Effect of screening by clinical breast examination on breast cancer incidence and mortality after 20 years: prospective, cluster randomised controlled trial in Mumbai
BMJ 2021; 372 doi: https://doi.org/10.1136/bmj.n256 (Published 24 February 2021) Cite this as: BMJ 2021;372:n256Linked Opinion
The story of the Mumbai breast screening study
All rapid responses
Dear Editor
The results of the Mumbai breast cancer mortality study should be considered with caution.
Mittra et al. performed 3 tests to reach their conclusion (the test planned in the protocol on all women regardless of age and the 2 post-hoc tests for women younger than 50 and women aged 50 and older). As a result, the significance threshold should have been adjusted due to these multiple tests. With 3 tests, a significance threshold of 0.0167 is required in order to keep the Type I error less than or equal to 0.05. With this adjusted threshold, the decrease in breast cancer mortality observed in the subgroup of women aged 50 and older is no longer statistically significant.
Further studies are therefore needed before concluding that screening by clinical breast examination is effective in reducing mortality from breast cancer.
Competing interests: No competing interests
Dear Editor,
We are not often so vividly brought to confront and feel what practising Medicine and research is like in third-world places as we were by the report [1] and Opinion piece [2] in the BMJ online of 25th February 2021.
What is Medicine for? Why do doctors practice Medicine? Has the age-old reason `to help people` gone, or does it still drive some of today`s doctors? That we all have to die sometimes seems to be an unacceptable truth in many Western cultures, as `affecting mortality` so often seems to take precedence over `affecting morbidity` in the prevention, research and practice we see here today. `Saving lives` at all costs can so often result in years of increasing and sometimes extreme morbidity, but is so often applauded. Preventable death, and dying before one`s time, are quite different matters. Life is precious, each life is unique, but preserving life `at all costs` is one example of the way that Medicine in the `western world` has lost its way, [3] from cradle (neonates) to grave (with multi-morbidities and incapacities). Prevention methods have become excessive, `finding it early` [4][5] to the point of using minutiae [6] the stated aim.
Relieving suffering amongst the world`s millions of poor and disadvantaged, who die well before their three-score years-and-ten from disease, exhaustion and poverty in the low- and middle-income areas of the world, is less fashionable and so often out of sight and out of mind in more affluent places. The coronavirus pandemic has brought the well-off up close and personal to the reality of premature death, to people who forget that that is the norm for many who live in the slums of Mumbai and other similar places over the globe. This example of care and compassion, the persistence and passion to find low cost means to prevent the horror of palpable and visible breast cancer, demonstrate to me that `helping people` as a motivation for practicing Medicine is alive and well. There are many lessons to be learned from the history [1] and practice [2] of this cluster randomised trial undertaken in the shadow of the Tata Memorial Hospital in Mumbai to determine the effect of screening by clinical breast examination on breast cancer incidence and mortality. It has already brought great benefit in India. [7] The dedication of the doctors and the trained female primary care workers who showed tenacity and compassion (as well as curiosity in their research question), going into those slums to give care to these disadvantaged people is one such that we should bear in mind as we Westerners expend huge resources, both human and financial, on saving lives at all costs, in population screening programmes which bring more (iatrogenic) harm than benefit.
Prioritising health care, prioritising order for vaccination in this pandemic, currently preoccupy the thoughts (and media!) of the whole population. A painful experience for everyone. May lessons be learned from it as we struggle to `think global` and then, hopefully, to `act global`. May we come to learn to thoroughly observe what is happening, not just from the data [8] but from the experience of doing such research; find the route to practising better, more just Medicine through showing concern for all our fellow-travellers.
[1] Mittra I. The Story of the Mumbai breast screening study. BMJ Opinion, 25th February 2021. https://blogs.bmj.com/bmj/2021/02/24/the-story-of-the-mumbai-breast-scre...
