Standard and Non-standard Diagnostic Approaches

The second point I'd like to highlight, discussed below, is the potential value of chemosensitivity testing for your tumor. These tests are controversial. Many oncologists don't believe they have value, but many patients and integrative practitioners do. These tests require fresh tumor material taken and handled carefully at the time of diagnosis or surgery. So this is an early decision to make.

Finally, the targeted therapies and molecular profiling section below is especially important—and another area for early attention, since these decisions can really affect treatment.

Most people just want to focus on treatment choices—conventional or integrative. The importance of diagnostic tests is widely overlooked. So these often complex decisions merit your careful attention.

Most of these tests are done by analyzing the tumor tissue sample. However, scans are quite common in diagnosing many cancers to determine the cancer location and assess the surrounding tissue. This is important for two reasons:

• Scans can localize the tumor, sometimes incredibly precisely, to define the surgical/radiation field for a local treatment such as surgery or radiation therapy and to minimize the amount of tissue that needs to be removed or radiated.
• Whether the cancer has spread to other areas of the body will affect decisions about whether or not to perform surgery, as well as the extent of surgery. It may also mean using systemic therapy (such as chemotherapy) in addition to or instead of local treatment.

Knowing about your condition is also important for developing a treatment plan. In conventional medicine, the healthcare team will assess your performance status—how well you are functioning physically.

Using the Karnofsky Performance Status Scale, they can see whether or not and how well you can carry out normal activity and work. Usually, the lower the performance score, the worse the prognosis and the less likely a person will be able to tolerate a rigorous treatment regimen. Though age is factored into treatment decisions, older age should not be an automatic reason to rule out arduous treatment. A healthy 80-year-old may be able to do as well with a rigorous treatment regimen as a debilitated much younger person.

Medical advocate and BCCT advisor Mark Renneker, MD, advises independent double-checking of all pathological diagnoses of your cancer(s). The second pathologist opinion should be in writing, and not just a verbal report. In general, the best pathologist to give a second opinion about your cancer diagnosis is one who specializes in your particular type of cancer, for he or she will have seen the most variations and false-positive cases. This pathologist may be in another part of the country or world.¹

If you're diagnosed with a rare cancer, the pathologist in a community hospital will be less likely to have  experience in examining this type of cancer. Pathology reports using words such as “borderline”, “inconclusive”, “atypia” or “atypical hyperplasia” indicate that the pathologist is unsure of the diagnosis. In the case of a rare cancer or uncertainty about the diagnosis, ask (or have your oncologist or surgeon ask) the pathologist to send your slides to a pathologist nationally recognized for expertise in the cancer in question.

If you are not responding to treatment that is usually effective, Dr. Renneker advises that your doctor may have become “anchored” in the diagnosis, unwilling to revisit it. This could prevent getting a more accurate diagnosis. We encourage you to speak up and question the diagnosis and ask for a second opinion on the pathology report.

Even common, solid-seeming tests—such as hormone receptor assays—can be erroneous, depending on the part of the tumor was sampled, the testing techniques were used and the cut-off values to determine if a result is positive or negative.²

If you’re thinking about a second pathology opinion, check with your insurance company whether costs are covered. Sometimes insurance companies pay only for a physician to give a second opinion about your original pathology results.³

• HER2
• EGFR
• BRCA
• BRAF
• MGMT

If you test positive for certain genes and protein molecules, a targeted therapy drug may be able to accomplish one or more of these actions:

• Block or turn off signals for cancer cells to grow and divide
• Keep cells from living longer than normal
• Kill the cancer cells

The Centers for Medicare & Medicaid Services (CMS) are poised to cover the cost of next-generation sequencing (NGS) tests for patients with advanced cancer. In December 2017, the FDA approved the FoundationOne CDx cancer diagnostic test, and on March 16, 2018, CMS finalized a National Coverage Determination for this diagnostic laboratory test and proposed reimbursement for it.

FoundationOne CDx is the first NGS-based in vitro diagnostic test and can detect genetic mutations in 324 genes and two genomic signatures in any solid tumor. It is a companion diagnostic for 15 targeted therapies.⁴

According to medical/clinical advocates (and BCCT advisors) such as Mark Renneker, MD, and Ralph Moss, PhD, molecular profiling in cancer cases is underused, even for some of the most agreed-upon tests. Evidently, many oncologists won’t even order molecular testing, much less use targeted agents, until more standard treatments have proven ineffective. In contrast, many integrative oncologists see value in obtaining test results that may identify nutraceuticals and nutritional supplements targeting errant pathways driving the tumor.⁷

Dr. Block suggests that you talk to your oncologist before any scheduled surgery about the status of targeted therapies that may be appropriate for your tumor and what procedures are necessary for obtaining a tissue sample. Even if you and your team decide not do such testing now, you can ask your oncologist or surgeon to have some tumor tissue preserved for future testing. The tissue needs to be preserved in tumor blocks, which is actually what pathologists in most hospitals routinely do. Even if you’ve already had your surgery, your tissue be properly preserved. You can request genomic and molecular testing on preserved tissue at any time, even months or years later.⁸

Gene testing is typically covered by insurance, but check your policy for coverage.

