Estrogen receptor variants in ER-positive basal-type breast cancers responding to therapy like ER-negative breast cancers

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.

The therapeutic response of ER+/HER2− breast cancers differs according to the molecular Basal or Luminal subtype

“…Our in silico analysis shows that the ER+/HER2− Basal subtype is very different from the ER+/HER2− Luminal subtype-and sometimes closer to the ER− Basal subtype-in terms of response and/or potential vulnerability to systemic therapies of BC. These results obtained on a large series reinforce the potential clinical value of the molecular subtypes within ER+/HER2− BCs, already suggested in smaller series 4,19 regarding the prognosis after HT and the sensitivity to chemotherapy and CDK4/6 inhibitors. They also suggest differential therapeutic vulnerability regarding PARP inhibitors and platinum salts, PIK3CA inhibitor, immune therapy and other targeted therapies under development.…”

“…Accumulating evidence suggests that these molecular subtypes provide clinically relevant information beyond clinicopathological classes [1][2][3] . In a recent study 4 , 13.1% of IHC estrogen receptor-positive HER2-negative (ER+/HER2−) BCs were reclassified as molecular Basal subtype by the 80-gene signature (80-GS) 5 . When compared to the ER+/ HER2− cases reclassified as Luminal subtype (74.1%), the Basal samples displayed lower ESR1 mRNA expression and increased relative ERΔ7 dominant-negative variant expression, shorter 3-year distant relapse-free interval (DRFI), and higher pathological complete response rate (pCR) to chemotherapy (CT).…”

Triple-negative breast lobular carcinoma: a luminal androgen receptor carcinoma with specific ESRRA mutations

“…TNBCs often overlap with basal-like breast carcinomas (BLBCs) as defined by gene expression profiling. However, 18-40% of BLBCs do express either hormone receptors or HER2, and therefore cannot be classified as TNBCs [43,44]. BLBCs are usually defined as tumors negative for both hormone receptors and HER2, and at the same time positive for at least one basal marker as defined by immunohistochemistry [45].…”

Breast cancer dormancy is associated with a 4NG1 state and not senescence

“…This correlates with a small proportion of patients, which are at high risk for disease recurrence, but which show significantly improved response to neoadjuvant chemotherapy. 41 These patients are ER + , but show low levels of ER at the transcriptional level, which was attributed to high expression of dominant negative ERΔ7 mRNA. Indeed, we also show that the cells have low expression of ER mRNA, but they are clearly responsive to 4OHT, suggesting they should have ERα at the protein level.…”