Re: Rethinking neoadjuvant chemotherapy for breast cancer
We wrote this paper because the ever-increasing use of neoadjuvant chemotherapy (NACT) in the management of localised breast cancer is, arguably, proceeding more rapidly than can be justified by the available evidence. For example, a large meta-analysis conducted by the EBCTCG confirmed no overall survival advantage as compared to conventional adjuvant chemotherapy regimens, but an increase in local recurrence rates. Boughey, Benson, Macpherson, Stein and co-authors concur with this important conclusion. We suggest that the risk of higher local recurrence rate, noted in the EBCTCG meta-analysis, may not necessarily be balanced by a material benefit to the patient. Some commentators suggest that this EBCTCG meta-analysis is outdated; however, it does remain - in certain respects - the best and most reliable we have. We are happy to use the results of the EBCTCG meta-analyses of even older trials for most other treatments; why then rubbish this one?
An excellent response to NACT will suggest a better prognosis, which on the face of it is very encouraging. However, on the negative side, more than half the patients will have to bear the psychological stress of living with the cancer in their breast for 4 to 6 months, while suffering the side effects of chemotherapy, and simultaneously bringing forward the news of their poor prognosis. As Macpherson and colleagues point out, such psychological stress often seen by clinicians facing a patient whose tumour may have grown while on NACT has not even been quantified. In fact, this anxiety may well be warranted, as Professor Baum points out, particularly if Boughey, Macpherson, Stein and colleagues' claim were true. If NACT really improved survival in those who have a pCR, then the non-responders must have lowered survival -because the total survival remains unchanged. Can this be justified in routine practice when patient benefit should be the paramount objective? Randomised trials incorporating NACT would need an imaginative design and adhere to the principle 'first-do-no-harm'.
Our other concern is that the NACT experiment does not even serve the altruistic cause of improving cancer treatment for future patients. Boughey, Macpherson, Stein and colleagues place great faith in the model of drug discovery that assumes that if a response in the primary tumour to an experimental drug regimen is associated with a better survival for a particular patient, then that regimen will automatically confer a survival advantage overall, ie for the whole intention to treat group, and therefore such a response could be used to test and allow rapid approval of new drugs.
To put it more clearly, it is true that if a patient achieves a pCR with an experimental drug given as a NACT, she will have a better EFS or even possibly OS compared with a patient given the same drug who does not achieve pCR; ie pCR is positively associated with EFS and OS. However, as randomised evidence shows, it does not follow that any drug that increases pCR will always increase EFS or OS. The association between pCR and EFS/OS does not appear to be a causal association in every case. This had already been demonstrated in the Cortazar overview, which showed very clearly that increasing HR for pCR does not increase the HR for either EFS or OS. We all need to acknowledge this evidence. Furthermore, over the last five years several pairs of randomised trials have confirmed this counterintuitive non-linear relationship.
The novel drugs in these trials (bevacizumab, lapatinib and pertuzumab) [3-9] were of particular interest because they resulted in a dramatic increase in pCR. Naturally, they were thought to be promising - unfortunately, however, they have had no effect on overall survival. See figure 1. http://www.ucl.ac.uk/~rmhkjsv/Rethinking_Neoadjuvant_Chemotherapy_BMJ_20...
This figure shows a sharp contrast between large improvement in pathological complete response in the neoadjuvant setting vs no difference in overall survival in the adjuvant setting.
New drugs therefore cannot be approved for routine use unless proven to improve OS: using NACT as a testbed 'shortcut' model of drug discovery falls short of its objective.
Macpherson and colleagues suggest that there is now a close to perfect pre-treatment viable-tissue marking as opposed to earlier times, when there was no way to 'mark' (ie accurately identify) the tumour. In fact, when we started achieving dramatic clinical responses to neoadjuvant chemotherapy in the 1990s, and surgery was being planned, clips were routinely inserted in the tumour before starting NACT: no different from what is done today. So this criticism made by some of the commentators may not hold water.