In February 2018, The Lancet published the first-ever study that sought to compare the value of the tests used to predict distant recurrences occurring 0 to 10 years and 5 to 10 years after diagnosis. The authors reported wide variability of accuracy of tests used to predict ER-positive breast cancer recurrence and to provide guidance on treatment decisions. Six tests were examined, two of which are used only in research for now. The other four are commercially available:⁹

• The Oncotype Dx Breast Recurrence Score (RS), from Genomic Health
• The PAM50-based Prosigna Risk of Recurrence (ROR), from NanoString
• The Breast Cancer Index (BCI), from bioTheranostics
• The EndoPredict (EPclin), from Myriad Genetics

The recommendations from the researchers:¹⁰

• The Oncotype Dx should be considered for patients with stage I or II invasive ER-positive, lymph-node negative breast cancer to make decisions about chemotherapy.
• The Prosigna ROR is recommended for postmenopausal women with HR+ stage I or II lymph node–negative disease and for women with stage II disease with one to three positive lymph nodes who have been treated with surgery and hormonal therapy.
• The BCI test is recommended for women with HER2-negative, HR+, lymph node–negative stage I to III breast cancer who have been receiving hormonal therapy for 4 to 5 years to determine whether further hormonal therapy may be beneficial.
• The EndoPredict test is recommended for women with stage I to II ER+, HER2-negative breast cancer with or without one to three positive lymph nodes to determine whether they are candidates for chemotherapy.

Also see Commercial Genomic/Molecular Testing Companies in Commentary below.

Proponents say testing helps oncologists figure out which drugs a specific tumor is or isn’t sensitive to. This technique evaluates cancer cells in the lab to determine which drugs and natural substances elicit the best response.¹¹

One method of chemosensitivity testing involves overnight shipping of cancer tissue obtained at biopsy or during surgery to a specialized lab. Cancer cells are separated into clusters, with each cluster then exposed to a different chemotherapy or targeted therapy. Those drugs that cause  cell death (apoptosis) in the cancer cells are identified. The lab prepares a report recommending drugs that are highly, moderately or not likely to kill cancer cells.

Robert Nagourney, MD, founder and medical director of Nagourney Cancer Institute, which performs chemosensitivity testing, explains that the test results will often suggest drugs or combinations that are less toxic to you than standard protocols, while still effectively treating your cancer.

Other methods of chemosensitivity tests use circulating tumor cells; however these methods have not be validated and their specificity and sensitivity (measures of accuracy and reliability) have not yet been determined.

Is your oncologist likely to use chemosensitivity testing? Probably not yet.

According to the professional organization, the American Society for Clinical Oncology (ASCO), chemosensitivity testing is not recommended for use outside a clinical trial. Thus, “oncologists should make chemotherapy treatment recommendations based on published reports of clinical trials and a patient’s health status and treatment preferences.”¹²

If your oncologist were to base treatment recommendations on results of chemosensitivity testing, they risk going against the standard of care and relying on unproven tests. However, ASCO considers conducting clinical trials on the effectiveness of chemosensitivity testing a priority.¹³

Insurance companies such as AETNA have published policies about chemosensitivity testing: “Aetna considers chemosensitivity assays experimental and investigational because there is insufficient evidence that these assays influence management decisions such that clinical outcomes are improved.” They provide a review of the literature, even citing promising results, but they also conclude that more study is needed..¹⁴

In 2016, esteemed cancer researchers from Harvard wrote an eloquent and highly technical paper evaluating next-generation functional diagnostics, including chemosensitivity testing: “We imagine that such trials over the next 3–5 years will ultimately result in identification of the specific clinical scenarios in which next-generation functional testing can help to guide oncologists in choosing the right therapy for their patients. It follows that such tests can also prevent the unnecessary use of therapeutics to which patients may be resistant, reducing toxicities as well as costs.”¹⁵

BCCT advisor and naturopathic oncologist Lise Alschuler, ND, FABNO, comments: “I think that chemosensitivity testing is fraught with challenges for good reasons. Tumors are comprised of many different cell lineages—each with different sensitivities/vulnerabilities. Additionally, there is constant evolution of tumors over time, making chemosensitivity testing challenging to implement and interpret. When tissue is tested, which tumor cell population does that represent? How long are the results valid? Further, what cells are being tested—actual tumor tissue for a tumor currently present in the body (the best option), circulating tumor DNA, or circulating tumor cells (not the best given the many methodologies and unproven accuracy and reliability of these tests). All that being said, I have had many patients who are into their third+ line of treatment and are getting desperate for a treatment that works. This is a time when I do endorse chemosensitivity testing, and ideally using a proteonomic approach on tumor tissue.”

