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The Dilemma of HER2 Double-equivocal Breast Carcinomas: Genomic Profiling and Implications for Treatment.

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.

SUBMITTER: Marchio C

PROVIDER: S-EPMC6110371 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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The Dilemma of HER2 Double-equivocal Breast Carcinomas: Genomic Profiling and Implications for Treatment.

Marchiò Caterina C Dell'Orto Patrizia P Annaratone Laura L Geyer Felipe C FC Venesio Tiziana T Berrino Enrico E Verdun di Cantogno Ludovica L Garofoli Andrea A Rangel Nelson N Casorzo Laura L dell'Aglio Carmine C Gugliotta Patrizia P Trisolini Elena E Beano Alessandra A Pietribiasi Francesca F Orlassino Renzo R Cassoni Paola P Pich Achille A Montemurro Filippo F Mottolese Marcella M Vincent-Salomon Anne A Penault-Llorca Frédérique F Medico Enzo E Ng Charlotte K Y CKY Viale Giuseppe G Sapino Anna A

The American journal of surgical pathology 20180901 9

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 expr ...[more]

PMID: 29975246

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Project description:PurposeThe 2018 American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guideline on HER2 testing in breast cancer permits reclassification of cases with HER2-equivocal results by FISH. The impact of such reclassification is unclear. We sought to determine the proportion of HER2-equivocal cases that are reclassified as HER2-negative and the impact of anti-HER2 therapy on survival in HER2-equivocal cases.MethodsWe reviewed medical records of breast cancer patients who had HER2 testing by fluorescence in stitu hybridization (FISH) and immunohistochemistry (IHC) performed or verified at The University of Texas MD Anderson Cancer Center during April 2014 through March 2018 and had equivocal results according to the 2013 ASCO/CAP guideline. The population was divided into 2 cohorts according to whether the biopsy specimen analyzed came from primary or from recurrent or metastatic disease. HER2 status was reclassified according to the 2018 ASCO/CAP guideline. Overall survival (OS) and event-free survival (EFS) were calculated using the Kaplan-Meier method, and the relationship between anti-HER2 therapy and clinical outcomes was assessed.ResultsWe identified 139 cases with HER2-equivocal results according to the 2013 ASCO/CAP guideline: 90 cases of primary disease and 49 cases of recurrent/metastatic disease. Per the 2018 ASCO/CAP guideline, these cases were classified as follows: overall, HER2-negative 112 cases (80%), HER2-positive 1 (1%), and unknown 26 (19%); primary cohort, HER2-negative 85 (94%), HER2-positive 1 (1%), unknown 4 (4%); and recurrent/metastatic, HER2-negative 27 (55%) and unknown 22 (45%). Five patients in the primary-disease cohort and 1 patient in the recurrent/metastatic-disease cohort received anti-HER2 therapy. There was no significant association between anti-HER2 therapy and OS or EFS in either cohort (primary disease: OS, p = 0.67; EFS, p = 0.49; recurrent/metastatic-disease, OS, p = 0.61; EFS, p = 0.78.ConclusionsThe majority of HER2-equivocal breast cancer cases were reclassified as HER2-negative per the 2018 ASCO/CAP guideline. No association between anti-HER2 therapy and OS or EFS was observed. HER2-equivocal cases seem to have clinical behavior similar to that of HER2-negative breast cancers.

