Absolutely quantitated protein levels to reveal an ER/PR framework governing the full spectrum of breast cancer

Abstract Cancer heterogeneity is traditionally attributed to multiple parallel signaling pathways. This belief is challenged here by proposing the ER/PR axis as the dominant pathway underlying the full spectrum of breast cancer. Absolutely quantitated ER, PR, Her2 and Ki67 protein levels were accumulated over 8 years from 1652 specimens collected non-selectively and measured with Quantitative Dot Blot (QDB) method over time. Cox analysis showed ER and Ki67 as independent adverse prognostic factors while PR was an independent favorable factor statistically. Their optimized stratification framework demonstrated that prognosis across all clinical subtypes was predominantly aligned along the ER/PR axis rather than being subtype-specific, including repeated identification of a subgroup with near-perfect 10-year survival probability from three independent cohorts to be proposed as the biological basis of the ultra-safe group in MINDACT trial. A parsimonious model is proposed where the ER/PR signaling hierarchy supersedes current prevailing clinical subtyping, with its balance essential for survival until ER levels become uncontrollable. This concept of pathway hierarchy may also exist in other major cancer types, and cannot be addressed without clinical epidemiology.