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

How an Expert Would Treat His Own Advanced Lung Cancer: An Update

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

Howard (Jack) West, MD, FASCO
Vice President, Clinical Development, Summit Therapeutics

A new cancer diagnosis is overwhelming. Patients often ask their doctors, “What would you do if you were me?” Here, our Curious Dr. George asks lung cancer expert Howard (Jack) West, MD, FASCO, how he would handle his own diagnosis of advanced lung cancer. Dr. West is a Princeton- and Harvard-educated oncologist with additional training and experience in Boston and Seattle focusing on lung cancer. He is now Vice President of Clinical Development at Summit Therapeutics. (Note: This piece was first published in March 2021. We now present it anew with Dr. West’s updated affiliation. His reply below remains up to date and relevant for people dealing with advanced lung cancer.)

Curious Dr. George: What would you do if you personally were discovered on a routine chest X-ray to have a unilateral pleural effusion which was found by cytopathology to contain mixed squamous and adenocarcinoma cells? How would you proceed?

Jack West, MD, FASCO: Though I’m a never-smoker, we know that is no guarantee of immunity from lung cancer, the cancer type I’ve focused on for the past two decades. Perhaps I develop a persistent cough and worsening shortness of breath over a few months. I get a chest X-ray that shows a large right pleural effusion, and a same-day chest CT confirms this and bilateral lung nodules, perhaps along with several enlarged right hilar and mediastinal lymph nodes. The effusion is drained, and the pathologist gives my doctor and me the immediate feedback that this is a carcinoma, and we quickly learn that the immunohistochemistry profile is consistent with an adenocarcinoma. Where do we go from here?

My next step is to order broad next-generation sequencing, which may entail a new biopsy, either CT-guided or an endobronchial ultrasound and biopsy of whatever is accessible. We need sufficient tissue to send off for broad molecular testing that includes a look for all of the growing collection of lung cancer “driver mutations.” These include long-established markers like a mutation in the epidermal growth factor receptor (EGFR) gene or a rearrangement in the anaplastic lymphoma kinase (ALK) gene, but now also a rearrangement in ROS1, mutation of BRAF V600E, a MET exon 14 skipping mutation, RET fusion, or fusion in the TRK gene. These genetic alterations are found in approximately 0.5% to 10% each in patients with non-small cell lung cancer (NSCLC) and far more commonly in patients with a non-squamous NSCLC tumor. They all have FDA-approved oral targeted therapies with efficacy that generally exceeds what we could expect with our best standard non-targeted approaches involving immunotherapy with or without chemotherapy. Most of these targeted therapies also better tolerated and can work for a prolonged period that may reach the range of years.

This mutation testing typically takes at least 2 to 4 weeks, but the importance of identifying one of these mutations, when present, makes it critical to seek this information at the time of initial diagnosis. Moreover, in addition to the array of markers we currently have targeted therapies for, we expect an FDA approval for an inhibitor of KRAS G12C-mutated NSCLC, seen in about 12% to 13% of advanced NSCLC, in the coming months; all in all, comprehensive molecular testing guides us to an optimal targeted therapy for at least 20% of patients, and that proportion will continue to increase as new targets with effective therapies become available.

In the hypothetical scenario of my own diagnosis, as this testing is being done we’re also testing for tumor PD-L1 expression, which identifies tumors most likely to respond well to immune checkpoint inhibitors, potentially sparing patients first line chemotherapy if they don’t receive a targeted therapy. And I’d seek to complete imaging with a PET/CT and brain MRI, in order to identify whether the cancer has spread to other sites beyond those already identified.

Once these tests are completed, I’d prioritize a targeted therapy if my tumor harbors a driver mutation. If not, I’d generally favor pembrolizumab monotherapy if my cancer is among the approximately 28% to 30% that demonstrates high tumor PD-L1 expression (greater than 50%). Otherwise, if my cancer has neither a driver mutation nor high tumor PD-L1 expression, I’d generally favor a platinum-based chemotherapy doublet with pembrolizumab—an option I would also favor in a patient with a tumor that doesn’t harbor a driver mutation and with high tumor PD-L1 if that patient had many cancer-related symptoms or otherwise showed a pattern of rapid progression in the early weeks of the workup. Though I’d be happy to sequence the immunotherapy with subsequent chemotherapy in patients in whom I’m confident they will still have the performance status to tolerate platinum doublet chemotherapy after progressing on chemotherapy, I’d favor “front-loading” with chemo-immunotherapy together in patients in whom I’m concerned I may only have “one shot on goal.”

Dr. West can be reached at JackWestMD@gmail.com or on Twitter at @JackWestMD.

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Copyright: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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

How an Expert Would Manage His Own Advanced Prostate Cancer: An Update

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Curious Dr. George
Cancer Commons Editor in Chief 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

When facing a new cancer diagnosis, some people ask their doctors, “What would you do if you were me?” Here, our Curious Dr. George asks Marc B. Garnick, MD, how he would handle his own advanced prostate 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. (Note: This piece was first published in June 2022 and has now been updated with additional information about neuroendocrine elements, mismatch repair deficiency, and cardiovascular considerations.)

Curious Dr. George: In 2021, you shared with our readers how you, as an expert, would proceed with handling your own severe back pain and spine lesions.

Let’s revisit that hypothetical scenario with some new developments: Further rapid lab studies demonstrated normal peripheral blood counts and no abnormal serum proteins. The back pain stabilized. Digital rectal exam discovered an enlarged, diffusely firm prostate gland with scattered hard foci. Ten transrectal prostate biopsy cores all contained adenocarcinoma with varying degrees of dedifferentiation, Gleason score of 8, repeat PSA was 25.

How should the pathologist handle the remaining tissues? What procedures should a reference laboratory perform? How would genomic, metabolomic, or proteomics inform next steps? And would imaging be helpful?

Marc B. Garnick, MD: With these new developments, the differential diagnosis has now been narrowed. The likelihood of the bone lesions being related to a plasmacytoma or multiple myeloma, though not completely excluded, are less likely. The lead diagnosis now has been established to be a Gleason score 8 prostate adenocarcinoma, which I presume is a Gleason 4+4. Please recognize that based upon the International Expert Consensus on Prostate Cancer nomenclature, this is now best described as Grade Group 4 (GG 4). Grade Group 1 (GG 1) contains Gleason patterns 3+3; GG 2 contains Gleason patterns 3+4; GG 3 contains Gleason patterns 4+3; GG 4 contains Gleason patterns 4+4; and GG 5 contains Gleason patterns 4+5 or 5+5. If this patient did not have suspected metastases to the bones (and even in the setting of metastatic prostate cancer), the pathology biopsy note should mention the presence of any intraductal component, perineural invasion, or lymphovascular invasion, all of which commonly accompany high-grade Gleason cancers. Neuroendocrine elements, although uncommon, can also accompany high-grade Gleason scores. If present, such transformation following treatment to neuroendocrine/small cell-like pathologies represents an ominous development, which is often accompanied by visceral involvement and the need for systemic chemotherapy.

