Dynamics of breast-cancer relapse reveal late-recurring ER-positive genomic subgroups.

The rates and routes of lethal systemic spread in breast cancer are poorly understood owing to a lack of molecularly characterized patient cohorts with long-term, detailed follow-up data. Long-term follow-up is especially important for those with oestrogen-receptor (ER)-positive breast cancers, which can recur up to two decades after initial diagnosis1-6. It is therefore essential to identify patients who have a high risk of late relapse7-9. Here we present a statistical framework that models distinct disease stages (locoregional recurrence, distant recurrence, breast-cancer-related death and death from other causes) and competing risks of mortality from breast cancer, while yielding individual risk-of-recurrence predictions. We apply this model to 3,240 patients with breast cancer, including 1,980 for whom molecular data are available, and delineate spatiotemporal patterns of relapse across different categories of molecular information (namely immunohistochemical subtypes; PAM50 subtypes, which are based on gene-expression patterns10,11; and integrative or IntClust subtypes, which are based on patterns of genomic copy-number alterations and gene expression12,13). We identify four late-recurring integrative subtypes, comprising about one quarter (26%) of tumours that are both positive for ER and negative for human epidermal growth factor receptor 2, each with characteristic tumour-driving alterations in genomic copy number and a high risk of recurrence (mean 47-62%) up to 20 years after diagnosis. We also define a subgroup of triple-negative breast cancers in which cancer rarely recurs after five years, and a separate subgroup in which patients remain at risk. Use of the integrative subtypes improves the prediction of late, distant relapse beyond what is possible with clinical covariates (nodal status, tumour size, tumour grade and immunohistochemical subtype). These findings highlight opportunities for improved patient stratification and biomarker-driven clinical trials.

Association of travel time, patient characteristics, and hospital quality with patient mobility for breast cancer surgery: A national population-based study.

BACKGROUND: This national study investigated hospital quality and patient factors associated with treatment location for breast cancer surgery. METHODS: By using linked administrative data sets from the English National Health Service, the authors identified all women diagnosed between January 2, 2016, and December 31, 2018, who underwent breast-conserving surgery (BCS) or a mastectomy with or without immediate breast reconstruction. The extent to which patients bypassed their nearest hospital was investigated using a geographic information system (ArcGIS). Conditional logistic regressions were used to estimate the impact of travel time, hospital quality, and patient characteristics. RESULTS: 22,622 Of 69,153 patients undergoing BCS, 22,622 (32.7%) bypassed their nearest hospital; and, of 23,536 patients undergoing mastectomy, 7179 (30.5%) bypassed their nearest hospital. Women who were younger, without comorbidities, or from rural areas were more likely to travel to more distant hospitals (p < .05). Patients undergoing BCS (odds ratio [OR], 1.85; 95% confidence interval [CI], 1.36-2.50) or mastectomy (OR, 1.52; 95% CI, 1.14-2.02) were more likely to be treated at specialist breast reconstruction centers despite not undergoing the procedure. Patients receiving mastectomy and immediate breast reconstruction were more likely to travel to hospitals employing surgeons who had a media reputation (OR, 2.41; 95% CI, 1.28-4.52). Patients undergoing BCS were less likely to travel to hospitals with shorter surgical waiting times (OR, 0.65; 95% CI, 0.46-0.92). The authors did not observe a significant impact for research activity, hospital quality rating, breast re-excision rates, or the status as a multidisciplinary cancer center. CONCLUSIONS: Patient choice policies may drive inequalities in the health care system without improving patient outcomes.

Transforming post pandemic cancer services.

This paper outlines the impact of the COVID-19 pandemic on cancer services in the UK including screening, symptomatic diagnosis, treatment pathways and projections on clinical outcomes as a result of these care disruptions. A restoration of cancer services to pre-pandemic levels is not likely to mitigate this adverse impact, particularly with an ageing population and increased cancer burden. New cancer cases are projected to rise to over 500,000 per year by 2035, with over 4 million people living with and beyond cancer. This paper calls for a strategic transformation to prioritise effort on the basis of available datasets and evidence-in particular, to prioritise cancers where an earlier diagnosis is feasible and clinically useful with a focus on mortality benefit by preventing emergency presentations by harnessing data and analytics. This could be delivered by a focus on underperforming groups/areas to try and reduce inequity, linking near real-time datasets with clinical decision support systems at the primary and secondary care levels, promoting the use of novel technologies to improve patient uptake of services, screening and diagnosis, and finally, upskilling and cross-skilling healthcare workers to expand supply of diagnostic and screening services.

