The objective of this study was to determine the conversion rate of human epidermal growth factor receptor 2 (HER2), estrogen receptor (ER) and progesterone receptor (PR) between primary tumors and metastatic lesions in advanced breast cancer. Patients with suspected diagnosis of locally recurrent or metastatic breast cancer, either at first relapse or after successive disease progressions, who had an appropriately preserved sample from a primary tumor and were scheduled for a biopsy of the recurrent lesion, were included. Blinded determinations of receptor status on paired samples were performed by immunohistochemistry and fluorescence in situ hybridization at a central laboratory and compared with those performed locally. Overall, 196 patients were included and 184 patients were considered evaluable. Reasons for non-evaluability included the inability to perform biopsy (n = 4) or biopsy results showing normal tissue (n = 3), benign disease (n = 3) or a second neoplasia (n = 2). Conversion rates determined at local level were higher than those determined centrally (HER2: 16 vs. 3 %, ER: 21 vs. 13 %, PR: 35 vs. 28 %, respectively). There was substantial agreement regarding the expression of HER2 in primary tumors and metastases, and ER at metastases, between local and central laboratories. PR at any site and ER at primary site showed moderate agreement. Oncologists altered their treatment plans in 31 % of patients whose tumor subtype had changed. These results reinforce the recommendation for performing confirmatory biopsies of metastases, not only to avoid misdiagnosis of breast cancer relapse, but also to optimize treatment (clinicaltrials.gov identifier: NCT01377363).

BackgroundTrastuzumab improves survival outcomes in patients with HER2+ metastatic breast cancer. The Long-Her study was designed to identify clinical and molecular markers that could differentiate long-term survivors from patients having early progression after trastuzumab treatment.MethodsData were collected from women with HER2-positive metastatic breast cancer treated with trastuzumab that experienced a response or stable disease during at least 3 years. Patients having a progression in the first year of therapy with trastuzumab were used as a control. Genes related with trastuzumab resistance were identified and investigated for network and gene functional interrelation. Models predicting poor response to trastuzumab were constructed and evaluated. Finally, a mutational status analysis of selected genes was performed in HER2 positive breast cancer samples.Results103 patients were registered in the Long-HER study, of whom 71 had obtained a durable complete response. Median age was 58 years. Metastatic disease was diagnosed after a median of 24.7 months since primary diagnosis. Metastases were present in the liver (25%), lungs (25%), bones (23%) and soft tissues (23%), with 20% of patients having multiple locations of metastases. Median duration of response was 55 months. The molecular analysis included 35 patients from the group with complete response and 18 patients in a control poor-response group. Absence of trastuzumab as part of adjuvant therapy was the only clinical factor associated with long-term survival. Gene ontology analysis demonstrated that PI3K pathway was associated with poor response to trastuzumab-based therapy: tumours in the control group usually had four or five alterations in this pathway, whereas tumours in the Long-HER group had two alterations at most.ConclusionsTrastuzumab may provide a substantial long-term survival benefit in a selected group of patients. Whole genome expression analysis comparing long-term survivors vs. a control group predicted early progression after trastuzumab-based therapy. Multiple alterations in genes related to the PI3K-mTOR pathway seem to be required to confer resistance to this therapy.

608 Background: Some patients with advanced HER2+ breast cancer survive in the long-term after receiving trastuzumab-based therapy. Long-HER study was an observational, multicenter study that compared long-term survivors and a control group from the clinical and molecular point of view. Methods: Patients with metastatic HER2+ breast cancer that had been treated with trastuzumab-based therapy and had an objective response or stable disease for at least 3 years were included. A control group having a progression in the first year of therapy was selected for comparison (similar first-line therapy). A microarray platform was used to assess whole genome expression analysis in paraffin-embedded samples. Differential expression, ontology and analysis of metabolic pathways were performed. Results: 103 patients were registered, 71 of who had a long-term complete remission. Only 5 of these patients had received trastuzumab in the adjuvant setting: this was the only clinical factor associated to long-term survival. The molecular study included 35 Long-HER and 18 control samples. Gene expression ontology revealed alterations in HIF, apoptosis, and EGF, PI3K and p53 pathways. The PI3K pathway was mostly related with a poor response to therapy. Conclusions: trastuzumab-based therapy achieves long-term survival in a selected group of women with advanced HER2-positive breast cancer. Whole genome analysis comparing such a group with a control group found some alterations that may predict early progression to trastuzumab.

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