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Association of increased tumor-infiltrating lymphocytes (TILs) with immunomodulatory (IM) triple-negative breast cancer (TNBC) subtype and response to neoadjuvant platinum-based therapy in PrECOG0105.
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2014
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Breast OncologyImmunologyPathologyBrca1/2 Mutation StatusImmunotherapyTumor BiologyHematological MalignancyOncologyNeoadjuvant Platinum-based TherapyTumor ImmunityMolecular OncologyCancer ResearchCancer TreatmentCancer GeneticsCell BiologyTumor MicroenvironmentPathologic ResponseTumor-infiltrating LymphocytesCancer ImmunosurveillanceBrca1/2 Mutation-associated BcCancer GenomicsImmune Checkpoint InhibitorBreast CancerTriple-negative Breast CancerMedicine
1000^ Background: Increased TILs are prognostic and predictive of therapy response in TNBC. PrECOG 0105, a neoadjuvant trial of carboplatin, gemcitabine and iniparib, enrolled 80 pts with clinical stage I-IIIA TN or BRCA1/2 mutation-associated BC. This correlative study was designed to assess the association of pre-therapy TILs in PrECOG 0105 with pathologic response, germline BRCA1/2 genotype & gene expression profiles, including TNBC subtypes. Methods: Evaluable pts had TNBC and completed at least 4 of 6 planned cycles of therapy. H and E stained tumor sections from pre-therapy biopsies were evaluated by a central pathologist for density of stromal (sTILs) and intratumoral (iTILs) lymphocytes. Pathologic response was assessed by the residual cancer burden (RCB) index. All patients had comprehensive BRCA1/2 genotyping. TNBC subtypes were derived from Affymetrix U133 plus 2.0 arrays. Results: 70 pts were included in this analysis. Median age = 47 yrs, median T size = 3.2 cm, 20% BRCA1/2 mutant & 48% node positive. 76% of tumors had at least 10% sTILs (range 10-80%) & 31% at least 10% iTILs (range 10-40%). Lymphocyte-predominant BC (LPBC), defined as ≥50% sTILs, was seen in 13%. pCR rate was highest (56%) in LPBC, though not significantly different from the non-LPBC group (38%, p=0.47). sTILs were significantly associated with TNBC subtype; median sTIL = 40% in the IM subtype, 15% in BL1, 20% in BL2, 10% in LAR, 0% in M, and 10% in MSL (p=0.0005). iTILs were also significantly associated with TNBC subtypes (p=0.0003); iTIL>0 for 10/14 (71%) in IM subtype, 1/7 (14%) in BL1, and 0 in others. Association with BRCA1/2 mutation status was not significant. In a multivariate model, each 10% increase in iTILs (OR 2.62 [95% CI 1.08 – 6.35]; p=0.03), but not sTILs (OR 1.17 [95% CI 0.87 – 1.58];p=0.28) was independently associated with pCR (RCB=0). However, both sTILs (p=0.02) and iTILs (p=0.009) were significantly associated with continuous RCB value. Conclusions: Both sTILs and iTILs are predictive of response to platinum-based neoadjuvant therapy and are significantly associated with TNBC subtypes, with the highest frequency in the IM subtype. Clinical trial information: NCT00813956.