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Immunohistochemistry and fluorescence in situ hybridization assessment of HER2 in clinical trials of adjuvant therapy for breast cancer (NCCTG N9831, BCIRG 006, and BCIRG 005).

Perez EA, Press MF, Dueck AC, Jenkins RB, Kim C, Chen B, Villalobos I, Paik S, Buyse M, Wiktor AE, Meyer R, Finnigan M, Zujewski J, Shing M, Stern HM, Lingle WL, Reinholz MM, Slamon DJ - Breast Cancer Res. Treat. (2013)

Bottom Line: Upon adjudication, consensus was reached on 16/30 and 18/30 of discordant IHC and FISH cases, respectively, resulting in overall concordance rates of 96 and 97 %.Among 53 N9831 patients with HER2-normal disease adjudicated as IHC-/FISH-(although locally positive), there was a non-statistically significant improvement in disease-free survival with concurrent trastuzumab compared to chemotherapy alone (adjusted hazard ratio 0.34; 95 % CI, 0.11-1.05; p = 0.06).Agreement was improved at adjudication (96 %).

View Article: PubMed Central - PubMed

Affiliation: Mayo Clinic, 4500 San Pablo Road S., Jacksonville, FL 32224, USA. perez.edith@mayo.edu

ABSTRACT
A comprehensive, blinded, pathology evaluation of HER2 testing in HER2-positive/negative breast cancers was performed among three central laboratories. Immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) analyses were performed on 389 tumor blocks from three large adjuvant trials: N9831, BCIRG-006, and BCIRG-005. In 123 cases, multiple blocks were examined. HER2 status was defined according to FDA-approved guidelines and was independently re-assessed at each site. Discordant cases were adjudicated at an on-site, face-to-face meeting. Results across three independent pathologists were concordant by IHC in 351/381 (92 %) and FISH in 343/373 (92 %) blocks. Upon adjudication, consensus was reached on 16/30 and 18/30 of discordant IHC and FISH cases, respectively, resulting in overall concordance rates of 96 and 97 %. Among 155 HER2-negative blocks, HER2 status was confirmed in 153 (99 %). In the subset of 102 HER2-positive patients from N9831/BCIRG-006, primary blocks from discordant cases were selected, especially those with discordant test between local and central laboratories. HER2 status was confirmed in 73 (72 %) of these cases. Among 118 and 113 cases with IHC and FISH results and >1 block evaluable, block-to-block variability/heterogeneity in HER2 results was seen in 10 and 5 %, respectively. IHC-/FISH- was confirmed for 57/59 (97 %) primary blocks from N9831 (locally positive, but centrally negative); however, 5/22 (23 %) secondary blocks showed HER2 positivity. Among 53 N9831 patients with HER2-normal disease adjudicated as IHC-/FISH-(although locally positive), there was a non-statistically significant improvement in disease-free survival with concurrent trastuzumab compared to chemotherapy alone (adjusted hazard ratio 0.34; 95 % CI, 0.11-1.05; p = 0.06). There were similar agreements for IHC and FISH among pathologists (92 % each). Agreement was improved at adjudication (96 %). HER2 tumor heterogeneity appears to partially explain discordant results in cases initially tested as positive and subsequently called negative.

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Kaplan–Meier curves of DFS in N9831 patients with IHC−/FISH− disease. All patients had IHC−/FISH− disease by central review and all blocks adjudicated in the current study as IHC−/FISH−
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Fig3: Kaplan–Meier curves of DFS in N9831 patients with IHC−/FISH− disease. All patients had IHC−/FISH− disease by central review and all blocks adjudicated in the current study as IHC−/FISH−

Mentions: Of the original 103 patients identified in N9831 as locally HER2-positive but centrally HER2-normal, 59 blocks were evaluable out of 62 cases with tissue. Three cases were technical failures due to insufficient tumor tissue. Of the remaining 59 patients, 53 (90 %) had disease adjudicated as IHC-negative/FISH-negative for HER2. Among 22 of these 53 with more than one block available for analysis, 1/22 (5 %) was adjudicated as HER2-positive (by either IHC or FISH) in the primary block and 4/22 (18 %) had a second block adjudicated as HER2-positive (by either IHC or FISH) (Tables 2, 3). Among the 53 N9831 HER2-normal cases adjudicated as IHC-negative and FISH-negative (despite a prior HER2-positive test locally), there was an unadjusted trend in improvement in DFS associated with trastuzumab given concurrently with paclitaxel after doxorubicin/cyclophosphamide compared to chemotherapy alone (HR = 0.31, p = 0.06, 95 % CI 0.11–0.91; AC-T: 23 pts, ten events; AC-TH: 30 pts, five events). When adjusted for hormone receptor and nodal status, there was a non-statistically significant improvement in DFS associated with trastuzumab administered concurrently with chemotherapy compared to chemotherapy alone, based on a relatively small number of events (HR = 0.34, p = 0.06, 95 % CI 0.11–1.05; AC-T: 23 pts, ten events; AC-TH: 30 pts, five events) (Fig. 3). When considering only those few cases in which two blocks were both adjudicated as IHC-negative/FISH-negative (n = 17/53), a similar non-significant trend in DFS improvement was observed (HR = 0.29, p = 0.16, 95 % CI 0.05–1.65; AC-T: 8 pts, four events; AC-TH: 9 pts, two events).Fig. 3


Immunohistochemistry and fluorescence in situ hybridization assessment of HER2 in clinical trials of adjuvant therapy for breast cancer (NCCTG N9831, BCIRG 006, and BCIRG 005).

