Friday, June 7, 2019

Medicare Diabetes Prevention Program (MDPP)

Expanded Model Fact Sheet Overview of MDPP

The MDPP expanded model includes an evidence-based set of services aimed to help prevent the onset of type 2 diabetes among Medicare beneficiaries with an indication of prediabetes. MDPP services will be available to eligible beneficiaries nationwide beginning April 1, 2018 under a performance-based payment model through the CMS Innovation Center.

Questions about MDPP

What is covered through the model?

• Structured sessions with a coach, using a CDC-approved curriculum to provide training in dietary change, increased physical activity, and weight loss strategies

• 12 months of core sessions for beneficiaries with an indication of prediabetes, and an additional 12 months of ongoing maintenance sessions for participants who meet weight loss and attendance goals.

How does the model pay for MDPP services?

MDPP suppliers are paid performance-based payments through the CMS claims system. Medicare payments to suppliers will range, and can be up to $670 per beneficiary over
2 years, depending on beneficiaries’ attendance and weight loss.

What does this mean for beneficiaries?
Beginning April 1, 2018, eligible beneficiaries have coverage of MDPP services with no costsharing through Medicare-enrolled MDPP suppliers.
Eligible beneficiaries are those who:
• Are enrolled in Medicare Part B
• Have a body mass index (BMI) of at least 25, or at least 23 if self-identified as Asian
• Meet 1 of the following 3 blood test requirements within the 12 months of the first core session:
    ? A hemoglobin A1c test with a value between 5.7 and 6.4% , or
    ? A fasting plasma glucose of 110-125 mg/dL, or
    ? A 2-hour plasma glucose of 140-199 mg/dL (oral glucose tolerance test)
• Have no previous diagnosis of type 1 or type 2 diabetes (other than gestational diabetes)
• Do not have end-stage renal disease (ESRD)

What does this mean for providers?

Although a referral from a physician is not required for beneficiaries to participate in MDPP services, clinicians have an important role to play in helping beneficiaries understand their risk of diabetes and their treatment options. This is particularly important because only 14% of adults aged 65 and older with prediabetes are aware of their condition. Clinicians may help Medicare patients obtain the blood tests they need to become aware of their risk and recommend they
participate in MDPP services.

What does this mean for organizations that wish to deliver MDPP services?

Organizations who wish to furnish MDPP services to beneficiaries and bill Medicare for those services must enroll in Medicare as an MDPP supplier.

To enroll as an MDPP supplier, organizations must:
• Have MDPP preliminary recognition or full CDC DPRP recognition
• Have an active and valid tax-identification number (TIN) or national provider identifier (NPI)
• Pass enrollment screening at the high categorical risk level
• On the MDPP enrollment application, submit a list of MDPP coaches who will lead sessions,including full name, date of birth, social security number (SSN), and active and valid NPI and coach eligibility end date (if applicable)
• Meet MDPP supplier standards and requirements, and other requirements of existing Medicare providers or suppliers
• Revalidate its enrollment every 5 years

Key Dates
• January 2018– MDPP supplier enrollment begins
• April 2018– Enrolled MDPP suppliers may begin furnishing services and billing Medicare

Centers for Disease Control and Prevention.
CDC twenty four seven. Saving Lives, Protecting People

National Diabetes Prevention Program
CDC-recognized lifestyle change programs are based on years of research showing that a year-long, structured lifestyle change intervention reduced the incidence of diabetes by 58% among adults with prediabetes and by 71% among those aged 60 years or older. The same study showed a 31% reduction with metformin compared with placebo. The researchers concluded that the lifestyle intervention was significantly more effective than metformin.

And the results last. Even after 10 years, people who completed a diabetes prevention lifestyle change program had a 34% lower rate of type 2 diabetes.

Participating in a program to lose weight through healthy eating and increased physical activity can also reduce the risk of heart attack and stroke.

Quality Standard

To ensure high-quality interventions, CDC only recognizes lifestyle change programs that meet evidence-based standards and show they can achieve results. These standards include:

• Following a CDC-approved curriculum
• Facilitation by a trained lifestyle coach
• Making regular data submission (according to the timeline dictated in the current DPRP Standards) to show that the program is having an impact.

Serious & Common

More than 84 million US adults—that’s 1 in 3—have prediabetes. With prediabetes, blood sugar is higher than normal but not high enough yet to be diagnosed as diabetes. People with prediabetes are at high risk for type 2 diabetes (the most common type of diabetes), heart disease, and stroke.