[2] Mittra I, Mishra GA, Dikshit RP, Gupta S, Kukami V, et al. Effect of screening by clinical breast examination on breast cancer incidence and mortality after 20 years: prospective, cluster randomised controlled trial in Mumbai. BMJ 2021;372:n256
https://www.bmj.com/content/372/bmj.n256
[3] Richard Smith: The most devastating critique of medicine since Medical Nemesis by Ivan Illich in 1975. February 13, 2019. BMJ Opinion piece. https://blogs.bmj.com/bmj/2019/02/13/richard-smith-most-devastating-crit...
[4] Michael Baum rapid response to [2]
[5] Thornton H. Randomised clinical trials: the patient`s point of view. In `Ductal Carcinoma in Situ of the Breast`s. Ed: Melvin J. Silverstein. Williams and Williams. 1997. Page 434.
[6] Ismail Jatoi rapid response to [2]
[7] Manus P. Roy rapid response to [2]
[8] Greenhalgh T, Howick J, Maskrey N. Evidence based medicine: a movement in crisis?
BMJ 2014; 348 doi: https://doi.org/10.1136/bmj.g3725 (Published 13 June 2014) BMJ 2014;348:g3725 https://www.bmj.com/content/348/bmj.g3725
Competing interests: No competing interests
Dear Editor
Steven Narod finds that several of the outcomes of the Mumbai trial are surprising. Careful reading of the scientific literature indicates that they are not.
« 1) The 20-year cumulative mortality from breast cancer was about the same in women under age 50 and over age 50, a far different situation from what see in Canada where older women are more likely to die of breast cancer. »
Explanation: Radiation-induced cancers explains the difference between North America and India, as radiation from medical exposure is a major driver in the incidence of breast cancer (1). Radiation-induced cancers from medical exposure are likely to change the age distribution of cancer, similarly to what is observed with mammography screening (2).
2) « In the under 50 group there were more cancers identified in the screening arm than the control arm (432 versus 389) whereas in the over 50 group there were fewer cancers identified in the screening arm than the control arm (167 versus 193) (table 2). »
Explanation: A slightly different age distribution in screened and control groups (supplementary Table 1) explains the difference. This does not change the conclusion of the study.
3) « the mortality benefit from CBE over the entire study population was most pronounced for reducing deaths which occurred ten or more years after randomization in women aged over 50 (figure 2). If the benefit were to come from a down-staging of locally-advanced breast cancers (stage III/IV) (table 2) would we not expect to see the benefit accrue earlier on? »
Explanation: The benefit of down staging is probably earlier, but it may be masked by early surgery in some cancers, where it could accelerate the appearance of metastases (3).
It is possible now to have a complete picture of the effect of screening and of radiation from imaging on breast cancer incidence and mortality. We just need to integrate all the data.
1) Gofman JW. Preventing Breast Cancer: The Story of a Major, Proven, Preventable Cause of this Disease: (2nd ed). San Francisco: Committee for Nuclear Responsibility, ISBN 0-932682-96-0., 1996.
2) Corcos D, Bleyer A. Epidemiologic signatures in cancer. N Engl J Med 2020; 382(1):96-97.
3) Baum M, Demicheli R, Hrushesky W, Retsky M. Does surgery unfavourably perturb the “natural history” of early breast cancer by accelerating the appearance of distant metastases? European Journal of Cancer 2005; 4: 508-515.
Competing interests: No competing interests
Dear Editor,
I am very pleased to see the results of the Mumbai trial published, and congratulate Indraneel Mittra and his colleagues for their achievements in bringing this trial to a conclusive conclusion.
As the authors point out, this trial complements the results of the Canadian National Breast Screening Study, demonstrating the value of well-conducted breast examinations in reducing mortality from breast cancer.
It is particularly important that these results should come from India, as they provide an example that other countries can follow.