Recent recommendations now suggest that genomic profiling of the patient both for germline and somatic mutations be assessed. The importance of BRCA (either germline or somatic) mutation has increased in significance, especially since there are emerging associations of prostate cancer being found in families of women with BRCA mutations. The finding of a BRCA2 mutation is associated with a more aggressive biology and could help inform treatments at some later day with the PARP class of therapeutics of platinum-containing agents, given the increased sensitivity of BRCA + cancers to respond to these therapies. Likewise, the presence of microsatellite instability (MSI high, or MSI-H) or mismatch repair deficient (dMMR) mutations may prompt treatment with an immunotherapy agent such as pembrolizumab.

The above consideration of more precise pathologic assessment is more important in a patient who has a GG 4 or 5, in whom there is no obvious evidence of metastatic disease. In such cases, one is trying to assess a probability of the patient having subclinical metastatic disease or being likely to develop metastatic disease. For the patient with already-established evidence of abnormal foci (in this case, the bone lesions), we in the past would have assessed with an Axumin scan; now, the availability of either Ga or F linked prostate-specific membrane antigen (PSMA) scanning would be indicated, both for diagnostic purposes as well as assessing down-the-line utility of PSMA-specific therapeutic ligands, such as Lutetium 177.

An assessment of cardiovascular history is increasingly important in helping determine a treatment program that helps minimize any therapy-induced increase in morbidity. Traditional androgen-deprivation therapy (ADT) has long been associated with cardiovascular issues, and now, with the standard addition of second-generation androgen receptor signaling inhibitors to ADT, the cardiovascular risk can double and even quadruple. Patient evaluation by experts in cardiology, internal medicine, or the emerging field of cardio-oncology is becoming increasingly important.

Curious Dr. George: What additional testing and what therapy would you deem to be most appropriate at this point?

Marc B. Garnick, MD: Please recall that this patient (hypothetically me) presented with back pain and multiple bony lytic lesions. Regardless of the etiology of these lesions, identification of any impending spinal cord compression must be assessed. While spinal cord compression is an unusual manifestation of de novo metastatic prostate cancer, it is clinically more common in the setting of treated prostate cancer that has progressed to become castration resistant. I would reassess the anatomic locations of the bone lesions, and then obtain a spinal MRI directed diagnostic evaluation, along with a good neurological examination to inform preemptive radiation or surgical considerations if either impending or actual compression is found.

For treatment of newly diagnosed presumably castration-sensitive metastatic prostate cancer, we now have multiple advances that have been established in this disease setting. First-line ADT (generally with an LHRH agonist or GnRH antagonist) is now supplanted with second-generation agents, such as abiraterone (+ prednisone) or enzalutamide, or other androgen-receptor signaling inhibitor agents, such as apalutamide. ADT + chemotherapy with docetaxel is also appropriate. Given the bone pain and potential neurological issues here, I would select a GnRH antagonist (either degarelix or relugolix) as the preferred therapy.

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

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Copyright: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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

The Personalized Power of the “N-of-1” Approach

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

Glenn Sabin
Director of Strategy & Business Development, Cancer Commons and Author of n of 1

Randomized, controlled clinical trials with a large N—number of participants—are the recognized “gold standard” of evidence-based medicine. Even so, the results of large-N trials can only reveal population averages, and are not predictive of any individual’s response to a given treatment. On the other hand, one can consider every patient with cancer as the sole participant in their own clinical trial with an Nof1, even if the trial is not officially registered, reported, or supported like a traditional trial.

Here, our Curious Dr. George discusses the value of the “n-of-1” approach with Glenn Sabin, director of strategy and business development at Cancer Commons. Sabin is a 33-year cancer thriver and author of n of 1: One Man’s Harvard-Documented Remission of Incurable Cancer Using Only Natural Methods.

Curious Dr. George: Among the many people whose cancer progresses beyond guideline-based standards of curative care, how might one become an n-of-1 trial participant, if they so choose? What actions should be taken by the physicians who bear responsibility for such individuals who desire to further collective knowledge—and their own welfare—by voluntary participation in use of investigational drugs or drug combinations, or off-label use of drugs approved for other contexts by the US Food and Drug administration (FDA)?

In my view, the n-of-1 approach is clinical care and should be paid for by reputable insurance companies. And, the patient can provide fully informed consent, even with the proviso that the process and outcome be shared for educational purposes. Could this approach become a nimble form of adaptive clinical trial? What are its pros and cons?

Glenn Sabin: From my perspective, randomized, controlled trials (RCTs) will continue to be important for population-based investigational cancer drug development—especially when effectively translated to clinical practice.  Standard-of-care treatment that follows guidelines from the National Comprehensive Cancer Network (NCCN) remains effective for many patients who host early-stage and more indolent disease.

However, for those living with advanced and rare cancers—and for whom standard care has not enabled deep and durable remissions after multiple lines of treatment—it is critical to consider a more personalized approach to testing and treatment.

After all, there is only one host (the unique person living with cancer) and one tissue/tumor type (no two malignancies are exactly alike). This is why we are each an Nof1—an experiment of one. This is the distinction between population-based investigations (RCTs) and truly personalized cancer care (Nof1): averages versus individualization.

I see a future close on the horizon where each patient goes through a deep set of diagnostic testing beyond today’s molecular testing (which itself is not used nearly often enough). The resulting data, consisting of multiple datasets, are then precisely interpreted to inform—with the assistance of artificial intelligence—the patient’s best option for their next treatment. Then, the chosen therapeutics are secured, typically in combinations and often as off-label, and administered to the patient.

Alas, in today’s reality, this type of n-of-1 care—even among the most affluent, educated and connected patients—is largely inaccessible. Access is key.

Novel Testing
Testing beyond certain FDA-approved molecular (sequencing of DNA/RNA) and other diagnostics is not currently covered by Medicare or commercial insurance. Those interested in functional testing—the testing of their own tumor tissue across scores of drugs and combinations—need to pay out of pocket, and some of these novel assays can get quite expensive.

Interpretation of Testing Results
These novel tests produce lots of data. Now what? The problem is that very few oncologists can interpret beyond the “targetable” biomarkers and mutations shown in molecular sequencing reports, which typically cover a small set of genes. Add to the mix novel multi-omics assays (looking at proteins, metabolism, the microbiome, and more) and functional testing, and oncologists are not trained to review in a way that supports the treatment decision-making process. Third-party professional services are needed.

