(Tils) During Neoadjuvant Dual HER2 Blockade in HER2-Positive
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San Antonio Breast Cancer Symposium® - December 4-8, 2018 Dynamics of tumor-infiltrating lymphocytes (TILs) during neoadjuvant dual HER2 blockade in HER2-positive (HER2+) breast cancer in the absence of chemotherapy Gaia Griguolo1,2, Esther Holgado3, Javier Cortés3, Roberta Fasani4, Tomás Pascual1,5, Laia Paré1,5, Begoña Bermejo6, Mafalda Oliveira7, Serafín Morales8, Noelia Martínez3, Maria Vidal1, Sònia Pernas9, Rafael López10, Montse Muñoz1, Patricia Galván1, Isabel Garau11, Luis Manso12, Jesús Alarcón13, Eduardo Martínez14, Patricia Villagrasa5, Antonio Llombart-Cussac15, Aleix Prat1,5, Paolo Nuciforo4 1 Hospital Clinic de Barcelona / IDIBAPS, Barcelona, ES; 2 Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova , IT; 3 Hospital Universitario Ramón y Cajal, Madrid, ES; 4 Molecular oncology group, Vall d´Hebron Institute of Oncology, Barcelona, ES; 5 SOLTI Breast Cancer Research Group, Barcelona, ES; 6 Hospital Clínico Universitario de Valencia / INCLIVA / CIBERONC, Valencia, ES; 7 Vall d'Hebrón University Hospital, Barcelona, ES; 8 Hospital Universitario Arnau de Vilanova de Lleida, Lleida, ES; 9 Institut Catala d'Oncologia, Hospitalet, Barcelona, ES; 10 Hospital Clínico Universitario de Santiago, CIBERONC, Santiago de Compostela, ES; 11 Hospital Son Llàtzer, Palma de Mallorca, ES; 12 Hospital Universitario 12 de Octubre, Madrid, ES; 13 Hospital Universitario Son Espases, Palma de Mallorca, ES; 14 Consorcio Hospitalario Provincial de Castellón, Castellón de la Plana, ES. 15 Hospital Universitario Arnau de Vilanova de Valencia, Valencia, ES Background Results ❑ TILs in HER2+ breast cancer (BC) predict 1) prognosis in early setting1, 2) pathological complete response Table 1. TIL levels at each timepoint according to clinicopathological characteristics and PAM50 TIL levels decrease at surgery in tumors achieving pCR 2 (pCR) following neoadjuvant antiHER2-based therapy and 3) response to trastuzumab and pembrolizumab Baseline TILs Day 15 TILs Post-NAC TILs A significant decrease in TIL levels was observed in tumors achieving pCR, irrespectively of HR status and in the metastatic setting3 intrinsic subtype (Fig.4). In tumors not achieving a pCR, no significant tendency was observed (26.4% increase N Median (IQR) p N Median (IQR) p N Median (IQR) p and 33.0% decrease in TILs between week 2 and surgery). ❑ However, little is known regarding changes in TILs during antiHER2-based treatment. HR Negative 71 10% (5-20) 64 20% (10-40) 63 7% (5-20) 0.072 <0.001 0.895 Figure 4. Changes in TIL levels between baseline and Day 15 according to response, HR and subtype ❑ In the neoadjuvant PAMELA trial4, only TILs at day 15 were significantly associated with pCR at multivariable status Positive 77 5% (5-20) 70 10% (5-20) 74 5% (5-15) 5 pCR RD analysis, while TILs at baseline were only significant in the univariate analysis . PAM50 HER2-E 100 10% (5-20) 86 20% (5-40) 90 5% (5-20) 0.006 <0.001 0.372 ❑ A significant increase in TIL levels was seen after 2 weeks of treatment as compared to baseline5. subtype NonHER2-E 48 5% (5-10) 48 10% (5-20) 47 5% (5-15) P<0.001 p=0.604 ❑ In the absence of chemotherapy, the dynamic activation of the immune system after exposure to HER2- pCR 44 15% (5-25) 36 30% (10-60) 40 5% (1-10) pCR 0.022 <0.001 0.662 targeted therapy might be relevant for clinical outcome5. RD 104 7% (5-20) 98 10% (5-20) 97 10% (5-20) N=32 ❑ Here, we investigate changes in TILs following treatment with lapatinib and trastuzumab without 0 45 10% (5-25) 37 30% (10-60) 40 5% (1-10) N=14 N=41 N=5 chemotherapy in the context of the PAMELA trial and their relationship with tumor heterogeneity 1 16 10% (10-30) 13 20% (5-40) 12 5% (5-10) RCB8 0.018 <0.001 0.871 2 66 5% (5-20) 63 10% (5-20) 64 10% (5-20) Patients and Methods 3 15 5% (5-10) 