Cancer Treatment Today » Tests

Afirma test for thyroid nodules: ACEG – pro

M Levin, MD — Thu, 03 Oct 2013 02:28:37 +0000

The majority of FNAs of tyroid nodules show benign histological findings but some are indeterminate or non-diagnostic. In an attempt to separate out patients with a worse prognosis, Afirma has develoiped a proprietory tests, Benign Gene Expression Classifier. In 2010, two modest-sized validation studies showed that the AGEC test could identify a benign gene expression signature in indeterminate cytology thyroid FNA samples with a negative predictive value >95%.

Independent evaluations of the test have been positive. Palmetto Government Benefits Administrators (Palmetto GBA), the CMS Medicare Administrative Contractor with oversight for the Afirma GEC, has published its assessment of the test as an update to its local coverage article on molecular diagnostics. This review determined that the test meets criteria for analytical and clinical validity, and clinical utility as a reasonable and necessary Medicare benefit, effective January 1, 2012.25. As part of the CLIA Laboratory licensure process, the analytical and clinical validation data for the Afirma GEC were independently assessed by reviewers from the California Department of Public Health and the New York State Department of Health.26,27 Both of these reviews resulted in a favorable licensure outcome.

The National Comprehensive Cancer Network (NCCN) thyroid carcinoma guidelines were updated in December, 2012 to state “Molecular diagnostics may be useful to allow reclassification of follicular lesions (follicular neoplasm or follicular lesion of undetermined significance) as more likely to be benign or more likely to be malignant…If molecular testing predicts a risk of malignancy comparable to the risk of malignancy seen with a benign FNA cytology (approximately 5% or less), consider observation.” The NCCN guidelines for abnormal gene/gene expression profile testing are associated with Level of Evidence 2A (lower level evidence, uniform NCCN consensus that the intervention is appropriate)

Daniel S. Duick et al, The Impact of Benign Gene Expression Classifier Test Results on the Endocrinologist–Patient Decision to Operate on Patients with Thyroid Nodules with Indeterminate Fine-Needle Aspiration Cytopathology, Thyroid. 2012 October; 22(10): 996–1001.

Syed Z. Ali, etal, Use of the Afirma® Gene Expression Classifier for Preoperative Identification of Benign Thyroid Nodules with Indeterminate Fine Needle Aspiration Cytopathology, PLoS Curr. 2013 February 11; 5

Bone marrow aspiration and biopsy

M Levin, MD — Thu, 10 Jan 2013 19:59:59 +0000

A fever of unknown origin is often worked up with a bone marrow, but this test is not appropraite before a full workup failes to reveal other explanation of fever. A bone marrow aspiration and biopsy is not the appropriate tests for workup of fever that is not FUO. For example, the medically necessary approach to rule out a suspected lymphoma involves locating a lymph area that may be invovled by it. This test remains important in investigating fever of unknown origin, which, however, is by definition prolonged and unexplained after appropriate clincial and radiologic approaches. Bone marrow aspiration should not be used early or routinely to investigate fevers.

In one recent study looking at the role of this procedure in patients in India, where granulomatous diseases are more common than in the USA, 121 patients with pyrexia of unknown origin underwent both bone marrow aspiration and trephine biopsy as a part of diagnostic work-up. Bone marrow aspiration was diagnostic in only 16.5% of cases, which revealed leishmaniasis or pure red cell aplasia. Granulomas were infrequent in marrow aspiration smears, as only two cases (1.6%) showed ill defined epithelioid cell collections. Compared to this, trephine biopsy offered a diagnosis in 76% of the cases. Granulomas were a frequent finding in the trephine biopsy, being present in 70% of the cases included. Additional cases diagnosed on biopsy (over those diagnosed with aspiration smears) included lymphoma, tuberculosis, fungal infection, sarcoidosis and hypocellular marrow.

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NMP-22 to screen for bladder cancer

M Levin, MD — Fri, 21 Dec 2012 17:57:09 +0000

NMP-22 urine assays for bladder cancer detect nuclear mitotic apparatus protein 1 (NUMA-1) using monoclonal antibodies. This protein can be elevated in the urine if bladder cancer cells that are rapidly dividing are present. It is not a partticularly specific tests, with many described non-cancer factors that elevate its values, and there is ongoing controversy as to whether its advantages in sensitivity over urine cytology are sufficient to recommend it as a routine screening test for bladder cancer.

Medicare has granted this test a CLIA exception but there are no guidelines that support its use at this time.

