The Dilemma of HER2 Double-equivocal Breast Carcinomas

Genomic Profiling and Implications for Treatment

Caterina Marchiò, Patrizia Dell'Orto, Laura Annaratone, Felipe C Geyer, Tiziana Venesio, Enrico Berrino, Ludovica Verdun di Cantogno, Andrea Garofoli, Nelson Rangel, Laura Casorzo, Carmine dell'Aglio, Patrizia Gugliotta, Elena Trisolini, Alessandra Beano, Francesca Pietribiasi, Renzo Orlassino, Paola Cassoni, Achille Pich, Filippo Montemurro, Marcella Mottolese & 6 others Anne Vincent-Salomon, Frédérique Penault-Llorca, Enzo Medico, Charlotte K Y Ng, Giuseppe Viale, Anna Sapino

Research output: Contribution to journalArticle

Abstract

The American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) 2013 guidelines for HER2 assessment have increased the number of HER2 equivocal breast carcinomas following in situ hybridization reflex testing, that is, HER2 "double equivocal" (equivocal protein expression and equivocal gene copy number). Forty-five double-equivocal carcinomas were subjected to Prosigna analysis. Twenty-seven cases were investigated for the expression of genes found to be differentially expressed between estrogen receptor (ER)-positive/HER2-positive (N=22) and ER-positive/HER2-negative (N=22) control cases. Twenty-nine of the 45 cases were also analyzed by targeted sequencing using a panel of 14 genes. We then explored the pathologic complete response rates in an independent series of double-equivocal carcinoma patients treated with trastuzumab-containing chemotherapy. All cases were ER-positive, with a mean Ki67 of 28%. Double-equivocal carcinomas were predominantly luminal B (76%); 9 cases (20%) were luminal A, and 2 cases (4%) HER2-enriched. The majority (73%) showed a high risk of recurrence by Prosigna, even when the carcinomas were small (<2 cm), node-negative/micrometastatic, and/or grade 2. Double-equivocal carcinomas showed TP53 (6/29, 20%), PIK3CA (3/29, 10%), HER2 (1/29, 3%), and MAP2K4 (1/29, 3%) mutations. Compared with grade-matched ER-positive/HER2-negative breast carcinomas from METABRIC, double-equivocal carcinomas harbored more frequently TP53 mutations and less frequently PIK3CA mutations (P<0.05). No significant differences were observed with grade-matched ER-positive/HER2-positive carcinomas. Lower pathologic complete response rates were observed in double-equivocal compared with HER2-positive patients (10% vs. 60%, P=0.009). Double-equivocal carcinomas are preferentially luminal B and show a high risk of recurrence. A subset of these tumors can be labeled as HER2-enriched by transcriptomic analysis. HER2 mutations can be identified in HER2 double-equivocal cases.

Original languageEnglish
Pages (from-to)1190-1200
Number of pages11
JournalAmerican Journal of Surgical Pathology
Volume42
Issue number9
DOIs
Publication statusPublished - Sep 2018

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Breast Neoplasms
Carcinoma
Estrogen Receptors
Mutation
Therapeutics
Recurrence
Gene Dosage
In Situ Hybridization
Reflex
Guidelines
Gene Expression
Drug Therapy
Genes
Neoplasms
Proteins

Cite this

The Dilemma of HER2 Double-equivocal Breast Carcinomas : Genomic Profiling and Implications for Treatment. / Marchiò, Caterina; Dell'Orto, Patrizia; Annaratone, Laura; Geyer, Felipe C; Venesio, Tiziana; Berrino, Enrico; Verdun di Cantogno, Ludovica; Garofoli, Andrea; Rangel, Nelson; Casorzo, Laura; dell'Aglio, Carmine; Gugliotta, Patrizia; Trisolini, Elena; Beano, Alessandra; Pietribiasi, Francesca; Orlassino, Renzo; Cassoni, Paola; Pich, Achille; Montemurro, Filippo; Mottolese, Marcella; Vincent-Salomon, Anne; Penault-Llorca, Frédérique; Medico, Enzo; Ng, Charlotte K Y; Viale, Giuseppe; Sapino, Anna.

In: American Journal of Surgical Pathology, Vol. 42, No. 9, 09.2018, p. 1190-1200.

Research output: Contribution to journalArticle

Marchiò, C, Dell'Orto, P, Annaratone, L, Geyer, FC, Venesio, T, Berrino, E, Verdun di Cantogno, L, Garofoli, A, Rangel, N, Casorzo, L, dell'Aglio, C, Gugliotta, P, Trisolini, E, Beano, A, Pietribiasi, F, Orlassino, R, Cassoni, P, Pich, A, Montemurro, F, Mottolese, M, Vincent-Salomon, A, Penault-Llorca, F, Medico, E, Ng, CKY, Viale, G & Sapino, A 2018, 'The Dilemma of HER2 Double-equivocal Breast Carcinomas: Genomic Profiling and Implications for Treatment', American Journal of Surgical Pathology, vol. 42, no. 9, pp. 1190-1200. https://doi.org/10.1097/PAS.0000000000001100
Marchiò, Caterina ; Dell'Orto, Patrizia ; Annaratone, Laura ; Geyer, Felipe C ; Venesio, Tiziana ; Berrino, Enrico ; Verdun di Cantogno, Ludovica ; Garofoli, Andrea ; Rangel, Nelson ; Casorzo, Laura ; dell'Aglio, Carmine ; Gugliotta, Patrizia ; Trisolini, Elena ; Beano, Alessandra ; Pietribiasi, Francesca ; Orlassino, Renzo ; Cassoni, Paola ; Pich, Achille ; Montemurro, Filippo ; Mottolese, Marcella ; Vincent-Salomon, Anne ; Penault-Llorca, Frédérique ; Medico, Enzo ; Ng, Charlotte K Y ; Viale, Giuseppe ; Sapino, Anna. / The Dilemma of HER2 Double-equivocal Breast Carcinomas : Genomic Profiling and Implications for Treatment. In: American Journal of Surgical Pathology. 2018 ; Vol. 42, No. 9. pp. 1190-1200.
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T1 - The Dilemma of HER2 Double-equivocal Breast Carcinomas

