Published Online: 08 December 2015
Open Access Article has an altmetric score of 69
DOI: http://dx.doi.org/10.1016/S0140-6736(15)01154-X |
Open access funded by Medical Research Council
showArticle Info
This article can be found in the following collections: Gastrointestinal cancer
Summary
Background
Uptake in the national colorectal cancer screening programme in England varies by socioeconomic status. We assessed four interventions aimed at reducing this gradient, with the intention of improving the health benefits of screening.
Methods
All people eligible for screening (men and women aged 60–74 years) across England were included in four cluster-randomised trials. Randomisation was based on day of invitation.
Each trial compared the standard information with the standard information plus the following supplementary interventions: trial 1 (November, 2012), a supplementary leaflet summarising the gist of the key information; trial 2 (March, 2012), a supplementary narrative leaflet describing people's stories; trial 3 (June, 2013), general practice endorsement of the programme on the invitation letter; and trial 4 (July–August, 2013) an enhanced reminder letter with a banner that reiterated the screening offer.
Socioeconomic status was defined by the Index of Multiple Deprivation score for each home address. The primary outcome was the socioeconomic status gradient in uptake across deprivation quintiles. This study is registered, number ISRCTN74121020.
Findings
As all four trials were embedded in the screening programme, loss to follow-up was minimal (less than 0·5%). Trials 1 (n=163 525) and 2 (n=150 417) showed no effects on the socioeconomic gradient of uptake or overall uptake. Trial 3 (n=265 434) showed no effect on the socioeconomic gradient but was associated with increased overall uptake (adjusted odds ratio [OR] 1·07, 95% CI 1·04–1·10, p<0·0001). In trial 4 (n=168 480) a significant interaction was seen with socioeconomic status gradient (p=0·005), with a stronger effect in the most deprived quintile (adjusted OR 1·11, 95% CI 1·04–1·20, p=0·003) than in the least deprived (1·00, 0·94–1·06, p=0·98). Overall uptake was also increased (1·07, 1·03–1·11, p=0·001).
Interpretation
Of four evidence-based interventions, the enhanced reminder letter reduced the socioeconomic gradient in screening uptake, but further reducing inequalities in screening uptake through written materials alone will be challenging.
Funding
National Institute for Health Research.
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