N-of-1 Physicians
Oncologists are trained to deliver standard-of-care cancer treatment as defined by NCCN guidelines. Across the US, some oncologists within community practices will consider prescribing outside of these guidelines when patients have relapsed multiple times. Other oncologists, especially within academia, will only depart from NCCN guidelines under an institutional review board (IRB) and investigative new-drug (IND) study setting, even if such a study is created for only one patient (N of 1). In general, oncologists need internal institutional support to prescribe off label, both from their tumor board colleagues and from colleagues who ensure they feel comfortable about potential toxicity when using drugs with limited or no studies capturing potential for severe adverse events.

Drug Access
Today, approximately 30% of all FDA-approved anticancer therapeutics are prescribed off label. Physicians always have the option to prescribe in this way. One major issue is getting off-label drugs covered by Medicare or commercial payors. Otherwise, providers must advocate for their patients (without reimbursement for their efforts) to apply to various programs such as Expanded Access and Compassionate Use. And there is no financial incentive to do so because drugs secured through these channels cannot be marked up.

Data Collection and Registry Studies
The most effective and efficient way to capture n-of-1 managed and treated patient data is within an IRB-compliant registry connected to a learning health system. This approach collects real-world evidence and allows us to learn from each patient in near-real time. The gold-standard comprehensive learning health system does not yet exist, but I understand that progress is moving apace.

Making N-of-1 Cancer Care a Reality
At Cancer Commons, we are actively pursuing solutions to making comprehensive, end-to-end, n-of-1 patient navigation and treatment a reality. Every day we are working on eliminating the obstacles to access, in service of improving the human condition for those hosting advanced disease, and their families and loved ones.

Progress is inexorable.

Mr. Sabin can be reached at glenn.sabin@cancercommons.org.

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Copyright: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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

How Would an Expert Manage His Own Acute Myelogenous Leukemia: an Update

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

Adam Asch, MD
Professor of Medicine; Nancy Johnson Records Chair of Oncology, University of Oklahoma College of Medicine

When facing a frightening new cancer diagnosis, some people ask their doctors, “What would you do if you were me?” Previously, our Curious Dr. George asked leukemia expert Adam Asch, MD, how he would handle his own hypothetical case of acute myelogenous leukemia (AML). Now, Dr. Asch provides an updated answer, highlighting the new option of clinical trials offering novel targeted therapies for some AML patients. Dr. Asch is Professor of Medicine and Nancy Johnson Records Chair of Oncology at the University of Oklahoma College of Medicine.

Curious Dr. George: Please consider this hypothetical scenario: You are an active clinical oncologist in generally good health, but lately, you have lacked energy, have been feeling a little more tired than usual, have some dizziness on exertion, have been bruising easily, and have lost a bit of weight without dieting. So, you decide to visit your primary care physician for a checkup. On physical examination, she notes that you are a little pale, finds arm bruises, and feels the tip of your spleen. She orders several lab tests. Your hematocrit is 38, hemoglobin 12, white blood cells (WBCs) 49,000 per microliter with many blasts, many promyelocytes, myelocytes, eosinophils, and basophils. Platelets are low. A diagnosis of acute myelogenous leukemia (AML) is made. How would you proceed?

Adam Asch, MD: This would be a fascinating case to discuss in the abstract. But in the first person, as you have been exploring in your Curious Dr. George series, diagnosis and therapy take on a special and sometimes personal urgency. For this 70-year-old oncologist, the hypothetical is a timely one and for the field a relevant one, since AML is, in so many ways, a disease of aging.

For most AML patients, I find that the most important question to ask is if there is a curative intervention. For some, chemotherapy induction and consolidation may lead to a prolonged remission and perhaps cure. But for some disease categories—notoriously, p53-mutated disease—response to traditional chemotherapy is poor. Second, assuming an initial remission follows an induction regimen, how a remission is consolidated is another critical question. For people with high-risk AML (complex cytogenetics, FLT3-mutated) or intermediate-risk AML, allogeneic transplant remains the best means of consolidating a remission and offering a cure to many.

To a great extent, treatment for AML is informed by genetic and molecular studies that have become standard in the field. Cytogenetics to assess chromosomal defects, molecular analysis to identify potentially targetable mutations, and multi-channel flow cytometry to identify a blast phenotype that can be followed to assess measurable residual disease post induction and consolidation are all standard. Translocation 15;17 or “acute promyelocytic leukemia” (APL)—once considered to be the worst type of AML prognostically—is now routinely treated with all-trans retinoic acid and arsenic trioxide, with long-term survival now approaching 90%. The clinical presentation in this hypothetical case does not sound like APL, though the bruising raises the question, and a coagulation profile, if indicative of disseminated intravascular coagulation, might make that more of a question.

Other good prognostic cytogenetics include the translocation of chromosomes 8 and 21—also known as t(8;21)—and inversion of chromosome 16. Each of these has a historical long-term survival rate of about 60 to 70% with standard induction chemotherapy. All other cytogenetic features are classified as intermediate risk or poor risk, with long-term survival rates of 30 to 40% or 10%, respectively. For each of these latter risk groups, transplant remains the only real chance of relapse-free, long-term survival.

Now, before we discuss treatment regimens for AML in general, there are some features of my presentation that would lead me to ask for some additional data. The presence of a spleen tip and the presence of early myeloid forms, eosinophils, and basophils in addition to blasts raise the possibility that my disease is a Ph+ blast crisis rather than de novo AML. If so, treatment with a kinase inhibitor directed at the BCR-ABL kinase—after initial cytoreduction of the elevated blast count—would be a reasonable initial approach to getting control of the disease. But without allogeneic transplant as consolidation, this would not offer me long-term control of the disease. So, more on transplant in a bit.

Standard induction for “fit” patients with AML has remained largely unchanged for several decades—until recently. The chemotherapy combination of 7+3 (7 days of cytosine arabinoside and 3 days of an anthracycline) has been the backbone of induction in the U.S. Consolidation chemotherapy with 3 to 4 subsequent cycles of high-dose cytosine arabinoside has been common practice. The development of a liposomal preparation containing a defined ratio of cytosine arabinoside and daunorubicin has shown increased efficacy in AML that arises from a pre-existing condition known as myelodysplastic syndrome (MDS). Also, drugs targeting specific mutations in genes such as FLT3, IDH1, or IDH2 are additional options that can now be used in combination with standard approaches—or alone in some instances. But perhaps most impressive has been the incorporation of the BCL2 inhibitor venetoclax in combination with azacytidine as a low-intensity regimen now approved by the U.S. Food and Drug Administration (FDA) for elderly and unfit patients with MDS.

