Standard and Non-standard Diagnostic Approaches

Key Points

  • Getting the cancer diagnosis right is a critical first step in determining the right treatment.
  • Some medical advocates advise 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.
  • If you have a rare cancer or if the pathologist is uncertain 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.
  • Many of the cancer diagnostic tests and procedures described in this summary are standard, with accepted guidelines and protocols concerning how and when to use them.
  • Other diagnostic approaches, such as genomic/molecular testing and chemosensitivity testing, are approved for diagnostic purposes but are often used later or not at all by conventional US oncologists. Integrative oncologists tend to use these tests more often and earlier in treatment.
  • Some of these tests can be expensive, with some covered by insurance but others not.
  • Chemosensitivity testing in a specialized lab uses live cancer cells to determine which drugs and natural substances elicit the best response.
  • Cells for chemosensitivity testing must be alive; arrangements for testing need to be made prior to tissue removal.
  • Many integrative oncologists find chemosensitivity testing useful in planning treatment after the initial diagnosis of cancer.
  • You may need to take the initiative with your oncologist to request tests that seem indicated.
  • If chemosensitivity testing was not conducted during your initial diagnosis, consider 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 and mandating consideration of re-analyzing the tumor
  • Many oncologists won’t order genomic/molecular testing or use targeted agents until more standard treatments have proven ineffective. In contrast, many integrative oncologists see value to obtaining test results that would also identify nutraceuticals and nutritional supplements that may target errant pathways.
  • Genomic/molecular testing is available, but the quality varies considerable across institutions.
  • BCCT advises talking to your oncologist before any scheduled surgery targeted therapies that may be appropriate for your tumor. Tumor tissue can be preserved for future testing.
  • This summary includes information about specific chemosensitivity testing labs and commercial genomic/molecular testing companies.

Many people do not appreciate what a critical issue getting the diagnosis right is in cancer. Some leading cancer authorities recognize that the reading of pathology reports is often the weak link in cancer treatment. The error rate in some hospitals is remarkably high. If you get the diagnosis wrong, you get the treatment wrong. So the value of getting a second reading—preferably from outside your medical center—can be significant. Some cancer centers do this routinely—especially if they are not certain of the reading. But it is certainly worth considering.

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.

Michael Lerner

Diagnostic Tests: General Information

In order to get the right cancer treatment for you, getting the diagnosis right is the most important first step.

In order to get the right cancer treatment for you, getting the diagnosis right is the most important first step. Conventional oncology care includes standard tests that will be performed to find out about the cancer itself:

  • The type of cancer (breast, colon, and so on).
  • The stage of the cancer (anywhere from pre-cancerous to metastasized to other parts of the body); for more information on staging, see the National Cancer Institute: Cancer Staging.
  • The grade of the tumor (how aggressive the cancer is, how likely it is to grow and spread); for more information on grading see the National Cancer Institute: Tumor Grade.

Then, depending on the kind of cancer you have, additional tests may include these:

  • Molecular and genomic testing to further characterize your cancer. For example, for breast cancer, your cancer will be assessed for estrogen and/or progesterone hormone receptors, as well as genetic mutations in the BRCA 1 and BRCA 2 genes.
  • Lab tests on blood and other samples to assess other evidence of cancer activity. Tumor markers such as PSA in prostate cancer are an example. A baseline level of tumor markers is important to compare levels before and after treatment and in follow-up after treatment is complete.
  • Testing to see if cancer has impaired organ and other bodily function

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 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 well with a rigorous treatment regimen compared to a debilitated younger person.

Non-standard Diagnostic Tests

All the tests listed above are fairly standard with a conventional cancer care diagnosis and workup. Integrative oncology clinicians will often assess other measures of health as well as recommend additional testing, such as chemosensitivity testing, in making an integrative treatment plan. For instance, during a cancer work-up, integrative oncologist Dr. Keith Block will look at these factors:

  • The pathology of your cancer from conventional diagnostic tests results.
  • What you eat and how you care for yourself (your biography). 
  • Biochemical disruptions that can promote cancer (your biology) such as insulin resistance and inflammation; he may run lab and other tests to measure some of these disruptions. The biography and biology of the person tell him about the environment (also known as the “soil” or “terrain”) hosting the cancer.
  • Perhaps advice to bank live tumor tissue to be examined for chemosensitivity testing or perhaps for an autologous cancer vaccine.
  • Perhaps targeted molecular testing not only to see if some targeted therapy may be useful, but also to see if there may be some specific nutraceuticals or nutritional supplements to prescribe.

Getting the Diagnosis Right

Many of your surgeon’s or oncologist’s treatment recommendations will be based on what the pathologist finds, so an accurate pathology report is vital. Unfortunately, some people diagnosed with cancer may discover later that the pathology report was wrong—they don’t have cancer. Or perhaps they may have a different cancer than what was diagnosed. One indicator that a diagnosis was wrong is that virtually all treatments that usually work fail to work.

