Sandeep K. Reddy, M.D., is the Chief of Staff at Los Alamitos Medical Center in Los Alamitos, Calif., and also serves as a Clinical Professor of Medicine at the David Geffen School of Medicine at the University of California, Los Angeles (UCLA). Dr. Reddy is board certified from the American Board of Hematology, American Board of Internal Medicine and the American Board of Medical Oncology. Along with maintaining a clinical oncology practice, Dr. Reddy also serves as a Senior Medical Director at Caris Life Sciences. Dr. Reddy generously agreed to answer questions for us on tumor profiling in general and tumor profiling for metaplastic breast cancer patient specifically.
Q: Can you define some common terms for us? For example: what are biomarkers and mutations, and how are they different? Are there other terms we need to understand?
A: Some common terms that would be helpful to know and understand when thinking about tumor profiling include:
Q: What is tumor profiling, and what information does it provide?
A: Tumor profiling is the use of a series of advanced pathology and genomic tests to identify a patient’s unique cancer biomarkers, which may then be associated with drugs that are more likely (or less likely) to be effective. In Caris’ tumor profiling service, these biomarker-drug associations are derived from assessing thousands of scientific and medical studies/data points. Tumor profiling is typically used in cases of rare, aggressive and/or difficult-to-treat cancers, often when the standard-of-care has been exhausted or is limited. A patient’s ability or likelihood of finding clinically useful drug associations from Caris’ service does NOT depend on the known results from other profiled patients with their same cancer type. Within the same cancer subtype, tumors can display very different molecular landscapes. For example, a colon cancer patient is profiled and finds that their tumor expresses HER2, making them a good candidate for lapatinib or trastuzumab (typically considered breast cancer drugs), which wouldn’t have been otherwise considered. Tumor profiling may also be highly useful to inform clinical trial selection. Each Caris tumor profiling report identifies open, relevant clinical trials based on the patient’s tumor type and biomarkers expressed. The report provides additional information related to the trials, including: protocol number, study title, phase, featured drug and biomarker, and locations accepting subjects.
Q: What types of genomic information do you gather?
A: Caris Molecular Intelligence includes DNA, RNA, proteomic (protein) and other types of genomic analysis. This analysis is performed through a combination of technologies, including immunohistochemistries (IHC), fluorescence and chromogenic in situ hybridization (FISH and CISH), polymerase chain reaction (PCR) and sequencing. This type of tumor profiling is typically called comprehensive tumor profiling, as it assesses all major biological components of the tumor. From a genomic perspective, Caris gathers mutational information through next-generation sequencing (NGS) and Sanger sequencing. We also collect gene copy number information through FISH or CISH. Additionally, we can measure gene expression indirectly through its effects on RNA, which is measured through PCR and protein via IHC.
Q: Can we see what a test report would look like? How do you read the report? What are the potential recommendations?
A: Several Caris sample test reports (called MI Profiles) for a variety of tumor types are available online here (http://www.carismolecularintelligence.com/sample_reports). These reports are designed to be interpreted and read by your oncologist. Each MI Profile report provides a summary listing of drugs associated with potential clinical benefit, drugs associated with potential lack of clinical benefit, and relevant, open clinical trials. The report also includes patient-specific information such as biomarker expression levels and pathologic diagnosis. All of this information is driven by your tumor’s unique biomarker expression levels.
Q: How does the tumor sample acquisition and submission process work?
A: Typically, tissue from a patient’s tumor is obtained during surgical removal of the tumor, or from a sample collected during a biopsy. Performing tumor profiling on as recent a tumor sample as possible is important, as your tumor’s biomarkers may change over time (as disease progresses) and may also change as a result of treatment. If your doctor elects to send your sample to Caris, the tissue is then sent to the company’s laboratory in Phoenix, Ariz., which is now the highest-quality lab of its kind in the world due to its multiple industry standards certifications (CLIA, ISO 15189 and New York State). Once the sample and required paperwork are received from an ordering physician, the entire profiling process takes approximately two weeks. The report is delivered directly to your physician for review. I would encourage you to ask your oncologist to walk through your results with you.
