Breast cancer is a highly heterogeneous disease due to its diverse morphological features, the variable clinical outcome and the response to different therapeutic options. It is therefore necessary ...to devise a clinically meaningful classification of the disease, which has to be scientifically sound, clinically useful and widely reproducible. The established histopathological classification has a limited clinical utility, due to insufficient prognostic and predictive power. More recent classification schemes, based on the immunohistochemical characterization of breast cancer for the assessment of hormone receptor status, HER2 gene over-expression or amplification and the proliferative fraction or on gene expression profiles, correlate much better with the clinical outcome and may be used to inform the choice of the systemic therapy.
A proliferative marker, expressed as the percentage of cells in a cell cycle, has been developed and used as a discriminant of more aggressive malignant phenotypes in early breast cancer (BC). The ...marker is usually expressed by the immunohistochemical staining of the cell cycle antigen Ki-67. It has not, however, yet been definitely evaluated, due to methodological concerns, which specific Ki-67 cut-off provide the strongest prognostic information in resected BC. We conducted a meta-analysis to explore the prognostic value of different cut-off levels of Ki-67 in terms of overall survival (OS) and disease-free survival (DFS) in early BC. The databases of PubMed, the ISI Web of Science, EMBASE, SCOPUS, the Cochrane Central Register of Controlled Trials, and CINHAL were used to identify the relevant literature. Data from studies reporting a hazard ratio (HR) and a 95 % confidence interval (CI) calculated as a multivariate analysis were pooled in a meta-analysis, with metaregression used to test for trends in predefined subgroups. All the statistical tests were 2-sided. Forty-one studies encompassing 64,196 BC patients were included in the analysis. Overall,
n
= 25 studies were available for the OS analysis. The pooled HR for high versus low Ki-67 was 1.57 (95 % CI 1.33–1.87,
P
< 0.00001). Twenty-nine studies were available for the DFS analysis. The pooled HR for high versus low Ki-67 was 1.50 (95 % CI 1.34–1.69,
P
< 0.00001). When a cut-off of Ki-67 staining ≥ 25 % was used, the pooled HR for OS was 2.05 (95 % CI 1.66–2.53,
P
< 0.00001), which was significantly different to studies where the cut-offs chosen were <25 %. In ER+ tumors, the HR for high versus low Ki-67 was similar and significant (HR = 1.51, 95 % CI 1.25–1.81,
P
< 0.0001). We conclude that Ki-67 has an independent prognostic value in terms of OS in BC patients. The Ki-67 threshold with the greatest prognostic significance is as yet unknown, but a cut-off >25 % is associated with a greater risk of death compared with lower expression rates.
Triple-negative breast cancer (TNBC) is a heterogeneous disease diagnosed by immunohistochemistry and is characterised by tumours that do not express estrogen receptor (ER) or progesterone receptor ...(PR) at all, and do not overexpress human epidermal growth factor receptor 2 (HER2). Prototypical TNBC is aggressive in nature and associated with a poor prognosis, making the accurate diagnosis of the disease vitally important for ensuring optimal therapy for patients. Morphological and biological analyses can identify subtypes of TNBC, which can have different prognoses, and (in the case of the latter) may eventually be used to predict response to treatment. This mini-review focuses on clinically relevant issues in the diagnosis of TNBC, including the importance of adherence to international guidelines for the detection of ER/PR/HER2 status, and the relationship between TNBC and the overlapping (yet distinct) intrinsic subtype of 'basal-like' breast cancer. In addition, we review the potential use of emerging biomarkers as surrogates for molecular subtypes and as a means of identifying potential responders to new therapies.
Purpose
The prognostic role of tumor-infiltrating lymphocytes (TILs) in ER+/HER2− breast cancer (BC) is debated. We evaluated the association of TILs and clinico-pathological features with distant ...disease-free survival (DDFS) in patients with ER+/HER2− BC treated at a single institution.
Patients and methods
A mono-institutional case-cohort series of 987 patients with early ER+/HER2− BC was retrospectively analyzed. TILs were considered both as continuous variable, and dichotomized in low (< 5%) vs high (≥ 5%). The main outcome was DDFS. Median follow-up was 7.5 years (0.1–10). Univariate and multivariable Cox proportional hazards regression with inverse sub-cohort sampling probability weighting were used to evaluate the risk across groups.
