Lab Daniel Giglio - Immune Responses and Survival Outcomes in HER2-Positive Breast Cancer

Clinical Effectiveness of HER2-Targeted Therapies in HER2-Positive Breast Cancer and Impact of the Immune System and COVID-19 pandemic on treatment outcomes

Background

Approximately 15% of patients with breast cancer (BC) have tumours with overexpression and/or gene amplification of the tyrosine kinase receptor HER2. Historically, overexpression of this receptor was associated with an increased risk of disease recurrence and bad prognosis. Survival improved significantly when therapy with trastuzumab, a monoclonal antibody that binds the extracellular domain of HER2, started in the 00´s. In 2015, FDA and EMA approved preoperative therapy with chemotherapy and dual HER2-blockade with trastuzumab and pertuzumab. Dual-blockade was later also approved in the adjuvant setting. HER2-targeted therapies are also highly effective in patients with HER2+ metastatic BC. In HER2+ metastatic BC, overall survival (OS) is longer in patients treated with dual blockade than with trastuzumab alone.

Presence of tumour-infiltrating lymphocytes (TILs) predicts clinical efficacy of immunotherapy in triple-negative BC (TNBC). Toll-like receptors (TLRs) are important components of the innate immune response and recognize pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) from bacteria and viruses and of cancer leading to immune activation. Stimulation of TLR7 and TLR9 on plasmacytoid CD303+ dendritic cells gives rise to a type 1 interferon response and drugs targeting TLR7 and TLR9 have been explored in cancer therapy. BC express different TLRs and expression patterns correlate with OS. Moreover, animal studies show that targeting TLRs may activate an adaptive immune response in BC.

In a short  period of time, the coronavirus disease 2019 (COVID-19) pandemic has transformed health care delivery around the globe. The crisis has dismantled how care is delivered and forced clinicians to make difficult triage decisions about what types and components of care that have limited immediate value and which are essential for optimal outcomes. At earlier time of the pandemic many centres delayed screening processes and accelerated the adjustment of chemotherapy and surgical protocols to face the risks and the shortage of accessibility to healthcare resulting in changes or delay in workup or treatment of cancer during the pandemic. Moreover, in the early phase of the pandemic when most screening programs where paused, leading to that BC patients presented with tumours that were larger and more aggressive.

Aims

The aim of the study is to define the rates of actual usage of Her2-targeted therapies and their clinical efficacy in Her2+ early breast cancer (EBC) and metastatic breast cancer (MBC) in four health regions in Sweden (Stockholm, Västra Götaland, Skåne and Halland). Whether the immune system in the metastatic setting responds differently to Her2+ target therapy and chemotherapy in long-term survival MBC (>5 years) vs. short-term survival (<1 year) will be assessed. Furthermore, we are going to study the impact of COVID-19 pandemic on outcomes and describe the risk factors that might be correlated with this empact.

Methods

In the first sub-project, HER2-targeted treatment use in early BC based on real-world evidence will be analyzed from four health care regions in Sweden (Stockholm, Västra Götaland, Skåne and Halland). The goal is to compare the actual usage and efficacy of HER2-targeted treatment based on real-world evidence in relation to data from pivotal studies. This study will assess the populations of Stockholm (2.3 million), Västra Götaland (1.7 million) Skåne (1.3 million) and Halland (approximately 0.3 million) as a basis. Regional cancer quality registry data and central cancer quality registry data (INCA) for BC will be used to identify all women with BC in the four regions from 2008 until 2020. Follow-up starts at the date of BC diagnosis and continues either until the date of death or until the individual is censored. The primary end point is BC recurrence-free survival (RFS). Secondary endpoint will be OS. Associations between survival and clinical pathologic factors will be assessed.

In the second sub-project, we will assess how the immune profile of HER2+  BC correlates with survival. De novo and recurrent HER2+ metastatic BC have different clinical outcomes and respond differently to oncological therapies. TILs are of importance for clinical outcome for triple-negative BC (TNBC) and HER2+ BC. However, at present it is not know whether innate and adaptive immune responses are of importance for clinical outcome in HER2+ MBC. This study will assess the populations of Stockholm (2.3 million), Västra Götaland (1.7 million) Skåne (1.3 million) and Halland (approximately 0.3 million) as a basis to identify patients with HER2+ MBC. Regional cancer quality registry data and INCA for BC will be used. Patients who are alive five years after diagnosis of metastatic BC (long survivors) will be compared with patients who have succumbed to BC within one year after diagnosis of metastatic BC (short survivors). Patients diagnosed with BC from 2008 to 2015 in the four regions will be assessed in the registries. We will select a representative cohort of 30 patients with de novo and 30 patients with recurrent HER2+ metastatic BC from the registries. Sections of paraffin-embedded tumour specimens will be immunostained against TILs (CD3, CD3, CD4, CD8, CD45RO, FoxP3), immune checkpoint proteins (PD-1, PD-L1, TIM-3, LAG-3 and TIGIT) and TLR1-10. Sections of tumour specimens will be examined blindly and the extent and intensity of expression of immune markers will be assessed and graded. Staining intensity and the degree of extent of individual antigens (innate, adaptive, immune checkpoint proteins) will be dichotomously categorized as weak (0-1) and strong (2-3) and compared between long and short survivors, between the primary and secondary tumour in recurrent HER2+ metastatic BC and between de novo and recurrent HER2+ metastatic BC. 

In the third sub-project, the impact of the COVID-19 pandemic on clinical outcomes in HER2+ and early TNBC and mBC will be investigated. We will compare three-year RFS in patients with HER2+ BC and TNBC diagnosed between March-December 2020 with patients diagnosed between March-December 2017. Whether regional differences in policies regarding BC treatments during the COVID-19 pandemic may explain any changes in RFS will be assessed.

Significance

By examining real world data in large data sets on the use of trastuzumab in Sweden in HER2+ BC we may identify regional differences on the use of trastuzumab and during the Covid-19 pandemic. Moreover, we may come closer to the real benefit of HER2/HER3 targeted therapy in the clinical setting compared to pivotal trials and find patient groups that benefit from additional HER2/HER3 targeted therapy. By studying the immune system in short-time vs. long-time survivors, we may identify new medical targets in the therapy of HER2+ BC.

Collaborators

at the University of Gothenburg and the Karolinska Institute

Daniel Giglio MD, PhD, Principal Investigator, Associate Professor, Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy.

Alaa Haidar, MD, PhD student, Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy.

Alexios Matikas, MD, PhD, Associate Professor, Department of Oncology-Pathology, Karolinska Institute.

Zakaria Einbeigi, MD, PhD, Associate Professor, Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy.

Nils Wilking, MD, PhD, Associate Professor, Department of Oncology-Pathology, Karolinska Institute.