T2 - Genomic Profiling and Implications for Treatment

AU - Marchiò, Caterina

AU - Dell'Orto, Patrizia

AU - Annaratone, Laura

AU - Geyer, Felipe C

AU - Venesio, Tiziana

AU - Berrino, Enrico

AU - Verdun di Cantogno, Ludovica

AU - Garofoli, Andrea

AU - Rangel, Nelson

AU - Casorzo, Laura

AU - dell'Aglio, Carmine

AU - Gugliotta, Patrizia

AU - Trisolini, Elena

AU - Beano, Alessandra

AU - Pietribiasi, Francesca

AU - Orlassino, Renzo

AU - Cassoni, Paola

AU - Pich, Achille

AU - Montemurro, Filippo

AU - Mottolese, Marcella

AU - Vincent-Salomon, Anne

AU - Penault-Llorca, Frédérique

AU - Medico, Enzo

AU - Ng, Charlotte K Y

AU - Viale, Giuseppe

AU - Sapino, Anna

PY - 2018/9

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N2 - The American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) 2013 guidelines for HER2 assessment have increased the number of HER2 equivocal breast carcinomas following in situ hybridization reflex testing, that is, HER2 "double equivocal" (equivocal protein expression and equivocal gene copy number). Forty-five double-equivocal carcinomas were subjected to Prosigna analysis. Twenty-seven cases were investigated for the expression of genes found to be differentially expressed between estrogen receptor (ER)-positive/HER2-positive (N=22) and ER-positive/HER2-negative (N=22) control cases. Twenty-nine of the 45 cases were also analyzed by targeted sequencing using a panel of 14 genes. We then explored the pathologic complete response rates in an independent series of double-equivocal carcinoma patients treated with trastuzumab-containing chemotherapy. All cases were ER-positive, with a mean Ki67 of 28%. Double-equivocal carcinomas were predominantly luminal B (76%); 9 cases (20%) were luminal A, and 2 cases (4%) HER2-enriched. The majority (73%) showed a high risk of recurrence by Prosigna, even when the carcinomas were small (<2 cm), node-negative/micrometastatic, and/or grade 2. Double-equivocal carcinomas showed TP53 (6/29, 20%), PIK3CA (3/29, 10%), HER2 (1/29, 3%), and MAP2K4 (1/29, 3%) mutations. Compared with grade-matched ER-positive/HER2-negative breast carcinomas from METABRIC, double-equivocal carcinomas harbored more frequently TP53 mutations and less frequently PIK3CA mutations (P<0.05). No significant differences were observed with grade-matched ER-positive/HER2-positive carcinomas. Lower pathologic complete response rates were observed in double-equivocal compared with HER2-positive patients (10% vs. 60%, P=0.009). Double-equivocal carcinomas are preferentially luminal B and show a high risk of recurrence. A subset of these tumors can be labeled as HER2-enriched by transcriptomic analysis. HER2 mutations can be identified in HER2 double-equivocal cases.

AB - The American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) 2013 guidelines for HER2 assessment have increased the number of HER2 equivocal breast carcinomas following in situ hybridization reflex testing, that is, HER2 "double equivocal" (equivocal protein expression and equivocal gene copy number). Forty-five double-equivocal carcinomas were subjected to Prosigna analysis. Twenty-seven cases were investigated for the expression of genes found to be differentially expressed between estrogen receptor (ER)-positive/HER2-positive (N=22) and ER-positive/HER2-negative (N=22) control cases. Twenty-nine of the 45 cases were also analyzed by targeted sequencing using a panel of 14 genes. We then explored the pathologic complete response rates in an independent series of double-equivocal carcinoma patients treated with trastuzumab-containing chemotherapy. All cases were ER-positive, with a mean Ki67 of 28%. Double-equivocal carcinomas were predominantly luminal B (76%); 9 cases (20%) were luminal A, and 2 cases (4%) HER2-enriched. The majority (73%) showed a high risk of recurrence by Prosigna, even when the carcinomas were small (<2 cm), node-negative/micrometastatic, and/or grade 2. Double-equivocal carcinomas showed TP53 (6/29, 20%), PIK3CA (3/29, 10%), HER2 (1/29, 3%), and MAP2K4 (1/29, 3%) mutations. Compared with grade-matched ER-positive/HER2-negative breast carcinomas from METABRIC, double-equivocal carcinomas harbored more frequently TP53 mutations and less frequently PIK3CA mutations (P<0.05). No significant differences were observed with grade-matched ER-positive/HER2-positive carcinomas. Lower pathologic complete response rates were observed in double-equivocal compared with HER2-positive patients (10% vs. 60%, P=0.009). Double-equivocal carcinomas are preferentially luminal B and show a high risk of recurrence. A subset of these tumors can be labeled as HER2-enriched by transcriptomic analysis. HER2 mutations can be identified in HER2 double-equivocal cases.

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DO - 10.1097/PAS.0000000000001100

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