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Amount of HER-2 gene amplification as assessed by FISH is linked to magnitude of survival benefit in patients with locally advanced breast cancer [Íîâîñòü äîáàâëåíà - 17.12.2007]

 Patients with locally advanced breast cancers whose tumours contain high numbers of copies of the gene for the human epidermal growth factor receptor 2 (HER-2), as assessed by fluorescence in situ hybridization (FISH), are more likely to have a complete response to treatment with an antibody to the receptor than patients with fewer copies of the gene in their tumours.
 
Around 20-30% of breast tumours contain several copies of the HER-2 gene and patients affected by this genetic lesion are more likely to relapse quickly and die sooner than non-affected women. Treatment with trastuzumab (Herceptin), a recombinant monoclonal antibody against HER-2, can significantly improve survival and reduce the risk of recurrence in women with various stages of HER2-positive breast cancer, but it is not clear exactly how the extent of overexpression of this gene relates to the survival benefit of treatment.
 
As part of the clinical decision-making process for administration of trastuzumab, all women with breast cancer undergo immunohistochemistry (IHC) or FISH on samples from their tumours to ascertain whether or not HER-2 is overexpressed. But Dr Arnould and colleagues wanted to better understand how the results of these tests relate to outcomes of treatment. They designed a study to ascertain whether there is a relationship between the specific level of HER-2 amplification, as assessed by FISH, and the rate of pathological complete response (absence of evidence of tumour in the breast or lymph nodes) in women diagnosed with HER-2–positive locally advanced breast cancer who were treated preoperatively with a combination of trastuzumab plus chemotherapy.
 
For the purpose of the study, breast biopsies were taken from 93 patients with HER-2–positive stage II/III breast cancer, most of whom had been enrolled in two clinical trials: TAXHER01 and GETNA01. All patients had received trastuzumab in combination with either docetaxel with or without carboplatin before undergoing surgery.
 
Although the patients had initially been tested for HER-2 status using IHC, and all had the most positive result, 3+, for the purposes of this study, HER-2 status was analyzed retrospectively again using both IHC and FISH. The HER-2 scores obtained by FISH were subsequently compared with several variables including treatment regimen, patient age, tumour staging, and pathological complete response rates, to determine if FISH testing could predict more accurately response to treatment than current methods.
 
After doing the analyses, the investigators found that the only variable related to pathological complete response was the level of HER-2 amplification as assessed by FISH. Pathological complete response was seen significantly more frequently in high-amplification FISH tumours than in low-amplification tumours---a degree of subclassification that would not have been possible using IHC. “Therefore,” the researchers conclude, “FISH may be a more accurate HER-2 testing method to predict pathologic complete response in the neoadjuvant setting [than IHC].” This technique may also help select those patients for whom trastuzumab confers the greatest clinical benefit, they add.
 
“To our knowledge, this is the first study to show a positive correlation between level of HER-2 amplification, as assessed by FISH, and rate of pathologic complete response to trastuzumab-based neoadjuvant treatment in locally advanced HER-2–positive breast tumors,” note the authors. “Although the number of cases included in this study is not large and despite the size of the confidence intervals, our analysis shows statistically significant differences between the two groups of amplification in term of pCR. These results have certainly to be confirmed in the future in a larger series.”
 
The study did not evaluate survival, but the researchers suggest that the fact that FISH and IHC positivity have different relationships to the likelihood of pathological complete response highlights the need to standardise these procedures. “In the neoadjuvant setting, initial IHC screening (which would be negative for the majority for tumours) could be used, followed by FISH testing for IHC 2+ or 3+ tumours. This supplementary FISH testing would exclude false-positive tumors by confirming HER-2 amplification and precisely determine the level of HER-2 amplification,” they suggest.
 
However, the researchers caution, it remains unknown whether a relationship exists between pathological complete response, HER-2 amplification as assessed by FISH, and postoperative survival rates.  
  
 
Pathologic complete response to trastuzumab-based neoadjuvant therapy is related to the level of HER-2 amplification.
Arnould L, Arveux P, Couturier J, Gelly-Marty M, Loustalot C, Ettore F, Sagan C, Antoine M, Penault-Llorca F, Vasseur B, Fumoleau P, Coudert BP.

Clin Cancer Res

November 1, 2007, 13: 6404-09