Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

Cancer Commons Adapts to Remain True to Our Mission

Shelley Frisbie
CFO & COO at Cancer Commons

Curious Dr. George
Cancer Commons Editor in Chief George Lundberg, MD, is the face and curator of this invitation-only column

People facing advanced cancer come to Cancer Commons to ensure they have all the information they need to make their best-possible cancer care decisions. Here, Curious Dr. George asks our CFO & COO Shelley Frisbie about recent updates to our organization.

Curious Dr. George: You have been the CFO of Cancer Commons for some time and recently added the COO title and duties to your position. How do you see Cancer Commons as a 501(c)(3) nonprofit organization as we seem to be emerging from the COVID-19 pandemic? I presume its core mission remains the same, but has the organization evolved, and do you anticipate additional changes?

Shelley Frisbie: There is no question that the pandemic profoundly affected nonprofits, because a significant percentage of philanthropic resources had to be redirected to the COVID-19 fight. Although things were lean at Cancer Commons, we learned from our clients what a tremendous need there is for compassionate, personalized support for those facing advanced cancer. The experience led us to commit even more deeply to our mission.

In support of this, we created the Director of Patient Services role and brought on a Patient Navigation Specialist. They serve as the crucial first points of contact, providing care to those who come to us feeling overwhelmed and uncertain. Together they guide clients through registration, assess needs and goals, and begin the process of identifying appropriate diagnostic and treatment options.

Thanks to an updated, more client-focused website—and the personal outreach done by our navigation team—we are seeing an increase in the number of registrations for Cancer Commons services. With philanthropy down, however, we have had to consider new ways of funding to meet the needs of those turning to us.

With this in mind, we launched several low-cost Enhanced Services, designed to provide a continuum of care:

  • Cancer Commons Plus, a subscription service that ensures registered patients stay connected with their Cancer Commons team for as long as needed;
  • Expanded Options & Navigation, to offer clients more detailed discussion and explanation of potential treatments, and assistance with obtaining molecular testing; and
  • Clinical Trials & Expanded Access Assistance, to address a need clients have been sharing for years.

Something that has not changed is Cancer Commons’ commitment to perpetual learning and open knowledge sharing to help current and future patients. We continue to work with our technology partner xCures on the XCELSIOR longitudinal study and are developing other collaborations to help us offer education and resources. Supported by a memorial sponsorship, we recently launched a series of quarterly webinars to provide critically needed information for cancer patients and caregivers—and introduce a whole new audience to our valuable services.

Everyone needs somewhere to turn when they hear those awful words “there’s nothing more to be done for your cancer.” The questions that arise seem endless. Patients and caregivers are looking for answers to be sure they have done everything possible. Cancer Commons helps provide those answers.

The organization has evolved and will continue to do so. In the near future, we will make Cancer Commons’ offerings even more interactive with the addition of chat service, and leverage partnerships with advocacy organizations and biotech companies so that we can offer new options as technology advances. Philanthropy will always be extremely important to sustain our free services, subsidize Enhanced Services for clients with demonstrated need, and to help us serve as many people as possible.

And as always, I invite anyone facing advanced cancer to sign up to receive one-on-one help from our compassionate experts. We are here for you.

Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

Cellular Aging and the Development of Cancer

Curious Dr. George
Cancer Commons Editor in Chief George Lundberg, MD, is the face and curator of this invitation-only column

Kaumudi Bhawe, PhD
Cancer Commons Scientist

Cancer is so often a disease of older people that a whole medical field, “oncogeriatrics,” exists to address the topic. Deeper understanding of the links between cancer and aging could lead to better treatments. Here, our Curious Dr. George asks Cancer Commons Clinical Scientist Kaumudi Bhawe, PhD, about the relationship between cancer and aging processes that occur in individual cells in our bodies—throughout our lives.

Curious Dr. George: As a molecular biologist, you have worked with many forms and elements of cancer cells. Are there any similarities between the processes of cellular aging and the development of cancer?

Dr. Bhawe: Cancer is a disease of aging. According to the National Cancer Institute (NCI), cancer incidence increases dramatically after age 50, with the median age of people diagnosed with cancer in the United States being 66. While chronological age is definitely a cause of cellular aging, it is not the only cause. In fact, the process of cellular aging is known to happen in cells right from the time a human embryo is still developing. What then, exactly, is cellular aging, and what does it have to do with cancer? This is a timely question with the recent publication of a paper in the scientific journal Cancer Discovery entitled “Hallmarks of Cancer: New Dimensions.” This article highlights aging—or “senescent”—cells as one of the newly acknowledged enabling characteristics of all cancers.

