Breast cancer treatment should be tailored to the tumour biology – not to its hormone-receptor status alone

New insights into breast cancer immunology and genomics support further segmentation of patient subgroups and treatment approaches, says Prof. Sherene Loi 

“Breast cancer has not been an obvious candidate for immunotherapy because it usually has a hormonal cause and is not recognised by the body in the same way as cancers caused by toxins or viruses – but this is set to change as our understanding of the immune response to breast cancer deepens,” says Prof. Sherene Loi, Professor of Oncology at the University of Melbourne and Head of the Peter MacCallum Cancer Centre’s Translational Breast Cancer Genomics and Therapeutics Lab, outlining a path to translate new knowledge of breast tumour biology into more personalised treatments for patients. Presented with the ESMO Breast Cancer Award 2020 in recognition of her practice-changing research works, Loi gave her award lecture “Stories in cancer immunology and genomics” at the ESMO Breast Cancer 2021 Virtual Congress following the change in format of last year’s event due to the COVD-19 pandemic.

What drew you to research in the field of breast cancer immunology?

During my graduate studies we were using gene expression arrays to learn more about breast cancer prognosis. Gene signatures related to tumour cell proliferation were found to be predictive of women’s risk of metastasis and recurrence (BMC Genomics 2008 May 22;9:239), but because these were important mainly in hormone receptor-positive breast cancer we decided to look specifically at the HER2-positive and triple negative subtypes. There we discovered that overexpression of gene sets related to immune function were significantly associated with better outcomes (Genome Biol. 2007 August 2;8(8):R157). This was an interesting finding because we previously had not thought of breast cancer as being immunogenic, that is to say capable of inducing an immune response that could help fight the tumour.

You and colleagues within the International Immuno-Oncology Biomarker Working Group on Breast Cancer have since standardised the assessment of tumour infiltrating lymphocytes (TILs), mononuclear immune cells that infiltrate the tumour tissue (Ann Oncol. 2015 February;26(2):259-271). What is the significance of TILs in breast cancer?

Developing a biomarker that could be applied by people everywhere, just using a microscope and a standard pathology slide rather than sophisticated gene expression assays to examine tumour tissue obtained from a core biopsy, allowed us and many other research teams around the world to demonstrate that TIL levels replicate the gene expression data in that higher quantities of immune infiltration are associated with better outcomes in triple negative and HER2-positive breast cancer – both in terms of survival (J Clin Oncol. 2013 March 1;31(7):860-867) and response to immunogenic chemotherapy (J Clin Oncol. 2015 March 20;33(9):983-991).

Today TIL scoring is recognised as a prognostic marker in early breast cancer, whereby each 10% increase in TILs observed in these patients is associated with a 15 to 20% relative improvement in their survival rates (Ann Oncol. 2019;30(8):1194-1220), and could be used in the future to identify patients with an excellent prognosis for whom adjuvant chemotherapy could be safely de-escalated. We are now also learning that TILs could be an effective predictive marker for response to immune checkpoint inhibitors: this has already been shown in the advanced setting (JAMA Oncol. 2019;5(1):74-82).

Immunotherapy is only just starting to show promise in the treatment of breast cancer (Br J Cancer 2018 May 29;119:4-11). What do you believe will be its place in the therapeutic armamentarium for this tumour type?

Contrary to melanoma, which is potentially curable directly through activation of the immune system (Semin Oncol. 2015 June;42(3):429-435), the role of immunity in fighting breast cancer is more complicated. The composition of the breast changes throughout a woman’s lifetime from puberty, through menstrual cycles, pregnancy and breastfeeding all the way to menopause, which makes it harder for the immune system to distinguish between malignant cells and normal dying tissue in the breast. That is why I believe we will have to combine immunotherapy with other proven treatments such as chemotherapy, hormone therapy and HER2 targeted agents in order to achieve real clinical benefits for our patients.

In the decade ahead, we will need to further refine our understanding of the biology of the immune response in breast cancer and of the biomarkers that will allow reliable identification of patients who can benefit from immunotherapy. As the use of PD-1/PD-L1 inhibitors is likely to become more widespread over the next five years, it will also be important to explore treatment options for the patients who develop resistance to these drugs.

Highly effective treatments like endocrine therapy have largely improved prognosis in hormone receptor-positive breast cancer. What still needs to be achieved for this breast cancer subtype in the era of personalised medicine?

Premenopausal and very young women under the age of 40 are still faring very poorly compared to older, postmenopausal women with the same tumour subtypes, and the disparity in prognosis is particularly marked for hormone receptor-positive disease. To understand why these tumours are more aggressive in younger women, we interrogated thousands of prospectively collected samples from clinical trials (JAMA Oncol. 2018 October;4(10):1335-1343; N Engl J Med. 2015 January 29;372:436-446) using next-generation sequencing techniques to map out the landscape of oncogenic drivers in postmenopausal versus premenopausal women. The results soon to be published suggest that the cancer biology differs widely between young and old: gene copy number amplifications and genomic alterations responsible for homologous recombination deficiency (HRD), for instance, both appear to be more prevalent among younger women and are associated with worse outcomes. The implication is that we will likely need to devise specific treatment strategies for breast cancer in young women, which will require starting dedicated clinical trials for this patient subset.

More generally, emerging knowledge about the clinical relevance of driver alterations in breast cancer will almost certainly lead to further segmentation into a multitude of disease subgroups with different treatment profiles – akin to the mutation-based classification of lung cancer – that will complement the three subtypes in use today and go hand in hand with the development of new targeted therapies.

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