Objective:
The ASCO/CAP guidelines for reporting HER2 in breast cancer, first released in 2007, aimed to standardize the reporting protocol, and were updated in 2013 and 2018, to ensure right treatment. Several studies have analyzed the changes attributed to 2013 updated guidelines, and majority of them found increase in positive and equivocal cases. However, the precise implication of these updated guidelines is still contentious, in spite of the latest update (2018 guidelines) addressing some of the issues. We conducted systematic review and meta- analysis to see the impact of 2013 guidelines on various HER2 reporting categories by both FISH and IHC.
Materials and Methods:
After extensively searching the pertinent literature, 16 studies were included for the systematic review. We divided our approach in three strategies: (1) Studies in which breast cancer cases were scored for HER2 by FISH or IHC as a primary test concurrently by both 2007 and 2013 guidelines, (2) Studies in which HER2 results were equivocal by IHC and were followed by reflex-FISH test by both 2007 and 2013 guidelines, and (3) Studies in which trends of HER2 reporting were compared in the two periods before and after implementation of updated 2013 guidelines. All the paired data in these respective categories was pooled and analyzed statistically to see the overall impact of the updated guidelines.
Results:
In the first category, by pooled analysis of primary FISH testing there has been a significant increase in the equivocal cases (P < 0.001) and positive cases (P = 0.037). We also found 8.3% and 0.8% of all the negative cases from 2007 guidelines shifted to equivocal and positive categories, respectively. Similarly by primary IHC testing there has been a significant increase in both equivocal cases (P < 0.001) and positive cases (P = 0.02). In the second category of reflex-FISH testing there was a substantial increase in the equivocal cases (P < 0.0001); however there is insignificant decrease (10% to 9.7%; P = 0.66) in the amplified cases. In the third approach for evaluating the trend, with the implementation of 2013 guidelines, there was increase in the equivocal category (P = 0.025) and positive category (P = 0.0088) by IHC. By FISH test also there was significant increase in the equivocal category (P < 0.001) while the increase in the positive category was non-significant (P = 0.159).
Conclusions:
The updated 2013 guidelines has significantly increased the positive and equivocal cases using primary FISH or IHC test and with further reflex testing, thereby increasing the double equivocal cases and increasing the cost and delaying the decision for definite management. However, whether the additional patients becoming eligible for HDT will derive treatment benefit needs to be answered by further large clinical trials.
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