Aging cells can be defined by accumulated damage to the macromolecules, such as DNA and proteins, that are important for the cells to maintain themselves, to grow, and to divide. Certain molecules in a cell, are involved in a mechanism that surveys and repairs DNA damage each time the cell undergoes division. If there is more damage than can be repaired, an aging cell either dies or cannot divide, and goes into what is called irreversible cell-cycle arrest. The above-mentioned mechanism ensures that cells with faulty macromolecules are not increasing in number, and in this sense, it is a disease-preventing mechanism. For a very detailed overview of the DNA-damage-response mechanism and its relevance to cancer, you can read this scientific review article that was published last year.

However, once an aging cell enters irreversible cell-cycle arrest, it can stay alive for quite some time; up to months, as demonstrated by lab-based research. Not only can it stay alive, it can also evolve based on the cues it is receiving from its environment, and importantly, it can alter the very environment it finds itself in. It has been discovered that such senescent cells have an abnormal metabolism and secrete hundreds of different signaling molecules including proteins and lipids. Readers interested in learning more about this exciting field of study can start with this article from the scientific journal Communications Biology and this video from the news site Technology Networks.

Some of the ways in which cells can be induced to undergo aging/senescence include the slow natural aging caused by going through multiple cell-cycles, leading to telomere shortening, exposure to toxic chemicals (including chemotherapy) and radiation, exposure to reactive oxygen species (ROS), and activation of cancer-causing genes (oncogenes). So, you can see that as a cancerous tumor is forming, or even during treatment, senescence mechanisms are at work in at least some of the cancer cells as well as some of the non-cancerous surrounding (stromal) cells, such as fibroblasts, blood-vessel-forming cells, and immune cells.

Three key common features shared between aging cells and cancer-developing cells are:

1) accumulation of DNA defects

2) altered metabolic activity, and

3) an increase in secretion of environment-modulating molecules.

The current challenge lies in discovering and cataloging the specific details of each of these three features in order to identify true molecular similarities, differences, antagonism, and cooperation between the processes of aging and cancer. The NCI funds initiatives for cancer and aging research at premier institutes across the U.S. in the hopes of addressing this challenge and developing new, better strategies for cancer prevention and treatment.

Dr. Bhawe can be reached at kaumudi.bhawe@cancercommons.org.

Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

More Information from Less Tissue: Strata Oncology Excels

Curious Dr. George
Cancer Commons Editor in Chief George Lundberg, MD, is the face and curator of this invitation-only column

Scott A. Tomlins, MD, PhD
Co-founder & Chief Medical Officer, Strata Oncology

Laura E. Lamb, PhD
Director of Translational Medicine, Strata Oncology

 

For a growing number of advanced cancer patients, molecular testing of tumor tissue is an essential step in identifying their best options for treatment. Strata Oncology is one company offering this kind of test. Here, our Curious Dr. George asks two of its leaders what sets Strata apart.

Curious Dr. George: No loop is stronger than its weakest link. In the “brain-to-brain” concept of laboratory testing for precision oncology, tumor specimen selection, collection, preservation, transportation, and processing are among the most important factors. What characteristics of your company’s approach to molecular diagnostics may be particularly advantageous for physicians to use to best guide cancer diagnosis and treatment?

Scott A. Tomlins, MD, PhD—Co-founder & Chief Medical Officer, Strata Oncology, and Laura E. Lamb, PhD—Director of Translational Medicine, Strata Oncology: Thank you for the opportunity to discuss this important topic. Strata Oncology’s mission is to accelerate the impact of precision medicine for patients with cancer by providing advanced molecular tests coupled to compelling clinical trials. To achieve this, we have carefully considered the brain-to-brain loop as it applies to clinical diagnostics. We are continuously innovating to ensure that all the steps involved in comprehensive molecular testing are optimized, standardized, and intelligently designed to improve benefit to the patient, while also working to reduce testing barriers to physicians and patients by partnering with healthcare systems and integrating Strata testing, education, and clinical trials system-wide.

All molecular testing at Strata is performed in a high-throughput, CAP-accredited and CLIA-certified laboratory, with numerous and redundant quality checks, controls, and standards in place. For example, all histology samples and molecular tests are reviewed and signed out by a single pathologist, which reduces variability, particularly for samples submitted as carcinoma of unknown primary. The latest clinical and molecular data is also reviewed by the lab director to ensure the most relevant information is used to guide downstream therapeutic decision-making. Our commercially-available test, StrataNGS®, has been clinically and analytically validated to assesses DNA and RNA in solid tumors. Importantly, as StrataNGS® sample requirements are some of the lowest in the industry (³2mm2), Strata has over a 99% success rate for patient samples passing all sample input requirements, resulting in over 60,000 tumor samples being tested.

