Clinical Pearls: Targeted Drug therapies for HER2+ Advanced Breast Cancer

October 21, 2022
By: Maria Ahmed 

This article is part of a series appearing in Interactions, our biweekly newsletter, written and researched by CSHP's students. We've created this series as a valuable learning activity for pharmacy students undertaking rotations at CSHP. Crafting these pieces not only helps students gain in-depth knowledge of specific conditions, treatments, and resources, it also helps them hone their skills in research, critical appraisal, evaluation, synthesis, and writing – all of which will serve them well in clinical practice. The Professional Practice Team works with the students to select hot topics that are of interest and utility to both the students and to you, the reader. We hope you enjoy this piece by one of our future colleagues! Let us know what you think: If you would like to provide any comments or constructive feedback for our students, please email us at practice@cshp.ca.

Background

Breast cancer is the 2nd most commonly diagnosed cancer in Canada among women which resulted in 5400 deaths in 20211.  About 1 in 8 Canadian women will develop breast cancer in their lifetime and about 1 in 24 will die from it1. Of those 1 in 8 individuals, about 15-20% of breast tumors have high levels of a protein known as Human epidermal growth factor receptor 22. These cancers are called HER2+ breast cancers, which demonstrate a poor prognosis3. HER2 is a proto-oncogene that is amplified and over-expressed and is associated with tumor aggressiveness which is likely to be treated with targeted drug therapies3. Targeting breast cancer through its vital oncogenic protein has been a major step in improving patient outcomes2. Targeted therapy can either be monoclonal antibodies or small-molecule drugs; refer to Table 1 for the common targeted therapies available2,3. However, resistance to treatment remains a challenge, which increases demand for the need for novel therapies.
 
Table 1: Summary table of the current targeted therapy and common considerations for treatment.
 

mAb = monoclonal anti-body; LVEF = left ventricular ejection fraction; HF = heart failure; PPE = Palmar-plantar erythrodysesthesia;  

 

Resistance

With the current treatments, most patients with advanced HER2+ gene amplified breast cancer can relapse after treatment, suggesting that the gene acquired or has intrinsically possessed mechanisms that prevent HER2 inhibition13. Many of these potential resistance mechanisms to anti-HER2 therapy have been described to reactivate the HER2 pathway or its downstream signaling, through redundancy or stimulation of alternative survival pathways13. Figure 1 demonstrates the multiple pathways where current novel medications target the cell and where resistance can take place that can cause treatment failure3. By incorporating an additional medication that can suppress or alter the resistance mechanism itself, it gives us a chance to bypass the resistance14. An example of this was demonstrated in the CLEOPATRA study where patients were randomized between pertuzumab vs placebo14-17.

Figure 1: Depiction of the tumor cell where resistance can occur and general mechanism of action of the targeted therapy. Adapted from Ferrario et al (2022).



Both the intervention and comparator arms incorporated the standard use of trastuzumab and docetaxel14-17. Trastuzumab is an anti-HER2 antibody that binds only to the HER2 protein and resistance to this medication is apparent, whereas pertuzumab is a monoclonal antibody that inhibits the HER2/HER3 dimerization 14-17. By adding pertuzumab to the combination therapy, the authors demonstrated how pertuzumab will complementarily provide a more complete blockage of HER2 signal transduction; ergo, bypassing the trastuzumab resistance 14-17. However, resistance to general antibody medications has been growing stronger and the need for novel therapy surges.

 

Overall resistance

As resistance evolves, so does the standard treatment of care. Antibody-drug conjugates (ADCs) have been introduced and have changed the treatment paradigm of HER2+ breast cancer (see Table 2 for a summary)18-20,26. These medications incorporate a monoclonal antibody, a linker and a cytotoxic payload26. Trastuzumab emtansine (T-DM1) was the first of its kind and is now a second/third-line treatment26. It is a HER2 monoclonal antibody, with a non-cleavable thioether linker and a cytotoxic payload called emtansine (DM1, a microtubule inhibitor)26. Once trastuzumab binds to HER2 receptors, internalization and lysosomal degrading occurs, resulting in delivering DM1 to malignant cells to bind to tubulin and cause cell arrest and apoptosis26. In the EMILIA and TH3RESA trials, T-DM1 showed significantly improved PFS compared to lapatinib + capecitabine or physician’s choice, respectively18-20,26. EMILIA was a randomized, open-label, multicenter study with a statistically significant progression-free survival of 9.6 vs 6.4 months18. The comparator arm (comprised of lapatinib + capecitabine) arm demonstrated more events of any grade diarrhea (N = 389 vs 114) and palmar-plantar erythrodysesthesia (N = 283 vs 6); however fewer events of any grade of thrombocytopenia (N = 12 vs 137)18. TH3ERiSA was a randomized, multicenter, open-label study with a statistically significant progression-free survival of 6.2 vs 3.3 months. T-DM1 demonstrated fewer neutropenic events at any grade (40% and 22% respectively) and only one grade 5 event occurred that resulted in a pulmonary embolism (only in the comparator arm)19-20.


