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 zhangh2@mskcc.org.

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 emma@cancercommons.org.

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

People With Prostate Cancer See Their Journey Differently From Their Doctors

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

Nicole Jardine, BASc
Associate Manager, Patient Journey Analytics, Self Care Catalysts

Typical approaches to cancer research don’t necessarily capture the whole picture of what a patient might experience. Here, our Curious Dr. George asks Nicole Jardine, BASc, how real-world evidence can improve cancer research. Jardine is Associate Manager, Patient Journey Analytics at the company Self Care Catalysts, recently acquired by Alira Health.

Curious Dr. George: In your role at Self Care Catalysts, you have access to a trove of self-reported linear patient data—including treatment outcomes—from a large number of patients who, over several years, have used the Health Storylines Platform to manage their journey and generate real-world evidence. Can you share how this process provides notable insights?

Nicole Jardine, BASc: The science and research behind a particular disease are essential to prevent, diagnose, treat, maintain, or cure. But knowing a condition versus understanding the experience of someone with it are quite different. The research put into treating physical and mental health conditions is crucial to the medical field; however, treatment cannot truly progress without understanding the patient’s experience and their quality of life over time. When check-in appointments are the only time patients can share what is working and what is not, a disconnect arises between health personnel and the people they intend to help.

Real-world evidence presents an opportunity to understand decision-making and patient outcomes, providing more context to a patient’s journey. As a person who studies the in-depth experience of patients through de-identified quantitative and qualitative patient-reported data and structured interviews, I can say that supplementing this information is necessary to understand how to improve the ways we support and engage patients.

Part of my job includes comparing scientific literature to the holistic patient experience. Although they are comparable in some respects, the scientific literature does not capture the full experience patients have through interactions with the healthcare system. When you look at a patient’s experience, you are looking at every part—even what they experienced before their diagnosis—to get the full picture. A notable experience I had when doing research on a patient journey was looking at the experience of men with prostate cancer. When comparing the treatment experience of a person with prostate cancer to the literature on prostate cancer treatment, I saw a notable difference on how treatment efficacy is viewed. When literature reports positive outcomes on the efficacy of treatment, it’s seen as a good thing, but when a patient has decreased quality of life despite positive efficacy, where does that lead patients?

For patients, unless the benefits exceed the risks, quality of life trumps treatment compliance. In our patient database, we have 1,900 people with different forms of cancer, including 412 people with prostate cancer who use Health Storylines to track their experience. When we analyzed qualitative and quantitative Patient Reported Outcomes of these men, as well as five patient interviews, various themes emerged from the patient-reported treatment process, highlighting why treatment is not just about efficacy. The first theme is that oftentimes men are wary of speaking to their doctor regarding prostate cancer; it can be difficult to muster up the courage to even get to the doctor to talk about prostate cancer and feelings of worry about the experience. Men tend not to think about prostate cancer until they are diagnosed, so when deciding on treatment they care about their doctor’s opinion; however, that does not come at the expense of wanting to be heard throughout the process. Although men want to be heard and emotionally supported, they do not receive that support because it is often not talked about from the patient or the doctor’s side. Similarly, men are conditioned to be proud, and they struggle to report treatment side effects that hinder their quality of life because they feel misunderstood. This experience is overwhelming for them; it changes their life and perception of the healthcare system.

Understanding the holistic patient experience provides the opportunity to supplement clinical trials for prostate cancer treatment by displaying the experience men had, the variables around treatment persistence, the challenges men experience, what their needs are, how to support them, and what doctors should tell patients when recommending treatment. By not incorporating the authentic patient experience and opinion, the whole story is not being told. Capturing that whole story is necessary to inform future directions in treatment and create a community of patients who are confident in the system that is treating them.

Jardine can be reached at nicole.jardine@alirahealth.com.

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

A New Champion for Cancer Caregivers

Michael A. Looney, Ph.D.
Founder/Facilitator/Head Warrior at Courage Groups

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

Many people with advanced cancer can benefit from helpful caregivers, but family and friends who take on this role may have little background or training to do such a difficult job well. A new organization called Courage Groups aims to provide education and guidance in this collaborative journey. The founder is Mike Looney, PhD, a client and generous supporter of Cancer Commons, whose family recently established our Pat Looney Educational Series for Client Empowerment.