StrataNGS® has been optimized for small tumor tissue samples and fills a critical unmet need. Unfortunately, as many as one out of every two patients with advanced cancer have insufficient tissue for other leading molecular tests. StrataNGS® requires 1/10th the tissue of other tests, which provides more patients the opportunity to benefit. By design, the StrataNGS® testing approach is modular: if the sample meets the overall sample requirements, the DNA, RNA, and tumor mutational burden are tested on three separate panels, which allows for the detected biomarkers to be reported from all or some of the panels, depending on whether the panel-specific quality control metrics had been met. Consequently, 94% of all samples tested by Strata will provide an informative result. Patients whose samples cannot be tested by Strata will not be charged for the test.

To simplify clinical reporting, StrataNGS®uses data-driven and clinical insights to provide an easy-to-follow report for confident clinical decision-making. The report summarizes matches to FDA-approved and guideline-recommended therapeutic regimens for all guideline-recommended genes, as well as matches to investigational therapies through clinical trials, including those available through Strata Oncology’s clinical trial partners, or the company’s own sponsored clinical trials Strata PATH and SENTINEL.

Strata Oncology builds processes within the company and through our partnerships with healthcare systems and biopharma companies to reduce testing hurdles for oncologists and their patients. In doing so, we aim to continue to bring the latest innovations in genomics, transcriptomics, and precision medicine to all patients with cancer, while collaborating with our partners to generate and test new biomarker-guided treatment hypotheses.

Dr. Tomlins can be reached at scott.tomlins@strataoncology.com, and Dr. Lamb at laura.lamb@strataoncology.com.

Meet Deb Christensen, Nurse Navigator for People Facing Advanced Cancer

Curious Dr. George
Cancer Commons Editor in Chief George Lundberg, MD, is the face and curator of this invitation-only column

Deb Christensen, MSN, APRN, AOCNS, OCN
Director of Patient Services at Cancer Commons

For people with advanced cancer, making sense of the complexities of cancer treatment can be truly daunting. Enter the oncology nurse navigator (ONN), a nurse with specialized training to help patients overcome any barriers they may face in accessing high-quality cancer care. At Cancer Commons, our Director of Patient Services Deb Christensen, MSN, APRN, AOCNS, OCN, applies her ONN training to ensure that every patient receives the guidance they need. Here, our Curious Dr. George asks her about her work.

Curious Dr. George: You are in charge of patient services at Cancer Commons. How would you describe how you use your ONN skills every day to assist patients with advanced cancer who seek help at Cancer Commons?

Deb Christensen, MSN, APRN, AOCNS, OCN: My first real exposure to oncology was as a nurse navigator in a large healthcare organization. Care coordination is one of the main roles of the ONN. Networking and forming partnerships with other departments and physician offices was key to successfully helping people navigate the complex landscape of oncology care. I had the opportunity to participate on a committee of nurses who updated the Oncology Nursing Association Nurse Navigator Competencies in 2017 and was coeditor of Oncology Nurse Navigation: Delivering Patient-Centered Care Across the Continuum (second edition).

These experiences allowed me to share my passion for the role of the ONN and grow in the profession. After working as an ONN, and then serving as the system lead for the navigation program, I retired from the organization and joined Cancer Commons as a nurse navigator.

I am peoples’ first point of contact at Cancer Commons. I assist people through the registration process and then contact them to learn more about their cancer history and assess their needs, goals, and expectations. An essential ONN skill that I use consistently is the ability to communicate in a way people can understand and follow. Our patient navigation specialist, Lauren Levine, and I assist the patients and their families with retrieving medical records, collaborating with our Scientists, and checking in at key points in the cancer journey. Our goal is to make the entire process personalized and as simple as possible. The entire Cancer Commons team collaborates to help clients create a plan to discuss with their local oncology team. This action plan is complimentary, informed by the latest scientific research, and curated by PhD scientists.

My new role as Director of Patient Services evolved out of the Cancer Commons team’s desire to provide a more personalized experience to clients and offer new services. Our team helps clients understand their treatment options and take potential next steps. Additional services being implemented include a Cancer Commons Plus subscription for ongoing follow up and communication with the science team, clinical trial enrollment assistance, and other assistance offered by the hour. The ability to put clients first by providing non-biased treatment options and timely compassionate care is at the heart of everything we do at Cancer Commons.

Deb can be reached at deb.christensen@cancercommons.org.

Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

Cardiometabolic Medications That Inhibit mTOR Might Help Prevent or Treat Cancer

Curious Dr. George Cancer Commons Contributing Editor George Lundberg, MD, is the face and curator of this invitation-only column

William H. Bestermann Jr, MD Senior Clinical Advisor at Congruity Health

Many people believe that cancer is a metabolic disease. A biological process known as the mTOR pathway controls cellular metabolism by way of central signaling, and it is involved in tumor growth. Here, our Curious Dr. George asks William H. Bestermann Jr, MD, an internal medicine doctor, how medications that target the protein mTOR and its associated pathway could prevent or treat cancer. Dr. Bestermann is Senior Clinical Advisor at Congruity Health.

Curious Dr. George: What drugs that are currently approved for use by the U.S. Food and Drug Administration (FDA) inhibit mTOR and might be worthy of testing for potential off-label use for cancer prevention or therapy?

William H. Bestermann Jr, MD: A search including the terms mTOR and cancer in PubMed brings up 125,000 articles on the subject. Aberrant mTOR activation and signaling play a central role in many malignancies. Mutations that persistently activate mTOR are a basis of many familial cancer syndromes.

So, what is mTOR? It is an abbreviation for the mechanistic target of rapamycin, which is a natural compound produced by a fungus. Rapamycin is an antibiotic that is slowly released from the most modern heart artery stents to keep them from blocking with scar tissue and inflammation. It accomplishes that by inhibiting the protein mTOR, a master metabolic genetic switch. The mTOR pathway regulates many metabolic processes. In the fetus and child, it is essential to coordinate food availability with growth. Overeating, excess abdominal fat, and tobacco smoke cause increased oxidant production and growth factor signaling, which activate mTOR to increase arterial thicknessheart size, and the likelihood of cancer. mTOR has a reciprocal relationship with the protein AMPK, another genetic master metabolic switch. When mTOR is switched on, AMPK is switched off. mTOR and AMPK are a final common signaling pathway for genetic signaling that causes heart disease and malignancy. Medications that block oxidant production from that signaling or directly impact the mTOR/AMPK axis inhibit malignant transformation and tumor growth.

Several cardiometabolic medications decrease oxidant production and epidermal growth factor receptor (EGFR) activation to switch off mTOR and switch on AMPK. These include ACE inhibitors like lisinopril, ARBs like losartan, statins, and mineralocorticoid receptors (MR) like spironolactone. Smoking cessation has the same effect. Caloric restriction, intermittent fasting, rapamycin, exercise, and metformin directly inhibit mTOR and activate AMPK. SGLT2 inhibitors directly activate AMPK. These components of optimal medical therapy interfere with the core biology that causes cardiovascular disease and cancer. That is why they have a greater impact on major cardiovascular events and all-cause mortality than their impact on the target risk factor. These interventions don’t merely lower the target risk factor, they interfere with the molecular biology that causes cardiovascular diseases and cancer. They protect cells and organs.

Medications with a structure and function similar to rapamycin are called rapalogs. These are used to treat cancer and prevent organ transplant rejection, and they have potential in several additional conditions. The cardiometabolic medications listed in the previous paragraph do the same thing by directly or indirectly switching off mTOR and activating AMPK. Rapalogs inhibit both mTORC1 and mTORC2. The effect on mTORC1 is beneficial, and inhibiting mTORC2 may have harmful side effects. Like rapalogs, metformin has a beneficial effect in cancer prevention and treatment, which it produces by directly and specifically inhibiting mTORC1 and activating AMPK. Statins and ACE inhibitors are also associated with decreased cancer incidence. Similarly, high aldosterone levels have been associated with increased cancer risk, and eplerenone blocks those effects in a highly specific manner.

Research to further evaluate cardiometabolic medications for cancer prevention and treatment benefit should be a priority.

Dr. Bestermann can be reached at whbester@gmail.com.

Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

Using Virtual Trials to Screen for Potential Glioblastoma Therapies

Curious Dr. George
Cancer Commons Editor in Chief George Lundberg, MD, is the face and curator of this invitation-only column

Al Musella, DPM
President, Musella Foundation For Brain Tumor Research & Information, Inc.

The existing drug development system “has failed miserably” for people with glioblastoma brain tumors, according to Al Musella, DPM, President of the Musella Foundation for Brain Tumor Research & Information, Inc. In partnership with Cancer Commons, his organization’s Brain Tumor Virtual Trial aims to speed discovery of promising new glioblastoma treatments.

Curious Dr. George: How might your Virtual Trial approach speed the process toward either validating or invalidating potential therapies for glioblastoma?

