Evaluation of chromosome 17 (Chr-17) polysomy in Her2 FISH-negative metastatic breast cancer (MBC) patients enrolled in a randomized phase III study of paclitaxel and lapatinib
Reviewer: Arpi Thukral, MD
Abramson Cancer Center of the University of Pennsylvania
Ultima Vez Modificado: 31 de mayo del 2008
Presenter: R. B. Livingston
Presenter's Affiliation: Arizona Cancer Center, Tuscon, AZ
Type of Session: Scientific
- Lapatinib is an oral small-molecule dual tyrosine kinase (TK) inhibitor which targets Her2 receptors and is being actively studied in metastatic breast cancer.
- Most clinical trials evaluating lapatinib have shown a benefit for this drug in Her2 FISH-positive breast cancer.
- EGF30001 is a phase III trial designed to test the combination of paclitaxel and lapatinib as first-line therapy in patients with Her 2 FISH-negative MBC, with time to progression (TTP) as the primary endpoint.
- Previous studies have suggested that chromosome 17 polysomy may cause an increase in Her-2 gene expression, which may be associated with a benefit in patients treated with Her2 inhibitors, such as lapatinib.
- Polysomy is a condition when the number of a particular chromosome is not diploid, meaning there may be three or more copies of the chromosome, rather than the expected two copies.
- In a recent trial by Seidman, et. al. (CALGB 9840), a benefit to lapatinib was confined to patients with Her-2 amplification or overexpression. However, a subset analysis by Kauffman et. al (presented at ASCO 2007) suggested that FISH-negative patients with Chr-17 polysomy (defined by Chr-17 centromere average > 2.2) may benefit from Her2 directed therapy such as lapatinib, due to an increase in the number of her 2 gene copies (or gene expression) rather than gene amplification.
- The purpose of this study was to examine the hypothesis that Her2 FISH-negative patients with Chr-17 polysomy may confer an advantage to patients treated with Her2 inhibitors, such as lapatinib.
Materials and Methods
- This is a retrospective study to evaluate a subset of Her2 FISH-negative patients enrolled in a phase III randomized trial of Paclitaxel and Lapatinib, EGF 30001.
- In this trial, 579 patients with metastatic breast cancer with no prior treatment were randomized to Paclitaxel vs. Paclitaxel and Lapatinib.
- The primary endpoints evaluated were progression-free survival (PFS) and response rate (RR) defined by RECIST criteria. PFS was determined by the Kaplan-Meier method and response rates were defined by RECIST criteria.
- Her2 expression level and Chr-17 values were defined using FISH and IHC in a central laboratory. Chromosome 17 polysomy was defined as chromosome centromere average of > 2.2 as defined in the previous study by Kauffman et. al.
- Of the 579 patients enrolled in the trial, 405 patients were found to be Her2 negative by FISH. 11% of these her 2 negative patients (n=44) had Chr-17 polysomy by the definition mentioned above.
- Median PFS in the chr-17 polysomy group was 20.9 weeks vs. 24.4 weeks for lapatinib and paclitaxel (L+P) group and the P (paclitaxel group), respectively. In the non-polysomy group, median PFS was 24.9 weeks vs 23.1 weeks for the L+P group and P groups respectively. No significant differences were seen between these 2 groups by log-rank testing.
- Response rates for the polysomy group were 19% in the L+P group vs. 10% in the P group. This comparison was also not statistically significant.
- The authors concluded that there was no significant difference in PFS or RR between the 2 groups for patients with chr-17 polysomy.
- Therefore, they could not support the hypothesis that chr-17 polysomy is associated with a benefit to the addition of lapatinib to chemotherapy in Her2 negative metastatic breast cancer patients.
- They stated they would not recommend further studies of Her2-directed therapy in patients with polysomy based on these results.
- However, the authors did note that the power of this study was limited to detect improvements in PFS or RR.
- This retrospective subset analysis provides valuable information to prevent the administration of lapatinib to patients who may not benefit from this drug.
- As the authors note, the hypothesis previously generated by Kauffman et. al. was not supported by this current analysis. It is unclear as to why this difference exists between the analyses for this study and that for the CALGB trial.
- One reason for this negative result may be due to the fact that the power of this study to detect differences in PFS and RR was limited by the small number of patients.
- Although polysomy may not be a clinically important factor in determining response to lapatinib, this study does have implications for future research on subsets of Her2 FISH negative patients.
- As outlined by the authors, Her2 gene amplification may not be the only important factor in determining response to lapatinib. Certain subsets of Her2 FISH-negative patients with overexpression of Her2 may also benefit from these Her2 targeted therapies, and therefore it is potentially useful to identify these groups.
- Future research should have increased numbers of patients and should attempt to identify other subsets of Her2 FISH-negative patients who may benefit from lapatinib.
Alternate Chromosome 17 Genes Detect True HER2 Status
Sep 29, 2011 - For patients with breast cancer and polysomy 17, the true gene status of human epidermal growth factor receptor 2 (HER2) can be effectively determined by use of additional chromosome 17 fluorescent in situ hybridization studies for Smith-Magenis syndrome, retinoic acid receptor alpha, and tumor protein p53 genes, rather than the HER2-to-centromeric probe ratio, according to a study published online Sept. 26 in the Journal of Clinical Oncology.
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