Curious Dr. George: What does Courage Groups offer and how may a caregiver best use these resources?

Mike Looney, PhD: It’s true, when a loved one receives an advanced cancer diagnosis, family and friend caregivers often just start “doing whatever is necessary.” In fact, many don’t even identify as “caregivers” per se; they often start in a passive role, performing such tasks as driving to appointments or picking up medications. But these passive caregivers have now entered the foreign and often bewildering world of medicine—and even worse: cancer.

In the world of cancer, there are new vocabularies, new experts with not-easily-understood specializations, competing treatment options, and built-in fear. This world is scary and intimidating. Regardless, it’s not uncommon that a caregiver will end up playing a vital role in the care of their loved one—typically without training, consultation, or guidance. Sometimes this role ends with making life-or-death decisions for a loved one with advanced cancer, and even administering treatment. Being a cancer caregiver is difficult, and it can also be a missed opportunity for the loved one’s primary cancer care team not to engage the caregiver early on.

Courage Groups was partially formed to assist caregivers in moving from passivity, confusion, and intimidation to confidence and engagement. The first thing that Courage Groups created is a Caregiver Dashboard. Like the dashboard in a car, it serves as a relatively quick snapshot to be referred to regularly about critical elements in the lives of the loved one and the caregiver. The dashboard’s mission is three-fold: 1) provide a road map (albeit different for every cancer and situation); 2) improve communication (among the caregiver, their loved one, the care team, and extended friends and family); 3) engage the caregiver as early as possible in the treatment plan.

The Dashboard is ideally used by the caregiver (and their loved one) to frequently assess the current status of the loved one across seven dimensions and subcategories: progression of disease, physical issues, pain management, participation in care decisions, attitude, communications, and wellbeing. Simultaneously, it asks the caregiver to rank four of those same dimensions and two that are specific to the caregiver: Their own support and issues relating to death and dying. The dashboard facilitates a quick analysis, and the caregiver can visually see where there is or is not alignment with their loved one, care team, or others. The potential benefits are greater confidence for the caregiver and improved comfort and communication for the loved one. There is also the real chance that outcomes for the loved one will be better: improved wellbeing, better treatment options pursued, side effects addressed faster, and more.

Courage Groups provides an online, free, short workshop on the Dashboard to help caregivers become familiar with the dimensions and subcategories, frequency of use, suggestions for addressing non-alignment, and more. Similarly, Courage Groups provides ongoing free online support and resource groups for caregivers by caregivers. These groups have a broad audience of caregivers not necessarily associated with any geography, hospital or cancer type. Current and former caregivers have “been there” and have great suggestions unique to the caregiver experience.

Caregivers are an untapped resource. Courage Groups’ mission is to champion and support these warriors.

Mike can be reached at mike@couragegroups.org.

Using AI and Drug Testing to Design Personalized Cancer Drug Combos

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

Noah Berlow, PhD
Chief Technology Officer at First Ascent Biomedical, Assistant Member at Children’s Cancer Therapy Development Institute

Advanced cancer treatment often involves combining multiple drugs. But with a huge number of possible combinations, it is difficult to know which mix might work best for each patient. Here, our Curious Dr. George asks two leaders to describe how the company First Ascent Biomedical is addressing this challenge.

Curious Dr. George: The U.S. Food and Drug Administration (FDA) has approved many thousands of drugs for marketing, including many hundreds of drugs for use in treating cancer. Some of these drugs are effective; many are not. Many cancers remain without effective therapies. The opportunity to combine FDA-approved drugs offers an additional potential treatment for people with cancer. Many—even most—such combinations have not been rigorously tested.

How does your tumor profiling technology attempt to alleviate that gap and provide hope to cancer patients through combination therapies?

Diana Azzam, PhD, and Noah Berlow, PhD: The development of combination chemotherapy regimens was one of the earliest revolutions in cancer care that led to improved outcomes across nearly every cancer type. The power of drug combinations has been established by decades of clinical data, which is why 25% of oncology clinical trials are designed around drug combinations. Combination therapies are valuable to pharma as well since drug combinations allow for development of new IP and build additional value around assets.

