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. 2024 Mar;9(3):102923.
doi: 10.1016/j.esmoop.2024.102923. Epub 2024 Mar 6.

Prognostic value of histopathologic traits independent of stromal tumor-infiltrating lymphocyte levels in chemotherapy-naïve patients with triple-negative breast cancer

L W de Boo  1 , K Jóźwiak  2 , N D Ter Hoeve  3 , P J van Diest  3 , M Opdam  1 , Y Wang  1 , M K Schmidt  4 , V de Jong  1 , S Kleiterp  1 , S Cornelissen  5 , D Baars  6 , R H T Koornstra  7 , E D Kerver  8 , T van Dalen  9 , A D Bins  10 , A Beeker  11 , S M van den Heiligenberg  12 , P C de Jong  13 , S D Bakker  14 , R C Rietbroek  15 , I R Konings  16 , R Blankenburgh  17 , R M Bijlsma  18 , A L T Imholz  19 , N Stathonikos  3 , W Vreuls  20 , J Sanders  21 , E H Rosenberg  21 , E A Koop  22 , Z Varga  23 , C H M van Deurzen  24 , A L Mooyaart  24 , A Córdoba  25 , E Groen  21 , J Bart  26 , S M Willems  26 , V Zolota  27 , J Wesseling  28 , A Sapino  29 , E Chmielik  30 , A Ryska  31 , A Broeks  5 , A C Voogd  32 , E van der Wall  33 , S Siesling  34 , R Salgado  35 , G M H E Dackus  36 , M Hauptmann  2 , M Kok  37 , S C Linn  38
Affiliations

Prognostic value of histopathologic traits independent of stromal tumor-infiltrating lymphocyte levels in chemotherapy-naïve patients with triple-negative breast cancer

L W de Boo et al. ESMO Open. 2024 Mar.

Abstract

Background: In the absence of prognostic biomarkers, most patients with early-stage triple-negative breast cancer (eTNBC) are treated with combination chemotherapy. The identification of biomarkers to select patients for whom treatment de-escalation or escalation could be considered remains an unmet need. We evaluated the prognostic value of histopathologic traits in a unique cohort of young, (neo)adjuvant chemotherapy-naïve patients with early-stage (stage I or II), node-negative TNBC and long-term follow-up, in relation to stromal tumor-infiltrating lymphocytes (sTILs) for which the prognostic value was recently reported.

Materials and methods: We studied all 485 patients with node-negative eTNBC from the population-based PARADIGM cohort which selected women aged <40 years diagnosed between 1989 and 2000. None of the patients had received (neo)adjuvant chemotherapy according to standard practice at the time. Associations between histopathologic traits and breast cancer-specific survival (BCSS) were analyzed with Cox proportional hazard models.

Results: With a median follow-up of 20.0 years, an independent prognostic value for BCSS was observed for lymphovascular invasion (LVI) [adjusted (adj.) hazard ratio (HR) 2.35, 95% confidence interval (CI) 1.49-3.69], fibrotic focus (adj. HR 1.61, 95% CI 1.09-2.37) and sTILs (per 10% increment adj. HR 0.75, 95% CI 0.69-0.82). In the sTILs <30% subgroup, the presence of LVI resulted in a higher cumulative incidence of breast cancer death (at 20 years, 58%; 95% CI 41% to 72%) compared with when LVI was absent (at 20 years, 32%; 95% CI 26% to 39%). In the ≥75% sTILs subgroup, the presence of LVI might be associated with poor survival (HR 11.45, 95% CI 0.71-182.36, two deaths). We confirm the lack of prognostic value of androgen receptor expression and human epidermal growth factor receptor 2 -low status.

Conclusions: sTILs, LVI and fibrotic focus provide independent prognostic information in young women with node-negative eTNBC. Our results are of importance for the selection of patients for de-escalation and escalation trials.

Keywords: fibrotic focus; lymphovascular invasion; prognostic biomarkers; stromal tumor-infiltrating lymphocytes; triple-negative breast cancer.

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Conflict of interest statement