Future cancer risk after urgent suspected cancer referral in England when cancer is not found: a national cohort study.

BACKGROUND: Following referral for investigation of urgent suspected cancer within the English National Health Service referral system, 7% of referred individuals are diagnosed with cancer. This study aimed to investigate the risk of cancer occurrence within 1-5 years of finding no cancer following an urgent suspected cancer referral. METHODS: This national cohort study used urgent suspected cancer referral data for England from the Cancer Waiting Times dataset and linked it with cancer diagnosis data from the National Cancer Registration dataset. Data were extracted for the eight most commonly referred to urgent suspected cancer referral pathways (breast, gynaecological, head and neck, lower and upper gastrointestinal, lung, skin, and urological) for the period April 1, 2013, to March 31, 2014, with 5-year follow-up for individuals with no cancer diagnosis within 1 year of referral. The primary objective was to investigate the occurrence and type of subsequent cancer in years 1-5 following an urgent suspected cancer referral when no cancer was initially found, both overall and for each of the eight referral pathways. The numbers of subsequent cancers were compared with expected cancer incidence in years 1-5 following referral, using standardised incidence ratios (SIRs) based on matched age-gender distributions of expected cancer incidence in England for the same time period. The analysis was repeated, stratifying by referral group, and by calculating the absolute and expected rate of all cancers and of the same individual cancer as the initial referral. FINDINGS: Among 1·18 million referrals without a cancer diagnosis in years 0-1, there were 63 112 subsequent cancers diagnosed 1-5 years post-referral, giving an absolute rate of 1338 (95% CI 1327-1348) cancers per 100 000 referrals per year (1038 [1027-1050] in females, 1888 [1867-1909] in males), compared with an expected rate of 1054 (1045-1064) cancers per 100 000 referrals per year (SIR 1·27 [95% CI 1·26-1·28]). The absolute rate of any subsequent cancer diagnosis 1-5 years after referral was lowest following suspected breast cancer referral (746 [728-763] cancers per 100 000 referrals per year) and highest following suspected urological (2110 [2070-2150]) or lung cancer (1835 [1767-1906]) referral. For diagnosis of the same cancer as the initial referral pathway, the highest absolute rates were for the urological and lung pathways (1011 [984-1039] and 638 [598-680] cancers per 100 000 referrals per year, respectively). The highest relative risks of subsequent diagnosis of the same cancer as the initial referral pathway were for the head and neck pathway (SIR 3·49 [95% CI 3·22-3·78]) and lung pathway (3·00 [2·82-3·20]). INTERPRETATION: Cancer risk was higher than expected in the 5 years following an urgent suspected cancer referral. The potential for targeted interventions, such as proactive monitoring, safety-netting, and cancer awareness or risk reduction initiatives should be investigated. FUNDING: Cancer Research UK.

The International Collaboration for Research methods Development in Oncology (CReDO) workshops: shaping the future of global oncology research.

Low-income and middle-income countries (LMICs) have a disproportionately high burden of cancer and cancer mortality. The unique barriers to optimum cancer care in these regions necessitate context-specific research. The conduct of research in LMICs has several challenges, not least of which is a paucity of formal training in research methods. Building capacity by training early career researchers is essential to improve research output and cancer outcomes in LMICs. The International Collaboration for Research methods Development in Oncology (CReDO) workshop is an initiative by the Tata Memorial Centre and the National Cancer Grid of India to address gaps in research training and increase capacity in oncology research. Since 2015, there have been five CReDO workshops, which have trained more than 250 oncologists from India and other countries in clinical research methods and protocol development. Participants from all oncology and allied fields were represented at these workshops. Protocols developed included clinical trials, comparative effectiveness studies, health services research, and observational studies, and many of these protocols were particularly relevant to cancer management in LMICs. A follow-up of these participants in 2020 elicited an 88% response rate and showed that 42% of participants had made progress with their CReDO protocols, and 73% had initiated other research protocols and published papers. In this Policy Review, we describe the challenges to research in LMICs, as well as the evolution, structure, and impact of CReDO and other similar workshops on global oncology research.

The impact of the COVID-19 pandemic on cancer deaths due to delays in diagnosis in England, UK: a national, population-based, modelling study.

