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.

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

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.

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

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

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

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

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

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

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

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

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

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

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

 

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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