Al Musella, DPM: I have watched how the current drug development system works since 1992, and think we could do much better. There are many problems but the top ones, as they relate to malignant brain tumors, are:

  1. The current system is set up to try to find one magic bullet that will successfully treat the disease. This concept has worked reasonably well for some diseases, but for brain tumors it has failed miserably. I feel that the ultimate cure for brain tumors will be a combination approach, and under the current system, it is very difficult to get the individual components of that ultimate cocktail approved by the U.S. Food and Drug administration (FDA).
  2. There are not enough patients for the number of trials needed. About 10% of adult glioblastoma patients—about 2,000 per year—enter clinical trials. There are currently 318 glioblastoma trials open for enrollment, which means only six patients are available per trial per year. And some trials require large numbers; it takes years to accrue enough patients, and many trials never do.
  3. Phase 3 trials are too long and inflexible. In the last 25 years, only one phase 3 glioblastoma study showed a statistically significant improvement in survival, adding only 3 months to median survival. As patients are treated, we learn how to use the treatments better, but the rigid structure of a phase 3 trial doesn’t allow for modifications midstream. Rather than stop a trial, discard the results and start over, researchers complete a trial anyway, knowing that there may be a better way to use the drug.

I propose an alternative approach:

  1. All patients must be watched in a regulatory-grade registry so we learn from every patient—not just the 10% who may not even represent the typical patient.
  2. A formal randomized trial is perfect to prove that a combination works, but we are not yet at the point where we have a combination worthy of a full-scale phase 3 trial. So, if a patient desires entry into a formal trial, I propose they be given access to the registry to pick the most promising trials.
  3. We need a system in which experimental treatments get fast conditional approvals when they are shown to be relatively safe, with early evidence that they have the intended effect—even if that effect doesn’t result by itself in prolonged life. This allows us to use them in combinations and figure out how best to use them.
  4. Paying for medical drugs is a problem. The only way this can work is if patients do not have to pay high costs for their treatments, and if drug companies get paid for the treatments. This will allow access to the drug. The Virtual Trial system should keep drug costs down, as it will take the vast majority of time and money out of the drug development process and break the monopolies currently preventing many new drugs from being developed. In fact, I have proposed a bill (see below) that basically requires Medicare and Medicaid to pay for them and encourages private insurance to pay. We are working out the exact wording and are considering a “pay for performance” model, or a compromise in which costs for non-standard treatments cannot exceed what the standard of care would have cost.
  5. Doctors, or teams of researchers, can then think up the best combinations for each individual patient, and test them in small, fast, inexpensive (or free) virtual trials. They can see the ongoing results in all patients and quickly determine if a conditionally approved drug is worthy of continued usage—perhaps tweaking how it is given or the combinations used, or if it should be dropped. Once the ultimate cocktail is found, it can then be tested in a formal phase 3 trial.

I have been working on the components of this plan. We already have “right-to-try” laws passed in the U.S., but these did not work out as intended, mainly because of cost issues and fear that the FDA would hold usage of this pathway against a drug company. So, I am now working on a much-improved version of early access called the “Promising Pathway Act,” which was recently introduced into Congress. It fixed most of the problems with right-to-try laws and the FDA’s Accelerated Approval Program. It provides for conditional approval of treatments and requires all patients who use any conditionally approved drug to participate in a registry.

My organization, in partnership with Cancer Commons and its for-profit spinoff xCures, has set up a patient-navigation program that should be the model for how we approach all serious diseases. Our team of neuro-oncologists, PhD researchers, and nurse navigators—aided by an artificial intelligence engine—can look at our rapidly growing patient registry (we now have over 1,250 patients) and evaluate medical research, the rationales presented in tumor board meetings, and patients’ medical histories in order to come up with a list of treatment plan options that may be best for any given patient. The patient and their own doctor can select a treatment from our list, or they can elect to try whatever other treatments they want. Whatever they choose, our team then follows up on every patient to see the outcome of their chosen treatment. This way we learn from every patient.

We try to help patients get access to their chosen treatments, but the most promising options are usually impossible to access because the components are not yet approved, and either they are unavailable under expanded access or the drug companies won’t allow us to combine the experimental drugs.

Nonetheless, any doctor or researcher who is using a new combination of FDA-approved drugs for a patient can submit that treatment plan option to our system to be run as a virtual trial, allowing the doctor or researcher to quickly test the theory in their patient and use our system as a screening tool. They can try many combinations quickly, and if a particular combination shows a lot of promise, it can then be promoted to a traditional phase 3 trial to validate the findings.

Any treatment plan options validated in this way would be made up of FDA-approved treatments, so any doctor could prescribe them, allowing every brain tumor patient to have access—not just those perfect patients that fit into existing clinical trials.

In summary, our Virtual Trials could be used as a screening tool to figure out the best combinations, and how best to use treatments, which then can be tested in formal trials. Conversely, this approach could be used to quickly eliminate bad combinations. Having all results available in a central registry would help doctors from around the country avoid trying the same ineffective combinations.

Dr. Musella can be reached at musella@virtualtrials.org.

