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

Are You Getting Trustworthy Prostate Cancer Information?

When standard-of-care is an excuse for licensed medical malpractice

Are you getting trustworthy prostate cancer information? The terms standard-of-care, medical practice guidelines, FDA approved and, covered by insurance certainly seem very reassuring. But let’s see if some of these long-held beliefs about prostate cancer testing and treatment are dependable or whether they are simply untrue.

Curious Dr. George: Most people with prostate cancer live a long and healthy life. But some die, with or without treatment. It can be a confusing disease. To what extent are American men and physicians receiving trustworthy information about prostate cancer?

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

Ronald Piana
Freelance science writer, specializing in oncology

Bert Vorstman, MD
Urologic Surgeon

The term prostate cancer.

Belief – All prostate cancers are deadly.

Evidence against the all-inclusive prostate cancer label – Prostate cancers are not all equally deadly. In fact, it’s mostly the 10 to 15 percent of high-grade, aggressive prostate cancers that are responsible for the 30,000 or so U.S. deaths annually.

Bottom line – The vast majority of men diagnosed with prostate cancer do not die of it. Furthermore, not only is the 10-year survival about the same whether treated or not but the 15-year survival rate, irrespective of treatment option, is about the same.

Prostate specific antigen (PSA) blood test.

Belief – The PSA test leads to early prostate cancer detection, early treatment and life-extension.

Evidence against PSA testing – The PSA has a false-positive rate of 78 percent because it is neither specific to the prostate or specific to prostate cancer; its so-called cut-off value of 0-4 n g/ml is an arbitrary and misleading metric; a PSA above 4 does not mean a diagnosis of prostate cancer; large prostates commonly generate high PSAs; the PSA value can be artificially raised or lowered without a cancer being present or progressing; the PSA cannot distinguish between aggressive and non-aggressive cancers; lowering the PSA does not lower a risk of cancer and, the subset of high-grade, aggressive and potentially deadly prostate cancers may produce little to no PSA and can go undetected. Incomprehensibly, although the reliability of the PSA was concerning from the outset, the FDA (Food and Drug Administration) approved the PSA test for prostate cancer screening in 1994. Unsurprisingly, in 2009 urologists clinical studies determined that PSA testing failed to save significant numbers of lives. More damning, the USPSTF (United States Preventive Services Task Force) gave PSA-based prostate cancer screening a “D” grade in 2011 concluding that, “the benefits do not outweigh the harms”. Shamefully, after pressure from self-interest groups the USPSTF “D” grading was watered-down to an ineffectual “C” warning in 2018.

Bottom line – PSA-based screening – includes the inaccurate digital prostate exam or digital rectal exam (DRE) – is highly unreliable, risky and fails to save significant numbers of lives. In fact, many cancers are detected by chance during evaluation for an elevated PSA as the PSA was generated by the BPH and not the cancer. Currently, there is no blood or urine test that can detect just high-grade prostate cancer reliably.

The ultrasound-guided prostate needle biopsy.

Belief – That an ultrasound-guided prostate needle biopsy can reliably detect a potentially deadly prostate cancer.

Evidence against the ultrasound-guided prostate needle biopsy – 1. Prostate cancer is commonly a multifocal disease – meaning that areas of cancer can arise in several different areas of the prostate at the same time or, later. Yet, so-called standard practice for detection calls for the use of an ultrasound, which can’t see the cancer and then randomly and blindly biopsy the prostate 12 times with a needle to evaluate whether or not a cancer is present. When the volume of these 12 needle cores is measured against the volume of an average prostate, only about 0.1 percent of the prostate ends up being sampled. It also means that the clinical state of the 99.9 percent of the un-sampled prostate remains unknown. Even if 120 biopsies were taken (10 times the standard number of 12) you would still be clueless about 99.0 percent of the prostate. 2. There are two techniques for prostate biopsy: transrectal or transperineal (with or without a template). The transrectal approach is riskier than the transperineal and is associated with potentially serious complications of sepsis and bleeding. 3. The concern about false negatives (missing cancers) is hardly surprising when only 0.1 percent of the prostate is sampled. The transrectal approach has recorded a false negative rate of more than 33 percent. On the other hand, others have claimed to find 6 percent more cancers using the transperineal route. Possibly because of the compressive effects on the prostate and the angle at which the transperineally placed needle enters the prostate.

Bottom line – The ultrasound-guided needle biopsy test is risky and embarrassingly unscientific because of its egregious sampling error. The perineal approach is less risky but equally unscientific. Additionally, there is no hard evidence that either technique detects significant numbers of the 10-15 percent of the potentially lethal high-risk tumors. However, the best current screening tool to detect significant cancer anywhere in the prostate is the non-contrast MRI conducted by a radiologist with expertise in MRI prostate imaging. Areas judged to be consistent with PI-RADS four or five disease on the MRI are suggestive of potentially lethal high-grade disease and can be confirmed with an MRI-guided targeted biopsy.

The Gleason grade and score.

Belief – A pathologist’s interpretation of what is judged to be a certain grade of cancer under the microscope is reliable.

Evidence against Gleason grading reliability – The Gleason grading and scoring system is complex and relies overly on a pathologist’s knowledge and interpretive skills for estimating what grades of cancer they believe to see under low-power microscopy. Because of potential errors of judgment, grade misclassifications and disagreements amongst pathologists are common – underscoring a profound lack of reproducibility of the Gleason system.

Bottom line – Patients can never be absolutely sure of their prostate cancer grades and scores. Getting a second opinion from an experienced prostate cancer pathologist and undertaking a screening non-contrast MRI of the prostate with an expert is appropriate.

The Gleason grade 3 and the 3+3=6 “cancer”.

Belief – The Gleason grade 3 (in the Gleason 3+3=6) is a “cancer”.

Evidence against the Gleason grade 3 being a cancer – Initially, the Gleason grade 3 appearance under low-power microscopy was thought to be consistent with an early low-grade, low-risk cancer. However, since then, both the clinical evidence and the fact that the genetic pathways enabling cancer development and spread are turned off indicate that the Gleason grade 3 lacks the features of a cancer.

Bottom line – The Gleason grade 3 fails to behave as cancerous since it is not a cancer. Shamefully, the grade 3 (3+3=6) is still labeled as a cancer, scaring untold numbers of patients towards unnecessary investigation and harmful treatment. Rather, the grade 3 disease appears to be simply a benign feature of aging.