Unfortunately, even today, an accurate method to mark viable tumour cells for the surgeon to accurately excise is yet to be conceived, let alone employed. The usual procedure today is to place a 1-2mm clip somewhere in the tumour mass. This clip does not always stay in the same place, nor do the live tumour cells magically collect around this clip. So conceptually, surgical precision is difficult or even impossible- which is what we meant by 'difficult' - because there is no way to know what exactly needs to be excised. The difficulty is the uncertainty about what to remove and where to cut rather than an inability to wield a knife or knowing how to cut. After NACT, the surgeon attempting to conserve the breast is truly blind and cannot see the viable tumour cells that he/she is supposed to excise. This difficulty is apparent only if the surgeon honestly recognises the discrepancy between the goal (to remove viable cancer cells) and the actual physical procedure (removing a portion of tissue around a clip placed 5 months before, which may bear no physical relationship to the viable cancer cells). In contrast, it is much 'easier' to feel the tumour or view it reliably on imaging, when it is still a concentrated mass of viable cancer cells in the breast before it has been softened and disintegrated by NACT. The pathological examination of the excised specimen and its margin is also much simpler, unless of course every patient were to have a mastectomy after NACT. If the greatest increase in local recurrence is seen in those undergoing 'no surgery' then inadequate surgery might be expected to have a smaller but still detrimental effect.
Macpherson and colleagues suggest that NACT could allow less extensive surgery in the axilla. However, there is no randomised evidence that can support either such ability or its safety and efficacy. If we take a clue from the results of inadequate surgery in the breast, then leaving previously involved nodes behind should leave a risk of higher axillary recurrence. Until the results of randomised trials are available, it should not be used as justification for routine clinical practice.
Using NACT for patients waiting for their BRCA gene test result would seem logical, but they need to be cautioned about the possibility of harm if they don't respond. Furthermore, the large POSH study  clearly found that the outcome of treatment of young women with breast cancer was similar whether they had a deleterious BRCA gene mutation or not. So knowing the BRCA status would not improve outcome.
Macpherson and colleagues present a scenario in which women undergoing immediate reconstruction following mastectomy have a higher risk of local complications compared with mastectomy alone, suggesting that NACT might have prevented a delay in giving chemotherapy in such patients. This may seem logical. However, firstly, immediate breast reconstruction is an evidence free zone - there is little randomised evidence demonstrating its safety or benefit in terms of patient satisfaction[11, 12] and there are good studies suggesting evidence and mechanisms of harm[13, 14]. The higher risk of complications could also delay radiotherapy. So if the evidence of detriment of delay in starting adjuvant therapy is clear, then it needs to be balanced with the evidence (or lack) of benefit from immediate reconstruction to make an informed choice in partnership with the patient.
One attractive purpose of using NACT stems from the fact that unlike adjuvant therapy, a response in the primary tumour is directly measurable. Therefore, if it becomes clear that a particular drug regimen is not effective (no pCR), then theoretically, the treatment could be switched to a different drug. Unfortunately, no trial has found that addition of another new drug improves survival differentially between those with or without ypCR. For example, CREATE-X trial  which recruited patients with triple negative cancers who had residual disease after NACT, found that capecitabine improved survival compared with placebo. However, even in those with no residual disease (ypCR), 20% died at 5 years and 40% at 8 years, and capecitabine could have improved their survival too, given that capecitabine improves survival in an adjuvant setting anyway.
Thus, NACT has yet to be shown to help in adjusting drug regimens and the 'pivot & adjust' strategy (RCT of 'pivot and adjust' vs control) remains to be proven to improve overall survival, even in the iSPY trials.