On the other hand, some integrative oncologists routinely use chemosensitivity testing. For example, BCCT advisor and integrative oncologist Keith Block, MD, finds chemosensitivity testing useful in planning treatment after the initial diagnosis of cancer but most especially “if your cancer cells have become resistant to or do not respond well to the first-line chemotherapy, if you experience a recurrence or if you are undergoing second- or later-line treatment."¹⁶

In most cases, however, this testing is not employed until after a recurrence of cancer. As BCCT advisor Mark Renneker, MD, explains, such testing is rarely done with a first surgery, since for most cancers, the type of chemotherapy (first-line) is standard, and most oncologists feel uncomfortable (and vulnerable to malpractice) deviating from that standard of care. Dr. Renneker suggests considering sending a specimen for testing under these conditions:

• If an additional surgery is performed
• If you develop lung or abdominal fluid containing cancer cells
• If the tumor has recurred or become widespread, indicating a change in its behavior, mandating consideration of re-analyzing the tumor

Fine-needle aspirate or core biopsies don’t usually result in enough tissue—at least 0.5 grams is needed, and more is preferable.¹⁷

BCCT has heard from patients who pushed to have chemosensitivity testing done. Some were frustrated and angry and didn’t understand why their oncologist wouldn’t use the results in planning first-line treatment. Others were glad they did insist on having this testing and found physicians who used the results in suggesting treatment options. One such person with advanced metastatic breast cancer, Lindsay McDonnel, has shared her stories with BCCT: Lindsay McDonell: Diagnostic Testing and Lindsay McDonell: Chemosensitivity Testing.

Very few oncologists in the US will do chemosensitivity testing right off the bat in cancers considered likely curable by following the National Comprehensive Cancer Network (NCCN) guidelines. It is possible that chemosensitivity testing results will suggest using a drug that is not in the guidelines. If the oncologist strays from the guidelines in this case, he/she could open themselves to malpractice lawsuits.

However, if you move forward with chemosensitivity testing and show the oncologist the results, he/she may follow them, especially if the guideline therapy is predicted to fail.

Of note, ovarian cancer is one of the few cancers I know of where oncologists will do chemosensitivity testing right after initial diagnosis. There may be others.

See our Breast Cancer handbook for more information about testing with breast cancer.

According to the Weisenthal Lab, Medicare doesn’t cover this testing. Private insurance companies may cover some portion of the cost. According to Dr. Renneker, this testing can cost up to $4000. The Weisenthal Lab lists a range of $2,200 to $9,000 depending on how many drugs/drug combinations they test for you. Check with your insurance company about coverage. Some labs, such as Rational Therapeutics, work with a foundation that may be able to provide financial assistance.

For a listing of other North American labs doing chemosensitivity testing, see the following resources. Note that BCCT has neither vetted nor endorsed any of the labs listed in these resources:

• Breast Health Project: Chemosensitivity Testing
• Moss Reports (purchase required)

Here we discuss liquid biopsies as testing samples of blood, urine, saliva or cerebrospinal fluid to detect circulating tumor cells or tumor DNA to see if cancer is present. While some companies refer to their molecular/genomic tests as liquid biopsies, BCCT discusses these tests above in the Molecular and Genomic Testing section. 

In March 2018, the American Society of Clinical Oncology and the College of American Pathologists published a review of the evidence and concluded that liquid biopsies to detect circulating tumor DNA (ctDNA) in blood samples are not yet ready for prime time in the diagnosis or management of early-stage or advanced solid tumors. "These assays are also not useful, outside of clinical trials, for monitoring patients for minimal residual disease following definitive treatment of cancer, nor for cancer screening."²⁰

An example of a liquid biopsy designed to detect the presence of cancer is CancerSEEK, which manufacturers claim can detect several common cancer types through assessment of the levels of circulating proteins and mutations in cell-free DNA. In studies, the test’s usefulness is “promising.”²¹

Commentaries on the study, such as from Paul Pharoah, PhD, professor of cancer epidemiology at the University of Cambridge, note that "There has been a lot of interest in using so called liquid biopsies as a relatively non-invasive way to detect cancer. The DNA from cancer cells is mutated and this mutated DNA can get into the blood stream (circulating tumour DNA, ctDNA) and be detected by sequencing the DNA in blood. There have been many studies demonstrating that this can detect cancers at the time of diagnosis or can be used to detect cancer relapses." He and other scientists conclude that the results of the study do not prove the test's ability to detect cancer early, even though this is a promising technology. More study is needed before this type of testing is ready for clinical use in early detection.²² To date, CancerSEEK is available only in clinical trials.