Disclosure PJvD has advisory relationships with Paige, Pantarei and Samantree, paid to the institution, and research grants paid to the institute from Pfizer. NS received institutional research funding from Pfizer. ZV has a consulting role for Roche. CHMvD received institutional research funding from AstraZeneca/Daiichi Sankyo. SMW has a consulting role for Roche, and received institutional research funding from Roche, Pfizer, Bayer, MSD, AstraZeneca/Merck and Amgen. SMW has a consulting role for IDDI, Sensorion, Biophytis, Servier, Yuhan, Amaris Consulting and Roche. JW received institutional research funding from Cancer Research UK and KWF Dutch Cancer Society. AR has a consulting role for MSD Oncology, Amgen, Roche, AstraZeneca/Daiichi Sankyo and Bristol Myers Squibb/Pfizer. SCL reports grants from ZonMw and A Sister’s Hope during the conduct of the study; has been an advisory board member for AstraZeneca, Cergentis, IBM, Novartis, Pfizer, Sanofi and Roche; and received institutional research grants from Agendia, AstraZeneca, Eurocept-pharmaceuticals and Merck and Pfizer. In addition, SCL received institutional research grants and institutional non-financial support from Agendia, Genentech, Novartis, Roche, Tesaro and Immunomedics and other institutional support from AstraZeneca, Pfizer, Cergentis, Daiichi Sankyo, IBM and Bayer outside the submitted work. MK is an advisory board member and/or received speakers’ fee for/from Alderaan, Bristol Myers Squibb (BMS), Domain Therapeutics, Gilead, Roche, Medscape, MSD and AZ/Daiichi and received institutional research support from AstraZeneca/Daiichi, BMS and Roche outside the submitted work. RS reports non-financial support from Merck and BMS, research support from Merck, Puma Biotechnology and Roche, and personal fees from Roche, BMS and Exact Sciences for advisory boards. IRK received research grants from Novartis and Gilead. RHTK is an advisory board member for Amgen, AstraZeneca, Bayer, BMS, MSD, Novartis, Pfizer, Pierre Fabre Sante, Sanofi and Servier. All other authors have declared no conflicts of interest.

Figures

Figure 1
Figure 1
LVI, fibrotic focus and sTILs in triple-negative breast cancer. Whole slide images of H&E-stained triple-negative breast cancer representative for (A) the presence of LVI, (B) fibrotic focus with >75% sTILs and (C) fibrotic focus with <30% sTILs. (D) A detailed region of panel A with LVI, (E) of panel B with a sTILs score of >75% and (F) of panel C with a sTILs score of <30%. Scale bar A, B and C: 500 μm. Scale bar D, E and F: 100 μm. H&E, hematoxylin and eosin; LVI, lymphovascular invasion; sTILs, stromal tumor-infiltrating lymphocytes.
Figure 2
Figure 2
Unadjusted and adjusted HRs for BCSS among young patients with node-negative triple-negative breast cancer by tumor characteristics. (A) Plot of unadjusted hazard ratios (unadj. HR) and (B) adjusted hazard ratios (adj. HR) for BCSS comparing young (<40 years) patients with a specific tumor characteristic (depicted in the figure) versus those without that specific characteristic. For every tumor characteristic separately a (A) univariable and (B) multivariable Cox proportional hazards model was built. In the multivariable models, HRs were adjusted for local treatment (lumpectomy, mastectomy, surgery not specified), sTILs (per 10% increment) and LVI (absent, present), unless otherwise specified. Models for sTILs and LVI as the covariate of interest were adjusted for local treatment (lumpectomy, mastectomy, surgery not specified) and LVI (absent, present) or sTILs (per 10% increment), respectively. T-stage (1/2, 3) and grade (1/2, 3) were not detected as prognostic or confounding variables and therefore not included in the multivariable models. The group with the highest number of events was used as the reference group. sTILs and AR positive were used as continuous variables with HR showing change in risk per 10% increment. Patients with unknown values were omitted. The square shows unadj./ adj. HR and its size reflects the number of patients included, while whiskers represent the 95% CI. AR, androgen receptor; BCSS, breast cancer-specific survival; CI, confidence interval; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; LVI, lymphovascular invasion; NST, carcinoma of no special type; sTILs, stromal tumor-infiltrating lymphocytes.
Figure 3
Figure 3
Risk stratification of young patients with node-negative triple-negative BC for death due to BC by survival tree analysis. Survival tree model partitioning of 481 patients with node-negative triple-negative BC (for four patients, no sTILs score was available). (A) The resulting tree with four terminal groups was split by sTILs and LVI. a20-year cumulative incidences for death due to BC. (B) Corresponding cumulative incidence functions of death due to BC for selected groups based on survival tree analysis. BC, breast cancer; CI, confidence interval; LVI, lymphovascular invasion; sTILs, stromal tumor-infiltrating lymphocytes.
Figure 4
Figure 4
Breastcancer deaths among patients stratified by LVI and sTILs. The effects of LVI (presence versus absence of LVI) on breast cancer-specific death in the different sTILs categories were estimated with a Cox proportional hazard model that included an interaction term between LVI and sTILs. The total effect of LVI was estimated with a univariable Cox proportional hazard model. Patients with missing information on sTILs (n = 4) were excluded from analyses. BCSS, breast cancer-specific survival; CI, confidence interval; HR, hazard ratio; LVI, lymphovascular invasion; sTILs, stromal tumor-infiltrating lymphocytes.
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See this image and copyright information in PMC

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