Stein et al invoke the well known fact that breast cancer is not one disease: this is true between patients, as well as within a single patient. The prospect of individualising treatment according to biological subtype is very attractive, but unfortunately, randomised evidence suggests that the biology of primary tumour is an unreliable surrogate for biology of distant disease. Therefore, approval or rejection of drugs based on clinical trials whose outcomes are solely based on response to NACT cannot be justified. Stein et al also suggest that surgery could be potentially omitted in certain patients - that would indeed be wonderful. However, all randomised trials in early breast cancer have consistently shown that omitting or delaying surgery is likely to have detrimental effect on patients.
There are two serious and new therapeutic concerns that should also be considered.
Accumulating evidence indicates that chemotherapy evokes a host repair response, during which bone marrow-derived cells (BMDCs) infiltrate the primary tumour microenvironment and facilitate neoangiogenesis and tumor regrowth. This elegant study has shown that through such BMDC recruitment, NACT induces breast cancer metastasis through a tumour microenvironment of metastasis (TMEM) -mediated mechanism. Therefore, despite decreasing tumour size, NACT may increase cancer cell dissemination and induce a more aggressive tumour phenotype with increased risk of metastatic dissemination. We may use novel drugs that mitigate this effect, but we are yet to show that they have a clinical benefit. Until then, clinicians and patients should be aware of this potential detrimental effect.
It also needs to be recognised that cancer cells within an individual patient undergo continuous evolution  and while designing new therapies, this should be taken into account. So by giving NACT, we might potentially significantly increase the evolutionary pressure on the cancer and stimulate it to evolve more rapidly while still in situ.
In the absence of randomised evidence of clear patient benefit, the only justifiable indication for NACT outside clinical trials at present appears to be for locally advanced inoperable cancers needing local control, where surgery (eg mastectomy) could be rendered possible by giving effective NACT.
A less clear indication is to allow a more conservative surgery - but, as pointed out by Prof John Benson and colleagues, this happens in a small proportion of cases, and perhaps surprisingly, 75% of patients see no change in their surgical treatment. Furthermore, the local recurrence rate is higher for the whole cohort, with no heterogeneity between those who were initially planned to have mastectomy or breast conservation (EBCTCG) suggesting that giving NACT increases local recurrence in those who would have otherwise been offered breast conservation at the outset anyway.
Until randomised evidence using newer and 'more promising' drugs, comparing their use in the neoadjuvant vs adjuvant setting, demonstrates a substantial benefit in terms of reducing mastectomy rates, this latter rationale needs to be used with extreme caution. Importantly, such trials will need to demonstrate that there is no detriment in the subset that does not initially respond. Patients need to be told the rate ratio of 1.28 (64.9% vs 49% absolute) for increase in breast conservation alongside the rate ratio of 1.37 (15.3% vs 11.4% absolute) for increase in local recurrence. We should find a way of explaining this in an easy-to-understand message. These differences may be lower in modern patients: in the large retrospective analysis, which Macpherson and colleagues cite, the difference in breast preservation between neoadjuvant and adjuvant therapy above a tumour size of 3cm was at most 10% (see figure 2), with a much larger reverse effect for smaller tumours, similar to that seen in the EBCTCG meta-analysis, suggesting that a patient initially suitable for breast conservation has an increased chance of mastectomy (rising from 40% to 60%) if they have NACT. This unwelcome finding seems clearly supported by Figure 2 taken from a particularly large study. Blue line adjuvant, Red line neoadjuvant http://www.journalacs.org/cms/attachment/2031353968/2048429280/gr1_lrg.jpg
[ also available at – but not in the submitted response -
This figure shows how the chances of having mastectomy greatly increases when NACT is given to tumours less than 3cm in size. Above 3cm, the mastectomy rate is reduced by at most 10% for any particular size of the tumour. The majority still cannot preserve the breast.
We are pleased that our paper has sparked such lively discussion on this complex topic. Many important points have been raised. Stein et al conclude their letter by suggesting that "the direction of travel is clear", but from the wide variety of views expressed, it seems equally clear that many would disagree.
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Competing interests: No competing interests