HER2-positive breast cancer

About 20% of the 3300 New Zealanders diagnosed with breast cancer each year will have HER2-positive breast cancer.

HER2 stands for 'human epidermal growth factor receptor-type 2'. It is a type of protein that sits on the surface of all normal cells and its job is to send messages to the cell, telling it to grow and replicate.

If you have HER2-positive breast cancer, your cancer cells have an abnormally large number of HER2 proteins on their surface. This means the tumour has the potential to grow and spread at a fast rate. HER2-positive breast cancer tends to be more aggressive than some of the other sub-types.

Fortunately, the HER2 protein can be specifically targeted by some very effective anti-cancer drugs. 

Herceptin® (also known as trastuzumab) is the best known of these and is particularly effective for women with HER2-positive breast cancer. Herceptin is a manufactured antibody that binds to the HER2 protein, and blocks the signals that would otherwise cause the cancer to grow. It is designed to specifically target and treat cancers that are HER2 positive.

The role of HER2 in cancer was discovered in 1989 [1] and Herceptin was developed by 1995. It was first trialled in women with metastatic HER2-positive breast cancer. Herceptin significantly improved survival in these patients, and these results led to its approval for this use in 1998. Trials were then carried out to see if Herceptin could also be used to treat early HER2-positive breast cancer. By 2005, the researchers were able to report that a 12-month treatment with Herceptin after surgery and chemotherapy could significantly reduce recurrence and improve survival in these patients as well.  Extended follow-up of over 4,000 patients confirmed these findings in 2012 [2]. A 12-month treatment programme of Herceptin has been available in New Zealand for women with HER2-positive breast cancer since 2008. 

Herceptin is given as an intravenous infusion, usually once every three weeks, for 12 months.

The side effects of Herceptin are generally mild, with the most common being flu-like symptoms, which usually occur shortly after the drug is given. More serious events, such as allergic reactions and breathing problems occur rarely.

Significant heart problems develop in a few women. Heart failure has occurred in 0.6 per cent of patients when Herceptin is given following chemotherapy, and up to 4 per cent when given at the same time as taxane-based chemotherapy. In some cases specific drug treatment was required but in most patients, heart function recovered after stopping Herceptin. The risk of heart failure is greater in women with previous heart problems. Patients must be checked for heart problems before receiving Herceptin and must have their heart function monitored during treatment.

Over the last few years, there have been several trials looking at whether Herceptin could be given over a shorter period than 12 months and still give the same benefits. Recent analyses of the results have concluded that one year of treatment leads to better outcomes than shorter treatments [3,4].

12 months of Herceptin is still the standard of care (August 2020), and shorter durations of treatment might only be considered where patients cannot tolerate side effects or have heart conditions that make any risk of cardiac toxicity unacceptable.

Herceptin is the original patented version of trastuzumab, but now that its patents have expired, other companies are manufacturing biosimilar copies of this drug. None of these is funded in New Zealand yet (August 2020), but it is likely that PHARMAC may switch to one of these in the future. (For more about Herceptin biosimilars click here.)

Perjeta® (also known as pertuzumab) is another drug that targets the HER2 protein, but binds to it at a different site from Herceptin.

In New Zealand, Perjeta is funded only for women with metastatic HER2-positive breast cancer, to be used in conjunction with Herceptin.

However, recent research [5, 6] has also shown that Perjeta can also be useful in treating early HER2-positive breast cancer, especially in cases where the features of the cancer at the time of diagnosis (such as stage, tumour size, nodal involvement) suggest a higher risk of the cancer returning after treatment (recurrence). Perjeta can be combined with Herceptin and chemotherapy in these cases, but the patient will have to pay for Perjeta and receive it in a private oncology clinic.  

Some patients with early HER2-positive breast cancer may benefit from treatment with Perjeta and Herceptin before their surgery. This is called neo-adjuvant therapy, which aims to shrink the tumour before surgery. Sometimes tumours treated in this way can become undetectable (called a pathological complete response). This use of Perjeta is not yet funded in New Zealand but can be paid for privately.

There is currently an application with PHARMAC asking for funding for Perjeta for early breast cancer but as yet no final decision has been made (August 2020).

Kadcyla® (also known as T-DM1 or trastuzumab emtansine) is another anti-HER2 drug. It differs from Herceptin and Perjeta in that it is a two-part molecule that uses a trastuzumab (Herceptin) molecule to carry a toxin (DM1, also known as emtansine) directly to the cancer cells that have lots of HER2 on their surfaces. There it locks on to the cell and only then releases the ‘payload’ toxin to kill that cell, with minimum collateral damage to other cells. Kadcyla is funded in New Zealand for women who have been diagnosed with metastatic HER2-positive breast cancer, have been treated with Herceptin and perhaps also Perjeta, but have had their cancer progress. 

Recent research has also demonstrated a role for Kadcyla in the treatment of early HER2-positive breast cancer. In patients at very high risk of recurrence, whose tumours did not shrink completely after neoadjuvant treatment with Herceptin and Perjeta, adding Kadcyla to Herceptin for their treatment after surgery reduced their risk of having a recurrence of invasive breast cancer or death by 50% [7].

The supplier of Kadcyla has applied to PHARMAC for funding for this drug for those with early breast cancer, and this is currently under consideration (August 2020).

Find out more

The pharmaceutical company, Roche, has a website with some useful information about HER2-positive breast cancer, Herceptin, Perjeta and Kadcyla. Visit https://cancertreatments.co.nz/breast-cancer/

References

[1] Slamon et al. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science, 12 May 1989: Vol. 244, Issue 4905, pp. 707-712
DOI: 10.1126/science.2470152

[2] Perez et al. Trastuzumab Plus Adjuvant Chemotherapy for Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer: Planned Joint Analysis of Overall Survival From NSABP B-31 and NCCTG N9831. J Clinical Oncology 32, no. 33 (Nov 20, 2014) 3744-3752. https://ascopubs.org/doi/10.1200/JCO.2014.55.5730

[3] Niraula S, Gyawali B. Optimal duration of adjuvant trastuzumab in treatment of early breast cancer: a meta-analysis of randomized controlled trials. Breast Cancer Res Treat. 2019;173(1):103-109. doi:10.1007/s10549-018-4967-8

[4] Deng H, Du X, Wang L, Chen M. Six Months vs. 12 Months of Adjuvant Trastuzumab Among Women With HER2-Positive Early-Stage Breast Cancer: A Meta-Analysis of Randomized Controlled Trials. Front Oncol. 2020;10:288. Published 2020 Mar 20. doi:10.3389/fonc.2020.00288

[5] Gianni L, Pienkowski T, Im Y-H, et al: 5-Year analysis of neoadjuvant pertuzumab and trastuzumab in patients with locally advanced, inflammatory, or early-stage HER2-positive breast cancer NeoSphere: A multicenter, open-label, phase 2 randomised trial. Lancet Oncol 17:791-800, 2016.

[6] Minckwitz et al. Adjuvant Pertuzumab and Trastuzumab in early HER2-Positive Breast Cancer. New England Journal of Medicine 2017; 377: 122-131. https://www.nejm.org/doi/10.1056/NEJMoa1703643

[7] Minckwitz et al. Trastuzumab Emtansine for Residual Invasive HER2-Positive Breast Cancer. New England Journal of Medicine 2019; 380: 617-628. https://www.nejm.org/doi/full/10.1056/nejmoa1814017