In the last 20 years, the number of adults diagnosed with diabetes has more than tripled as the US population has aged and become more overweight. Now more than 30 million Americans have diabetes, which increases their risk for a long list of serious health problems, including:

•Heart attack
•Kidney failure
•Loss of toes, feet, or legs
The good news: the CDC-led National Diabetes Prevention Program’s lifestyle change program can help people with prediabetes prevent or delay type 2 diabetes and other serious health problems and improve their overall health. It’s scientifically proven, and it works.

Diabetes Is Expensive
Diabetes has an enormous economic impact on millions of individuals and their families, on workplaces, and on the US health care system.

In 2017, the total estimated cost of diagnosed diabetes was $327 billion ($237 billion in direct medical costs and $90 billion in lost productivity), up 26% over a 5-year period.
About 1 in 4 health care dollars is spent on people with diagnosed diabetes.
Medical expenses for people diagnosed with diabetes—$16,750 annually on average—are about 2.3 times higher than for people without diabetes.

The Time To Act Is Now
Don’t let the “pre” in prediabetes fool you—prediabetes is a serious health condition that can develop into even more serious health conditions.

Program Eligibility

CDC-recognized lifestyle change programs are designed for patients who have prediabetes and are at high risk for developing type 2 diabetes.

Follow the guidelines below to know which patients are eligible for the program.
Which Patients to Refer
To be eligible for referral to a CDC-recognized lifestyle change program, patients must meet the following requirements:

•Be at least 18 years old and
•Be overweight (body mass index =25; =23 if Asian) and
•Have no previous diagnosis of type 1 or type 2 diabetes and
•Have a blood test result in the prediabetes range within the past year:
    •Hemoglobin A1C: 5.7%–6.4% or
    •Fasting plasma glucose: 100–125 mg/dL or
    •Two-hour plasma glucose (after a 75 gm glucose load): 140–199 mg/dL or
•Be previously diagnosed with gestational diabetes

Prediabetes can be diagnosed via oral glucose tolerance tests, fasting blood glucose tests, or an A1C test. Blood-based testing is the most accurate way to determine if a patient has prediabetes.

Thursday, May 23, 2019

Does out of state patient eligible for coverage ?


A member, who is temporarily out of the state but still a resident of Arizona, is entitled to receive AHCCCS benefits under any of the following conditions:

1. Medical services are required because of a medical emergency. Documentation of the emergency must be submitted with the claim to AHCCCS.

2. The member requires a particular treatment that can only be obtained in another state.

3. The member has a chronic illness necessitating treatment during a temporary absence from the state or the member’s condition must be stabilized before returning to the state. Services furnished to AHCCCS members outside of the United States are not covered.


* We have patients that come from other states and have Medicaid from other states. How do we handle this?

Florida Medicaid cannot be billed for Medicaid recipients from other states.  Each state’s Medicaid program operates independently essentially 50 separate programs).Florida Medicaid  beneficiaries are covered for emergency care or prior approved care in other states. You would have to contact the other state’s Medicaid program to find out if they have a similar provision for their beneficiaries who need out-of-state care.


Non-Emergency Medical Transportation (NEMT)

- All requests for out-of-state transportation and certain related expenses must have prior approval from the broker, except for travel to those facilities which have been granted in-network status. Facilities granted innetwork status are considered in-state providers. Members are required to contact the broker to schedule the travel for all medical appointments or visits, regardless of the in-network or out-of-network status.

NOTE: Individuals who receive both Medicare and Medicaid do not require prior approval for out-of-state transportation

Hospital - An entity that is licensed as an acute care hospital in accordance with applicable state laws and regulations, or the applicable state laws and regulations of the state in which the entity is located when the entity is out-of-state, and is certified under Title XVIII of the federal Social Security Act. The term “hospital” includes a Medicare- or state-certified distinct rehabilitation unit, a “psychiatric hospital” as defined in this section, or any other distinct unit of the hospital. (WAC 182-550-1050)

Out-of-state hospital admissions (does not include hospitals in designated bordering cities)

The agency pays for emergency care at an out-of-state hospital for Medicaid and CHIP clients only.

Note: The agency considers hospitals in designated bordering cities, listed in WAC 182-501-0175, as in-state hospitals for coverage and as out-of-state hospitals for payment, except for critical border hospitals. The agency considers critical border hospitals “in-state” for both coverage and payment.