But the driving challenge is always who, which, and when. Who needs which combination, and when? Given that the FDA has approved over 200 cancer drugs, there are over 19,000 possible 2-drug combinations, over 1.3 million 3-drug combinations, and 64 million 4-drug combinations. Setting up 19,000 clinical trials across every cancer type to explore every 2-drug combination is an intractable clinical problem, much less 3- or 4-drug combinations. Correspondingly, finding the right combination for the right patient at the right time is a profoundly difficult problem—but one that our technologies are working to address.

Our approach to this problem is driven first and foremost by functional drug testing, the process of testing a variety of anti-cancer drugs on live cancer cells derived from the patient’s own tumor. This process allows us to identify which drugs are more likely to be effective on the patient’s tumor. The unique way we perform drug sensitivity testing allows us to rapidly test more than 100 cancer agents on the patient’s cancer cells with a median 7-day turnaround time from tissue receipt to return of drug sensitivity results—both for solid and hematological cancers. This is fast enough to support clinical decisions for patients, especially those who have exhausted standard-of-care treatment options.

Our process primarily tests single drugs to identify which drugs show potential, which is where our artificial intelligence/machine learning (AI/ML) comes into play. The AI/ML platform uses the drug sensitivity data—which drugs worked, and which did not—and the patient’s genomic profile to identify multivariate mechanisms driving drug sensitivity. By understanding those critical vulnerabilities, identifying drug combinations becomes a matter of matching FDA-approved, clinically available drugs to the tumor vulnerabilities. We can then use the AI/ML to inform combination design, which, alongside physician input on combinations of interest, guides follow-up combination drug testing. The AI/ML enables us to close the feedback loop in drug combination testing for any cancer patient.

The AI/ML right now is focused on building a deep understanding of an individual patient. As we continue to work with new patients and accumulate more data, we plan to leverage the same AI/ML to identify patterns of patient response within cancer populations to support the development of drug combination studies or even monotherapy trials for the right population. We can support new trial development from insights built on drug response data from direct testing of hundreds or thousands of cancer patients, paving the way for more combination therapies for more cancer types, with a better understanding of who will respond and why.

Dr. Azzam can be reached at dazzam@fiu.edu and Dr. Berlow at nberlow@firstascentbio.com.

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

How an Emory Professor would Treat Her Own Advanced Endometrial Cancer

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

Jane Meisel, MD
Associate Professor of Hematology and Medical Oncology, Winship Cancer Institute at Emory University

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 Jane Meisel, MD, how she would handle her own advanced endometrial cancer. Dr. Meisel is Associate Professor of Hematology and Medical Oncology at Winship Cancer Institute at Emory University in Atlanta, GA.

Curious Dr. George: Please consider a hypothetical scenario in which, as a very busy gynecologic and breast oncologist, you noticed that your menstrual periods had recently become heavier and more prolonged, but you thought little about it. But now you have lost 8 pounds without a change of diet or exercise. You consult your gynecologist who finds a normal pelvic exam but is concerned by possible ascites (fluid buildup in the abdomen). She performs an endometrial biopsy, and after abdominal ultrasound, aspirates 10 ml of clear peritoneal fluid. The endometrial biopsy yields a diagnosis of poorly differentiated adenocarcinoma, and the peritoneal fluid is found to contain malignant cells. How do you proceed?

Jane Meisel, MD: The treatment options for endometrial cancer have evolved significantly since I finished my oncology fellowship in 2015, so while advanced endometrial cancer is never a diagnosis one wants to receive, patients have many more potential treatment options now than they did even five years ago. I stress this to patients in clinic every day, and I would try to remind myself of this fact as well, even though I know it might be hard to think rationally like this in the wake of a difficult diagnosis.