Response rates appear to essentially equal those of the standard high-intensity induction regimens. Importantly, this regimen generally has lower toxicity and is most often administered outpatient. Recent data show that patients achieving a complete response with this regimen do as well with allogeneic transplant as folks who received more intensive induction. And for younger, fit patients, venetoclax added to more intensive regimens is producing results that are likely significant improvements over the old 7+3.

So, getting back to the first question I posed, am I looking at the possibility of a cure? Possibly. It is not likely, at my age, that cytogenetics would be favorable. Complex cytogenetics and AML arising from MDS are much more prevalent. Even if this were to be a Ph+ AML blast crisis, my long-term survival would depend on allogeneic transplant as consolidation post remission.

Am I a candidate at 70 for an allogeneic transplant? Possibly. Recent studies show that arbitrary age limits on allo transplantation have virtually disappeared across transplant centers. Less ablative regimens and improved supportive care around infection control and prevention of graft-versus-host disease have led to a situation where transplantation for older patients is a viable option with reasonable outcomes. Unfortunately, it is one that is currently afforded to only about 5% of older AML patients.

So, what would I want in this situation? I would, of course, look for any relevant clinical trials, as all advances in the field are dependent on trials of novel therapies. There are now several trials looking at the addition of novel targeted therapies as a component of induction therapy for patients with appropriate molecular features. But in the absence of an appropriate trial, for my intermediate- or poor-risk AML, I would likely opt for azacytidine and venetoclax as an induction/consolidation regimen, which would give me a better chance of escaping potentially debilitating complications of induction and consolidation that might put a definitive transplant out of reach. And, I would consider transplant as consolidation if in complete remission and still in good shape.

Some reality here: if these approaches didn’t get me to a complete remission, my discussions would center on defining the best way to preserve quality of life with family and friends during my remaining time.

Dr. Asch can be reached at adam-asch@ouhsc.edu.

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A message from Curious Dr. George:

The goal of Cancer Commons is to help patients identify and access their best possible treatments, one patient at a time, while moving the field forward. If you have advanced cancer, let our molecular oncology scientists provide personalized information about your options.

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Copyright: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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

How Would an Expert Manage His Own Advanced Hodgkin Lymphoma: an Update

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

Kevin Knopf, MD Chief Medical Officer, Cadex Genomics; CMO and Division Chief of Hematology/Oncology, Highland Hospital (Oakland)

When facing a frightening new cancer diagnosis, some people ask their doctors, “What would you do if you were me?” Here, our Curious Dr. George asks oncologist Kevin Knopf, MD, how he would handle his own advanced Hodgkin lymphoma.

Curious Dr. George: Please consider this hypothetical scenario—as a very busy practicing clinical oncologist during the COVID-19 pandemic, you were not paying much attention to your own health when you noticed a weight loss of 7 pounds, a dry cough, and a little fever and sweating at night. Your home COVID-19 antigen tests were negative, but you found some enlarged cervical lymph nodes. Your physician confirmed the lymphadenopathy and palpated an enlarged spleen. Your hematocrit was 39, and WBC 16, 000. CT scan detected both para aortic and mediastinal lymphadenopathy. Biopsy of a cervical node was diagnosed as nodular sclerosing Hodgkin lymphoma. How do you proceed?

Kevin Knopf, MD, MPH: First, which chemotherapy regimen would I pick, given the treatment is with curative intent? Three standard choices: ABVD, BEACOPP, and A-AVD foster intense debate amongst oncologists. A recent Twitter poll by Dr. Aaron Goodman (of the University of California, San Diego) had opinions split evenly between ABVD, R-BEACOPP, and A-AVD. The choice has subtle nuances; my feeling is ABVD is probably fine for young patients where the risk of bleomycin pulmonary toxicity can be monitored closely; for myself I would choose A-AVD and monitor carefully for neuropathy.

Where to be treated? Where I work in the East Bay of California’s San Francisco Bay Area, there are centers for the University of California, San Francisco (UCSF) and Stanford, and Dr. Andreadis—a friend—is at UCSF, and Dr. Barbara Galligan, my former resident whom I helped mentor into oncology, are all excellent. By a thin margin I would choose Dr. Rajesh Behl in Berkeley in the East Bay. He is a smart oncologist and I appreciate his dry sense of humor. Getting in and out of his office for treatment would be easy, and it is with the infusion nurses that I would spend 98% of my time.

I am fortunate that my insurance would cover the complete cost and my choice of physicians, but this illustrates an area of oncology I spend a lot of time thinking and writing about: cost effectiveness and health equity. There are broad disparities in cancer care—within the U.S. and worldwide—such that many patients with a curable cancer, such as Hodgkin lymphoma, are not cured.

Pricing for cancer care seems arbitrary and is not really negotiated. In classic economics, one would pick amongst my 5 treatment options based on the lowest cost of care, as the outcome is almost certainly equal. There is a mind-blowing aspect of American health insurance: when Obamacare was enacted, insurance companies’ net profit was capped at 15% of the medical loss ratio, meaning the more my insurance company spends, the more money they can make. My premiums have jumped 15% in 2023. A-AVD is 108-fold more costly than ABVD. Cancer care in the U.S. is virtually “all accelerator, no brake,” and the cost of care keeps rising each year, and health disparities widen.

Sociologist C. Wright Mills quipped “the most important thing you can do in a capitalistic society is choose the right parents.” I chose wisely and ended up with “Cadillac” health insurance. All other industrialized nations have a single-party payer system to pay for care, while U.S. health care delivery is based on a for-profit model. American health care works out well in this particular hypothetical example, but overall, we rank about 50th in the world in terms of healthcare efficiency—tied with Bulgaria.

There are casualties. Half of the U.S. has medical debt, 50% of women with metastatic breast cancer are being pursued by debt collectors, and 42% of newly diagnosed cancer patients will go bankrupt within 3 years of diagnosis. We have a tragic and widening cancer disparity gap in the U.S. and a large care gap between first-world nations and low- and middle-income countries. In many parts of the world, a similar patient would not receive curative chemotherapy. People speak of the American health care “system,” but that would imply a formal interconnected design rather than our Byzantine way of paying for health care. So I might come out of this diagnosis just fine, and not bankrupt, but that was just a simple twist of fate.

Dr. Knopf can be reached at kevinbknopf@gmail.com.

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Copyright: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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

SAGE Oncotest: Entering the Next Generation of Tailored Cancer Treatment

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Chris Apfel, MD, PhD, MBA
Founder, CEO, and Board Chair of SageMedic Corp.