The agency requires PA for elective, non-emergency care. Providers should request PA when:

• The client is on a medical program that pays for out-of-state coverage. Example: Aged, Blind, Disabled (ABD) Assistance (formerly Disability Lifeline clients) have no out-ofstate benefit except in designated bordering cities.


The following general guidelines apply to eligibility effective dates:

1. For most members, eligibility is effective from the first day of the month of application, the first day of the month in which the member meets the qualifications for the program, or their date of birth, whichever is later.

2. For KidsCare members, if the eligibility determination is completed by the 25th day of the month, eligibility begins on the first day of the following month. For eligibility determinations completed after the 25th day of the month, eligibility begins on the first day of the second month following the determination of eligibility.

3. For Medicare Savings Program (MSP) – QMB members, eligibility begins with the month following the month that QMB eligibility is determined.

4. For Breast and Cervical Cancer Treatment Program (BCCTP) members, eligibility begins on the later of the first date of the month (the application month for BCCTP is the month of the BCCTP diagnosis), or the first day of the month in which the customer meets all the BCCCTP eligibility requirements.

5. For a move into state or release from prison, the begin date is no sooner than that date.

Thursday, May 2, 2019

CPT code 99231, 99232. 99233 - Medical necessity tips

Define Medical necessity:

Medical necessity of a service is the overarching criterion for payment in addition to the individual requirements of a CPT code. It would not be medically necessary or appropriate to bill a higher level of evaluation and management service when a lower level of service is warranted. The volume of documentation should not be the primary influence upon which a specific level of service is billed. Documentation should support the level of service reported.

Practice that is reporting a higher number of these 99233 and 99214 codes than their peers may
substantially increase their risk of audit and review. the CERT study gives the opportunity identify potential errors the same way that the auditor's do.

This article focuses on the most common coding errors identified in the report to help you understand how to prevent them from occurring at your practice.

The key point to using 99233 is the provider must be sure to meet two of the three components:
• Detailed interval history
• Detailed examination
• High complexity Medical decision making (MDM)

Alternatively, they could spend 35 minutes or more of face-to-face time with the patient. Comorbidities and other underlying diseases cannot be considered when selecting 99233 unless their presence significantly increases the complexity of the medical decision making. Also if the provider chooses to use time to base the assignment of 99233, the time must be documented in the patient’s medical record and the documentation must have sufficient detail to justify the code selection.

Documentation Tips:

1. Documentation must be entered in a timely manner and must be decipherable to members of the healthcare team as well as other individuals who may need to review the information (e.g., auditors). Proper credit cannot be given for documentation that is difficult to read.

2.Information should include historical review of past/interim events, a physical exam, medical decision-making as related to the patient’s progress/response to intervention, and modification of the care plan (as necessary). The reason for the encounter should be evident to support the medical necessity of the service. Because various specialists may participate in patient care, documentation for each provider’s encounter should demonstrate personalized and non-duplicative care.

3.Each individual provider must exhibit a personal contribution to the case to prevent payors from viewing the documentation as overlapping and indistinguishable from care already provided by another physician. Each entry should be dated and signed with a legible identifier (i.e., signature with a printed name).

Consider Patient's condition:

Neither guidelines provide fully objective, quantitative criteria by which medical necessity for an E/M Service may be judged. Understanding the medical necessity for ordering a lab or radiologic exam is comparatively easy:

Example: A provider orders a chest x-ray for suspected pneumonia, or serial troponins are ordered for chest pain to rule out acute coronary syndrome. Connecting the dots between a 99233 and medical necessity is not as clear.

Fortunately, CPT provides a clue in the full descriptor for CPT 99233. Usually, the patient is unstable or has developed a significant complication or new problem.

''Usually'' statement referencing the stability of the patient
• 99231 “Usually, the patient is stable, recovering or improving.”
• 99232 “Usually, the patient is responding inadequately to therapy or has developed a minor complication.”
• 99233 “Usually, the patient is unstable or has developed a significant complication or a significant new problem
Based on these statements, it is the documented stability of the patient that determines the medical necessity of these subsequent care levels (when not billing based on time)

Differentiate between ''Significant'' and ''Unstable'':

''Significant'' and ''Unstable'' these terms are not specifically defined, we can use Medicare's 1995 and 1997 Documentation guidelines for E/M services to point us in the right direction—Specifically, the examples for a high level of risk under the presenting problem in the table of risk:
• One or more chronic illnesses with mild exacerbation, progression, or side effects of treatment.
• Acute or chronic illnesses or injuries that pose a threat to life or bodily function, e.g., multiple trauma, acute MI, pulmonary embolus, severe respiratory distress, progressive severe rheumatoid arthritis, psychiatric illness with potential threat to self or others, peritonitis, acute renal failure.
• An abrupt change in neurologic status, e.g., seizure, TIA, weakness, sensory loss.