Q: How is tumor profiling different from genetic tests like BRCA, BROCA, BART, etc., testing? Or different than a Mammaprint?
A: There are different ways a tumor can be molecularly assessed. Some companies/services look to identify genes in a patient’s DNA that can indicate an increased risk of developing certain cancers (BRCA1 and BRCA2 are examples of this type of cancer gene). This is genetic testing for cancer patients. Tumor profiling (and specifically services like Caris Molecular Intelligence) performs genomic testing. Genomic testing looks at the unique compilation of proteins, genes, (including somatic mutations) and other biological molecules in your tumor to provide you and your doctor treatment insights for your cancer.
Mammaprint and comprehensive tumor profiling are different types of tools. Mammaprint is a prognostic/predictive tool that analyzes a set number of genes (typically from an early-stage breast cancer patient) to determine if the cancer has a high or low risk of recurrence (coming back) within the first five years post-diagnosis. Tumor profiling (specifically services like Caris Molecular Intelligence) is intended to provide a doctor and patient with the biomarkers expressed in the patient’s tumor, along with associations for drugs that may be more likely to work, less likely to work and/or open and enrolling clinical trials based on what biomarkers are expressed.
Q: What is chemotherapy sensitivity testing, and how is it different from tumor profiling?
A: The American Society of Clinical Oncology (ASCO) defines chemotherapy sensitivity testing as laboratory tests that have been studied to help predict how well chemotherapy may work. However, ASCO has issued their opinion that these tests should not be used to determine treatment options for a patient. Essentially, these tests have been looked at in research studies as a way to predict whether chemotherapy will help treat the tumor, or if the tumor is resistant to chemotherapy. Tumor profiling, in contrast, looks at the genomic characteristics of a tumor to illuminate possible drugs of benefit, drugs unlikely to benefit the patient. Additionally, tumor profiling, because of the genomic information it uncovers, can also help inform clinical trial selection, as many trials are now being structured around biomarker expression status.
Q: What is the cost of tumor profiling and is it typically covered by insurance?
A: Should your doctor order Caris Molecular Intelligence, Caris will bill your insurance company directly as an independent service provider and work directly with them to process the claims. You may receive a bill for the deductible or co-payment (according to the terms of your insurance plan). Typically, the deductible for an in-network plan should not exceed $500. For out-of-network plans, Caris limits the maximum out-of-pocket patient charges to $550. On average, it typically takes 60 to 90 days for most insurance companies to respond to Caris’ claims. Caris Molecular Intelligence is routinely reimbursed by most insurance providers, however, if coverage is denied, the company may be able to work with the insurance provider to file appeals and pursue coverage on your behalf. If a patient is uninsured, Caris has created payment programs, including self-pay discounts, to help provide additional financial flexibility. If a patient opts to pay the full price of the testing in cash, the cost is $5,500.
Q: Is there value in having tumor profiling performed AFTER a patient has begun therapy?
A: As I mentioned above, your tumor’s biomarkers can change as your disease progresses and the drugs regimens you take alter your tumor’s characteristics. Therefore, there may be value in profiling even after you’ve begun treatment.
Q: Metaplastic patients have up to 50% recurrence rates, however, the secondary tumors are not always the same as the first. For a woman with a recurrence, does it make sense to have both tumors profiled? Is there any information that can be gained by comparing the two or following the change in the cancer and how it has become resistant to treatment?
A: Yes. It certainly makes sense for a patient with a recurrence to have a second biopsy and second tumor profile performed. Tumor heterogeneity is a real issue, and it is well described in lung and colon cancers that the molecular signature and the sensitivity to various treatments can change over time in response to treatment. Learning the mechanism of resistance to a treatment can give us new ways to prevent resistance and hopefully improve outcomes.
Q: With the mixed nature of our tumors, do you need a larger sample or more areas sampled to get a fuller picture? How can we be certain that the area sampled is the most relevant area? Or that a complete picture is obtained?