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New type of brochoscopy: ENB

M Levin, MD — Sun, 16 Dec 2012 20:11:12 +0000

ENB (Electromagnetic Navigation Bronchoscopy) or EMN bronchoscopy is a type of bronchoscopy that uses electromagnetic guidance to project catheters into and through bronchial passages. Using a virtual, three-dimensional (3D) bronchial map from a recent CT scan and disposable catheters, it makes it possible toget to preselected spaces and to take biopsies or plan radiation. FDA cleared it in 2004 through the 510(k) process. Studies suggest a higher success rate, but less so for lower lung lobes than the rest of the lung. The British Thoracic Society guidelines for advanced diagnostic and therapeutic flexible bronchoscopy in adults (Du Rand et al, 2011) said that electromagnetic bronchoscopy may be considered for the biopsy of peripheral lesions or to guide trans-bronchial needle aspiration for sampling mediastinal lymph nodes (grade D). Undortunately, one one randomized study had been eprformed and the British Society’s guideline is at a fairly low level of confidence.

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Colovantage test

M Levin, MD — Sun, 28 Oct 2012 16:12:23 +0000

ColoVantage is a new test available from Quest. Although it is a screening test, Quest says that it is not meant to be a substitute for colonoscopy. It was approved by NY State in March of 2011. It detects circulating methylated DNA from the SEPT9 gene, which is involved in cell frowth and cell cycle control. A case-control study performed at Quest Diagnostics showed that the ColoVantage test is 70% sensitive for colorectal cacner detection at a specificity of 89%. ColoVantage has successfully detected cancer at all stages; however, the number of patients at each stage of cancer was too small to derive stage-specific sensitivity data. A similar test demonstrated a sensitivity of 67% and a specificity of 88% in a prospective study of almost 8000 people. Unfortinately, at this time, it remains a proprietary test that has not been sufficiently studied. These findings need to be confirmed in larger studies that evaluate the clinical utility of this test. Support for this test in guidelines from professional organizations is lacking.

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Genetic test for Coumadin

M Levin, MD — Sun, 16 Sep 2012 20:32:25 +0000

Warfarin (Coumadin®) dose is sometimes difficult to adjust. Now there is a genetic tests that can identify people who have an increased response to conventional doses of Coumadin, which can cause bleeding. The labeling for a popular formulation of warfarin was revised in August 2007 and February 2010 to include information about how the three most widely studied pharmacogenetic mutations (CYP2C9*2, CYP2C9*3, and VKORC1 -1639G>A) affect dose requirements (NDA 9-218/S-105). The Warfarin-Sensitivity test idendifies that most common mutations that affect warfarin metabolism. CYP2C9 genotype accounts for up to 18% of the variability in warfarin dosing, VKORC1 genotype accounts for up to 29% of the variability in warfarin dosing. Combining genotypes with clinical factors may account for 50-70% of variability in warfarin dosing.

Approval was based on a study involved 896 participants with an average age of 65 who were members of prescription benefit plans managed by Medco. Hospitalization rates for this group were matched against a historical control group of 2,688 individuals. Researchers collected DNA from either blood or buccal cells and determined patients’ genotypes for the CYP2C9 and VKORC genetic variants. Mutations in the CYP2C9 gene have been associated with decreased warfarin metabolism, while mutations in the VKORC1 gene are associated with warfarin sensitivity. Based on each individual’s genotype, clinicians used a dosing algorithm to determine that person’s initial dose. The study followed patients for 6 months after the start of their treatment. Compared with the control group, the genotyped patients had 31% fewer hospitalizations overall and 28% fewer hospitalizations for bleeding or thromboembolism during the follow-up period. The study results were first reported at theAmericanCollegeof Cardiology’s annual meeting in March of 2010 and are available online: J Am Coll Cardiol (doi:10.1016/j.jacc.2010.03.009).

This is the relevant information from the label for Warfarin: ”

The dose of COUMADIN must be individualized by monitoring the PT/INR. Not all factors causing warfarin dose variability are known. The maintenance dose needed to achieve a target PT/INR is influenced by:

Clinical factors including age, race, body weight, sex, concomitant medications, and comorbidities and
Genetic factors (CYP2C9 and VKORC1 genotypes).

Select the starting dose based on the expected maintenance dose, taking into account the above factors. Routine use of loading doses is not recommended as this may increase hemorrhagic and other complications and does not offer more rapid protection against clot formation. If the patient’s CYP2C9 and VKORC1 genotypes are not known, the initial dose of COUMADIN is usually 2 to 5 mg per day. Modify this dose based on consideration of patient-specific clinical factors. Consider lower initiation doses for elderly and/or debilitated patients.

The patient’s CYP2C9 and VKORC1 genotype information, when available, can assist in selection of the starting dose. Table 5 of the Prescribing Information describes the range of stable maintenance doses observed in multiple patients having different combinations of CYP2C9 and VKORC1 gene variants. Consider these ranges in choosing the initial dose.”

