Molecular profiling after short-term preoperative endocrine therapy to identify oestrogen receptor positive (ER+)/HER2+ early breast tumours with favourable prognosis.
Authors: Bergamino Sirvén Milana , Lopez-Knowles Elena , Zhu Xixuan , Tovey Holly , Xiao Hui , Kilburn Lucy , Alataki Anastasia , Holcombe Chris , Skene Anthony , Smith Ian E. , Robertson John Forsyth Russell , Bliss Judith , Schuster Eugene F. , Dowsett Mitchell , Cheang Maggie Chon U 
Published: May 2024

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Background: The impeded anti-proliferative response of Estrogen Receptor positive (ER+) HER2+ breast cancer (BC) to endocrine therapy (ET) has been considered negated by treatment with anti-HER2 therapies but residual disease after anti-HER2 therapy remains at risk of recurrence. Studying the molecular changes (MolC) of ER+HER2+ BC in response to ET will provide clinical insights to treatment options. Methods: POETIC was a phase III trial of post-menopausal patients with ER+ BC randomized 2:1 to 2-weeks of peri-operative aromatase inhibitors (POAI) vs control, followed by standard-of-care. Paired pre-treatment (B) and on-treatment (2wk) samples from 313 ER+HER2+ BC (213 POAI/100 controls) were gene expression profiled (BC 360 codeset; NanoString). Association of MolC with Early biological response to AI was assessed by residual Ki672wk (low ≤10%; high >10%) by T-test, multiple testing corrected by Benjamini & Hochberg (FDR); with time to recurrence (TTR) was estimated using multivariable Cox regression models adjusted for post-surgery clinicopathological variables and age as adjuvant treatment surrogate. Results: In POAI tumours, immunity-related signatures and mammary stemness were significantly upregulated in responders while proliferation, DNA-damage repair (DDR), TP53mutational status and ER-signaling were downregulated (FDR<0.05). Controls had exclusive downregulation of PDL1 and upregulation of hypoxia (FDR < 0.05). We previously identified 5 new molecular subgroups based on baseline gene expression (1- Immune high, ESR1 low; 2- ECM, ESR1 low, highest ERBB2; 3- DDR deficiency, 4- Endocrine signalling high and 5- Endocrine and PI3K/MAPK/RAS signalling high) which were associated with different response to AI and differential outcome. Endocrine-signalling, PI3K/MAPK/RAS signalling, tumour-immunity and chemokines were upregulated at a higher magnitude in AI sensitive subgroups (3 and 4) while the molecular subgroup with early resistance to AI and poorer outcome at baseline (2) did not show significant changes. Intrinsic subtype (IS) shifting was significantly more prevalent in treated (37%, 79/213) than in controls (14%, 14/100) (p <0.001). In POAI most Luminal B (LumB) shifted to Luminal A (LumA; 79%, 59/75), driven by a reduction in proliferation. LumA2wk was associated with better outcome compared to LumB2wk (HR 0.2; CI95% 0.06-0.72, p=0.01). IS2wk provides additional information predicting TTR, than ISB (AIC value = 217.2 vs 221.6). Conclusions: We provide a comprehensive picture on how ER+HER2+ BC gene expression profile changes in response to ET. Most LumB BC shift to LumA, being LumA2wk IS significantly associated with better outcome. There is a clinical utility of peri-operative ET for ER+HER2+ BC, guiding who would have good prognosis for adjuvant ET and who may need additional therapy. Clinical trial information: NCT02338310 .