Medical advocate 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. Realize that this pathologist may be in another part of the country or world.1

If you’re being worked up for a rare cancer, chances are the pathologist in a community hospital will have less practice in examining this type of cancer. Pathology reports using words such as “borderline”, “inconclusive”, “atypia” or “atypical hyperplasia” are a clue 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 to be aware if your doctor has become “anchored” in the diagnosis, which could prevent questioning the original diagnosis. Speak up and question the diagnosis and ask for a second opinion on the pathology report.

Also be aware that even such common, solid-seeming tests as hormone receptor assays can be erroneous, depending on what part of the tumor was sampled, what 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, call your insurance company to see if this service is covered. Sometimes insurance companies pay only for a physician to give a second opinion about your original pathology results.3

Molecular and Genomic Testing

 Success of Targeted Therapies

A 2018 review of genome-driven cancer therapies that target aberrations on tumor cells estimated that the percentage of US patients with cancer who might benefit from genome-targeted therapy in 2006 was 0.70 percent, and in 2018 it had increased to 4.90 percent. Thus to date these drugs have helped a very small minority of patients with advanced cancer.4

Molecular Profiling

Oncology has been undergoing a “molecular and genomic revolution” since the 1990s. Molecular profiling, the basis of personalized or precision medicine, looks for genes and proteins in cancer cells or in cells related to cancer growth, such as blood vessel cells. Some of these genes and protein molecules may actually block other genes that tell the cell to stop dividing or to undergo programmed cell death. Many of these gene/protein markers exist. Some examples:

  • 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 that tell cancer cells to grow and divide
  • Keep cells from living longer than normal
  • Kill the cancer cells

Proper Collection and Storage of Biologic Samples

Patients preparing for surgery or further biopsies of a tumor might be thinking about these options:

  • Having your tumor tested to assess which chemotherapy drugs it responds to (chemosensitivity testing)
  • Saving tissue for an autologous cancer vaccine

If so, you will need to make arrangements before surgery for the tumor sample to be properly collected, prepared and sent to a reputable lab to perform these tests or store cryopreserved tissue. You may also wish to have samples of tumor tissue properly preserved for future targeted molecular testing. See boxes below for more information regarding tissue preservation and testing.

The Centers for Medicare & Medicaid Services (CMS) are poised to cover the cost of next-generation sequencing (NGS) tests forpatients 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.5

Targeted Therapies and Your Cancer

A targeted agent does not yet exist for every genomic abnormality, nor does having a targeted agent always mean your tumor will respond to the drug. Regardless, the field is burgeoning so that either now, or not far into the future, one or more targeted agents may be worth considering for your cancer.

Many integrative oncologists see value in obtaining test results that may identify nutraceuticals and nutritional supplements targeting errant pathways driving the tumor.

According to medical/clinical advocates such as Dr. Mark Renneker and Dr. Ralph Moss, 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.6

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, chances are high that your tissue is properly preserved. You can then have genomic and molecular testing done on preserved tissue at any time, even months or years later.7

Gene Testing to Determine Risk of Recurrence

Commercial Genomic/Molecular Testing Companies

Dr. Mark Renneker explains that many hospitals say they can do genomic profiling, but in reality results are not as thorough as those from larger, better established commercials companies. We provide a listing of companies that Dr. Renneker has assessed favorably, and which are generally highly regarded by oncologists and which insurance usually pays (but check with your insurance):8

  • 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

Testing for risk of recurrence is becoming routine for certain cancers, such as early stage breast and prostate cancers. Test results provide additional information on how aggressive a cancer is and how likely it is to recur. For instance, the OncotypeDXTM or the MammaPrint tests evaluate a sample of breast cancer cells for certain genes that are characteristic of cancer. Analysis gives the cells a recurrence score indicating the likelihood for the breast cancer to recur within the first 10 years after diagnosis. National treatment guidelines for a low recurrence score of an ER-positive breast cancer would recommend using only endocrine therapy instead of more aggressive treatment. Testing may be able to spare someone from going through chemotherapy needlessly. A similar test for prostate cancer, called the Oncotype DX®, predicts if a prostate cancer is likely to grow and spread. 

This type of testing is typically paid for 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 in research. 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.

Chemosensitivity Testing

Other Names for Chemosensitivity Testing

  • Ex Vivo Analysis of Programmed Cell Death: EVA-PCD
  • Cell Culture Drug Resistance Testing: CCDRT

If chemotherapy and/or targeted therapies are indicated to treat your cancer, the next step is to determine which drug or drugs are best. Right now, oncologists primarily rely on studies of drugs tried in large groups of people with cancer that predict how the “average” patient will respond. Doctors will typically recommend a protocol of drugs based on clinical trial results that determine fixed doses, routes and schedules of administration. To some degree, oncologists will also consider a person’s general physical condition to adjust dosages or drug choice appropriately. But even with all these considerations, doctors still cannot be certain that a particular drug will kill a particular person’s cancer cells.

