Abstract P5-14-06: Lapatinib reverses endocrine resistance in select patients with HER2 negative, hormone positive metastatic breast cancer
Authors: Sharma P , Kimler BF , Ward C , Wang K , Ali S , Balasubramanian S , O'Dea AP , Madhusudhana S , Baccaray S , Fabian CJ , Schmitt SB , Godwin AK , Khan QJ 
Published: May 2016

Introduction: A significant proportion of breast cancer (BC) patients show primary or acquired resistance to endocrine therapy (ET). The cross-talk between estrogen receptor and other growth factor receptor (GFR) families is suggested to play a crucial role in the development of endocrine resistance and dual targeting of these pathways can potentially reverse endocrine resistance. Lapatinib (Lap) is an oral, dual inhibitor of EGFR/HER2 and preclinical studies have demonstrated combination of Lap and ET to be effective in setting of endocrine resistance. Aims: 1) To evaluate if Lap can restore efficacy of aromatase inhibitor (AI) or fulvestrant(F) in metastatic BC, 2) Study blood/tissue response biomarkers.

Methods: Eligible patients with HER2 negative (IHC and FISH) hormone positive metastatic BC who had progression of disease while on AI or Fulvestrant (+/-AI), or developed metastatic disease on adjuvant AI were enrolled on an IRB approved phase II study. Study treatment included continuation of same dose and schedule ET on which last progression was noted with the addition of Lapatinib 1500 mg PO/QD. Patients could have unlimited prior ET. The study end points included clinical benefit rate (CBR) at 16wks (CBR16), CBR at 24 wks (CBR24) and PFS. Correlative studies included blood markers (HER2/ECD, CTC, CTC HER2 phenotyping) and tumor next generation sequencing (NGS) (315 cancer-related genes, Foundation Medicine, Inc).

Results: Between 2009 and 2014, thirty-two patients were enrolled. Median age: 61.5 yrs, median number of prior endocrine regimens: 2 (range 1-4), 72% had visceral disease, 28% had bone only disease, 67% were considered to be responsive to the last ET. For 28 patients evaluable for efficacy the ET was AI =29%, F= 32%, AI+F=39%. The CBR16 was 25% (7/28) and the CBR24 was 14%(4/28). Median PFS for the entire cohort was 2.1 mths and the median PFS for patients with CB at 16 weeks was 7.4 mths. 12% of patients had Grade 3/4 AE (Diarrhea: 6%, Vomiting: 6%, Rash: 3%). Serum HER2/ECD was elevated in 43%, &gt;1 CTC detected in 57%, HER2 positive CTC noted in 18%. HER2/ECD and HER2 positive CTC did not correlate with CBR16. Tumor NGS done on partial sample set (n=7, patients without early progression) demonstrate PI3K pathway activating mutations in 55% (4/7) of patients (PIK3CA mutations=3, AKT3 amplification & PTEN homozygous deletion=1). No ESR1 alterations were observed. All 4 patients with PIK3CA pathway mutations demonstrate CB at 16 wks, and 3/4 demonstrate CB at 24 wks.

Conclusion: Addition of Lap restored sensitivity to ET (AI/Fulvestrant) in 25% of patients with HER 2 negative BC. Response was independent of HER 2 positive CTC and HER2/ECD levels. Genomic profiling suggests a relationship between PIK3CA mutation and benefit from this approach. NGS of the entire study cohort is in process and will be reported. HER2-negative breast cancers harboring PIK3CA mutations may rely more on GFR/PI3K signaling than on estrogen for growth; thus, blocking GFR signaling with lap might restore hormonal sensitivity. A randomized study of lap + ET in selected patients with HER2 negative BC is warranted and biomarker results from this study may help identify subgroups that should be targeted in a larger study.

Citation Format: Sharma P, Kimler BF, Ward C, Wang K, Ali S, Balasubramanian S, O'Dea AP, Madhusudhana S, Baccaray S, Fabian CJ, Schmitt SB, Godwin AK, Khan QJ. Lapatinib reverses endocrine resistance in select patients with HER2 negative, hormone positive metastatic breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-14-06.