Imaging for the staging of prostate cancer.

Belief – That bone scans, ultrasounds and CT scans can determine whether a cancer is localized or has spread.

Evidence against bone scans, ultrasounds and CT scans for staging – Bone scans, ultrasounds and CT scans are quite insensitive for detecting small volume cancer spread making their use in staging unreliable. Underscoring this concern is the fact that prostate cancer cells have been found in the bone marrow of patients with so-called localized disease. These metastases may begin when high-grade cancers are as small as 0.25 mm in size and barely detectable within the prostate.

Bottom line – Staging of prostate cancer using bone scans, ultrasounds and CT scans is unreliable due to their insensitivity. The PMSA PET/CT scan and the whole body diffusion MRI studies have greater reliability for detecting small-volume spread to lymph nodes and bones. 

Prostate cancer surgical “treatment”.

Belief – That cutting out prostate cancer – whether open or robotically gets rid of it and “saves lives”.

Evidence against surgeryH.H. Young M.D. claimed early diagnosis, cure and “the remarkably satisfactory functional results furnished” from his surgical technique. In contrast, he gave zero evidence for early diagnosis or cure, two patients died and the other two were left with lifelong urinary leakage. And, when robotics entered the business of surgery not only was the device given an FDA approval without demonstrating clear benefits but the FDA’s fallacious 510(K) process was then manipulated to permit use of the tool in radical prostate surgery. Again, without sufficient evidence for safety or benefits. Unsurprisingly, the robotic prostatectomy has a similar incidence of residual cancer (positive margins occurred in 11- 48 percent of patients) and a similar incidence of impotence and incontinence to open surgery. These complications are common and typically managed with radiation, counseling and rehabilitation programs or, implantable devices for ongoing limp and leaking issues. The breakdown of these gadgets often results in more surgery, costs and suffering. In fact, the number of complications associated with the robotic device is highlighted in the FDA’s MAUDE (Manufacturer and User Facility Device Experience) site which recorded a great increase in adverse events. Irrationally, radical prostatectomy is still considered standard-of-care despite physicians concluding in 2012 that surgery failed to save significant numbers of lives. And, despite the evidence against surgery, the SPCG4 article and its conclusion “Radical prostatectomy was associated with a reduction in the rate of death from prostate cancer”, is often quoted by urologists to support their opinion that radical prostatectomy saves lives. Aside from this work recording a substantial number of impotence and incontinence complications, the study is also flawed because of the commingling of participants with various Gleason grades and scores (both well differentiated and moderately well differentiated), unknown tumor volumes and the arbitrary use of anti-androgens in others – issues that can skew results. Additionally, the relatively short follow up time for this study (15 years) is troubling since the particular prostate cancers that the researchers targeted grow very slowly. For the low Gleason score/low-risk/well-differentiated, grade 1 tumor a mean cell doubling time of about 577 ± 68 days has been recorded. This figure means that it can take some 40 years or more from the time of cell mutation for the cancer to reach a diameter of 1 cm and be big enough to be felt on manual prostate examination. Clearly, such a slow cell division rate and a median follow up time of 12.8 years can only deliver a semblance of cure.

Bottom line – Cutting out prostate cancer whether by robotic or open techniques is unsafe and fails to save significant numbers of lives. Worse still, life extension has not been demonstrated for any focal or whole-gland prostate cancer treatment options. In part, because most, if not all, studies are flawed by the inclusion of participants with the bogus Gleason 6 “cancer”, incorporating patients with dissimilar Gleason grades, scores and tumor volumes, reliance on insensitive staging methods and, arbitrarily treating others with testosterone suppression.

Active surveillance for low-risk prostate cancer.

Belief – That by using 6 monthly PSAs, 12 monthly DREs, 12 monthly biopsies (a random 12-core) and maybe a 12 monthly MRI urologists can assess if a low-risk prostate cancer was progressing and required treatment. Urologists initiated this program for monitoring low-risk disease after appreciating the facts that most prostate cancers grow slowly and that the treatments were often worse than the disease. Enthusiastic support also came from the NIH.

Evidence against active surveillance – 1. PSA testing (and all other tests incorporating the PSA), DREs and 12-core biopsies (whether transrectal or transperineal) are highly unreliable as detailed above. 2. A prostate cancer diagnosis was likely established on the basis of a 0.1 percent random and blind sampling of the prostate. The follow up biopsy is likely done in exactly the same way. Clearly such an unscientific process can fail to detect a cancer, is unable to target reliably the original cancer and determine if the original cancer has “progressed” or, whether the cancer now detected was already present but missed by the previous biopsy. 3. Since non-contrast MRIs of the prostate (by a radiologist experienced in prostate MRI imaging) are able to examine the whole prostate and reliably identify the 10-15 percent of potentially lethal cancers their use has become more common. However, not all MRI’s are equal. Although MRI-guided targeted biopsies have been recorded as being dependable, most prostate needle biopsies are not undertaken using MRI-guided targeted techniques but by urologists using “fusion” studies. There are a number of concerns associated with the reliability of this fusion method. The MRI is commonly undertaken by a radiologist of unknown experience, knowledge and interpretative ability for PI-RADS findings – PI-RADS 4 or 5 changes on the MRI may reflect potentially lethal disease. However, this PI-RADS classification, like the Gleason grading and scoring system, is complex and has concerns for errors of interpretation. Additionally, the quality of the MRI study generated can be impacted by the radiologist’s particular study methodology, the particulars of the MRI machine and its software. Then, this previously recorded MRI study is “fused” with the ultrasound study on the day that the prostate biopsy is undertaken. Now, there are additional concerns relating to the type of ultrasound machine to be used and the ability of the urologist to interpret the images. Once “suspicious” areas are “identified” with this fusion method they can be targeted for biopsy. Absurdly, many urologists will add a random biopsy sampling 0.1 percent of the prostate to the targeted biopsy of the high-risk area located in the fusion study. This additional biopsy may only increase the risk of complications and the detection of non-lethal disease. Also bothersome, although MRI-guided targeted biopsies of PI-RADS 4 and 5 areas by radiologists may be more reliable, the fusion technique keeps the biopsy (and revenue) in the hands of urologists. 4. The definitions used to determine “progression” of low-risk disease are variable, unreliable and also impacted by laboratory and observer error – PSA level, PSA velocity or density, clinical staging, DRE, biopsies, Gleason grades and scores, tumor volumes and the number of positive cores and core lengths – none truly reflect what’s happening in the entire prostate. 5. PSA testing and surgical treatment do not save significant numbers of lives. 6. Whether you are treated or not the 10 year survival is about the same.