The Importance of Live Cells

Tissue samples on slides or in paraffin blocks will not work in chemosensitivity testing. The cells must be alive, and so arrangements for chemosensitivity testing need to be made ahead of the time that the tissue is removed.

This is where chemosensitivity testing can be useful. This technique evaluates an individual’s cancer cells in the lab to determine which drugs and even which natural substances elicit the best response.11 A person’s live cancer tissue obtained at biopsy or during surgery is shipped overnight to a specialized lab. The cancer cells will be separated into clusters, with each cluster then exposed to a different chemotherapy or targeted therapy. Those drugs that cause apoptosis (programmed cell death) in the cancer cells are identified as the ones the cancer is sensitive to. The lab prepares a report recommending drugs that are highly, moderately or not likely to kill cancer cells. Robert Nagourney, MD, explains that the test will often suggest less toxic drugs or combinations than standard protocols.

Improvements in Chemosensitivity Testing

Originally, chemosensitivity testing looked at drugs’ effects on cancer cell proliferation (growth), not the effects on apoptosis (programmed cell death). These earlier tests were not useful, and because of that, chemosensitivity testing lost favor with oncologists. Even with the superior effectiveness of the newer apoptotic assays, many oncologists are not likely to use this testing or bring it up as an option. Therefore, if you want this testing, you are likely going to have to take the initiative with your oncologist and request tests that seem indicated.

Finding Chemosensitivity Testing

Chemosensitivity testing is performed in a specialized lab, not in your hospital lab. Many European labs provide this test, which is much more common in Europe compared to the US, and in German Cancer Clinics in particular. However, A number of labs in North America perform this testing. Several BCCT advisors are impressed with Dr. Robert Nagourney’s Rational Therapeutics chemosensitivity testing lab in Long Beach, California. Dr. Renneker is also impressed with Weisenthal Lab in Orange County, California. Note that the Weisenthal Lab not only does chemosensitivity testing, but can also test sensitivity for some immunologicals and natural medicines.

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:

Using Cancer Organoids to Model Therapy Response

Cancer organoids are miniature, three-dimensional cell culture models that can be made from primary patient tumors and studied in the laboratory. A study asked whether such “tumor-in-a-dish” approaches can be used to predict drug responses in the clinic.

Researchers generated a live organoid biobank from patients with metastatic gastrointestinal cancer who had previously been enrolled in phase I or II clinical trials. This allowed the authors to compare organoid drug responses with how the patient actually responded in the clinic. Encouragingly, the organoids had similar molecular profiles to those of the patient tumor, reinforcing their value as a platform for drug screening and development.12

Dr. Block finds chemosensitivity testing useful in planning treatment after the initial diagnosis of cancer. In most cases, however, this testing is not employed until after a recurrence of cancer. As Dr. Mark Renneker 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. But consider sending a specimen for testing under these conditions:

  • If an additional surgery is performed
  • If a person develops 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.”13

Liquid Biopsies

A liquid biopsy is a test done on a sample of blood or other fluid to look for cancer cells from a tumor that are circulating in the blood or for pieces of DNA from tumor cells that are in the blood. A liquid biopsy may be used for several reasons:14  

  • To find or diagnose cancer at an early stage
  • To identify useful therapies
  • To assess treatment effectiveness
  • To check for recurrence or molecular changes happening in a tumor

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."15

Several examples of liquid biopsies designed to detect the presence of cancer are available.

  • The Ivy Gene Test replaces its predecessor, the Oncoblot test. According to the company, the Ivy Gene Test is not classified as a screening test for cancer but is a supplement to other standard-of-care diagnostic testing, providing additional insights.16
  • CancerSEEK, which manufacturers claim can detect eight 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.”17 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.18

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.

Other Types of Testing

Many other additional tests, both novel and standard, can provide information about your cancer cells or your terrain, which hosts the cancer cells. For instance, The Moss Report for Prostate Cancer describes two novel tests, The 4K Test and the Prosta Scint®, as well as a number of genetic tests for this cancer. Moss also provides a list of the various genetic tests, the companies that provide them, when the tests are performed, what’s analyzed, what it tells you and the benefits. See Moss Reports (purchase required).

Written by Laura Pole, RN, MSN, OCNS, and reviewed by Nancy Hepp, MS; most recent update on June 26, 2018.

View All References

More Information

Targeted Therapies and Molecular and Genomic Testing in Conventional Cancer Treatment

Chemosensitivity Testing

Other Testing

You can 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.

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