For a new complication or problem to be considered “Significant” it should be comparable to the table of risk examples.

''Unstable'' also follows this guideline, but for ongoing conditions rather than new problems or complications.
CPT CODE 99231, 99232, 99233, 99291 - PATIENT STABILITY

Example: A patient admitted yesterday for sepsis with respiratory failure and acute kidney injury, who today remains presents tachypnea and tachycardic, with worsening oxygen requirements and significantly elevated blood urea nitrogen (BUN), creatinine and lactate levels. Accounting for the presenting problems and the usually statements in the CPT and factoring in critical care, you can create a spectrum of patient stability that points to the medical necessity requirements for each subsequent care code level, as shown mentioned below table.

One condition documented as ''Improving'' does not mean the patients overall condition is stable.

Time-based coding changes the Criteria:

The physician may document time spent with the patient in conjunction with the medical decision-making involved and a description of the coordination of care or counseling provided.

Documentation must be in sufficient detail to support the claim:

Physicians must document both the counseling/coordination of care time and total visit time. The format may vary: “Total visit time = 35 minutes; more than 50% spent counseling/coordinating care,” or “30 of 35 minutes spent counseling/coordinating care.” Any given payer may prefer one documentation style over another. It always is best to query payers and review their documentation standards to determine the local preference.

In addition to the time, physicians must document the medical decision-making and details of the counseling/coordination of care. For example, patients with newly diagnosed diabetes need to be educated about their condition, lifestyle, and medication requirements. Physicians should include information regarding these factors in their progress notes as necessary.


The Centers for Medicare and Medicaid Services (CMS) released the results from their Comprehensive Error Rate Testing (CERT) earlier this year. The results showed a 9.5% overall improper payment rate for 2017, representing $36.21 billion in improper payments.

Friday, March 29, 2019

Arizona Long Term Care System (ALTCS) program Basic information



All Arizona residents can apply for AHCCCS services or the Arizona Long Term Care System (ALTCS) program. There are many programs that individuals may qualify for in order to receive AHCCCS medical or behavioral health services or ALTCS coverage.

The programs have a number of different financial and non-financial requirements that applicants must meet, including, but not limited to:

1. Proof of Arizona residency at the time of application.
2. Proof of U.S. citizenship and identity or proof of qualified alien status.

 If a non-citizen does not meet the qualified alien status requirements for full services, but meets all other requirements for the Caretaker Relative, SOBRA Child, SOBRA Pregnant Woman, Young Adult Transitional Insurance (YATI), Adult, or SSI-MAO category, the individual is eligible to receive Federal Emergency Services (FES) only.

3. An income test that requires applicants to identify all individual and/or family earned and unearned income and to provide documentation if needed.

4. A resource test that requires applicants to identify resources (e.g., homes, other property, liquid assets, vehicles, and any other item of value) and provide documentation of their value.

NOTE: A resource test is only required for the ALTCS program.

5. Other requirements
    * Each program has certain non-financial and/or financial requirements that are unique to the program and are aimed at servicing specific groups of people.


Eligibility determination is not performed under one roof, but by various agencies, depending on the eligibility category.

For example:

* Pregnant women, caretaker relatives, children, and single individuals enter AHCCCS by way of the Department of Economic Security.

* The blind, aged or disabled, who receive Supplemental Security Income, enter through the Social Security Administration.

* Eligibility for categories such as ALTCS, SSI – Medical Assistance Only (Aged, Blind and Disabled, who do not qualify for Supplemental Security Income cash payment),

KidsCare, Freedom to Work, Breast and Cervical Cancer Treatment Program and Medicare Cost Sharing programs are handled directly by the AHCCCS Administration.

Each eligibility category has its own eligibility criteria.

