February 2013, Vol 2, No 1

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Mayo Clinic Researchers Propose Screening Algorithm for HER2 in Esophageal Cancer

The preferred screening test for HER2 status in surgical esophageal adenocarcinoma specimens is immunohistochemistry (IHC), with fluorescence in situ hybridization (FISH) restricted to cases with an indeterminate (2+) IHC score, according to investigators from the Mayo Clinic, Rochester, MN, who proposed a testing algorithm at the 2013 GI Cancers Symposium.

“Our findings support a testing algorithm for resected esophageal adenocarcinomas where IHC is used for initial screening, and FISH testing is restricted to cases with equivocal IHC results,” said Harry H. Yoon, MD, lead investigator.

HER2 oncoprotein overexpression is a known driver of tumor aggressiveness in esophageal adenocarcinoma; the HER2 gene is amplified in 7% to 22% of cases. HER2-positive patients treated with trastuzumab have improved survival; therefore, it is important to test for HER2 with IHC or FISH, he said.

A previous exploratory, single-center study suggested that IHC is more predictive of trastuzumab benefit than FISH, but this superiority has not been established, and each testing method has its advantages. IHC is faster, less labor intensive, and less expensive (due to lower cost of reagents). FISH, on the other hand, is less vulnerable to tissue artifacts and offers a more objective scoring system, Yoon said.

The current study evaluated the concordance of HER2 test results between IHC and FISH assays in 673 unselected surgically resected esophageal adenocarcinomas. Each tumor was evaluated by IHC in parallel with FISH in a blinded manner using FDA-approved assays. A consensus IHC score was determined by 2 pathologists using tumor-specific criteria (negative, 0-1+; equivocal, 2+; positive, 3+). Gene amplification by FISH was defined as a HER2/CEP17 (chromosome 17) ratio ?2.

By FISH, 17% of tumors tested positive. By IHC, 13% tested positive, 25% were indeterminate, 23% were negative by 1+, and 39% were negative by a 2+ score.

Among the 89 patients with IHC 3+ scores, 79 were FISH+ and 10 were FISH–. Of the 167 indeterminate (2+) patients, 21 were FISH+ and 146 were FISH–. Of the 417 IHC– patients, 16 were FISH+ and 401 were FISH–.
This yielded a concordance rate of 95% between FISH and IHC 3+ patients and IHC–negative patients, and a 74% concordance rate when IHC 2+ patients were included.

HER2 amplification was detected in 89% of IHC 3+ cases, 13% of IHC 2+ cases, and 4% of IHC 0-1+ cases (Table). Accordingly, using FISH as the reference standard, the positive predictive value of a positive IHC test (3+) was 89%, and the negative predictive value of a negative test was 96%. Importantly, the positive predictive value of an equivocal IHC score (2+) for detecting HER2 amplification was 13%, he said.

The sensitivity of IHC 2+ or 3+ was calculated to be 89%, and the specificity of IHC 3+ was 98%.

“In the largest study to date comparing HER2 testing methods in esophageal adenocarcinoma, a negative IHC result nearly excludes the presence of gene amplification by FISH,” Yoon said, “whereas a positive result (3+) strongly predicts for the presence of amplification, and an equivocal IHC result (2+) is a weak predictor.



Uncategorized - February 20, 2013

Molecular Subtyping Reclassifies Early Breast Cancer in a Proportion of Patients

Molecular subtyping of early breast cancers using MammaPrint and BluePrint allows precise and accurate prediction of the molecular phenotype of the disease, which has the potential to guide selection of personalized therapy if the tests are used prospectively. A retrospective study of 208 tumor samples found that molecular subtyping with [ Read More ]

Uncategorized - February 20, 2013

Women With Triple-Negative Breast Cancer Highly Likely to Carry BRCA1 Gene

Triple-negative breast cancer (TNBC) was strongly associated with BRCA1 status, but not with BRCA2 status, in a large study of medically insured women. The study showed that the number of patients with BRCA mutations with a TNBC profile is statistically significant. The authors of this poster, presented at the 2012 [ Read More ]