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Meet the Researcher: Sherene Loi, MD, PhD
Tackling the challenges today for successful immunotherapy in breast cancer tomorrow
Dr. Loi received her first BCRF research grant in 2014, but was no stranger to the BCRF researcher community. She spent more than a decade in Brussels, completing her PhD and MD and conducting clinical trials with BCRF investigator, Martine Piccart, Chair of the Breast International Group (BIG), the largest international network totally focused on breast cancer research and Christos Sotiriou, another BCRF investigator. A native of Australia, Dr. Loi dreamed of becoming a doctor and traveling the world. A busy travel and speaking schedule attests to her success in achieving her dream. What she may not have envisioned was how breast cancer research, particularly immunotherapy for breast cancer would shape and define her career. BCRF had an opportunity to meet with Dr. Loi at the AACR Advances in Breast Cancer Research meeting in 2015 and shares this conversation.
BCRF: Tell us about yourself and how you became interested in breast cancer research.
SL: I think I knew I would become a doctor from an early age. My uncle died from colon cancer at age 35 when I was 8 yrs old. His illness must have had a real effect on me, and drove my early interest in medicine. I also initially wanted to be a doctor so I could travel. Australia is a long way from anywhere and I really wanted to see the world.
My path to breast cancer research really came from the time I spent in Brussels with Drs. Piccart and Sotiriou and the breast cancer community I was exposed to through the Breast International Group.
At the end of my medical oncology training, I had the opportunity to go to Brussels and work with Dr. Piccart as a research fellow. This was shortly after Laura van ‘t Veer’s group in the Netherlands had published their first papers on the Mammaprint assay, a 70-gene signature to predict whether a breast cancer is likely to spread. It was also about the time that Chuck Perou had published his papers on gene expression profiling that identified the breast cancer subtypes. It was becoming clear that genomics was going to be the future of cancer research and would be the foundation of personalized treatments for cancer.
While in Brussels, I completed my PhD studying genomics and expression profiling, with an interest in applying that technology to clinical medicine. My gene expression analyses suggested that certain types of breast cancer were particularly immunogenic– meaning that the tumors stimulated an immune response, and this revived my interest in tumor immunology.
BCRF: Describe your BCRF-funded research project. What are your primary goals for this research?
SL: While I was in Brussels, we had some preclinical proof-of-concept data supporting the combination of trastuzumab with checkpoint blockade as a very promising strategy. This led to a clinical trial that is currently ongoing with an immune checkpoint inhibitor (pembrolizumab) in trastuzumab resistant patients. From this, I have focused my BCRF project on understanding immune cell infiltrates, called TILs, in breast cancer. We want to know how we can manipulate them to improve treatments and outcomes. For instance, we know that PD1, an immune checkpoint protein, is an important regulator of TILs in breast cancer. We’re interested in seeing if there are other checkpoint proteins than can be targeted as well. Our team is examining gene expression in breast tumors both before and after immune therapy, so we can understand the immune profiles of patients who are responders or who are resistant.
Secondly, we want to understand why some women do have a good immune response (a high number of TILs) and how we can enhance that. We’re testing drug combinations that could increase TILs, as well as looking at the genes in the tumors to see if there is something in particular that is triggering the immune response. If we can identify the trigger, we may be able to boost TILs in other women. Overall, we want to understand why the TILs are there, what’s drawing them and how can we enhance that to improve outcomes. We are currently treating a lot of advanced breast cancer patients with immune checkpoint inhibitors, so we have great opportunity to study these tumors and ask these questions.
What do you think are the challenges for the future of immunotherapy in breast cancer?
SL: Unfortunately, most breast cancers are probably never going to be as responsive to immunotherapy as lung cancer or melanoma – two cancers that have seen significant success with immunotherapy. I think the strategy for immune therapy in breast cancer will be combinations; one drug to make the tumor cells “visible” to the immune cells, followed by a second drug, like a checkpoint inhibitor, that prevents the tumor from shutting down the immune system so that it can attack and destroy the tumor cells. This may be combination with other checkpoint inhibitors, radiotherapy or chemotherapy. We also need to work out how to select patients for different combinations, based on what their immune profiles look like.
BCRF: Are there specific scientific developments and/or technologies that have made your work possible? What additional advancements can help to enhance your progress?
SL: Technologies that allow us to study individual cancer cells are constantly advancing and may lead us to new immune ‘profiles’ that can predict response to therapy. New imaging technologies have also greatly improved our ability to visually study TILs. So far, just being able to see the TILs has been a good predictor of who is most likely to respond to immune therapy. While not perfect, it’s a relatively cheap and easy test, and we may not need complicated gene signatures to predict response to immune therapies.
One of the limitations in our work in understanding immune subsets is that we have to have to process the patient tissue very quickly after surgery. This is logistically challenging and can only be done in specialized centers. Collaboration between centers will be important to getting enough samples to effectively study the profile of TILs and their corresponding breast cancers so that we can answer some of these important questions.
I would say that the breast cancer research community is very organized, progressive and collaborative, and there’s an enormous amount of support to advance the research, which is so critical. Worldwide, breast cancer is the biggest killer of women between the ages of 35 and 65 and so I think that’s the population we need to be focused on.
BCRF: What trends do you see emerging in breast cancer research in the next 10 years?
SL: Overall, I think the trends are very promising, but there are challenges. I am confident that we are on track to achieve a cure for HER2-positive breast cancers within the next ten years, even in some advanced cancers. Triple negative breast cancers (TNBC) are still very perplexing and we have a lot of work to do there. New subtypes are emerging as we delve deeper into the genomics of these tumors, the more complexity and genomic diversity we see is likely to affect our ability to cure TNBC. I think breast cancer prevention is going to continue to be challenging. Certainly many breast cancers could be prevented by lifestyle modification, particularly factors that lead to obesity, but I don’t know that we’ll ever be able to prevent all breast cancers from happening. I do think we’ll continue to see patients living longer after a breast cancer diagnosis and the hope is that for most women, they will live productive lives and die of something other than breast cancer. I think that immunotherapies will also likely play a big part in the future of HER2-posiitve and TNBC.
BCRF: What do you think will be the next big breakthrough in breast cancer?
SL: I think immunotherapy is here to stay. We have already seen success with TNBC and I suspect that it will be a backbone in future treatment. I believe we will find the right targets to hit in triple negative as well as estrogen receptor positive breast cancers. I think genomics will continue to improve breast cancer treatments, including circulating DNA (liquid biopsies). We are already combining genomics with pathology to characterize the biology and prognosis of a particular tumor. We all want a future where we achieve “precision medicine” – the right therapy for the right patient at the right time.
BCRF: In your opinion, how has BCRF impacted breast cancer research?
SL: BCRF is doing more to accelerate research than probably any other funding agency in the world by allowing investigators the freedom to take risks on new ideas that they couldn’t otherwise pursue. For me personally, it has allowed me to hire the right people quickly and invest in assays and technologies that are novel and cutting edge. That has made a big difference on our progress. In the first six months, we have far surpassed the number of patient samples we expected to have and that’s because we were able to hire a dedicated person who could collect and process the samples. We are already planning the next phase, which will be a clinical trial and we hope, new immune therapy development.