Neoadjuvant trials with antiestrogen therapy offer an opportunity to discover functional genomic alterations associated with drug resistance that could, in turn, inform the choice of adjuvant therapy. A high preoperative endocrine prognostic index (PEPI) score after 3 to 4 months of neoadjuvant therapy with an aromatase inhibitor (AI) correlates with an increased risk for cancer recurrence.1 This suggests that the residual cancer in the breast after prolonged estrogen deprivation can be considered a surrogate of drug-resistant micrometastases that harbors molecular alterations causally associated with endocrine resistance.
At SABCS 2017, the authors presented results of studies of targeted DNA and RNA sequencing from paraffin-embedded, formalin-fixed tumor sections from a cohort of 68 elderly patients (median age, 77 years) with stage II to III estrogen receptor (ER)-positive breast cancer treated with letrozole for a median of 7.2 months (range, 5.4-9.2 months) before surgery.2 With a median follow-up of 58 months (range, 50-80 months), 13 patients (8 with PEPI ≥4; 5 with PEPI 1-3) exhibited breast cancer recurrence (12 metastatic, 1 locoregional). The 5-year recurrence-free survival was 100%, 85%, and 61% for PEPI 0, PEPI 1-3, and PEPI ≥4, respectively (P = .001). Patients with PEPI ≥4 continued to exhibit a poor prognosis after adjusting for adjuvant chemotherapy (risk for relapse, hazard ratio [HR], 2.84; P = .052). Resistant tumors (cancer relapse and/or PEPI ≥4) were enriched in signatures related to cell proliferation, stemness, DNA repair, EGFR, and PI3K signaling. Integration of the 47 most upregulated genes in letrozole-resistant tumors with transcription binding data from ChIP-sequencing studies showed highly significant overlap with 20 E2F4-regulated genes, which were overexpressed in MCF-7 and T47D cells adapted to long-term estrogen deprivation and were markedly suppressed by treatment with the CDK4/6 inhibitor palbociclib, but only modestly by fulvestrant or paclitaxel.
In patients treated with palbociclib for 14 days before surgery in the PreOperative Palbociclib (POP) trial, treatment with the CDK4/6 inhibitor significantly decreased expression of 24 of the 47 most upregulated genes in letrozole-resistant tumors; among these were 18 of the 20 E2F4 target genes. When an E2F4 activation signature was generated using the 24 genes enriched in the original cohort of letrozole-resistant tumors that were also downregulated by palbociclib in tumors in the POP trial, this signature was strongly associated with resistance to AIs in the ACOSOG Z1031B neoadjuvant trial: on treatment Ki67, <2.7% rate was 18% versus 50% for high and low baseline E2F4 score, respectively (P <.001). Finally, a high E2F4 signature score was associated with an increased risk for relapse (HR, 2.96; 95% confidence interval [CI], 2.18-3.67) and death (HR, 1.59; 95% CI, 1.32-1.94) in ER-positive tumors in the METABRIC cohort.
The authors concluded that they have identified a CDK4/6 inhibitor–sensitive E2F4 gene expression signature that is associated with estrogen-independent proliferation in ER-positive breast cancers resistant to AIs. This signature can potentially identify patients with ER-positive breast cancer who are candidates for adjuvant therapy with CDK4/6 inhibitors in combination with antiestrogens.
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