Note that BCCT does not recommend specific tests. With regard to liquid biopsy testing, we emphasize that the high cost of these tests paired with insufficient evidence of their accuracy and effectiveness warrant caution in considering using them in clinical practice.

• Caris in Phoenix: performing both genomics/gene testing and IHC/protein testing leading to chemotherapy and targeted therapy recommendations
• Foundation Medicine in Boston: performing only genomics testing and generally only leading to recommendations for targeted therapies; often available only in clinical trials
• Omics in Los Angeles: a relatively new company offering still more comprehensive genomic profiling of both the tumor and the patients’ regular cells. Dr. Renneker sees them as a good choice if the tumor behavior changes, indicating a call to re-profile a tumor.
• Consultative Proteomics, of the Department of Pathology at the University of Texas, Houston. Dr. Renneker finds this one most useful for clinical and integrative applications:.
  • In-depth testing and written analysis
  • Payment usually out-of-pocket, at about $4000
  • Cutting-edge interrogation of the tumor’s proteins (proteomics), using special stains to look for the key pathways that are driving the tumor
  • Testing for immunological parameters such as tumor-infiltrating lymphocytes, PD-L1, and PD-1 expression
  • Testing leads to recommendations to consider using various medications but also natural medicines
  • Highly referenced research and professional standing of the founding pathologists gives validity to such recommendations

• American Society of Clinical Oncology (ASCO): Assays and Predictive Markers. These guidelines are written for physicians, but they are accessible to anyone who wants to dig deeper to see what is being recommended for conventional oncology diagnostics.
• National Comprehensive Cancer Network: NCCN Guidelines for Patients, guidelines related to specific cancers including a discussion of the testing done to diagnose the specific cancer and determine treatment, including molecular and genomic testing.
• ASCO Cancer.Net: Understanding Targeted Therapy
• Moss Reports (purchase required), especially for testing specific to your type of cancer. Moss provides one of the most thorough discussions and resource list of testing and places to have specialized testing done.
• My Cancer Genome:
  • Overview of Targeted Therapies for Cancer, includes a very helpful table listing all the approved targeted therapies, their targets and the cancers in which they’re used.
  • My Cancer Genome: Types of Molecular Tumor Testing
• National Cancer Institute: Targeted Cancer Therapies
• Block KI. Life Over Cancer: The Block Center Program for Integrative Cancer Care. New York: Bantam Dell. 2009.
• Lindeman NI, Cagle PT et al. Updated molecular testing guideline for the selection of lung cancer patients for treatment with targeted tyrosine kinase inhibitors: guideline from the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology. Archives of Pathology & Laboratory Medicine. 2018 Jan 22.
• Roschewski M, Dunleavy K et al. Circulating tumour DNA and CT monitoring in patients with untreated diffuse large B-cell lymphoma: a correlative biomarker study. Lancet Oncology. 2015 May;16(5):541-9.
• Moss Reports Podcast: Is Personalized Medicine the Future of Cancer Treatment? with Robert Nagourney, MD

• Block Center for Integrative Cancer Treatment: Ask Dr. Block: Do you recommend chemosensitivity testing of tissue samples?
• Nagourney Cancer Institute Blog: Chemosensitivity Testing—What It Is and What It Isn’t
• Breast Health Project: Chemosensitivity Testing
• Renneker M. No Stone Unturned: Medical Advocacy Techniques for People with Cancer and Other Serious Conditions. Healing Circles workshop presentation, Commonweal. June 5, 2015.
• Moss Reports (purchase required), especially for testing specific to your type of cancer. Moss provides one of the most thorough discussions and resource list of testing and places to have specialized testing done.
• Vlachogiannis G, Hedayat S et al. Patient-derived organoids model treatment response of metastatic gastrointestinal cancers. Science. 2018 Feb 23;359(6378):920-926.

• Find additional information on other testing used by Keith Block in his book, Life Over Cancer.
• Medical advocate Mark Renneker, MD, also provides additional information on diagnostic testing used in integrative cancer treatment planning in No Stone Unturned: Medical Advocacy Techniques for People with Cancer and Other Serious Conditions.
• Ralph Moss, PhD: The Ultimate Guide to Cancer: DIY Research
• EmpowHER: Keith Block: My Activity
• Raymond Chang, MD: Beyond the Magic Bullet: The Anti-Cancer Cocktail
• Donald I. Abrams, MD, and Andrew T. Weil, MD: Integrative Oncology, 2nd Edition
• Neil McKinney, BSc, ND: Naturopathic Oncology, 3rd Edition
• Lise Alschuler, ND, FABNO, and Karolyn Gazella: The Definitive Guide to Cancer, 3rd Edition
• National Comprehensive Cancer Network Patient and Caregiver Resources
• Michael Lerner: Choices In Healing: Integrating the Best of Conventional and Complementary Approaches to Cancer