There are now many studies that support the thesis that patients who receive a treatment matched to a tumor molecular profile have a longer progression free survival (PFS).  Von Hoff et al JCO 2010;28 4877-4883, Tsimberridou et al., Clin Cancer Res 2014;20 4827-4836, Schwaederle et al (Abstract 11097) presented at ASCO summarized the analysis of 570 Phase II Studies of single agents published from 2010-2012 encompassing 32,149 patients across malignancy types. They concluded that a “personalized strategy was independently associated with higher response rates, longer PFS and overall survival, as well as fewer toxic deaths”. The “non-personalized targeted arms led to poorer outcomes than cytotoxics”.  Intermountain Health published 2 compelling studies in abstract form.  The first study was an internal retrospective health economic analysis of 72 patients, 36 of who received treatment match to a NGS molecular profile and 36 matched control patients (age, gender, histological diagnosis and previous treatment lines) who received chemotherapy. The PFS was 22.9 weeks for the “precision medicine” treatment group and 12 weeks for the historical control group.  Costs per week were $3204 per week in the targeted group and $3501 in the control cohort. They concluded that additional survival is not associated with increased healthcare costs although it is clear that the overall cost is increased since these patients lived longer.  Additionally, the costs of treatment-related morbidities is significantly lower for patients receiving genomic cancer medicine compared to standard chemotherapy approaches. (Nadauld et al.,J Clin Oncol 33, 2015 (suppl; abstr e17641)).  In a second study the Intermountain Health group studied the impact of NGS results on physician decision making for 243 patients with a variety of tumor types.  188 patients (77%) had actionable mutation.  The NGS results changed treatment decisions with 117 patients being treated with a targeted drug while an additional 38 patients (20%) have targeted options available but are awaiting disease progression from their current treatment. (Nadauld et al., J Clin Oncol 33, 2015 (suppl; abstr e17647).

SHIVA is a randomized phase II trial comparing therapy based on tumor molecular profiling versus conventional therapy in patients with refractory cancer (the feasibility part of this trial was presented at ASCO 2015 Le Tourneau et al Abstract 11113). This is the only trial that shows no PFS benefit for therapy selected via molecular profiling.

The other ongoing and planned randomized control trials (Summary in Herbst et al Clin Cancer Res 2015;21 1541-1524) include Umbrella trials such as BATTLE, Lung-Map, Focus 4 etc. and Basket Trials such as NCI MATCH (launched at the meeting), MD Anderson’s M-PACT and IMPACT 2 and of course ASCO’s own TAPUR trial also announced at the meeting.  The Novartis Signature trial program is also a very innovative tissue agnostic, genetic alteration-specific signal finding set of studies with trial sites being opened wherever an eligible patient is identified. Between March 2013 – January 2015, 16 academic and 151 unique community/network sites have dosed 368 pts; buparlisib (142), dovitinib (73), binimetinib (90), encorafenib (9), ribociclib (30), BGJ398 (12), ceritinib (3) and sonidegib (9) with completed cohorts for buparlisib (CRC, ovarian, sarcomas, HNSCC, cervix), dovitinib (CRC, GIST), and binimetinib (lung). Preliminary activity was observed in various tumors; buparlisib (vaginal, HNSCC), dovitinib (ovarian), and binimetinib (AML, ovarian, thyroid).  This data is expected to lead to subsequent confirmatory trials.

The one caveat here for all these studies is that molecular profiling means different things to different people!

In an adjacent proposed local coverage decision (LCD) Palmetto (Medicare contractor) suggests the following guidelines for oncological molecular profiling and sign outs.  Some of the analytical requirements are timely but it continue to amaze me how prescriptive these coverage policies are getting.  (Analytical Performance Specifications for Comprehensive Genomic Profiling (M00118, V1))

It includes the following language which is pretty amazing considering they put these codes on the CLFS (clinical lab fee schedule)


Post-Analytical Testing Requirements

  1. The variants identified, clinical interpretations, and therapeutic recommendations must be reported by a physician, board certified in Molecular Genetic Pathology by the American Board of Pathology, or in Molecular Genetics by the American Board of Medical Genetics and Genomics, or has equivalent experience and expertise.  A PhD is not a recognized Medicare provider.
  2. Each sequenced run must include a control to document that quality control metrics for the assay (including at least read depth and sequence quality) have been met for that run for all variant classes reported.
  3. The bioinformatics pipeline must exclude specimen contamination as the source of identified variants for the variant classes and variant allele frequencies (VAFs) reported3,4.