1. Coverage for parents and caretaker relatives is provided under Caretaker Relatives.
2. Coverage for children is provided under the following eligibility categories:
b. KidsCare
i. KidsCare is Arizona’s version of the Title XXI State Children’s Health
Insurance Program.
ii. It covers low-income children under age 19, if the family income is less
than 200 percent of the Federal Poverty Level (FPL).
c. Child Group
d. SSI Cash (Title XVI) or SSI MAO
e. Young Adult Transitional Insurance (YATI) for former Foster Care Children
aged 18 to 26
f. Foster Care Children
g. Adoption Subsidy Children
h. Newborns

All babies born to AHCCCS-eligible mothers are also deemed to be AHCCCS eligible and may remain eligible for up to one year, as long as the newborn continues to reside in Arizona.
i. Newborns born to mothers receiving Federal Emergency Services (FES) also are eligible up to one year of age. While the mother will be covered on a Fee-For-Service basis under FESP, the newborn will be enrolled with a health plan.

ii. Newborns born to mothers enrolled in KidsCare will be approved for KidsCare beginning with the newborn’s date of birth, unless the child is Medicaid eligible.

iii. Newborns receive separate AHCCCS ID numbers and services for them must be billed separately using the newborn's ID. Services for a newborn that are included on the mother's claim will be denied.

3. Coverage for single individuals and couples is provided under the following eligibility  categories:

b. Breast and Cervical Cancer Treatment Program
c. Family Planning Services (FPS) provides family planning services for up to 24
months to SOBRA pregnant women after a 60-day post partum period.
d. SOBRA Pregnant Women
e. SSI Cash (Title XVI) or SSI MAO
f. Adults
g. Freedom to Work
h. Transplants
i. Medicare Cost Sharing
j. Hospital Presumptive Eligibility (HPE)

Various Medicare Savings Programs help members pay Medicare Part A & B premiums,deductibles, and coinsurance.
1. Qualified Medicare Beneficiary (QMB)
2. Qualified Individual 1 (QI-1)
3. Specified Low Income Medicare Beneficiary (SLMB)

Thursday, January 10, 2019

CPT 81538 - Proteomic Testing for Targeted Therapy in Non-Small Cell Lung Cancer

Coding Code DescriptionCPT

81538 Oncology (lung), mass spectrometric 8-protein signature, including amyloid A, utilizing serum, prognostic and predictive algorithm reported as good versus poor overall survival

Proteomic Testing for Targeted Therapy in Non-Small Cell Lung Cancer


Genes in our DNA tell a cell how to make proteins. The study of proteins in a cell is called “proteomics.” Doing tests on the proteins in a cell (“proteomic testing”) may help to identify which drugs might be helpful in treating non-small cell lung cancer and how aggressive the cancer is. Proteomic testing used for this and all other reasons is unproven (investigational). Medical studies have not determined the types of patients in which proteomic testing could predict the course of the disease. Studies also have not shown that patients whose treatments were chosen based on proteomic testing survived longer than those whose treatments were selected without proteomic testing.

Note: The Introduction section is for your general knowledge and is not to be taken as policy coverage criteria. The rest of the policy uses specific words and concepts familiar to medical professionals. It is intended for providers. A provider can be a person, such as a doctor, nurse, psychologist, or dentist. A provider also can be a place where medical care is given, like a hospital, clinic, or lab. This policy informs them about when a service may be covered.

Policy Coverage Criteria

Testing Investigational
Proteomic testing The use of proteomic testing, including but not limited to the VeriStrat® assay, is considered investigational for all uses in the management of non-small cell lung cancer.

Related Information N/A Evidence Review Description

Proteomic testing has been proposed as a way to predict survival outcomes, as well as the response to and selection of targeted therapy for patients with non-small cell lung cancer (NSCLC). One commercially available test (the VeriStrat® assay) has been investigated as a predictive marker for response to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs).

Background Non-Small Cell Lung Cancer

Lung cancer is the leading cause of cancer death in the United States, with an estimated 221,200new cases and 158,040 deaths due to the disease in 2015.1 Non-small cell lung cancer (NSCLC) accounts for approximately 85% of lung cancer cases and includes nonsquamous carcinoma (adenocarcinoma, large cell carcinoma, other cell types) and squamous cell carcinoma.


The stage at which lung cancer is diagnosed has the greatest impact on prognosis.2 Localized disease confined to the primary site has a 55.6% relative 5-year survival but accounts for only 16% of lung cancer cases at diagnosis. Mortality increases sharply with advancing stage. Metastatic lung cancer has a relative 5-year survival of 4.5%. Overall, advanced disease, defined as regional involvement and metastatic, accounts for approximately 80% of cases of lung cancer at diagnosis. These statistics are mirrored for the population of NSCLC, with 85% of cases presenting as advanced disease and up to 40% of patients with metastatic disease.