Bottom line – Clearly, misinterpretations about the presence or absence of cancer, stability of a low-risk cancer or the “progression” of disease are inevitable because of multiple inaccuracies. The potential benefits of active surveillance for low and moderate risk prostate cancer and the saving of significant numbers of lives because of so-called “timely” identification of disease progression have not been supported by hard data. This is not surprising when a number of highly unreliable tests are conflated to generate an unreliable endpoint before initiating a treatment option for which there is no evidence that significant numbers of lives are saved.

Why prostate cancer information is untrustworthy.

PSA-based testing and prostate cancer surgery are both risky and fail to save significant numbers of lives. How then, did the standard-of-care dogma about prostate cancer testing and treatment become so disconnected from the clinical evidence?

Meta-researcher John Ioannidis M.D. discovered the likely cause of this uncoupling of treatment beliefs from the evidence after reviewing multiple healthcare papers. He concluded that “most published research is false”. False, because most studies were commonly not founded on sound scientific principles and corrupted by errors of judgment, approximations, opinions, assumptions and conflicts-of-interest. Making this “research information” more suspect was the inevitable manipulation of study design and results by sponsoring organizations to produce “facts” supporting their biases.

Reliable healthcare information can only be developed from data sourced from studies delivering irrefutable and reproducible results. In contrast, much of the material used to develop the guidelines for prostate cancer management came from very poorly designed studies and beliefs. An all too common junk science that results in prescriptions for care that are untrustworthy, commonly exploitative and make a mockery of the Hippocratic Oath.

More references.

The Great Prostate Hoax by R. Ablin and R. Piana.

The Rise and Fall of the Prostate Cancer Scam by A. Horan M.D. 


This article is dedicated to Anthony Horan MD, a urologist and author (The Rise and Fall of the Prostate Cancer Scam) who fearlessly challenged the culture and the business of prostate cancer. He was always on the right side of what should never have been a controversy. Sadly, the prostate cancer testing and treatment industry is a 32.7 billion dollar market for which there is no hard evidence that significant numbers of lives are being saved.


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 Sordid “Truth” about Prostate Cancer

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

Ronald Piana
Freelance science writer, specializing in oncology

Bert Vorstman, MD
Urologic Surgeon

Prostate cancer has long been one of the most common types of cancers in American men. Our Curious Dr. George asks retired urologic surgeon Bert Vorstman, MD, and freelance science writer Ronald Piana about the quality of prostate cancer information available to U.S. patients and doctors.

Curious Dr. George: Most people with prostate cancer live a long and healthy life. But some die, with or without treatment. It can be a confusing disease. To what extent are American men and physicians receiving trustworthy information about prostate cancer?

Bert Vorstman and Ron Piana: For men entering the prostate cancer arena, the terms “standard-of-care,” “medical practice guidelines,” and “FDA-approved” are very reassuring. But are they trustworthy? Let’s see if the evidence supports the stamp of standard practice:

  • In 1994, the U.S. FDA (Food and Drug Administration) approved the PSA (prostate specific antigen) test, despite the fact that it had a false-positive rate of 78 percent because it is neither specific to the prostate nor to prostate cancer. As well, its so-called cut-off value of 0 to 4 ng/mL is an arbitrary and misleading metric that can lead to unnecessary and potentially harmful therapies. Along with a host of other PSA inaccuracies, the 10 to 15 percent subset of prostate cancers that are high-grade and potentially deadly can be missed as they often produce little to no PSA—a major problem, since it’s essentially these aggressive prostate cancers that are responsible for the 30,000 or so U.S. prostate cancer deaths annually.
  • The 12-core ultrasound-guided prostate needle biopsy samples only about 0.1 percent of the prostate blindly and randomly. Along with this egregious sampling error, the biopsy exposes men to the risk of significant complications of sepsis and bleeding.
  • Examination of a prostate biopsy under low-power microscopy overly relies on the pathologist’s knowledge and interpretive skills of the complex Gleason grading and scoring system. Because of potential errors of judgment, grade misclassifications and disagreements about a given patient’s diagnosis amongst pathologists are common.
  • The Gleason grade 3 (in the 3+3=6) was judged initially to be consistent with a low-grade, low-risk cancer under low-power microscopy. However, clinical evidence—and the discovery that the genetic pathways enabling cancer development and spread are inactive—mean that grade 3 has features inconsistent with a cancer.
  • The safety and benefits of prostate cancer surgery were always in doubt. In 1904, H. Young MD claimed early diagnosis, cure, and remarkably satisfactory functional results from radical prostate surgery. However, he gave no actual evidence for early diagnosis or cure, two patients died, and the other two were left with lifelong urinary leakage. And, when robotics entered the business of surgery, not only was this approach given an FDA approval without demonstrating clear benefits, but the FDA’s fallacious 510(K) process was manipulated to permit use of the device for radical prostatectomy—again, without sufficient evidence of safety or benefits. Unsurprisingly, robotic prostatectomy, like open surgery, had a similar rate of residual cancer, incontinence and impotence problems. These complications were managed with radiation, pre- and post-operative counseling and rehabilitation programs, or implantable devices for ongoing limp and leaking issues. The breakdown of these gadgets resulted in even more surgery, costs, and suffering.

Warning: Prostate cancer testing and treatment are unreliable, unsafe, and fail to extend life. Since most men outlive their prostate cancer, and prostate cancer information is untrustworthy, vulnerable and unwitting men are in great jeopardy of being harmed.

For more invaluable information for patients and physicians on the unreliability of prostate cancer testing and treatment, readers can consult the books The Great Prostate Hoax by Ronald Piana and Richard J. Ablin, PhD, and The Rise and Fall of the Prostate Cancer Scam by A. Horan M.D.

Ronald Piana can be reached at and Dr. Vorstman at

Related links:


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

A New Biomarker to Optimize Immunotherapy for People with Cancer

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

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

Immunotherapy—a type of treatment that harnesses a patient’s own immune system to fight cancer—has been a “game changer” for many patients. It can be difficult, however, to predict whether or not a given person would benefit from immunotherapy, especially when it comes to drugs that target the immune system molecules PD-1 and PD-L1. Our Curious Dr. George asks Scott Tomlins, MD, PhD, Co-founder and Chief Medical Officer of Strata Oncology, about his company’s new tool to help ensure that anyone who could benefit from these drugs is identified.