BACKGROUND: Since a national lockdown was introduced across the UK in March, 2020, in response to the COVID-19 pandemic, cancer screening has been suspended, routine diagnostic work deferred, and only urgent symptomatic cases prioritised for diagnostic intervention. In this study, we estimated the impact of delays in diagnosis on cancer survival outcomes in four major tumour types. METHODS: In this national population-based modelling study, we used linked English National Health Service (NHS) cancer registration and hospital administrative datasets for patients aged 15-84 years, diagnosed with breast, colorectal, and oesophageal cancer between Jan 1, 2010, and Dec 31, 2010, with follow-up data until Dec 31, 2014, and diagnosed with lung cancer between Jan 1, 2012, and Dec 31, 2012, with follow-up data until Dec 31, 2015. We use a routes-to-diagnosis framework to estimate the impact of diagnostic delays over a 12-month period from the commencement of physical distancing measures, on March 16, 2020, up to 1, 3, and 5 years after diagnosis. To model the subsequent impact of diagnostic delays on survival, we reallocated patients who were on screening and routine referral pathways to urgent and emergency pathways that are associated with more advanced stage of disease at diagnosis. We considered three reallocation scenarios representing the best to worst case scenarios and reflect actual changes in the diagnostic pathway being seen in the NHS, as of March 16, 2020, and estimated the impact on net survival at 1, 3, and 5 years after diagnosis to calculate the additional deaths that can be attributed to cancer, and the total years of life lost (YLLs) compared with pre-pandemic data. FINDINGS: We collected data for 32 583 patients with breast cancer, 24 975 with colorectal cancer, 6744 with oesophageal cancer, and 29 305 with lung cancer. Across the three different scenarios, compared with pre-pandemic figures, we estimate a 7·9-9·6% increase in the number of deaths due to breast cancer up to year 5 after diagnosis, corresponding to between 281 (95% CI 266-295) and 344 (329-358) additional deaths. For colorectal cancer, we estimate 1445 (1392-1591) to 1563 (1534-1592) additional deaths, a 15·3-16·6% increase; for lung cancer, 1235 (1220-1254) to 1372 (1343-1401) additional deaths, a 4·8-5·3% increase; and for oesophageal cancer, 330 (324-335) to 342 (336-348) additional deaths, 5·8-6·0% increase up to 5 years after diagnosis. For these four tumour types, these data correspond with 3291-3621 additional deaths across the scenarios within 5 years. The total additional YLLs across these cancers is estimated to be 59 204-63 229 years. INTERPRETATION: Substantial increases in the number of avoidable cancer deaths in England are to be expected as a result of diagnostic delays due to the COVID-19 pandemic in the UK. Urgent policy interventions are necessary, particularly the need to manage the backlog within routine diagnostic services to mitigate the expected impact of the COVID-19 pandemic on patients with cancer. FUNDING: UK Research and Innovation Economic and Social Research Council.

Increases in arm volume predict lymphoedema and quality of life deficits after axillary surgery: a prospective cohort study.

BACKGROUND: Lymphoedema develops after axillary clearance (ANC) in 25% of patients. This prospective, multi-centre study compared multi-frequency bioimpedance spectroscopy (BIS) with arm volume measurement to: (1) determine which test has better diagnostic accuracy, (2) identify factors predicting development of lymphoedema, and its effect on quality-of-life. METHODS: Participants (N = 1100) underwent measurements pre and post-ANC surgery for breast cancer. Relative arm volume increase (RAVI) of >10% diagnosed lymphoedema. Predictors of lymphoedema were determined using logistic regression. Optimal diagnostic method was assessed using diagnostic accuracy. Quality-of-life was assessed using the FACT B + 4 questionnaire. RESULTS: Lymphoedema was diagnosed in 22.8% women using RAVI > 10%, 45.6% using BIS criteria, while 24.5% underwent compression sleeve application by 24 months. BMI > 30 was an independent factor for both development (p = 0.005) and progression (p = 0.015) of lymphoedema. RAVI at 1 month, BMI > 30 and number of involved nodes contributed to a novel scoring model to predict lymphoedema by 36 months. Larger decreases in QoL scores post-surgery occurred in lymphoedema patients (p < 0.001). Progression to moderate lymphoedema occurred in 15% patients after sleeve application. CONCLUSIONS: RAVI measurement was the best diagnostic tool for lymphoedema. BIS alone is not appropriate for lymphoedema screening or diagnosis. BMI > 30 predicted lymphoedema diagnosis and progression.