Endometrial cancer, when it metastasizes, is most likely to metastasize locally in the pelvis, to pelvic and para-aortic nodes, the peritoneum, and the lungs. In any situation where metastatic cancer is suspected, a biopsy is key, and there is much my treating physicians and I would be able to learn about the cancer from the biopsy. First, the histology—is it endometrioid, clear cell, or serous? Serous and clear cell are associated with worse overall survival compared to endometrioid cancers, and clear cell cancers tend to be more chemoresistant than other subtypes. If it were endometrioid, we would want to do receptor testing for estrogen and progesterone, as this can help with treatment planning; and if it were serous, we would want to do HER2 testing for the same reasons.

All patients with endometrial cancer should have mismatch repair protein (MMR) or microsatellite instability (MSI) testing to understand options for immunotherapy. Somatic mutation testing is often also done (using a next-generation sequencing panel), but this could be done at a point of progression rather than at initial diagnosis, since the first-line treatment is unlikely to change regardless of NGS results.

Given that I am young and healthy, if I had never been treated for endometrial cancer before (in the early-stage setting) and was felt to be a good surgical candidate based on extent of disease, then surgical cytoreduction would be appropriate, followed by adjuvant chemotherapy. If I were not a surgical candidate or if this were a metastatic recurrence (as opposed to de novo disease), chemotherapy as an initial treatment would be appropriate.

The first-line chemotherapy used for advanced endometrial cancer is almost uniformly carboplatin plus paclitaxel. In a clinical trial known as GOG 209, this combination was compared with a cisplatin triplet-based regimen (cisplatin, doxorubicin and paclitaxel) and it was found to have a similar overall response rate, similar progression-free survival, and similar overall survival, with much lower rates of neuropathy and less overall toxicity.

I always tell my patients with advanced or metastatic cancer that the goals of treatment are to help you live as long as you can and as well as you can—and the “living well” part is very important. So, carboplatin and paclitaxel would likely be my first line of treatment (with trastuzumab if I had serous cancer and were HER2+, given that trastuzumab improves progression-free and overall survival in this situation).

While on carboplatin and paclitaxel (plus or minus trastuzumab), I would monitor with CT chest/abdomen/pelvis every three cycles (or more often if I developed signs of progression while on treatment). There is not a distinct tumor marker defined for endometrial cancer, but in some cases (particularly with high-grade serous endometrial cancer), CA 125 can be elevated at diagnosis, and if that’s the case, can be helpful to follow with each cycle or two to help get a window into the response to treatment.

Upon progression or intolerance of chemotherapy +/- trastuzumab, additional options would have to be considered, and along with that, some of the histologic variables previously discussed. If my tumor were mismatch-repair deficient, had evidence of microsatellite instability, or had a high tumor mutation burden (as assessed via genomic testing), immune checkpoint inhibitors such as pembrolizumab or dostarlimab could be used as single agents. These are very well-tolerated agents when given on their own. Endocrine therapy is also an option, particularly for patients who have hormone-receptor positive, low-grade endometrioid cancer. Otherwise, progression would depend on the treatment-free interval.

If my cancer had not progressed until six months or more after completing my last dose of platinum-based chemotherapy (platinum-sensitive), I could be re-treated with carboplatin and paclitaxel again. If my cancer had come back sooner (platinum-resistant is typically defined as recurrence within six months of last platinum agent), then I would consider pembrolizumab plus the oral VEGF receptor inhibitor lenvatinib, which is effective in patients with advanced endometrial cancer that is not MSI-high or mismatch-repair deficient. This could also be employed after another round of platinum-based chemotherapy, if I were platinum-sensitive initially but after another round of platinum-based chemotherapy, either became intolerant of side effects or treatment resistant.

There are other alternatives as well, such as liposomal doxorubin, bevacizumab, and re-treatment with taxanes. There are also a number of clinical trials that are very exciting; among them, trials looking at additional anti-HER2 targeted agents in patients with HER2+ high-grade serous cancer (such as trastuzumab deruxtecan and tucatinib), and trials evaluating different endocrine therapy options for patients with hormone-sensitive endometrial cancer (CDK 4/6 inhibitors and serum estrogen receptor downregulators are good examples).

Overall, I would try to pace myself, as advanced cancer is a marathon rather than a sprint, and make sure that above all, I felt comfortable with my treatment team and in our shared decision making every step of the way.

Dr. Meisel can be reached at jane.l.meisel@emory.edu.