WATCH the 11th Annual Lundberg Institute Lecture: The COVID Labyrinth: Where Are We In It and How Do We Escape?

Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

How an Expert Would Manage His Wife’s Metastatic Breast Cancer

Curious Dr. George
Cancer Commons Contributing Editor George Lundberg, MD, is the face and curator of this invitation-only column.

Richard B. Schwab, MD

Professor of Medicine – Division of Hematology/Oncology; Medical Director, Koman Family Outpatient Pavilion Infusion Center – UC San Diego Moores Cancer Center

For most people with breast cancer, a lump is the first sign that leads to diagnosis. But some cases are not detected until after spread has already occurred. Here, our Curious Dr. George asks Richard B. Schwab, MD, how he would approach such a case if his own wife were the patient. Dr. Schwab is Professor of Medicine in the Division of Hematology/Oncology and Medical Director of the Koman Family Outpatient Pavilion Infusion Center at U.C. San Diego Moores Cancer Center.

Curious Dr. George: How would you, as a breast cancer expert, manage your wife’s cancer if it were to present as shortness of breath or back pain, with a breast mass only then detected?

Richard B. Schwab, MD: Doctors frequently take care of their family members for minor problems; cancer is not one of them. Even caring for patients, managing one’s own anxiety about the normal uncertainties of medicine is not easy. Managing of my wife’s cancer would not be possible, so I would have one of my excellent colleagues be her oncologist.

That said, I would be answering my wife’s questions about this frightening situation and trying to guide her. She gets her screening mammogram every year, so presenting with metastatic breast cancer would be very unusual. Only 5% of breast cancer is de novo metastatic, and many of these patients did not have recommended screening before diagnosis. However, screening mammograms are not perfect, so your hypothetical scenario is possible.

If she was short of breath, I think we would utilize the emergency department. Although cancer is usually a relatively slow process, there are rare times when patients can become very ill during the normal time required for diagnosis and treatment initiation. CT scans can be done quickly and could identify a pulmonary embolism, pleural effusion, or lymphangitic spread. Starting appropriate therapy quickly (anti-coagulation, thoracentesis, or chemotherapy respectively) could be critically important.

Making a pathologic diagnosis would be the next step, and would radically alter treatment (and life) plans. Breast cancer is not one disease. Oddly we would be hoping for an aggressive estrogen receptor-negative and HER2-positive cancer. These cancers are highly responsive to numerous treatments, and cures—even with metastatic disease—are becoming more and more common. A triple-negative cancer would be complicated. Some patients with triple-negative breast cancer, particularly limited to the lungs, do end up cured, but these cases are rare and overall this type of breast cancer has the fewest treatment options. Last but most common, particularly if her cancer had spread to the bones, would be estrogen receptor-positive disease. These cancers generally grow more slowly and on average patients survive longer with this type of disease. However, these cancers are never truly cured, although for older patients lifelong disease control can sometimes be obtained. For a patient as young as my wife new therapies would be needed to have any reasonable hope of lifelong disease control.

Which location to biopsy is a common challenge we would need to address. Biopsy of the breast is the easiest, but may not reflect the more dangerous disease that has spread to other organs. Lung biopsy has some additional risk, it is anxiety provoking, and sample quantity (or even successful sampling) can be challenging. Biopsy of the bone, while very safe, can give unreliable results due to the need to decalcify the sample prior to testing. The details of the patient’s case and the expertise of the doctor performing the biopsy matter. Having expert trusted colleagues in radiology and pulmonology would be a significant advantage for my wife.

I mentioned the idea of truly curing my wife. I define true cure as a lack of cancer progression for at least 5 years after stopping therapy. I have cared for many patients with metastatic disease that has been cured, and that knowledge would help my family get through what is fortunately only a hypothetical situation.

Dr. Schwab can be reached at rschwab@health.ucsd.edu.

Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

How an Expert Would Handle His Own Cancer of Unknown Origin Causing Severe Back Pain?

Curious Dr. George
Cancer Commons Contributing Editor George Lundberg, MD, is the face and curator of this invitation-only column.

Marc B. Garnick, MD

Gorman Brothers Professor of Medicine at Harvard Medical School and Beth Israel Deaconess Medical Center

Treating cancer that has been fully diagnosed can be a complex challenge. But sometimes the process of diagnosis itself presents an urgent puzzle. Here, our Curious Dr. George asks Marc B. Garnick, MD, how he would approach his own case of an unknown form of cancer. Dr. Garnick is the Gorman Brothers Professor of Medicine at Harvard Medical School (HMS) and Beth Israel Deaconess Medical Center in Boston, MA. He is also Editor in Chief of the HMS Annual Report on Prostate Diseases.