Current status of human papillomavirus vaccination in India's cervical cancer prevention efforts.

Efforts are being made to scale up human papillomavirus (HPV) vaccination for adolescent girls in India. Bivalent and quadrivalent HPV vaccines were licensed in the country in 2008, and a nonavalent vaccine was licensed in 2018. Demonstration projects initiated in Andhra Pradesh and Gujarat in 2009 introduced HPV vaccination in public health services in India. Following a few deaths in these projects, although subsequently deemed unrelated to vaccination, HPV vaccination in research projects was suspended. This suspension by default resulted in some participants in a trial evaluating two versus three doses receiving only one dose. Since 2016, the successful introduction of HPV vaccination in immunisation programmes in Punjab and Sikkim (with high coverage and safety), government-sponsored opportunistic vaccination in Delhi, prospects of a single dose providing protection, and future availability of an affordable Indian vaccine shows promise for future widespread implementation and evaluation of HPV vaccination in India.

Developing institutions for cancer care in low-income and middle-income countries: from cancer units to comprehensive cancer centres.

Global cancer centres operate across different sizes, scales, and ecosystems. Understanding the essential aspects of the creation, organisation, accreditation, and activities within these settings is crucial for developing an affordable, equitable, and quality cancer care, research, and education system. Robust guidelines are scarce for cancer units, cancer centres, and comprehensive cancer centres in low-income and middle-income countries. However, some robust examples of the delivery of complex cancer care in centres in emerging economies are available. Although it is impossible to create an optimal system to fit the unique needs of all countries for the delivery of cancer care, we summarise what has been published about the development and management of cancer centres in low-income and middle-income countries so far and highlight the need for clinical and political leadership.

The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups.

The elucidation of breast cancer subgroups and their molecular drivers requires integrated views of the genome and transcriptome from representative numbers of patients. We present an integrated analysis of copy number and gene expression in a discovery and validation set of 997 and 995 primary breast tumours, respectively, with long-term clinical follow-up. Inherited variants (copy number variants and single nucleotide polymorphisms) and acquired somatic copy number aberrations (CNAs) were associated with expression in ~40% of genes, with the landscape dominated by cis- and trans-acting CNAs. By delineating expression outlier genes driven in cis by CNAs, we identified putative cancer genes, including deletions in PPP2R2A, MTAP and MAP2K4. Unsupervised analysis of paired DNA­RNA profiles revealed novel subgroups with distinct clinical outcomes, which reproduced in the validation cohort. These include a high-risk, oestrogen-receptor-positive 11q13/14 cis-acting subgroup and a favourable prognosis subgroup devoid of CNAs. Trans-acting aberration hotspots were found to modulate subgroup-specific gene networks, including a TCR deletion-mediated adaptive immune response in the 'CNA-devoid' subgroup and a basal-specific chromosome 5 deletion-associated mitotic network. Our results provide a novel molecular stratification of the breast cancer population, derived from the impact of somatic CNAs on the transcriptome.

Effect of patient choice and hospital competition on service configuration and technology adoption within cancer surgery: a national, population-based study.

