164MO - Impaired Ki67 response towards neoadjuvant endocrine therapy in luminal breast cancer is associated with mutations conferring endocrine resistance: WSG-ADAPT HR+/HER2- translational results

Background

Adjuvant endocrine therapy is a cornerstone in the treatment of hormone receptor (HR)-positive/HER2-negative breast cancer (BC). Neoadjuvant endocrine induction therapy (EIT) suppresses tumor cell proliferation and provides a clinically applicable read-out system for endocrine responsiveness. In a proof-of-principle study, we hypothesized, that incomplete growth suppression following to EIT is associated with genetic alterations in endocrine resistance genes.

Methods

Genetic alterations in candidate endocrine resistance genes (ARID1A, CCND1, ERBB2, ESR1, FGFR1, PAK1, and TP53) [1] were determined by next generation sequencing (NGS) and/or digital PCR (dPCR) in n=622 early BC cases treated with EIT in the West German Study Group (WSG) ADAPT trial (NCT0177920). Further, PIK3CA mutation status was determined because of its potential as target to selective inhibition treatment. Significance of association between distinct genetic alterations and incomplete growth suppression (post-EIT Ki67 <10%, versus 10-19%, 20-34%, ≥35%; provisional criteria for this translational research project) was determined with Chi square test for trends.

Results

A total of n=351/622 (56.4%) BC cases harbored genetic alterations in at least one candidate gene. ARID1A, ERBB2, ESR1, PIK3CA, and TP53 gene mutations were affected in 5.3%, 2.9%, 0.6%, 43.3% and 9.0% of BC cases, respectively. CCND1, FGFR1, and PAK1 copy number gains were detected in 16.1%, 3.0% and 2.5% of tested patient samples. Of these candidate genes tested, only mutation of TP53 was significantly associated with incomplete growth suppression following EIT (P<0.0001). Mutation of TP53 was also associated with incomplete growth suppression in patient subsets treated with either tamoxifen or aromatase inhibitors for EIT (P=0.0005 each).

Conclusions

Our findings indicate that mutations associated with endocrine resistance and metastatic breast cancer [1], are enriched in short term endocrine treated primary luminal breast cancers with impaired Ki67 response. Ki67 response towards neoadjuvant endocrine treatment appears to reflect the genetic risk in breast cancer.

Clinical trial identification

NCT0177920.

Editorial acknowledgement

Legal entity responsible for the study

West German Study Group.

Funding

The study was supported by a grant from the Deutsche Krebshilfe to SB, MC, and HK (Grant Number 70112954).

Disclosure

S. Kümmel: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Roche; Honoraria (self), Advisory/Consultancy: Genomic Health; Honoraria (self), Advisory/Consultancy: Novartis; Honoraria (self), Advisory/Consultancy: Amgen; Honoraria (self), Advisory/Consultancy: Celgene; Honoraria (self), Travel/Accommodation/Expenses: Daiichi Sankyo; Honoraria (self), Advisory/Consultancy: AstraZeneca; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): Somatex; Honoraria (self), Advisory/Consultancy: MSD; Honoraria (self), Advisory/Consultancy: Pfizer; Honoraria (self), Advisory/Consultancy: PFM; Honoraria (self), Advisory/Consultancy: Medical; Honoraria (self), Advisory/Consultancy: Lilly; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Sonoscape; Leadership role, Shareholder/Stockholder/Stock options: WSG; Leadership role: AGO. M. Braun: Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: AstraZeneca; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Celgene; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Exact Sciences; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Medac; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: MSD; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Novartis; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Pfizer; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Roche; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Teva. R. Wuerstlein: Honoraria (self): Agendia; Honoraria (self): Amgen; Honoraria (self): Aristo; Honoraria (self): AstraZeneca; Honoraria (self): Boehringer Ingelheim; Honoraria (self): Carl Zeiss; Honoraria (self): Celgene; Honoraria (self): Clinsol; Honoraria (self): Daiichi Sankyo; Honoraria (self): Eisai; Honoraria (self): Genomic Health; Honoraria (self): Glaxo Smith Kline; Honoraria (self): Hexal; Honoraria (self): Lilly; Honoraria (self): Medstrom Medical; Honoraria (self): MSD; Honoraria (self): Mundipharma; Honoraria (self): Nanostring; Honoraria (self): Novartis; Honoraria (self): Odonate; Honoraria (self): Paxman; Honoraria (self): Palleos; Honoraria (self): Pfizer; Honoraria (self): Pierre Fabre; Honoraria (self): PumaBiotechnology; Honoraria (self): Riemser; Honoraria (self): Roche; Honoraria (self): Sandoz/Hexal; Honoraria (self): Seattle Genetics; Honoraria (self): Tesaro Bio. All other authors have declared no conflicts of interest.