More recently, a new medication has been introduced in the market, trastuzumab deruxtecan (T-DXd), that can potentially replace T-DM1 in second/ third-line treatmenty21-23. This ADC consists of a human anti-HER2 monoclonal antibody linked to topoisomerase I inhibitor payload through a tetrapeptide-base cleavable linker21-23. It delivers a potent cytotoxic payload that is internalized and selectively cleaved by lysosomal enzymes that are overexpressed in cancerous cells21-23. This results in DNA damage, leading to apoptosis of the tumor cell21-23. The deruxtecan is also membrane soluble, this allows the molecule to diffuse out of the cell and conduct its cytotoxic effect on surrounding HER2 tumor cells, also known as the “bystander effect”21-23. In 2021, the DESTINY-Breast-03 trial, a multi-center, open-label, randomized trial compared the efficacy and safety of T-DM1 and T-DXd in a total of 524 patients that demonstrated a statistically significant 12-month progression-free survival rate of 75.8% vs 34.1%, respectively21. Drug-related interstitial lung disease (ILD) occurred in 10.5% of patients (0.8% grade), but no deaths were reported21. The DESTINY-Breast-03 trial also had 82 patients with stable brain metastases, where T-DXd demonstrated a reduction in risk of disease progression or death by 75% relative to T-DM121. In June 2022, Health Canada approved T-DXd indicated for patients with unresectable or metastatic HER2+ breast cancer who have received at least one prior anti-HER2-based regimen either in a metastatic setting or in a neoadjuvant or adjuvant setting that developed disease recurrence during or within 6 months of completed neoadjuvant or adjuvant therapy21-23.

Table 2: Summary table of the ADC targeted therapy and common considerations for treatment


mAb = monoclonal anti-body; LVEF = left ventricular ejection fraction; HF = heart failure; PPE = Palmar-plantar erythrodysesthesia;
GFR = glomerulus filtration rate; T-DM1 = trastuzumab emtansine; T-DXd = trastuzumab deruxtecan.

Pharmacist's Role

In a multidisciplinary team, pharmacists have a crucial role in helping patients with breast cancer to acquire the best treatment outcomes, reduce the impact of adverse events, prevent medication toxicity, monitor drug interactions, increase adherence and improve patient quality of life28-30. As the number of options for treating metastatic breast cancer grows, the need for pharmacists arises with it28-30. Pharmacists are often the first healthcare providers to identify and manage the adverse effects of treatment and maintain their patients to be compliant28,30. Some common adverse effects and toxicities include myelosuppression, nausea, vomiting, neurotoxicity, and diarrhea28. Monitoring these parameters can include routine check-ins, laboratory assessments and other specific markers such as the need for cardiac evaluation in patients receiving trastuzumab. Prior to taking medications for breast cancer, patients may be required to take pre-medications to mitigate the adverse effects experienced by the medications themselves28. Ordering appropriate pre-medications include antiemetic drugs and medications that prevent hypersensitivity reactions13. This can increase the chances of drug interactions. Pharmacists play a vital role to determine both pharmacodynamic and pharmacokinetic interactions and how to best modify the dose or toxicity given the interaction. In addition, pharmacists are also involved in conducting medication reconciliation and educating other healthcare providers and patients about medications28.

In 2017, Dong et al developed a randomized, prospective study where patients were randomly distributed in an intervention arm and received pre-chemotherapy counseling 28-30.  The counseling session included pharmacist-led pre-chemotherapy counseling that followed a consistent checklist30.  In the session, patients raised several common queries that include “can I take a supplement?”, “Will these side effects be permanent?” and were answered appropriately30. The study found significant improvement in the understanding of the chemotherapy regimen and its side effects in the intervention arm30. Dong et al demonstrated that pharmacist-led pre-chemotherapy counseling improves patient knowledge and understanding30. Prior surveys have shown that less than 70% of the information given to cancer patients was understood despite the prior discussion with their physicians31. Pharmacists have been suggested to be the ideal bridge of information between physicians and patients30. Therefore, incorporating a pharmacist through interprofessional collaboration provides added value to patient-centered care28-30.
 

References

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