BACKGROUND: There is a scarcity of evidence about the role of patient choice and hospital competition policies on surgical cancer services. Previous evidence has shown that patients are prepared to bypass their nearest cancer centre to receive surgery at more distant centres that better meet their needs. In this national, population-based study we investigated the effect of patient mobility and hospital competition on service configuration and technology adoption in the National Health Service (NHS) in England, using prostate cancer surgery as a model. METHODS: We mapped all patients in England who underwent radical prostatectomy between Jan 1, 2010, and Dec 31, 2014, according to place of residence and treatment location. For each radical prostatectomy centre we analysed the effect of hospital competition (measured by use of a spatial competition index [SCI], with a score of 0 indicating weakest competition and 1 indicating strongest competition) and the effect of being an established robotic radical prostatectomy centre at the start of 2010 on net gains or losses of patients (difference between number of patients treated in a centre and number expected based on their residence), and the likelihood of closing their radical prostatectomy service. FINDINGS: Between Jan 1, 2010, and Dec 31, 2014, 19 256 patients underwent radical prostatectomy at an NHS provider in England. Of the 65 radical prostatectomy centres open at the start of the study period, 23 (35%) had a statistically significant net gain of patients during 2010-14. Ten (40%) of these 23 were established robotic centres. 37 (57%) of the 65 centres had a significant net loss of patients, of which two (5%) were established robotic centres and ten (27%) closed their radical prostatectomy service during the study period. Radical prostatectomy centres that closed were more likely to be located in areas with stronger competition (highest SCI quartile [0·87-0·92]; p=0·0081) than in areas with weaker competition. No robotic surgery centre closed irrespective of the size of net losses of patients. The number of centres performing robotic surgery increased from 12 (18%) of the 65 centres at the beginning of 2010 to 39 (71%) of 55 centres open at the end of 2014. INTERPRETATION: Competitive factors, in addition to policies advocating centralisation and the requirement to do minimum numbers of surgical procedures, have contributed to large-scale investment in equipment for robotic surgery without evidence of superior outcomes and contributed to the closure of cancer surgery units. If quality performance and outcome indicators are not available to guide patient choice, these policies could threaten health services' ability to deliver equitable and affordable cancer care. FUNDING: National Institute for Health Research.

Gene expression modules in primary breast cancers as risk factors for organotropic patterns of first metastatic spread: a case control study.

BACKGROUND: Metastases from primary breast cancers can involve single or multiple organs at metastatic disease diagnosis. Molecular risk factors for particular patterns of metastastic spread in a clinical population are limited. METHODS: A case-control design including 1357 primary breast cancers was used to study three distinct clinical patterns of metastasis, which occur within the first six months of metastatic disease: bone and visceral metasynchronous spread, bone-only, and visceral-only metastasis. Whole-genome expression profiles were obtained using whole genome (WG)-DASL assays from formalin-fixed paraffin-embedded (FFPE) samples. A systematic protocol was developed for handling FFPE samples together with stringent data quality controls to identify robust expression profiling data. A panel of published and novel gene sets were tested for association with these specific patterns of metastatic spread and odds ratios (ORs) were calculated. RESULTS: Metasynchronous metastasis to bone and viscera was found in all intrinsic breast cancer subtypes, while immunohistochemically (IHC)-defined receptor status and specific IntClust subgroups were risk factors for visceral-only or bone-only first metastases. Among gene modules, those related to proliferation increased the risk of metasynchronous metastasis (OR (95% CI) = 2.3 (1.1-4.8)) and visceral-only first metastasis (OR (95% CI) = 2.5 (1.2-5.1)) but not bone-only metastasis (OR (95% CI) = 0.97 (0.56-1.7)). A 21-gene module (BV) was identified in estrogen-receptor-positive breast cancers with metasynchronous metastasis to bone and viscera (area under the curve = 0.77), and its expression increased the risk of bone and visceral metasynchronous spread in this population. BV was further orthogonally validated with NanoString nCounter in primary breast cancers, and was reproducible in their matched lymph nodes metastases and an external cohort. CONCLUSION: This case-control study of WG-DASL global expression profiles from FFPE tumour samples, after careful quality control and RNA selection, revealed that gene modules in the primary tumour have differing risks for clinical patterns of metasynchronous first metastases. Moreover, a novel gene module was identified as a putative risk factor for metasynchronous bone and visceral first metastatic spread, with potential implications for disease monitoring and treatment planning.

Progression of breast cancer following locoregional ipsilateral recurrence: importance of interval time.

BACKGROUND: Studies comparing prognosis of breast cancer (BC) patients with and without locoregional recurrence (LR) present conflicting results. We aimed to improve our understanding of the impact of LR on prognosis by examining a large cohort of patients treated at Guy's and St Thomas' NHS Foundation Trust. METHODS: Risk factors associated with BC-specific death were investigated using Cox proportional hazards regression in 5199 women diagnosed between 1975 and 2007. Breast cancer-specific death following LR was assessed with Poisson regression. RESULTS: Overall, 552 women (11%) developed LR, with a median follow-up time of 4.28 years. Known factors associated with BC-specific death (tumour stage, grade, and nodal status) were of significance in our data. Women with a shorter disease-free interval had a worse prognosis. For instance, the HR for BC-specific death among women undergoing mastectomy with an LR 0.5-1 year after diagnosis of their primary tumour was 6.67 (95% CI: 3.71-11.99), when compared with women who did not experience LR. CONCLUSIONS: It often remains difficult to distinguish between a genuine LR and a new primary. The HRs for risk of BC-specific death following a second lesion suggest that they may act as a marker of systemic disease, large tumour burden, or depleted host defence. The clinically highly relevant impairment in prognosis calls for further research into the underlying mechanisms. We showed that for at least 15 years of follow-up, the prognosis in women following the occurrence of an LR may benefit from careful diagnostic and therapeutic management.

