Podcast transcript
Could you lay some groundwork on the evolution of personalized medicine in breast cancer care? I'd like to start by talking about potentially less reliance on biomarkers to the use of organoids. In general, why do organoids represent a really exciting breakthrough in the care that we can provide patients?
Despite advances in biomarker-directed cancer therapies to predict tumor response, precision oncology still remains an imprecise science. Treatments ultimately need to prioritize and give into patients serially. Tumor organoid drug screens present an opportunity for us to test potentially more effective therapies simultaneously, and this would occur prior to giving this to a patient who would then have to undergo side effects prior to knowing whether the treatment will be effective.
When we give cancer treatments or chemotherapy, we are using treatments that work best for most people based on clinical trials, but there is still a subset of patients who may not respond as well. Organoids would be a potential opportunity to then test the drugs prior to giving it to the patient. Our goal would be to give clinicians a way to pick a chemotherapy or treatment regimen that works best for that individual patient.
Our goal is to individualize cancer treatments to that person, and everyone who has a cancer diagnosis has really unique aspects of that tumor. Giving a broad chemotherapy regimen to everyone may not work for everyone. So with our studies and our goal at RUSH is to really be able to individualize that treatment plan to that patient, and organoid research is a very exciting opportunity to do that even better.
Specific to breast cancer care, you are engaged with a pilot study to evaluate the clinical validity of tumor organoid drug screens. Can you give us some background on the study?
We are very excited to have this study opening soon at RUSH. With organoid studies, there is data on the analytical validity, which means that in the lab they've shown that they were able to develop tumor organoids by taking a piece of someone's tumor and grow it in a lab, but still retain the pathologic and molecular characteristics of the original tumor. And the next step is that we want to see if there is clinical validity, meaning can we use this tumor organoid to validate that testing drug screens on the tumor organoid does correspond to the treatment that people get when they're undergoing systemic therapy? Is there correlation between what the drug screens show on the tumor organoid with regards to response to people who are undergoing the treatments? Does it have similar concordance in the response both in a person and in the tumor organoid?
So we propose a metastatic disease model to evaluate the clinical validity of tumor organoid screens and systemic treatments. We chose metastatic disease because this gives us an opportunity to assess the organoid drug screen across multiple cancer types, and at the time of progression or a new metastatic diagnosis. So no matter what point a person is in their cancer treatment, whether it's a new diagnosis or if the cancer stopped responding to their initial therapy and they're looking to start a second line of therapy, this presents an opportunity to get testing on that tumor to see if there is a response. We will have this open to across all cancer subtypes, including breast. And this will also give us an opportunity to be able to create that tumor organ because it does require a biopsy of that site to create that organoid.
But patients already need a biopsy when they need to either confirm a metastatic diagnosis or sometimes when there is progression there is a need for additional biopsy. So it gives us a great opportunity at the time that a patient already needs to get a biopsy done for their cancer care, and also gives them an opportunity to participate in this trial.
Are there any limitations to the types of treatment that you can test on the organoid tissue?
The human body is very complex, so that is one reason why that we still need more data to figure out whether the tumor organoids correlate to the response in a person. And it's really to see if this organoid is a window the clinician can use to see if this will have a response. But there are some drugs that, at this time, we would not be able to test on tumor organoids, including treatments that utilize either the body's immune system or hormone changes in the body to treat the tumor. For example, in breast cancer, some forms of therapy include hormone therapy, and so, at this time, we would not be able to test because it does require the human body's ability to change your hormone levels to induce a response, which we obviously could not do in a lab and a tumor organoid. We do see hopefully more data coming out for this, but our first step is to really focus on the cytotoxic chemotherapies that are used and targeted therapies as well.
Does the information gleaned from organoid drug screening change the treatment approach for the oncologist?
What's great about this study is that, at this time, it won't change any of the recommendations that the doctors recommend for the patient, whether that's they get a mastectomy or they do a cancer treatment. It really is looking at response to therapy on the tumor organoid and also in the patient. What's also great about the study is that we will have our primary drug screen, which looks at the most common chemotherapy you use for that particular disease type, whether it's breast, prostate or testicular cancer, whatever treatment they're getting. And then we'll be doing additional drug screens to look for targeted therapy options, PARP inhibitors if they have a BRCA mutation or other therapies just to see what the response is. So we're going to be testing beyond just the specific drug that the patient is getting. We're doing a whole panel. We're really trying to explore what are these responses? And if that patient in the future uses any of those lines of therapy, does it still have a similar response?
