Personalized Medicine- Cancer treatment at the molecular level
In this roundtable, Eisenhower Health physicians join those from UC San Diego Health who participate in the UC San Diego Health Cancer Network affiliation that expands Eisenhower patients’ access to university-level care. This includes the Molecular Tumor Board, where Moores Cancer Center at UC San Diego Health and Eisenhower Lucy Curci Cancer Center oncologists collaborate virtually up to three times per month to review challenging patient cases.
Read on to delve deeper into the ways physicians are integrating personalized treatments, from molecular targeting to how prevention and risk factors play into molecular profiling.
The panel includes:
• Constantin Dasanu, MD, PhD, Board Certified Hematologist/Oncologist, and Director of Research at Eisenhower Lucy Curci Cancer Center. Dr. Dasanu is also the principal investigator for a number of National Cancer Institute and pharma clinical trials at Eisenhower Lucy Curci Cancer Center.
• Shumei Kato, MD, Board Certified in Medical Oncology, a UC San Diego Health oncologist who travels monthly to the Cancer Center in Rancho Mirage to see patients in the Personalized Medicine Clinic. Dr. Kato has a special interest in targeted molecular therapy and his approach to care emphasizes personalized medicine and experimental therapeutics.
• Lisa Madlensky, PhD, a Board Certified Genetic Counselor who provides cancer risk assessment and genetic counseling for patients and their families. Madlensky helps people investigate their family health history, navigate the genetic testing process and understand and adapt to the medical or psychological implications of genetic diseases. She is director of the Family Cancer Genetics Program and researcher at Moores Cancer Center at UC San Diego.
• Justin Thomas, MD, Board Certified in Pulmonary Disease, Interventional Pulmonary Disease, Critical Care Medicine and Internal Medicine, moderated the discussion.
Dr. Thomas: Thank you for joining us for the oncology roundtable. We’re going to be discussing personalized medicine and how that relates to oncology. Dr. Dasanu, could you begin with a description of personalized medicine?
Dr. Dasanu: Personalized medicine is a sophisticated approach to cancer treatment based on recognizing differences between patients with the same disease.
Dr. Kato: Personalized medicine for me is understanding the patient’s underlying molecular or immune profiling and working from there.
Dr. Madlensky: I would say personalized medicine is using biological information from the patient or their tumor to maximize the probability of successful treatment and minimize the probability of harms.
Dr. Thomas: It’s important to state that not every tumor is the same and not every patient is the same. Even different tumors within the same patient can be different and respond differently to treatment. How does that differ from a traditional cancer treatment?
Dr. Kato: For the past three or four decades, we’ve been trying our best to find the one-size-fits-all approach. Now we know that patients are different molecularly - even if they have the same cancer diagnosis - and the cancer gene can change. When it comes to a personalized therapy approach, I think we will have to understand as much as we can for each patient’s underlying cancer and its biology.
Dr. Dasanu: I would add that there are three Ps of personalized medicine. Firstly, it is precise, by targeting the unique signature of a particular cancer in a given patient. Secondly, it’s preventive: the more information you have, the more efficiently you’re able to prevent occurrence of a cancer originating in the same organ or other organs. Thirdly, it’s predictive, meaning that you are able to predict occurrence of some cancers after you’ve identified the individual’’s genetic information. To add a fourth, personalized medicine is also participatory, as both the physician and the patient participate in how to tackle management.
Dr. Thomas: What does it mean to treat cancer at the molecular level?
Dr. Dasanu: The treatment focuses on a precise genetic and molecular signature. That signature includes the genetics of the cancer and the patient, but also considers environment, diet, lifestyle and socioeconomic factors of the individual.
Dr. Thomas: Could you explain what is molecular targeting and what is its significance?
Dr. Kato: Molecular targeting transforms how we treat cancer patients. In certain cancers, targeting specific genes has really transformed the care, but we have more work to do to optimize the targeting for a better response in survival for patients.