Short-term breast cancer survival in relation to ethnicity, stage, grade and receptor status: national cohort study in England.

BACKGROUND: In the re-organisation of cancer registration in England in 2012, a high priority was given to the recording of cancer stage and other prognostic clinical data items. METHODS: We extracted 86 852 breast cancer records for women resident in England and diagnosed during 2012-2013. Information on age, ethnicity, socio-economic status, comorbidity, tumour stage, grade, morphology and oestrogen, progesterone and HER2 receptor status was included. The two-year cumulative risk of death from any cause was estimated with the Kaplan-Meier method, and univariate and multivariate Cox proportional hazards regressions were used to estimate hazard ratios (HR) and their 95% confidence intervals (95% CI). The follow-up ended on 31 December 2014. RESULTS: The completeness of registration for prognostic variables was generally high (around 80% or higher), but it was low for progesterone receptor status (41%). Women with negative receptor status for each of the oestrogen, progesterone and HER2 receptors (triple-negative cancers) had an adjusted HR for death of 2.00 (95%CI 1.84-2.17). Black women had an age-adjusted HR of 1.77 (1.48-2.13) compared with White women. CONCLUSIONS: The excess mortality of Black women with breast cancer has contributions from socio-economic factors, stage distribution and tumour biology. The study illustrates the richness of detail in the national cancer registration data. This allows for analysis of cancer outcomes at a high level of resolution, and may form the basis for risk stratification.

Global cancer surgery: delivering safe, affordable, and timely cancer surgery.

Surgery is essential for global cancer care in all resource settings. Of the 15.2 million new cases of cancer in 2015, over 80% of cases will need surgery, some several times. By 2030, we estimate that annually 45 million surgical procedures will be needed worldwide. Yet, less than 25% of patients with cancer worldwide actually get safe, affordable, or timely surgery. This Commission on global cancer surgery, building on Global Surgery 2030, has examined the state of global cancer surgery through an analysis of the burden of surgical disease and breadth of cancer surgery, economics and financing, factors for strengthening surgical systems for cancer with multiple-country studies, the research agenda, and the political factors that frame policy making in this area. We found wide equity and economic gaps in global cancer surgery. Many patients throughout the world do not have access to cancer surgery, and the failure to train more cancer surgeons and strengthen systems could result in as much as US $6.2 trillion in lost cumulative gross domestic product by 2030. Many of the key adjunct treatment modalities for cancer surgery--e.g., pathology and imaging--are also inadequate. Our analysis identified substantial issues, but also highlights solutions and innovations. Issues of access, a paucity of investment in public surgical systems, low investment in research, and training and education gaps are remarkably widespread. Solutions include better regulated public systems, international partnerships, super-centralisation of surgical services, novel surgical clinical trials, and new approaches to improve quality and scale up cancer surgical systems through education and training. Our key messages are directed at many global stakeholders, but the central message is that to deliver safe, affordable, and timely cancer surgery to all, surgery must be at the heart of global and national cancer control planning.

Comparison of multi-frequency bioimpedance with perometry for the early detection and intervention of lymphoedema after axillary node clearance for breast cancer.

The importance of early detection of lymphoedema by arm volume measurements before surgery and repeated measurements after surgery in women undergoing axillary node clearance (ANC) in order to enable early intervention is recognised. A prospective multi-centre study was performed which studied the difference between multi-frequency bioimpedance electrical analysis (BIS) and perometer arm measurement in predicting the development of lymphoedema. Women undergoing ANC underwent pre-operative and regular post-operative measurements of arm volume by both methods. The primary endpoint is the incidence of lymphoedema (≥10 % arm volume increase compared to contralateral arm by perometer) at 2 and 5 years after ANC. The threshold for intervention in lymphoedema was also assessed. Out of 964 patients recruited, 612 had minimum 6 months follow-up data. Using 1-month post-operative measurements as baseline, perometer detected 31 patients with lymphoedema by 6 months (BIS detected 53). By 6 months, 89 % of those with no lymphoedema reported at least one symptom. There was moderate correlation between perometer and BIS at 3 months (r = 0.40) and 6 months (r = 0.60), with a sensitivity of 73 % and specificity of 84 %. Univariate and multivariate analyses revealed a threshold for early intervention of ≥5 to <10 % (p = 0.03). Threshold for early intervention to prevent progression to lymphoedema is ≥5 to <10 % but symptoms alone do not predict lymphoedema. The modest correlation between methods at 6 months indicates arm volume measurements remain gold standard, although longer term follow-up is required.

