Background: Immunotherapy with checkpoint inhibitors (CPI) targeting PD-1 or CTLA-4 has emerged as an important treatment modality for several cancer forms. In hormone receptor positive breast cancer (HR + BC), this therapeutic approach is largely unexplored. We have started a clinical trial, ICON (CA209-9FN), evaluating CPI combined with selected chemotherapy in patients with metastatic HR + BC. The tumor lymphocyte infiltration is predictive for the effect of chemotherapy in BC. In ICON, we use anthracycline, which are considered as "immunogenic" chemotherapy, and low-dose cyclophosphamide, which has been reported to counter immunosuppressive cells. Methods: ICON is a randomized exploratory phase IIb study evaluating the safety and efficacy of combining nivolumab (nivo; anti-PD-1) and ipilimumab (ipi; anti-CTLA-4) with chemotherapy in subjects with metastatic HR + BC. Primary objectives are aassessment of toxicity and progression-free survival. The trial will enrol 75 evaluable subjects, randomized 2:3 into two arms (A:B). Patients in Arm A receive only chemotherapy, i.e. pegylated liposomal doxorubicin (PLD 20 mg/m 2 intravenously every 2nd week) + cyclophosphamide (cyclo; 50 mg per day, first 2 weeks in each 4 week cycle). Patients in Arm B receive PLD + cyclo + ipilimumab (1 mg intravenously every 6th week) + nivolumab (240 mg intravenously every 2nd week). Patients in arm A will be offered ipi + nivo after disease progression. Discussion: ICON is among the first clinical trials combining chemotherapy with PD-1 and CTLA-4 blockade, and the first in BC. There is a strong preclinical rationale for exploring if anthracyclines, which are considered to induce immunogenic cell death, synergize with CPI, and for combining PD-1 and CTLA-4 blockade, as these checkpoints are important in different phases of the immune response. If the ICON trial suggests acceptable safety and provide a signal of clinical efficacy, further studies are warranted. The cross-over patients from Arm A receiving ipilimumab/ nivolumab without concomitant chemotherapy represent the first BC cohort receiving this therapy. The ICON trial includes a series of translational sub-projects addressing clinically important knowledge gaps. These studies may uncover biomarkers or mechanisms of efficacy and resistance, thereby informing the development of novel combinatory regimes and of personalised biomarker-based therapy.
Background: Breast cancer is known to be a heterogeneous disease both at the clinical and molecular level. In addition, heterogeneity can also exist within a given tumor, and subpopulations can have distinct phenotypic and genomic features. Little is known about the relationship between intra-tumor heterogeneity and prediction of response to treatment. This study aimed at using a combination of immunofluorescence and fluorescence in situ (FISH) technique (“double immunoFISH”) to identify intra-tumor heterogeneity in tumors from neo-adjuvant treated patients prior to and after therapy, searching for features predicting the response to neo adjuvant treatment. Material and methods: Twentytwo patients diagnosed with HER2 positive, neo-adjuvant treated breast cancer ((3–4 FEC100 followed by 4 docetaxel plus trastuzumab, 3qw) were selected. Half of the patients had complete response and the others had partial response. By double immunoFISH both phenotypic (ER and HER2 protein) and genomic changes (copy number of HER2 gene and centromere 17) were assessed in the same cells simultaneously on biopsies before and after treatment. The samples were photographed in a Zeiss Axio Imager M1 with 5 fluorescence channels and analyzed with axiovision software. The intensity and localization of HER2 and ER immunofluorescence were semi-quantitatively estimated while the HER2 and centromere 17 FISH signals were counted in 100 cells. Results: The patients with partial response displayed a high grade of cell-to-cell diversity regarding HER2 copy number, nuclear shape and size and the expression of the membrane protein HER2. This was in contrast to the results from the complete responders who showed a reduced diversity and were more frequently ER negative. In the patients with partial response, a higher diversity was seen after treatment. Conclusion: The genomic variability prior to therapy was higher in the partial-responders vs. the complete responders, and the remaining tumor was even more heterogeneous after treatment than prior to treatment. Double immunoFISH is a valuable tool for visualization of both phenotypic and genomic alterations in the same cell in FFPE sections. The cohort will be expanded to explore the diversity further, and the results will be presented. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-05-04.
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