Background: Circulating tumor cells (CTCs) with evidence of HER2 amplification can occur in patients (pts) with clinically HER2 negative metastatic breast cancer. While these findings potentially have profound implications for CTCs as a biomarker for treatment, prospective validation and characterization of this subgroup is necessary. Methods: We created a prospective cohort of pts with metastatic breast cancer that were HER2 negative by IHC and/or FISH on all available primary and metastatic biopsies. Blood samples were collected at study entry and then again at ≥ 3 weeks if available. CTCs were enumerated by a modification of the Veridex CellSearch Profile kit. FISH was performed on each CTC sample and reported as positive if the HER2/CEP17 ratio was ≥ 2.0. Analyses are descriptive. Results: 66 pts were consented for study and this report includes the 65 pts with detectable CTCs. Median number of CTCs was 226 (range 112 to > 3000). At initial testing, 23 pts (35%) had HER2 positive CTCs, median HER2:CEP17 ratio of 3.4. 50% (11 of 22) of the pts with lobular or ductal/lobular histology had HER2 amplified CTCs, compared to only 27% (10 of 36) of patients with ductal histology. Women with ER positive disease had HER2 positive CTCs in 40% of cases (20 of 49) compared to 19% of ER negative pts (3 of 16). To assess concordance of HER2 amplification of CTCs over time, 34 pts consented to be retested at a median 5.9 weeks after initial screening (range 3.3 - 17 weeks) and all but 1 had detectable CTCs. Baseline characteristics of these 34 pts were similar to the original population, with HER2 amplified CTCs detected in 35% (12 of 34) pts at initial screening. HER2 positive CTCs were concordant at time of retesting in 83% (10 of 12) pts; the 2 women with discordant CTCs were receiving HER2 directed therapy. Of the pts with HER2 negative CTCs at initial screening, 81% (17 of 21) continued to have HER2 negative CTCs at time of retesting. Conclusion: We observed a higher prevalence of HER2 positive CTCs among pts with ER positive disease and evidence of lobular histology. The presence of HER2 positive CTCs is concordant over time in the majority of pts. The functional significance of HER2 positive CTCs in patients with clinically HER2 negative breast cancer will be tested in a prospective study with HER2−directed therapy. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PD05-07.
Background We evaluated the safety and efficacy of L+T in pts with 0–2 prior lines of chemotherapy (CT) for HER2+ MBC. In the context of this phase II trial, we evaluated metabolic response by FDG-PET and explored the relationship between metabolic response and clinical outcomes. Methods: Pts with measurable, HER2+ MBC were eligible. Cohort 1: No prior T, L, or CT +T for MBC, and >1 yr from adjuvant T, if received. Cohort 2: 1–2 prior lines of CT for MBC, including T, or relapse within 1 yr of adjuvant T. Pts received L 1,000 mg QD + T (2 mg/kg weekly or 6 mg/kg Q3W). Staging studies were done with CT or MRI at baseline (BL) and every 2 cycles (1 cycle=4 weeks [wks]). Objective response was assessed by local investigator according to RECIST 1.0. FDG-PET/CT was performed at BL, Wk 1, and Wk 8 per NCI guidelines. Central quality assurance, review, and analysis were performed on FDG-PET studies. Up to 5 target lesions were identified on BL FDG-PET images based on hypermetabolic uptake. Percent change in the summed maximum standardized uptake value (SUVmax) of target lesions was calculated at Wk 1 or Wk 8, compared to BL. Metabolic response was assessed according to EORTC criteria for % change in SUVmax (progressive disease [PD]: ≥25% increase; partial response [PR]: ≥25% decrease; stable disease [SD]: <25% change). Metabolic response at Wk 1 was compared to Wk 8 as well as to clinical outcome, including objective response, clinical benefit, and progression-free survival (PFS). Results: 87 pts were registered to the study. Of these, one pt did not begin protocol therapy and one pt did not have MBC on further testing, and are not included. 81/85 pts had FDG-PET data at Wk 1; 75/85 had data at Wk 8. Metabolic PR at Wk 1 was observed in 28/39 (72%) pts in Cohort 1 and 20/42 (48%) pts in Cohort 2. Metabolic PR at Wk 8 was observed in 27/34 (79%) pts in Cohort 1 and 18/41 (44%) pts in Cohort 2. Wk 1 and Wk 8 metabolic responses were similar. In cohort 1, 18/28 (64%) pts who achieved Wk 1 metabolic PR had clinical benefit by RECIST. Of pts with Wk 1 metabolic SD, 2/9 (22%) had clinical benefit. In cohort 2, 9/20 (45%) pts who achieved Wk 1 metabolic PR had clinical benefit; 5/22 (23%) who achieved Week 1 metabolic SD had clinical benefit. Exploratory analysis of progression-free survival (PFS) showed that pts in Cohort 1 who achieved Wk 1 metabolic PR experienced a median PFS of 9.3 months ([mos]; 95% CI 5.6−22.3); for pts with metabolic SD, median PFS was 1.9 mos (95% CI 0.8−5.5). For pts in Cohort 2, Wk 1 metabolic PR was associated with median PFS of 5.6 mos (95% CI 3.7−7.8), whereas for pts with metabolic SD, median PFS was 3.7 mos (95% CI 1.8−5.5). Conclusions: L+T is associated with a high rate of early and sustained metabolic response by FDG-PET. Exploratory analyses suggest that metabolic PR may be associated with clinical benefit and longer PFS. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-09-07.
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