IMPAKT 2015 News: AP-2gamma Tumour Expression Is a New Biomarker for Resistance to Endocrine Therapy in Patients with Metastatic Breast Cancer

A genetic signature is identified that associates with decreased patient benefit from fulvestrant monotherapy

Findings from a molecular analysis of samples from two independent cohorts of patients with metastatic breast cancer that establish AP-2gamma as a predictive biomarker for endocrine resistance were presented during a Genomics and Proteomic Analysis of Breast Cancer sector of the Poster Walk at the IMPAKT Breast Cancer Conference held 7–9 May 2015 in Brussels, Belgium.

Luca Malorni, Hospital of Prato, Istituto Toscano Tumori, Prato, Italy, headed an international team in evaluating the predictive utility of AP-2gamma for response to endocrine therapy in patients with metastatic breast cancer.

The investigators had recently concluded the TransCONFIRM study, which was an analysis of samples from patients with metastatic breast cancer participating in the Confirm trial that compared fulvestrant given at either 500 mg or 250 mg. Findings from TransCONFIRM showed that AP-2gamma is differentially expressed between responders and non-responders to fulvestrant.

The study reported at IMPAKT 2015 sought to confirm whether the expression in tumours of AP-2gamma, a transcription factor implicated in breast cancer, could serve as a predictive marker for response to fulvestrant.

AP-2gamma levels were characterised by immunohistochemistry on tissue microarrays of 124 primary breast cancer samples. Samples were derived from the TransCONFIRM cohort and from a separate cohort of primary breast cancer samples from an institutional tissue bank. The level of AP-2gamma levels in the nucleus, plus levels of the hormone receptors, ki-67 and HER2 status were reviewed centrally.

Higher expression of AP-2gamma seen in higher grade tumours and associates with poorer outcome

Samples were stratified per molecular subtypes according to the St. Gallen definition. By subtype, 29% of 51 luminal A samples, 62% of 50 of luminal B/HER2-negative samples, 90% of 10 the luminal B/HER2-positive subtype, 36% of 11 of the triple negative, and 100% of 2 HER2-positive subtype samples scored positive for AP-2gamma in the transCONFIRM cohort.

AP-2gamma positivity occurred more frequently in higher grade tumours and in tumours that expressed a marker for cell proliferation, both predictors of poorer prognosis; 76% of grade 3 tumours compared to 26.7% of grade 1 were positive for AP-2gamma, as were 66% of tumours with high ki-67 versus 32% with low levels of ki-67.

An analysis of survival data from all 124 patients in the TransCONFIRM cohort showed that patients with AP-2gamma positive tumours experienced significantly shorter progression-free survival (PFS) compared to patients with AP-2gamma negative tumours; median PFS was 5.4 months in 61 patients with AP-2gamma positive tumours versus 9.6 months in patients negative for AP2gamma, hazard ratio 1.082;  p =  0.02.

Analysis of data from the subgroup of 103 luminal A/B samples showed a similar trend that did not reach statistical significance (p = 0.08).

Results from an identical analysis of an independent cohort of samples from an institutional tissue bank confirming AP-gamma as a predictive biomarker for fulvestrant was ongoing at time of abstract submission.

Conclusion

A novel biomarker, AP-2gamma, for fulvestrant resistance was identified in this study. Furthermore, findings from this analysis demonstrated that high expression of AP-2gamma associated with poorer outcome.

PFS in patients with primary tumours that express AP-2gamma was nearly half of that seen in similar patients having negative tumours after fulvestrant treatment for metastatic breast cancer. 

The authors remarked that studies to elucidate the mechanism behind AP-2gamma endocrine resistance are warranted.

Reference

60P AP-2gamma as a novel biomarker of endocrine resistance: Results from the TransCONFIRM study