Authors' second response Re: Rethinking neoadjuvant chemotherapy for breast cancer
Here is a considered response mainly to statements that were factually inaccurate, internally inconsistent or unsubstantiated by evidence. Many of the points raised had already been covered in detail previously.
1. The EBCTCG meta-analysis offered three main results comparing neoadjuvant chemotherapy (NACT) with adjuvant chemotherapy (ACT): a) small increase in local recurrence with NACT, b) no difference in survival, c) small increase in breast conservation rate with NACT. We suggest that those objecting to our paper seem to have disregarded the first result whilst inappropriately emphasising the second point and exaggerating the third.
The EBCTCG meta-analysis did not include randomised trials of HER2-directed therapies comparing NACT vs ACT: but there aren’t any. A meta-analysis of randomised trials comparing NACT regimens with or without HER2-targeted therapies found that trastuzumab improved pathological response rates, but there was no improvement in breast conservation rate (Risk Ratio 0.98, 95% CI: 0.80-1.19, p-value 0.82)1. So HER2-directed therapy does not help the case for using NACT to improve breast conservation.
A large contemporary study2 of the effect NACT on breast conservation included over 350,000 patients treated between 2006 to 2011 and found that it improved this rate by at most 10%. Remarkably, when tumours were <= 3 cm, the mastectomy rate was higher if NACT was given. A meeting abstract about a retrospective series of 47 patients treated over 2 years in which 23 patients out of 37 had breast conservation, with no comparator group, is inadequate proof of the contrary.
The statement that ‘few patients do not respond to chemotherapy’ ignores the fact that such response is often incomplete. For example, in the NeoSphere trial, the pCR rates (breast and axilla) with dual HER2-blockade were: ER-positive 11/50 (22%), ER-negative 31/57 (54.4%) and overall 42/107 (39.5%) (personal communication from Dr Gianni and Dr Valagussa)3. So even in the best-case scenario, nearly half of the patients still had residual cancer after completing NACT.
2. Bearing this in mind, a woman’s understandable stress of living with the cancer intact whilst undergoing NACT can hardly be regarded as irrational. To say that this is “manageable” is entirely unfounded since there is lack of comparative data about this very important issue. One small study of 84 patients in which depression as assessed with HADS score, found that while no patient had depression before the NACT, 41.6% were found to have depression after NACT, and it was much more marked (71%) in those who did not respond to NACT4. This further underscores the key importance of the initial patient consent discussion.
3. As regards the marker clip, it is important to reiterate that viable cancer cells do not magically gather near, or shrink concentrically around, the clip. Therefore, resection of tissue around the clip amounts to only a poorly guided surgical excision.
4. We reiterate that there is no randomised clinical trial evidence to support the oncological safety or benefit of the potential reduction in axillary surgery by use of NACT.
5. The fact that pertuzumab has a licence for use only the neoadjuvant setting should never be the reason for promoting the use of NACT. The relevant NICE guidance suggesting this as an option has been overtaken by new evidence: Pertuzumab is now proven to have no survival benefit even in an adjuvant setting.
6. We were genuinely shocked by the unequivocal claim by Dixon et al that “MDTs are poor at assimilating response data and making the correct decision”. Many active and expert members of MDTs around the world might feel that this is contemptuous, ill-judged and offensive. A well run MDT with its multiple inputs and skills is surely in the best position to offer thoughtful advice to each individual patient, tailored to her specific needs and concerns.
In principle, when NACT is being offered, patients should be made aware of a number of important points. Most importantly, NACT does not improve survival and that there is a 50-80% (tailored as per the tumour type) chance of residual cancer at the end of the 4-6 months’ of treatment. They need to understand that the only clear-cut benefit of NACT is for patients whose cancer is so large that breast conservation is technically not possible, and in which case NACT may allow a smaller surgical excision. While considering this benefit, they need to understand the trade-off between the 10-15% improvement in chance of breast conservation and a 3-15% increase local recurrence. They need to recognise that when breast conservation is possible at the outset (e.g. tumours less than 3cm), NACT may even increase the chance of needing a mastectomy. In a proportion of patients (depending on the tumour type), the tumour will not respond or even progress, and this could have a significant psychological impact. Finally, they should be offered an equally effective option of initial surgery that can eradicate the cancer in the breast and axilla right away. These explanations are necessary even when NACT is being offered as part of an ethically approved clinical trial.
As clinicians and scientists, when well-being and lives of vulnerable patients are at stake, we must preserve an open mind and recognize that inconvenient new evidence may well challenge our current recommendations, perhaps requiring a significant alteration in our therapeutic approach.
1. Valachis A, Mauri D, Polyzos NP, et al. Trastuzumab combined to neoadjuvant chemotherapy in patients with HER2-positive breast cancer: a systematic review and meta-analysis. Breast 2011;20(6):485-90. doi: 10.1016/j.breast.2011.06.009
2. Killelea BK, Yang VQ, Mougalian S, et al. Neoadjuvant chemotherapy for breast cancer increases the rate of breast conservation: results from the National Cancer Database. Journal of the American College of Surgeons 2015;220(6):1063-9. doi: 10.1016/j.jamcollsurg.2015.02.011
3. Gianni L, Pienkowski T, Im Y-H, et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. The lancet oncology 2012;13(1):25-32. doi: 10.1016/s1470-2045(11)70336-9
4. Chintamani, Gogne A, Khandelwal R, et al. The correlation of anxiety and depression levels with response to neoadjuvant chemotherapy in patients with breast cancer. JRSM Short Rep 2011;2(3):15. doi: 10.1258/shorts.2010.010072
Competing interests: No competing interests