Adverse events should be reported. Reporting forms and information can be found at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store. Adverse events should also be reported to Roche Products Ltd. Please contact Roche Drug Safety Centre by emailing email@example.com or calling +44 (0)1707 367554.
Tailoring Treatment for Patients with HER2-positive Early Breast Cancer
In 2020, Roche launched the virtual Future Positive Lite meeting series, an alternative learning experience to our flagship Future Positive meeting. These interactive meetings aim to bring together the UK breast cancer community to share expertise, knowledge and solutions in the ever-changing treatment landscape of breast cancer.
To support your continuing professional education, we are pleased to share recordings of the CPD® accredited meetings within the Future Positive Lite series.* Once you have watched the video recording in full, a link to download your CPD® accredited certificate will appear at the end of the video.
CPD® accreditation for this meeting was certified by the CPD® Certification Service.*
The first virtual meeting in the Future Positive Lite series discussed tailoring treatment for patients with HER2-positive early breast cancer (eBC). This meeting was chaired by Dr Julie Doughty (Consultant Breast Surgeon, Gartnavel General Hospital, Glasgow) and Dr Judy King (Consultant Medical Oncologist, The Royal Free Hospital, London), and included the following presentations:
- Professor Sarah Pinder (Professor of Breast Pathology, King's College London, London) discussed pathological evaluation before and after neoadjuvant treatment in eBC and explained how this information can be used to make personalised treatment decisions. Start time: 5 min 30 s. Duration: 14 min 1 s
- Dr David Miles (Consultant Medical Oncologist, Mount Vernon Cancer Centre, Middlesex) explored the objectives and benefits of neoadjuvant treatment, and explained how the use of neoadjuvant therapy provides an opportunity to adapt adjuvant treatment selection in the eBC setting. Start time: 19 min 33 s. Duration: 16 min 32 s
- Dr Duncan Wheatley (Consultant Clinical Oncologist, Royal Cornwall Hospital, Truro) presented the key efficacy and safety results from the Phase III KATHERINE trial and described the positioning of adjuvant Kadcyla® (trastuzumab emtansine) in the HER2-positive eBC treatment pathway. Start time: 36 min 5 s. Duration: 11 min 25 s
Question and Answer Session
Following the three presentations, our co-chairs facilitated a virtual Q&A with the delegates. The questions submitted by the audience and the speaker responses are shown below.
Questions and Answers
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.
Kadcyla (trastuzumab emtansine) Access Guidance in Early Breast Cancer**
National Institute for Health and Care Excellence (NICE) recommendation
Kadcyla is recommended, within its marketing authorisation, as an option for the adjuvant treatment of HER2-positive eBC in adults who have residual invasive disease, in the breast or lymph nodes, after neoadjuvant taxane-based and HER2-targeted therapy.†10,11
Scottish Medicines Consortium (SMC) recommendation
Kadcyla is accepted, as a single agent, for the adjuvant treatment of adult patients with HER2-positive eBC who have residual invasive disease, in the breast and/or lymph nodes, after neoadjuvant taxane-based and HER2-targeted therapy.§11,12
- Hariri N et al. Appl Immunohistochem Mol Morphol 2019;27:1‒7.
- Gahlaut R et al. Eur J Cancer 2016;60:40‒48.
- Kuehn T et al. The Lancet 2013;14:609‒618.
- King T et al. SABCS 2017. PL3.
- NICE. Guideline: Early and Locally Advanced Breast Cancer NG101. 2018.
- Trastuzumab Emtansine. NHS National Cancer Drugs Fund List. Available at: https://www.england.nhs.uk/wp-content/uploads/2017/04/National-Cancer-Drugs-Fund-List_ver1.194_-02112021_MASTER.pdf. Last accessed: 9th November 2021.
- von Minckwitz G et al. N Engl J Med 2019;380:617–628.
- von Minckwitz G et al. N Engl J Med 2019;380:617–628. Supplementary Appendix.
- Kadcyla Prescribing Information. Available at: http://www.roche-images.co.uk/pi/Kadcyla_BC.pdf. Last accessed: 9th November 2021.
- NICE. Technology Appraisal Guidance TA632. 2020
- Kadcyla Summary of Product Characteristics
- SMC. SMC2298. 2020
Date of preparation: November 2021