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  • br Materials and methods br Results


    Materials and methods
    Discussion Accurate HER2 assessment for patients with invasive breast cancer is crucial to determining which patients may benefit from HER2-targeted therapy. The most recent ASCO/CAP guidelines have again redefined HER2 gene amplification as determined by dual-probe FISH since some studies have reported an increase in number of equivocal cases after the 2013 update [[17], [18], [19]]. Some other studies reported an increase of HER2 positive rate [20]. The current HER2 testing protocol in patients with breast cancer is to assess samples initially with IHC and follow up with FISH for samples with equivocal or discordant results. For this Tamoxifen sale reason, our study focused on cases of IHC 2+. We studied the distribution of FISH results in each group. We also compared the 2013 ASCO/CAP HER2 testing guidelines for breast cancer with the updated 2018 guidelines. The single center retrospective study observed that for IHC 2+ breast cancer patients FISH results of group 5 was the majority, which was consistent with some other studies [21,22]. Michael F.Press et al reported that the proportion of group 2 was 0.4%–0.7% and most group 2 breast cancers had IHC 0/1+ immunostaining [21]. Morgan Ballard et al also demonstrated a low frequency of monosomy cases(group 2), accounting for 1.4%, and only 12.4% of these cases were IHC 3+ [23]. In our study, none of the FISH results met the criteria of group 2. This may due to our small sample size and that all of the breast cancer patients were IHC 2+. Few patients were in group 3, which was consistent with several recent studies [[21], [22], [23]]. And we also found that patients in group 4 accounted for a significant portion, which was probably because our patients were all IHC 2 + . The 2018 ASCO/CAP HER2 testing guidelines recommend that FISH results of group 2 to group 4 need to be interpreted combined with IHC. If the IHC result is 2+, the FISH result should be recounted by another observer [16]. In our experience, repeat counting rarely shows different results. Several recent studies also supported this point [17,24]. Thus, the majority of FISH results with breast cancer patients in group 2 and group 4 will be finally interpreted as HER2 negative, FISH results in groups 3 will be interpreted as HER2 positive according to the 2018 ASCO/CAP guidelines. It is conceivable that the negative rate of FISH results will increase according to the new guidelines. In comparing to the results according to the 2013 ASCO/CAP guidelines, the positive rate was the same, the negative rate was increased from 62.5% to 75.8%, and 13.3% changed from equivocal to negative. Our data suggested that the increase in HER2 FISH negative rate according to the 2018 ASCO/CAP guidelines was mainly due to the reclassification of cases in group 4. Bethune GC et al reported that traditional pathological features such as tumor size, tumor grade and nodal involvement of the HER2 equivocal group(group 4) appeared to be intermediate between HER2 positive and HER2 negative tumors [17]. Morgan Ballard et al also supported the concept that the HER2 equivocal cases have features intermediate between HER2 positive and HER2 negative cases [23]. Another study found that cases of group 4 were significantly associated with some worse prognostic factors, such as higher ki67 index, higher tumor grade, more frequent lymph node metastasis, and lower hormone receptor expression compared with HER2 negative cases [24]. In our study, tumor size and Ki67 index of cases in group 4 were higher than in group 5, while nodal involvement and hormone receptor status did not have a significant difference. The reason for these differences between studies is unclear, but may be related to small sample size. Larger sample studies are needed to better identify pathological differences between the newly defined HER2 negative group(group 4) and the original HER2 negative group(group 5). Patients in FISH group 4 were HER2 equivocal according to the 2013 ASCO/CAP guidelines, all of these patients in our studies did not receive Herceptin therapy, nor did the patients in group 5. We compared outcomes between these two groups. Totally 1 patient died in group 4 because of tumor metastasis, 5 patients in group 5 died for the same reason. Survival analysis did not show any difference between these two groups. In trial BCIRG-005/006/007, outcomes of 176 patients in group 4 did not differ from outcomes in group 5, which suggested that patients in group 4 seem to be HER2 not amplified [25]. Although our research sample size and number of events were small, it illustrated the same point. However, further direct randomized controlled trials that compare group 4 patients that receive Herceptin therapy with those who do not may better determine whether group 4 patients can benefit from Herceptin-targeted therapy.