14 10% (5-20) 13 5% (5-20) IQR, interquartile range; HER2-E, HER2-enriched; HR, hormonal receptor; RD, residual disease. N=63 N=60 N=45 Figure 1. PAMELA trial design Figure 2. Flow chart of the study N=42 TIL levels increase between baseline and Day 15 in HR-negative and HER2-E tumors TILs levels in residual disease TILs levels correlate with genes linked to activated CD8 T-cells Patients included in A significant increase in TILs was observed in HR- and HER2-enriched (HER2-E) tumors (Fig.3). PAMELA N=151 The majority of RD at surgery had TILs scoring across and within Figure 5. Genes associated with HER2+ Trastuzumab 6 mg/kg q3w In HR- and HER2-E tumors, increase in TILs was observed regardless of pathological response at surgery. TILs above ≥5% (Table 2). each timepoint was highly enriched TILs across the 3 time-points Breast Lapatinib 1000 mg/day Cancer Baseline samples Day15 samples Surgery samples Figure 3. Changes in TIL levels between baseline and Day 15 according to HR, subtype and response Table 2. TIL levels at surgery in RD (FDR<1%) for immune genes Stage I-IIIA + Letrozole or Tamoxifen if HR+ N=151 N=144 N=144 tracking activated CD8 T-cells (i.e. HR-negative HR-positive HER2-E Non HER2-E TIL levels N % CD8A, CD3G, LAG3, PD1) with <5% 9 9.5% Evaluable Evaluable Evaluable p<0.001 p=0.133 p=0.001 p=0.067 correlation coefficients of 0.45- * gene-expression gene-expression gene-expression 5-9% 36 37.9% 0.60. N=151 N=144 N=144 10-19% 22 23.2% Trastuzumab 6 mg/kg q3w 20- 40% 16 16.8% Lapatinib 750 mg/day Evaluable TILs Evaluable TILs Evaluable TILs Genes correlated with TIL levels 2 Paclitaxel 80 mg/m weekly n=12 N=148 N=134 N=137 ≥40% 12 12.6% were consistent across the 3 time- * LAG3, MS4A1, PD1, CD8A, CD19, Evaluable cases 95 points (Fig. 5). IKBKE, IDO1, TYMP, TAP1, CD3G ❑ In the PAMELA (NCT01973660) neoadjuvant phase II trial4, 151 women with HER2+ breast cancer were treated with lapatinib and trastuzumab, and hormonal therapy if hormone receptor (HR) positive, for 18 weeks Conclusions (Fig.1). ❑ In early HER2+ BC, a general increase in TILs is observed following 2 weeks of dual HER2 blockade ❑ Stromal TILs6 where evaluated centrally using H/E slides in tumor samples (Fig.2). HR- and pCR HR- and RD HER2-E and pCR HER2-E and RD ❑ The increase is observed in HR- and HER2-E tumors, regardless of pCR at surgery ❑ Expression of 560 genes, including immune-related genes (e.g. CD8A, CD4, PD1 and PDL1) was measured p=0.008 p=0.037 p=0.010 p=0.056 ❑ At surgery, TILs consistently decrease in patients achieving a pCR at the same timepoints (Fig.2) using the nCounter® platform. ❑ Most residual tumors at surgery are inflamed (i.e. TILs ≥5%) and might be good candidates for clinical trials ❑ Intrinsic subtyping at baseline was determined using the PAM50 gene expression predictor7. evaluating adjuvant immune checkpoint inhibitors. ❑ Changes in TILs between 2 time-points were determined by paired t-tests. All statistical tests were two-sided References Acknowledgements and considered significant when p<0.05. 1. Salgado R, et al. JAMA Oncol 2015 5. Nuciforo P, et al. Ann Oncol 2018 This study was funded, in part, by Instituto de Salud Carlos III - PI16/00904, The 2. Solinas C, et al. Cancer Treat Rev 2017 6. Salgado R, et al. Ann Oncol. 2015 Breast Cancer Research Foundation, and Fundación Científica Asociación ❑ Correlation of TILs with gene expression was assessed by quantitative SAM analysis using a False Discovery 3. Loi S, et al. SABCS 2017 7. Parker JS, et al. J Clin Oncol. 2009 Española Contra el Cáncer (Ayuda Postdoctoral AECC 2017) 4. Llombart-Cussac A, et al. Lancet Onc 2017 8. Symmans WF et al. JCO 2017 Rate (FDR) <1%. This presentation is the intellectual property of the author/presenter. ❑ All statistical analyses were carried out using the R software. Contact them at [email protected] for permission to reprint and/or distribute..