In addition to tumor stage; age, sex, and performance status are independent prognostic factors for survival particularly in early-stage disease. Wheatley-Price et al (2010) reported on a retrospective pooled analysis of 2349 advanced NSCLC patients from 5 randomized chemotherapy trials.3 Women had a higher response rate to platinum-based chemotherapy than men. Greater overall survival (OS) than men were among those with adenocarcinoma histology.

A small survival advantage exists for squamous cell carcinoma over non-bronchiolar nonsquamous histology.4

The oncology clinical care and research community use standard measures of performance status: Eastern Cooperative Oncology Group scale and Karnofsky Performance Scale.


Treatment approaches are multimodal and generally include surgery, radiotherapy, and chemotherapy (either alone or in combination with another treatment, depending on disease stage and tumor characteristics). The clinical management pathway for stage I or II NSCLC is\ shown in Figure

The clinical management pathway for newly diagnosed advanced NSCLC is shown in Figure 2.1 Treatment recommendations are based on the overall health or performance status of the patient as well as the presence or absence of a treatment-sensitizing genetic variant. The latter is  used to select for targeted therapy or platinum-based chemotherapy.The clinical management pathway for advanced NSCLC after progression on first-line treatment or recurrence is shown in Figure 3. Treatment options are based on objective response to prior therapy, duration of response, as well as the type of and duration of prior therapy (either targeted therapy or chemotherapy).

Genomic Alterations

Several common genetic alterations in NSCLC have been targets for drug therapy, the most well-established of which are tyrosine kinase inhibitors (TKIs) targeting the epidermal growth factor receptor (EGFR) and crizotinib targeting the anaplastic lymphoma kinase (ALK) gene rearrangement.

EGFR Variants

EGFR, a tyrosine kinase receptor (TK), is frequently overexpressed and activated in NSCLC. Drugs that inhibit EGFR-signaling either prevent ligand-binding to the extracellular domain (monoclonal antibodies) or inhibit intracellular TK activity (small molecule TKIs). These targeted therapies dampen signal transduction through pathways downstream to the EGFR, such as the RAS/RAF/MAPK cascade. RAS proteins are G proteins that cycle between active and inactive

forms in response to stimulation from cell surface receptors such as EGFR, acting as binary switches between cell surface EGFR and downstream signaling pathways. These pathways are important in cancer cell proliferation, invasion, metastasis, and stimulation of neovascularization. Variants in 2 regions of the EGFR gene, including small deletions in exon 19 and a point mutation in exon 21 (L858R), appear to predict tumor response to TKIs such as erlotinib. The prevalence of EGFR variants in NSCLC varies by population, with the highest prevalence in nonsmoking, Asian women with adenocarcinoma; for that subpopulation EGFR variants have been reported as high as 30% to 50%. The reported prevalence of EGFR variants in lung adenocarcinoma patients in the United States is approximately 15%.5

ALK Variants

In 2% to 7% of NSCLC patients in the United States, tumors express a fusion gene comprising portions of the echinoderm microtubule-associated protein-like 4 (EML4) gene and the ALK gene (EML4-ALK), which is created by an inversion on chromosome 2p.6 The EML4 fusion leads to ligand-independent activation of ALK, which encodes a receptor TK whose precise cellular function is not completely understood. EML4-ALK variants are more common in never-smokers or light smokers, tend to be associated with younger age of NSCLC onset, and typically do not occur in conjunction with EGFR variants.

Testing for the EML4-ALK fusion gene in patients with adenocarcinoma-type NSCLC is used to predict response to the small molecule TKI crizotinib.

Other Genetic Variants

Other genetic variants, identified in subsets of patients with NSCLC, are summarized in Table 1.