Curious Dr. George: What would you do if you began to experience unrelenting back pain and visited your primary care physician, only to be informed that X-rays taken of your lower back demonstrated multiple lytic lesions of several lumbar vertebrae? In this hypothetical scenario, a prostate-specific antigen (PSA) blood test shows a level of 30 ng/ml, and you also recently lost 10 pounds unintentionally—but you have no significant urinary symptoms. How would you proceed?

Marc B. Garnick, MD: The findings of multiple lytic lesions of several lumbar vertebrae in the setting of unrelenting back pain constitute an oncologic emergency. If I, as a physician and oncologist in this case, were to face such a serious set of medical circumstances, there are things that need to be done immediately and hopefully within the next 24 hours.

The critical and most time-sensitive issue that I would want urgent input on is whether spinal cord compression with impending paralysis is present. Regardless of whether these lytic lesions are caused by an underlying plasma cell dyscrasia or prostate cancer—the two highest differentials on my list—a prompt evaluation of the spinal anatomy is urgently needed. My biggest concern is whether the findings represent a plasmacytoma in association with a plasma cell dyscrasia or prostate cancer. I know that the presence of spinal osteolytic lesions can also accompany metastatic lung cancer, renal cell carcinoma, or colorectal cancers as well, but given my overall history, this would be of less concern. I would not completely rule out prostate cancer, knowing that purely lytic osseous lesions are less common in prostate cancer, but that they do occur, often mixed in with osteoblastic lesions.

In anticipation of my emergent evaluation at the emergency ward (EW). I would expect that a full set of chemistries—especially looking at serum Ca++ level, and complete blood count—would be evaluated by EW staff. My concern is that the back pain, which has been really excruciating, is now accompanied by some leg weakness and some inklings of saddle anesthesia. I had not had a recent digital rectal exam (DRE) and would hope that the intern or resident in the EW knows how to perform this important examination (since DRE learning is completely de-emphasized in current-day medical training). The PSA of 30 is of obvious concern, but my history of benign prostatic hyperplasia (BPH) and prostatitis in the past, as well as multiple prostate evaluations, would place this as number two on my differential. I could also consider that there may be some underlying urinary retention ongoing as a possible result of some neurological dysfunction, giving rise to the elevation in PSA. A bladder scan check of post-void residual would be helpful here as well, and accomplished in less than 30 seconds with a bladder scanner.

On my way to the MRI scanning center, I would ask if my peripheral smear showed any evidence of rouleaux formation, a hint of an underlying blood dyscrasia, as well as my Ca++ levels. I would remember that hypercalcemia is distinctly unusual in widespread metastatic prostate cancer (as opposed to myeloma) and would recall an article that Dr. Rob F. Todd III and I wrote decades ago underscoring the rarity of this association, and when present, think of other etiologies such as sarcoidosis to account for the hypercalcemia.

As I am thinking about next steps, I would compartmentalize the two important scenarios. I first would assume that the scans will show no evidence of spinal cord compression: This is unlikely, especially given the widespread extent of the spinal lytic lesions and new subtle saddle anesthesia as well as continuing pain. Obtaining a tissue diagnosis will be dictated by the radiologic findings: if there is no evidence of spinal cord compression, and the cross sectional and other routine imaging do not suggest intra-abdominal or thoracic involvement, then consideration of the site to biopsy again would be dictated by the lab findings. Hematologic findings of plasma cell dyscrasia or plasmacytoma would be further evaluated by either a bone marrow biopsy and aspirate, or consideration of directly biopsying an accessible lytic lesion. If the DRE suggested prostate cancer, and a repeat PSA was confirmed to be elevated, a prostate needle biopsy could be performed.

I would then assume the most likely explanation—that there is evidence of spinal cord compression: Here the situation is different. I would urge the administration of dexamethasone, and consultation with radiation oncology and neurosurgery would be mandated to assess optimal approach management. If an operative intervention is recommended for decompression, tissue for pathologic analysis can be obtained at that juncture and then the therapy can be tailored according to the pathology. If surgical intervention is not recommended, then biopsy of lytic lesion and initiation of radiation therapy would be next. There would be some discussion as well at this juncture to determine the optimal sequencing of treating first and diagnosing later, or diagnosing first and and then treating—especially since the systemic therapies are so different. If neurosurgical decompression was mandated, then I would vote for the “treat first” option.

I would want the hierarchy of diagnostic and therapeutic decision making to address, first and foremost, the structural abnormalities induced the lytic lesion. It would be beneficial but not necessarily critical to know the specific pathologic diagnosis before the anatomic lesions were treated by surgery, since tissue would be obtained at that juncture. As stated above, tissue would be needed prior to initiating radiation. I would then select the most appropriate systemic therapies to be informed by the tissue of origin. These would include initial standard programs for a hematologic neoplasm or intensified androgen deprivation therapies with or without chemo if it turned out to be metastatic prostate cancer. Genomic profiling, of course, would be part of any diagnostic evaluation, using any one of a number of platforms such as Foundation Medicine.