And so we're gathering a lot of information beyond just the specific drug that they're getting at the time that they are on the study. We're kind of working together rather than, at this time, having our drug organoid results dictate what treatment the patient gets. Eventually, as we get more data and it supports the hypothesis that tumor organoids can be used as a drug screen to predict response, we would eventually start moving towards seeing if we can use a tumor organoid to pick the therapy for the patient. But our data's not there yet. We first need to establish that there is importance between the drug screen and what the patient is getting.
The use of organoids for drug testing sounds really promising, and I don't want to jump too far ahead. But I'm really wondering if this holds up and this is a valid approach, how close do you think you and RUSH will be able to actualize organoid drug testing within clinical practice?
That's really our goal, which is to move towards using this in clinical practice, then better individualize patients’ care. It will be some years before we can get there because there are steps that we need to take to be able to establish efficacy for that and safety for patients. But the first step really is to establish clinical validity, and RUSH is trying to take that step.
Do you foresee any potential drawbacks with data that you may get from organoid drug screening?
There are a couple of things that we are assessing at the same time. First, we have to establish that we can successfully develop an organoid. When we get the tumor, we want to see the percentage of viable organoids that are able to be grown from specimens. And from prior studies, that can be anywhere from 50 percent to 80 percent. And so that's the first thing we need to assess. Second is we need to know the timeliness because, when someone has a cancer diagnosis, we need to be able to develop organoids quickly, do the drug screen quickly to get the information quickly to make a therapeutic decision. So we are also going to be looking at how quickly can we get this done, and is it within a reasonable timeframe to help clinicians make clinical decisions.
And then we're also going to look at the drug screens. Can we run the drug screens and are they consistent with what we see when patients undergo cancer treatment? We want to see if the response in an organoid is similar enough to the response that we see in patients, and we use that through different quantification methods. And so there are a lot of steps that we are taking and assessing at the same time to make sure that it will be ready for patients, once we get there, to be an effective and safe tool for clinicians and patients to use.
For context, do you know offhand how unique RUSH is in this space of looking at organoid drug testing? Are we one of only a few centers looking at this or there are many centers around the country that are looking to the very same issue?
Organoid technology is becoming a hotter topic in cancer research, and more and more institutions are looking into this. To my knowledge, RUSH has been on the forefront of a lot of this, working with companies to help produce the organoids. And we've already been developing these for a couple years now. Our group's goal is to try to take this to the clinical, from the bench to the bedside. We're really trying to use what the researchers have found in labs to be able to make it helpful and useful for both clinicians and patients.
It seems to me that organoid drug testing could ultimately spark an exponential growth in the development of novel therapies, whether that is for a specific patient or perhaps an entire subset of patients, because clinicians can iterate with multiple therapies in real time. What are your thoughts on this?
We are very excited about this technology. Our goal is always to personalize medicine to the patient, and our clinical trials are great. It helps a lot of patients, but not all patients respond. By being able to find novel, unique ways to try to fill that gap in our knowledge, we think organoids have great potential. But it's just now trying to get the data to support our hypothesis. This is an exciting step towards that.
I want to pivot in our conversation and talk about pregnancy-associated breast cancer or PABC. How prevalent is pregnancy-associated breast cancer and why is the incidence of it increasing?
Breast cancer is the most common cancer of women of reproductive age. Pregnancy-associated breast cancer is diagnosed from pregnancy up to one to two years postpartum, but some people even include it anytime as long as women are lactating. Some women may breastfeed for three, four years, however long they want. So, this is really the definition of what we consider pregnancy-associated breast cancer. There are some changing definitions. Now there's a kind of pregnancy-associated breast cancer and also postpartum breast cancer, because there's more data showing slight differences within these tumors when they're developed during pregnancy versus when they develop in the postpartum period or lactating period. For breast cancer in pregnancy, it's in about one in 3,000 pregnancies. And it's the most common cancer during pregnancy, particularly when women are above the age of 35.
When you look at breast cancer in women under 50 years old, it's less common, about five percent. But when you look at women under the age of 30, it goes up to about 20 percent. So, you can see, based on what ages the women are, the risk of that changes slightly. The majority of the cases of pregnancy-associated breast cancer were diagnosed in later stages, stage 2 or 3, compared to stage 1. And there are a lot of theories regarding why that is.
