TNBC is the most aggressive breast cancer subtype, with a higher recurrence rate. TNBC proportion within breast cancer incidence in the Indian population is 22-30%. Despite the high incidence rate, the heterogeneity within TNBC subtype in Indian cohorts is not studied at scale. Here, leveraging an Indian cohort of 93 TNBC patients, we evaluated the basal and LAR subtypes in terms of the expression of known markers such as EGFR and AR and further assessed the association of marker gene expression with patient outcome and treatment response. In our cohort, 65% of the patients were EGFR-positive, 38% had positive AR expression, where both the subsets showed shorter disease-free survival outcomes. Additionally, 25% of the cohort showed AR and EGFR co-expression. Upon closer observation, using IHC and duplex staining, we noted that 15% of the tumors, in fact, had double-positive cancer cells, i.e., cellular co-expression of AR and EGFR. Patients with double-positive cells had poorer disease-free survival compared to the ones with the tissue-level co-expression of EGFR and AR but without cellular co-expression. The presence of EGFR+AR+ double-positive cells was further validated in publicly available single-cell data sets for TNBC patients from other ethnic backgrounds, albeit to a lesser extent than what was observed in our Indian cohort. Overall, our results highlight the heterogeneous nature of Indian TNBC tumors and provide further insight into ethnic variation in TNBC presentation that can be further exploited for precision and personalized targeted therapy.

The authors have declared no competing interest.

MK would like to acknowledge the DBT- Ramalingaswami re-entry fellowship and DBT-Basic Research in Biology awarded by DBT-India. LSS would like to acknowledge the DST-JC Bose Research Fellowship, a Mphasis grant to TSB at Ashoka University. The research grant to CTCR is supported by Bajaj Auto Ltd. PV would like to acknowledge Ashoka University for PhD fellowship.

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