Only Four of the new Genomic Sequencing Procedure (GSPs) were priced in the latest gapfilling proposal by CMS and only in limited jurisdictions.

81435          Hereditary colon cancer syndromes (eg, Lynch syndrome, familial adenomatosis polyposis); genomic sequence analysis panel, must include analysis of at least 7 genes, including APC, CHEK2, MLH1, MSH2, MSH6, MUTYH, and PMS2  $795.95

81436          Hereditary colon cancer syndromes (eg, Lynch syndrome, familial adenomatosis polyposis); duplication/deletion gene analysis panel, must include analysis of at least 8 genes, including APC, MLH1, MSH2, MSH6, PMS2, EPCAM, CHEK2, and MUTYH  $795.95

81445          Targeted genomic sequence analysis panel, solid organ neoplasm, DNA analysis, 5-50 genes (eg, ALK, BRAF, CDKN2A, EGFR, ERBB2, KIT, KRAS, NRAS, MET, PDGFRA, PDGFRB, PGR, PIK3CA, PTEN, RET), interrogation for sequence variants and copy number variants or rearrangements, if performed  $90 (AL/GA/TN)

81450          Targeted genomic sequence analysis panel, hematolymphoid neoplasm or disorder, DNA and RNA analysis when performed, 5-50 genes (eg, BRAF, CEBPA, DNMT3A, EZH2, FLT3, IDH1, IDH2, JAK2, KRAS, KIT, MLL, NRAS, NPM1, NOTCH1), interrogation for sequence variants, and copy number variants or rearrangements, or isoform expression or mRNA expression levels, if performed. $90  (AL/GA/TN)


The file located on this public website (click to view)  includes mostly the GSP test codes and interim prices, by locality, for clinical diagnostic laboratory tests that CMS determined should be priced by Medicare Administrative Contractors (MACs) for 2015 using the gapfilling methodology.  The criteria and process for gapfilling are specified in 42 CFR 414.508(b).  A reconsideration process for tests that are gapfilled is specified in § 414.509.  The final pricing file will be posted on the CLFS web site around September 2015 and will also include the national limitation amount and midpoint for each test.

The public is invited to submit comments on the preliminary pricing decisions.  Please submit any comments to by July 20, 2015.


27 November 2014

The Centers for Medicare and Medicaid Services (CMS) recently published its final payment determination for the new and reconsidered laboratory codes for Calendar Year 2015. Highlights include a decision to use gapfilling to set the pricing for the Genomic Sequencing Procedures (GSPs) codes, CPT 81410 through 81471. Professional societies and industry members had recommended both crosswalking or gapfilling the new GSPs codes at the annual Lab Public Meeting in July. Additionally, the majority of specialty societies also recommended crosswalking the new Tier 1 Molecular Pathology codes (CPT 81246, 81288, and 81313); however, CMS made the decision to gapfill these codes in 2015.

There are a number of implications from these decisions:

  • It would now appear that for new molecular codes (other than infectious disease codes) we are in an era of gapfilling on the clinical laboratory fee schedule.
  • This means that laboratories and providers will need to ensure that both technical and professional costs are incorporated into the pricing they submit to CMS contractors.
  • In addition as payment models evolve over the next few years, NGS laboratories will need to become more savvy about communicating the value they bring via these diagnostic, prognostic and predictive procedures.
  • Last time around the gapfilling procedure was chaotic, resulting in slashed pricing for molecular tests. Laboratories should take note and be well prepared for interactions with the MAC’s and other payers. In order to help prepare its membership, the AMP has engaged TynanDx and Boston Healthcare Associates to develop templates to help laboratories micro-cost some of these assays appropriately. These adaptable templates will be available on the AMP website in mid-January.
  • In addition, the AMP has invested in health economic evaluations for a subset of these tests such that providers and laboratories can communicate effectively with both public and private payers about the value they bring to the system. These models will also be available on the AMP website in January.

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