Competing interests: No competing interests
Dear Editor
The article by Mittra and colleagues is very interesting. [1] With 10% share of the all cancers, breast cancer is the most common cancer in India. [2] In order to diagnose the cases at an earlier stage, a population based screening aimed at common Non-Communicable Diseases (NCDs), including breast cancer, was launched in 2017 in the country. The strategy aims to educate its first line health workers (Accredited Social Health Activists/ Auxillary Nurse Midwives) in screening cancers in all women above 30 years of age and refer them to nearest health centres, if suspected. Besides, the activities at the grass root level will increase acceptability of breast self-examination among the community. Referral chain will ensure mammography in all indicated cases. Apart from that, the activity will also focus on raising health awareness among common people. [3] Till 4.12.2020, more than 19.5 million screenings for breast cancer in women have been done through 50,927 Health and Wellness Centres, the unit for providing Comprehensive Primary Health Care across the country. [4]
National Programme for Prevention and Control of Cancer, Diabetes, Cardiovascular Diseases and Stroke, India’s flagship program for NCDs, gives much importance to information, education and communication activities at every level of health care to help the community come forward to make this screening a success. To highlight the importance of screening, there is plan for using local gathering as a platform for publicity. On a fixed day at Village level, the frontline health workers would screen women for breast cancer. Festive gathering will be used to highlight the importance of the screening. Keeping a special focus to reach the marginalized, the initiative is expected to ensure early detection, bring suspected cases to hospital in a treatable condition and avoid complications as well as mortality. Link to accessible high quality treatment at affordable costs, regular follow up and management are envisaged to give this intervention an extra edge and may yield high dividend in the battle against breast cancer in the long run.
References
1. Mittra I, Mishra GA, Dikshit RP, Gupta S, Kukami V, et al. Effect of screening by clinical breast examination on breast cancer incidence and mortality after 20 years: prospective, cluster randomised controlled trial in Mumbai. BMJ 2021;372:n256
https://www.bmj.com/content/372/bmj.n256
2. National Cancer Registry Programme (2016) Three-year report of population based cancer registries: 2012-2014, Chapter-10 Trends over time for all sites and on selected sites of cancer and projection of burden of cancer. Indian Council of Medical Research. New Delhi.
3. Directorate General of Health Services. National Program for Prevention and Control of Cancer, Diabetes, Cardiovascular Diseases and Stroke: Training module for medical officers for prevention, control and population level screening of hypertension, diabetes and common cancers (oral, breast and cervical). New Delhi: Ministry of Health & Family Welfare, 2017.
4. Ministry of Health and Family Welfare. 2020-21 Annual Report. New Delhi. Ministry of Health & Family Welfare, 2021.
Competing interests: No competing interests
Dear Editor
Mittra and colleagues have written an intriguing piece on the outcomes of clinical breast examination screening in Mumbai India. I enjoyed reading this paper as well as the other responses. Several of the outcomes are surprising. First, the 20-year cumulative mortality from breast cancer was about the same in women under age 50 and over age 50, a far different situation from what see in Canada where older women are more likely to die of breast cancer. This emphasizes the need to discover effective interventions for young women in India.
Second, In the under 50 group there were more cancers identified in the screening arm than the control arm (432 versus 389) whereas in the over 50 group there were fewer cancers identified in the screening arm than the control arm (167 versus 193) (table 2).
Third, the mortality benefit from CBE over the entire study population was most pronounced for reducing deaths which occurred ten or more years after randomization in women aged over 50 (figure 2). If the benefit were to come from a down-staging of locally-advanced breast cancers (stage III/IV) (table 2) would we not expect to see the benefit accrue earlier on?
The data suggests that most of the benefit from CBE derives from preventing deaths from women in their seventies and eighties. The ages of death for women in the young cohort would range from age 35 to 70 and the ages of death in the older cohort would range from age 51 to 83. This raises questions about tumor dormancy and the natural history of breast cancer. I would very much like to see a table where the 464 deaths from breast cancer were broken down by age of death in the screening arm and the control arm.