A: This is the issue of heterogeneity. We know that the molecular profile of metastatic lesions and the primary tumors can be different. In fact, different areas of the same primary tumor can show different molecular signatures. So, it helps to have as much tissue as possible to try to get a representative sample of the tumor biology. We can’t be certain that the area sampled is the most relevant area, but we do review the specimens before molecular analysis to make sure that tumor nuclei are present and we are not just sampling the stromal tissue. By using multiple types of molecular analysis (i.e., DNA, protein, etc.), we hope to have a more complete picture than if we rely solely on one technology platform such as DNA sequencing alone.
Q: We often discuss if there are similarities between metaplastic breast cancer and other types of cancer (for example, women with squamous cell carcinoma). Should be considering skin cancer chemo regimens or a combination of breast and skin cancer regimens?
A: Caris has a hypothesis about this, which we often refer to as the “pan-tumor approach.” Rather than looking at the histology of a cancer alone, it’s critical to look at the cancer’s biology. So if a cancer looks like a melanoma from a molecular standpoint (e.g., harbors a BRAF mutation), then shouldn’t we treat it with an anti-BRAF drug? Now, let’s pretend this was instead a breast cancer tumor, not a melanoma, but it still presented the same BRAF mutation…now what? Obviously, studies need to be done in this population, but early evidence suggests that these patients may benefit from a “melanoma” drug. So, I think we need to stop thinking about these drugs or regimens as limited to a specific lineage of cancer, but rather match them to the appropriate biology. For some breast cancer patients, it may be that the right regimen is a “skin cancer” regimen, a “colon cancer” regimen, or even a “prostate cancer” regimen. While a prostate drug may seem radical for a breast cancer patient, Androgen Receptor is actually expressed in many of these cancers and is actively being studied today as a target in clinical trials for women with breast cancer.
Q: Caris is often used by patients with disease progressions, chemo-resistant tumors or metastasis. Because metaplastic breast cancer is so often chemo-resistant and so many of us get a recurrence, should women with this diagnosis consider molecular testing for their FIRST tumor?
A: The best use for molecular profiling is in rare or refractory tumors for which there really is no accepted standard of care. Metaplastic breast cancer fits this description (it accounts for less than 1% of all breast cancers), so I think women with this diagnosis should strongly consider a molecular profile to inform first line treatment because our clinical trial data in the larger breast cancer population may not adequately reflect the unique nature of metaplastic breast cancer. Also, early in the course of the disease is the best time to find the most efficacious therapy that might eradicate the disease and offer the greatest opportunity for a survival benefit. If we wait until much later in the disease’s progression, it’s more likely that the profile will reveal less drug targets and a more resistant genotype/phenotype.
Q: What does the future look like for tumor profiling? How is it helping to drive personalized medicine for cancer patients?
A: Without question, tumor profiling is becoming a standard tool used by many practicing oncologists. This is especially evident in breast cancer, where a patient will almost certainly undergo some type of genomic test, and likely more than one, to determine the expression levels of certain key genes in their tumor. These analyses are a critically important part of the treatment determination process, as they help indicate to an oncologist which drugs may be effective or ineffective. Tumor profiling is not only good clinical practice, potentially leading to better patient outcomes and potentially less suffering and pain related to ineffective therapy, but also more cost-efficient, as the expense of the genomic testing is generally much less expensive than the cost of ineffective treatment.
Fortunately, the impact of tumor profiling isn’t relegated to the far-off future – patients are benefiting from this type of testing right now. Caris Life Sciences, who pioneered this approach beginning in 2006, has profiled more than 60,000 patients around the world, and has also developed the industry’s first tumor profiling registry, which has collected data on the demographics, presentation, diagnosis, treatment, resource use, and outcomes of eligible patients who previously have undergone Caris testing. This data has been tracked over multiple years and allowed to mature, and will be used to publish key insights on new biomarker relationships to help drive clinical decision-making. Caris, along with other companies/institutions who perform forms of tumor profiling, also publishes genomic research at multiple medical congresses and research conferences each year, which helps advance a better understanding of genomics in cancer and how to continue to further personalize care for patients.