SABCS 2020 at a glance

Rachel Schiff, Houston, USA, explored HER2-targeted therapy, with a focus on determinates of response and mechanisms of resistance. HER2+ breast cancer accounts for 15–20% of all breast cancer types and a number of clinically available HER2-targeted treatments have revolutionised the outcome of this disease. These include monoclonal antibodies, tyrosine kinase inhibitors (TKIs), and antibody-drug-conjugates (ADCs). However, despite these effective therapies, intrinsic and acquired resistance still occurs in HER2+ breast cancer and this remains a major challenge in the clinical management of this disease, particularly in the advanced setting.

Treatment resistance is multifaceted and context specific

Even in HER2-addicted tumours, the efficacy of anti-HER2 therapy can be jeopardised by deregulations in the downstream PI3K pathway (e.g. PIK3CA mutations), leading to constitutive activation of the PI3K/AKT pathway and subsequent therapeutic resistance. Dual anti-HER2 therapy is therefore more likely to achieve superior anti-tumour efficacy over single agents alone. In addition, where HER2+ tumours co-express oestrogen receptors (ER), concurrent blockade of HER2 and ER signalling is required. The tumour microenvironment, including host immune components (e.g. tumour-infiltrating lymphocytes [TILs]) and extracellular matrix components signalling via integrins, have been shown to play a role in modulating tumour response to treatment and in resistance. For example, high baseline TILs are associated with increased pathologic complete response (pCR) rates in the neoadjuvant setting with anti-HER2 agents plus chemotherapy. Activation of selective immune pathways are associated with increased pCR rates and more favourable prognosis in the early and metastatic settings. Of note, both innate and adaptive immune systems participate in trastuzumab anti-tumour activity. Summarising, Dr Schiff noted that better understanding of the tumour biology and underlying mechanisms of resistance, as well as new diagnostic tools are essential to guide new treatment strategies and patient stratification for personalised treatments and improved patient outcomes.

“Reduced immune system activation plays a role in resistance to anti-HER2-targeted therapies.”

Rachel Schiff, Houston, USA

Key resistance mechanisms in HER2+ breast cancer

Aleix Prat, Barcelona, Spain, explored personalised treatment for early stage HER2+ breast cancer. When considering stage I disease, Dr Prat suggested that trastuzumab emtansine (T-DM1) may be an efficacious alternative to standard paclitaxel plus trastuzumab (TH) for selected patients with stage I HER2+ disease who are concerned about specific TH-related side effects, but fully understand the potential for T-DM1-related toxicities. In the personalised treatment setting for stage II–III disease, there are three HER2-selective drugs available in the curative setting – pertuzumab, neratinib, and T-DM1. However, to properly calculate how aggressively to systemically treat an individual remains complicated, and this can be further exacerbated by an oncologist’s fear of unwittingly undertreating a patient and contributing to the development of incurable disease. A multivariable prognostic score has subsequently been developed to guide systemic therapy in early-stage HER2+ breast cancer. The HER2DX combined prognostic score identifies patients with early-stage, HER2+ breast cancer who might be candidates for escalated or de-escalated systemic treatment. HER2DX integrates clinical, genomic, and TILs to predict prognosis. Future clinical validation of HER2DX seems warranted to establish its use in different scenarios, especially in the neoadjuvant setting.

“Adapting adjuvant therapy based on response to preoperative therapy is a paradigm shift for HER2+ breast cancer.”

Aleix Prat, Barcelona, Spain

Nancy U. Lin, Boston, USA, explored advances and challenges in the treatment of HER2+ MBC. Over the last 20 years, there have been many advances in treatment options for patients with HER2+ MBC. In 2001, median overall survival (OS) in the control arm of the pivotal trastuzumab plus chemotherapy study was reported to be 20.3 months. In contrast, data from the CLEOPATRA study published nearly 20 years later reported a median OS with taxane/trastuzumab/pertuzumab arm of approximately 5 years, along with an 8-year landmark OS of 37%. OS improvements have also been demonstrated in the pivotal trials of T-DM1, tucatinib/capecitabine/trastuzumab, and trastuzumab deruxtecan in pre-treated patients with HER2+ MBC – such findings suggest a continued trend for further improvements in median OS. Despite these improvements in OS, a number of clinical challenges remain. Once patients develop MBC, there is a continuous and unabated risk of central nervous system (CNS) involvement over time – brain metastases continue to contribute substantial morbidity and mortality in at least half of all patients with MBC. While there have been advances in local therapy for brain metastases, a breakthrough in systemic therapy and prevention strategies are needed to fully manage this problem. In addition, while drug resistance nearly always occurs over time, the current understanding of HER2-resistance mechanisms remains poor.

Current management algorithm of HER2+ MBC

Advances and challenges in the treatment of HER2+ MBC

“We are at a pivotal moment – over the next decade we will fundamentally change the treatment intent and outcomes for patients with HER2+ MBC.”

Nancy U. Lin, Boston, USA

SABCS 2020 was a successful meeting with attendees able to remotely access new data and clinical insights, and ‘virtually’ interact with clinical experts. This will hopefully stimulate new ways of thinking and ultimately translate into optimal care for the breast cancer patient. In addition, the virtual format provided the opportunity for participants, particularly those outside the US, to attend SABCS perhaps for the first time. This revised format for 2020 also enabled more institutions around the world to conveniently gain access to ‘on demand’ meeting content.