Some physians argue that this test should not routinely obtained and that only if it is “available” should it play a role in dose modification. I do not find this a credible interpretation of the Prescribing Information langauge. Considering that the label of Warfarin includes CYP2c9 testing, this test should be considered medically necessary.

For the Professional version see here

FAP and AFAP testing: Genetic colon cancer

M Levin, MD — Fri, 24 Aug 2012 13:48:34 +0000

A small proportion of colon and rectal cancers arise in individuals who have genetic mutations. Familial Adenomatous Polyposis(FAP) and AFAP are autosomal dominant disorders with 50% risk of inheritance and about 75–80% of individuals with these conditions have an affected parent. Autosomal dominant inheritance means that an offspring of an affected individual has a 50% risk of inheriting the altered APC gene.
Adenomas develop in approximately half of all patients with FAP by age 15, and in 95% by age 35. Without intervention, most individuals with FAP will develop colon or rectal cancer by the fourth decade of life. Thus, screening and intervention for at-risk persons is critical and typically begins at puberty (National Comprehensive Cancer Network® [NCCN®], 2012). AFAP is an attenuated variety of FAP. Evidence in the published, peer-reviewed scientific literature indicates that genetic testing for mutations in the APC gene is appropriate for a specific subset of individuals who have been identified as at high-risk for FAP or AFAP. Among the specialty organizations that have recognized the role of FAP and AFAP genetic testing are the American Gastroenterological Association (AGA), American College of Medical Genetics (ACMG), NCCN and National Cancer Institute (NCI). It is generally accepted that genetic testing for FAP and AFAP is appropriate for the following purposes:
• to confirm the diagnosis of FAP and AFAP in an affected patient
• to provide predictive testing for at-risk relatives of AFAP and FAP-affected patients with known APC gene mutation.
MYH-Associated Polyposis (MAP), also known as MUTYH-associated polyposis, is a recently described syndrome that is related to FAP and that is also characterized by adenomatous polyps. It is, however, an autosomal-recessive syndrome, in which half of the affected individuals are carriers of the disease but are not affected, unless they receive one gene from each parent.

American College of Medical Genetics (ACMG) and the American Society of Human Genetics (ASHG) and American Gastroenterological Association (AGA) also offer guidelines. For genetic counseling and testing for adenomatous polyposis syndromes, including FAP, and AFAP, the guidelines include the following (NCCN, 2012):
• FAP Inclusion criteria include:
Presence of over 100 polyps, or fewer polyps at younger ages, especially in family known to have FAP
Autosomal dominant inheritance
Possible associated additional findings, including:
o Congenital hypertrophy of retinal pigment epithelium (CHRPE)
o Osteomas, supernumerary teeth, odontomas
o Desmoids, epidermoid cysts
o Duodenal and other small bowel adenomas
o Gastric fundic(body) gland polyps
increased risk of medulobastoma, papillary carcinoma of the thyroid (<2%) or hepatobalstoma (usually ?age 5 years)
Pancreatic cancers (<1%)
Gastric cancers (<1%)
• AFAP inclusion criteria include:
Fewer than 100 adenomas (range 0 – >1000) (average of 30 polyps)
Frequent right-sided distribution of polyps
Adenomas and cancers at age older than classic FAP (i.e., mean cancer age greater than 50)
Upper GI findings and thyroid cancer risk is similar to classic FAP
?Other extraintestinal manifestations, including CHRPE and desmoids are rare
• If personal history is positive, then refer to genetic screening
• If family mutation is known, then refer at-risk family members to genetic screening
For genetic counseling and testing for MAP, the guidelines include the following (NCCN, 2012):
• MAP inclusion criteria include:

Polyposis or colon cancers consistent with autosomal recessive (i.e., parents unaffected, siblings affected)
Fewer than 100 adenomas (range 0–100s and uncommonly >1000)
Adenomas and colorectal cancer at age older than classical FAP (median age >50)
Duodenal adenomas are uncommon
Attenuated polyposis with negative APC gene mutation

• If personal history is positive, then refer to genetic screening
• Testing for APC gene mutations usually precedes testing for MYH mutations, except in families in which only siblings are affected
• Recommend genetic counseling and testing for germ line MYH mutations for siblings of affected patients
• If family mutation is known, then refer at-risk family members to genetic screening

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Veristrat: Current Status

M Levin, MD — Fri, 03 Aug 2012 20:39:54 +0000

Veristrat is a new test that was presented in April 2012. at the 3rd European Lung Cancer Conference in Geneva, Switzerland. The Veristrat test was validated through a retrospective analysis was performed on serum samples from advanced non-squamous non-small cell lung cancer (NSCLC) patients treated with the combination therapy of Avastin and plus erlotinib. This means that after the study was finished, the researchers when back and checked tissue samples with Veristrat and then looked to see what happened to patients whose cases they analyzed. Veristrat test was able to identify patients likely to have better and worse survival outcomes in these trials.