One is that, during pregnancy, a lot of the care is really focused on the baby. Women may undergo their mammograms or not get their breast exams done, or they may have breast swelling that is normal in pregnancy, so they don't think much of it. But a takeaway point for that is anytime a woman has a breast lump that is there for greater than two weeks, it should undergo evaluation. And so that's really important. So, for breastfeeding or pregnant women, if there's a lump there for greater than two weeks, it should undergo testing.
For your question of why is this occurring and increasing in incidence, there are a couple of theories of why. One is that, with the increasing incidence of women delaying childbearing, it's being a main consideration just because we know the incidence of breast cancer also goes up with age. The median age of when women are diagnosed with pregnancy-associated breast cancer is 33. And the rate of pregnancy-associated breast cancer, based on the study you look at, can be anywhere from 2.6 percent to 6.9 percent. It's also important to know that BRCA carriers are kind of overrepresented in this population. And so that is why knowing your family history and considering getting tested is very important, if that's the case.
There are some risk factors beyond just increasing age of childbearing that can be associated with this. Family history is really important, BRCA1 or 2 carrier status or other mutations; having a higher age of your first pregnancy, so particularly above age 25 or age 30 in particular, and then over 30 years at your first delivery. Also having an early age of menarche, so less than 13 years old at your age of your first period and having a higher VMI are also associated with pregnancy-associated breast cancer.
Besides what the risk factors of those are, what are things that have been shown to decrease the risk of pregnancy-associated breast cancer? And one of the really important ones is breastfeeding, which is thought to be protective from pregnancy-associated breast cancer. They don't really know exactly all the reasons why. Some interesting hypotheses that I think is interesting is that, when women are pregnant, the breast cells express these oncogenes that help promote proliferation survival to them to be able to lactate. These cells need to be eliminated at the end of pregnancy in involution. A longer duration of breastfeeding helps promote cells that terminally differentiate, and then kill the oncogene expressing cells. And so when you have little-to-no breastfeeding, this might allow an inflammatory environment leading to a breast cancer development. So that's one theory, although I think we still need to learn more and more about this particular type of cancer because it's very unique than the usual breast cancers that we see.
I would think that treating pregnant mothers with breast cancer is challenging, and I would assume that you would need a tertiary care center like RUSH to treat patients with this condition. I'm curious why. What specific tools or infrastructure does RUSH have to support women diagnosed with this condition?
It is recommended for all adolescent and young adult—or AYA—population, particularly during cancer and pregnancy, to be considered being treated by a tertiary academic center. And these are very challenging cases that required a lot of complex multidisciplinary care. And so that includes, of course, the medical oncologist, but also the psychologist, chaplains, surgery, breast surgery and plastic surgery. If a woman decides to get a bilateral mastectomy, a lot of times you need a social worker, child life and financial counselors. A lot of these women, when they're younger, they're kind of in the early stage of their career. They might not have as established finances, have young children. If you have to have a treatment where you have to go every day or once a week for radiation, it might be very difficult if they have young children at home or whatever circumstance they're in. You need genetic counselors, of course, you need an anesthesiologist that is trained, especially in these difficult cases when they're undergoing surgery, physical therapy, occupational therapy, nutrition, sometimes even cancer rehab, reproductive endocrinology, primary care, pediatrician, neonatologist, pathologist, lactation specialist, maternal fetal medicine, specialized OB.
There's a whole wide group of people in the healthcare field that are needed to treat the individual patient. They have a lot of very unique challenges being someone who's younger, particularly under the age of 40 that needs support to help them through this diagnosis. And then survivorship after that. What are their fertility considerations? What are their plans? There's a lot that goes into it. RUSH has these, particularly they do have support groups specific to the AYA population which is also very highly recommended, because having someone that the person who has a cancer diagnosis can help connect with and relate to or get advice from people who underwent a similar situation, all of those are very helpful.
I'm curious about how you harness all those tools, that multidisciplinary approach to caring for women with PABC. Can you go into some more specifics about the treatment strategies you might employ and the challenges that you may encounter when treating women with this?
I think first, communication is key. There's a whole wide variety of people that are needed. Here at RUSH, we have a comprehensive breast clinic where a lot of these resources are actively available or can come visit during that time. We have, during the tumor board discussions, specialists from other specialties who may not typically come to our tumor boards. We can invite them to listen in and give their expertise. So, having ways to help with communication and come up with a treatment plan as a team is very crucial. As far as the treatment, it can be challenging because the goal is we want to appropriately treat breast cancer to benefit the mother's life, and we want to be aggressive in treating that to give the mother the best chance for outcomes, but we also need to protect the fetus and the newborn from the harmful effects of cancer treatment. So you really have two patients you're thinking about here when you're treating someone who is pregnant.