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

How an Expert Would Manage His Own Advanced Prostate Cancer

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.

Curious Dr. George: Last year, 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.

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.

Additionally, if MSI high is noted during molecular testing of tumor tissue, the patient may at some later time be eligible for treatment with an immune checkpoint inhibitor, 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.

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 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.

Related links:

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

Harnessing Each Patient’s Data to Help Many More

Cancer Commons Adapts to Remain True to Our Mission

A message from Curious Dr. George:

The goal of Cancer Commons is to help patients find 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 free, personalized information about your options.

***

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

Harnessing Each Patient’s Data to Help Many More

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

Kaumudi Bhawe, PhD
Cancer Commons Scientist

At Cancer Commons, we don’t just help people navigate cancer treatment; we learn from everyone we help. Here, our Curious Dr. George asks Cancer Commons Clinical Scientist Kaumudi Bhawe, PhD, to share how new knowledge can be captured from every patient to help many more.

Curious Dr. George: Cancer Commons has accumulated in-depth data on many hundreds of patients with various cancers. Because of the molecular nature of cancers, many are very complex—even unique. How might these data be best studied and reported to help inform diagnostic and therapeutic decisions for many additional patients, who are in need of information to guide their own journeys in precision oncology?

Dr. Bhawe: We are more than just the sum of our body parts.

We are stories, waiting to be told.

This is especially true for cancer patients who are suddenly put face-to-face with the fear of death. Most of the time, their stories remain untold, and this wealth of information and insights may be lost upon the medical community. Most organizations developing new oncology drugs and preventative screens realize the need for deep “N-of-1” studies—essentially, rigorous analyses of individual patients’ testing and treatment outcomes—the nuances of which can be mined for novel, testable insights. But many organizations are not equipped for employing an N-of-1 approach.

Enter Cancer Commons.

Here at Cancer Commons, we communicate in-depth with each person who contacts us to understand their cancer-care possibilities, considering their own unique cancer context. Since we place high value on such a holistic understanding, we can tailor our recommendations of clinical trials and diagnostic testing possibilities in a truly personalized manner. Most patients come back to us when they are faced with a new decision point in their journey, and as a result, we have longitudinal information on these patients, capturing a specific window of time in their lives. Cancer Commons has been helping patients for over ten years now, so we have accumulated a wealth of such information that can be mined for important insights.

Our patients’ interests always come first, so data de-identification to preserve patient anonymity is a must. Once that is done, there are multiple ways to use patient data in order to better understand the relationships between variables that have been captured in the dataset.

One very powerful way to conduct this kind of analysis is by employing a Bayesian machine-learning approach. I will explain below, but in technical terms, this is a statistical strategy in which current knowledge in the field can be used to construct an initial directed acyclic graphical model of an initial multifactorial hypothesis, which itself is a set of nested, interconnected sub-hypotheses wherein there is an initial 50/50 probability of both the overall hypothesis (model) and any nested sub-hypothesis (relationship between two variables in the model) being true. The beauty of such an approach is that the initial model (termed “prior”) can be tested and modified continually in real time as real-world data is added to the dataset, and as new clinical information is added to the larger body of medical literature. See this presentation by Cancer Commons founder Marty Tenenbaum, PhD, for a deeper understanding of the larger conceptual framework of using Bayesian machine learning and artificial intelligence to beat cancer.

So what does the above paragraph really mean?

Let’s take a realistic but fictional example to understand this better. Suppose our question is: “What is an ovarian cancer patient’s likelihood of benefitting from treatment with a novel KRAS inhibitor?” The factors influencing patient benefit might include: cancer stage, grade, histological subtype, number of prior treatments, type of prior treatments, KRAS mutation type, and tumor mutational burden (TMB) status, among others. Our initial directed acyclic graph model (prior) might state that each of the known factors independently, and with equal weightage, feeds into a binary output called “benefit from trial” with two possible states being “yes” and “no”. We assign an initial 50/50 probability to believing that our proposed “prior” is the best representative model of the situation. We can then feed real-world data into a machine-learning algorithm that tests the model (prior) and proposes a “better fit” model based on the data we have at hand. The “better fit” model becomes the “prior” for the next step, and as new clinical information becomes available—in our fictional example, let’s suppose that the novel KRAS inhibitor in question showed benefit to lung cancer patients with a G12D mutation—it can also be accounted for. The above process is thus carried out iteratively, and has the potential to generate novel testable hypothesis-generating insights, such as the following fictional example: “KRAS G12D mutations are associated with low TMB status in some third-line platinum-resistant high-grade serous ovarian cancer patient tumors, and our historic-data-based model predicts these patients as having a higher probability of experiencing greater than one year of progression-free-survival from the novel KRAS inhibitor in question as compared to patients with any other KRAS mutations or TMB status.”