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

For people with recurring or drug-resistant cancer, choosing the best-possible next treatment can pose a huge challenge. Our Curious Dr. George asks Chris Apfel, MD, PhD, MBA—Founder, CEO, and Board Chair of SageMedic Corp.—about his company’s solution for many of these patients.

Curious Dr. George: Despite the application of curative surgical, radiation, and systemic treatments, cancer remains the “emperor of all maladies” with 600,000 Americans dying of cancer every year. With many more patients battling recurrent or resistant disease, even with adherence to standard guidelines from the National Comprehensive Cancer Network (NCCN), selecting the next line of treatment—whether cytotoxic chemotherapies, targeted therapies, or immunotherapies—often follows a trial-and-error approach.

To address this unresolved challenge, SageMedic, a CMS and CLIA-accredited and California-based company, has developed the SAGE Oncotest™. In comparison to next-generation genomic sequencing, which provides actionable insights for a smaller number of patients, SageMedic claims that its Oncotest, an extreme drug resistance (EDR) assay, provides actionable insights for virtually all patients within 10 days, thereby avoiding likely failures.

Dr. Apfel, I understand that this is only possible because you are using fresh, live cancer tissue, right? Can you share more about how your test works and how it can help cancer patients?

Chris Apfel, MD, PhD, MBA: The SAGE Oncotest is a next-generation EDR assay in which we use a patient’s biopsy specimen to create microtumors in the lab. We then expose the microtumors to a wide range of drug concentrations, and we measure which drugs at which concentrations are most effective at killing the cancer cells.

Within one day of receiving a fresh biopsy specimen, we can create hundreds of microtumors from virtually all types of solid cancer, including breast, ovarian, prostate, and pancreatic cancers, glioblastoma, and cancers of unknown origin. Thanks to our proprietary technology, these live microtumors maintain the patient’s tumor heterogeneity and microenvironment for virtually every biopsy specimen.

Furthermore, in contrast to organoid approaches that usually take weeks or months for organoid growth, if growth occurs at all, the SAGE Oncotest one-day aggregation step allows for next-day drug exposure, with actionable information generated for virtually every patient within just 7 to 10 days.

Our predicate EDR predicted tumor resistance with about 96% accuracy, and it is highly unlikely that a tumor will respond to a therapy that does not work ex vivo in supra-physiological concentrations, as in the context of the SAGE Oncotest. By ruling out ineffective therapies, we project this assay to identify the most promising drugs with about 80% accuracy, doubling a patient’s chance for a tumor response, significantly improving quality of life, and significantly extending the patient’s life expectancy.

SAGE can test the potential sensitivity and resistance of dozens of drugs and drug combinations, though our current technology does not test for anti-hormonal or immuno-oncology drugs.

If any readers are interested in having their patient’s tissue tested to help inform their treatment plan, we ask them to please let us know at least a week ahead of the patient’s biopsy or surgery, so that we can send the shipment kit to ensure overnight delivery of viable tissue. SAGE Oncotest requires fresh, live cancer tissue rather than formalin fixation, which kills cells within minutes and renders the sample unusable for our assay.

Physicians can choose from two Sage Oncotest panels. The standard panel (“Superior Care within Standard of Care”) tests the microtumors against NCCN guideline-recommended drugs and can inform, especially, initial treatment plans, e.g., stage II or III patients expected to require adjuvant therapy. The expanded panel (“Beyond Standard of Care”) includes the standard panel plus special requests, including targeted therapies and repurposed drugs, which becomes meaningful when standard treatment regimens fail. Of note, if a fresh biopsy is not feasible, we have also been able to retrieve sufficient cancer tissue from pleural effusions, ascites, and even bone metastases.

In summary, the SAGE Oncotest complements other precision oncology approaches by providing actionable information for virtually all patients within 7-10 days to avoid ineffective drugs and significantly increase the chance for best-possible outcomes.

Dr. Apfel can be reached at capfel@sagemedic.com.

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Copyright: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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

Treating Pancreatic Cancer: Could Metabolism—Not Genomics—Be the Key?

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Thomas Seyfried
Biology Department
science

Derek Lee, MS
PhD Candidate (Seyfried Lab), Department of Biology at Boston College

Tomás Duraj, MD, PhD
Postdoctoral Research Fellow, Department of Biology at Boston College

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

In 2018, we published a Curious Dr. George post featuring Thomas N. Seyfried, PhD, about cancer possibly being mostly a metabolic—rather than genetic—disease. Since then, the field of cancer genomics has expanded enormously, and we have published many posts in support of better understanding and treatment of many types of cancer based on the genomic approach. Here, Dr. Seyfried and two of his colleagues at Boston College—Derek Lee, MS, and Tomás Duraj, MD, PhD—provide an update on their perspective.

Curious Dr. George: Our recent Curious Dr. George post on pancreatic cancer stimulated you to push back on existing therapeutic strategies that have been failures for so long, and suggest an entirely different approach. Why do the current treatments of pancreatic cancer fail, and what new approach might be worth considering?

Thomas N. Seyfried, PhD; Derek Lee, MS; and Tomás Duraj, MD, PhD: Current therapeutic approaches for managing the most common form of pancreatic cancer (pancreatic ductal adenocarcinoma , or PDAC)—and many other cancers, for that matter—have failed to significantly reduce deaths in severe cases. The promise of effective precision medicine based on the somatic mutation theory of cancer has not been realized. This is evident from the latest statistics published by the American Cancer Society showing that, every day, almost 1,700 people die of cancer or cancer-treatment-related causes. While it is understandable and important to highlight recent advancements, the long-term (10-year) survival rate for PDAC is still less than 5%.

It is also important to be realistic about the side effects of many first-line treatments for PDAC. Many of the current “targeted” treatments can result in severe fatigue, gastrointestinal disturbances, liver failure, and myriad other complications. These adverse effects are unacceptable and contribute further to the physical and mental stress already associated with a cancer diagnosis. Treatment modalities based on an incorrect theory of cancer origin will not provide optimal management for most patients.

In contrast to the somatic mutation theory, the mitochondrial metabolic theory can better explain the origin of cancer and provide more rational therapeutic strategies for management. For example, KRAS mutations negatively impact oxidative phosphorylation (OxPhos), thus forcing tumors to be more dependent on aerobic fermentation than on OxPhos for driving dysregulated growth. OxPhos inefficiency coupled to energy synthesis through aerobic glucose and glutamine-dependent fermentation is now recognized in nearly all cancers. Unfortunately, the metabolic dependencies of cancer cells are just an afterthought, if considered at all.