Dr. Madlensky: One thing to think about is the idea that the older treatments for cancer developed decades ago were based on the simple premise that cancer cells grow faster than normal cells. The harsh chemotherapies were designed to target fast-growing cells, but in doing so, they also caused collateral damage to normal cells; that’s a lot of the side effects that happen after someone has cancer treatment. Then, there was recognition that fast growing versus slow growing is not the only differentiator. Cancer cells have a lot of different biological characteristics that make them different from normal cells. The idea of: Can we get better at separating out cancer cells and getting rid of them while protecting the normal cells, is all based on the incremental increases in understanding of how cancer cells are different and what can we use to exploit those differences. That progression is at the individual tumor level: What makes this tumor a cancer? What are the molecular changes? What are the biomarkers that are unique to this tumor? And, do we have treatments that can target those differences?
Dr. Thomas: And would you say the development of molecular targeting therapies has led to a decrease in side effects or an increase in efficacy?
Dr. Dasanu: It’s a complex question,
Dr. Thomas: Personalized medicine has been occupying more and more territories in cancer medicine. Over time, personalized therapies tend to be more efficient and accurate because they target better. They produce somewhat less collateral damage than chemotherapy, yet toxicity can still be significant. As of today, I’m not ready to throw in the towel on traditional chemotherapy agents. For instance, in pancreatic cancer, testicular cancer, glioblastoma and most ovarian cancers, the mainstay remains traditional chemotherapy. In many cancers, a combined approach of traditional and targeted agents is preferred. As a result, today we still use “the best of two worlds,” new targeted agents, old chemotherapy and a combination thereof.
Dr. Kato: For some patients in my practice, for whatever reason, chemotherapy works for a long time and we just don’t know who those patients will be. There’s a portion of patients who may respond to everything- so we try everything in an effort to achieve better overall patient outcomes.
Dr. Dasanu: In combined approaches, chemotherapy is used for a limited time - four to six cycles - and then the targeted agent or immunotherapy will be continued often in the event the cancer returns. In the future though, sensitivity to chemotherapy will likely be tested for before offering it to all cancer patients.
Dr. Thomas: What is an immune checkpoint inhibitor?
Dr. Dasanu: Immune checkpoints are receptor proteins on the surface of T lymphocytes, or T cells, a subset of cells of the immune system. Some of these cells live long, such as the memory T cells, but most of them have a predestined lifespan of 30 to 80 days. Ligands (proteins manufactured to interact with the receptors) bind to these checkpoints, sending inhibitory signals inside cells. As a result, the T cells have a limited lifespan, which is necessary to prevent autoimmune conditions (an attack against the body’s own tissues). Immune checkpoint inhibitors disrupt this interaction between the receptor and its inhibitory ligand. As a result, T cells are activated and live longer lives, many of them for years, not just 80 days. By living longer, they also multiply, and this activated “army” of T cells attacks the cancer cells and destroys them. In the process, healthy organs can be affected to a certain degree, a process known as autoimmune side effects of immune checkpoint inhibitors.
Dr. Thomas: You mentioned earlier about prevention being one of the Ps in personalized care. Dr. Madlensky, do you have anything to add about molecular targets and prevention and counseling for patients and families?
Dr. Madlensky: One of the main questions I get in the genetics clinic from cancer patients who are going through genetic testing or molecular profiling is: Why did this happen? Why me? Often, going through how a cancer develops and what turns a normal cell into a cancer cell, and how that knowledge can be used to direct treatment gives patients a real sense of empowerment - either for cancer treatment or determining their genetic risk for cancer, as well as opportunities for prevention, early detection or risk reduction. The body has trillions and trillions of normal cells and they each have a particular genome packed inside. They’re constantly growing and dividing through a person’s entire life. The old cells die off and the new cells replace them. As a person goes through life, genetic errors occur in the body’s cells by exposures to carcinogens. For example, smoking. Smokers are putting cancer-causing agents right into the lining of the lung, in effect, accelerating that process and creating more damage to the DNA in those cells. Over time, if the body accumulates enough damage in the DNA of a single cell - UV light from sun tanning or maybe it’s just the randomness of the genetic changes that occur - these genetic changes occur and if enough of them occur in important areas of the body’s genome that are responsible for controlling the normal pattern of cell growth, a normal cell can turn into a cancer cell.
