Cost-effectiveness of a Dual (Immunohistochemistry and Fluorescence In Situ Hybridization) HER2/neu Testing Strategy on Invasive Breast Cancers

Abstract

The American Society of Clinical Oncology and the College of American Pathologists recommend that human epidermal growth factor receptor 2 (HER2)/neu status be determined for all invasive breast cancers. Although the most commonly used modalities to determine HER2/neu status, immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), generally give concordant results, a small but consistent discordance rate between them has been demonstrated in prior studies. Most institutions in the United States use a “reflex testing strategy” for determining HER2/neu status. In a reflex testing strategy, cancers are screened with IHC, and FISH is reflexively performed only if the IHC results are classified as equivocal. Other institutions perform both tests on all cancers to maximize diagnostic accuracy (dual testing strategy). The cost-effectiveness of dual testing and reflex testing strategies are comparatively assessed herein. A decision analysis model was established comparing these 2 testing strategies. Model probabilities were obtained from an institutional invasive breast cancer cohort. Quality-adjusted life-years (QALYs) and cost estimates were extracted from published literature. All costs were converted to 2018 US$ values using the consumer price index. One-way sensitivity analysis was performed, as well as probabilistic sensitivity analyses with acceptability curves. A total of 1247 consecutive invasive breast cancer specimens were tested with a dual strategy. By IHC, 65%, 28%, and 10% were negative, equivocal, and positive, respectively. By FISH, 87% and 13% were HER2/neu-negative and HER2/neu-positive, respectively. Six patients whose cancers were IHC-positive (3+) were found to be FISH-negative. These 6 represented 5% of the 119 cases with HER2/neu 3+ scores and 0.55% of the 1082 cases with HER2/neu-negative results by FISH. Sixteen (2%) of 809 cases with a negative IHC result were ultimately classified as HER2/neu-amplified by FISH. These 16 cases constituted 10% of all cases that were ultimately classified as HER2/neu-amplified by FISH. Overall, a reflex testing strategy was found to be less costly than a dual testing strategy ($44,470.99 vs. $45,908.86, respectively), but was also less effective (10.28 vs. 10.30 QALYs). The incremental cost-effectiveness ratio was $70,051.55/QALY. In conclusion, in this single institutional cohort of breast cancers, a dual testing strategy to determine HER2/neu status was found to be more cost-effective than a reflex testing strategy.

Impact of the Updated Guidelines on Human Epidermal Growth Factor Receptor 2 (HER2) Testing in Breast Cancer

“…Although further studies are required to identify the prognostic impact of this group, performing both HER2 IHC and ISH simultaneously would be necessary to ensure that the patients do not miss the chance to receive adequate therapy. Our study showed a similar proportion of HER2 IHC/SISH discordance seen in previous studies [ 29 ] and suggested that dual testing was more cost-effective than the current IHC-first strategy.…”

HER2 Equivocal (Score = 2+) Breast Carcinoma Cases Identified by Immunohistochemistry at a South African Hospital. What is the Impact of Fluorescent In Situ Hybridization Testing?

“…22,28,29 Some laboratories practice reflex testing, that is, referral for HER2 FISH only on HER2 IHC score = 2+ cases, whereas others adopt a dual testing approach, that is, HER2 IHC and FISH are performed on all invasive breast carcinomas. Hariri et al 30 suggested that although reflex testing costs less, it may be less effective than a dual testing strategy. They showed that some (n = 6) breast tumors that were HER2 IHC-positive tested HER2 FISHnegative, and others (n = 16) that were HER2 IHCnegative were actually amplified on HER2 FISH testing.…”

“…Hariri et al 30 suggested that although reflex testing costs less, it may be less effective than a dual testing strategy. They showed that some (n = 6) breast tumors that were HER2 IHC-positive tested HER2 FISH-negative, and others (n = 16) that were HER2 IHC-negative were actually amplified on HER2 FISH testing 30 . However, in a resource-constrained setting, reflex testing remains the favored approach.…”

The PTEN Conundrum: How to Target PTEN-Deficient Prostate Cancer

“…It has been suggested that FISH analysis should be performed when inconclusive IHC/IF results are observed. However, a dual testing strategy could also be employed whereby both IHC and FISH are implemented simultaneously, similarly to a new cost-effective HER2 screening strategy developed for invasive breast cancer [ 2 , 64 ]. Interestingly, new artificial intelligence-based algorithms are now being developed for automated detection and localization of PTEN loss, which have shown high accuracy in prostate cancer IHC stained sections and could further streamline PTEN screening [ 65 ].…”