Project description:ImportanceThe 2013/2014 American Society of Clinical Oncology and College of American Pathologists (ASCO-CAP) guidelines for HER2 testing by fluorescence in situ hybridization (FISH) designated an "equivocal" category (average HER2 copies per tumor cell ≥4-6 with HER2/CEP17 ratio <2.0) to be resolved as negative or positive by assessments with alternative control probes. Approximately 4% to 12% of all invasive breast cancers are characterized as HER2-equivocal based on FISH.ObjectiveTo evaluate the following hypotheses: (1) genetic loci used as alternative controls are heterozygously deleted in a substantial proportion of breast cancers; (2) use of these loci for assessment of HER2 by FISH leads to false-positive assessments; and (3) these HER2 false-positive breast cancer patients have outcomes that do not differ from clinical outcomes for patients with HER2-negative breast cancer.Design, setting, and participantsWe retrospectively assessed the use of chromosome 17 p-arm and q-arm alternative control genomic sites (TP53, D17S122, SMS, RARA, TOP2A), as recommended by the 2013/2014 ASCO-CAP guidelines for HER2 testing, in patients whose data were available through Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) and whose tissues were available through the Breast Cancer International Research Group clinical trials. We used data from an international cohort database of invasive breast cancers (1980 participants) and international clinical trial of adjuvant chemotherapy in invasive, node-positive breast cancer patients.Main outcomes and measuresThe primary objectives were to (1) assess frequency of heterozygous deletions in chromosome 17 genomic sites used as FISH internal controls for evaluation of HER2 status among HER2-equivocal cancers; (2) characterize impact of using deleted sites for determination of HER2-to-internal-control-gene ratios; (3) assess HER2 protein expression in each subgroup; and (4) compare clinical outcomes for each subgroup.ResultsOf the 1980 patients in METABRIC,1915 patients were fully evaluated. In addition, 100 HER2-equivocal breast cancers by FISH and 100 comparator FISH-negative breast cancers from the BCIRG-005 trial were analyzed. Heterozygous deletions, particularly in specific p-arm sites, were common in both HER2-amplified and HER2-not-amplified breast cancers. Use of alternative control probes from these regions to assess HER2 by FISH in HER2-equivocal as well as HER2-not-amplified breast cancers resulted in high rates of false-positive ratios (HER2-to-alternative control ratio ≥2.0) owing to heterozygous deletions of control p-arm genomic sites used in ratio denominators. Misclassification of HER2 status was observed not only in breast cancers with ASCO-CAP equivocal status but also in breast cancers with an average of fewer than 4.0 HER2 copies per tumor cell when using alternative control probes.Conclusions and relevanceThe indiscriminate use of alternative control probes to calculate HER2 FISH ratios in HER2-equivocal breast cancers may lead to false-positive interpretations of HER2 status resulting from unrecognized heterozygous deletions in 1 or more of these alternative control genomic sites and incorrect HER2 ratio determinations.

Project description:In one of every four or five cases of breast cancer, the human epidermal growth factor receptor-2 (HER2) gene is overexpressed. These carcinomas are known as HER2-positive. HER2 overexpression is linked to an aggressive phenotype and a lower rate of disease-free and overall survival. Drugs such as trastuzumab, pertuzumab, lapatinib, neratinib, and the more recent afatinib target the deregulation of HER2 expression. Some authors have attributed somatic mutations in HER2, a role in resistance to anti-HER2 therapy as differential regulation of HER2 has been observed among patients. Recently, studies in metastatic ER?+?tumors suggest that some HER2 mutations emerge as a mechanism of acquired resistance to endocrine therapy. In an effort to identify possible biomarkers of the efficacy of anti-HER2 therapy, we here review the known single-nucleotide polymorphisms (SNPs) of the HER2 gene found in HER2-positive breast cancer patients and their relationship with clinical outcomes. Information was recompiled on 11 somatic HER2 SNPs. Seven polymorphisms are located in the tyrosine kinase domain region of the gene contrasting with the low number of mutations found in extracellular and transmembrane areas. HER2-positive patients carrying S310F, S310Y, R678Q, D769H, or I767M mutations seem good candidates for anti-HER2 therapy as they show favorable outcomes and a good response to current pharmacological treatments. Carrying the L755S or D769Y mutation could also confer benefits when receiving neratinib or afatinib. By contrast, patients with mutations L755S, V842I, K753I, or D769Y do not seem to benefit from trastuzumab. Resistance to lapatinib has been reported in patients with L755S, V842I, and K753I. These data suggest that exploring HER2 SNPs in each patient could help individualize anti-HER2 therapies. Advances in our understanding of the genetics of the HER2 gene and its relations with the efficacy of anti-HER2 treatments are needed to improve the outcomes of patients with this aggressive breast cancer.

Dataset Information

The Dilemma of HER2 Double-equivocal Breast Carcinomas: Genomic Profiling and Implications for Treatment.

Publications

The Dilemma of HER2 Double-equivocal Breast Carcinomas: Genomic Profiling and Implications for Treatment.

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