When younger women are diagnosed with breast cancer, they generally have poorer outcomes than older women. Incidence is on the rise for young women in the U.S.: In the last 10 years alone, there has been an eight percent increase in diagnoses in women under 40—underscoring the need for research focused on these patients.
Researchers like Dr. Sherene Loi, a BCRF investigator since 2015, are working to uncover why this is happening—and how we can better treat the disease, reduce recurrence, and prevent it entirely. Through the landmark BCRF-supported SOFT trial, Dr. Loi and her colleagues have already developed treatment strategies that have improved outcomes for women under 40. Now, she’s working to understand the immune microenvironment of breasts cancers in younger women—including the role of tumor-infiltrating lymphocytes—and continue to improve treatment.
Below is an edited transcript of Dr. Loi’s conversation with BCRF staffer and breast cancer thriver Sadia Zapp.
TILs are immune cells. When a pathologist looks down the microscope they can see the breast cancer and all the surrounding tissue in a row that surrounds the breast cancer. And they can also see lots of different cells apart from cancer cells, and some of these cells are immune cells. And we call these cells tumor-infiltrating lymphocytes or TILs.
A long time ago we looked at the quantity of immune cells [for people with cancer] and correlated that to whether they had recurrences from their breast cancer in the future. And it was actually quite remarkable, because we did find in these first studies that the amount of immune cells did predict whether you did better from your breast cancer. So, the more immune cells you had, we [realized] that your immune system was actively fighting the cancer. And then once you remove the tumor, your immune system was able to, with the one or the other treatment you receive, mop up the rest of the cancer cells and protect you from cancer recurrence in the long term. So that's subsequently been reproduced by many other investigators, and it really seems to be particular for patients with triple-negative breast cancer (TNBC), [which is more common in younger patients]. This also seems to be the case with certain types of hormone receptor–positive breast cancer. We're exploring that in more detail, using the [BCRF-supported] SOFT trial.
But getting back to TNBC. We’re in an era now of immunotherapy. We've done quite a lot of work with other investigators that we know that your level of TIL does suggest that you might have a higher rate of pathological complete response [with a drug called] Keytruda and a shorter duration of chemotherapy. So, my belief at the moment is that if we can see your immune system is active, we can enhance that with agents such as Keytruda. And ultimately, we will be able to safely shorten the type of chemotherapy that you require. At the moment, everyone requires a big, intensive chemotherapy regimen. But I think for patients who have existing immune cells or evidence that the immune systems are really active, then they won't need that much additional chemotherapy. The Keytruda will kind of do the job for us.
I have a number of theories. So, for younger people to develop cancer, it has to be a little bit more aggressive to get through the natural barriers that we all have to prevent cancer from occurring. For women who are young, they're potentially of childbearing age. They'd have very strong menstrual cycle, and the breast changes during that cycle. So, you have your menstrual cycles, and every month you've got this growth in your breast. And then you have cells die, but a cell that's learned to not die every month is getting this strong growth signal. Naturally women’s fertility drops after the age of 40. We see that breast cancers seem to be a little bit less aggressive in women as they reach their mid-40s and move into a natural menopause.
There are other things that we don't really know, but we suspect. In countries such as America and Australia, women are having children later. There are also some issues with obesity, alcohol, etc. So that probably contributes as well. They're not breastfeeding for long, and we know that breastfeeding particularly does attenuate the risk of triple-negative breast cancer. And other things that we don't really understand like pollution or our environment may be contributing to some of the increased rates or younger onset breast cancer we're seeing. And also, maybe why they're a little bit more aggressive. So, there's potentially lots of reasons there. And no one really knows the answer. It's probably multifactorial, unfortunately, but with trying to study the individual parts to see if making a difference to one of those parts will help a lot.
These studies, which were managed by the International Breast Cancer Study Group are a collaboration between Europe, America, Australia, and many countries in the world. It was really a remarkable feat for the global breast cancer community to answer an important question that is still highly relevant today. Most premenopausal women will receive concurrent ovarian function [to suppress estrogen]. If a woman’s cancer is high risk, that makes a huge difference to their outcomes, even though we are trying to obviously deal with some of the side effects. International collaboration is essential for all good breast cancer research. Getting people together in the one room is really important, and BCRF does that well.
I'm hoping in the future, we might incorporate more biomarkers, because I feel we have a lot of biomarkers, but we don't really look to incorporate [them all] in routine practice. I'm hoping in the future, we will be able to incorporate TIL, tumor size, liquid biopsies and more to really understand who needs lesser treatment. We'll be able to individualize therapies for our patients in the future. And, I really do think that hopefully, we will understand a lot more about how we can prevent breast cancer in the future with some of the factors I’ve been talking about. We don't want to just treat, we want to prevent.
BCRF gives you a lot of freedom to try out some riskier ideas. Fortunately for me, we did one of the first papers on single-cell RNA sequencing. And that was very successful, but at the time, it was extremely expensive. So, BCRF allowed us to work that technique up and apply that to human TILs. So that was very labor intensive and very expensive. But if I didn't have BCRF funding, no one would have given me money to do that. So that was really very helpful and helped us understand a lot about the TIL and certain subsets of the TIL. The whole community is lovely, and there's lots of interaction and networking and discussion about science. The annual meetings are really very motivational. From a scientific and research point of view, you really come back thinking, “I need to do this and this and this.” And [BCRF] gives you the freedom to explore a few things that you think might pay off. I've been very grateful for the support of BCRF. They're just such a fantastic organization.
I think the cure is near for breast cancer. So hopefully the next generation of women won't have to suffer as much as ours.
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