The role of testing for these variants to help select targeted therapies for NSCLC is less wellestablished than for EGFR variants

Non-EGFR Mutations in NSCLC Gene Gene Function Estimated Mutation Prevalence in NSCLC Patient and Tumor Characteristics KRAS Encodes RAS proteins; variants associated with constitutively activated protein
20%-30% Adenocarcinomas Heavy smokers ROS1 Encodes a receptor TK in the insulin receptor family
0.9%-3.7% Adenocarcinoma Never smokers RET Proto-oncogene that encodes a receptor TK growth factor
0.6%-2% MET Oncogene that encodes a receptor TK that is activated in response to binding of hepatocyte growth factor
2-4% of previously untreated NSCLC; 5%-20% of patients with acquired resistance to EGFR TKIs Patients with acquired resistance to EGFR TKIs BRAF Serine-threonine kinase downstream from RAS in RAS-RAF-ERK-MAPK pathway
1%-3% of adenocarcinomas Heavy smokers HER HER (EGFR) family of TK receptors; dimerizes with EGFR family members when activated
1%-2% of NSCLC Adenocarcinomas Nonsmoking women

PIK3CA Intracellular signaling pathway *4% of NSCLC

EGFR: epidermal growth factor receptor; HER: human epidermal growth factor receptor; NSCLC: non-small cell lung cancer; TK: tyrosine kinase; TKI: tyrosine kinase inhibitor.

Targeted Treatment Options

EGFR-Selective Small Molecule TKIs

Three orally administered EGFR-selective small molecule TKIs have been identified for treating NSCLC: gefitinib (Iressa), erlotinib (Tarceva®), and afatinib (Gilotrif™). Although the Food and Drug Administration (FDA) approved gefitinib in 2004, a phase 3 trial suggested gefitinib was not associated with a survival benefit. In 2003, the FDA revised gefitinib labeling, further limiting its use to patients who had previously benefitted or were currently benefiting from the drug; no new patients were to be given gefitinib. However, in 2015, the FDA approved gefitinib as firstline treatment for patients with metastatic NSCLC for patients with EGFR-mutated tumors. Erlotinib and afatinib also have approval by the FDA.

In 2015, osimertinib (Tagrisso), an irreversible selective EGFR inhibitor that targets T790M variant-positive NSCLC, received FDA approval for patients with T790M-variant-positive NSCLC who have progressed on an EGFR TKI.

A meta-analysis by Lee et al (2013) assessing 23 trials on the use of erlotinib, gefitinib, and afatinib in patients with advanced NSCLC reported improved progression-free survival (PFS) in EGFR variant*positive patients treated with EGFR TKIs in the first- and second-line settings and as maintenance therapy.7 Comparators were chemotherapy, chemotherapy and placebo, and placebo in the first-line, second-line, and maintenance therapy settings. Among EGFR variant*
negative patients, PFS was improved with EGFR TKIs compared with placebo for maintenance therapy but not in the first- and second-line settings. Overall survival (OS) did not differ between treatment groups in either variant-positive or variant-negative patients. Statistical heterogeneity was not reported for any outcomes. Reviewers concluded that EGFR mutation testing is indicated to guide treatment selection in NSCLC patients.

On the basis of the results of 5 phase 3 randomized controlled trials, the American Society of  Clinical Oncology recommended that patients with NSCLC being considered for first-linetherapy with an EGFR TKI (patients who have not previously received chemotherapy or an EGFR TKI) should have their tumor tested for EGFR variants to determine whether an EGFR TKI or chemotherapy is the appropriate first-line therapy.

The primary target population for TKIs in NSCLC is for EGFR variant*positive patients with  advanced NSCLC. The use of TKIs in NSCLC in EGFR variant*negative patients is controversial. The TITAN trial as reported by Ciuleanu et al (2012) demonstrated no significant differences in OS between erlotinib and chemotherapy as second-line treatment for patients unselected on the basis of EGFR mutation status, with fewer serious adverse events in erlotinib-treated patients.8 Karampeazis et al (2013) reported similar efficacy between erlotinib and standard chemotherapy (pemetrexed) for second-line therapy in patients unselected on the basis of EGFR mutation status.9 By contrast, in the TAILOR trial as reported by Garassino et al (2013), standard chemotherapy was associated with longer OS than erlotinib for second-line therapy in patients with wild-type EGFR.10 Auliac et al (2014) compared sequential erlotinib plus docetaxel with docetaxel alone as second-line therapy among patients with advanced NSCLC and EGFR wildtype or unknown status.11 Based on Simon’s optimal 2-stage design, the erlotinib plus docetaxel strategy was rejected. Despite the rejection, it is worth noting that in the erlotinib plus docetaxel arm 18 of 73 patients achieved PFS at 15 weeks; comparatively, in the docetaxel arm, 17 of 74 patients achieved PFS at 15 weeks.