Results
Median TIL count was 2% (Q1–Q3 1–4%). Higher TILs were positively associated with number of lymph nodes involved (
p
= 0.003), tumor grade (
p
< 0.0001), peritumoral vascular invasion (
p
= 0.003), higher Ki-67 (
p
= 0.0001), luminal B subtype (
p
< 0.0001), and chemotherapy use (
p
< 0.00019). In multivariable regression analysis, only higher Ki-67 expression retained significant association with TILs. At univariate Cox regression analysis, TIL expression (≥ 5% vs. < 5%) was not associated with DDFS (HR 1.08, 95% CI 0.80–1.46,
p
= 0.62). In patients treated with adjuvant chemotherapy, high TILs were associated with better DDFS (HR 0.52, 95%CI 0.33–0.83,
p
= 0.006), particularly in the group with Ki-67 ≥ 20% (HR 0.50, 95%CI 0.29–0.86,
p
= 0.01).
Conclusion
High TILs in ER+/HER2− BC are significantly associated with clinico-pathological features of dismal outcome. TIL prognostic value seems different in patients treated with or without chemotherapy. Our findings suggest that the high-risk subgroup might be more immunogenic, thus deserving the exploration of immunotherapy approaches.
Evidence is strengthening for the morphological evaluation of tumor infiltrating lymphocytes (TILs) in breast cancer. Herein, the concepts for TILs assessment are laid out by pathologists to ...facilitate their wider evaluation and consistent interpretation. The goal of this article is to promote the evaluation of TILs as a biomarker in research, clinical trial settings and day-to-day practice.
The morphological evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer (BC) is gaining momentum as evidence strengthens for the clinical relevance of this immunological biomarker. Accumulating evidence suggests that the extent of lymphocytic infiltration in tumor tissue can be assessed as a major parameter by evaluation of hematoxylin and eosin (H&E)-stained tumor sections. TILs have been shown to provide prognostic and potentially predictive value, particularly in triple-negative and human epidermal growth factor receptor 2-overexpressing BC.
A standardized methodology for evaluating TILs is now needed as a prerequisite for integrating this parameter in standard histopathological practice, in a research setting as well as in clinical trials. This article reviews current data on the clinical validity and utility of TILs in BC in an effort to foster better knowledge and insight in this rapidly evolving field, and to develop a standardized methodology for visual assessment on H&E sections, acknowledging the future potential of molecular/multiplexed approaches.
The methodology provided is sufficiently detailed to offer a uniformly applied, pragmatic starting point and improve consistency and reproducibility in the measurement of TILs for future studies.
There is a need to develop surrogates for treatment efficacy in the neoadjuvant setting to speed-up drug development and stratify patients according to outcome. Preclinical studies showed that ...chemotherapy induces an antitumor immune response. In order to develop new surrogates for drug efficacy, we assessed the prognostic value of tumor-infiltrating lymphocytes (TIL) on residual disease after neoadjuvant chemotherapy (NACT) in patients with triple-negative breast cancer (TNBC).
Three hundred four TNBC patients with residual disease after NACT were retrospectively identified in three different hospitals. Hematoxylin and eosin-stained slides from surgical postchemotherapy specimens were evaluated for intratumoral (It-TIL) and stromal (Str-TIL) TIL. Cases were classified as High-TIL if It-TIL and/or Str-TIL >60%.
TIL were assessable for 278 cases. Continuous It-TIL and Str-TIL variables were strong prognostic factors in the multivariate model, both for metastasis-free hazard ratio (HR) 0.86, 95% confidence interval (CI) 0.77–0.96, P = 0.01 and HR 0.85, 95% CI 0.75–0.98, P = 0.02 for Str-TIL and It-TIL, respectively and overall survival (HR 0.86, 95% CI 0.77–0.97, P = 0.01 and HR 0.86, 95% CI 0.75–0.99, P = 0.03 for Str-TIL and It-TIL, respectively). The 5-year overall survival rate was 91% (95% CI 68% to 97%) for High-TIL patients (n = 27) and 55% (95% CI 48% to 61%) for Low-TIL patients (HR 0.19, 95% CI 0.06–0.61, log-rank P = 0.0017). The major prognostic impact of TIL was seen for patients with large tumor burden following NACT (residual tumor >2 cm and/or node metastasis). In all but one High-TIL case, It-TIL and Str-TIL values were lower on the prechemotherapy sample.
The presence of TIL in residual disease after NACT is associated with better prognosis in TNBC patients. This parameter may represent a new surrogate of drug efficacy to test investigational agents in the neoadjuvant setting and a new prognostic marker to select patients at high risk of relapse.