A similar analysis of the Phase III trial, EGF30008, was presented at the 2011 CTRC-AACR San Antonio Breast Cancer Symposium. Results showed that the Veristrat test was able to identify a group of patients whose breast cancer came back sooner when treated with Femara alone.

Veristrat test may eventually become accepted to be useful for clinical decision-making, representing about treatment with erlotinib and erlotinib combinations. Prospective trials are ongoing, including a Phase III trial in advanced squamous cell lung cancer, sponsored by the European Thoracic Oncology group. Once these are reported and analyzed, Veristrat may join the current treatment armamentarium but it is still premature to make treatment decisions based on a retrospective analysis. Generally, showing that a test is predictive is not enough. Researchers need to show that selecting treatments based on a test has a beneficial result.

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MRI in the Diagnosis and Followup of Multiple Sclerosis

M Levin, MD — Tue, 17 Jul 2012 16:28:21 +0000

Magnetic Resonance Imaging (MRI) of the brain is useful in the diagnosis and treatment of multiple sclerosis (MS), because it is an inflammatory, demyelinating condition of the central nervous system (CNS) that MRI can visualize. Therefore, the activity of the disease can be quantified and tracked over time, with treatment. White matter tracts are affected, including those of the upper brain, lower brain, and spinal cord. MS lesions, known as plaques, may form in white matter in any location; thus, clinical symptoms may be diverse depending on where in the brain or spinal cord the disease is most active. MRI can identify the activity and explain the symptoms. MRI was widely used to in the diagnosis of multiple sclerosis (MS) and increasingly in follow-up. At the same time, it was not entirely clear how to use MRI. A consensus meeting was convened in 2008 to review and update the guidelines. The new guidelines incorporate new information and practice recommendations that will benefit patients and will be useful for physicians and care providers. This consensus recommends a for a baseline evaluation for patients with a Clinically Isolated Syndrome (CIS) and suspected MS. A Brain MRI with gadolinium, a Spinal Cord MRI if there is persisting uncertainty about the diagnosis and/or the findings on Brain MRI are equivocal should be performed, as well as a Spinal Cord MRI if presenting symptoms or signs are at the level of the spinal cord.

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OVA-1 Testing in Ovarian Cancer

M Levin, MD — Mon, 02 Jul 2012 16:44:37 +0000

OVA1 test is FDA cleared for women who meet the following criteria: (i) over age 18, (ii) ovarian mass present for which surgery is planned, and (iii) not yet referred to an oncologist. It is an aid to assess the likelihood that ovarian cancer is present when a physician is not sure. The test should not be used without a prior independent prior clinical/radiological evaluation and is not intended to be a screening test or to determine whether a patient should proceed to surgery. Incorrect use of the OVA1 Test carries the risk of unnecessary testing, surgery, and/or delayed diagnosis. The test has certain advantages. Two recent articles in Obstetrics and Gynecology suggest that it is a more sensitive test than Ca-125. However, sensitivity comes at the price of more false positive tests. The OVA1 test incorrectly identified non-cancerous masses about twice as often as CA 125 or clinical assessment. A higher false positive rate may increase patient distress and the number of surgeries that end up being performed.

Of more importance is the decreased number of false negatives or undetected cancers when OVA1 is added to a physician’s assessment This number is reduced from 28% to 8% in non-gynecologic oncologist assessment and from 21% to 1% in gynecologic oncologist assessment. This translates into potentially more cancers being referred to a gynecologic oncologist for initial surgery. The investigators go on to say, “Hopefully, earlier referral of patients with ovarian cancer will improve survival and reduce the number of required re-operation.” However, guidelines have not fully incorporated this test into their follow-up strategy or their assessment of recommendations on how to assess an ovarian mass. NCCN does not recommend or discuss this test.

ACOG/SGO Committee Opinion: Number 477 (March 2011) recommends that a woman with a suspicious or persistent complex ovarian mass requires surgical evaluation by a physician trained to appropriately stage and reduce the bulk of ovarian cancer. When referring to OVA1, the Committee states that OVA1 “appears to improve the predictability of ovarian cancer in women with pelvic masses. “A letter dated September 2009 issued by the Society of Gynecologic Oncologists recognized the importance of OVA1 stating that it “…may help healthcare providers better detect when referral to a gynecologic oncologist is indicated.”

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