Competing interests: No competing interests
Dear Editor,
Indraneel Mittra and his colleagues are to be congratulated for completing a 20 year follow up of a trial of more than 150,000 women from the slums of Mumbai. Already snide comments on social media have dismissed the study as not relevant to the wealthy countries in which they live. Such critics need to be reminded that the majority of clinically detected breast cancers in the world arise in conditions akin to the slums of Mumbai. Furthermore, as one of the few surviving specialists working in this field more than 50 years ago, I can remember seeing many stage III/IV breasts’ cancers presenting at diagnosis and the horrid consequences of uncontrolled breast cancer on the chest wall that impaired the quality of life amongst those poor women predetermined to die from their disease.
This study is of great importance for two reasons, firstly, to let us judge whether clinical breast cancer examination (CBE) should be used as an affordable method of screening for breast cancer in low- and middle-income countries and, secondly, what it teaches us about the natural history of the disease.
Many of your readers will recognise that I am a screening sceptic and that in 2013 I published a paper in the BMJ suggesting that screening by mammography was a zero-sum game because the harms of over-diagnosis balanced the advantages of “early diagnosis”. [1]
Note that I put early diagnosis in inverted commas. That’s because what is central to our understanding of this controversy is the nature of “early”. Effectively mammography screening trials are comparing sub-clinical v clinical detection of breast cancer. We have learnt to our cost that up to 50% of these occult lesions are over-diagnosed and therefore over-treated and suffer from the toxicity of fruitless treatment. [2]
CBE is very different in that it identifies those cases that were predetermined to progress to clinical detected breast cancers where the outcome can now be determined both by the biology of the cancer and its chronology. Sure, there are breast cancers that are clinically apparent but are indolent in their behaviour and that might account for the excess of cancers detected by CBE compared with controls (198 v 151) in the short term, but the trial is not testing incidence of breast cancers in the first 10 years but cause specific mortality in the long term. They estimate that the lead time before the incidence of breast cancers catch up in the control arm is 16 months, so the question is whether this relatively short “chronological” advantage leads to a reduction in mortality. Overall, the reduction in cause-specific mortality is 15% and not statistically significant but for post hoc subgroup over the age of 50 that number rises to 30% that reaches statistical significance.
Personally, I would judge that as adequate justification for introducing CBE is the slums and favelas of the third world but here I’m influenced not so much by mortality but quality of life. There was a 10% difference in the incidence of stage III/IV breast cancer between all age groups that is likely to lead to difference in the incidence of uncontrolled advanced breast cancer on the chest wall at the time of death. Therefore, before we make final decisions, I would like to see those observations published in a companion paper as soon as possible.
[1] Harms from breast cancer screening outweigh benefits if death caused by treatment is included. BMJ 2013; 346: f385
[2] Bleyer A, Welch HG. Effect of three decades of screening mammography on breast-cancer incidence. N Engl J Med 2012;367: 1998-2005.
Competing interests: No competing interests
Dear Editor:
Mittra et al assessed the efficacy of screening clinical breast examination (CBE) in reducing breast cancer-specific mortality in Mumbai, and their results are consistent with those from the older mammography screening trials, demonstrating an age-interaction with respect to the efficacy of breast cancer screening (1) (2). Specifically, the mortality benefit of breast cancer screening seems to be largely confined to women aged 50 and older, with little or no benefit for women below age 50.
However, the Canadian National Breast Screening Study (CNBSS), demonstrated no mortality benefit from mammography screening when women aged 50 and older were randomized to screening mammography + screening CBE versus screening CBE alone, and the results of that trial might be interpreted to mean that screening mammography provides no additional mortality benefit beyond that which can be achieved by screening CBE alone(3). Clearly, over-diagnosis is a major concern with screening mammography, and much less so with screening CBE, and the risk of over-diagnosis will increase with use of more modern screening technology (i.e., tomosynthesis, magnetic resonance imaging), which increases the detection rates of more occult (non-palpable) cancers (4).
