Ramón María Pérez Carrión

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).

BACKGROUND: Trastuzumab 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. METHODS: Data 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. RESULTS: 103 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. CONCLUSIONS: Trastuzumab 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.

e19014 Background: In NS-NSCLC CPB achieved median OS > 1 y and supported use of B. A broad range of predictive/prognostic markers explored for B use. In VEGF pathway ligands and receptors play an important role in tumor angiogenesis and therapeutic efficacy. Altered levels of angiogenic factors in tumor or serum/plasma have been associated with prognosis and may be related with outcome when B is used. Methods: Advanced NS-NSCLC p were treated 1st-line with CPB. Primary end-point: PFS; secondary end-points: OS, RR, toxicity. Ancillary study designed to investigate relationship between angiogenic mediators, response and outcomes . 200 p St IIIB/IV NS-NSCLC and ECOG 0–2 prospectively included and treated with CPB 6 cycles followed by B maintenance. Ethical approval and informed consent for collecting peripheral blood samples and associated clinical data. Samples collected before treatment (basal) and at response evaluation (post). DNA obtained from leukocyte fraction (n=168). SNPs of angiogenic genes genotyped by PCR. Plasma levels of VEGFA and VEGFR2 determined by ELISA. Response RECIST.1 and toxicity CTCAEv.1. Results: P characteristics: median age 61 years [37-80], 67.2% male, 97.8% stage IV, 15.8% never-smokers, 100% caucasian, 88.2% adenoca. Median number of delivered CPB cycles 5. ITT RR (143 p): CR 1 (0.7%), PR 70 (48.9%), SD 52 (36.4%), PD 18 (12.6%), NE 2 (1.4%) Median PFS 6.91 months [6.16-7.65]; OS 14.57 months [11.83- 17.31]. No significant correlations between best response and the analyzed SNPs or plasmatic levels of VEGF and VEGFR2. VEGFR1 SNP rs9582036 (CC) was associated with shorter PFS (p=0.01) and OS (p=0.01). VEGFA SNP rs3025039 (CC) correlated with reduced OS compared with other genotypes (CT+TT) (p=0.009). No significant differences in PFS or OS were observed according to other SNPs . Lower levels (<median) of circulating VEGF (basal) with significant longer PFS (p=0.04 ) and a trend for OS (p=0.10). Conclusions: Multicentric trial with median OS 14.5 m achieved with CPB 1st-line in advanced NS-NSCLC p. Some VEGFR1 and VEGFA SNPs reduce CPB efficacy. In p with lower basal VEGF levels outcomes are improved. Clinical trial information: NCT01814163.

1143 Background: Following the approval of bevacizumab for the treatment of MBC, this study was devised to identify the profile of patients (pt) treated under real conditions of use, their relationship with the regime used and the MBC subtypes by their genetic signature and tolerability of treatment. Methods: Multicentric observational transversal study in 40 centers. We present the results from the first 108 pts who received at least one dose of bevacizumab. Results: Of the women treated, 98.1% were Caucasian, with a mean age of 50.7 years (30-82) and ECOG 0-1 in 88%. In terms of prior history, 3.7% suffered from cardiopathies, 11.1% vascular disorders and 4.8% had kidney pathology. Neoadjuvant or adjuvant chemotherapy (CT) was given to 88% of them. The predominant histology was infiltrating ductal (82%) and histological grade 3 (49%). Positive results for hormone receptors were found in 68.5%, of which 65% were luminal A and 3.5% luminal B; 3.5% were HER2 positive, while 28% were triple negative. The disease-free interval for patients who received adjuvant or neoadjuvant CT was greater than 12 months in 86.3%. The most frequent metastatic locations were liver (38%), bone (59%), and lung (29%). The drugs most commonly used with bevacizumab were taxanes (87%). Of the 71 pt evaluated so far, 59.2% have shown a response (95% CI: 47-71%), 8.5% complete, and 22% stable disease, with 81.7% (95% CI: 73-91) obtaining a benefit from the treatment, without differences being found between subtypes. The main grade 1-2 toxicities were arterial hypertension (17%) and bleeding (18.5%). One case of grade 3-4 toxicity (proteinuria) was detected although only 30% of patients had a urine analysis. Conclusions: Bevacizumab combined with chemotherapy is well-tolerated, safe, and effective as first-line treatment of MBC, with a clinical benefit being obtained in 81.7% of patients. The results are consistent with the data from the three phase III studies in 1L and MO19391 from the clinical practice. No significant financial relationships to disclose.

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.