CPTAC: Microscaled Proteogenomic Methods for Precision Oncology

Cancer proteogenomics combines genomics, transcriptomics and mass spectrometry-based proteomics to gain insights into cancer biology and treatment outcomes. To promote clinical investigation, we developed a "microscaled" proteogenomics approach for tumor-rich frozen core needle biopsies. Tissue-sparing specimen processing ("Biopsy Trifecta EXTraction", BioTExt) and microscaled proteomics (MiProt) generated deep-scale proteogenomics datasets. As a proofof- concept, biopsies were accrued from ERBB2 positive (ERBB2+) breast cancers before and 48 to 72 hours after the first dose of neoadjuvant trastuzumab-based chemotherapy. Multi-omics comparisons were conducted between samples associated with residual disease versus complete pathological response (pCR). Integrated analyses diagnosed diverse molecular causes of treatmentresistance including: 1) absence of ERBB2 amplification (false-ERBB2+); 2) insufficient ERBB2 activity for therapeutic sensitivity despite ERBB2 amplification (pseudo-ERBB2+); 3) resistance features in true-ERBB2+ cases including androgen receptor signaling, mucin expression and an inactive immune microenvironment; 4) lack of acute phospho-ERBB2 down-regulation in nonpCR cases. We conclude microscaled cancer proteogenomics could improve diagnostic precision.]]>
Following informed consent, patients diagnosed with either ERBB2- positive or Triple Negative breast cancer via diagnostic breast biopsy were enrolled in the National Surgical Adjuvant Breast and Bowel Project (NSABP) Biospecimen Discovery Project (DP) for ERBB2+ breast cancer. In accordance with consent, regular cancer care and optional additional 14-gauge needle biopsies preserved in optimal cutting temperature (OCT) fixative collected at diagnostic breast biopsy and 48 to 72 hours following paclitaxel and trastuzumab treatment along with blood samples collected and compacted to a frozen pellet before the start of standard treatment, up to 3 weeks after the first dose but before second dose, and at the time of surgery were sent to Washington University (St. Louis, MO) for research purposes. Biopsy samples, blood samples, and medical information (including pathology reports about your breast cancer) were collected and labeled with a study number, which was a unique code assigned to samples and medical information. This unique code number which links a patient's name was separate from sample information. Sample information was given a separate BCN number (i.e. BCN"XXXX") upon enrollment in the study. All subsequent sample derivatives were associated with their BCN number and has its own unique label ID. Patients were able to withdraw samples without any penalty or loss of benefits entitled. ]]>