High-risk triple-negative breast cancers (TNBCs) are characterized by poor prognosis, rapid progression to metastatic stage and onset of resistance to chemotherapy, thus representing an area in need ...of new therapeutic approaches. Programmed death-ligand 1 (PD-L1) expression is an adaptive mechanism of tumour resistance to tumour-infiltrating lymphocytes, which in turn are needed for response to chemotherapy. Overall, available data support the concept that blockade of PD-L1/programmed cell death protein 1 checkpoint may improve efficacy of classical chemotherapy.
Two hundred and eighty patients with TNBC were enrolled in this multicentre study (NCT002620280) and randomized to neoadjuvant carboplatin area under the curve 2 and nab-paclitaxel 125 mg/m2 intravenously (i.v.) on days 1 and 8, without (n = 142) or with (n = 138) atezolizumab 1200 mg i.v. on day 1. Both regimens were given q3 weeks for eight cycles before surgery followed by four cycles of an adjuvant anthracycline regimen. The primary aim of the study was to compare event-free survival (EFS), and an important secondary aim was the rate of pathological complete response (pCR defined as the absence of invasive cells in breast and lymph nodes). The primary population for all efficacy endpoints is the intention-to-treat (ITT) population.
The ITT analysis revealed that pCR rate after treatment with atezolizumab (48.6%) did not reach statistical significance compared to no atezolizumab 44.4%: odds ratio (OR) 1.18; 95% confidence interval 0.74-1.89; P = 0.48. Treatment-related adverse events were similar with either regimen except for a significantly higher overall incidence of serious adverse events and liver transaminase abnormalities with atezolizumab.
The addition of atezolizumab to nab-paclitaxel and carboplatin did not significantly increase the rate of pCR in women with TNBC. In multivariate analysis, the presence of PD-L1 expression was the most significant factor influencing the rate of pCR (OR 2.08). Continuing follow-up for the EFS is ongoing, and molecular studies are under way.
•Atezolizumab with neoadjuvant carboplatin/nab-paclitaxel led to non-significantly higher pCR rate in PD-L1+ TNBC.•In other trials neoadjuvant ICIs and chemotherapy significantly improved pCR rate, but EFS was independent of pCR.•Our analysis of NeoTRIP supports that pCR may not be an appropriate surrogate endpoint for the role of ICIs in early TNBC.•Lack of pCR improvement may be misleading as to the impact of atezolizumab on long-term efficacy in high risk TNBC.
Although stromal tumor-infiltrating lymphocytes (sTILs) have been considered an important prognostic factor in early-stage triple-negative breast cancer (TNBC), there have been limited data on their ...prognostic value in the absence of adjuvant chemotherapy.
A pooled analysis was carried out using four cohorts of TNBC patients not treated with chemotherapy. sTILs were evaluated in the most representative tumoral block of surgical specimens. Cox proportional hazards regression models were used for invasive disease-free survival (iDFS), distant disease-free survival (D-DFS), and overall survival (OS), fitting sTILs as a continuous variable adjusted for clinicopathologic factors.
We analyzed individual data of 476 patients from 4 centers diagnosed between 1989 and 2015. Their median age was 64years. The median tumor size was 1.6cm and 83% were node-negative. The median level of sTILs was 10% (Q1−Q3, 4%−30%). Higher grade was associated with higher sTILs (P<10−3). During follow-up, 107 deaths, and 173 and 118 events for iDFS and D-DFS were observed, respectively. In the multivariable analysis, sTILs obtained an independent prognostic value for all end points (likelihood ratio χ2=7.14 for iDFS; P<10−2; χ2=9.63 for D-DFS, P<10−2; χ2=5.96 for OS, P = 0.015). Each 10% increment in sTILs corresponded to a hazard ratio of 0.90 95% confidence interval (CI) 0.82−0.97 for iDFS, 0.86 (95% CI 0.77−0.95) for D-DFS, and 0.88 (95% CI 0.79−0.98) for OS, respectively. In patients with pathological stage I tumors with sTILs ≥30% (n=74), 5-year iDFS was 91% (95% CI 84% to 96%), D-DFS was 97% (95% CI 93% to 100%), and OS was 98% (95% CI 95% to 100%).
sTILs add important prognostic information in systemically untreated early-stage TNBC patients. Notably, sTILs can identify a subset of stage I TNBC patients with an excellent prognosis without adjuvant chemotherapy.
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