AACR Outstanding Investigator Award for Breast Cancer Research: Using genomics to better understand the breast cancer microenvironment


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Sherene Loi, PhD, FRACP
Sherene Loi, PhD, FRACP

Tumor infiltrating lymphocytes (TILs) are an immunologic novelty that is moving toward clinical utility in breast cancer prognosis and treatment selection. A decade of basic research has confirmed that the presence or absence of TILs can distinguish between tumors more likely to respond to chemotherapy and those more likely to respond to immune checkpoint blockade.

“Patients with higher TILs could do just as well with less chemotherapy or no chemotherapy, and that chemotherapy could be replaced by agents that harness this immune response,” said Sherene Loi, PhD, FRACP, Professor and Head of the Translational Breast Cancer Genomics and Therapeutics Laboratory, Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, Australia.

“TIL as a biomarker does not currently change clinical practice, but it may do so in the future,” she said.

Dr. Loi described ongoing research into the role of TILs in breast cancer prognosis and progression during her AACR Outstanding Investigator Award for Breast Cancer Research presentation “Journey into Breast Cancer Immunology Using Genomics” at SABCS 20.

TILs are predominately activated T cells, Dr. Loi continued. They are comprised largely of CD4+ and CD8+ T cells. Higher quantity of TILs indicates a higher number of CD8+ T cells, enhancing the cytotoxic tumor response.

An international working group established in 2014 has built a strong international consensus around TILs based on findings from more than 10,000 patients in clinical trial cohorts. The working group has concluded that increased TIL levels predicts improved neoadjuvant response in all breast cancer subtypes and improved prognosis in early TNBC and early HER2+ with Level 1B evidence.

“Large absolute differences in recurrence rates and survival by TIL levels suggest that inducing or improving immunity can improve survival,” Dr. Loi said. “Higher TIL is also associated with greater magnitude of benefit from PD-(L)1 inhibitors in advanced disease.”

PD-1 and CTLA-4 are the dominant checkpoints on T cells in breast cancer, with PD-1 the more prominent. Single-cell profiling on breast cancer T cells revealed a novel subset of tissue resident memory T cells (TRM) that are associated with improved prognosis.

The TRM population is composed of CD8+ T effector cells that enter healthy tissue and do not recirculate. They are specialized for regional immunity defense when re-exposed to a pathogen. Their role in breast cancer is still unclear, Dr. Loi said, but there is good evidence they could have therapeutic and immunosurveillance roles.

What is clear is that dual PD-1 and CTLA-4 blockade improves TRM quantity, function, and killing over PD-1 inhibition alone, she continued. That suggests that pre-existing TILs with a strong TRM component represent some type of anti-tumor response that can be harnessed to improve outcomes.

What is already clear is that TIL is a simple, pragmatic biomarker that is both prognostic and predictive of response,” Dr. Loi said. It is a useful adjunct to PD-L1 and other biomarkers, and it is likely that TRM and other immune cell subsets will advance understanding of immune biology.

“We still have a bit of work to do to understand how this affects immunity and other treatments,” she concluded.

SABCS registrants have exclusive on-demand access to Dr. Loi’s lecture and other virtual SABCS programming until March 13, 2021.