Cicenas et al (2016) reported results of the IUNO randomized controlled trial, which compared maintenance therapy using erlotinib followed by second-line chemotherapy if progression occurred to placebo followed by erlotinib if progression occurred in 643 patients who had advanced NSCLC and no known EGFR variant.12 Because there were no significant differences between groups in terms of PFS, objective response rate, or disease control rate, maintenance therapy with erlotinib in patients without EGFR variants was not considered efficacious.

Anti-EGFR Monoclonal Antibodies

For the treatment of KRAS-mutated NSCLC, anti-EGFR monoclonal antibodies have been investigated as possible treatment options. Available anti-EGFR monoclonal antibodies include cetuximab and panitumumab. Neither drug has an established role in the treatment of NSCLC either as a component of initial therapy or as second-line therapy.

Programmed Death Ligand 1 Inhibitors

Some tumors, including some NSCLCs, express a programmed death-ligand 1 (PD-L1) on the cell surfaces to interact with host T cells and evade the immune system. Several humanized monoclonal antibodies have been developed to act as immune checkpoint inhibitors by interferingwith this interaction, to interact with the PD-L1, block the cancer/T-cell interaction, and thus act as immune checkpoint inhibitors. Pembrolizumab, nivolumab, and atezolizumab, which inhibit the programmed death 1 receptor, and atezolizumab, which inhibits the PD-L1, are used in NSCLC that have PD-L1 expression on its cells. Durvalumab also targets the PD-L1 protein but is used in unresectable, stage III NSCLC whose disease has not progressed following concurrent platinum-based chemotherapy and radiotherapy.

Other Targeted Therapies

Crizotinib is a novel MET, ROS1, and ALK TKI, and associated with improved PFS in patients with advanced NSCLC who are ALK gene rearrangement*positive.13 Crizotinib is considered first-line therapy for advanced ALK-positive lung adenocarcinoma.1 Other small molecule TKIs, designed to selectively bind to and inhibit ALK activation, have FDA approval: ceritinib, alectinib, and brigatinib.

Proposed targeted therapies for other genetic alterations in NSCLC are trastuzumab for HER2 variants, crizotinib for MET amplification and ROS1 rearrangement, vemurafenib and dabrafenib for BRAF variants, and cabozantinib for RET rearrangements.

Proteomics Testing in Selecting Targeted Treatment for NSCLC

The term proteome refers to the entire complement of proteins produced by an organism or cellular system and proteomics refers to the large-scale comprehensive study of a specific proteome. The proteome may differ from cell to cell and may vary over time and in response to selected stressors.

A cancer cell’s proteome is related to its genome and to genomic alterations. The proteome may be measured by mass spectrometry (MS) or protein microarray. For cancer, proteomic signatures in the tumor or in bodily fluids (ie, pleural fluid or blood) other than the tumor have been investigated as a biomarker for cancer activity. A commercially available serum-based test (VeriStrat) has been developed and proposed to be used as a prognostic tool to predict expected survival for standard therapies used in the treatment of NSCLC. The test is also proposed to have predictive value for response to EGFR TKIs.14

The test uses matrix-assisted laser desorption ionization MS analysis, and a classification algorithm was developed on a training set of pretreatment sera from 3 cohorts (Italian A, Japan A, Japan B) totaling 139 patients with advanced NSCLC who were treated with second-line gefitinib.15 The classification result is either “good” or “poor. Two validation studies using pretreatment sera from 2 cohorts of patients (Italian B, Eastern Cooperative Oncology Group 3503) totaling 163 patients have been reported.

This assay uses an 8-peak proteomic signature; 4 of the 8 have been identified as fragments of serum amyloid A protein 1.16 This protein has been found to be elevated in individuals with a variety of conditions associated with acute and chronic inflammation.17-21 The specificity for malignant biologic processes and conditions has not been determined.22 With industry support, Fidler et al (2018) used convenience biorepository samples to investigate 102 analytes for potential correlations between the specific peptide and protein biomarkers and VeriStrat classification.23

Although the VeriStrat matrix-assisted laser desorption ionization MS-based predictive algorithm has the largest body of literature associated with it, other investigators have used alternative MS methods, such as surface-enhanced laser desorption ionization/time-of-flight MS, and alternative predictive algorithms, to assess proteomic predictors of lung cancer risk.24 Best practices for peptide measurement and guidelines for publication of peptide and protein identification have been published for the research community.

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