Curious Dr. George: One predictor of response to immunotherapy, tumor mutation burden (TMB), has been very helpful for patients whose tumors have a high TMB score. But the tumors of many other patients may also respond to immunotherapy, providing substantial benefits in both progression-free and overall survival. What is Strata Oncology’s Immunotherapy Response ScoreTM (IRSTM), how effective is it, and how can patients with solid tumors access it?

Scott Tomlins, MD, PhDCurrent biomarkers for immunotherapy are not enough. Immune checkpoint inhibition with monoclonal antibodies targeting PD-1 and PD-L1 has revolutionized the care of patients with advanced cancer. TMB is an important pan-tumor biomarker for anti-PD-1/PD-L1 therapy, but it does not identify most patients who benefit.

For example, let’s look at the KEYNOTE-158 study of 10 tumor types that led to pan-solid tumor approval by the U.S. Food and Drug Administration (FDA) of second-line pembrolizumab monotherapy in patients who are TMB-high (TMB-H). While a higher objective response rate (ORR) was observed in TMB-H patients versus TMB-low (TMB-L), numerically more objective responses were observed in TMB-L patients (43 out of 688 in TMB-L versus 30 out of 102 in TMB-H). This study demonstrates that TMB alone is not sufficient to identify all responders.

Likewise, in an analysis of TMB in 1,772 patients treated with pembrolizumab monotherapy across 24 tumor types, although ORR was significantly higher in TMB-H versus TMB-L patients, numerically similar numbers of responding patients were again observed (136 out of 433 in TMB-H versus 127 out of 1339 in TMB-L).

Clearly, there is more to the story when it comes to who will benefit from anti-PD-1/PD-L1 therapy. An improved predictive biomarker is needed to ensure that all patients who can benefit from immunotherapy are given the opportunity.

In our recent publication in Communications Medicine, we describe the development, validation, and clinical utility of a new biomarker that fulfills this unmet medical need—the Immunotherapy Response Score or “IRS”.

Immunotherapy Response Score (IRS) is an improved predictive biomarker

IRS combines TMB with four target gene expression measurements (PD-L1, PD-1, TOP2A, and ADAM12) from simultaneous, analytically valid, comprehensive genomic profiling (CGP) plus quantitative transcriptional profiling (qTP) of formalin-fixed paraffin-embedded (FFPE) tumor specimens.

We developed IRS using molecular profiling data combined with treatment and outcome data from the Strata Trial® (NCT03061305), an ongoing observational clinical trial evaluating the impact of molecular profiling for patients with advanced solid tumors.

IRS was trained to predict real-world progression-free survival (rwPFS, by time-to-next-therapy) in a discovery cohort (26 tumor types) of patients treated with pembrolizumab systemic therapy and was then validated in an independent cohort (24 tumor types) of patients treated with non-pembrolizumab anti-PD-1/PD-L1 monotherapy.

In the validation cohort, IRS-high (IRS-H) versus IRS-low (IRS-L) patients had significantly longer anti-PD-1/PD-L1 monotherapy rwPFS (median rwPFS 23.1 months versus 10.2 months, adjusted hazard ratio = 0.52) and overall survival (OS; median OS 40.4 months versus 21.4 months, adjusted hazard ratio = 0.49).

The predictive nature of IRS was confirmed in a case-crossover analysis of 146 patients from the pembrolizumab cohort who had received a previous line of systemic therapy prior to pembrolizumab monotherapy, and by a lack of association with rwPFS in 3,184 patients treated with a non-anti-PD-1/PD-1 or anti-CTLA4 containing first line systemic therapy.

IRS-H/TMB-L patients had similar outcomes as IRS-H/TMB-H patients, demonstrating the clinical utility of IRS beyond TMB alone. Across all Strata Trial patients, IRS-H identified a population nearly twice the size of the TMB-H population (n=24,463; 20.9% versus 10.8%). Critically, 7.6% of patients with tumor types not approved for PD-1/PD-L1 monotherapy were IRS-H/TMB-L, representing a sizable population predicted to have benefit but not currently eligible for treatment.

Bringing new options to people with cancer

We are excited to put this novel biomarker into the hands of physicians to help them ensure every patient gets their best-possible therapy. We are currently providing early access to IRS to a select group of key opinion leaders. IRS will be more broadly available later in 2023.

IRS is just the beginning. By leveraging data from tens of thousands of patients collected under the Strata Trial protocol we are discovering, validating, and demonstrating clinical utility for multiple new, highly quantitative, DNA- and RNA-based multivariate predictive treatment selection biomarker algorithms that span therapeutic modalities.

Dr. Tomlins can be reached at

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

Learnings from Pilot Study: Creating Treatment Templates to Serve More Glioblastoma Patients

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

Adrienne Nugent, PhD
Cancer Commons Senior Scientist

A recent pilot study between Cancer Commons and the Musella Foundation for Brain Tumor Research & Information is identifying patterns that are being translated into treatment templates to better serve a larger group of GBM patients. Our Curious Dr. George asks Cancer Commons Scientist Adrienne Nugent, PhD, to discuss key factors that point to the best courses of action a patient might take, and about the clinical utility of a Virtual Tumor Board.

Curious Dr. George: Patients with postoperative Glioblastoma multiforme (GBM) are among the most difficult oncology cases to manage. In your work as a Clinical Scientist at Cancer Commons you have worked directly with many such registered patients/clients who seek the information and options that may help them. You coordinate neuro-oncologists who may constitute Virtual Tumor Boards. What are the key factors you seek to identify to determine what courses of action a patient might take and whether a Virtual Tumor Board may be helpful? Is a template useful?

Adrienne Nugent, PhD: As a Cancer Commons scientist, I feel very grateful to be able to work with such wonderful and inspiring patients and caregivers on a daily basis. The patients and families who have been handed the especially difficult diagnosis of Glioblastoma face myriad decisions and challenges due to the aggressive nature of the disease and the fact that the standard of care (SOC) treatment has not changed all that much since 2005.

