Previous preclinical studies showed that mutations in ERBB2 might represent an alternative mechanism for HER2 activation and the rate of mutations in BC is around 2%. They occur more frequently in HER2-negative (HER2-) BC and are associated with poor survival. On these bases, HER2- pts with mutation are potentially candidates for HER2-targeted therapy, as already showed by Neratinib. We evaluated the incidence of ERBB2 mutations in 14 hormone receptor (HR) positive BC and in their matched endocrine-resistant recurrences. Using an NGS technology, we evaluated a panel of genes including ERBB2, in FFPE tissues. We analysed 14 HR positive BCs and their matched recurrences. All the relapses have been developed during an endocrine treatment. 29% of pts were diagnosed with HER2+ BC, while 71% of pts developed HER2- BC. 3 pts were diagnosed at stage I, 6 pts at stage II, 5 pts at stage III. We found 8 different mutations in 9 samples: A356D, Q1206X, Q396X, Q393X, P523L, I654V, G1220C, 135+3G>T. Only I654V was previously described in literature. All but one (135+3G>T) of these mutations are exonic variants. 5 mutations were in the extracellular domain, 1 in the tyrosine kinase domain and 2 in the carboxy tail. 28.6% of pts had ERBB2 mutations in the primary BCs and 35.7% in the relapsed site. 66.6% of HER2+ primary BCs showed an ERBB2 mutation, while only 21% of HER2- samples brought a mutation. 2 patients acquired a new mutation in the relapsed site, while 1 patient lost the mutation in the relapsed tissue. The mDFS was 35.3 months. mDFS in HER2+ and/or mutated pts was 46.4 months, while mDFS in HER2- wild type pts was 28.5. The mOS was 104 months (6 pts still alive). mOS in HER2+ and/or mutated pts was 115.6 months while mOS in HER2- wild type pts was 97.5. We found an overall detection rate of mutations higher than that described in literature (ERBB2 mutations were present in 32.1% of our samples), meaning that our pts have been highly selected. In fact, only tumors relapsing 26 Tumori Journal 104(4S) under an endocrine treatment, and thus with proved endocrine resistance, have been included in our analyses. The identification of an ERBB2 mutation in primary BCs might justify a more targeted neo/adjuvant approach and, might guide the subsequent treatment choices when the mutation is identified in the relapsed tissue. Contrary to previous literature, in our study the majority of mutations occurred in HER2+ samples and HER2+ and/or mutated samples did not show worse outcomes.

ERBB2 mutations in hormone receptor positive primary breast cancers samples and in their matched endocrine-resistant recurrences / Venturelli, M.; Toss, A.; Piacentini, F.; Artuso, L.; Bernardis, I.; Parenti, S.; Tenedini, E.; Omarini, C.; Moscetti., 1; Cascinu, S.; Tagliafico, E.; Cortesi, L.. - (2018). ((Intervento presentato al convegno XX CONGRESSO NAZIONALE ASSOCIAZIONE ITALIANA ONCOLOGIA MEDICA tenutosi a ROMA nel 7-9.11.2018.

ERBB2 mutations in hormone receptor positive primary breast cancers samples and in their matched endocrine-resistant recurrences.

Venturelli M.;Toss A.;Piacentini F.;Artuso L.;Bernardis I.;Parenti S.;Tenedini E.;Omarini C.;Cascinu S.;Tagliafico E.;
2018

Abstract

Previous preclinical studies showed that mutations in ERBB2 might represent an alternative mechanism for HER2 activation and the rate of mutations in BC is around 2%. They occur more frequently in HER2-negative (HER2-) BC and are associated with poor survival. On these bases, HER2- pts with mutation are potentially candidates for HER2-targeted therapy, as already showed by Neratinib. We evaluated the incidence of ERBB2 mutations in 14 hormone receptor (HR) positive BC and in their matched endocrine-resistant recurrences. Using an NGS technology, we evaluated a panel of genes including ERBB2, in FFPE tissues. We analysed 14 HR positive BCs and their matched recurrences. All the relapses have been developed during an endocrine treatment. 29% of pts were diagnosed with HER2+ BC, while 71% of pts developed HER2- BC. 3 pts were diagnosed at stage I, 6 pts at stage II, 5 pts at stage III. We found 8 different mutations in 9 samples: A356D, Q1206X, Q396X, Q393X, P523L, I654V, G1220C, 135+3G>T. Only I654V was previously described in literature. All but one (135+3G>T) of these mutations are exonic variants. 5 mutations were in the extracellular domain, 1 in the tyrosine kinase domain and 2 in the carboxy tail. 28.6% of pts had ERBB2 mutations in the primary BCs and 35.7% in the relapsed site. 66.6% of HER2+ primary BCs showed an ERBB2 mutation, while only 21% of HER2- samples brought a mutation. 2 patients acquired a new mutation in the relapsed site, while 1 patient lost the mutation in the relapsed tissue. The mDFS was 35.3 months. mDFS in HER2+ and/or mutated pts was 46.4 months, while mDFS in HER2- wild type pts was 28.5. The mOS was 104 months (6 pts still alive). mOS in HER2+ and/or mutated pts was 115.6 months while mOS in HER2- wild type pts was 97.5. We found an overall detection rate of mutations higher than that described in literature (ERBB2 mutations were present in 32.1% of our samples), meaning that our pts have been highly selected. In fact, only tumors relapsing 26 Tumori Journal 104(4S) under an endocrine treatment, and thus with proved endocrine resistance, have been included in our analyses. The identification of an ERBB2 mutation in primary BCs might justify a more targeted neo/adjuvant approach and, might guide the subsequent treatment choices when the mutation is identified in the relapsed tissue. Contrary to previous literature, in our study the majority of mutations occurred in HER2+ samples and HER2+ and/or mutated samples did not show worse outcomes.
XX CONGRESSO NAZIONALE ASSOCIAZIONE ITALIANA ONCOLOGIA MEDICA
ROMA
7-9.11.2018
Venturelli, M.; Toss, A.; Piacentini, F.; Artuso, L.; Bernardis, I.; Parenti, S.; Tenedini, E.; Omarini, C.; Moscetti., 1; Cascinu, S.; Tagliafico, E.; Cortesi, L.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11380/1168660
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