We have yet to find a report showing any cancer cells that can grow in the absence of glucose and glutamine. Ketone bodies and fatty acids are non-fermentable fuels and cannot therefore replace either glucose or glutamine for sufficient energy production in cancer cells with OxPhos insufficiency. An effective non-toxic therapeutic strategy for managing cancer would therefore involve the simultaneous down-regulation of the glucose-driven glycolysis and the glutamine-driven glutaminolysis pathways using diet-drug combinations, while transitioning the body to non-fermentable fuels, e.g., fatty acids and ketone bodies.

A transition of the body from glucose to nutritional ketosis—glucose/ketone index (GKI) values of 2.0 or below—will induce significant physiological stress on the already metabolically inflexible cancer cells while, at the same time, providing an efficient energy source for healthy cells that evolved to transition from glucose to ketone bodies under dietary energy reduction. A combination of both carbohydrate restriction and high-intensity exercise will stimulate glucose and glutamine clearance from circulation.

Adherence to this approach can be challenging for some, but shifting the role of the patient from passive observer to active participant in their non-toxic metabolic treatment strategy will help enable longer-term management of their cancer.

Dr. Seyfried can be reached at thomas.seyfried@bc.edu, Dr. Lee at leebig@bc.edu, and Dr. Duraj at tomas.duraj@bc.edu.

Additional references for successful application of ketogenic metabolic therapy in animals and humans:

İyikesici MS, Slocum AK, Slocum A, Berkarda FB, Kalamian M, Seyfried TN.Efficacy of Metabolically Supported Chemotherapy Combined with Ketogenic Diet, Hyperthermia, and Hyperbaric Oxygen Therapy for Stage IV Triple-Negative Breast Cancer. Cureus. 2017 Jul 7;9(7):e1445. doi: 10.7759/cureus.1445.

Elsakka AMA, Bary MA, Abdelzaher E, Elnaggar M, Kalamian M, Mukherjee P, Seyfried TN. Management of Glioblastoma Multiforme in a Patient Treated With Ketogenic Metabolic Therapy and Modified Standard of Care: A 24-Month Follow-Up. Front Nutr. 2018 Mar 29;5:20. doi: 10.3389/fnut.2018.00020.

Augur ZM, Doyle CM, Li M, Mukherjee P, Seyfried TN. Nontoxic Targeting of Energy Metabolism in Preclinical VM-M3 Experimental Glioblastoma. Front Nutr. 2018 Oct 5;5:91. doi: 10.3389/fnut.2018.00091. eCollection 2018.

Mukherjee P, Augur ZM, Li M, Hill C, Greenwood B, Domin MA, Kondakci G, Narain NR, Kiebish MA, Bronson RT, Arismendi-Morillo G, Chinopoulos C, Seyfried TN. Therapeutic benefit of combining calorie-restricted ketogenic diet and glutamine targeting in late-stage experimental glioblastoma. Communications Biol. 2019 May 29;2:200. doi: 10.1038/s42003-019-0455-x.

Seyfried TN, Shelton L, Arismendi-Morillo G, Kalamian M, Elsakka A, Maroon J, Mukherjee P. Provocative Question: Should Ketogenic Metabolic Therapy Become the Standard of Care for Glioblastoma? Neurochem. Res. 2019 Apr 25. doi: 10.1007/s11064-019-02795-4.

Seyfried TN, Mukherjee P, Iyikesici MS, Slocum A, Kalamian M, Spinosa JP, Chinopoulos C. Consideration of Ketogenic Metabolic Therapy as a Complementary or Alternative Approach for Managing Breast Cancer. Front Nutr. 2020 Mar 11;7:21. doi: 10.3389/fnut.2020.00021.

İyikesici MS, Slocum AK, Winters N, Kalamian M, Seyfried TN. Metabolically Supported Chemotherapy for Managing End-Stage Breast Cancer: A Complete and Durable Response. Cureus. 2021 Apr 26;13(4):e14686. doi: 10.7759/cureus.14686.PMID: 33927959.

Seyfried TN, Shivane AG, Kalamian M, Maroon JC, Mukherjee P, Zuccoli G. Ketogenic Metabolic Therapy, Without Chemo or Radiation, for the Long-Term Management of IDH1-Mutant Glioblastoma: An 80-Month Follow-Up Case Report. Front Nutr. 2021 May 31;8:682243. doi:10.3389/fnut.2021.682243. eCollection 2021.PMID: 34136522.

Seyfried TN. The effects of diet on prostate cancer outcomes. Nat Rev Urol. 2022 Jul;19(7):389-390. doi: 10.1038/s41585-022-00612-2.PMID: 35676538.

 

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Copyright: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

How Would an Expert Manage His Own Acute Myelogenous Leukemia: an Update

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

Adam Asch, MD
Professor of Medicine; Nancy Johnson Records Chair of Oncology, University of Oklahoma College of Medicine

When facing a frightening new cancer diagnosis, some people ask their doctors, “What would you do if you were me?” Previously, our Curious Dr. George asked leukemia expert Adam Asch, MD, how he would handle his own hypothetical case of acute myelogenous leukemia (AML). Now, Dr. Asch provides an updated answer, highlighting the new option of clinical trials offering novel targeted therapies for some AML patients. Dr. Asch is Professor of Medicine and Nancy Johnson Records Chair of Oncology at the University of Oklahoma College of Medicine.

Curious Dr. George: Please consider this hypothetical scenario: You are an active clinical oncologist in generally good health, but lately, you have lacked energy, have been feeling a little more tired than usual, have some dizziness on exertion, have been bruising easily, and have lost a bit of weight without dieting. So, you decide to visit your primary care physician for a checkup. On physical examination, she notes that you are a little pale, finds arm bruises, and feels the tip of your spleen. She orders several lab tests. Your hematocrit is 38, hemoglobin 12, white blood cells (WBCs) 49,000 per microliter with many blasts, many promyelocytes, myelocytes, eosinophils, and basophils. Platelets are low. A diagnosis of acute myelogenous leukemia (AML) is made. How would you proceed?

Adam Asch, MD: This would be a fascinating case to discuss in the abstract. But in the first person, as you have been exploring in your Curious Dr. George series, diagnosis and therapy take on a special and sometimes personal urgency. For this 70-year-old oncologist, the hypothetical is a timely one and for the field a relevant one, since AML is, in so many ways, a disease of aging.

For most AML patients, I find that the most important question to ask is if there is a curative intervention. For some, chemotherapy induction and consolidation may lead to a prolonged remission and perhaps cure. But for some disease categories—notoriously, p53-mutated disease—response to traditional chemotherapy is poor. Second, assuming an initial remission follows an induction regimen, how a remission is consolidated is another critical question. For people with high-risk AML (complex cytogenetics, FLT3-mutated) or intermediate-risk AML, allogeneic transplant remains the best means of consolidating a remission and offering a cure to many.