Dr. Garnick can be reached at mgarnick@bidmc.harvard.edu.

Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

How an Expert Would Treat Her Own Metastatic Melanoma

Curious Dr. George
Cancer Commons Contributing Editor George Lundberg, MD, is the face and curator of this invitation-only column.

Pauline Funchain, MD

Director of the Melanoma Medical Oncology and Genomics Programs at Taussig Cancer Institute, Cleveland Clinic

Cancer patients often ask their doctors, “What would you do if you were me?” Here, our Curious Dr. George asks Cleveland Clinic oncologist Pauline Funchain, MD, how she would handle her own diagnosis of advanced melanoma.

Curious Dr. George: What would you do if you personally were discovered on a routine exam to have abnormal liver function tests that led to scans and the finding of several liver masses? Remembering back some 15 years, you had surgery to remove a 7-mm-diameter, 2-mm-thick melanoma from the skin of your lower leg, treated by wide excision with clear margins. No spread detected at that time. No tumor testing then, aside from light microscopy. How would you proceed?

Pauline Funchain, MD:

Starting line: First, I would take a deep breath. I would remind myself that stage IV melanoma of the skin has become a disease state that can have durable remissions well over 5 years, and that such remissions are not rare. I would be heartened knowing that results approaching cure are possible for some stage IV melanomas.

Next, I would contact my nearest academic medical center. I would carefully research teams known to have good bedside manners, clear communication, and melanoma expertise. The field of melanoma is rapidly changing for the better, and I would want a team that is not only well aware of these developments, but also would be able to clearly explain the multiple therapy options available to me in the context of a briskly moving field. Lastly, I would prefer a medical center where medical subspecialists were readily available and accustomed to timely multidisciplinary communication, as immune-mediated adverse events (irAEs) are commonly elicited during the course of systemic therapy for melanoma.

Workup: At this center, I would first undergo a biopsy of a liver mass. I would ensure BRAF mutation screening was performed by immunohistochemistry (IHC), the most rapid of available BRAF testing modalities. If enough tissue was available, I would send for next generation sequencing (NGS) of the tumor specimen, to prepare for possible second- or third-line therapies. If I had a family history of cancer, personal history of multiple cancers, or was relatively young, I would see a genetic counselor to discuss germline genetic testing. For staging I would get either a CT chest/abdomen/pelvis or PET CT. MRI brain is absolutely essential, as brain metastases are common, often asymptomatic, and may influence first-line therapy choices.

First-line therapy: With staging complete, I would inquire about first-line immunotherapy-based trials. While the best outcomes for stage IV disease, particularly involving liver and/or brain, have been seen with combination ipilimumab/nivolumab, I would welcome the opportunity to try something new in a rapidly evolving melanoma treatment landscape. I would be reassured knowing that all gold standard therapies would still be available to me should a first-line clinical trial fail. If I was not eligible or did not like available clinical trials, I would proceed to first-line treatment with ipilimumab/nivolumab. If I had a personal history of autoimmune disease, I would request a consultation with the appropriate medical subspecialty prior to starting immunotherapy. Other medical conditions might influence me to prefer single-agent immunotherapy, and it is these situations that highlight the importance of having a medical team who is able to have a careful discussion with me to understand my individual needs.

While on therapy I would undergo systemic imaging every three months to assess response to therapy. If my original staging did not demonstrate brain metastases, I would undergo MRI brain every 6 months in the stage IV setting. If I had fast-growing disease, was rapidly losing weight, had a very large burden of disease, or some combination of these factors, I may prefer to invoke the rapid response typically seen with targeted BRAF/MEK therapy. On targeted therapy, I would consider imaging every 2 months, given a higher likelihood of developing therapeutic resistance with the combination of factors that led me to start targeted therapy. I would follow my status closely with serial LDH levels, which correlate well with BRAF-mutant disease burden.

Closing thoughts: In the landmark trial of first-line combination immunotherapy for stage IV melanoma, median melanoma-specific survival has not yet been reached after 6.5 years of follow-up. In plain English, more than half of those who underwent combination immunotherapy have survived stage IV melanoma at the 6.5-year mark. Because not everyone experiences prolonged survival, I would be realistic about having a stage IV cancer diagnosis that might be fatal, yet remain optimistic given the pace of new drug development that immunotherapy and targeted therapy have precipitated in the last decade.

Requests for Dr. Funchain’s email address can be sent to Curious Dr. George at gdlundberg@gmail.com.