If the immune system recognizes that as an abnormal cell and eliminates it, that’s wonderful. We think that happens all the time. But if it evades the immune system, then that can be the beginning of a cancer.
Where this ties into personalized medicine is that all of those genetic changes that happened over time, those are the changes that make up the molecular profile of that tumor. And that’s why every tumor is unique because every tumor went through a different process.
he other concept that people often find really helpful is the idea that some of these genetic changes that we’’ve accumulated over our lifetime in cells turn a switch on and lead to accelerated growth. That’s where tumors come from. Other genetic changes we have are something that’s normally doing maintenance work in the cell, like proteins that are busy repairing damage to our cells, that get turned off and shut down.
Molecular profiling helps people understand the biology of what is going on in a cancer cell and why one person would get this personalized treatment, but isn’t offered to others. Or, how does one person get cancer in the first place when they’ve lived a healthy lifestyle? All of those things go together and help empower people to make decisions about their choices for treatment and why something is being offered as an alternative treatment or as a primary treatment.
Dr. Dasanu: Environment and diet are important as well. A study conducted in women with breast cancer showed that saturated and trans fats speed development of breast cancer. Obesity is associated with a number of cancers, about 13 or more different ones. We recommend weight loss to patients who are overweight or obese, because they are at increased risk for several cancers. In cancer patients, obesity tends to make their outcomes worse. This is now proven in colon, breast and prostate cancer. Interestingly, kidney cancer is one type of cancer where weight loss is not typically recommended. Research has shown that stage 4 kidney cancer patients who are overweight or obese tend to have better survival rates compared to those with lower body weight.
Dr. Thomas: Dr. Madlensky, you had mentioned we’ve got cancer cells all the time that are in our body and our immune system is fighting them. What are some ways that a cancer cell would evade the immune system?
Dr. Madlensky: Not only is our knowledge evolving, but the tumor within one individual is evolving. I think a lot of people are familiar with the idea of antibiotic resistance. If you treat a bacterial infection with some type of antibiotic, you’ll kill off the majority. But if there’s even a single bacterium in there that is resistant to that antibiotic, it will survive and multiply and now you have a population of resistant bacteria.
The exact same concept applies to cancer. Again, it’s mutations occurring within the cancer cells that develop in real time, which make the cancer resistant to some of the earlier treatments that occur. It’s really this very complicated back and forth. This is the idea of cancers that are resistant to treatment or as was mentioned earlier, start responding really, really well. The idea is called subclones of cancer. There’s a tumor, but it’s not like every cell within that tumor is identical. You might have a cell within a tumor that acquires another mutation that the rest of them don’t have, and now it starts kind of going off and doing its own thing. Maybe that subclone of cells will respond to a certain treatment when the main tumor didn’t. So, treatment can be a constant cat and mouse game of trying to get as much coverage as possible for as many of the subtypes that have happened as that tumor has grown and evolved over time.
Dr. Thomas: You’re saying I could start on one of the personalized medicine therapies and respond well, but then eventually stop responding. Then my cancer can grow and I might need to be put on another type of treatment. How often would you say that happens to patients with advanced cancers?
Dr. Kato: At some point, a lot of patients will experience the tumor progression along with a new mutation. We try to always repeat the molecular profiling from a biopsy or at least from cell-free DNA, and try to understand the biology and hopefully define additional targets for each patient. Similar to the genomic complexity, heterogeneity from patient to patient, the resistant mechanism is also very heterogeneous. There’s not only one way that the cancer finds a way to become resistant.
Dr. Thomas: How do we determine what molecular targets a patient has? What type of testing is needed?
