Abstract P3-10-42: Stromal Caveolin-1 Is a Powerful Marker That Further Enhances a Multi-Marker Prognostic Profile
Authors: Linke SP , Krajewski S , Bremer TM , Man AK , Zeps N , Spalding L. 
Published: April 2011

Background: We previously reported development and validation of a prognostic profile with a continuous risk of recurrence algorithm for patients with operable, hormone receptor-positive breast cancer to help guide the appropriate level of adjuvant treatment. The prognostic profile includes six IHC markers (ER, PR, HER2, EGFR, BCL2, and p53), one FISH marker (MYC/8q24), and three clinicopathologic risk factors (tumor size, tumor grade, and nodal status). p27 is an additional marker that is predictive of chemotherapy benefit. When a single risk threshold is chosen for the prognostic profile to divide patients into high and low risk categories, a hazard ratio of ∼4-10 is consistently achieved with a ∼4-6% 10-year recurrence rate (95% CI, ∼0-9%).

Several additional markers, including caveolin-1, MTA1, and TIMP1, were identified in previous pilot studies as candidates to add prognostic power to the profile. This was based on their ability to stratify patients and their implicated roles in invasion and metastasis pathways that are not covered by the current markers. The goal of this study was to validate these additional candidates.

Methods: TMAs of patients from Royal Perth Hospital (RPH), on which the current profile had already been run, were stained by IHC for the new markers, caveolin-1, MTA1, and TIMP1. Pathologists recorded intensity (0, 1, 2, or 3) and percentage (0-100%) scores, and the products of the scores were calculated to generate immunoscores. Membranous/cytoplasmic caveolin-1 was scored separately in tumor epithelial and stromal cells. Nuclear MTA1, nuclear TIMP1, and cytoplasmic TIMP1 were scored in tumor cells. Kaplan-Meier survival and Cox proportional hazards analyses were then conducted using various marker thresholds and known patient outcome.

Results: In univariate analyses, only stromal caveolin-1 reached statistical significance. In patients treated with hormone therapy with or without chemotherapy (n=173), stromal caveolin-1 (immunoscore threshold of 200) achieved a hazard ratio of 5.6 (95% CI, 2.4-13) for time to recurrence. Similar results were achieved in the hormone therapy-only group (n=131). However, the caveolin-1 low-risk group had a 10-year recurrence rate that exceeded 10%, so its clinical utility is limited as a single marker. When caveolin-1 was assessed within the profile high-risk patients of the hormone therapy with or without chemotherapy group (baseline 10-year recurrence rate of ∼50%), it separated them into sub-groups with -30% and -80% recurrence rates (P&lt;0.0001). And, when it was assessed in the profile low-risk group, it identified two of the three recurrence events (previously false negatives).

Conclusion: Stromal caveolin-1 appears to be a powerful independent marker, and it will be incorporated into the current profile for future validation studies. Such stromal markers cannot easily be assessed in transcript-based prognostics due to tissue processing requirements.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-10-42.