Given the current outcomes with SOC, patients are encouraged to look for clinical trials and novel treatment options, but quickly face many barriers to accessing and enrolling in these more promising therapies. This lack of access to the latest developments in medicine and technology reflects a growing gap between many cancer patients and optimized precision cancer treatment.

To try and bridge this gap, Cancer Commons partnered with the Musella Foundation for Brain Tumor Research & Information to launch a pilot study for GBM patients. We provided 10 patients with complete review of their medical history by a Cancer Commons scientist and a virtual tumor board (VTB) comprised of three neuro-oncologists. The scientist identified a list of evidence-based treatment options and the VTB provided their recommendations based on a unique combination of factors for that patient.

Many valuable patterns emerged from this initial pilot study that we are now translating into treatment templates to better serve a larger group of GBM patients. The key features we’ve identified for creating templates of prioritized treatment options include:

  • Location of the tumor(s): Tumors on the brain stem or involving leptomeningeal metastases are frequently excluded in clinical trials or have unique trials specifically for these conditions
  • Eligibility for surgery and/or radiation: Some clinical trials involve a combination of systemic therapy, surgery, and/or radiation. Eligibility for further surgery or radiation must be determined by the treating neuro-oncologist, neurosurgeon, and radiation oncologist
  • Treatment line: Newly diagnosed, on SOC or adjuvant therapy, at progression/recurrence, or on later-line treatment
  • KPS/ECOG: Patient performance status based onKPS (Karnofsky Performance Status) or ECOG (Eastern Cooperative Oncology Group) scale. Most clinical trials will only accept patients with ECOG <2 or KPS >60 or 70
  • Tumor biomarkers: MGMT methylation status, EGFR/PTEN/TERT alterations, NTRK/ROS1/FGFR oncogenic fusions, tumor mutation burden, PD-L1 expression
  • Treatment history: Some trials restrict patients with specific prior treatments. In particular, prior Bevacizumab/Avastin treatment excludes patients from many, but not all, clinical trials
  • Geographic location of the patient: Prioritization of trials near the patient’s home with the option for regional or nationwide trial search given the ability of the patient to travel
  • Patient goals and quality of life: Prioritization of trials to meet the desires of the patients, such as identifying trials that avoid randomization to SOC, avoid chemotherapy at recurrence, require fewer hospital/clinic visits, involve oral rather than infusion treatments, etc.

When these features are known, we feel most GBM patients can benefit from our templated treatment recommendations without needing to convene a full VTB. However, VTBs can be particularly helpful for patients who do not have access to neuro-oncologists or are receiving conflicting information, such as if more surgery or radiation are indicated or if they have progression versus pseudoprogression. In these cases, a VTB can yield valuable insights to resolve open questions.

Dr. Nugent can be reached at

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

Using Live Cells from Patients to Find the Right Cancer Drug

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

Clifford A. Reid, PhD
CEO, Travera

Today, many cancer patients benefit from targeted drugs that are matched to the distinct genetic mutations found in their tumors. However, especially in late-stage cancer, this “precision oncology” strategy has not proven to be as transformative as people once hoped. Here, Curious Dr. George asks Clifford A. Reid, PhD, CEO of Travera, how his company is addressing this problem.

Curious Dr. George: The U.S. Food and Drug Administration (FDA) has approved about 270 anti-cancer drugs. The National Comprehensive Cancer Network publishes guidelines for treatment of about 61 major cancer types. There is consensus on 1st– and 2nd-line therapy for most, but great divergence on best 3rd-line treatment. Precision oncology based on population studies not only usually fails but is a false premise. What is Travera doing to convert the promise of effective and efficient targeted drug therapy into reality?

Clifford A. Reid, PhD: The original goal of what we now know as “precision oncology” was to understand the root genetic cause of each cancer, and then design a set of targeted drugs to attack each of these cancer-causing DNA mutations. At the time, this was called “personalized oncology,” and its promise was to deliver “the right drug to the right patient at the right time” based on the DNA mutations in each cancer. Unfortunately, this approach has not worked. While the cancer research community has identified hundreds of cancer-causing DNA mutations, drugs that target these mutations inexplicably don’t work for many patients that have the targeted mutations. To our great disappointment, the promise of personalized oncology is not being realized by these genetically targeted drugs.

A small part of the cancer research community has long recognized that it is simply impossible for the results of a clinical trial to generate personalized therapies for each individual patient. Clinical trials are fundamentally designed to include a population of “similar” patients, and get drugs approved for that population. But we know that cancers are highly heterogeneous, especially in late-stage patients, and that no “one size fits all” result of a clinical trial can address each individual patient’s unique cancer.

That part of the cancer research community has focused on developing tests that directly measure the response of an individual’s live cancer cells to a large set of cancer drugs. This direct-measurement approach not only incorporates everything we know about how cancers and cancer drugs work, but also incorporates everything we don’t know. It simply tries a variety of cancer drugs on each patient’s live cancer cells to find the drug or drug combination that will work for that patient at that moment in time.

While this direct-measurement approach may seem quite obvious, as it works beautifully for selecting the right antibiotics for patients with bacterial infections, it has never really worked in cancer, despite decades of efforts. The fundamental problem is that cancer cells, which are so robust inside a patient, become extremely fragile when removed from the patient, and typically die before most cancer drugs can be tested against them. Efforts to keep the cells alive long enough to test them have backfired: cancer cells forced to stay alive change how they respond to cancer drugs, and no longer behave like the cancer cells inside the patient.

Travera is the first company to develop a test that is fast enough to measure the response of cancer cells to cancer drugs without having to force the cancer cells to stay alive for many days outside the patient. Using a new measurement tool invented at the Massachusetts Institute of Technology (MIT), Travera measures the weight change of individual cancer cells in response to cancer drugs. It turns out that for most cancers and most cancer drugs, if the drug is going to kill the cancer cells in a few days, then it changes the weights of the cancer cells in a few hours, but by an amount too small to be detected prior to the MIT invention. Travera uses this exquisitely sensitive measurement tool to offer its Rapid Therapy Guidance test with 2-day turnaround time and high predictive accuracy. The test is now available for most cancers (including all carcinomas) and for over 100 FDA-approved cancer drugs.

For more information, please visit Travera at

Dr. Reid can be reached at

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

How Would an Expert Manage His Own Advanced Hodgkin Lymphoma?