Dr. Dasanu: It depends on the cancer type. There are many commercial tests available. Each cancer type comes with a molecular/genetic panel. For example, in colon cancer, do they have KRAS or NRAS mutations present? This is one of several questions that has to be answered in order to select optimal therapy. But in reality, it’s much more complex than that.
Dr. Thomas: Are the molecular targets found in testing a tumor tissue or a blood sample?
Dr. Kato: Both the tissue and blood sample testing have strengths and weaknesses but both testing should be done for every patient.
Dr. Thomas: One can see certain mutations with one modality that you wouldn’t with another? How accessible is this testing for patients? What are the pitfalls, the costs, the difficulties in obtaining these tests for patients or for doctors for that matter?
Dr. Dasanu: In the United States, we are able to perform molecular testing in most patients, but this is not inexpensive. In many parts of the world, physicians don’t have the luxury of offering this testing to patients. We’re privileged in this country in that regard.
Dr. Madlensky: To paint a broader picture, when somebody is first suspected of having a cancer and if it’s in a location that is amenable to getting a biopsy, the first tumor profiling that happens is in the pathology lab under a microscope. The first three things you’ll read about any breast cancer are estrogen receptor, progesterone receptor and a protein called HER2. Is the tumor expressing it or is it not expressing it? Every single colon cancer should be tested in the pathology lab for something called mismatch repair deficiency. That can be done with some stains on the tumor cells.
The goal is, even though the physician is starting out with a type of cancer right away, we’re sub classifying it. Then, as we get into the more advanced profiling, we can again look at the tumor tissue itself, send it to a molecular lab where they’’re going to check the sequence of the genes in the tumor and identify which genes have mutations, which ones are turned on, which ones are turned off, what are the potential targets, and put that in a report.
Cell-free testing is getting a blood sample. The idea there is that tumor cells are dying and breaking open in the body wherever they may be, and they’re shedding some of their DNA into the bloodstream. When an oncologist orders a cell-free DNA test, they’re getting a blood sample and then the laboratory is trying to find little fragments of tumor DNA that can give clues as to the genetic makeup of the tumor itself. I focus on germline testing, which is not testing anything related to the tumor, but the DNA that a patient got from their biological parents. Sometimes people are born with one of these mutations in every single cell of their body that they inherited from a parent, and that is the first mutation that potentially can kick off the road to cancer development.
to your point about cost, there was a consortium of academic medical centers in California last year that advocated to the state of California to improve insurance coverage for biomarker testing for cancers. It speaks to the point that this is something that’s considered standard of care for treatment because we know there’s an evidence-based treatment and we need the biomarker to guide the treatment. Those are typically going to be covered by insurance. If something is very novel and it’s not really clear yet, often that’s being tested in a clinical trial and they’re usually the ones that are paying for the profiling if it’s going to help them enroll people into the trial.
Dr. Dasanu: Cell-free DNA testing tends to be not very accurate because it doesn’t reflect solely the cancer process, but may also reflect aging and inflammation in the body. I’m more excited about circulating tumor DNA (ctDNA) to monitor the response to treatment. These are minute amounts of cancer DNA that can be detected early, leading to treatment being started in a timely fashion and to better outcomes. Conversely, if the ctDNA is not detected, it represents great news for the patient and no further treatment is needed.
Dr. Madlensky: It’s extremely complicated, and is one of our biggest topics at the Molecular Tumor Board. We always have to take a step back and say, well, before we answer this, what lab did the testing and what are their technical specifications and what did they count? How did they count it? How did they measure it? What are they comparing it to? What’s their interpretation? And often we end up calling the laboratory about specific cases to say, can we get into the weeds with this one a little bit more because this seems really low, but the tumor’s behaving as if this marker was really high. And they may have just changed the way they report this on tests. When we teach oncology residents and fellows, we do some lectures called Tumor Profiling 101 or the Anatomy of a Tumor Profile. The lectures have to be updated constantly because the laboratories, technology and evidence base for what does and what does not go on a report is all dynamic and happening quickly. One of the benefits of the Molecular Tumor Board is that we can all have input and talk through what we think makes the most sense based on all of these parameters.