In order for researchers to use computers to carry out the above sort of modeling, data from structured and unstructured sources must be parsed, tabulated, and processed before it can be used as input. But it is important to remember that the above fictional scenario also describes an analytical process that has been used for centuries by practicing physicians and caregivers.

At Cancer Commons, we are a dedicated team of professionals helping each patient navigate next-step possibilities in real time, while curating our collective learning, so as to help future patients navigate their own experiences with precision oncology.

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

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

Plain Language Summaries Improve Access to Medical Research

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

Chris Winchester, DPhil
Chief Executive Officer, Oxford PharmaGenesis

Adeline Rosenberg, MSc
Senior Medical Writer, Oxford PharmaGenesis

Cancer Commons helps people make sense of the latest research on treatments for their distinct type of cancer. Meanwhile, a growing number of research papers now include a plain language summary (PLS)—an overview of the paper written for anybody to understand. Here, our Curious Dr. George discusses plain language summaries with Adeline Rosenberg, MSc, Senior Medical Writer at the healthcare communications company Oxford PharmaGenesis, and Chris Winchester, DPhil, Chief Executive Officer at Oxford PharmaGenesis.

Curious Dr. George: Patients and the public are very interested in the results of much clinical research. In the internet age, many medical articles intended for a research or physician audience are available open access. Yet, even structured abstracts may be difficult to understand. Some journals are now including plain language summaries (PLS) written by the authors. Can you tell us about this movement?

Adeline Rosenberg, MSc, and Chris Winchester, DPhil: Open-access publishing has been a pivotal step in the open-science movement, ensuring that peer-reviewed evidence of the highest quality is available to anyone who needs it, anywhere in the world. Research foundations and charities have taken the lead in funding transitions to open access, with pharmaceutical companies following in their wake.

The logical next step is to make sure that peer-reviewed evidence is understandable by all—this is an area in which pharmaceutical companies are leading the way. Article-associated plain language summaries (PLS) are elements of peer-reviewed journal articles written in jargon-free, accessible language for anyone to read—from patients, policymakers, and the public to non-specialist or time-poor researchers and clinicians. By communicating in a way that is understandable by all, PLS provide equity of information and a basis for shared decision making.

PLS are particularly important in cancer care, where the pace of scientific discovery and the expanding range of treatments can be overwhelming. PLS give clinicians, policymakers, patients, and caregivers the tools they need to empower patients and make decisions about patient care together.

As you can imagine, with a practice that’s still evolving, there is a variety of opinions on what works best. Some journals offer different formats of PLS, such as videos and infographics. Increasingly, journals are publishing short, text-based PLS, which can be indexed on directories such as PubMed alongside the abstract (such as in this cancer research paper). PLS need to be discoverable in order to be found and used, and indexing on PubMed is a great way of optimizing this.

Besides format, there are other PLS aspects on which a clear consensus is beginning to emerge. For example, many people involved in scientific publishing believe that PLS should be an integral part of each journal article and included in the peer-review process for reliability and credibility; that PLS development should involve the authors of the journal article for scientific accuracy and consistency with the overall message; and finally, that drafts of PLS should be user-tested with the target audience to help ensure that they are fit for their purpose and meet end-user needs.