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

Chief of Oncology, Alameda Health System; Institute for Health Policy, University of California San Francisco

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 R-CHOP, 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 live 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

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

All-Clear Follow-Up: Hydrogen Peroxide Appears to Treat Oral and Skin Lesions

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

Bert Vorstman, MD
Urologic surgeon (retired)

Ronald Piana
Freelance science writer, specializing in oncology

In 2020, writer Ronald Piana shared with our readers his own experience of using hydrogen peroxide to quickly eradicate a clinically diagnosed pre-malignant oral leukoplakia—a condition that can develop into oral cancer. Here, Curious Dr. George follows up with him and hears an additional perspective from retired urologic surgeon Bert Vorstman, MD, MS, FAAP, FRACS, FACS.

Curious Dr. George: About 2 years have passed since you shared your story.  Has the lesion reappeared or does it remain “disappeared”?

Ronald Piana: As noted in my 2020 Curious Dr. George post, in 2018 I presented to my dentist with a raised 3-cm lesion on the lateral border of my tongue, where most cases of squamous cell carcinoma (SCC) occur. After treating the lesion with four separate topical applications of high-concentration H2O(hydrogen peroxide), it disappeared. To date, there has been no recurrence, which indicates that direct-contact application of high-concentration H2Ohad sufficient cell-kill penetration to “cure” the premalignant lesion.

Curious Dr. George: Have you learned of any other people who have tried the peroxide treatment for similar lesions? If so, what are the results?

Ronald Piana: Since the publication of the 2020 blog post, I have received several emails from people around the country seeking advice on treating suspicious lesions with high-concentration H2O2. All, except for one, have been oral lesions similar to the one I presented in the original blog post. Every oral lesion was treated successfully, and on follow-up emails 6-months post treatment, there has been no recurrence.

I would like to introduce to you Bert Vorstman, MD, MS, FAAP, FRACS, FACS, a retired urologic surgeon in Coral Springs, Florida, who has offered to share a case history of the exception, which involved squamous cell carcinomas of the face and leg.

Bert Vorstman, MD, MS, FAAP, FRACS, FACS: Some months ago, I happened on the Curious Dr. George blog post about Ronald Piana’s experience with the treatment of a suspicious tongue growth with high-concentrate hydrogen peroxide—a simple over the counter application that cured his precancerous lesion.

As a physician and outdoorsman, I was intrigued by this easy self-treatment as I had been visiting the dermatologist for years to have various squamous cell cancers burnt off with liquid nitrogen, an uncomfortable and costly procedure. Superficial skin cancers and precancers consistently recur, a reason why dermatologists have you coming back for office visits every few months or so for a check and burn, and maybe a biopsy or two for good measure.

I decided to try the treatment and purchased a bottle of food-grade 33 percent H2O2. I used a dropper to soak a Q-tip with H2O2 and applied it to a squamous cell cancer on the right side of my face. After 10 to 15 seconds, I could feel some tingling and mild discomfort. After 30 seconds or so I could see that the area in question had turned a speckled white. The tingling and mild discomfort soon settled. I applied the peroxide morning and evening for 2 to 3 days and stopped. Within a few days there was no sign of the lesion.

In between dermatology visits I noticed the development of another typical skin cancer on my right lower cheek; red, scaly and sensitive. I used the H2Otreatment, and the skin cancer disappeared.  After this success, I became concerned about a small spot on the right side of my nose and one on the outer part of my left lower leg. Both of these areas received the same treatment as I had done to my face. These areas also disappeared. And, three months later when I returned to the dermatologist. I didn’t tell her about the areas I had treated but she could not find any areas of concern. Periodic self-examination and self-treatment with 33 percent H2Owas a lot easier, more convenient, and much less costly than visiting the skin doctor. This process also eliminates the long waiting time to get a referral and convenient appointment, which can also prevent treatment delay and potential disease progression.

Moreover, simple H2Otreatment can obviate the potential for Mohs surgery, an expensive procedure that can result in surgical defect requiring a plastic surgeon to undertake a complex closure to fully reconstruct the surgical site. The self-diagnosis and self-treatment of superficial squamous cell cancers with food strength hydrogen peroxide is easy, convenient and cheap.

Ronald Piana: The cytotoxic potency of H2O2 is well documented; however, its clinical value in cancer treatment has largely remained overlooked. In the report by Mundi, et al, the authors offered several hypotheses about the mechanism of action by which H2Oeradicated squamous cell carcinomas. It is beyond the scope of this post to delve at length into those complex biochemical processes. However, my research of the literature concerning the cytotoxic properties of H2Ohas found a scientifically sound hypothesis based on the cancer cell’s own inherent weakness. Studies have shown that all but one human cancer cell type, a human renal adenocarcinoma, have low levels of catalase, thus, the vast majority of cancer cells lack the biochemical machinery needed to detoxify higher fluxes of H2O2.

More important, lysosomes (aka “suicide bags”) do not contain hydrogen-peroxide-degrading enzymes, such as catalase or glutathione peroxidase. During oxidative stress, large amounts of hydrogen peroxide enter the lysosomal compartment, with the formation of abundant hydroxyl radicals, or highly reactive iron-centered radicals, destabilizing the lysosome to the point of rupture, leading to cell death. In short, H2O2 is a proven Trojan Horse compound that permeates the cancer cell and induces a cascade of suicidal events. This post argues that given its enormous anticancer potential, H2Otherapy deserves further testing so that it can be integrated into appropriate clinical settings.

Ronald Piana can be reached at

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

10 Things I Learned in 10 Years at Cancer Commons That Could Save Your Life

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

Marty Tenenbaum, PhD
Founder of Cancer Commons

After facing his own cancer, Marty Tenenbaum, PhD, founded Cancer Commons to help others dealing with the disease. Here, Curious Dr. George asks him to share what he has learned.

Curious Dr. George: As a well-known survivor of metastatic melanoma, and as the founder of Cancer Commons, you are often sought out by friends and acquaintances who have just been diagnosed with cancer or have been told that their cancer has spread. What do you typically tell them?

Marty Tenenbaum, PhD: In my experience as a patient and as the founder and Chair of Cancer Commons, I have gleaned wisdom that every patient should know to have the best chance of beating the odds.

When I was a patient 25 years ago, much less was known about cancer than is known today, and there were far fewer options for treating it. Today, we know that cancer covers thousands of molecularly distinct diseases, and that hundreds of therapies are available to treat it. What no one knows is the optimal way to treat your cancer. The best treatment likely involves an individualized combination of targeted- and immuno-therapies. There are far more rational regimens than can be tested in clinical trials. I founded Cancer Commons to help patients navigate this maze and achieve the best possible outcome.

