Comprehensive multi-omic analyses of “islands of resistance” tumour cells to identify aromatase inhibitor resistant subclones in oestrogen receptor positive breast cancer at Institute of Cancer Research on FindAPhD.com

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Dr M Cheang No more applications being accepted Funded PhD Project (Students Worldwide)

London United Kingdom Cancer Biology Computational Mathematics Epidemiology Medical Statistics

PhD Programmes, Institute of Cancer Research

About the Project

Over 80% of breast cancer (BC) patients in the developed western world have oestrogen receptor (ER)–positive disease; their treatment normally includes surgery and adjuvant endocrine therapy, and sometimes chemotherapy which greatly improves survival outcome (1). In postmenopausal women, the most effective endocrine therapy agents are aromatase inhibitors (AIs). Many patients recur because of de novo or acquired resistance to AI.

Currently, abemaciclib is approved for high-risk, node positive hormone receptor (HR)+/HER2- early BC in US and UK, supported based on the results from the phase 3 MonarchE randomised controlled trial (2). HR+/HER2+ BCs are molecularly heterogeneous with 30% of them are HER2-Enriched (HER2-E). We showed that HR+HER2-E is characterised by an immune-activated stroma with elevated tumour infiltrating lymphocytes, lower expression of luminal-related genes than the HR+/Luminal subtypes and benefit greatly from anti-HER2 therapies but poorly from endocrine therapy (ET) (3).

Resistance to endocrine therapies has been mainly studied in HR+/HER2- BC, but those mechanisms might differ between HER2+ and HER2- tumours, in part due to the differential distribution of intrinsic subtypes within each BC subgroup. Cells within a single tumour can be genetically diverse and respond differently to treatment. Even in tumours with good response to treatment, there may be a few resistant cells that remain growing and might be responsible for recurrences if not removed or killed by other methods.

The PeriOperative Endocrine-Therapy for Individualised Care (POETIC) trial (4) provides a framework to study endocrine resistance mechanisms in a large set of ER+ HER2+ and HER2- BC patients. The objective of this PhD project is work on method(s) to isolate these resistant tumour cells and discover genomic changes that are specific to these resistant cells. This will allow us to understand why these cells do not respond to treatment and may allow additional personalised treatment targeting these resistant cells.

References

[1] Early Breast Cancer Trialists' Collaborative G.: Aromatase inhibitors versus tamoxifen in premenopausal women with oestrogen receptor-positive early-stage breast cancer treated with ovarian suppression: a patient-level meta-analysis of 7030 women from four randomised trials. Lancet Oncol. 2022;23(3):382-92
[2] Martin M, Hegg R, Kim SB, et al.: Treatment with adjuvant abemaciclib plus endocrine therapy in patients with high-risk early breast cancer who received neoadjuvant chemotherapy: a prespecified analysis of the monarchE randomized clinical trial. JAMA Oncol. 2022 Aug 1;8(8):1190-1194.
[3] Bergamino MA, López-Knowles E, Morani G, et al.: HER2-enriched subtype and novel molecular subgroups drive aromatase inhibitor resistance and an increased risk of relapse in early ER+/HER2+ breast cancer. eBioMedicine,2022.
[4] I Smith, J Robertson, L Kilburn, et al.: Long-term outcome and prognostic value of Ki67 after perioperative endocrine therapy in postmenopausal women with hormone-sensitive early breast cancer (POETIC): an open-label, multicentre, parallel-group, randomised, phase 3 trial Lancet Oncol, 21 (2020), pp. 1443-1454
[5] Schuster ER, Zabalgo L, Perou CP, et al.: Multi-parameter FACS sorting identifies higher mutational burden in aromatase inhibitor resistant subclones in estrogen positive breast cancer at diagnosis San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA)2019.