To a great extent, treatment for AML is informed by genetic and molecular studies that have become standard in the field. Cytogenetics to assess chromosomal defects, molecular analysis to identify potentially targetable mutations, and multi-channel flow cytometry to identify a blast phenotype that can be followed to assess measurable residual disease post induction and consolidation are all standard. Translocation 15;17 or “acute promyelocytic leukemia” (APL)—once considered to be the worst type of AML prognostically—is now routinely treated with all-trans retinoic acid and arsenic trioxide, with long-term survival now approaching 90%. The clinical presentation in this hypothetical case does not sound like APL, though the bruising raises the question, and a coagulation profile, if indicative of disseminated intravascular coagulation, might make that more of a question.

Other good prognostic cytogenetics include the translocation of chromosomes 8 and 21—also known as t(8;21)—and inversion of chromosome 16. Each of these has a historical long-term survival rate of about 60 to 70% with standard induction chemotherapy. All other cytogenetic features are classified as intermediate risk or poor risk, with long-term survival rates of 30 to 40% or 10%, respectively. For each of these latter risk groups, transplant remains the only real chance of relapse-free, long-term survival.

Now, before we discuss treatment regimens for AML in general, there are some features of my presentation that would lead me to ask for some additional data. The presence of a spleen tip and the presence of early myeloid forms, eosinophils, and basophils in addition to blasts raise the possibility that my disease is a Ph+ blast crisis rather than de novo AML. If so, treatment with a kinase inhibitor directed at the BCR-ABL kinase—after initial cytoreduction of the elevated blast count—would be a reasonable initial approach to getting control of the disease. But without allogeneic transplant as consolidation, this would not offer me long-term control of the disease. So, more on transplant in a bit.

Standard induction for “fit” patients with AML has remained largely unchanged for several decades—until recently. The chemotherapy combination of 7+3 (7 days of cytosine arabinoside and 3 days of an anthracycline) has been the backbone of induction in the U.S. Consolidation chemotherapy with 3 to 4 subsequent cycles of high-dose cytosine arabinoside has been common practice. The development of a liposomal preparation containing a defined ratio of cytosine arabinoside and daunorubicin has shown increased efficacy in AML that arises from a pre-existing condition known as myelodysplastic syndrome (MDS). Also, drugs targeting specific mutations in genes such as FLT3, IDH1, or IDH2 are additional options that can now be used in combination with standard approaches—or alone in some instances. But perhaps most impressive has been the incorporation of the BCL2 inhibitor venetoclax in combination with azacytidine as a low-intensity regimen now approved by the U.S. Food and Drug Administration (FDA) for elderly and unfit patients with MDS.

Response rates appear to essentially equal those of the standard high-intensity induction regimens. Importantly, this regimen generally has lower toxicity and is most often administered outpatient. Recent data show that patients achieving a complete response with this regimen do as well with allogeneic transplant as folks who received more intensive induction. And for younger, fit patients, venetoclax added to more intensive regimens is producing results that are likely significant improvements over the old 7+3.

So, getting back to the first question I posed, am I looking at the possibility of a cure? Possibly. It is not likely, at my age, that cytogenetics would be favorable. Complex cytogenetics and AML arising from MDS are much more prevalent. Even if this were to be a Ph+ AML blast crisis, my long-term survival would depend on allogeneic transplant as consolidation post remission.

Am I a candidate at 70 for an allogeneic transplant? Possibly. Recent studies show that arbitrary age limits on allo transplantation have virtually disappeared across transplant centers. Less ablative regimens and improved supportive care around infection control and prevention of graft-versus-host disease have led to a situation where transplantation for older patients is a viable option with reasonable outcomes. Unfortunately, it is one that is currently afforded to only about 5% of older AML patients.

So, what would I want in this situation? I would, of course, look for any relevant clinical trials, as all advances in the field are dependent on trials of novel therapies. There are now several trials looking at the addition of novel targeted therapies as a component of induction therapy for patients with appropriate molecular features. But in the absence of an appropriate trial, for my intermediate- or poor-risk AML, I would likely opt for azacytidine and venetoclax as an induction/consolidation regimen, which would give me a better chance of escaping potentially debilitating complications of induction and consolidation that might put a definitive transplant out of reach. And, I would consider transplant as consolidation if in complete remission and still in good shape.

Some reality here: if these approaches didn’t get me to a complete remission, my discussions would center on defining the best way to preserve quality of life with family and friends during my remaining time.

Dr. Asch can be reached at adam-asch@ouhsc.edu.

Related links:

A message from Curious Dr. George:

The goal of Cancer Commons is to help patients identify and access their best possible treatments, one patient at a time, while moving the field forward. If you have advanced cancer, let our molecular oncology scientists provide personalized information about your options.

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Protean BioDiagnostics: One Way to Access Full-Service Precision Oncology Testing

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

Anthony M. Magliocco, MD
Founder & CEO, Protean BioDiagnostics

The use of advanced molecular testing of various cancers over the last 10-15 years has driven development of the field of precision oncology. Now, many patients with a variety of cancer types can benefit from targeted therapies. However, accessing precision testing and treatment can be a major challenge. Our Curious Dr. George asks Anthony M. Magliocco, MD, Founder and CEO of Protean BioDiagnostics, how his company enables better access.

Curious Dr. George: Proper selection of precision treatment requires reliable testing of individual, potentially lethal tumors. While comprehensive cancer centers and academic medical centers have pioneered this service, some 80% of Americans with cancer are treated elsewhere. Your Orlando, Florida-based company, Protean BioDiagnostics, purports to be “the only cancer diagnostic system that integrates pathology review with evidence-based testing.” How does that work and how can physicians and patients anywhere access your services?

Anthony M. Magliocco, MD: Thank you for this important question. As you mentioned, with the completion of the Human Genome Project and tremendous advances in understanding cancer biology, we have learned that there are many molecular subtypes of cancer that can be treated with specific targeted agents, creating the discipline of precision oncology. A great example is lung cancer, where we have learned that a significant proportion of cases are driven by development of EGFR mutations and that these cases will respond well to anti-EGFR therapies. This sounds great so far, but the problem is that less than half of Americans with lung cancer get access to proper EGFR molecular testing, and even if they do, many do not end up getting access to effective therapies.

One of the key problems in the U.S. is that cancer care is fragmented, and the majority of cases are treated by generalist oncologists outside of major academic centers. This creates many challenges, as the field of molecular diagnostics and precision oncology is moving very quickly and becoming extremely complicated, with different classifications and treatment options for cancers that arise in different organs. The choices for testing and treatment have become overwhelming for the generalist.