Perez EA, Press MF, Dueck AC, Jenkins RB, Kim C, Chen B, Villalobos I, Paik S, Buyse M, Wiktor AE, Meyer R, Finnigan M, Zujewski J, Shing M, Stern HM, Lingle WL, Reinholz MM, Slamon DJ - Breast Cancer Res. Treat. (2013)

Kaplan–Meier curves of DFS in N9831 patients with IHC−/FISH− disease. All patients had IHC−/FISH− disease by central review and all blocks adjudicated in the current study as IHC−/FISH−
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3585916&req=5

Fig3: Kaplan–Meier curves of DFS in N9831 patients with IHC−/FISH− disease. All patients had IHC−/FISH− disease by central review and all blocks adjudicated in the current study as IHC−/FISH−
Mentions: Of the original 103 patients identified in N9831 as locally HER2-positive but centrally HER2-normal, 59 blocks were evaluable out of 62 cases with tissue. Three cases were technical failures due to insufficient tumor tissue. Of the remaining 59 patients, 53 (90 %) had disease adjudicated as IHC-negative/FISH-negative for HER2. Among 22 of these 53 with more than one block available for analysis, 1/22 (5 %) was adjudicated as HER2-positive (by either IHC or FISH) in the primary block and 4/22 (18 %) had a second block adjudicated as HER2-positive (by either IHC or FISH) (Tables 2, 3). Among the 53 N9831 HER2-normal cases adjudicated as IHC-negative and FISH-negative (despite a prior HER2-positive test locally), there was an unadjusted trend in improvement in DFS associated with trastuzumab given concurrently with paclitaxel after doxorubicin/cyclophosphamide compared to chemotherapy alone (HR = 0.31, p = 0.06, 95 % CI 0.11–0.91; AC-T: 23 pts, ten events; AC-TH: 30 pts, five events). When adjusted for hormone receptor and nodal status, there was a non-statistically significant improvement in DFS associated with trastuzumab administered concurrently with chemotherapy compared to chemotherapy alone, based on a relatively small number of events (HR = 0.34, p = 0.06, 95 % CI 0.11–1.05; AC-T: 23 pts, ten events; AC-TH: 30 pts, five events) (Fig. 3). When considering only those few cases in which two blocks were both adjudicated as IHC-negative/FISH-negative (n = 17/53), a similar non-significant trend in DFS improvement was observed (HR = 0.29, p = 0.16, 95 % CI 0.05–1.65; AC-T: 8 pts, four events; AC-TH: 9 pts, two events).Fig. 3

Bottom Line: Upon adjudication, consensus was reached on 16/30 and 18/30 of discordant IHC and FISH cases, respectively, resulting in overall concordance rates of 96 and 97 %.Among 53 N9831 patients with HER2-normal disease adjudicated as IHC-/FISH-(although locally positive), there was a non-statistically significant improvement in disease-free survival with concurrent trastuzumab compared to chemotherapy alone (adjusted hazard ratio 0.34; 95 % CI, 0.11-1.05; p = 0.06).Agreement was improved at adjudication (96 %).

View Article: PubMed Central - PubMed

Affiliation: Mayo Clinic, 4500 San Pablo Road S., Jacksonville, FL 32224, USA. perez.edith@mayo.edu

ABSTRACT
A comprehensive, blinded, pathology evaluation of HER2 testing in HER2-positive/negative breast cancers was performed among three central laboratories. Immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) analyses were performed on 389 tumor blocks from three large adjuvant trials: N9831, BCIRG-006, and BCIRG-005. In 123 cases, multiple blocks were examined. HER2 status was defined according to FDA-approved guidelines and was independently re-assessed at each site. Discordant cases were adjudicated at an on-site, face-to-face meeting. Results across three independent pathologists were concordant by IHC in 351/381 (92 %) and FISH in 343/373 (92 %) blocks. Upon adjudication, consensus was reached on 16/30 and 18/30 of discordant IHC and FISH cases, respectively, resulting in overall concordance rates of 96 and 97 %. Among 155 HER2-negative blocks, HER2 status was confirmed in 153 (99 %). In the subset of 102 HER2-positive patients from N9831/BCIRG-006, primary blocks from discordant cases were selected, especially those with discordant test between local and central laboratories. HER2 status was confirmed in 73 (72 %) of these cases. Among 118 and 113 cases with IHC and FISH results and >1 block evaluable, block-to-block variability/heterogeneity in HER2 results was seen in 10 and 5 %, respectively. IHC-/FISH- was confirmed for 57/59 (97 %) primary blocks from N9831 (locally positive, but centrally negative); however, 5/22 (23 %) secondary blocks showed HER2 positivity. Among 53 N9831 patients with HER2-normal disease adjudicated as IHC-/FISH-(although locally positive), there was a non-statistically significant improvement in disease-free survival with concurrent trastuzumab compared to chemotherapy alone (adjusted hazard ratio 0.34; 95 % CI, 0.11-1.05; p = 0.06). There were similar agreements for IHC and FISH among pathologists (92 % each). Agreement was improved at adjudication (96 %). HER2 tumor heterogeneity appears to partially explain discordant results in cases initially tested as positive and subsequently called negative.

Show MeSH
Related in: MedlinePlus