DIFFERENTIAL GENOMIC PROFILING of PR neg and ER low subtypes

This study explores the role of ctDNA in low estrogen receptor (ER) tumours, particularly luminal breast cancer. The research started with the premise that not all luminal breast cancers are the same. The researchers divided ER-positive breast cancer into PR-positive and PR-negative, hypothesising that PR-negative cancers have intrinsic endocrine resistance. They also examined a subgroup of luminal breast cancer with low ER expression (less than 10%).

Clinically, ER-low tumours exhibited a lower incidence of bone involvement and a higher incidence of visceral involvement, similar to triple-negative breast cancer. When analysing the mutant allele frequency (MAF) in ctDNA, ER-low tumours showed higher levels, akin to triple-negative breast cancer. This was significant because it provided a biological readout and helped correct the model for higher ctDNA detectability.

The key finding was that the mutational profile of ER-low tumours resembled that of triple-negative breast cancer more than full luminal breast cancer. Specifically, TP53 single nucleotide variants were more common in ER-low and triple-negative tumours. In contrast, estrogen receptor genes such as ESR1 had a lower incidence in ER-low and PR-negative tumours compared to ER-positive and PR-positive tumours. This suggests that ER-low and PR-negative subgroups have distinct endocrine resistance mechanisms, which is important for developing new endocrine-based clinical trials.

The study also analysed the impact on overall survival, finding that the prognosis for ER-low tumours was similar to that of triple-negative breast cancer despite these patients receiving endocrine therapy. This raises questions about the effectiveness of endocrine therapy in this subgroup. The study suggests that ER-low patients might benefit more from immunotherapy and other treatments rather than traditional endocrine therapy, supported by both mutational and transcriptomic data.