Taken together, the results of the Mumbai trial and the CNBSS suggest that a clinical trial randomizing women aged 50 and older to screening mammography versus screening CBE is now warranted. If such a trial demonstrates that there is no added benefit to mammography screening beyond that achievable with screening CBE, then screening CBE should replace screening mammography as the optimal breast cancer screening method.
1. Mittra I, Mishra GA, Dikshit RP, Gupta S, Kulkarni VY, et al. Effect of screening clinical breast examination on breast cancer incidence and mortality after 20 years: prospective, cluster randomized controlled trial in Mumbai. British Medical Journal, 2021
2. Kerlikowske K, Grady D, Rubin SM, Sandrock C, Ernster VL. Efficacy of screening mammography. A meta-analysis. JAMA. 1995;273(2):149-54.
3. Miller AB, Wall C, Baines CJ, Sun P, To T, Narod SA. Twenty five year follow-up for breast cancer incidence and mortality of the Canadian National Breast Screening Study: randomised screening trial. BMJ. 2014;348:g366.
4. Jatoi I, Pinsky PF. Breast Cancer Screening Trials: Endpoints and Over-diagnosis. J Natl Cancer Inst. 2020.
Competing interests: No competing interests
Dear Editor,
We have patiently waited for 20 years to see the results of this cluster randomised controlled trial in Mumbai, presenting the results of the effect of screening on breast cancer incidence and mortality [1]: they were worth waiting for. The thoughtful, meticulous and painstaking activity to produce this evidence is a model of tenacity, the outcomes useful to guide practice, especially in low- and middle-income countries. Its remarkable genesis and history are told by its lead author, Professor Neel Mittra. https://blogs.bmj.com/bmj/2021/02/24/the-story-of-the-mumbai-breast-scre... [2]
Much has happened in the intervening twenty years since the question was asked `Would clinical breast examination be an acceptable alternative to mammographic screening`? [3] Systematic reviews have been produced; treatments have improved; imaging has advanced; means of communication have increased; better information for prospective participants, including the mention of harms, has been forthcoming at least in western cultures. The public here is better informed; citizens are contributing more to the debate about the acceptability of mammographic screening. But, in that time, the poor have become poorer; the rich have become richer. We must now think globally.
In the last year, a pandemic and environmental issues have resulted in recognition that the time has come to re-evaluate how we should be using resources of every kind to achieve a more effective and just distribution. I would suggest that the oft-repeated desire today of `returning to normal` is not the best aim. Rather, we should use this time to decide what is necessary and needed as opposed to what is excessive to the benefit of all humankind, for all inhabitants of this planet earth, rich and poor alike, and make necessary changes.
A good time, in the light of this new evidence to act to avoid the wastage of resources, and iatrogenic harms, that population screening by mammography has produced. As was advocated back in 2000 [3], we can now, with confidence, `shift the diagnosis by screening to that point in the spectrum of presentation that will cost least both in human and financial terms` for a large proportion of women. Furthermore, as advocated, `a change to clinical breast examination would reduce the unnecessary detection of indolent, non-invasive cancers – thus restricting activity in outlying, expensive, non-productive areas of screening and focusing on the centre of the window of opportunity`. The costs, distress, fear and misunderstanding generated by the considerable proportion of women currently diagnosed with DCIS (ductal carcinoma in situ) would then be much reduced. Use of clinical breast examination for population screening also reduces the rates of biopsy of benign lumps, of mutilating unnecessary mastectomies and other futile procedures that are the painful consequences of overdiagnosis which occurs when screening is done by mammography.
The authors conclude by suggesting that clinical breast cancer screening should be considered for use in low- and middle-income countries where, in some cases, efforts are being made to introduce screening by mammography. Therefore, there is potential for a huge number of women to be affected by decisions being made by authorities about how screening programmes will be offered. Countries` economies worldwide have been dealt a severe blow by the coronavirus pandemic. Every country`s health budget is affected; many countries will face shrinking health budgets. Screening by clinical breast examination could more widely become the preferred option, especially when taking into account the reduction in morbidities that women would have to suffer.