Protean seeks to solve this problem in two main ways. First, we have created a full precision oncology system, the Protean MAPS™ platform, which provides easy access to Protean services in which tests are organized into guideline-based bundles, and results are integrated into easy-to-understand reports. In addition, Protean provides pathology review services to ensure that the primary diagnosis is correct and the correct tissue samples are being selected for molecular testing. Protean also supports community-based general oncologists with access to decision-support tools and virtual tumor boards, as well as support for clinical trial matching.

Protean provides quick and easy access to testing services in our Orlando CAP CLIA lab, which is licensed for all U.S. states including California, Pennsylvania, and New York, and supports diagnostics with a large network of specialist pathologists and molecular experts. The lab provides a full menu of proprietary testing, including cancer screening and monitoring tests, genetic risk tests, pathology services including Pathology AI assessments, rapid molecular testing and comprehensive molecular analysis with large panels, 3D genomics, and access to global methylation profiling.

Clients can easily access Protean’s lab services using secure electronic portals. Protean then organizes tissue acquisition, blood testing with a network of phlebotomists, and genetics when needed with at-home testing and counselling. It makes life easy for oncologists and their office staff. Protean’s ultra-rapid testing services provide results within a few days, enabling patients to obtain faster access to treatments and clinical trial options. Protean’s data services include secure cloud-based medical data management and integrations using current interoperability standards, as well as data tools, including bioinformatics and machine-learning and AI approaches.

In summary, Protean provides easy access to the latest advances in precision oncology for any practitioner or patient in the U.S. or beyond. Our advanced testing, digital pathology, and telemedicine coupled with complex data management make Protean a unique health technology company focused on delivering better access to novel treatments and clinical trials for cancer patients everywhere. Protean maintains a very active research program and is continuously updating its menu of services to accommodate the rapid advances in cancer diagnostics and treatments.

Our goal is to close the existing cancer care gap and accelerate access to the best cancer treatments for all.

Curious Dr. George: Thank you for telling us all about Protean. What is the best way for patients and caregivers to contact Protean? Can they access the process directly, or must they go through a licensed provider?

Dr. Magliocco: Patients can certainly come to us directly to request reviews and testing at this link. We do not need a healthcare provider to order services, although they certainly can, and we can work with patient care teams as needed. Many services are covered by insurance plans as well.

For direct-pay patients, we typically will charge $400 for registration and review of the case materials and pathology slides, with full recommendations for any additional testing, if needed, and a telemedicine consultation with an expert is included.

After registration, we work with the patient to collect their medical records using secure communications and can arrange for any additional testing that might be required, including accessing previous specimens, coordinating genetic testing, or arranging for blood and liquid biopsy testing services.

I also have an educational YouTube channel for patients, Cancer Informant, where I post periodic videos. Patients can find more information and updates on the Cancer Informant website.

Dr. Magliocco can be reached at magliocco@proteanbiodx.com.

 

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Copyright: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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

How Would a Harvard Oncologist Manage His Own Metastatic Kidney Cancer?

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

David J. Einstein, MD
Assistant Professor of Medicine, Harvard Medical School & Genitourinary Oncologist, Beth Israel Deaconess Medical Center

When facing a frightening new cancer diagnosis, some people ask their doctors, “What would you do if you were me?” Here, our Curious Dr. George asks kidney cancer expert David J. Einstein, MD, how he would handle his own hypothetical case of kidney cancer. Dr. Einstein is Assistant Professor of Medicine in the Genitourinary Oncology Program at Harvard Medical School’s Beth Israel Deaconess Medical Center.

Curious Dr. George: Please consider this hypothetical scenario—you are an active clinical oncologist in general good health. But lately you have been feeling a little more tired than usual and have lost a bit of weight without dieting, so you decide to visit your primary care physician for a checkup. On physical examination, you are within normal limits, but a routine urinalysis demonstrates microscopic hematuria. A CT scan finds a rounded, 7-cm mass in the upper pole of your left kidney. On chest x-ray, one 2-cm rounded mass is found in the lower lobe of your right lung, and another similar mass is seen in the upper lobe of your left lung. How would you proceed?

David J. Einstein, MD: Before I dive into any of the oncology specifics, I would first acknowledge that this is a very difficult experience and that the most anxiety-provoking time of all is between hearing the diagnosis and learning of a treatment plan. I would definitely want to make sure that I have adequate social supports in place, understand my disability insurance and leave policies, and have access to a dedicated palliative care team to support me physically and emotionally as I embark on cancer-directed treatment.

The scenario outlined here is one of presumed metastatic disease, albeit without widespread metastases. We would first confirm that the pulmonary nodules are in fact metastatic kidney cancer with a biopsy, if feasible. We would then have a multidisciplinary evaluation. Assuming the pulmonary nodules are involved, I would think of this as “oligometastatic,” meaning a gray zone in between widely metastatic and localized.

I would start by assessing symptoms. In this case, it sounds like I have been feeling somewhat unwell, so I do need to start treatment. There are some situations in which we encounter de novo or recurrent metastatic kidney cancers that are asymptomatic and low-volume, and can sometimes be safely watched with close surveillance. We also do a clinical risk stratification. This is mostly for prognostic purposes, although there are some subtle distinctions regarding which systemic therapies are approved for which risk groups.

Then, I would be faced with the decision between systemic therapy first versus some combination of local and systemic therapy. In a situation of more widely metastatic disease, I would certainly opt for systemic therapy first, with some question of coming back to surgery later on, depending on my response and how much disease was within the kidney versus elsewhere.

In this situation, however, it may be reasonable to be aggressive with local therapies, assuming I am in good health. I would consider nephrectomy—removal of the kidney entirely—and some form of local therapy to the lung nodules, either surgery or radiation. By using all of these local therapies, we would be trying to render me disease-free, at least macroscopically. However, I would be concerned that microscopically, there could be some leftover cancer cells that could cause later recurrences. Therefore, I would consider receiving “adjuvant” immunotherapy with the goal of decreasing my risk of recurrence.

We have been using immunotherapies, especially immune checkpoint inhibitors, in metastatic kidney cancer for years. More recently, a study showed benefit for using one year of an immune checkpoint inhibitor, pembrolizumab, after surgery for patients with high-risk localized or oligometastatic kidney cancer, resulting in FDA approval. I would be receiving infusions of this every 3-6 weeks, depending on the dose, and monitoring closely for signs of excess immune activation against my own body, creating essentially an autoimmune condition. The fundamental goal here would be long-term remission, trying to be free of both cancer and treatment, for as long as possible.

Dr. Einstein can be reached at deinstei@bidmc.harvard.edu.

 

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Copyright: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.