Here’s my advice:

  1. Patients who take charge of their care fare better. No one else has the time or motivation that you do to dig into your case. Keep your eyes open. A clinical trial you hear about, or something subtle you see can make a life-or-death difference. My life was saved by a clinical trial someone told me about, involving a treatment that ultimately failed clinical testing. But I was fortunate to be an exceptional responder, and the treatment saved my life. But maybe that wasn’t an accident. Early on, I noticed that I was getting a much stronger reaction to a vaccine when it was administered by a particular nurse. Thereafter, I demanded that nurse, and sometimes stayed overnight if she was unavailable that day. Years later, I asked the principal investigator whether he had ever re-analyzed the trial data according to which nurse was administering the treatment. He answered, “why would I do that?” I responded, “because your trial might have been successful.”
  2. Your first and most important decision is choosing the right doctor. The difference between the best and worst doctors can be measured in years of survival. Generally speaking, major academic cancer centers deliver much better outcomes for complicated cases than community oncology centers. Their physicians specialize in particular cancers so it is easier for them to stay up to date. They also participate in clinical research and hence can offer access to clinical trials. There are exceptions. My own life was saved by an extraordinary physician-scientist named Don Morton, MD, who chose to practice in a community setting because he felt that gave him more freedom to try innovative things beyond the standard of care. Major cancer centers expect their physicians to adhere to evidence-based guidelines, which raises the average outcome but holds back top performers like Dr. Morton.

  3. Get your tumor tested for genetic mutations. Knowing the molecular drivers of your cancer allows your doctor to precisely target them using a cocktail of drugs that attack specific types of cancer cells. Such targeted therapies can deliver better results, with fewer side effects than traditional chemotherapies, which target all rapidly replicating cells, including those comprising your hair and intestinal linings. A minority of patients get this testing. Demand it, and don’t be afraid to request that your tumor be sent out to a world-class lab. Cancer Commons can guide you to appropriate providers.
  4. Avoid trial and error. When possible, have your care team test potential therapies for efficacy in a lab or on a computer before giving them to you. This might involve, for example, applying a proposed therapy to fresh tumor tissue from a biopsy, or to an organoid or cell line grown from fresh tissue, or testing a proposed therapy virtually on a computer model of your tumor. You can only try a handful of treatments over the course of your disease. Make sure they’re the best. Then monitor your actual response to therapy and be prepared to pivot if necessary.
  5. If you’re fortunate enough to drive your cancer into remission, stay vigilant. Regular scans and blood tests are essential to detect and respond in a timely fashion to a recurrence. Getting PET/CT scans every six months saved my life; a metastasis was detected five and half years after I thought I was cured. Very sensitive blood tests can now detect minimal residual disease 10 to 100 times smaller than what can be seen on a scan.
  6. Many patients, upon achieving remission, celebrate by suspending treatment, hoping their cancer will not return. But battling cancer is not a boxing match, where you knock your opponent down and the ref sends you to your corner until they get up. It’s a knife fight. When your opponent goes down, step on their throat and finish them off. Remission is the time to try immunotherapies that can mop up remaining lethal cells.
  7. Many oncologists dismiss surgery as an option for metastatic cancer. You shouldn’t. While surgery is not indicated for widely disseminated disease, it can control isolated metastases and reset the clock to give systemic therapies a chance. I speak from first-hand experience.
  8. Most tumors are not homogeneous. They are evolutionary ecosystems of molecularly distinct sub-populations competing for survival. They have different rates of replication, evolutionary fitness, sensitivity to a chemotherapy, and different potential to kill you. It’s important to understand these dynamics in choosing a therapeutic regimen—which therapies, in what order, dosing, and timing—because the last thing you want to do is to wipe out all the easily killed cells that are holding the lethal cells in check.
  9. Don’t let dire survival statistics intimidate you. By definition, half of all patients exceed the median survival, and there’s a long tail that can stretch many years. Following my advice will help you beat the odds. Case in point, me.
  10. The best way to cure cancer is to catch it early. A new generation of molecular screening tests is making that possible. If you test positive, Cancer Commons will help you identify and access the best treatments.

While Cancer Commons is committed to helping everybody regardless of their means, the reality is that some treatments may only be available to those who can pay for them out of pocket. If you are so fortunate, be advised that there are options available far beyond what can be offered to most patients, ranging from experimental, personalized vaccines to engaging a scientific team specifically to research your cancer and how most effectively to treat it. Cancer Commons can help you access these options, and what we learn can help many other patients.

Dr. Tenenbaum can be reached at

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

A Powerful Knowledge Base for Precision Oncology

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

Hongxin Zhang
Lead Software Engineer OncoKB, Center for Molecular Oncology Memorial Sloan Kettering Cancer Center

Genetic mutations found in a tumor can be important clues to the patient’s best treatment options. Memorial Sloan Kettering Cancer Center (MSK) in New York has developed a product called OncoKB, which enables anyone to access and navigate key clinical information about the various genetic abnormalities that may be found in tumors. Here, Curious Dr. George asks MSK Lead Software Engineer Hongxin Zhang about this tool.

Curious Dr. George: At the 2022 Precision Medicine World Conference in Santa Clara, CA, you outlined how OncoKB can be of great value for investigators, drug developers, regulators, educators, clinical oncologists, and patients. Offered through a 501(c)(3) organization, how can OncoKB help other 501(c)(3) charities access focused information and options for people with advanced cancer?

Hongxin Zhang: Precision oncology is defined as using molecular profiles to identify clinically actionable driver alterations in patient tumor samples. It has become the standard of care for many cancer types, and there are many steps between having a patient consent to tumor sequencing and having a clinical oncologist make a decision on the basis of the patient’s tumor molecular results. Interpretation of sequencing results is confounded by the sheer number of alterations that can surface from next-generation sequencing (NGS), but is a critical step in the utility of clinical NGS testing and consequent clinical decision making.

Tumor-specific (or “somatic”) mutations are divided into those that are causal in tumor development, so-called driver mutations, and those that are benign bystander mutations, or “passengers”. Most of the variants detected in a patient tumor sample are passenger mutations. A small subset of driver mutations can serve as predictive biomarkers of response or resistance to targeted therapies, and these mutations are considered clinically actionable.

