Abstract
Immunohistochemically ER-positive HER2-negative (ER+HER2−) breast cancers are classified clinically as Luminal-type. We showed previously that molecular subtyping using the 80-gene signature (80-GS) reclassified a subset of ER+HER2− tumors to molecular Basal-type. We report here that molecular reclassification is associated with expression of dominant-negative ER variants and evaluate response to neoadjuvant therapy and outcome in the prospective neoadjuvant NBRST study (NCT01479101). The 80-GS reclassified 91 of 694 (13.1%) immunohistochemically Luminal-type tumors to molecular Basal-type. Importantly, all 91 discordant tumors were classified as high-risk, whereas only 66.9% of ER+/Luminal-type tumors were classified at high-risk for disease recurrence (i.e., Luminal B) (P < 0.001). ER variant mRNA (ER∆3, ER∆7, and ERα-36) analysis performed on 84 ER+/Basal tumors and 48 ER+/Luminal B control tumors revealed that total ER mRNA was significantly lower in ER+/Basal tumors. The relative expression of ER∆7/total ER was significantly higher in ER+/Basal tumors compared to ER+/Luminal B tumors (P < 0.001). ER+/Basal patients had similar pathological complete response (pCR) rates following neoadjuvant chemotherapy as ER−/Basal patients (34.3 vs. 37.6%), and much higher than ER+/Luminal A or B patients (2.3 and 5.8%, respectively). Furthermore, 3-year distant metastasis-free interval (DMFI) for ER+/Basal patients was 65.8%, significantly lower than 96.3 and 88.9% for ER+/Luminal A and B patients, respectively, (log-rank P < 0.001). Significantly lower total ER mRNA and increased relative ER∆7 dominant-negative variant expression provides a rationale why ER+/Basal breast cancers are molecularly ER-negative. Identification of this substantial subset of patients is clinically relevant because of the higher pCR rate to neoadjuvant chemotherapy and correlation with clinical outcome.
Highlights
Diagnostic testing of breast cancers for hormone receptor (HR)and HER2 status by immunohistochemistry and/or in-situ hybridization is routinely performed as an integral step to clinically define tumor characteristics and predict tumor behavior.[1,2] Advancement of technology has made it possible to molecularly characterize these tumors at the genomic level by evaluating underlying and intrinsic differences in tumor biology.[3,4] clinical subtypes overlap with these molecular subtypes, a significant number of patients will be reclassified based on the functionality of molecular pathways.[5,6] This reclassification may have important consequences for treatment allocation, response and clinical outcome
We have shown previously in a small case-control study that estrogen receptor (ER)+/Basal tumors have relatively high levels of the dominant-negative ERΔ7 splice variant, consequences for response to adjuvant therapy and clinical outcome were unknown in those cases.[15]
We have examined the expression of total ER and ER variants mRNA in ER+/Basal breast cancer patients enrolled in the prospective neoadjuvant NBRST registry trial (NCT01479101) and compared these expression values to patients with ER+/Luminal B breast cancer
Summary
Diagnostic testing of breast cancers for hormone receptor (HR)and HER2 status by immunohistochemistry and/or in-situ hybridization is routinely performed as an integral step to clinically define tumor characteristics and predict tumor behavior.[1,2] Advancement of technology has made it possible to molecularly characterize these tumors at the genomic level by evaluating underlying and intrinsic differences in tumor biology.[3,4] clinical subtypes overlap with these molecular subtypes, a significant number of patients will be reclassified based on the functionality of molecular pathways.[5,6] This reclassification may have important consequences for treatment allocation, response and clinical outcome. 1234567890():,; normalized total ERα mRNA expression complete response rates to neoadjuvant therapy and 3-year follow-up data for both patient groups within the NBRST trial and compared those to ER−/Basal breast cancer patients.
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