And there can be a lot of challenges. One, it's very psychologically and emotionally challenging for the mother and the family. And there's also, unfortunately, a lack of clinical data to help guide clinicians because pregnant women are often left out of clinical trials to help develop treatment plans. So there's a lack of safety data. That can bring a lot of anxiety for both the patient and clinicians, and it can be quite challenging. How to treat it really depends on what trimester the patient is in. For example, in the first trimester, we really want to avoid using chemotherapy, radiation and some other therapies. So really when the patient is diagnosed, the timing of their destination really helps us develop a treatment plan. Depending on that, the time that they're diagnosed and depending on their stage, sometimes we'll do chemotherapy first or surgery first.
In general, the surgery is felt to be safe in second trimester and beyond. It is usually recommended to avoid in the first trimester just because there's a perceived increased risk of spontaneous abortion or miscarriage. In this time, it's unknown if it's directly related to surgery. However, there are also some considerations when you're undergoing surgery, such as what type of dye you use when you're doing a sentinel lymph node biopsy.
As far as radiation therapy, it's not considered safe at any point in the treatment when someone's pregnant. That is safe for the postpartum period. As for chemotherapy, in general, it is recommended to wait to the second trimester to start chemotherapy. But there are some chemotherapies that have some data suggesting safety in women undergoing treatment. In general, depending on the type of cancer and based on standard of care treatments, we would give chemotherapy, if indicated, starting in the second trimester. There are some cancer treatments that cannot be used during pregnancy, and that includes HER2-targeted therapy antibody treatments as well as hormone therapy. We wait till the postpartum period.
Overall, what's the prognosis for mothers and the babies, and what are the expected outcomes for them if they get treatment?
Fortunately, prognosis is pretty similar to age match controls in modern studies. There were some older meta-analyses that suggested increased mortality and recurrence, but this was felt rather too delayed and less effective therapies being given rather than it being from having a breast cancer during pregnancy itself. Pregnancy does not necessarily indicate that they will have a higher risk of recurrence mortality. It's more so when they get diagnosed, if they're at a later stage, that likely has more impact. So delaying diagnosis should be avoided. And like I mentioned before, making sure any woman who is pregnant or breastfeeding has a lump that is present more than two weeks should get evaluation. And this is particularly important.
You might hear women who are breastfeeding say, "Oh, I thought it was a milk duct cyst or something like that." They should still be evaluated if it's persistent over two weeks. Risk of metastases increases by 5 percent to 10 percent every few months with a delay in treatment. So that's why early detection is crucial.
As far as fetal neonatal outcomes, there was a larger study published in 2018 that had 428 women diagnosed with breast cancer during pregnancy. 86 percent of these patients had a live birth, and about 50 percent of patients did have premature birth at this time. So when you look at fetal neonatal outcomes in cancer over the years, it has been shown that the amount of live births have increased over the years, probably just because of better supportive cares and better knowledge about the chemotherapy. There is a higher risk for small gestational age in newborns who had intrauterine chemotherapy exposure.
There was about a four percent malformation in this study that was done as well. Although when you look at newborns who were born after intrauterine chemotherapy exposure, the data is very scarce. The long-term outcomes in children are uncertain. But most data suggests actually no significant neonatal complications, which is reassuring. There was one study looked at children who had exposure for hematologic malignancies with a follow-up about 18.7 years, and there was no neurocognitive, physical or psychological complications at that time, and that was 84 children in this study. So I would say overall, the data that we have, although limited, is promising, although having more data in this would be very helpful.
Another question that a lot of patients may ask is, if I had breast cancer and I want to get pregnant in the future, is it safe? That's a big thing that a lot of women ask. And from the data we have, yes, the answer is that it appears to be safe after pregnancy. The timing, especially with what treatments they get during pregnancy, needs to be considered. There are certain medications where you have to wait a certain time prior to conceiving. That's something that I believe that, when developing a treatment patient, right when the patient comes in, keeping in mind their fertility desires and plans for the future should be incorporated and discussed with every patient that you see. And that's just a crucial part of the patient survivorship plan, and it's very important to them. It's something I do and here at RUSH that we try to focus on as well.
