Welcome to SABCS 2020

SABCS 2020 at a glance

In response to the COVID-19 global pandemic, the 43rd SABCS took place on a new virtual congress platform from the 8th to the 11th December 2020. This year’s meeting continued the tradition of bringing together breast cancer researchers and clinicians from around the world, providing a virtual format to present new and late-breaking data on the experimental biology, aetiology, prevention, diagnosis, and therapy of breast cancer, along with premalignant breast disease. SABCS is the premier event for researchers, health professionals, and those with a special interest in breast cancer and this year included more than 40 oral presentations in four general sessions. Also included were commentaries from expert discussants, as well as poster sessions consisting of short audio overviews from the authors. Co-Chair Carlos L. Arteaga, Dallas, USA, opened the meeting and welcomed attendees.

Oestrogen-receptor positive (ER+) breast cancer

David Cameron, Edinburgh, UK, explored special topics in early-stage ER+, HER2- breast cancer, also known as luminal breast cancer. Luminal breast cancer is the most common form of early breast cancer, comprising approximately three-quarters of all breast cancers. In addition, it causes the most deaths from breast cancer and its incidence is increasing at a more rapid rate than other types of breast cancers. One of the enduring problems in treating ER+ breast cancer is its persistent tendency to recur. HER+ and triple negative breast cancers (TNBC) usually recur within the first few years after treatment, but ER+ cancers have a steady rate of relapse over decades.

Factors favouring overall survival

Most luminal breast cancer tumours are sensitive to endocrine therapy, with arguably their adjuvant use “saving more lives” than any other medicine used for cancer. Patients also benefit from other standard interventions, such as chemotherapy, surgery, radiotherapy, and the use of bisphosphonates. However, Dr Cameron noted that it remains unclear if targeted agents can be added to endocrine therapy to enhance efficacy and improve survival. While bisphosphonates reduce bone metastases in post-menopausal women, leading to an OS benefit, these agents are not currently approved to treat ER+ breast cancer. Of note, the use of bisphosphonates provides little or no therapeutic benefit in premenopausal women, in whom bone metabolism may be fundamentally different.

Key variables to consider when customising HR+ MBC treatment

Approximately 70% of all diagnosed breast cancers express hormone receptors (HR+). Despite an overall good prognosis, the clinicopathological and molecular heterogeneity of these tumours results in a diverse natural history of disease – thus, some patients can develop distant metastatic recurrence anytime during the disease course, regardless of endocrine therapy. Ingrid Mayer, Nashville, USA, explored treatment considerations in HR+ metastatic breast cancer (MBC). Dr Mayer explained that chemotherapy is the typical option for women with life-threatening visceral metastases, while those individuals with less aggressive disease are treated with a variety of endocrine therapies (aromatase inhibitor, fulvestrant, or combination therapy) with the subsequent addition of CDK4/6 inhibition. However, the clinical activity of endocrine therapy plus CDK4/6 inhibition in early-line treatment of ER+ MBC appears to be superior to chemotherapy in premenopausal women, even in the presence of visceral disease. In some special circumstances (de novo MBC, oligometastatic disease, long disease-free interval without prior aromatase inhibitor), CDK4/6 inhibition could probably be deferred to the second-line treatment setting after first-line (mono)endocrine therapy.

Resistance to hormonal therapy and CDK4/6 inhibition is driven largely by PIK3CA and ESR1 mutations, although BRCA mutations can also be responsible. As all three pathways have therapeutic options, genomic testing is recommended in those women who fail endocrine therapy plus CDK4/6 inhibition. However, more refined clinical and molecular biomarkers are needed to better determine which patients truly need the addition of these targeted treatments, along with the optimal timing of this strategy. PI3K pathway inhibitors could be considered in patients with HR+ MBC refractory to endocrine therapy with/without CDK4/6 inhibition due to a modest (but real) progression-free survival (PFS) advantage in ≥ second-line phase III studies:

• For patients with PIK3CA mutations: alpelisib + fulvestrant
• For patients without PIK3CA mutations: everolimus + endocrine therapy (partner unlikely to matter as everolimus works with many different ones)

ER+ breast cancers frequently develop resistance to endocrine therapies. Robert Clarke, Manchester, UK, briefly explored mechanisms for this resistance. ER+ breast cancer recurs because a small population of cancer stem cells that are positive for aldehyde dehydrogenase (ALDH+) survive endocrine treatment – these surviving ALDH+ cells then proliferate, repopulate the tumour, and metastasise. ALDH+ cells have upregulated cytokine signalling, particularly interleukin (IL)-1β. IL1β production by the bone marrow induces activation of breast cancer colony formation. As endocrine therapy treatment increases IL-1 receptor expression, this drives treatment resistance and metastasis. Inhibition of IL1β signalling should prevent metastatic breast cancer colonisation. Dr Clarke noted that animal models have shown IL-1 receptor inhibitors can reduce the development of resistance and bone metastases. IL-6 inhibitors, such as tocilizumab, may also prove useful given that ALDH+ cells also upregulate IL-6, which signals via the JAK-STAT3 pathway to promote CKD4/6 resistance. Targeting these pathways using therapeutic combinations has the potential to improve clinical outcomes.

Closing Remarks