Dr. Thomas: What do you see as the future of cancer treatment at the molecular level? Are there new therapies or ideas coming out that seem promising?
Dr. Kato: Right now, the molecular or immune markers are being tested very routinely; however, not only that, but the RNA level or functional level or epigenomic level. Hopefully, we can come up with a truly individualized cancer therapy approach for every patient in the future.
Dr. Thomas: Where are we with the development of vaccines for cancer?
Dr. Dasanu: Therapeutic vaccines in cancer medicine are still very much in their infancy. We have a vaccine approved for low-volume metastatic prostate cancer, but its manufacturing process is laborious and expensive. Its efficacy is marginal, making it unpopular among oncologists. Another one is the BCG vaccine used only in early-stage bladder cancer when it is injected repeatedly into the bladder by urologists. I am more excited about lifileucel, a (vaccine-like) tumor-derived autologous T cell immunotherapy for patients with heavily pretreated metastatic melanoma, approved in 2024. Roughly one in three patients respond, but it’s almost prohibitively expensive at about $3 million dollars per course of treatment. I would add that mRNA cancer vaccines are one of the ongoing research fields, but there are a few other platforms being developed.
Dr. Madlensky: Let’s imagine 10 years down the road, cost is no object and we have all the technicalities worked out. You can imagine a newly diagnosed cancer patient getting a genetic test for their inherited DNA. Was this cancer caused by something that’s potentially running in my family? And that has opportunities for prevention for the patient and for their family members. You can imagine that the tumor profiling has advanced. And so, there’s better techniques to really understand what are the things that are in excess in a tumor and what are the things that are missing in a tumor and how do the treatments exploit that? But then there’s also all of these tangential but important things that come down to avoiding some of the difficult side effects that happen with cancer treatment. So, pharmacogenomics is one.
There are a few chemotherapies that have a genetic test companion test. For example, before you give a particular type of chemotherapy, maybe there’s 1% of the population that genetically doesn’’t make the enzyme that can help break down the molecules in that treatment. It builds up very quickly and causes some very toxic side effects. Knowing that before you treat the patient is going to be very important. The other really interesting area is predicting who may have a difficult response to radiation treatment and have increased levels of radiation toxicity. The way our bodies repair the damage in the normal cells that radiation treatments can cause is highly variable from person to person.
And then, this goes along with the cell-free DNA and the circulating tumor DNA, but more the long-term monitoring over time that goes into survivorship. At the end of the day, that is where we hope most of our patients land.
Dr. Thomas: What is Eisenhower’s affiliation with UC San Diego Health Cancer Network and how does that impact our patients?
Dr. Dasanu: It’s a very rewarding and beautiful experience. We periodically review our cases at the Molecular Tumor Board at the Moores Cancer Center at UC San Diego Health via Zoom with our exceptional colleagues who help us navigate through those difficult cases. Drs. Kato and Madlensky are almost always there. They helped me understand my cases at the molecular and genetic levels, and identify potential new therapies. This collaboration has translated into a longer life span in some of my patients with advanced cancer. I’m very grateful, and so are our patients and families.
Dr. Kato: It’s a pleasure working with the Eisenhower team, and hopefully, we can try to come up with the best solution for each patient.
Dr. Madlensky: I’ve had a clinic with Eisenhower patients going on 10 years now. But I think the one thing that has really stood out to me over the years is the Eisenhower surgeons, oncologists and all of their treatment teams. I’ve found that Eisenhower patients are often forward-thinking and want to understand their tumor biology. And I think for that reason, the relationship with a lot of the clinical trial offerings at Moores Cancer Center at UC San Diego Health and the patient population and the care teams at Eisenhower has been a really wonderful collaboration and affiliation.
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