Novel techniques for sentinel lymph node biopsy in breast cancer: a systematic review.

The existing standard for axillary lymph node staging in breast cancer patients with a clinically and radiologically normal axilla is sentinel lymph node biopsy with a radioisotope and blue dye (dual technique). The dependence on radioisotopes means that uptake of the procedure is limited to only about 60% of eligible patients in developed countries and is negligible elsewhere. We did a systematic review to assess three techniques for sentinel lymph node biopsy that are not radioisotope dependent or that refine the existing method: indocyanine green fluorescence, contrast-enhanced ultrasound using microbubbles, and superparamagnetic iron oxide nanoparticles. Our systematic review suggested that these new methods for sentinel lymph node biopsy have clinical potential but give high levels of false-negative results. We could not identify any technique that challenged the existing standard procedure. Further assessment of these techniques against the standard dual technique in randomised trials is needed.

Delivery of affordable and equitable cancer care in India.

The delivery of affordable and equitable cancer care is one of India's greatest public health challenges. Public expenditure on cancer in India remains below US$10 per person (compared with more than US$100 per person in high-income countries), and overall public expenditure on health care is still only slightly above 1% of gross domestic product. Out-of-pocket payments, which account for more than three-quarters of cancer expenditures in India, are one of the greatest threats to patients and families, and a cancer diagnosis is increasingly responsible for catastrophic expenditures that negatively affect not only the patient but also the welfare and education of several generations of their family. We explore the complex nature of cancer care systems across India, from state to government levels, and address the crucial issues of infrastructure, manpower shortages, and the pressing need to develop cross-state solutions to prevention and early detection of cancer, in addition to governance of the largely unregulated private sector and the cost of new technologies and drugs. We discuss the role of public insurance schemes, the need to develop new political mandates and authority to set priorities, the necessity to greatly improve the quality of care, and the drive to understand and deliver cost-effective cancer care programmes.

The growing burden of cancer in India: epidemiology and social context.

Cancer can have profound social and economic consequences for people in India, often leading to family impoverishment and societal inequity. Reported age-adjusted incidence rates for cancer are still quite low in the demographically young country. Slightly more than 1 million new cases of cancer are diagnosed every year in a population of 1.2 billion. In age-adjusted terms this represents a combined male and female incidence of about a quarter of that recorded in western Europe. However, an estimated 600,000-700,000 deaths in India were caused by cancer in 2012. In age-standardised terms this figure is close to the mortality burden seen in high-income countries. Such figures are partly indicative of low rates of early-stage detection and poor treatment outcomes. Many cancer cases in India are associated with tobacco use, infections, and other avoidable causes. Social factors, especially inequalities, are major determinants of India's cancer burden, with poorer people more likely to die from cancer before the age of 70 years than those who are more affluent. In this first of three papers, we examine the complex epidemiology of cancer, the future burden, and the dominant sociopolitical themes relating to cancer in India.

Cancer research in India: national priorities, global results.

Over the past 20 years, cancer research in India has grown in size and impact. Clinicians, scientists, and government and state policy makers in India have championed cancer research, from studies to achieve low-tech, large-scale health outcomes to some of the most advanced areas of fundamental cancer science. In this paper, we frame public policy discussions about cancer with use of an in-depth analysis of research publications from India. Cancer research in India is a complex environment that needs to balance public policy across many competing agendas. We identify major needs across these environments such as those for increased research capacity and training and protected time for clinical researchers; for more support from states and enhanced collaborative funding programmes from government; for development of national infrastructures across a range of domains (ie, clinical trials, tissue banking, registries, etc); and for a streamlined and rational regulatory environment. We also discuss improvements that should be made to translate research into improvements in cancer outcomes and public health.