[1] Mittra I, Mishra GA, Dikshit RP, Gupta S, Kukami V, et al. Effect of screening by clinical breast examination on breast cancer incidence and mortality after 20 years: prospective, cluster randomised controlled trial in Mumbai. BMJ 2021;372:n256
https://www.bmj.com/content/372/bmj.n256
[2] Mittra I. The Story of the Mumbai breast screening study. BMJ Opinion, 25th February 2021. https://blogs.bmj.com/bmj/2021/02/24/the-story-of-the-mumbai-breast-scre...
[3] Mittra I, Baum M. Thornton H, Houghton J. Is clinical breast examination an acceptable alternative to mammographic screening. BMJ 2000;321:107-3, doi:10:1136/bmj.321.7268.1071
Competing interests: No competing interests
Re: Effect of screening by clinical breast examination on breast cancer incidence and mortality after 20 years: prospective, cluster randomised controlled trial in Mumbai
Dear Editor
In the past two decades, several trials have concluded that breast cancer screening for women between the ages of 50 and 69 years can reduce the rate of death from breast cancer by approximately 25% (1). Nevertheless, the role of mammography and other screening tools in breast cancer are still debated, chiefly because of concern regarding methodologic and procedural drawbacks of most randomized trials.
In this context, Mittra et al need to be complimented for doing a prospective, randomized controlled trial on the effect of screening by clinical breast examination (CBE) on breast cancer incidence and mortality(2). In the context of developing nations, the trial brings forth crucial in-house evidence related to an increasing health problem. This is further so, since this trial investigates and presents a cheap and readily available means for breast cancer screening.
However, some of the findings of the study need further introspection. A 30% reduction in mortality in women > 50 years is a promising outcome of the study. Why the strategy of CBE combined with awareness worked well only for women > 50 years needs further answers. Akin to mammography, it is possible that as the suppleness of breast increases with age, the sensitivity/specificity of CBE increases as well (3) ? In the same vein, women < 50 years of age who attended all four rounds of screening benefitted significantly from mortality reduction, likely because younger women risked a higher chance of getting the lump missed in CBE, if subjected to fewer rounds(4).
The increase in breast cancer mortality in the early years of screening has always been a controversial topic and has once again been brought up by this study. There is some evidence that connects increased CTC’s to the process of surgery (5). Is it the act of detection of cancer or an act of surgery that is leading to this increase in mortality? This is a question that begs answers in appropriately designed trials in future.
References
1. Duffy SW, Vulkan D, Cuckle H, Parmar D, Sheikh S, Smith RA, Evans A, Blyuss O, Johns L, Ellis IO, Myles J, Sasieni PD, Moss SM. Effect of mammographic screening from age 40 years on breast cancer mortality (UK Age trial): final results of a randomised, controlled trial. Lancet Oncol. 2020 ;21:1165-1172
2. Mittra I, Mishra GA, Dikshit RP, Gupta S, Kulkarni VY, Shaikh HKA et al Effect of screening by clinical breast examination on breast cancer incidence and mortality after 20 years: prospective, cluster randomised controlled trial in Mumbai. BMJ. 2021 Feb 24;372:n256.
3. Kerlikowske K, Grady D, Barclay J, Sickles EA, Ernster V. Effect of age, breast density, and family history on the sensitivity of first screening mammography. JAMA. 1996;276:33-8
4. Chen TH, Yen AM, Fann JC, Gordon P, Chen SL, Chiu SY et al Clarifying the debate on population-based screening for breast cancer with mammography: A systematic review of randomized controlled trials on mammography with Bayesian meta-analysis and causal model. Medicine (Baltimore). 2017;96:e5684
5. Li, S., Yan, W., Yang, X. Chen L, Fan L, Liu HKun Liu, Less micrometastatic risk related to circulating tumor cells after endoscopic breast cancer surgery compared to open surgery. BMC Cancer 2019;19:1070
Competing interests: No competing interests