Abstract:
Background: Pathology-supported genetic testing (PSGT) enables transitioning of risk stratification
from the study population to the individual.
Research Design and Methods: We provide an overview of the translational research performed in
postmenopausal breast cancer patients at increased risk of osteoporosis due to aromatase inhibitor
therapy, as the indication for referral. Both tumor histopathology and blood biochemistry levels were
assessed to identify actionable disease pathways using whole exome sequencing (WES).
Results: The causes and consequences of inadequate vitamin D levels as a modifiable risk factor for
bone loss were highlighted in 116 patients with hormone receptor-positive breast cancer. Comparison
of lifestyle factors and WES data between cases with vitamin D levels at extreme upper and lower
ranges identified obesity as a major discriminating factor, with the lowest levels recorded during winter.
Functional polymorphisms in the vitamin D receptor gene contributed independently to therapy-
related osteoporosis risk. In a patient with invasive lobular carcinoma, genetic counseling facilitated
investigation of the potential modifying effect of a rare CDH1 variant co-occurring with BRCA1 c.66dup
(p.Glu23ArgfsTer18).
Conclusion: Validation of PSGT as a three-pronged pharmacodiagnostics tool for generation of adap-
tive reports and data reinterpretation during follow-up represents a new paradigm in personalized
medicine, exposing significant limitations to overcome.