Abstract PD7-02: Value-based medicine: Are the 2013 guidelines for HER2 testing clinically significant and cost effective?
Authors: Sharma A , Vadehra D , Talal K , Hegde P , Wu R , Tannenbaum S 
Published: February 2018

Background: In the U.S., around 252,710 new breast cancer cases will be diagnosed in the year 2017. About 15-20% of these patients will be candidates for treatment with Her-2 directed therapy. The College of American Pathologists (CAP) published initial guidelines for immunohistochemistry (IHC) in 2003 with revisions in 2007 and 2013. 2013 guidelines define 3+(positive) as &gt;10% intense complete membrane staining similar to 2003; &gt;30% complete in 2007. Equivocal 2+ category in 2013 includes incomplete staining &gt; 10% for the first time; this was negative in 2003 and 2007.Hypothesis: The 2013 guidelines do not result in more true positives but increased equivocal cases resulting in clinical uncertainty and increased cost. Methods : A retrospective analysis was performed of all IHC and FISH testing done at a single institution with a single pathology reader from 2003-2016. Criteria for IHC and FISH positivity were followed for each time period and compared to one another for positive and negative HER2 expression. The equivocal categories than compared for outcome by FISH. Ultimate numbers for percentage in each category compared for statistical significance. Results:

IHC NegativeEquivocalPositiveTotal(1) 2003279, 70.6%71, 17.9%45, 11.3%395(2) 2007187, 71.6%49, 18.7%25, 9.5%261(3) 2013181, 61.7%79, 26.9%33, 11.2%293Total647199103949Chi-SquareDFValueProbOverall410.40.03 Period 1 vs 220.50.75Period 1 vs 328.20.01Period 2 vs 326.40.04

IHC Equivocal Reflex to FISH NegativeEquivocalPositiveTotal(1) 200358, 82.8%1, 1.4%11, 15.7%70(2) 200734, 80.9%0, 0.0%8, 19.0%42(3) 201362, 82.6%6, 8.0%7, 9.3%75Total154726187DF4Chi-Square8.3Asymptotic Pr&gt; ChiSq0.08Exact Pr ≥ ChiSq0.07

When further analysis was carried out, period 1 and 2 were added together and compared to period 3. When all positives and negatives were compared, there was no statistical difference between the periods. However in the equivocal category, Period 1 and 2 were statistically different than period 3. In fact the only change in period 3 was the increase in the equivocal cases (same case-equivocal IHC and FISH).

Conclusion: In the 2013 CAP guidelines, 2+ IHC now includes incomplete staining in &gt;10% of cells. This does not result in more positive cases as was the intention but an increase in the equivocal category by 8.19%. This adds to clinical uncertainty as to how to treat this group of patients. A send out for FISH is labor intensive, slow and costs on average of $650/case. With over 250,000 new cases expected this year in the U.S. this cost exceeds $13million. From all our data, the best parameters for IHC testing would be; positive-strong, complete staining in &gt;10% cells and equivocal to eliminate the incomplete staining category. This would yield the highest number of true positives by FISH and almost eliminate ultimate equivocal cases.

Citation Format: Sharma A, Vadehra D, Talal K, Hegde P, Wu R, Tannenbaum S. Value-based medicine: Are the 2013 guidelines for HER2 testing clinically significant and cost effective? [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD7-02.