Background: HER-2/neu is over-expressed in approximately 25% of primary invasive breast cancers and selection of patients for consideration of trastuzumab is a critical step in defining the treatment plan. We have previously reported that quantitative measurements of HER2 protein expression (H2T) and HER2 homodimers (H2D) using the HERmark assay identifies sub-populations of “HER2-positive” patients (by IHC and/or FISH) that have different clinical outcomes on trastuzumab (Leitzel, ASCO 2008; Lipton, SABCS 2008). Previous studies report up to a 20 % discordance in HER2 status using conventional IHC or FISH analysis between the primary and metastatic breast tumors. Here we correlate HER2 total and homodimer levels in matched primary and metastatic tissue from the same patient. Methods: 27 patients had matched primary and metastatic FFPE (formalin-fixed, paraffin-embedded) specimens tested in the HERmark assay to quantitate and compare their H2T and H2D expression levels. Results: FFPE tissue was available from 27 primary breast cancers and metachronous metastatic sites. Metastatic lesions included 7 skin, 5 lymph node, 3 bone, 3 pleura, 2 brain, 2 chest wall, and 5 other soft tissue lesions. The median elapsed time between matched primary and metastatic sites was 71 mo. (range 9-137 mo). During the time period between the primary specimen harvest and the metastatic biopsy, 6 patients were treated with chemotherapy alone, 10 received hormonal therapy without trastuzumab, 3 patients received trastuzumab, and 3 received no treatment. Treatment was not known for 5 patients. For the whole population, there was a weak to moderate positive correlation between primary and metastatic cancers with H2T (r2=0.36, p<0.001) and for H2D (r2=0.27, p<0.006). Using the optimized time to progression (TTP) positional scanning cutpoints for H2T and H2D defined in our previous reports, 4/20 patients (20%) converted from low to high, and 1/7 (14%) converted from high to low H2T. Using the H2D cutpoint, 7/15 patients (47%) converted from low to high, and 3/12 (25%) converted from high to low H2D. Overall discordance between primary and metastatic sites was 19% for H2T, and 37% for H2D. Conclusions: HERmark analysis of matching primary and metastatic breast cancers revealed 19% discordance for H2T, and 37% for H2D. The most frequent conversion was from low HER2 in the primary tissue to high HER2 in the metastatic site.

Discordant HER2 Total and HER2 Homodimer Levels by HERmark Analysis in Matched Primary and Metastatic Breast Cancer FFPE Specimens / Leitzel, K; Conte, Pierfranco; Guarneri, Valentina; Barbieri, Elena; Huang, W; Ali, Sm; Haddad, M; Sperinde, J; Lie, Y; Weidler, J; Bates, M; Lipton, A.. - In: CANCER RESEARCH. - ISSN 0008-5472. - STAMPA. - 69, s3:(2009), pp. 635S-635S. ((Intervento presentato al convegno 32nd Annual San Antonio Breast Cancer Symposium tenutosi a San Antonio, TX nel DEC 09-13, 2009.

Discordant HER2 Total and HER2 Homodimer Levels by HERmark Analysis in Matched Primary and Metastatic Breast Cancer FFPE Specimens.

CONTE, Pierfranco;GUARNERI, Valentina;BARBIERI, Elena;
2009

Abstract

Background: HER-2/neu is over-expressed in approximately 25% of primary invasive breast cancers and selection of patients for consideration of trastuzumab is a critical step in defining the treatment plan. We have previously reported that quantitative measurements of HER2 protein expression (H2T) and HER2 homodimers (H2D) using the HERmark assay identifies sub-populations of “HER2-positive” patients (by IHC and/or FISH) that have different clinical outcomes on trastuzumab (Leitzel, ASCO 2008; Lipton, SABCS 2008). Previous studies report up to a 20 % discordance in HER2 status using conventional IHC or FISH analysis between the primary and metastatic breast tumors. Here we correlate HER2 total and homodimer levels in matched primary and metastatic tissue from the same patient. Methods: 27 patients had matched primary and metastatic FFPE (formalin-fixed, paraffin-embedded) specimens tested in the HERmark assay to quantitate and compare their H2T and H2D expression levels. Results: FFPE tissue was available from 27 primary breast cancers and metachronous metastatic sites. Metastatic lesions included 7 skin, 5 lymph node, 3 bone, 3 pleura, 2 brain, 2 chest wall, and 5 other soft tissue lesions. The median elapsed time between matched primary and metastatic sites was 71 mo. (range 9-137 mo). During the time period between the primary specimen harvest and the metastatic biopsy, 6 patients were treated with chemotherapy alone, 10 received hormonal therapy without trastuzumab, 3 patients received trastuzumab, and 3 received no treatment. Treatment was not known for 5 patients. For the whole population, there was a weak to moderate positive correlation between primary and metastatic cancers with H2T (r2=0.36, p<0.001) and for H2D (r2=0.27, p<0.006). Using the optimized time to progression (TTP) positional scanning cutpoints for H2T and H2D defined in our previous reports, 4/20 patients (20%) converted from low to high, and 1/7 (14%) converted from high to low H2T. Using the H2D cutpoint, 7/15 patients (47%) converted from low to high, and 3/12 (25%) converted from high to low H2D. Overall discordance between primary and metastatic sites was 19% for H2T, and 37% for H2D. Conclusions: HERmark analysis of matching primary and metastatic breast cancers revealed 19% discordance for H2T, and 37% for H2D. The most frequent conversion was from low HER2 in the primary tissue to high HER2 in the metastatic site.
69, s3
635S
635S
Leitzel, K; Conte, Pierfranco; Guarneri, Valentina; Barbieri, Elena; Huang, W; Ali, Sm; Haddad, M; Sperinde, J; Lie, Y; Weidler, J; Bates, M; Lipton, A.
Discordant HER2 Total and HER2 Homodimer Levels by HERmark Analysis in Matched Primary and Metastatic Breast Cancer FFPE Specimens / Leitzel, K; Conte, Pierfranco; Guarneri, Valentina; Barbieri, Elena; Huang, W; Ali, Sm; Haddad, M; Sperinde, J; Lie, Y; Weidler, J; Bates, M; Lipton, A.. - In: CANCER RESEARCH. - ISSN 0008-5472. - STAMPA. - 69, s3:(2009), pp. 635S-635S. ((Intervento presentato al convegno 32nd Annual San Antonio Breast Cancer Symposium tenutosi a San Antonio, TX nel DEC 09-13, 2009.
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