Fortunately, many complementing projects are working towards developing consensus on best-practice guidelines. These include the Patient Focused Medicines Development initiative and the International Society for Medical Publication Professionals’ PLS Perspectives Working Group to name a few. Open Pharma (a collaboration facilitated by ourselves and colleagues at Oxford PharmaGenesis) contributed by publishing our recommendations, which were supported by a commentary on the value of standardizing publishing practices. One pharmaceutical company active in oncology, Ipsen, has even introduced a policy to include PLS in all journal articles reporting Ipsen-sponsored research involving human data. This represents a heartening commitment to transparency and trustworthiness.

As PLS grow in popularity, we hope to see more journals encouraging (or even requiring) the inclusion of PLS, more authors producing them, and more readers engaging with and advocating them. You can join the conversation on social media using #PlainLanguageSummaries—we look forward to hearing from you!

Rosenberg can be reached at adeline.rosenberg@pharmagenesis.com and Dr. Winchester at chris.winchester@pharmagenesis.com.

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

Can Immunotherapy Be Effective for Brain Cancer?

Matt Warner, PhD
Scientist at Cancer Commons

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

Immunotherapy has reshaped the cancer treatment landscape. This type of treatment boosts the immune system to fight cancer. However, for people with advanced brain cancer, immunotherapy options remain slim. Here, our Curious Dr. George asks Cancer Commons Scientist Matt Warner, PhD, about the challenges and future potential of immunotherapy for brain cancer.

Curious Dr. George: An accomplished molecular oncologist, you have now helped many brain cancer patients consider their options, both on your own and as part of virtual tumor boards. Immunotherapy has successfully revolutionized the treatment of many potentially lethal cancers. Why has the use of immunotherapy for brain malignancies seemed to lag?

Matt Warner, PhD: There are several reasons why cancers of the central nervous system (CNS) have been more challenging than other cancers to treat with immunotherapies. Despite recent studies demonstrating that the CNS is not as “immune privileged” as we once believed, it is still clear that 1) the unique anatomy of the brain and spinal cord, 2) the role of the blood-brain barrier at controlling which substances and immune cell subtypes can access the CNS, and 3) the limited presence of the lymphatic system within the CNS all decrease the ability of the immune system to patrol and attack cancers within the CNS versus other organs of the body.

Furthermore, CNS cancers often display fewer mutations in comparison to other cancers and therefore lack the immunogenicity to help the immune system identify and distinguish the cancer from the healthy neuronal tissue.

Lastly, as with all other cancers, you then have to compete with the immunosuppressive tumor microenvironment and the knowledge that chronic and excessive neuroinflammation as a result of hyperactivation of the immune system could also be detrimental to a patient. This presents concerns from a quality-of-life standpoint due to the impact of inflammation and swelling on the function of healthy neuronal tissue. It also poses disease management concerns because the immune system’s response to CNS cancer may also impact the survival, proliferation and invasiveness of gliomas.

CNS cancers therefore present some unique challenges for the immunotherapy-based treatments we currently have available in the clinic, highlighting why the clinical development of immunotherapies for these cancers has been less successful.

Despite these setbacks, I still believe immunotherapies will play a significant role in treating CNS cancers in the future. However, in order to be successful, this approach will most likely require novel combinations of immunotherapy-based treatments (for example, immune checkpoint inhibitors, dendritic cell and peptide-based anti-cancer vaccines, oncolytic viral therapies, and cellular therapy) with radiation, chemotherapies, targeted therapies, and/or Optune. Such combinations will no doubt help us move beyond the prior failings of immunotherapies being investigated as single agents, which lack the necessary activity to single-handedly enhance the immune system and treat cancers within the CNS.

Recent research findings provide some hope in this regard. For example, interim analyses from ongoing clinical studies and retrospective analyses from closed trials that investigated immune checkpoint inhibitors in glioma patients demonstrate that these drugs may need to be used around the time that patients are receiving their surgery, radiation therapy, or Optune treatment, and they may need to be targeted to patients with unique tumor mutational profiles. Additionally, more trials are now exploring combinations of immunotherapies and pharmacological agents to (hopefully) modulate the tumor microenvironment and make it more amenable to immunotherapy-based treatments.

Given how little we still understand about the brain and the activity of the immune system within the CNS, I am confident that we will one day celebrate the successes of immunotherapies in the treatment of CNS cancer patients.

Matt can be reached at matt.warner@cancercommons.org.