The challenge for clinicians and researchers is how to reliably identify a clinically actionable variant. Information describing a variant’s biological and oncogenic effect and clinical actionability is buried in various unstructured resources, such as the text of scientific research papers. Therefore, the process for a clinical oncologist or molecular pathologist to accurately and reliably identify actionable mutations and make a timely clinical decision is time-consuming and laborious. Also, new data regarding predictive biomarkers is always emerging, making NGS sequencing-based clinical decisions require the practitioner to be completely up to date on advancements in molecular and clinical oncology.

OncoKB is a precision oncology knowledge base developed at MSK that contains biological and clinical information about genomic alterations in cancer. Alteration- and tumor type-specific therapeutic implications are classified using the OncoKB Levels of Evidence system, which assigns clinical actionability to individual mutational events. Annotations are provided based on sample biomarkers and through high-performance programmable access. This ensures the timely delivery of clinical interpretation.

OncoKB implements multiple steps to ensure content quality. First, all content is curated by oncology medical fellows, translational cancer biology postdoctoral fellows, or graduate students. All scientific and clinical content is supervised and reviewed by the OncoKB PhD-level Scientific Content Management team per the OncoKB standard operating procedure. Second, all clinical evidence must be approved by our Clinical Genomics Annotation Committee, which consists of about 50 clinicians across all disease teams at MSK. Third, we introduced an External Advisory Board (EAB) composed of leaders in the cancer genomics field across major cancer hospitals. The EAB members oversee OncoKB development and mitigate any issues arising from conflicts of interest. Based on this model, OncoKB has been annotating patient results from MSK-IMPACT™, an NGS-based multiple-panel sequencing assay, since 2016, with roughly 12,000 samples annotated yearly.

Initially introduced to the public space in 2016, OncoKB became the first somatic cancer human variant database to be partially recognized by the U.S. Food and Drug Administration (FDA), in October 2021.

Our mission is to make accurate genomic biomarker annotation available to as many users as we can. We believe that an expert-curated resource like ours would benefit the whole oncology community. Institutions frequently lack the tools and expertise required to conduct a thorough analysis of genetic data, especially those located in underrepresented communities. OncoKB is free to use in an academic setting, which includes all research projects in all 501(c)(3) organizations. Additionally, a commercial license can be provided if annotation is used in the report. The cost is determined by report volume, business size, and particular usage. If you are interested, don’t hesitate to get in touch with us.

Zhang can be reached at

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

Cancer Commons Helps Patients Benefit from Clinical Trials

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

Emma Shtivelman, PhD
Cancer Commons Chief Scientist

For many years, people with advanced cancer who turn to Cancer Commons have benefitted from working with Chief Scientist Emma Shtivelman, PhD. Here, she shares three patients’ stories.

Curious Dr. George: You have helped many hundreds of patients with advanced cancer to feel valued, to better understand their disease and their clinical situation, and to explore their options. Will you please share with our readers a few de-identified examples of patients who benefited from your assistance?

Emma Shtivelman, PhD: In my years of work with numerous advanced cancer patients, I have experienced many sad developments—as expected when dealing with advanced cancers—but also some moments of satisfaction with the results of my efforts. Here are a few examples:

Case 1: A 64-year-old woman came to us with triple-negative breast cancer metastatic to her lung and significant thoracic lymphadenopathy. She had been treated with two lines of chemotherapy and stereotactic body radiation therapy (SBRT) to her lung tumors, with poor response. Cancer Commons suggested and facilitated mutational analysis through our partner Tempus, which showed a TP53 mutation and RB1 copy number loss, as well as amplification of several genes, including PD-L1 and PD-L2. PD-L1 protein was, however, negative in immunohistochemistry (IHC) testing.

At this time, a single scientific publication documented a high rate of durable responses to anti-PD-1 drugs in solid tumors that have amplification of PD-L1/L2 (a very rare event), even in the absence of detectable PD-L1 protein. Based on these results, I suggested to the patient that she seek enrollment in a clinical trial known as DART, which offers the immune checkpoint drug nivolumab with or without the drug ipilimumab for rare tumors and includes a patient cohort specifically for people with PD-L1 amplification.

The patient started treatment with nivolumab and had a remarkable response, with resolution of her lung tumors and significant reduction of her lymphadenopathy. Now, more than two years later, she is maintaining this remarkable response with some slightly enlarged mediastinal lymph nodes as the only sign of cancer.

Case 2: I began working with a 58-year-old woman with metastatic endometrial cancer after she had received three lines of chemotherapy, followed by recurrence each time. Next-generation sequencing (NGS) analysis of tumor DNA detected loss of function mutations in ARID1A and ATM, as well as amplification of HER2.

At this time, the U.S. Food and Drug Administration (FDA) had approved the drugs pembrolizumab and lenvatinib as treatment for endometrial cancer, and this was planned as the next line of treatment for her. I suggested she also consider treatment in two trials, with the more preferable one offering the drug ceralasertib (an ATR inhibitor) in combination with trastuzumab deruxtecan (an antibody drug conjugate to HER2 with so-far unsurpassed activity in HER2+ breast cancers). Ceralasertib has shown significant activity in ARID1A-deficient endometrial cancer patients. This combination would have been a perfect fit for the patient based on DNA alterations present. The second trial I found offered ceralasertib as monotherapy.

Unfortunately, the first trial never responded to the patient’s email or calls, but she successfully enrolled in the second trial, with ceralasertib as monotherapy. Treatment for 5 months led to a 75% decrease in her serum cancer markers and a 45% decrease in tumor burden by RECIST criteria. Her response is ongoing.

Case 3: A 69-year-old woman was diagnosed with recurrence of HPV-related anal squamous carcinoma. She had initially been diagnosed with localized anal cancer 5 years earlier, which was treated with radiation and chemotherapy. In subsequent years she experienced 4 oligometastatic recurrences in lungs and one in the rectum, which were treated with surgeries, radiation, and chemotherapy. In 2019 three metastatic tumors were detected in her lungs.

I suggested some trials—including one known as Hestia—offering HPV E6/7 specific T cells (T cells isolated from peripheral blood and stimulated with HPV peptides). The patient has now undergone treatment in Hestia with a complete response, and remains disease-free almost 3 years later. Apparently, she was the only patient who had a durable response to this trial treatment.

Dr. Shtivelman can be reached at