The responses provided here are the opinions of the speakers.

Do you routinely repeat pathological assessment of receptors in residual invasive disease after neoadjuvant therapy?

Professor Sarah Pinder: At present there are no guidelines that recommend repeat testing of receptors after neoadjuvant chemotherapy and we do not do this as routine. There is evidence that in some cases receptors may differ from the pre-treatment core biopsy.¹ In a single UK centre series, 12% (16/133) of (non-pathologic complete response [pCR]) cases changed oestrogen receptor (ER) status (approximately half from negative to positive) and 7.1% changed HER2 status overall.² However, in only approximately 1% of these patients was this a change from HER2-negative to HER2-positive disease.² In summary, the answer is ‘not at the present’, but worth thinking about if the original disease was receptor-negative.

As a pathologist, do you recommend that we use residual cancer burden (RCB) for pathological examination after neoadjuvant therapy?

Professor Sarah Pinder: Pathologists need to provide some assessment of the degree of response to neoadjuvant therapy. I report RCB score and give RCB class, partly because it is required in several clinical trials (and we never know which patients are in the relevant trials where it will be needed) and because it is more difficult to assess retrospectively. There is no real evidence that it is superior to other published systems for defining the degree of response to neoadjuvant chemotherapy, as there are no good head-to-head comparisons of it with other methods. However, I personally believe it is the method with the most evidence behind it and suspect there is no going back.

I would add, that, in my opinion, although it may at first appear complex and time-consuming, in practice it only involves estimating the cellularity and the tumour in two dimensions (rather than one) and measurement of the largest node metastasis (which we actually do anyway). Conversely, I would not recommend it (or any other scoring method) as mandatory if not being requested/used by the clinicians – we have enough other work to do in pathology without providing unused pieces of information in our histopathology reports.

Do you have a preference between pre- and post-neoadjuvant sentinel lymph node (SLN) assessment?

Dr Julie Doughty: For me, SLN biopsy in patients who are node-negative at presentation should be performed after neoadjuvant chemotherapy.

Why do I not do upfront SLN biopsy in patients who are node-negative? The SENTINA trial (a prospective, multicentre cohort study) demonstrated that re-doing a SLN biopsy is not an option due to a low identification rate and high false negative rate (FNR).³ If the upfront SLN is positive, you are committing the patient to a subsequent axillary clearance.

If the patient had neoadjuvant chemotherapy and had a complete response, the patient would avoid axillary clearance if the SLN biopsy was completed following neoadjuvant chemotherapy.

The identification rate and FNR is similar in node-negative patients regardless of whether the SLN biopsy is completed before or after neoadjuvant chemotherapy.⁴ The FNR is similar in patients who undergo SLN biopsy at the time of primary surgery prior to adjuvant therapy and we all accept this.

The identification rate is lower and FNR higher in patients who are node-positive at presentation and then have a SLN biopsy following neoadjuvant chemotherapy. This is why in these patients we use dual technique for SLN biopsy, which involves taking at least three nodes, and if possible, clipping the positive node.^4,5 All of these measures reduce the FNR.

Would you suggest to pause treatment whilst we wait for surgical results? Does this risk needing to reload Perjeta^® (pertuzumab)-trastuzumab if a pCR is not achieved?

Dr Judy King: There is no need to pause treatment. The Cancer Drugs Fund (CDF) allows patients to receive one cycle of dual antibody treatment post-surgery to allow time for histology review.⁶

Dr David Miles: The practical issue here is the timing of initiating Kadcyla. According to the CDF, patients must not have had more than one cycle of dual-antibody treatment post-surgery, before switching. The time to get pathology results back can sometimes cause delays here.⁶

Dr Duncan Wheatley: I would usually wait until the pathology results are back and I have seen the patient before starting any treatments, especially since the results from the KATHERINE trial.

For a small residual focus of 1 mm (T1a), would you suggest we switch to Kadcyla?

Dr Duncan Wheatley: I would always discuss it. The highest risk patients are those who were higher stage pre-neoadjuvant treatment and who had a bigger residual cancer burden. However, even those with 1 mm/ low volume residual invasive disease had a higher risk of recurrence which was lowered by Kadcyla.⁷ If a patient was really struggling with toxicity, you can always re-discuss the pros and cons.

Do you recommend pausing adjuvant Kadcyla when giving adjuvant radiotherapy?

Dr Duncan Wheatley: I would usually give the radiotherapy first. For most patients the wait will be just one week now, or three for some node-positive patients requiring an additional field. The rates of pneumonitis were higher with Kadcyla and there are always concerns regarding marrow suppression and increased acute toxicity if given concurrently.⁷ I have not heard of any cases of radiation recall with Kadcyla.

Is an echocardiogram or MUGA assessment required when a patient is receiving Kadcyla?

Dr Duncan Wheatley: It was done in the study and is standard practice on any HER2 therapy.^5,8,9 I expect with time we will gradually do less as we get more real-life data, as long as it shows very low cardiac toxicity.

Should all patients with residual invasive disease be offered 14 cycles of Kadcyla, or can we reduce number of cycles based on the amount of residual invasive disease?

Dr Duncan Wheatley: All patients received 14 cycles unless stopped due to toxicity or patient choice.^7,8 Therefore, no data exist on a shortened schedule. However, if Kadcyla treatment needs to stop due to toxicity this is another issue and I would switch to trastuzumab if they had received under a year. It is tempting and plausible to think that a small amount of residual invasive disease needs little, and large residual invasive disease needs lots but we do not know.