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PAM50 Molecular Intrinsic Subtypes in the Nurses' Health Study Cohorts
Kevin H Kensler1,2, Venkat N Sankar3, Jun Wang4,5
1Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
Summary
Two preprocessing methods for assigning PAM50 breast cancer subtypes showed comparable results. Either method is suitable for epidemiologic studies, with Luminal A and Normal-like subtypes being most common in tumors and adjacent tissues, respectively.
Area of Science:
- Oncology
- Genomics
- Epidemiology
Background:
- Accurate breast cancer molecular subtyping is crucial for prognosis and treatment.
- PAM50 gene signature is a key tool for classifying breast cancer subtypes.
- Preprocessing methods, such as modified median and subgroup-specific gene centering, are essential for reliable PAM50 subtype assignment.
Purpose of the Study:
- To evaluate and compare two essential PAM50 gene signature preprocessing methods: modified median and subgroup-specific gene centering.
- To correlate PAM50-derived subtypes with immunohistochemistry (IHC) surrogates in breast cancer.
- To characterize PAM50 subtype distribution, proliferation scores, and risk of relapse (ROR-PT) in the Nurses' Health Study (NHS) and NHSII cohorts.
Main Methods:
- Calculated PAM50 subtypes, proliferation scores, and ROR-PT scores for 882 invasive breast tumors and 695 adjacent normal tissues.
- Employed Cox proportional hazards models to assess the association between PAM50 subtypes or ROR-PT scores and recurrence-free survival (RFS).
- Compared PAM50 subtypes derived from modified median and subgroup-specific gene centering methods.
Main Results:
- PAM50 subtypes derived from both preprocessing methods demonstrated high comparability.
- Agreement between PAM50 subtypes and IHC surrogates improved when Luminal subtypes were combined.
- The modified median method revealed Luminal A (46%) as the most prevalent subtype in tumors, while Normal-like (53%) predominated in adjacent tissues. Basal-like subtypes showed higher early relapse rates, and HER2-enriched subtypes had poorer outcomes pre-1999.
Conclusions:
- Both modified median and subgroup-specific gene centering preprocessing methods are suitable for deriving PAM50 subtypes in epidemiologic studies.
- The study identified Luminal A as the most common breast cancer subtype and Normal-like in adjacent tissues within the NHS/NHSII cohorts.
- Findings support the utility of either preprocessing method for future research on breast cancer molecular subtypes.